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7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Atrioventricular node ablation : Bradley P Knight, MD, FACC : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2023. INTRODUCTION In patients with atrial fibrillation (AF), the ventricular rate is determined in large part by the conduction properties of the atrioventricular (AV) node. In the typical patient with untreated AF, the ventricular rate can reach 150 beats per minute or higher. There are three important reasons to prevent a rapid ventricular response in patients with AF: Avoidance of hemodynamic instability. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Avoidance of bothersome symptoms. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'History and physical examination'.) Avoidance of a tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) A rapid ventricular response can be prevented either by restoring sinus rhythm (ie, rhythm control) or by using therapies that reduce the ventricular response (ie, rate control) to AF. When rate control is chosen, it can usually be accomplished with pharmacologic therapy. However, some AF patients will respond poorly to or be intolerant of rate control medications. Options for such patients include reconsideration of a rhythm control strategy or nonpharmacologic methods to control the ventricular rate. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Management of atrial fibrillation: Rhythm control versus rate control".) https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 1/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate The use of AV node ablation to achieve rate control in AF will be reviewed here. Pharmacologic therapies for rate control in AF are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) GENERAL PRINCIPLES Choosing the appropriate rate control therapy for a patient with AF is guided by an understanding of the determinants of the ventricular rate and an assessment of the adequacy of rate control. The discussions of rate control and the determinants of ventricular rate in patients with AF are found elsewhere. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) There are several strategies for assessing the adequacy of rate control efforts. With any strategy, rate control should be assessed both at rest and with exertion. Rate control goals are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) INDICATIONS AV node ablation is an option for rate control in AF patients who have failed medical therapy for rhythm control, have failed or are not candidates for catheter ablation for rhythm control, and have failed aggressive attempts at pharmacological rate control. Many of these patients are labeled as having permanent AF, which is the term used to identify individuals with persistent AF where a joint decision by the patient and clinician has been made to no longer pursue a rhythm control strategy. Patients who are candidates for AV node ablation should be highly symptomatic, hemodynamically intolerant of AF, or have cardiomyopathy that is thought to be at least some part tachycardia induced. In general, the procedure is most commonly performed in elderly patients, many of whom have a preexisting pacemaker or implantable cardioverter-defibrillator (ICD) ( table 1). Other patients include those who are not candidates for rhythm control with catheter ablation or drug therapy, those with refractory AF with tachycardia-induced cardiomyopathy, or those with a preexisting pacemaker. Careful thought needs to be given to other treatment options, including curative attempts with catheter ablation before proceeding to AV node ablation in patients in whom medical therapy has failed to control the ventricular rate. The specific clinical scenario will dictate the appropriateness of AV node ablation vis-a-vis other treatment options. In younger patients, all https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 2/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate treatment options should be considered/exhausted before proceeding to AV node ablation. AV node ablation may be more appropriate in older patients, particularly those with preexisting pacing devices, and in those in whom curative attempts at AF ablation are unlikely to be successful (eg, very longstanding/permanent AF, marked left atrial dilatation, etc). Prior to performing AV node ablation, the patient needs to be informed about the invasive nature of the procedure, the requirement for lifelong permanent pacemaker therapy, and the long-term risk of a pacing-induced cardiomyopathy when RV apical pacing is used. PROCEDURE AV node ablation usually produces complete AV block and often leaves the patient with a slow junctional or idioventricular escape rhythm. Consequently, patients require implantation of a permanent pacing device to adequately control the ventricular rate ( waveform 1A-B). If a preexisting pacemaker or ICD is not already in place, a permanent pacemaker or ICD is implanted prior to AV node ablation. This is usually carried out immediately prior to the AV node ablation, but in some cases the device may be implanted in advance of the ablation procedure. Traditional leaded devices are implanted in the subclavicular region; a leadless pacemaker may be implanted directly in the right ventricle. (See 'Device selection' below and "Permanent cardiac pacing: Overview of devices and indications", section on 'General considerations'.) If a functional pacemaker or ICD is in place and no system revision is planned, the femoral vein is generally used for access for ablation of the AV node. An ablation catheter is advanced to the AV junction where a bundle of His potential can be recorded. Radiofrequency ablation of the AV node/bundle of His is performed. Ablation lesions should be delivered at a site proximal in the AV conduction system where a large atrial electrogram is also recorded to increase the likelihood of a junctional escape rhythm after creation of AV bock to avoid pacemaker dependency. With a successful lesion, there is usually an accelerated junctional rhythm and then heart block. If initial ablation is ineffective, or if conduction recurs, a larger lesion can be created with either a larger tip or saline-irrigated catheter.(See "Overview of catheter ablation of cardiac arrhythmias".) On rare occasions, AV node ablation cannot be accomplished via the right heart. In these cases, establishing femoral arterial access allows passage of an ablation catheter retrograde across the AV node. A bundle of His potential can be recorded just below the aortic valve, in the septal aspect of the left ventricular (LV) outflow tract. Alternatively, ablation by way of the left heart can be accomplished using a patent foramen ovale or transseptal puncture. If left heart access is necessary, systemic anticoagulation with intravenous heparin is generally administered while the left heart is instrumented. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 3/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate If a leadless pacemaker is placed, the same femoral venous sheath can then be used to advance the ablation catheter (see "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'). Care must be taken to make sure that newly placed leads or a leadless pacemaker are not dislodged by the ablation catheter. In rare cases, when right heart ablation of the AV node is ineffective and a new leaded pacing system has just been placed, it may be reasonable to defer the left heart AV node ablation for days/weeks to obviate the need for intravenous heparin with the attendant risks of bleeding. Device selection Following AV node ablation (see 'Procedure' above), most patients are pacemaker dependent. Therefore a device with pacemaker capability must be in place prior to the ablation procedure. The choice of which type of pacing device is implanted depends on the patient's clinical profile. Single-chamber ventricular pacemaker In patients with persistent AF, a single-chamber (right) ventricular pacemaker is often adequate. After AV node ablation, the patient's ventricular rate will not naturally respond to increased demand; therefore, a device with rate-adaptive capabilities is used (ie, VVIR pacing). All contemporary pacemakers have rate-adaptive capabilities. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Rate responsiveness'.) Leadless RV pacing (see "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems') has also been used in association with AV node ablation [1]. Dual-chamber pacemaker In patients with paroxysmal AF, dual-chamber pacemakers are preferred to single-chamber devices because they maintain AV synchrony during periods of sinus rhythm (eg, DDDR pacing). (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Physiologic pacing'.) In order to prevent rapid ventricular pacing during episodes of AF, patients with dual-chamber pacemakers following AV node ablation should have devices with automatic mode-switching capabilities. All contemporary pacemakers have this ability. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Mode switching'.) In patients with paroxysmal AF, two randomized trials demonstrated that dual-chamber pacemakers with mode-switching capabilities improve symptoms and quality of life compared with single- or dual-chamber pacemakers without mode-switching capabilities [2,3]. Many patients who undergo AV node ablation with pacemaker implantation for paroxysmal AF eventually progress to persistent AF [4]. Although dual-chamber pacing has not been shown to prevent this progression [5], we favor dual-chamber pacing in patients with paroxysmal AF https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 4/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate because of the clinical benefits of physiologic pacing. (See "The role of pacemakers in the prevention of atrial fibrillation".) A leadless RV pacemaker capable of sensing atrial mechanical systole and providing AV synchrony has been approved by the U S Food and Drug administration. At this point, leadless RV pacing is not able to pace the atrium, so it would not be an optimal choice in a patient with sinus node dysfunction and paroxysmal AF who is to undergo AV node ablation. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) Cardiac resynchronization therapy The majority of well-selected patients improve hemodynamically following AV junction ablation and standard right ventricle (RV) pacing. However, RV pacing causes the RV to contract before the LV (interventricular dyssynchrony), which may impair LV systolic function, reduce functional status, and increase mortality. In patients with significant dyssynchrony due to intrinsic conduction disease or pacing, cardiac resynchronization therapy (CRT) can improve ventricular synchrony. Use of CRT in patients with AF with or without AV node ablation is presented separately. (See "Cardiac resynchronization therapy in atrial fibrillation", section on 'Atrioventricular node ablation'.) There is a trend toward using CRT in many patients who undergo AV node ablation. If the implant and ablation are to be done concurrently, we use CRT with an atrial lead if the AF is paroxysmal and no atrial lead if persistent/permanent. In addition to providing CRT, two ventricular leads mitigate the unlikely but potentially disastrous effects of RV lead dislodgment and loss of RV capture. If transient pacing inhibition due to RV lead malfunction is noted, the sensing vector can sometimes be reprogrammed to an LV vector, which may mitigate the need for urgent lead revision. If, however, in the unlikely event that RV lead dislodgement or fracture results in continuous oversensing and inhibition of pacing, the additional LV pacing lead will not prevent asystole. If the patient has a preexisting non-CRT device and is undergoing AV node ablation, we will usually see how the patient responds to unopposed RV pacing, particularly if LV function is preserved. If LV function is significantly depressed and/or systolic heart failure has already been an issue, we may upgrade the patient to a CRT pacing or defibrillator system (as appropriate) at the time of AV node ablation. The main "downsides" to concurrent device upgrade are the associated procedural risks, most notably the risk of infection in a patient who will be pacemaker dependent. Adding a device upgrade procedure to an AV ablation increases procedure time considerably, so in patients who are very tenuous hemodynamically due to rapid ventricular rates and/or rate controlling, it may be reasonable to initially perform AV node ablation alone, and then upgrade the device if the patient does not improve. The relative efficacy of CRT with AV node ablation for rate control and pulmonary vein isolation for rhythm control in patients with HF is discussed separately. (See "The management of atrial https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 5/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate fibrillation in patients with heart failure", section on 'Atrioventricular node ablation with pacing' and "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.) Implantable cardioverter-defibrillators All of the aforementioned pacing modalities (eg, single chamber, dual chamber, and CRT) and functions (eg, rate adaptive pacing and mode switching) are available on contemporary ICDs. Thus, patients with an ICD who require an AV node ablation procedure can sometimes be managed without changing the device. As most of these patients have significant LV dysfunction and systolic heart failure (given the indications for prophylactic ICD implantation), consideration should be given to upgrading to a CRT-D system with an atrial lead, if appropriate, at the time of AV node ablation. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) Physiological pacing CRT (or biventricular pacing) is a strategy to avoid the dyssynchrony associated with standard RV apical pacing in patients who become pacemaker dependent after AV node ablation (see 'Cardiac resynchronization therapy' above). A potential alternative to CRT is the positioning of a pacing lead near the His bundle ( image 1) or deep in the ventricular septum near the area of the left bundle branch. A pacing lead near the His bundle will activate the native conduction system, resulting in less dyssynchrony and a more normal QRS complex. It is technically difficult to place a conventional pacing lead in a position that results in capture of the His bundle at a reasonable pacing output because the His bundle is insulated from the endocardium. Newer, small caliber, screw-in pacing leads that are delivered using a guiding sheath rather than a stylet may improve the ability to accomplish permanent His bundle capture [6]. The value of this approach was evaluated in a prospective single-center trial of 52 patients with heart failure and refractory AF who underwent attempted AV node ablation and permanent His bundle pacing; backup RV or LV leads were placed as well [7]. During His bundle pacing, the average QRS duration was 105 msec, compared with 107 msec at baseline. The mean New York Heart Association functional class improved from baseline 2.9 in patients with heart failure with reduced ejection fraction to 1.4 with His bundle pacing, and from baseline 2.7 in patients with heart failure with preserved ejection fraction to 1.4. LV end-diastolic dimension, LV ejection fraction (LVEF), and mitral regurgitation all improved with His bundle pacing compared with baseline. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 6/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Successful His bundle pacing is technically difficult to accomplish. In addition, lead dislodgement may be more likely compared with conventional pacing sites. Pacing thresholds may also be higher with His bundle pacing, leading to shorter generator longevity. Lead dislodgement would have serious complications in this setting due to complete heart block after ablation of the AV node. Another alternative to CRT is left bundle branch area pacing. Pacing the left bundle branch has been shown to avoid some of the limitations of His-bundle pacing such as high pacing thresholds and atrial oversensing, and has been used in patients undergoing AV node ablation. This is accomplished by placing an active fixation, sheath-delivered, pacing lead deep into the RV septum to capture the left bundle branch, giving rise to a relatively narrow QRS complex to minimize pacing-induced ventricular dyssynchrony. An image shows the position of the tip of a left bundle branch pacing lead in the RV septum during administration of contrast through the delivery sheath at the time of implant. (See "Permanent cardiac pacing: Overview of devices and indications".) Further studies in larger populations are necessary to clarify both the clinical benefits and safety of these physiological pacing approaches in patients undergoing AV node ablation. In addition, given the risks of lead dislodgement, the safety and efficacy of His bundle pacing should be compared against biventricular pacing. At this point, a backup RV lead is generally placed when His bundle pacing is employed, particularly in pacemaker-dependent patients. Ventricular rate regularization Ventricular rate regularization (or ventricular rate stabilization) is a pacemaker mode that can attenuate the rate and irregularity of the ventricular response during AF [8]. The ventricle is paced at a variable rate at or near the mean native rate. This causes concealed retrograde conduction into the AV node, which makes it refractory to subsequent anterograde impulses from the atria. This tends to reduce the number of short RR intervals, which may improve symptoms by making the ventricular rate more regular during AF and sometimes slower. A potential advantage of this approach is that no catheter ablation of the AV junction is performed. However, this technique may be less effective at controlling AF during physical activity than at rest. EFFICACY AV node ablation is highly effective, as demonstrated by the following reports: AV node ablation was acutely successful in 97.4 percent of 646 patients, although 3.5 percent had recurrence of AV conduction during follow-up [9]. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 7/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate In a report from the prospective Ablate and Pace trial, the procedure was successful in all but 1 of 156 patients who underwent radiofrequency ablation of the AV node [10]. Persistent complete heart block was present in 96 percent; 33 percent of patients had no escape rhythm, while 35 percent had an escape rhythm with an escape rate <40 beats per minute. OUTCOMES Symptoms and quality of life are significantly improved in patients with poorly controlled AF who undergo AV node ablation and permanent pacemaker implantation [11-15]. In a series of 107 such patients, ablative treatment was associated with significant reductions in [11]: Physician visits (5 versus 10 prior to ablation) Hospital admissions (0.17 versus 2.8 prior to ablation) Episodes of heart failure (8 versus 18 prior to ablation) Antiarrhythmic drug trials Further support for the benefits of this approach come from a meta-analysis of 21 studies, involving 1181 patients [12]. This report noted significant improvement in all 19 outcome measures evaluated, including quality of life, ventricular function, exercise duration, and health care use [12]. While such benefits are often due to improved LV systolic function, improvement in some patients occurs independent of changes in LVEF and probably results from the slower and more regular heart rate [13,14]. To date, there is no convincing evidence of a mortality benefit with AV node ablation [12,15,16]: AV node ablation has also been compared with other nonpharmacologic therapies. In the 2008 PABA-CHF study, in which 81 patients were randomly assigned to AV node ablation with cardiac resynchronization therapy pacing or pulmonary vein isolation, the composite primary endpoint (Minnesota Living with Heart Failure score, 6MW distance, EF) favored the pulmonary vein isolation group [17]. COMPLICATIONS AV node ablation incurs risks similar to other catheter ablation procedures that require right heart access, though typically only a single venous sheath is required. If a pacemaker or ICD is implanted immediately prior to AV node ablation, the risks of device implantation are also https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 8/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate incurred. If simple RV pacing is used, there will be a risk of developing LV dysfunction and/or heart failure. (See "Cardiac implantable electronic devices: Periprocedural complications".) Specific to patients who undergo AV node ablation and pacing is a very rare but catastrophic risk of ventricular fibrillation (VF) and sudden cardiac death (SCD). In a review of 334 patients who underwent AV node ablation, nine (2.7 percent) experienced SCD [18]. Four events occurred within four days of the procedure, an additional three events occurred within three months, and two occurred late and were thought to be unrelated to the procedure. Possible causes of post-ablation VF include [18-20]: Underlying heart disease Activation of the sympathetic nervous system Prolongation in action potential duration Repolarization abnormalities induced by bradycardia Increased dispersion of ventricular refractoriness The potential for reducing the frequency of early VF with post-ablation pacing at a higher rate was evaluated in a report of 235 patients [21]. The incidence of VF was 6 percent in the first 100 patients in whom the post-ablation chronic pacing rate was 70 beats per minute. In the next 135 patients, however, a pacing rate of 90 beats per minute was used for the first three months after the ablation, and there were no episodes of VF. Pacing at a rate of 90 beats per minute decreases sympathetic activity, which may contribute to the reduction in VF or SCD [19]. Other procedural risks are those related to catheter ablation and pacemaker/ICD implant/upgrade procedures. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) NEED FOR ANTICOAGULATION While AV node ablation results in adequate heart rate control, it does not stop the atria from fibrillating. Thus, the risk of thromboembolic events is not affected [22]. As a result, there is a need for long-term anticoagulation similar to that in patients with chronic AF whose heart rate control is achieved pharmacologically. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) RECOMMENDATIONS OF OTHERS https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 9/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Our recommendations for patients with AF in whom a rate control strategy has been chosen are in general agreement with those made in major societal guidelines [23-25]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Background Atrioventricular (AV) node ablation is an option for rate control in atrial fibrillation (AF) patients who have failed medical therapy for rhythm control, have failed or are not candidates for catheter ablation for rhythm control, and have failed aggressive attempts at pharmacological rate control. Indications For AF patients with a rapid ventricular response who do not respond to or are intolerant of aggressive attempts at pharmacologic therapy to slow the ventricular rate, and in whom nonpharmacologic approaches, including curative attempts at AF ablation, are not successful or appropriate, we recommend AV node ablation in association with implantation of a permanent pacing device to improve symptoms and quality of life (Grade 1B). (See 'Indications' above.) Pacing procedure For AF patients who undergo AV node ablation, a pacing device is needed to prevent symptomatic bradycardia. A single-chamber ventricular pacemaker with rate-adaptive capability may be appropriate for patients with persistent AF, and a dual- chamber pacemaker with both mode switching and rate-adaptive capabilities may be appropriate for patients with paroxysmal AF. The roles of cardiac resynchronization therapy, physiological pacing, and implantable cardioverter-defibrillator depend on left ventricular function, heart failure symptoms, and history. (See 'Device selection' above.) No need for anticoagulation AV node ablation has no impact on thromboembolic risk and most individuals require long-term oral anticoagulation. (See 'Need for anticoagulation' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 10/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Yarlagadda B, Turagam MK, Dar T, et al. Safety and feasibility of leadless pacemaker in patients undergoing atrioventricular node ablation for atrial fibrillation. Heart Rhythm 2018; 15:994. 2. Marshall HJ, Harris ZI, Griffith MJ, et al. Prospective randomized study of ablation and pacing versus medical therapy for paroxysmal atrial fibrillation: effects of pacing mode and mode- switch algorithm. Circulation 1999; 99:1587. 3. Kamalvand K, Tan K, Kotsakis A, et al. Is mode switching beneficial? A randomized study in patients with paroxysmal atrial tachyarrhythmias. J Am Coll Cardiol 1997; 30:496. 4. Gribbin GM, Bourke JP, McComb JM. Predictors of atrial rhythm after atrioventricular node ablation for the treatment of paroxysmal atrial arrhythmias. Heart 1998; 79:548. 5. Gillis AM, Connolly SJ, Lacombe P, et al. Randomized crossover comparison of DDDR versus VDD pacing after atrioventricular junction ablation for prevention of atrial fibrillation. The atrial pacing peri-ablation for paroxysmal atrial fibrillation (PA (3)) study investigators. Circulation 2000; 102:736. 6. Dandamudi G, Vijayaraman P. How to perform permanent His bundle pacing in routine clinical practice. Heart Rhythm 2016; 13:1362. 7. Huang W, Su L, Wu S, et al. Benefits of Permanent His Bundle Pacing Combined With Atrioventricular Node Ablation in Atrial Fibrillation Patients With Heart Failure With Both Preserved and Reduced Left Ventricular Ejection Fraction. J Am Heart Assoc 2017; 6. 8. Wood MA. Trials of pacing to control ventricular rate during atrial fibrillation. J Interv Card Electrophysiol 2004; 10 Suppl 1:63. 9. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. 10. Curtis AB, Kutalek SP, Prior M, Newhouse TT. Prevalence and characteristics of escape rhythms after radiofrequency ablation of the atrioventricular junction: results from the registry for AV junction ablation and pacing in atrial fibrillation. Ablate and Pace Trial Investigators. Am Heart J 2000; 139:122. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 11/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate 11. Fitzpatrick AP, Kourouyan HD, Siu A, et al. Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation. Am Heart J 1996; 131:499. 12. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation : a meta-analysis. Circulation 2000; 101:1138. 13. Brown CS, Mills RM Jr, Conti JB, Curtis AB. Clinical improvement after atrioventricular nodal ablation for atrial fibrillation does not correlate with improved ejection fraction. Am J Cardiol 1997; 80:1090. 14. Weerasooriya R, Davis M, Powell A, et al. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). J Am Coll Cardiol 2003; 41:1697. 15. Ozcan C, Jahangir A, Friedman PA, et al. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med 2001; 344:1043. 16. Garcia B, Clementy N, Benhenda N, et al. Mortality After Atrioventricular Nodal Radiofrequency Catheter Ablation With Permanent Ventricular Pacing in Atrial Fibrillation: Outcomes From a Controlled Nonrandomized Study. Circ Arrhythm Electrophysiol 2016; 9. 17. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 18. Ozcan C, Jahangir A, Friedman PA, et al. Sudden death after radiofrequency ablation of the atrioventricular node in patients with atrial fibrillation. J Am Coll Cardiol 2002; 40:105. 19. Hamdan MH, Page RL, Sheehan CJ, et al. Increased sympathetic activity after atrioventricular junction ablation in patients with chronic atrial fibrillation. J Am Coll Cardiol 2000; 36:151. 20. Evans GT Jr, Scheinman MM, Bardy G, et al. Predictors of in-hospital mortality after DC catheter ablation of atrioventricular junction. Results of a prospective, international, multicenter study. Circulation 1991; 84:1924. 21. Geelen P, Brugada J, Andries E, Brugada P. Ventricular fibrillation and sudden death after radiofrequency catheter ablation of the atrioventricular junction. Pacing Clin Electrophysiol 1997; 20:343. 22. Gasparini M, Mantica M, Brignole M, et al. Thromboembolism after atrioventricular node ablation and pacing: long term follow up. Heart 1999; 82:494. 23. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 12/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 24. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 25. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1012 Version 28.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 13/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate GRAPHICS Clinical factors favoring atrioventricular node ablation in patients with refractory atrial fibrillation Favors atrial fibrillation ablation Favors atrioventricular node ablation/pacing Clinical characteristics Age Younger Older, particularly very elderly Atrial fibrillation pattern Paroxysmal Persistent, particularly very longstanding ("permanent") Left atrial size Normal/near normal Markedly dilated Comorbidities Minimal Extensive Overall health Robust Frail Miscellaneous High infection risk Previous failed atrial fibrillation ablation Courtesy of Leonard Ganz, MD. Graphic 129004 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 14/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study in a person with atrial fibrillation Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the atrioventricular unction region (HBE1-2, HBE3-4), and the right ventricular apex (RVA3-4) in a patient with atrial fibrillation. The patient has extremely symptomatic, medically refractory atrial fibrillation with rapid ventricular rates and recurrent heart failure. The mapping catheter (HBE) has been maneuvered from the area of maximal His bundle activity to a more proximal position, where a larger atrial (A) and smaller His electrogram (H) are recorded. ECG: electrocardiograph; V: ventricular electrogram. Graphic 74286 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 15/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study and radiofrequency catheter ablation of the AV junction in atrial fibrillation Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the region of the atrioventricular junction (HBE1-2, HBE3-4), and the right ventricular apex (RVA3- 4) in a patient with atrial fibrillation. Application of radiofrequency (RF) energy from the tip of the mapping catheter (HBE1-2) causes complete AV nodal block; pacing (P) is initiated from the right ventricular apex. A permanent VVIR pacemaker was implanted, and the patient has noted a marked improvement in symptoms. ECG: electrocardiograph; AV: atrioventricular. Graphic 67363 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 16/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Para Hisian pacing lead Patient #6. Right anterior oblique (RAO) and left anterior oblique (LAO) fluoroscopic projections showing leads position during the "ablate and pace" procedure and Hisian pacing; 1 = quadripolar Hisian mapping catheter; 2 = screw-in bipolar lead positioned in close proximity to the His-bundle; 3 = bipolar passive fixation positioned in right ventricular apex. Reproduced with permission from: Occhetta E, Bortnik M, Magnani A, et al. Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation in chronic atrial brillation: a crossover, blinded, randomized study versus apical right ventricular pacing. J Am Coll Cardiol 2006; 47:1938. Copyright 2006 American College of Cardiology Foundation. Graphic 56944 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 17/18 7/5/23, 7:59 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 18/18
7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Catheter ablation : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 27, 2022. INTRODUCTION The three principal goals of therapy in patients with atrial fibrillation (AF) are the alleviation of symptoms, the prevention of tachycardia-mediated cardiomyopathy, and the reduction in the risk of stroke. The first two goals can be achieved with either a rate or rhythm control strategy (see "Management of atrial fibrillation: Rhythm control versus rate control"). For patients in whom a rhythm control strategy is chosen, catheter ablation (CA) and antiarrhythmic drug therapy are the two principle therapeutic strategies to reduce the frequency or eliminate episodes of AF. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) This topic will discuss the use of CA in patients with AF and provide the clinician with much of the information needed to discuss the procedure with the patient. The discussion of surgery to prevent recurrent AF is found elsewhere. (See "Atrial fibrillation: Surgical ablation".) Stroke prevention is usually achieved with anticoagulation. This topic is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) WHAT TO TELL YOUR PATIENT When discussing CA to reduce symptoms in an AF patient, the following information should be provided: https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 1/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate CA is a reasonable treatment option for AF patients when medications are unable to adequately control symptoms or are not tolerated. All patients who undergo CA must take oral anticoagulation for at least two to three months after the procedure. Anticoagulation should be continued long term in many patients with risk factors for stroke even if AF is not present after the ablation. This is because patients may continue to have some AF episodes that may be asymptomatic; in addition, the reduction in AF burden seen post-ablation has not yet been shown to reduce stroke risk. It is a common misconception that patients who undergo successful ablation can stop oral anticoagulation. About 70 to 75 percent of patients are symptom free at one year [1]. A lower percentage is likely for persistent AF (about 60 percent). About 50 percent of patients have detectable AF at one year (this includes symptomatic and asymptomatic patients) [2,3]. The success rate for ablation in patients with long-standing persistent AF (over one year) is poor. The risk of a major complication is about 4 percent, with vascular access complications being the most common. Other important, less common complications include stroke, cardiac perforation, or damage that includes injury to the pulmonary veins, esophagus, or phrenic nerve. The risk of dying within 30 days after an AF ablation procedure is about 1 in 1000 patients. The risk of a major complication is significantly higher at low-volume ablation centers. [4]. TECHNICAL CONSIDERATIONS Technical considerations for CA are presented separately. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) COMPARISON WITH ANTIARRHYTHMIC THERAPY For patients with symptomatic paroxysmal AF in a rhythm- rather than a rate-control strategy, either a trial of an antiarrhythmic drug or CA is a reasonable approach. We are more inclined to https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 2/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate perform CA in patients for whom the odds of success are high and if they prefer to avoid the use of long-term antiarrhythmic drug therapy. Studies comparing these strategies are discussed separately. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients without prior antiarrhythmic drug treatment'.) EFFICACY CA leads to significant symptom improvement in most patients. Over 70 to 75 percent are symptom free at one year. Some symptoms may be due to atrial or ventricular premature complexes rather than AF. The absence of symptomatic AF recurrence is the primary efficacy outcome in most studies. However, with continuous invasive monitoring, approximately 50 percent of patients have had one or more documented episodes lasting 30 seconds or longer at one year. This becomes part of the rationale to continue long-term oral anticoagulation in many patients. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Our approach to anticoagulation'.) How is recurrence defined and measured? Recurrence of AF after CA is categorized as early or late. Each have distinct mechanisms and management implications [5]. From a clinical perspective, recurrences after the initial two-to-three-month post-ablation healing phase are more clinically relevant. Early recurrences of AF are defined as those that occur within the first two to three months after CA. This period is often referred to as the "blanking period," and recurrences during this time are not included in studies examining the long-term success of AF ablation. Early recurrences occur as often as 40 percent of the time with radiofrequency ablation (RFA) [6] and about 17 percent of the time for those treated with second-generation cryoballoon [7]. It is postulated to be related to several potential mechanisms including sterile pericarditis, recovered pulmonary vein (PV) conduction, or proarrhythmic effects of the ablation procedure [8]. Some studies suggest that early recurrence appears to be a predictor of late recurrence, especially when the episodes occur late in the blanking period. However, most clinicians will treat early recurrences with antiarrhythmic drug therapy before consideration of repeat ablation in these patients. Episodes of AF occurring after three months are considered to be recurrent AF and are referred to as "late recurrent AF." The possible mechanisms for late recurrent AF following CA are discussed separately. (See "Mechanisms of atrial fibrillation", section on 'Specific clinical situations'.) https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 3/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate The frequency of late recurrent AF varies significantly across studies in part due to factors such as the method and intensity of surveillance, whether other atrial arrhythmias such as atrial flutter are counted, whether patients remained on antiarrhythmic drug therapy, and patient characteristics (eg, paroxysmal or persistent AF). In some studies, success has been defined as the absence of recurrent AF or other atrial arrhythmias with or without antiarrhythmic drug therapy; a more rigorous definition requires the absence of AF >30 seconds in patients not taking antiarrhythmic drugs. The following studies illustrate the rates of late recurrence [9]: The DISCERN AF study evaluated episodes of symptomatic and asymptomatic AF (as well as atrial flutter and atrial tachycardia) before and after the procedure in 50 patients (80 percent with paroxysmal AF), using an implantable cardiac monitor capable of recording all AF episodes [10]. The total atrial arrhythmia burden was significantly reduced by 86 percent from a mean of two hours per day per patient before to 0.3 hours per day after. The ratio of asymptomatic to symptomatic episodes increased significantly after ablation from 1.1 to 3.7. After 18 months and a mean of 1.4 ablations, 58 percent of patients were symptom free. A 2013 meta-analysis of 19 observational studies (n = 6167) with outcomes at 3 years found that freedom from atrial arrhythmia at long-term follow-up (mean 24 months) after a single procedure was about 53 percent [11]. With multiple procedures, the long-term success rate was nearly 80 percent. However, there are several limitations of this analysis, including significant heterogeneity among the studies, disparities in post-ablation AF surveillance, and the inclusion of patients ablated with early-generation technologies no longer in current use. In the MANTRA and RAAFT-2 randomized trials, which allowed for antiarrhythmic drug use after CA, freedom from AF at two years was 85 and 72 percent, respectively [12,13]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients without prior antiarrhythmic drug treatment'.) In a meta-analysis of seven studies of first-generation cryoballoon ablation, one-year freedom from AF was 73 percent, but the analysis evaluated studies that allowed inclusion of patients taking antiarrhythmic drug therapy in the CA group [14]. Two real-world population studies found significantly lower rates of freedom from AF when only patients not taking antiarrhythmic drug therapy were counted (40 and 41 percent at one year) [3,15]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 4/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate The 2019 CIRCA-DOSE study randomly assigned 346 patients with drug-refractory, paroxysmal AF to contact-force-guided RFA or two differing duration protocols for cryoballoon ablation [1] (see 'Technical considerations' above). All patients received an implantable loop recorder, and they also received noninvasive surveillance. Follow-up was for 12 months. The primary endpoint of one-year freedom from atrial tachyarrhythmia (symptomatic or asymptomatic) as detected by continuous rhythm monitoring was about 53 percent in the three groups. One-year freedom from symptomatic atrial tachyarrhythmia, defined by continuous monitoring, ranged between 73 and 79 percent (p = 0.87). AF burden was reduced by about 99 percent in the three groups (p = 0.36). Predictors of recurrence Recurrence is more likely in patients with underlying cardiovascular disease such as hypertension, complicated heart disease (including valvular heart disease), older age, persistent as opposed to paroxysmal AF, procedure performed at a low-volume center, untreated obstructive sleep apnea, obesity, increasing plasma B-type natriuretic peptide level, or left atrial (LA) dilation [8,16-22]. LA dilation We rarely perform CA in patients with long-standing persistent AF and severe LA dilation (>5.5 cm). LA dilation should be assessed by volume determination rather than linear measurements if possible [23]. One study has shown that an LA volume 130 cc, assessed by computed tomography, predicts a recurrence rate of >90 percent at one year [24]. Other LA remodeling parameters Greater atrial wall thickness, lipid composition, and epicardial fat volume on cardiac computed tomography also predict AF recurrence in observational studies, but low measurement reproducibility may limit their clinical use [25]. Among 732 patients undergoing CA, 270 had AF recurrence after seven months. Patients with AF recurrence had higher LA wall thickness (anterior wall 1.9 versus 1.7 mm), 3 epicardial adipose volume (145 versus 129 mm ) and lower LA wall attenuation reflective of higher lipid composition (-69.1 versus -67.5 Hounsfield Units). Comparison of radiofrequency and cryothermal ablation The commonly used approved energy sources for CA are RF and cryothermal ablation. The efficacy and safety associated with these two energy sources have been found to be similar in multiple studies [1,14,26-30]. The three major randomized trials comparing the two energy sources are as follows: In the FIRE AND ICE trial, 762 patients with symptomatic, drug-refractory, paroxysmal AF were randomly assigned to cryoballoon ablation or RFA [31]. The primary efficacy endpoint https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 5/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate was the first documented clinical failure (eg, recurrence of AF, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day blanking period after the index ablation. Arrhythmia surveillance was noninvasive. The mean duration of follow-up was 1.5 years. The primary efficacy endpoint was similar in both groups (34.6 versus 35.9 percent, respectively; hazard ratio 0.96, 95% CI 0.76-1.22). In the FreezeAF trial, 315 patients with paroxysmal AF were randomly assigned to RFA or cryoballoon ablation [26]. The primary endpoint of freedom from atrial arrhythmia with absence of persistent complications was similar in the two groups at 12 months (70.7 versus 73.6 percent). Arrhythmia surveillance was noninvasive. In the 2019 CIRCA-DOSE study, which is discussed above, the two energy sources led to similar efficacy outcomes. (See 'How is recurrence defined and measured?' above.) Complications of cryoballoon ablation may differ somewhat from standard RFA. Pericardial effusions, tamponade, and atrioesophageal fistula have been reported less frequently in cryoballoon ablation. Non-AF atrial tachyarrhythmias have also been less frequently reported in long-term follow-up of cryoballoon ablation. However, phrenic nerve paralysis has been reported in up to 6.3 percent of 1349 procedures, significantly higher than seen with standard RFA. Resolution occurs acutely in most patients and in >90 percent within one year [14]. The use of larger balloons that prevent distal ablation and the assessment of diaphragmatic compound motor action potentials have lowered the rate of this complication. Recordings of diaphragmatic electromyograms during cryoballoon ablation for AF accurately predict phrenic nerve injury [32]. Patients with persistent atrial fibrillation The majority of patients in the studies of CA presented above had paroxysmal AF. The efficacy of CA in patients with persistent AF is lower than in patients with paroxysmal AF [33]. Our threshold for recommending CA is higher for patients with persistent AF given the lower success rates. Also, we avoid the use of CA as first- line therapy in patients with persistent AF. We believe CA is a reasonable choice for individuals with symptomatic persistent AF who either fail or cannot tolerate antiarrhythmic drug therapy or, in certain circumstances (ie, tachycardia- mediated cardiomyopathy), where there may be a benefit to maintaining sinus rhythm even in the absence of symptoms. To improve outcomes, standard pulmonary vein isolation (PVI) with or without additional ablative lesions can be performed. However, the utility of these additional lesion sets has not been consistently demonstrated, and we recommend standard PVI without the creation of additional lesions for the first ablation attempt in the majority of patients. We consider https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 6/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate additional lesions in patients with long-standing persistent AF or a markedly enlarged LA (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'). In patients with persistent AF, one small randomized trial (VENUS) found that the addition of vein-of-Marshall ethanol (see "Mechanisms of atrial fibrillation", section on 'Role of premature atrial complex and other arrhythmia triggers') infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF at 6 and 12 months [34]. Further study of this procedure is needed. A 2014 systematic review and meta-analysis identified 46 randomized trials and observational studies of 3819 patients who underwent CA for persistent AF [35]. Compared with medical therapy, CA reduced the risk of recurrent AF (odds ratio 0.32, 95% CI 0.20-0.53). Various ablation strategies were employed in the studies, and the most efficacious combined isolation of the PVs with limited linear ablation (eg, roof ablation, mitral isthmus ablation) within the LA. The success rate after two procedures was about 60 percent in all groups. (See 'Comparison with antiarrhythmic therapy' above.) The STAR AF II trial was published subsequently to the meta-analysis [2]. In this trial, 589 patients with persistent AF were randomly assigned in a 1:4:4 ratio to ablation with PVI alone, PVI plus ablation of electrograms showing complex fractionated activity, or PVI plus additional linear ablation across the LA roof and mitral valve isthmus. There was no significant difference in the rates of the primary endpoint of freedom from any documented recurrence of AF lasting longer than 30 seconds after a single ablation procedure at 18 months (59 versus 49 versus 46 percent, respectively). Although serious adverse events appeared to be lower in the PVI-alone group, there were too few events for this endpoint to achieve statistical significance. Patients with concomitant atrial flutter Atrial fibrillation and flutter often coexist in part due to their common risk factors. In many atrial flutter patients, AF is thought to be the inciting arrhythmia, and as much as 55 percent of patients who undergo ablation for typical atrial flutter are also found to have AF on long-term follow-up [36]. Some studies have shown that PV triggers play an important role in the development of flutter [37]. While ablation of the tricuspid annulus-inferior vena cava (TA-IVC) isthmus is a highly successful treatment option for atrial flutter, the ablation approach to the patient with concomitant AF and atrial flutter requires a more extensive approach and has been evaluated: In a study of 108 patients with both AF and typical atrial flutter, patients were randomly assigned to either a dual-ablative procedure (PVI and TA-IVC isthmus ablation, 49 patients) or PVI alone (59 patients) [38]. After ablation, the following observations were made: https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 7/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate During the first eight weeks post-procedure, none of the dual-procedure patients and 32 patients treated with PVI alone developed atrial flutter and required cardioversion and/or antiarrhythmic drugs. After eight weeks, all antiarrhythmic drugs were discontinued. Only three patients treated with PVI alone had further recurrences of atrial flutter, which was successfully treated with TA-IVC ablation. Seven of the dual-procedure patients and six of those treated with PVI alone developed recurrent AF. Of these 13 patients (12 percent of the total group), 10 underwent successful repeat PVI, and three remained in sinus rhythm on antiarrhythmic drugs. These findings suggest that AF initiated by PV triggers may be the precursor rather than the consequence of atrial flutter. This conclusion is consistent with the observation that atrial flutter often starts after a transitional rhythm of variable duration, usually AF [39,40]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Attempts to control all atrial arrhythmias in patients with atrial flutter by performing PVI alone or at the time of an atrial flutter ablation have been studied: In the Triple A trial, 60 patients with atrial flutter but no documented AF were randomized to receive antiarrhythmic drugs alone, ablation of the cavotricuspid isthmus (CTI), or PVI. The primary endpoint, defined as any recurrent atrial tachyarrhythmia, occurred in 82.4 percent of the drug-treated group, 60.9 percent in the CTI group, and 10 percent in the PVI group during a mean follow-up time of 1.42 years [37]. In the PReVENT AF study [41], 50 patients with atrial flutter and no documented AF were randomized to CTI ablation alone or with concomitant PVI. More patients in the isthmus- ablation-only group experienced new-onset AF during follow-up (52 versus 12 percent), and the one-year burden also favored the combined ablation group compared with the isthmus-ablation-only group (8.3 versus 4 percent). These findings suggest that PVI either alone or in conjunction with atrial flutter ablation may have a beneficial effect on long-term suppression of all atrial arrhythmias. However, we do not recommend performing this procedure in lieu of or at the time of TA-IVC ablation in patients whose only documented arrhythmia is atrial flutter given the potential risks associated with additional ablation. (See "Atrial flutter: Maintenance of sinus rhythm".) Patients with structural heart disease The presence of structural heart disease may influence both the safety and efficacy of ablation procedures. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 8/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Heart failure CA appears to be safe and effective for the prevention of AF recurrence in patients with heart failure or impaired left ventricular function. The experience with ablation in this setting is discussed elsewhere. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Cardiac resynchronization therapy CA as an alternative to cardiac resynchronization therapy with atrioventricular node ablation in patients with heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Preference for rhythm over rate control'.) Mitral valve prosthesis A potential concern with CA in patients with a mitral valve prosthesis is injury to the valve. Furthermore, entrapment of the ablation catheter in a mechanical mitral valve, necessitating open-heart surgery, has been reported in patients undergoing left-sided ablation procedures. This issue was addressed in a report of 26 patients with mitral valve prostheses who were compared with a matched group of 52 patients without a mitral valve prosthesis [42]. The rate of maintenance of sinus rhythm was the same in the two groups, but the patients with a mitral valve prosthesis had longer fluoroscopy times with greater radiation exposure and a higher rate of post-ablation atrial tachycardia (23 versus 2 percent). Rheumatic heart disease The role of CA for chronic AF in patients with rheumatic heart disease is not well defined. One study performed electrophysiologic mapping in 17 patients with mitral stenosis who had chronic AF and were converted to sinus rhythm after balloon valvulotomy [43]. An organized atrial arrhythmia, which degenerated into AF, was induced in all patients; the focus was most often near the coronary sinus ostium. RFA was successful in 13 patients and, after a mean follow-up of 32 weeks, 10 were still in sinus rhythm. Cardiac surgery Either the Maze procedure or off-pump CA using an epicardial approach should be considered in patients with AF and an indication for open-heart surgery. These approaches are not generally recommended for patients without an indication for cardiac surgery, except in special circumstances, because of the mortality and morbidity associated with surgery. (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure'.) Patients with hypertension Renal sympathetic nerve denervation has been proposed as an adjunctive treatment to CA in hypertensive AF patients. We do not feel the available evidence supports its use in this setting. The rationale for the adding renal nerve denervation to CA is that hypertension is a major risk factor for the development of AF and that many hypertensive AF patients have increased https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 9/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate sympathetic tone. Renal nerve denervation has been evaluated as a treatment for hypertension, but its efficacy has not yet been established. (See "Treatment of resistant hypertension".) The issue of whether renal nerve denervation, when added to CA, can further lower the rate of AF recurrence was evaluated in the ERADICATE-AF trial [44]. In this study, 302 hypertensive (paroxysmal) AF patients were randomly assigned to CA or CA plus renal nerve denervation. The primary endpoint of freedom from AF, atrial flutter, or tachycardia at 12 months occurred in 56.5 and 72.1 percent of the two groups, respectively (hazard ratio 0.57, 95% CI 0.38-0.85). There was no significant difference in the rate of procedural complications between the two groups. Although the use of renal denervation as adjunctive therapy to CA improved the primary outcome, the lack of a sham-control group, that is CA plus sham renal denervation, is a major limitation of this study. COMPLICATIONS The types and rates of complications that occur in patients undergoing CA vary from series to series ( table 1 and table 2). The overall rate of major complications is about 4 percent, with vascular access complications being the most frequent [45]. There may be an increased rate of adverse effects with more extensive circumferential ablation [46-50]. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) Two large studies published in 2013 came to somewhat differing conclusions as to whether the complication rate was falling with time: An analysis of 93,801 CA procedures performed in community hospitals in the United States between 2000 and 2010 did not identify a trend toward lower mortality [51]. The majority (81 percent) of procedures were performed in low-volume hospitals by low-volume operators. The overall frequency of complications was 6.29 percent, and there was a small but nonsignificant rise with time. In a meta-analysis of 192 published studies, including 83,236 patients, there was a significant decrease in the acute complication rate from 2007 to 2012 compared with 2000 to 2006 (2.6 versus 4 percent; p = 0.003) [52]. In these studies, cardiac complications accounted for at least 50 percent of all complications. Most [51,53], but not all [54], studies have suggested that advanced age and female sex are risk factors for complications. In addition, annual operator (<25 procedures) and hospital volume (<50 procedures) have been associated with adverse outcomes [51]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 10/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Complications reported in series of patients undergoing CA to prevent recurrent AF will be reviewed here. Other complications that might occur with any electrophysiology study, such as radiation exposure and valve, vascular, or myocardial injury, are discussed separately. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) Mortality Early case series found a death rate of about 1 to 1.5 in every 1000 patients [55,56]. More recent studies suggest a mortality closer to 5 per 1000. In the two large series (2000 to 2010 and 2007 to 2012) discussed directly above, the in-hospital mortality rates varied between 4.6 and 0.6 per 1000 patients [51,52]. The leading causes of death were cardiac tamponade (n = 8, 25 percent), stroke (n = 5, 16 percent), and atrioesophageal fistula (n = 5, 16 percent). Other causes included pneumonia, pulmonary vein (PV) perforation, and sepsis [55]. Cardiac tamponade Cardiac tamponade resulting from perforation is the most frequent serious complication of CA for AF, occurring in slightly more than 1 percent of procedures using radiofrequency (RF) [53,55,57], and it is the leading cause of death [55]. Tamponade results from either catheter perforation of an atrial or ventricular free wall, especially with overheating during energy delivery, or less frequently with transseptal puncture. Some cases of tamponade may be delayed in onset. In one study of delayed tamponade, the median duration was 10 days, with a range of several hours up to 30 days [55]. Pericardial effusion associated with PV isolation (PVI) was significantly less common in patients who underwent cryoballoon ablation (0.8 versus 2.1 percent) in one meta-analysis [30]. The treatment of tamponade caused by CA is similar to that in other settings. (See "Cardiac tamponade", section on 'Treatment'.) Catheter entrapment Entrapment of the circular mapping (LASSO) catheter in the mitral valve apparatus is a rare complication that can require cardiac surgery to resolve. The estimated incidence of this complication ranges between 0.01 and 0.9 percent, and specific sites of transeptal puncture or catheter manipulation may predispose to this adverse event [58-60]. Pulmonary vein stenosis PV stenosis is a potential complication of ablation near or within the PVs. The lesion is characterized by fibrosis and scarring of the PV; specific pathologic changes include intimal thickening, thrombus formation, endocardial contraction, and proliferation of elastic laminae [61]. The diagnosis may be delayed or missed entirely, as symptomatic patients may come to attention months after their initial ablation. In one series, symptoms developed 4 3 months after the most recent ablation, and the average delay between the onset of symptoms and diagnosis was 4.4 5.4 months. Symptoms of PV stenosis include dyspnea with exertion (or less often at rest), cough, chest pain, hemoptysis, and recurrent lung infections [62,63]. The mean onset of symptoms is two to five months after the https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 11/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate procedure [62-64]. The intensity of symptoms may be directly related to the degree of obstruction and inversely related to the duration of time to develop the stenosis [65]. Incorrect diagnoses including pneumonia, bronchitis, or suspected malignancy are often considered and result in unnecessary testing, treatment, and delayed intervention. Delays in diagnosis and treatment may allow for progression of stenosis and irreversible intraparenchymal lung damage. The reported rate of PV stenosis depends not only on the factors described above, but also on the definition of stenosis severity and the intensity of screening. Early reports cited rates as high as 38 percent, but more studies cite rates for severe stenosis as low as 1 to 3 percent [53,58,63,66]. A minority of diagnosed patients appear to develop symptoms [67,68]. The incidence of severe PV stenosis is between 0.32 and 3.4 percent, but the risk may be lower with cryoballoon compared with radiofrequency energy [69]. The rate of PV stenosis requiring intervention may be as low as 0.1 to 0.3 percent [57]. Diagnostic evaluation for PV stenosis should be performed in patients who develop respiratory symptoms after RF ablation (RFA). The joint Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement of catheter and surgical ablation of AF suggests computed tomography or magnetic resonance imaging (MRI) as the preferred tests in suspected cases [65]. A ventilation/perfusion lung scan can also be used to diagnose PV stenosis. Stent placement is a more effective therapy for PV stenosis compared with balloon angioplasty [69]. It is associated with a significant and almost immediate improvement in symptoms and pulmonary blood flow [62-64]. In series of patients who underwent balloon angioplasty with or without stenting, in-segment or in-stent stenosis requiring repeat intervention developed in approximately 50 percent of patients [63,64]. The roles of either elective stenting or surgery are not well defined [65]. However, the incidence of PV stenosis has significantly decreased due to improvement in ablative techniques, especially with moving the ablation lesions toward the atrial side of the PV-atrial junction. Periprocedural embolic events Patients undergoing CA to prevent recurrent AF are at risk for embolic events before, during, and after the procedure. The incidence of clinical stroke or transient ischemic attack is between 0 and 2 percent [9]. The role of anticoagulant therapy in this setting is discussed in detail separately. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) MRI-detected brain lesions and cognitive impairment Stroke and transient ischemic attack are not the only neurologic sequelae of CA. Multiple MRI studies performed within 24 hours https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 12/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate after RFA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [70-72]. However, in a study of 60 AF patients at relatively low risk for stroke who underwent CA, only one patient developed new asymptomatic lesions on MRI soon after the procedure [73]. These lesions were presumed secondary to microemboli [74]. Studies of the impact of these lesions on neurocognitive function have come to differing conclusions as to the significance of these lesions, as illustrated by the following studies: The prevalence of cognitive impairment after RFA was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal AF, 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [75]. All RFA patients received periprocedural enoxaparin, and most patients with AF had a CHADS 2 score of 0 or 1 ( table 3). All patients underwent eight neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively. In a study of 37 patients with paroxysmal AF who underwent 41 ablation procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [72]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing. Vascular complications Vascular complications are among the most common adverse events related to AF ablation, likely due to the number and size of intravascular sheaths and the need for anticoagulation both during and immediately following the procedure. These complications include hematoma at the sites of catheter insertion, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Pseudoaneurysm and arteriovenous fistulae rates of 0.53 and 0.43 percent, respectively, have been reported [57,58]. This risk can be significantly reduced by the use of vascular ultrasound, which was demonstrated, in one study of 689 patients, to reduce the risk of vascular access complications from 5.3 to 1.1 percent [76]. Conservative management alone is usually sufficient for large hematomas and retroperitoneal bleeding, though anticoagulation may need to be held, and transfusion may be necessary in those patients where the risks of such interventions are warranted. Echo-guided manual compression and percutaneous intervention are usually effective treatments of femoral pseudoaneurysms or arteriovenous fistula, but direct surgical intervention is sometimes required [77]. Atrial esophageal fistula This is a potentially life-threatening medical emergency for which the exact mechanism is unknown. The overall incidence is 0.3 to 0.54 percent, and mortality is between 50 and 83 percent [78]. Early recognition can be missed due to the low awareness of https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 13/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate this rare complication. It is important for patients to be educated as to warning signs and to contact their AF ablation center should any suggestive symptoms develop. Clinical manifestations usually present one to four weeks post-ablation (range of 2 to 60 days), and the most common symptoms are fever, chest pain, and recurrent neurologic events from septic emboli. Chest computed tomography is the preferred diagnostic modality. Endoscopy with air insufflation should not be performed. Arrhythmic complications New reentrant circuits created by the ablation lesions can lead to atypical left atrial (LA) flutter. These circuits tend to develop around regions of LA scar and often involve the perimitral region. Due to anatomic variability and technical challenges, successful ablation is more difficult than that for typical right atrial flutter involving the isthmus of the inferior vena cava and tricuspid annulus. A significant percentage of LA flutter following PVI may also involve the musculature of the coronary sinus or the roof of the left atrium [79]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Typical atrial flutter may also occur after LA ablation due to alterations in activation patterns of the LA and may have an unusual electrocardiographic morphology. LA flutter appears to be more common following circumferential (as opposed to segmental) PVI [49,79-82]. In a randomized comparison of circumferential and segmental PVI, LA flutter developed in 9 of the 50 patients undergoing circumferential PVI, and in 1 of the 50 patients in the segmental PVI group [49]. In addition, many of the recurrent LA arrhythmias following segmental PVI are focal atrial tachycardias, as opposed to macroreentrant flutter circuits, and are often successfully treated with repeat isolation of the PVs. Other Other complications with their respective incidences are summarized: Phrenic nerve injury (<1 percent) [57,58] in patients receiving RFA (and up to 6.3 percent in those receiving cryoablation). (See 'Comparison of radiofrequency and cryothermal ablation' above.) Periesophageal vagal injury (gastric hypomotility) [48,83]. Acute coronary artery occlusion/injury (<1 percent) [65,84]. Iatrogenic atrial septal defect after cryoballoon ablation without clinical consequence (20 percent) [85]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 14/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate PREVENTION OF RECURRENCE The following therapies have been evaluated for their ability to prevent late recurrent AF; only treatment of obstructive sleep apnea (OSA) seems to be beneficial: Glucocorticoid therapy We do not believe there is sufficient evidence to recommend the use of prophylactic glucocorticoid therapy. Two observations raise the possibility that corticosteroid therapy might be useful for the prevention of early recurrence. Firstly, inflammation is associated with the development of AF, and systemic and local inflammatory responses may result from radiofrequency ablation (RFA) [86] (see "Epidemiology, risk factors, and prevention of atrial fibrillation",
the preferred tests in suspected cases [65]. A ventilation/perfusion lung scan can also be used to diagnose PV stenosis. Stent placement is a more effective therapy for PV stenosis compared with balloon angioplasty [69]. It is associated with a significant and almost immediate improvement in symptoms and pulmonary blood flow [62-64]. In series of patients who underwent balloon angioplasty with or without stenting, in-segment or in-stent stenosis requiring repeat intervention developed in approximately 50 percent of patients [63,64]. The roles of either elective stenting or surgery are not well defined [65]. However, the incidence of PV stenosis has significantly decreased due to improvement in ablative techniques, especially with moving the ablation lesions toward the atrial side of the PV-atrial junction. Periprocedural embolic events Patients undergoing CA to prevent recurrent AF are at risk for embolic events before, during, and after the procedure. The incidence of clinical stroke or transient ischemic attack is between 0 and 2 percent [9]. The role of anticoagulant therapy in this setting is discussed in detail separately. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) MRI-detected brain lesions and cognitive impairment Stroke and transient ischemic attack are not the only neurologic sequelae of CA. Multiple MRI studies performed within 24 hours https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 12/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate after RFA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [70-72]. However, in a study of 60 AF patients at relatively low risk for stroke who underwent CA, only one patient developed new asymptomatic lesions on MRI soon after the procedure [73]. These lesions were presumed secondary to microemboli [74]. Studies of the impact of these lesions on neurocognitive function have come to differing conclusions as to the significance of these lesions, as illustrated by the following studies: The prevalence of cognitive impairment after RFA was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal AF, 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [75]. All RFA patients received periprocedural enoxaparin, and most patients with AF had a CHADS 2 score of 0 or 1 ( table 3). All patients underwent eight neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively. In a study of 37 patients with paroxysmal AF who underwent 41 ablation procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [72]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing. Vascular complications Vascular complications are among the most common adverse events related to AF ablation, likely due to the number and size of intravascular sheaths and the need for anticoagulation both during and immediately following the procedure. These complications include hematoma at the sites of catheter insertion, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Pseudoaneurysm and arteriovenous fistulae rates of 0.53 and 0.43 percent, respectively, have been reported [57,58]. This risk can be significantly reduced by the use of vascular ultrasound, which was demonstrated, in one study of 689 patients, to reduce the risk of vascular access complications from 5.3 to 1.1 percent [76]. Conservative management alone is usually sufficient for large hematomas and retroperitoneal bleeding, though anticoagulation may need to be held, and transfusion may be necessary in those patients where the risks of such interventions are warranted. Echo-guided manual compression and percutaneous intervention are usually effective treatments of femoral pseudoaneurysms or arteriovenous fistula, but direct surgical intervention is sometimes required [77]. Atrial esophageal fistula This is a potentially life-threatening medical emergency for which the exact mechanism is unknown. The overall incidence is 0.3 to 0.54 percent, and mortality is between 50 and 83 percent [78]. Early recognition can be missed due to the low awareness of https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 13/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate this rare complication. It is important for patients to be educated as to warning signs and to contact their AF ablation center should any suggestive symptoms develop. Clinical manifestations usually present one to four weeks post-ablation (range of 2 to 60 days), and the most common symptoms are fever, chest pain, and recurrent neurologic events from septic emboli. Chest computed tomography is the preferred diagnostic modality. Endoscopy with air insufflation should not be performed. Arrhythmic complications New reentrant circuits created by the ablation lesions can lead to atypical left atrial (LA) flutter. These circuits tend to develop around regions of LA scar and often involve the perimitral region. Due to anatomic variability and technical challenges, successful ablation is more difficult than that for typical right atrial flutter involving the isthmus of the inferior vena cava and tricuspid annulus. A significant percentage of LA flutter following PVI may also involve the musculature of the coronary sinus or the roof of the left atrium [79]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Typical atrial flutter may also occur after LA ablation due to alterations in activation patterns of the LA and may have an unusual electrocardiographic morphology. LA flutter appears to be more common following circumferential (as opposed to segmental) PVI [49,79-82]. In a randomized comparison of circumferential and segmental PVI, LA flutter developed in 9 of the 50 patients undergoing circumferential PVI, and in 1 of the 50 patients in the segmental PVI group [49]. In addition, many of the recurrent LA arrhythmias following segmental PVI are focal atrial tachycardias, as opposed to macroreentrant flutter circuits, and are often successfully treated with repeat isolation of the PVs. Other Other complications with their respective incidences are summarized: Phrenic nerve injury (<1 percent) [57,58] in patients receiving RFA (and up to 6.3 percent in those receiving cryoablation). (See 'Comparison of radiofrequency and cryothermal ablation' above.) Periesophageal vagal injury (gastric hypomotility) [48,83]. Acute coronary artery occlusion/injury (<1 percent) [65,84]. Iatrogenic atrial septal defect after cryoballoon ablation without clinical consequence (20 percent) [85]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 14/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate PREVENTION OF RECURRENCE The following therapies have been evaluated for their ability to prevent late recurrent AF; only treatment of obstructive sleep apnea (OSA) seems to be beneficial: Glucocorticoid therapy We do not believe there is sufficient evidence to recommend the use of prophylactic glucocorticoid therapy. Two observations raise the possibility that corticosteroid therapy might be useful for the prevention of early recurrence. Firstly, inflammation is associated with the development of AF, and systemic and local inflammatory responses may result from radiofrequency ablation (RFA) [86] (see "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'). Secondly, glucocorticoid prophylaxis reduces the risk of the development of perioperative AF in patients undergoing coronary artery bypass graft surgery. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The possible benefit from prophylactic glucocorticoid therapy was evaluated in a study of 125 patients with paroxysmal AF who were randomly assigned to either three days of glucocorticoid therapy or placebo starting immediately after the procedure [87]. The rate of AF recurrence (primary endpoint) was significantly lower in the glucocorticoid group at one month (27 versus 49 percent), with most of the benefit occurring during the first three days (7 versus 31 percent). Treatment of OSA OSA is a predictor of recurrent AF after RFA. Patients with OSA who undergo CA should be encouraged to be evaluated for treatment with continuous positive airway pressure [88,89]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".) Colchicine Colchicine, another drug with antiinflammatory properties, has been shown to decrease the risk of postoperative AF after cardiac surgery, particularly in patients with post-pericardiotomy syndrome. However, pending additional studies showing benefit, we do not use prophylactic colchicine. (See "Post-cardiac injury syndromes", section on 'Prevention'.) The potential ability of colchicine to reduce the incidence of early recurrent AF after pulmonary vein isolation was evaluated in a study of 206 individuals with paroxysmal AF who were randomly assigned to colchicine 0.5 mg twice daily or placebo beginning on the day of CA and continuing for three months [90]. After follow-up of about 15 months, there https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 15/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate was a lower recurrence rate of AF in patients taking colchicine (31.1 versus 49.5 percent; odds ratio [OR] 0.46, 95% CI 0.26-0.81). Angiotensin inhibition The data are mixed as to whether angiotensin converting enzyme inhibitors/angiotensin II receptor blockers reduce AF after CA procedures. This issue is discussed elsewhere. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation", section on 'Catheter ablation of atrial fibrillation'.) Periprocedural weight reduction Some studies suggest that periprocedural weight reduction may be a helpful adjunct to CA. Pre-procedure weight reduction In a retrospective study of 600 patients, weight reduction before CA was associated with reduced AF occurrence [91]. Freedom from AF was observed in 420 patients (70 percent) at 15 months. Percent weight loss during the year before CA independently predicted freedom from AF through the next 15 months (OR 1.17, 95% CI 1.11-1.23). Post-procedure weight reduction The SORT-AF Study compared one-year AF burden in patients with obesity participating in a weight loss program versus usual care after CA [92]. The intervention group had a small reduction in weight loss (5 versus 1 kg in controls). AF burden (measured with implantable loop recorder) after ablation did not differ between the two groups (OR 1.14, 95% CI 0.37-3.6). However, a reduction in body mass index was associated with a decrease in AF recurrence in persistent compared with paroxysmal AF patients. FOLLOW-UP Surveillance for recurrence of atrial arrhythmias is important in patients who have undergone CA. We agree with the joint Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement of catheter and surgical ablation of AF [65], which recommends the following: First visit with electrophysiologist at a minimum of three months, and then every six months for at least two years. Electrocardiograms (ECGs) at all visits; symptomatic (eg, palpitations) patients should be evaluated with some form of event monitoring. The optimal method for screening for episodes of AF after ablation is not known. In the above studies, late recurrent AF was detected by patient symptoms, serial ECGs, 24- to 48-hour Holter https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 16/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate monitoring, and implantable cardiac monitor [10,16,93,94]. Rhythm transmitters were also used in the first few months [94]. With the exceptions of implantable cardiac monitor, preexisting dual-chamber pacemaker, or implantable cardioverter-defibrillator with AF detection capabilities, these methods may underestimate the incidence of recurrence due to sampling error [95]. In addition, as has been well demonstrated, patients with AF have a high rate of asymptomatic episodes. (See "Paroxysmal atrial fibrillation", section on 'Natural history' and 'Efficacy' above.) MANAGEMENT OF RECURRENCE Some patients with symptomatic AF after CA are candidates for a repeat procedure. The decision to do so is usually based on a patient's assessment of the potential benefit and risks. Other patients may choose a trial of antiarrhythmic drug therapy to reduce symptoms. The most common reason for recurrence of paroxysmal AF is reconnection of previously ablated electrically active tissue. Based upon the recurrence rates of AF after ablation, many patients are candidates for repeat ablation. We tell our patients that the success rate is in the range of 50 to 85 percent for a single procedure based primarily on AF type and anatomy, and that about 20 percent of patients have at least a second procedure. Success rates after a second procedure can be as high as 90 percent. Some experts and patients have agreed to repeat the procedure a third time. Patients with a history of persistent AF have a lower success rate and are less often felt to be good candidates for repeat procedures. The issue of whether patients with AF recurrence should undergo a repeat procedure or be placed on antiarrhythmic drug therapy was addressed in a study that randomly assigned 154 patients with symptomatic, paroxysmal AF recurrence to either repeat ablation or antiarrhythmic drugs [96]. During three-year follow-up, fewer patients in the repeat ablation group demonstrated AF progression, defined as an increase in AF burden >30 percent relative to baseline based on insertable cardiac monitor (also sometimes referred to as implantable cardiac monitor or implantable loop recorder) data or development of persistent AF (25 versus 79 percent; p<0.01). Despite limitations of this study, it supports our approach of offering a second ablation procedure to most patients. CONTRAINDICATIONS While there are few absolute contraindications, the risks and benefits of AF ablation should be carefully considered in each patient. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 17/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Contraindications to AF ablation include preexisting left atrial or left atrial appendage thrombus, inability to safely administer anticoagulation during or after the procedure, inability to tolerate sedation, patients with atrial septal defect closure devices in whom transseptal access cannot be performed, and those with interruption of the inferior vena cava. While not contraindicated, ablations performed on those with very long-standing persistent AF (ie, >2 years), severe mitral stenosis or regurgitation, or large left atria are expected to have lower success rates. (See 'Predictors of recurrence' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of catheter ablation (CA) CA for atrial fibrillation (AF) leads to symptom improvement in many patients. However, it has not convincingly been shown to decrease the risks of embolization (eg, stroke) or death. (See 'Efficacy' above.) https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 18/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Efficacy Current techniques for CA should lead to one-year freedom from symptomatic AF while off antiarrhythmic drug therapy in about 75 to 90 percent of patients with drug- resistant paroxysmal AF and no significant structural heart disease. (See 'Efficacy' above.) Complications Important complications of CA include death, cardiac tamponade, stroke, vascular trauma, and phrenic nerve palsy ( table 1). Specific signs and symptoms can help identify complications ( table 2). (See 'Complications' above.) Recurrence For patients who have recurrent AF after a first ablation, there are two reasonable management strategies: a clinical trial of an antiarrhythmic agent or proceeding directly to a second ablation. Patients may have a preference for one or the other. (See 'Management of recurrence' above.) 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Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Circulation 2003; 108:2479. 39. Waldo AL, Cooper TB. Spontaneous onset of type I atrial flutter in patients. J Am Coll Cardiol 1996; 28:707. 40. Waldo AL. Mechanisms of atrial flutter and atrial fibrillation: distinct entities or two sides of a coin? Cardiovasc Res 2002; 54:217. 41. Steinberg JS, Romanov A, Musat D, et al. Prophylactic pulmonary vein isolation during isthmus ablation for atrial flutter: the PReVENT AF Study I. Heart Rhythm 2014; 11:1567. 42. Lang CC, Santinelli V, Augello G, et al. Transcatheter radiofrequency ablation of atrial fibrillation in patients with mitral valve prostheses and enlarged atria: safety, feasibility, and efficacy. J Am Coll Cardiol 2005; 45:868. 43. Nair M, Shah P, Batra R, et al. Chronic atrial fibrillation in patients with rheumatic heart disease: mapping and radiofrequency ablation of flutter circuits seen at initiation after cardioversion. Circulation 2001; 104:802. 44. Steinberg JS, Shabanov V, Ponomarev D, et al. Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension: The ERADICATE-AF Randomized Clinical Trial. JAMA 2020; 323:248. 45. Bertaglia E, Stabile G, Pappone A, et al. Updated national multicenter registry on procedural safety of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2013; 24:1069. 46. Pappone C, Oral H, Santinelli V, et al. Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation 2004; 109:2724. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 22/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate 47. Scanavacca MI, D' vila A, Parga J, Sosa E. Left atrial-esophageal fistula following radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2004; 15:960. 48. Shah D, Dumonceau JM, Burri H, et al. Acute pyloric spasm and gastric hypomotility: an extracardiac adverse effect of percutaneous radiofrequency ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:327. 49. Karch MR, Zrenner B, Deisenhofer I, et al. Freedom from atrial tachyarrhythmias after catheter ablation of atrial fibrillation: a randomized comparison between 2 current ablation strategies. Circulation 2005; 111:2875. 50. Oral H, Scharf C, Chugh A, et al. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. Circulation 2003; 108:2355. 51. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013; 128:2104. 52. Gupta A, Perera T, Ganesan A, et al. Complications of catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol 2013; 6:1082. 53. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 54. Zado E, Callans DJ, Riley M, et al. Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in the elderly. J Cardiovasc Electrophysiol 2008; 19:621. 55. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 56. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:32. 57. Maan A, Shaikh AY, Mansour M, et al. Complications from catheter ablation of atrial fibrillation: a systematic review. Crit Pathw Cardiol 2011; 10:76. 58. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005; 111:1100. 59. Zeljko HM, Mont L, Sitges M, et al. Entrapment of the circular mapping catheter in the mitral valve in two patients undergoing atrial fibrillation ablation. Europace 2011; 13:132. 60. Kesek M, Englund A, Jensen SM, Jensen-Urstad M. Entrapment of circular mapping catheter in the mitral valve. Heart Rhythm 2007; 4:17. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 23/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate 61. Taylor GW, Kay GN, Zheng X, et al. Pathological effects of extensive radiofrequency energy applications in the pulmonary veins in dogs. Circulation 2000; 101:1736. 62. Saad EB, Marrouche NF, Saad CP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med 2003; 138:634. 63. Packer DL, Keelan P, Munger TM, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation 2005; 111:546. 64. Qureshi AM, Prieto LR, Latson LA, et al. Transcatheter angioplasty for acquired pulmonary vein stenosis after radiofrequency ablation. Circulation 2003; 108:1336. 65. European Heart Rhythm Association (EHRA), European Cardiac Arrhythmia Scoiety (ECAS), American College of Cardiology (ACC), et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4:816. 66. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003; 108:3102. 67. Arentz T, Weber R, Jander N, et al. Pulmonary haemodynamics at rest and during exercise in patients with significant pulmonary vein stenosis after radiofrequency catheter ablation for drug resistant atrial fibrillation. Eur Heart J 2005; 26:1410. 68. Di Biase L, Fahmy TS, Wazni OM, et al. Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up. J Am Coll Cardiol 2006; 48:2493. 69. Fender EA, Widmer RJ, Hodge DO, et al. Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation: Presentation, Management, and Clinical Outcomes. Circulation 2016; 134:1812. 70. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 71. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 72. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 24/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Circ Arrhythm Electrophysiol 2013; 6:843. 73. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 74. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 75. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 76. Sharma PS, Padala SK, Gunda S, et al. Vascular complications during catheter ablation of cardiac arrhythmias: A comparison between vascular ultrasound guided access and conventional vascular access. J Cardiovasc Electrophysiol 2016; 27:1160. 77. Waigand J, Uhlich F, Gross CM, et al. Percutaneous treatment of pseudoaneurysms and arteriovenous fistulas after invasive vascular procedures. Catheter Cardiovasc Interv 1999; 47:157. 78. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 79. Chugh A, Oral H, Good E, et al. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:83. 80. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001; 24:1774. 81. Cummings JE, Schweikert R, Saliba W, et al. Left atrial flutter following pulmonary vein antrum isolation with radiofrequency energy: linear lesions or repeat isolation. J Cardiovasc Electrophysiol 2005; 16:293. 82. Gerstenfeld EP, Callans DJ, Dixit S, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004; 110:1351. 83. Dumonceau JM, Giostra E, Bech C, et al. Acute delayed gastric emptying after ablation of atrial fibrillation: treatment with botulinum toxin injection. Endoscopy 2006; 38:543. 84. Roberts-Thomson KC, Steven D, Seiler J, et al. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation 2009; 120:1465. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 25/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate 85. Sieira J, Chierchia GB, Di Giovanni G, et al. One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014; 25:11. 86. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009; 103:1249. 87. Koyama T, Tada H, Sekiguchi Y, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56:1463. 88. Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62:300. 89. Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013; 10:331. 90. Deftereos S, Giannopoulos G, Efremidis M, et al. Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life. Heart Rhythm 2014; 11:620. 91. Peigh G, Wasserlauf J, Vogel K, et al. Impact of pre-ablation weight loss on the success of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2021; 32:2097. 92. Gessler N, Willems S, Steven D, et al. Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial. Europace 2021; 23:1548. 93. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 94. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 95. Senatore G, Stabile G, Bertaglia E, et al. Role of transtelephonic electrocardiographic monitoring in detecting short-term arrhythmia recurrences after radiofrequency ablation in patients with atrial fibrillation. J Am Coll Cardiol 2005; 45:873. 96. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013; 6:754. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 26/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Topic 949 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 27/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate GRAPHICS Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation
American College of Cardiology (ACC), et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4:816. 66. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003; 108:3102. 67. Arentz T, Weber R, Jander N, et al. Pulmonary haemodynamics at rest and during exercise in patients with significant pulmonary vein stenosis after radiofrequency catheter ablation for drug resistant atrial fibrillation. Eur Heart J 2005; 26:1410. 68. Di Biase L, Fahmy TS, Wazni OM, et al. Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up. J Am Coll Cardiol 2006; 48:2493. 69. Fender EA, Widmer RJ, Hodge DO, et al. Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation: Presentation, Management, and Clinical Outcomes. Circulation 2016; 134:1812. 70. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 71. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 72. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 24/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Circ Arrhythm Electrophysiol 2013; 6:843. 73. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 74. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 75. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 76. Sharma PS, Padala SK, Gunda S, et al. Vascular complications during catheter ablation of cardiac arrhythmias: A comparison between vascular ultrasound guided access and conventional vascular access. J Cardiovasc Electrophysiol 2016; 27:1160. 77. Waigand J, Uhlich F, Gross CM, et al. Percutaneous treatment of pseudoaneurysms and arteriovenous fistulas after invasive vascular procedures. Catheter Cardiovasc Interv 1999; 47:157. 78. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 79. Chugh A, Oral H, Good E, et al. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:83. 80. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001; 24:1774. 81. Cummings JE, Schweikert R, Saliba W, et al. Left atrial flutter following pulmonary vein antrum isolation with radiofrequency energy: linear lesions or repeat isolation. J Cardiovasc Electrophysiol 2005; 16:293. 82. Gerstenfeld EP, Callans DJ, Dixit S, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004; 110:1351. 83. Dumonceau JM, Giostra E, Bech C, et al. Acute delayed gastric emptying after ablation of atrial fibrillation: treatment with botulinum toxin injection. Endoscopy 2006; 38:543. 84. Roberts-Thomson KC, Steven D, Seiler J, et al. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation 2009; 120:1465. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 25/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate 85. Sieira J, Chierchia GB, Di Giovanni G, et al. One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014; 25:11. 86. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009; 103:1249. 87. Koyama T, Tada H, Sekiguchi Y, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56:1463. 88. Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62:300. 89. Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013; 10:331. 90. Deftereos S, Giannopoulos G, Efremidis M, et al. Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life. Heart Rhythm 2014; 11:620. 91. Peigh G, Wasserlauf J, Vogel K, et al. Impact of pre-ablation weight loss on the success of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2021; 32:2097. 92. Gessler N, Willems S, Steven D, et al. Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial. Europace 2021; 23:1548. 93. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 94. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 95. Senatore G, Stabile G, Bertaglia E, et al. Role of transtelephonic electrocardiographic monitoring in detecting short-term arrhythmia recurrences after radiofrequency ablation in patients with atrial fibrillation. J Am Coll Cardiol 2005; 45:873. 96. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013; 6:754. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 26/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Topic 949 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 27/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate GRAPHICS Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation Back pain Musculoskeletal, retroperitoneal hematoma Physical exam, CT imaging Chest pain Pericarditis, pericardial effusion, Physical exam, chest coronary stenosis (ablation radiograph, ECG, related), pulmonary vein stenosis, musculoskeletal (after echocardiogram, stress test, cardiac catheterization, chest CT cardioversion), worsening reflux Cough Infectious process, bronchial irritation (mechanical, Physical exam, chest radiograph, chest CT cryoballoon), pulmonary vein stenosis Dysphagia Esophageal irritation (related to Physical exam, chest CT, MRI transesophageal echocardiography), atrioesophageal fistula Early satiety, nausea Gastric denervation Physical exam, gastric emptying study Fever Infectious process, pericarditis, atrioesophageal fistula Physical exam, chest radiograph, chest CT, urinalysis, laboratory blood work Fever, dysphagia, neurological symptoms Atrial esophageal fistula Physical exam, laboratory blood work, chest CT or MRI; avoid endoscopy with air insufflation Groin pain Pseudoaneurysm, AV fistula, hematoma Ultrasound of the groin, laboratory blood work; consider CT scan if ultrasound negative Hypotension Pericardial effusion/tamponade, bleeding, sepsis, persistent Echocardiography, laboratory blood work vagal reaction Hemoptysis Pulmonary vein stenosis or Chest radiograph, chest CT or occlusion, pneumonia MR scan, VQ scan Neurological symptoms Cerebral embolic event, atrial Physical exam, brain imaging, esophageal fistula chest CT or MRI https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 28/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Shortness of breath Volume overload, pneumonia, Physical exam, chest pulmonary vein stenosis, radiograph, chest CT, laboratory phrenic nerve injury blood work CT: computed tomography; ECG: electrocardiogram; MRI: magnetic resonance imaging; AV: atrioventricular. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127127 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 29/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Intraprocedural risks of ablation for atrial fibrillation Complication Incidence Diagnostic testing Air embolism <1% Nothing or cardiac catheterization Asymptomatic cerebral emboli 2 to 15% Brain MRI Cardiac tamponade 0.2 to 5% Echocardiography Coronary stenosis/occlusion <0.1% Cardiac catheterization Death <0.1 to 0.4% N/A Mitral valve entrapment <0.1% Echocardiography Permanent phrenic nerve paralysis 0 to 0.4% Chest radiograph, sniff test Radiation injury <0.1% None Stroke or TIA 0 to 2% Head CT/MRI, cerebral angiography Vascular complications 0.2 to 1.5% Vascular ultrasound, CT scan MRI: magnetic resonance imaging; TIA: transient ischemic attack; CT: computed tomography. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127125 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 30/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate CHADS score, thromboembolic risk, and effect of warfarin anticoagulation 2 Clinical parameter Points Congestive heart failure (any history) 1 Hypertension (prior history) 1 Age 75 years 1 Diabetes mellitus 1 Secondary prevention in patients with a prior ischemic stroke or a transient 2 ischemic attack; most experts also include patients with a systemic embolic event Events per 100 person-years* CHADS score 2 NNT Warfarin No warfarin 0 0.25 0.49 417 1 0.72 1.52 125 2 1.27 2.50 81 3 2.20 5.27 33 4 2.35 6.02 27 5 or 6 4.60 6.88 44 NNT: number needed to treat to prevent 1 stroke per year with warfarin. The CHADS score estimates the risk of stroke, which is defined as focal neurologic signs or symptoms that persist for more than 24 hours and that cannot be explained by hemorrhage, trauma, 2 or other factors, or peripheral embolization, which is much less common. Transient ischemic attacks are not included. All differences between warfarin and no warfarin groups are statistically significant, except for a trend with a CHADS score of 0. Patients are considered to be at low risk with a score of 0, at intermediate risk with a score of 1 or 2, and at high risk with a score 3. One exception is that most experts would consider patients with a prior ischemic stroke, transient ischemic attack, or 2 systemic embolic event to be at high risk, even if they had no other risk factors and, therefore, a score of 2. However, the great majority of these patients have some other risk factor and a score of at least 3. Data from: Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial brillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685; and CHADS2 score from Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. Graphic 61615 Version 8.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 31/32 7/5/23, 8:10 AM Atrial fibrillation: Catheter ablation - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 32/32
7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 13, 2022. INTRODUCTION The primary trigger for most episodes of atrial fibrillation (AF) is an electrical discharge(s) within one of the four pulmonary veins (see "Mechanisms of atrial fibrillation", section on 'Triggers of AF'). The cornerstone of any procedure aimed at reducing AF burden is the electrical isolation of the pulmonary veins so that these discharges do not trigger the initiation of AF. In those with persistent and longstanding persistent AF, and in some patients with paroxysmal AF, additional areas, often in one or both of the atria or surrounding structures, are targeted for ablation, as they may also serve as a source of AF triggers or maintenance. Catheter ablation (CA) is the procedure that is used to prevent the initiation of AF by electrically isolating these triggers from the rest of the atrial chamber tissue. This topic is intended to be viewed primarily by non-electrophysiologists. Electrophysiologists may be more interested in other topics: (See "Overview of catheter ablation of cardiac arrhythmias".) (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) (See "Atrial fibrillation: Catheter ablation".) (See "Invasive diagnostic cardiac electrophysiology studies".) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 1/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) PATIENT SELECTION A major clinical goal of CA is a reduction in AF-related symptoms. CA is superior to medical therapy at improving quality of life. Therefore, it is generally reserved for individuals with symptoms attributable to the arrhythmia, which most often include palpitations, shortness of breath, or generalized fatigue [1,2]. Even if they have no AF-related symptoms, older individuals with early AF (duration <1 year) and additional cardiovascular conditions also benefit from therapies aimed at maintaining sinus rhythm; these therapies include CA [3]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Recommendations of others'.) Patients should be considered for ablation for AF after the history and physical exam have been reviewed and there is documentation of symptomatic correlation with AF on electrocardiogram (ECG) or other forms of monitoring. Modifiable risk factors including obesity, excessive alcohol intake, and sleep apnea should be addressed, as they are important components of AF treatment and impact the success of any rhythm control intervention [4-8]. AF CA may be appropriate in the following groups: Patients with paroxysmal or persistent AF who have tried a class I or III antiarrhythmic drug ablation can be considered if such medications are either unsuccessful or are not tolerated. Some individuals may choose ablation as first-line therapy. For patients with long-standing persistent AF, a trial of one or more class I or III antiarrhythmic drugs is recommended. Ablation as first-line therapy can be considered in those with contraindications to drugs. Asymptomatic younger individuals and patients with heart failure due to reduced ejection fraction may also benefit from ablation [9,10]. We do not perform CA in: Individuals who are too frail to safely undergo the procedure. Patients with a left atrial appendage thrombus. Individuals with bleeding diathesis who cannot receive intra- and postprocedural anticoagulation. PREPROCEDURAL PREPARATION https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 2/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Once a patient has been selected for AF ablation, the clinician performing the procedure or their designee should obtain informed consent from the patient. This involves shared decision- making after discussing the indications, benefits, risks, and alternatives of the planned procedure. Sedation options include general anesthesia that requires an endotracheal tube or monitored anesthesia care with sedation but not requiring intubation. Most procedures are performed under general anesthesia. Medication management Most physicians performing ablation will discontinue antiarrhythmic drugs prior to the ablation with the rationale that it may help to identify the triggers of the AF at the time of the procedure. We acknowledge that many other electrophysiologists will continue them. There are no well-performed studies to guide practice. With regard to oral anticoagulation, randomized trials have demonstrated superior efficacy and safety of uninterrupted anticoagulation throughout the ablation procedure compared with temporary discontinuation of anticoagulation and bridging with low molecular weight heparin. Most operators, including the authors, perform the procedure on uninterrupted or minimally interrupted direct-acting oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) such as warfarin. A meta-analysis of 17,434 patients from 12 observational trials and one randomized trial compared uninterrupted warfarin with interrupted warfarin and heparin bridging at the time of AF ablation. Uninterrupted warfarin was associated with significant reductions in stroke and major and minor bleeding [11]. Studies have shown that patients on uninterrupted DOACs have either lower (dabigatran, edoxaban [12,13]) or similar (rivaroxaban, apixaban) [14,15] bleeding risks compared with those on uninterrupted VKA. Studies of DOACS with lower bleeding risks compared with VKA: The RE-CIRCUIT trial randomized 704 patients undergoing AF ablation to uninterrupted dabigatran or VKA. The incidence of major bleeding events during and up to eight weeks after ablation was lower with dabigatran than with warfarin (1.6 versus 6.9 percent) [12]. In a trial of 614 patients undergoing CA, participants were randomly assigned to uninterrupted edoxaban or VKA. Major bleeds were nonsignificantly lower in persons assigned to edoxaban compared with VKA (0.2 versus 2 percent; hazard ratio 0.16; 95% CI 0.02-1.73) [13]. Studies of DOACS with similar bleeding risks compared with VKA: https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 3/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate In a trial of rivaroxaban or VKA in people undergoing AF ablation, bleeding events were similar in the two study arms [14]. In a trial that compared uninterrupted apixaban with placebo, the rates of clinically significant and major bleeding were also similar for both groups (10.6 versus 9.8 percent) [15]. Imaging All patients with AF, not just those being considered for CA, should undergo transthoracic echocardiography (TTE) to evaluate for factors that may affect treatment including the presence and extent of valvular disease, chamber size, and ventricular function. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Echocardiogram'.) Transesophageal echocardiography (TEE), which is superior to TTE for finding atrial thrombus, is often performed within 24 hours prior to ablation since the presence of thrombus in the left atrium or left atrial appendage is a contraindication to AF ablation. Some operators may choose to forego TEE in patients with a low risk of stroke (ie, CHA DS -VASc 1) who are expected to be 2 2 in sinus rhythm at the time of the procedure and who have been and will be maintained on uninterrupted anticoagulation throughout the periprocedural timeframe. Some operators will individualize the need for preprocedure TEE and tend to only perform it in higher-risk patients. Risk factors for left atrial appendage thrombus prior to ablation include hypertrophic cardiomyopathy, ejection fraction <30 percent, persistent or longstanding persistent AF, and elevated CHA DS -VASc score [16]. In a study of 1058 preprocedure TEEs, the rate of detection of 2 2 left atrial thrombus or prethrombus was 1 percent in patients with paroxysmal AF in sinus rhythm and 2 percent for patients with paroxysmal AF who were in AF at the time of the procedure. The risk increased with increasing CHADS score [17]. 2 Computed tomography (CT) or cardiac magnetic resonance imaging (cMRI) may be performed preablation to define the left atrial anatomy, specifically the number, size, and location of the pulmonary veins ( figure 1). Data are emerging to suggest that these imaging techniques are also highly sensitive for left atrial thrombus, and many operators use CT or cMRI to evaluate for left atrial thrombus instead of TEE in low-risk individuals. A comparison of cMRI with TEE to evaluate preablation left atrial appendage thrombus demonstrated 100 percent sensitivity and 99.2 percent specificity for equilibrium phase delayed enhancement CMR with a long inversion time [18]. New high-dimensional mapping catheters used during the procedure can create high- definition structural geometry, and for many operators has obviated the need for preprocedure imaging. PROCEDURAL ISSUES https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 4/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Ablation for AF is among the most complicated procedures performed by electrophysiologists. The procedure should be performed in centers with experience with complex electrophysiologic procedures and capabilities in managing acute complications. Advancements in procedural technologies and techniques have significantly shortened the duration of ablation procedures for AF. Total procedure time typically ranges from 1.5 to 4 hours [19]. The ablation is performed using uni- or bilateral femoral venous access and transseptal puncture for accessing the left atrium. Anesthesia Ablation for AF is performed in the fasting state with general anesthesia or monitored anesthesia care (MAC) using sedation. In a retrospective cohort study of CA performed under either general anesthesia or conscious sedation, conscious sedation had shorter total procedure times and equivalent success rates compared with general anesthesia [20]. In a retrospective cohort study of CA performed under either general anesthesia or MAC, MAC had shorter total procedure times and equivalent success rates with general anesthesia [19]. Agents typically used for conscious sedation include short-acting benzodiazepines (eg, midazolam) and opioids (eg, fentanyl) in divided doses [21]. The type of anesthesia used for AF ablation procedures is dependent on several variables including the expected complexity and duration of the procedure, energy source being utilized, patient comorbidities, patient preference, and availability of anesthesia support. Patient immobility is important to optimize catheter contact and reduce movement error in the anatomic mapping systems. Paralytics should not be used when testing for phrenic nerve capture during ablation. High frequency ventilation, also called jet ventilation, which utilizes a respiratory rate greater than four times the normal value. (>150 [Vf] breaths per minute) and very small tidal volumes, is used in some centers to aid catheter stability and has been associated with improved outcomes [22]. Intraprocedural medications In addition to anesthetic agents, intravenous heparin is administered throughout the AF ablation procedure to reduce the risk of thrombus formation on the catheters, sheaths, left atrium and left atrial appendage, and at ablation sites. Heparin is administered prior to or immediately after transseptal access has been achieved with a targeted activated clotting time (ACT) of >300 seconds. Target ACT may be reached faster and with lower loading doses in patients undergoing ablation on uninterrupted vitamin K antagonists (VKA) compared with non-vitamin K antagonist oral anticoagulants (NOACs; also referred to as direct acting oral anticoagulants [DOAC]) [23]. Additionally, time to target ACT varies amongst the NOACs, with average time in minutes required to achieve a target ACT of >300 seconds https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 5/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate significantly longer in those receiving uninterrupted dabigatran or apixaban compared with those receiving rivaroxaban [24]. Protamine can be used to reverse anticoagulation at the time of sheath removal post-procedure. Esophageal imaging and temperature monitoring The proximity of the esophagus to the posterior left atrium makes it susceptible to thermal injury (see 'Complications' below). Atrioesophageal fistula, typically occurring one to four weeks post-ablation, is a potentially lethal consequence of AF ablation, with a reported incidence of 0.02 to 0.11 percent. To minimize risk, operators will limit energy delivery in the posterior wall in areas adjacent to the esophagus. As the esophagus can have a highly variable position that can vary throughout the procedure, visualization of the esophagus can be performed using electroanatomic mapping, intracardiac ultrasound (ICE), or barium paste. Many operators use an esophageal temperature probe to assess the effects of ablation on intraluminal temperature, though this practice has not yet been shown to reduce the risk of fistula formation given the low incidence of these events. Given the very low overall incidence of fistula, there have been no randomized data to demonstrate superiority of one esophageal monitoring strategy over another. Consequently, minimization of power delivery to the atrial tissue adjacent to the esophagus or minimization of temperature elevation remain surrogates for procedural safety Vascular ultrasound CA for AF requires multiple sheaths with large diameters in one or both femoral veins in patients receiving oral and intravenous anticoagulation. These issues make vascular complications the most common complications of AF ablation. Access can be obtained through the modified Seldinger approach. Vascular ultrasound has been used for venipuncture guidance and postprocedural evaluation. In a cohort study of 1435 patients undergoing cryoballoon ablation for AF, major clinical events occurred in 1.7 percent of those patients who had their procedure performed without ultrasound guidance versus 0 percent in those that did have ultrasound guidance [25]. In a multicenter, randomized trial, 320 patients were randomized to ultrasound guided versus conventional venipuncture. Major complications were low and not significantly different between groups. Puncture time, inadvertent arterial puncture, and need for extra puncture attempts were all significantly reduced in the ultrasound arm [26]. Intracardiac ultrasound Intracardiac ultrasound allows for real-time imaging of cardiac anatomy. The probe is placed in the right atrium via the inferior vena cava. Common uses of ICE include the identification of intra- and extracardiac anatomic structures such as the esophagus, facilitation of transseptal puncture, guidance of catheter placement, and recognition of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 6/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate complications including thrombus formation on sheaths and catheters and early recognition of pericardial effusion. Fluoroscopy Mapping and ablation of AF requires precise navigation of catheters within the left atrium and localization of intra- and extracardiac structures. Fluoroscopy is used to assess catheter placement, to visualize catheter movement, and to assess proximity to adjacent structures such as the esophagus when marked by an intraluminal catheter or barium paste. Patient and physician exposure to ionizing radiation during AF ablation are highly variable, and radiation injury to the patient is reported in <0.1 percent of cases. Efforts to reduce patient and physician exposure to ionizing radiation have successfully relied on alternative imaging modalities, including ICE and electroanatomic mapping. (See "Radiation-related risks of imaging".) Electroanatomic mapping Electroanatomic mapping systems combine real-time, detailed information of the anatomy and electrical properties of the cardiac structures under evaluation. These systems (Carto [Biosense Webster], NAVX [Abbott], and Rhythmia [Boston Scientific]) use diagnostic and ablation catheters and navigation patches on the patient's skin to create a three- dimensional anatomical map used to help localize critical sites for ablation. ABLATION TECHNIQUES AND TARGETS Energy sources There are three US Food and Drug Administration (FDA)-approved energy sources for AF ablation: radiofrequency energy, cryothermal energy in the form of cryoballoon, and laser balloon. This issue is discussed in detail elsewhere. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Energy sources used for ablation'.) The commonly used and approved energy sources for CA are radiofrequency and cryothermal. The efficacy and safety associated with these two energy sources have been found to be similar in multiple studies. This issue is discussed elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Comparison of radiofrequency and cryothermal ablation'.) Pulmonary vein isolation Complete electrical isolation of all PVs using circumferential, wide area pulmonary vein isolation (PVI) is the goal of most procedures. The following explains the rationale. The initiation of AF requires a trigger either within or near the atrium (eg, PVs, crista terminalis, superior vena cava), and substrate within the atrium to maintain AF [9] (see "Mechanisms of atrial fibrillation", section on 'Basic atrial electrophysiology'). The anatomic significance of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 7/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate triggers and substrate differs somewhat, depending upon whether the AF is paroxysmal, persistent, or permanent (see "Paroxysmal atrial fibrillation", section on 'Introduction'). In patients with paroxysmal AF, PV triggers are the primary stimulus in most cases. As AF becomes more persistent, non-PV sources become more important [27]. The following important observations regarding triggers came from early studies of patients with paroxysmal AF and have guided the development of successful ablation techniques for AF [28-30]. AF is commonly triggered by ectopic beats from muscle fibers (fascicles) extending from the left atrium into the PVs ( figure 1). Ectopic foci are localized to the PVs in approximately 90 percent of patients with predominantly structurally normal hearts [31]. Most patients have multiple foci that can act as triggers. Most (94 percent) of the foci are 2 to 4 cm inside the PVs, with the left superior vein being the most common site [28]. The remaining foci are usually in the right or left atrium. The superior vena cava is a much less common site of triggering ectopic beats [28]. Because of these observations, early attempts at ablation targeted these focal ectopic beats within the PV [28]. This approach was limited by: Inconsistent ability to identify the triggering beats during electrophysiology study. Difficulties with precise localization of appropriate ablation sites. The risk of PV stenosis, which can occur following ablation within the PVs. (See "Atrial fibrillation: Catheter ablation".) These limitations lead to the adoption of ablative techniques focused on the complete electrical isolation of all PVs using circumferential wide area PVI. The majority of ablations performed use radiofrequency energy or cryothermy (cryoballoon ablation). Infrared laser received FDA approval in 2018. Circumferential PVI involves the creation of confluent ablation lesions that encircle the ostia of all four PVs, usually in two pairs (ie, a left- and right-sided circles) [32-34]. The goal is to electrically isolate the PVs from the left atrium. For ablation using radiofrequency energy, power, duration, and the catheter contact force determine the size and the depth of the lesion created. It is generally felt that some lesions create edema but not scars, leading to temporary but not permanent ablation, and this ultimately leads to electrical reconnection of the left atrium to the https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 8/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate PVs. Greater power, longer duration, and greater contact force improve the efficacy of the procedure but lead to an increase in complications such as cardiac perforation [35,36]. The efficacy and safety of high-power, short-duration ablation, which creates larger, shallower, and more homogeneous lesions, is under evaluation [37]. Circumferential PVI results in extensive ablation across a wider area of the left atrium. Because of the more extensive ablation, this technique may provide additional methods for preventing AF, including autonomic denervation, elimination of triggering foci outside the PVs, and alteration of the left atrial substrate necessary for perpetuating AF. However, more extensive ablation, particularly in the posterior left atrium, may increase the rate of complications, including the development of left atrial tachycardias or flutters months or years after the ablation. The relative efficacy and safety of these methods are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) Use of a contact force-sensing catheter We use a contact force-sensing catheter in all patients with AF undergoing radiofrequency CA (RFA). The TOCCASTAR study found that patients who underwent CA with this catheter and who received a higher force ( 10 grams) had significantly lower rates of AF recurrence at one year. Use of adenosine-guided pulmonary vein isolation The administration of intravenous adenosine can be used to unmask dormant conduction at the time of CA. Reconnection rates are high in RFA, with three large studies finding rates of 21 (ADVICE), 27 (UNDER-ATP), and 34 percent [38-40]. The use of adenosine to guide additional CA has been shown to improve arrhythmia-free survival in some studies using RFA. Some technical aspects of the procedure are discussed separately. (See 'Ablation techniques and targets' above.) In the ADVICE study, 534 patients with paroxysmal AF who had failed drug therapy underwent a standard PV isolation procedure using radiofrequency energy [38]. Patients were observed for spontaneous recovery of conduction over 20 minutes to allow for reconnected PVs to be reisolated before adenosine administration. Intravenous adenosine was then given to all patients. The 284 patients in whom dormant conduction (evidence of persistent PV conduction) was unmasked by adenosine were randomly assigned to additional adenosine-guided ablation to abolish dormant conduction or to no additional ablation. Among the 250 patients without dormant conduction, 117 were enrolled in a registry. The primary endpoint of the time to first recurrence of symptomatic electrocardiographically documented atrial tachyarrhythmia was between 91 and 365 days. The following findings were noted: Dormant PV conduction was present in 284 (53 percent) of patients. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 9/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Freedom from symptomatic atrial tachycardia occurred more often with adenosine-guided further ablation (69.4 versus 42.3 percent; hazard ratio [HR] 0.44, 95% CI 0.31-0.64). Among patients in the registry, approximately 56 percent remained free from symptomatic atrial tachyarrhythmia. The rate of serious adverse events was similar in both groups. Limitations of this study include lack of generalizability (does not apply to patients undergoing cryoablation), lack of use of force-sensing catheters, which are used by many of our experts, and the use of "dormant connection" as an endpoint rather than AF recurrence. In the UNDER-ATP trial, 2113 patients with paroxysmal, persistent, or long-lasting AF were randomly assigned to either adenosine-guided PV isolation (1112 patients) or conventional PV isolation (1001 patients) [39]. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 seconds or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at one year with the blanking period of 90 days post-ablation. Among patients assigned to adenosine-guided PV isolation, adenosine provoked dormant PV conduction in 307 patients (27.6 percent). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4 percent). At one year, 68.7 percent of patients in the adenosine-guided PV isolation group and 67.1 percent of patients in the conventional PV isolation group were free from the primary endpoint, with no significant difference (adjusted HR 0.89; 95% CI 0.74-1.09; p = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the one-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; p = 0.16). Based on these studies, the use an adenosine in patients undergoing CA with radiofrequency energy is at the discretion of the operator. Confirmation of complete isolation Unlike many other cardiac ablation procedures, AF does not need to be present or induced at the time of the ablation procedure nor is termination of AF or inability to reinduce the arrhythmia a required endpoint of the procedure. For PVI, acute procedural success is defined as electrical isolation of all PVs [41]. This is defined by entry block or the inability to electrically capture PV myocardial tissue distal to the area of ablation when pacing is performed proximal to the ablation line. To do this, a circular catheter is positioned just distal to the PV ostium for the purpose of recording electrograms within the PVs. Confirmation is attempted after a 30-minute waiting period after isolation. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 10/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Some operators also test for exit block, defined by the inability to capture atrial myocardium when pacing is performed within the PV distal to the ablation line. There is a high correlation between AF recurrences and the demonstration of persistent or recurrent conduction between the PVs and left atrium (see "Atrial fibrillation: Catheter ablation", section on 'Efficacy'). Recurrent PV conduction explains most cases of recurrence; it is thought to be due to recovery of function of tissue that has been acutely injured (ie, edema and inflammation) but not permanently scarred. Administration of adenosine has been shown to identify PVs with dormant conduction by transiently restoring excitability and conduction across circumferential ablation lines at risk of reconnection [38]. However, improvements in ablation tools and techniques have significantly reduced the routine use of adenosine. It is used at the discretion of the operator. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) Ablation targets in persistent atrial fibrillation In contrast to patients with paroxysmal AF, patients with persistent AF (and in particular longstanding persistent AF) often have multiple triggers distributed throughout the atria in addition to triggers within the PV [42]. It is thought that mechanisms that maintain rather than trigger the arrhythmia are more important in these individuals. These observations may explain the reduced efficacy of CA procedures that are limited to PVI in patients with longstanding persistent AF seen in most studies. In these patients, additional lesions are often needed to prevent recurrence of AF. These lesions are often placed anatomically in the left atrial posterior wall and roof, in the left atrial appendage, coronary sinus, or in the right atrium. Additional targets include sites of complex fractionated electrograms and rotors [43,44] (see "Mechanisms of atrial fibrillation", section on 'Mechanisms of atrial fibrillation: triggers and substrates'). Though the goal of additional lesion sets are to modify the AF substrate, these approaches may also result in proarrhythmia through the creation of new reentrant circuits. Data supporting the benefits and optimal approach for the treatment of persistent AF are inconclusive and are often individualized by patient and operator. Additional ablation targets/techniques outside the PVs include: Non-PV triggers (eg, coronary sinus, posterior left atrium, crista terminalis) Complex fractionated electrograms (CFAEs) Linear ablation (LA roof, mitral isthmus) Other thoracic veins (superior vena cava, coronary sinus) Posterior wall isolation Left atrial appendage isolation Ablation of cardiac autonomic nerves (ganglionic plexi) Focal impulse and rotor modulation (FIRM) phase mapping-guided ablation Stepwise approach (PVI, CFAE, linear, coronary sinus) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 11/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate POSTPROCEDURAL ISSUES After the procedure, patients usually remain supine for a fixed period (usually two to four hours) following sheath removal to promote hemostasis at the venous puncture sites. Vascular closure devices allow for more rapid hemostasis and shorter time to ambulation. Most centers keep patients overnight following the procedure. Same-day discharge has become increasingly common given the shorter procedure times and use of venous closure techniques [45,46]. Post-discharge medications Oral anticoagulation is usually continued [47] for at least two months to ensure that the increased risk of embolization associated with the procedure has returned to a baseline risk, regardless of CHADS VA Sc score. This also allows for adequate time 2 2 to document an absence of recurrence of AF for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [48]. Importantly, there are no randomized data on the safety of discontinuing anticoagulation post-ablation for patients who have presumably maintained sinus rhythm. The risk of AF recurrence, the recognized proportional increase in the burden of asymptomatic AF, and the uncertainty surrounding the causal association between the arrhythmia itself and stroke all support the recommendation to risk stratify patients for oral anticoagulation use based on CHA DS -VASc no differently than if an 2 2 ablation had not been performed. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Postprocedural anticoagulation'.) Antiarrhythmic medications may or may not be continued after the procedure. Our preference is to stop them after the procedure. Patients in whom consideration should be given to continuing them include patients with long-standing persistent AF or patients with debilitating AF symptoms. Post-discharge follow-up At the time of discharge, patients are given instructions on activity and what potential complications to look for. They should refrain from heavy physical activity, including exercise and weight lifting, for the week post-procedure to allow for complete healing of the vascular access sites. Baths should also be avoided for one week to reduce infection risk. In patients without identified post-procedural complications such as vascular access site problems, we wait three months to reevaluate the patient [9] (see 'Complications' below). Patients with potential complications should be seen immediately. Patients who develop symptoms should contact either their primary care physician, general cardiologist, or electrophysiologist to discuss the need for early evaluation. Yearly follow-up with a physician thereafter is also recommended. These ongoing interactions with the medical profession allow the patient's clinical status to be evaluated, including an https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 12/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate assessment of the presence or absence of AF, as well as their stroke risk profile and anticoagulation needs. These interactions also provide an opportunity to focus on the treatment of associated diseases and lifestyle modifications [9]. Routine ECG should be performed at the time of follow-up visits, and more intense monitoring may be performed as dictated by patient symptoms and the clinical impact of AF detection [41]. Evaluation for recurrent atrial fibrillation The primary purpose of the first follow-up visit around the three-month mark is to determine the success of the procedure. Screening for post- procedure AF is discussed separately. (See "Atrial fibrillation: Catheter ablation", section on 'Follow-up'.) In general, we do not evaluate the patient for the presence of AF prior to three months, as early episodes do not necessarily predict the long-term success or failure of the procedure. They can often be managed with antiarrhythmic drugs or cardioversion. Repeat ablation during this time is rarely necessary. During this three-month healing phase, there is resolution of inflammation and consolidation of lesion formation. This time period is referred to in clinical research trials as the "post-procedure blanking period." Anticoagulants are continued throughout this period regardless of the patient's CHA DS -VASc score ( table 1). Antiarrhythmic drugs and/or electrical cardioversion 2 2 are used during this blanking period at the discretion of the treating physician and usually reserved for those with debilitating symptoms or recurrent persistent AF. Success rates The success rate of AF ablation is dependent on multiple factors including patient selection, technique, definition of success, and the intensity and duration of rhythm monitoring post-ablation. For research purposes, the primary endpoint of AF ablation trials is freedom from recurrent AF/ atrial tachycardia (AT) defined as the absence of any recurrent AF/AT >30 seconds without antiarrhythmic drugs. Using this strict definition, the one-year success rate for paroxysmal AF is approximately 70 to 80 percent and 60 to 70 percent for persistent AF at most experienced centers. However, a greater proportion of patients will derive an improvement in AF-related symptoms from ablation, and studies using implantable cardiac monitors or other devices that can record all episodes of AF have shown an AF burden reduction of over 98 percent [49]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients with prior antiarrhythmic drug treatment'.) Complications Complications are discussed in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 13/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pulmonary vein origin of atrial fibrillation (AF) The primary trigger for most episodes
11/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate POSTPROCEDURAL ISSUES After the procedure, patients usually remain supine for a fixed period (usually two to four hours) following sheath removal to promote hemostasis at the venous puncture sites. Vascular closure devices allow for more rapid hemostasis and shorter time to ambulation. Most centers keep patients overnight following the procedure. Same-day discharge has become increasingly common given the shorter procedure times and use of venous closure techniques [45,46]. Post-discharge medications Oral anticoagulation is usually continued [47] for at least two months to ensure that the increased risk of embolization associated with the procedure has returned to a baseline risk, regardless of CHADS VA Sc score. This also allows for adequate time 2 2 to document an absence of recurrence of AF for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [48]. Importantly, there are no randomized data on the safety of discontinuing anticoagulation post-ablation for patients who have presumably maintained sinus rhythm. The risk of AF recurrence, the recognized proportional increase in the burden of asymptomatic AF, and the uncertainty surrounding the causal association between the arrhythmia itself and stroke all support the recommendation to risk stratify patients for oral anticoagulation use based on CHA DS -VASc no differently than if an 2 2 ablation had not been performed. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Postprocedural anticoagulation'.) Antiarrhythmic medications may or may not be continued after the procedure. Our preference is to stop them after the procedure. Patients in whom consideration should be given to continuing them include patients with long-standing persistent AF or patients with debilitating AF symptoms. Post-discharge follow-up At the time of discharge, patients are given instructions on activity and what potential complications to look for. They should refrain from heavy physical activity, including exercise and weight lifting, for the week post-procedure to allow for complete healing of the vascular access sites. Baths should also be avoided for one week to reduce infection risk. In patients without identified post-procedural complications such as vascular access site problems, we wait three months to reevaluate the patient [9] (see 'Complications' below). Patients with potential complications should be seen immediately. Patients who develop symptoms should contact either their primary care physician, general cardiologist, or electrophysiologist to discuss the need for early evaluation. Yearly follow-up with a physician thereafter is also recommended. These ongoing interactions with the medical profession allow the patient's clinical status to be evaluated, including an https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 12/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate assessment of the presence or absence of AF, as well as their stroke risk profile and anticoagulation needs. These interactions also provide an opportunity to focus on the treatment of associated diseases and lifestyle modifications [9]. Routine ECG should be performed at the time of follow-up visits, and more intense monitoring may be performed as dictated by patient symptoms and the clinical impact of AF detection [41]. Evaluation for recurrent atrial fibrillation The primary purpose of the first follow-up visit around the three-month mark is to determine the success of the procedure. Screening for post- procedure AF is discussed separately. (See "Atrial fibrillation: Catheter ablation", section on 'Follow-up'.) In general, we do not evaluate the patient for the presence of AF prior to three months, as early episodes do not necessarily predict the long-term success or failure of the procedure. They can often be managed with antiarrhythmic drugs or cardioversion. Repeat ablation during this time is rarely necessary. During this three-month healing phase, there is resolution of inflammation and consolidation of lesion formation. This time period is referred to in clinical research trials as the "post-procedure blanking period." Anticoagulants are continued throughout this period regardless of the patient's CHA DS -VASc score ( table 1). Antiarrhythmic drugs and/or electrical cardioversion 2 2 are used during this blanking period at the discretion of the treating physician and usually reserved for those with debilitating symptoms or recurrent persistent AF. Success rates The success rate of AF ablation is dependent on multiple factors including patient selection, technique, definition of success, and the intensity and duration of rhythm monitoring post-ablation. For research purposes, the primary endpoint of AF ablation trials is freedom from recurrent AF/ atrial tachycardia (AT) defined as the absence of any recurrent AF/AT >30 seconds without antiarrhythmic drugs. Using this strict definition, the one-year success rate for paroxysmal AF is approximately 70 to 80 percent and 60 to 70 percent for persistent AF at most experienced centers. However, a greater proportion of patients will derive an improvement in AF-related symptoms from ablation, and studies using implantable cardiac monitors or other devices that can record all episodes of AF have shown an AF burden reduction of over 98 percent [49]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients with prior antiarrhythmic drug treatment'.) Complications Complications are discussed in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 13/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pulmonary vein origin of atrial fibrillation (AF) The primary trigger for most episodes of AF involves electrical discharges within one or more pulmonary veins (PVs) ( figure 1). A principal goal of any procedure is to reduce the frequency of AF and electrically isolate the PVs so that these discharges do not activate atrial tissue. (See 'Introduction' above.) Clinical goal of catheter ablation (CA) The major clinical goal of CA is a reduction in AF- related symptoms. CA is superior to medical therapy at improving a patient's quality of life. Therefore, it is generally reserved for individuals with symptoms attributable to the arrhythmia, which most often include palpitations, shortness of breath, or generalized fatigue. Even if they have no AF-related symptoms, older individuals with early AF (duration <1 year) and additional cardiovascular conditions also benefit from therapies aimed at maintaining sinus rhythm; these therapies include CA. (See 'Patient selection' above.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 14/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Role of shared decision-making AF ablation is a complicated procedure with defined risks. Shared decision-making among the patient, primary care physician, general cardiologist, and electrophysiologist is essential. Ablation techniques Radiofrequency, cryothermal, and laser energy are the approved energy sources for CA of AF. (See 'Energy sources' above.) Various methods of CA have been used, and most focus on isolating the triggers in the PVs from the vulnerable substrate in the left atrium. The most common technique is circumferential PV isolation. (See 'Pulmonary vein isolation' above.) Complications Treating physicians should be aware of three serious complications that can occur postprocedurally: pericardial effusion causing cardiac tamponade, an atrial esophageal fistula, and PV stenosis ( table 2 and table 3). (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1275. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Heart Rhythm 2017; 14:e445. 3. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1305. 4. Larsson SC, Drca N, Wolk A. Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis. J Am Coll Cardiol 2014; 64:281. 5. Congrete S, Bintvihok M, Thongprayoon C, et al. Effect of obstructive sleep apnea and its treatment of atrial fibrillation recurrence after radiofrequency catheter ablation: A meta- analysis. J Evid Based Med 2018; 11:145. 6. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014; 64:2222. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 15/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 7. 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Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 10. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 11. Nairooz R, Sardar P, Payne J, et al. Meta-analysis of major bleeding with uninterrupted warfarin compared to interrupted warfarin and heparin bridging in ablation of atrial fibrillation. Int J Cardiol 2015; 187:426. 12. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017; 376:1627. 13. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40:3013. 14. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805. 15. Reynolds MR, Allison JS, Natale A, et al. A Prospective Randomized Trial of Apixaban Dosing During Atrial Fibrillation Ablation: The AEIOU Trial. JACC Clin Electrophysiol 2018; 4:580. 16. Gunawardene MA, Dickow J, Schaeffer BN, et al. Risk stratification of patients with left atrial appendage thrombus prior to catheter ablation of atrial fibrillation: An approach towards an individualized use of transesophageal echocardiography. J Cardiovasc Electrophysiol 2017; 28:1127. 17. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 16/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 18. Kitkungvan D, Nabi F, Ghosn MG, et al. Detection of LA and LAA Thrombus by CMR in Patients Referred for Pulmonary Vein Isolation. JACC Cardiovasc Imaging 2016; 9:809. 19. Kuck KH, Brugada J, F rnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016; 374:2235. 20. Wasserlauf J, Knight BP, Li Z, et al. Moderate Sedation Reduces Lab Time Compared to General Anesthesia during Cryoballoon Ablation for AF Without Compromising Safety or Long-Term Efficacy. Pacing Clin Electrophysiol 2016; 39:1359. 21. Di Biase L, Conti S, Mohanty P, et al. General anesthesia reduces the prevalence of pulmonary vein reconnection during repeat ablation when compared with conscious sedation: results from a randomized study. Heart Rhythm 2011; 8:368. 22. Sivasambu B, Hakim JB, Barodka V, et al. Initiation of a High-Frequency Jet Ventilation Strategy for Catheter Ablation for Atrial Fibrillation: Safety and Outcomes Data. JACC Clin Electrophysiol 2018; 4:1519. 23. Briceno DF, Villablanca PA, Lupercio F, et al. Clinical Impact of Heparin Kinetics During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and Meta-Regression. J Cardiovasc Electrophysiol 2016; 27:683. 24. Nagao T, Inden Y, Yanagisawa S, et al. Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation. Heart Rhythm 2015; 12:1972. 25. Str ker E, de Asmundis C, Kupics K, et al. Value of ultrasound for access guidance and detection of subclinical vascular complications in the setting of atrial fibrillation cryoballoon ablation. Europace 2019; 21:434. 26. Yamagata K, Wichterle D, Roub cek T, et al. Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA-FAST trial). Europace 2018; 20:1107. 27. Kurotobi T, Iwakura K, Inoue K, et al. Multiple arrhythmogenic foci associated with the development of perpetuation of atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:39. 28. Ha ssaguerre M, Ja s P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659. 29. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999; 100:1879. 30. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 17/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate radiofrequency ablation. Circulation 2000; 102:67. 31. Lee G, Spence S, Teh A, et al. High-density epicardial mapping of the pulmonary vein-left atrial junction in humans: insights into mechanisms of pulmonary vein arrhythmogenesis. Heart Rhythm 2012; 9:258. 32. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation 2000; 102:2619. 33. Pappone C, Santinelli V. The who, what, why, and how-to guide for circumferential pulmonary vein ablation. J Cardiovasc Electrophysiol 2004; 15:1226. 34. Oral H, Knight BP, Tada H, et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002; 105:1077. 35. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012; 9:1789. 36. Neuzil P, Reddy VY, Kautzner J, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study. Circ Arrhythm Electrophysiol 2013; 6:327. 37. Bourier F, Duchateau J, Vlachos K, et al. High-power short-duration versus standard radiofrequency ablation: Insights on lesion metrics. J Cardiovasc Electrophysiol 2018; 29:1570. 38. Macle L, Khairy P, Weerasooriya R, et al. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet 2015; 386:672. 39. Kobori A, Shizuta S, Inoue K, et al. Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial. Eur Heart J 2015; 36:3276. 40. Ghanbari H, Jani R, Hussain-Amin A, et al. Role of adenosine after antral pulmonary vein isolation of paroxysmal atrial fibrillation: A randomized controlled trial. Heart Rhythm 2016; 13:407. 41. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012; 14:528. 42. Lin JL, Lai LP, Tseng YZ, et al. Global distribution of atrial ectopic foci triggering recurrence of atrial tachyarrhythmia after electrical cardioversion of long-standing atrial fibrillation: a bi- https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 18/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate atrial basket mapping study. J Am Coll Cardiol 2001; 37:904. 43. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004; 43:2044. 44. Narayan SM, Patel J, Mulpuru S, Krummen DE. Focal impulse and rotor modulation ablation of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up: a video case study. Heart Rhythm 2012; 9:1436. 45. Bartoletti S, Mann M, Gupta A, et al. Same-day discharge in selected patients undergoing atrial fibrillation ablation. Pacing Clin Electrophysiol 2019; 42:1448. 46. Natale A, Mohanty S, Liu PY, et al. Venous Vascular Closure System Versus Manual Compression Following Multiple Access Electrophysiology Procedures: The AMBULATE Trial. JACC Clin Electrophysiol 2020; 6:111. 47. Eitel C, Koch J, Sommer P, et al. Novel oral anticoagulants in a real-world cohort of patients undergoing catheter ablation of atrial fibrillation. Europace 2013; 15:1587. 48. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long- term follow-up in nationwide cohort of Denmark. Eur Heart J 2015; 36:307. 49. Lohrmann G, Kaplan R, Ziegler PD, et al. Atrial fibrillation ablation success defined by duration of recurrence on cardiac implantable electronic devices. J Cardiovasc Electrophysiol 2020; 31:3124. Topic 95704 Version 21.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 19/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate GRAPHICS Junction of left atrium and pulmonary veins The common pattern of the superficial myocardial fibers of the left atrium (posterior aspect). A main circular fascicle (a, a', a", and a"') runs peripherally around the area of the openings of the pulmonary veins. An interatrial fascicle (b) runs between the right (RA) and the left (LA) atrium. Some fibers (c) descend from the left atrium into the left part (a') of the main circular fascicle. Circular fibers leaving the main fascicle turn around the openings of the pulmonary veins, forming sphincter-like structures; other fibers extend over the https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 20/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate veins as myocardial sleeves. Loops of fibers coming from the atrium are seen over the right superior pulmonary vein (RSPV) and returning to the atrium. Oblique, vertical (e), and transverse (f, f') fascicles of fibers are also seen on the posterior atrial surface. LA: left atrium; RA: right atrium; SVC: superior vena cava; IVC: inferior vena cava; RSPV: right superior pulmonary vein; LSPV: left superior pulmonary vein; RIPV: right inferior pulmonary vein; LIPV: left inferior pulmonary vein. From: Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. Circulation 1966; 34:412. DOI: 10.1161/01.cir.34.3.412. Copyright 1966. Adapted with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 127240 Version 3.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 21/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc 2 2 (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients Stroke and 2 2 (n = 73,538) thromboembolism event rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 5 8942 15.26 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 22/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 23/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Intraprocedural risks of ablation for atrial fibrillation Complication Incidence Diagnostic testing Air embolism <1% Nothing or cardiac catheterization Asymptomatic cerebral emboli 2 to 15% Brain MRI Cardiac tamponade 0.2 to 5% Echocardiography Coronary stenosis/occlusion <0.1% Cardiac catheterization Death <0.1 to 0.4% N/A Mitral valve entrapment <0.1% Echocardiography Permanent phrenic nerve 0 to 0.4% Chest radiograph, sniff test paralysis Radiation injury <0.1% None Stroke or TIA 0 to 2% Head CT/MRI, cerebral angiography Vascular complications 0.2 to 1.5% Vascular ultrasound, CT scan MRI: magnetic resonance imaging; TIA: transient ischemic attack; CT: computed tomography. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127125 Version 1.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 24/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation Back pain Musculoskeletal, retroperitoneal hematoma Physical exam, CT imaging Chest pain Pericarditis, pericardial effusion, coronary stenosis (ablation Physical exam, chest radiograph, ECG, related), pulmonary vein stenosis, musculoskeletal (after echocardiogram, stress test, cardiac catheterization, chest CT cardioversion), worsening reflux Cough Infectious process, bronchial Physical exam, chest irritation (mechanical, cryoballoon), pulmonary vein stenosis radiograph, chest CT Dysphagia Esophageal irritation (related to transesophageal Physical exam, chest CT, MRI echocardiography), atrioesophageal fistula Early satiety, nausea Gastric denervation Physical exam, gastric emptying study Fever Infectious process, pericarditis, atrioesophageal fistula Physical exam, chest radiograph, chest CT, urinalysis, laboratory blood work Fever, dysphagia, neurological Atrial esophageal fistula Physical exam, laboratory blood symptoms work, chest CT or MRI; avoid endoscopy with air insufflation Groin pain Pseudoaneurysm, AV fistula, Ultrasound of the groin, hematoma laboratory blood work; consider CT scan if ultrasound negative Hypotension Pericardial effusion/tamponade, bleeding, sepsis, persistent Echocardiography, laboratory blood work vagal reaction Hemoptysis Pulmonary vein stenosis or occlusion, pneumonia Chest radiograph, chest CT or MR scan, VQ scan Neurological symptoms Cerebral embolic event, atrial esophageal fistula Physical exam, brain imaging, chest CT or MRI Shortness of breath Volume overload, pneumonia, Physical exam, chest pulmonary vein stenosis, radiograph, chest CT, laboratory https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 25/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate phrenic nerve injury blood work CT: computed tomography; ECG: electrocardiogram; MRI: magnetic resonance imaging; AV: atrioventricular. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127127 Version 1.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 26/27 7/5/23, 8:11 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 27/27
7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 05, 2022. INTRODUCTION Ischemic stroke and systemic embolization are major causes of death and disability in patients with atrial fibrillation (AF). This topic will focus on the role of anticoagulant therapy to prevent embolization in patients scheduled to undergo catheter ablation (CA). The role of anticoagulant therapy in the broad population of patients with AF is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Other aspects of CA are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation" and "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy" and "Overview of catheter ablation of cardiac arrhythmias" and "Patient education: Catheter ablation for the heart (The Basics)" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists".) OUR APPROACH TO ANTICOAGULATION There are three periods when a decision or decisions have to be made about anticoagulation in a patient scheduled for catheter ablation (CA). Preprocedural We effectively anticoagulate most patients, irrespective of CHA DS -VASC 2 2 score ( table 1) or presence or absence of sinus rhythm, with either a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC; also referred to as non-vitamin K oral https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 1/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate anticoagulants [NOAC]) for at least three weeks prior to CA. It is reasonable to not use preprocedural anticoagulation in AF patients in sinus rhythm (and who are likely to remain in sinus rhythm for three weeks prior to the procedure) with a CHA DS -VASC score of 0. 2 2 (See 'Preprocedural issues' below.) Periprocedural We continue VKA in the periprocedural period. For most patients taking once-a-day DOACs, we hold the dose the day before and the morning of the procedure. For twice-a-day DOACs, some of our experts hold both doses the day before the procedure while others hold only the evening dose before the procedure; no drug is given the morning of the procedure. Uninterrupted DOAC may be reasonable for the uncommon patient who is at very high risk of a periprocedural stroke. Studies support the fact that uninterrupted DOACs may be superior to uninterrupted warfarin for patients who require continued anticoagulation due to high risk of thromboembolism. All patients receive a continuous infusion of unfractionated heparin (UFH); the activated clotting time is maintained at greater than 300 seconds during the procedure. (See 'Periprocedural issues' below.) Postprocedural UFH is stopped at the end of the procedure and the sheaths are pulled when the activated clotting time is <180 to 200 seconds. For patients previously taking a VKA, the next dose is given approximately 24 hours after the prior dose. For those patients in whom the international normalized ratio was <2.0 prior to the procedure, we restart UFH without a bolus six hours after sheath pull, increase the oral warfarin the night of the procedure, and we continue UFH until the INR is 2.0. Another reasonable approach is to stop UFH the morning after the procedure and start low molecular weight heparin, usually at half the normal dose (0.5 mg/kg twice daily) to avoid bleeding. (See 'Postprocedural anticoagulation' below.) For patients previously taking a DOAC, we suggest restarting it - six hours after sheath removal (and in the absence of any related bleeding). Some experts give intravenous heparin (no bolus; drip at 1000 to 1200 units per hour) or low molecular weight heparin (enoxaparin 0.5 mg/kg) starting six hours after sheath pull, that is uncomplicated by bleeding, and continue until the morning after the ablation. Other experts no longer give a heparin after sheath pull. Long-term We continue oral therapy with the previously prescribed oral anticoagulant for two to three months regardless of CHA DS -VASc score. After this period, the decision 2 2 to continue on long-term anticoagulation is based on the patients underlying stroke risk regardless of whether rhythm control has been achieved. For those patients whose risk for https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 2/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate embolization is very low, such as those with a CHA DS -VASc score of 0 ( table 1), we stop 2 2 anticoagulation at the two-to-three-month visit. INCIDENCE, TIMING, AND MECHANISM OF EMBOLISM The risk of stroke, transient ischemic attack, or other manifestation of embolization is increased at the time of catheter ablation (CA) and is in the range of 0.4 to 2.0 percent [1-3]. These rates come from studies of patients who are receiving anticoagulant therapy and would be higher off such treatment. Most strokes occur within 24 to 48 hours after the procedure [3]. However, embolic events thought attributable to the procedure have been reported to occur for up to one week [4]. The following are potential causes of periprocedural embolization: Withdrawal of anticoagulation before the procedure Catheter manipulation within the left atrium, which may dislodge preexisting thrombus Catheter trauma to the left atrial endothelium, which increases the risk of thrombus formation Thrombus formation on the ablation catheters or left atrial guide sheaths Conversion to sinus rhythm during the procedure in some patients (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation") Asymptomatic embolism Not all emboli to the brain are symptomatic. Multiple magnetic resonance imaging (MRI) studies performed within 24 hours after CA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [5-10]. These lesions are presumed secondary to microemboli [11]. Studies of the subsequent impact of these lesions on neurocognitive function have come to somewhat differing conclusions as to the significance of these lesions: The prevalence of cognitive impairment after radiofrequency CA (RFA) was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal atrial fibrillation (AF), 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [12]. All CA patients received periprocedural enoxaparin and most patients with AF had a CHADS score of 0 or 1 ( table 1). All patients underwent eight 2 neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively, in these four groups of patients. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 3/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate In a study of 37 patients with paroxysmal AF who underwent 41 CA procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [8]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing performed after six months. PREPROCEDURAL ISSUES All patients not at low risk of stroke should be treated with long-term anticoagulant therapy using one of the novel oral anticoagulants or warfarin. Thus, many patients will be receiving anticoagulation when scheduled for catheter ablation (CA) and should continue their anticoagulant. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) For patients not taking long-term anticoagulant therapy due to a low risk of stroke, there are no studies that have compared differing anticoagulant strategies prior to CA; thus, the optimal preprocedural anticoagulation strategy is not known. For these patients, including those in sinus rhythm, most of our experts carry out a minimum of three weeks of effective oral anticoagulation prior to the procedure. The rationale for doing so is that many episodes of atrial fibrillation (AF) are asymptomatic and these episodes will have placed the patient at risk of embolization at the time of catheter manipulation. We also believe it is reasonable to not use preprocedural anticoagulation in AF patients in sinus rhythm (and who are likely to remain in sinus rhythm for three weeks prior to the procedure) with a CHA DS -VASc score of 0. 2 2 When three weeks of effective anticoagulant therapy has not been carried out, preprocedural transesophageal echocardiography (TEE) should be performed (see 'Role of transesophageal echocardiography' below); patients with evidence of left atrial thrombus are not candidates for CA unless it resolves with anticoagulation. Choice of anticoagulant For patients started on oral anticoagulant therapy prior to catheter ablation, we prefer one of the direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) group to warfarin. This preference is based on our preference for these agents in the general AF population. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Most but not all observational studies comparing one NOAC to warfarin have found similar efficacy [13] and safety [14-21]. At least three meta-analyses of observational studies comparing https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 4/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate warfarin to dabigatran have come to similar conclusions [22-24]. A 2016 meta-analysis of 25 studies (11,686 patients) comparing DOACs with uninterrupted VKAs found no significant difference in the rate of stroke or transient ischemic attacks (odds ratio 1.35, 95% CI 0.62-2.94) and major bleeding (odds ratio 0.80, 95% CI 0.65-1.00) [25]. Switching oral anticoagulant As stated directly above, we prefer one of the DOAC group to warfarin for patients undergoing catheter ablation. For patients receiving long-term warfarin therapy, there is no evidence that switching to DOAC prior to catheter ablation improves outcomes. Thus, we do not switch from warfarin to an DOAC. We do not have a preference for one DOAC over another and thus we do not switch DOAC. Based on the evidence presented above that suggests that uninterrupted dabigatran is superior to uninterrupted warfarin, we switch patients from warfarin to dabigatran. Role of transesophageal echocardiography Most patients, including those with effective preprocedural oral anticoagulation, should have a TEE performed prior to (generally the day before) CA. The presence of left atrial thrombus is a contraindication to the procedure [26,27]. Transthoracic echocardiography is not a replacement for TEE in this setting. Two reasons to perform TEE prior to (generally the day before) CA are that it adds significant length to the CA, and some complications of TEE, such as a retropharyngeal hematoma, can be aggravated by the unfractionated heparin used during the procedure. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'LA/LAA thrombi'.) We acknowledge that some experts will omit a TEE in the lowest-risk patients who have been taking effective anticoagulant therapy for at least three weeks, such as those in sinus rhythm who have no significant structural heart disease or those with a CHA DS -VASc score of 0 2 2 ( table 1) [27]. These experts often prefer that a pre-ablation magnetic resonance image confirms the absence of left atrial appendage thrombus in these patients who do not undergo preprocedural TEE. In a study of 97 patients undergoing pulmonary vein isolation, contrast- enhanced MRI demonstrated 100 percent concordance with TEE for the presence and absence of left atrial appendage thrombus [28,29]. An attempt to determine the need for preprocedural TEE in patients at low risk for embolization was made in an analysis of 1058 patients who had TEE performed within 24 hours of pulmonary vein isolation [30]. The frequency of left atrial thrombus or sludge was evaluated according to the CHADS score. (See "Echocardiography in detection of cardiac and aortic sources of systemic 2 embolism".) A CHADS score of 0 was present in 47 percent of patients. Left atrial or left atrial 2 appendage thrombus or sludge was found in 0.6 and 1.5 percent of all patients and the https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 5/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate frequency increased with ascending CHADS scores (percents in parentheses): 0 (0), 1 (2), 2 (5), 3 2 (9), 4 to 6 (11). We do not use intracardiac echocardiography or computed tomography as a substitute for TEE. Each of these has been shown to be inferior in this setting [31,32]. PERIPROCEDURAL ISSUES The two principal periprocedural anticoagulant issues are how to manage the oral anticoagulant and whether/how to use parenteral anticoagulant. Management of oral anticoagulants For patients taking long-term oral anticoagulant who present for catheter ablation, the approach depends on which anticoagulant the patient has been taking. Patients taking long-term vitamin K antagonist For patients taking a VKA prior to catheter ablation, we prefer the strategy of uninterrupted VKA to a strategy of a heparin bridge. We do not hold doses of VKA unless the international normalized ratio (INR) is >3.0. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.) One randomized trial [33] and most observational studies [3,34,35] have shown that continuous anticoagulation with warfarin, compared with warfarin discontinuation with a heparin bridge, is associated with a lower rate of embolization and an equivalent or lower bleeding rate [36]. In the COMPARE trial, 1584 patients with paroxysmal or persistent atrial fibrillation (AF) (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology') and CHADS score 1 were randomly assigned to warfarin discontinuation two 2 to three days before ablation and bridging with low molecular weight heparin (1 mg/kg enoxaparin twice daily until the evening before the procedure) or continuation of therapeutic warfarin (three to four weeks with an INR 2.0 to 3.0) [33]. The primary end point of the incidence of thromboembolic events (stroke, transient ischemic attack, or systemic thromboembolism) in the 48 hours after ablation occurred more frequently with warfarin discontinuation (4.9 versus 0.25 percent; odds ratio 13, 95% CI 3.1-55.6). The incidence of major bleeding complications was similar in the two groups (0.76 versus 0.38 percent, respectively). The majority of events occurred in patients with persistent AF. One limitation of the trial is that operators were not blinded to the anticoagulation strategy. For patients in whom a strategy of continuous anticoagulation with warfarin has been chosen, the optimal immediate-preprocedural range for the INR is not known. In a retrospective study of https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 6/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 1113 patients undergoing radiofrequency catheter ablation for AF, bleeding and vascular complications were less prevalent when the INR was 2.0 and 3.0 (5 percent), compared with 2.0 (10 percent) or 3.0 (12 percent) [37]. The optimal INR range was calculated to be 2.1 to 2.5. Patients taking DOACs In most studies that have evaluated periprocedural outcomes in patients taking direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]), the DOAC was held prior to the procedure. In one trial, 326 patients undergoing AF ablation were randomized to uninterrupted DOAC, procedure day single-dose skipped DOAC, or 24-hour skipped DOAC [38]. The intraprocedural heparin dose was higher in the 24-hour skipped group, but the incidence of major bleeding and postprocedural hemoglobin levels were not significantly different among the treatment groups and different DOACs. There were no fatal events or thromboembolic complications. For most patients taking once-a-day DOACs in the morning, we hold the dose the day before and also the day of the procedure. For those that take once-a-day DOACs with the evening meal or later, we hold only a single dose the day before the procedure. For twice-a-day DOACs, some of our experts hold both doses the day before the procedure while others hold only the evening dose before the procedure and the morning of the procedure. For a small minority of patients, such as those at particularly high risk of a periprocedural stroke, including those with a high CHA DS -VASc score in whom intraprocedural cardioversion is 2 2 planned, no interruption of (continuous) oral anticoagulation with a DOAC is a reasonable alternative to interruption. (See 'Choice of anticoagulant' above.) Small randomized trials of dabigatran, rivaroxaban, edoxaban, and apixaban suggest that outcomes with uninterrupted DOACs are similar to those with uninterrupted warfarin [39-42]. Use of intravenous heparin As catheter ablation (CA) is associated with an increase (from baseline) in the risk of a periprocedural thromboembolic event, we recommend that all patients receive intraprocedural heparin. (See 'Incidence, timing, and mechanism of embolism' above.) We start with a loading dose of 100 units/kg at the beginning of the procedure. Others start the loading dose before transeptal puncture, while others give half the dose before and half the dose after transeptal puncture [43]. A continuous infusion is used to maintain the activated clotting time greater than 300 seconds; the first activated clotting time is performed 10 to 15 minutes after the loading dose. Heparin is stopped at the end of the procedure and the sheaths are pulled when the activated clotting time is <180 to 200 seconds. Protamine can be given after the procedure before removing vascular sheaths. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 7/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Intracardiac echocardiography is done at the end of the CA procedure to ensure that there is no pericardial effusion. If a pericardial effusion is found we take the following approach: For small effusions, we observe and continue with the anticoagulation protocol. If moderate, we reverse anticoagulation and observe. If large, we reverse anticoagulation and perform pericardiocentesis. (See "Diagnosis and treatment of pericardial effusion", section on 'Treatment'.) For patients with hemodynamic compromise, regardless of the size of the effusion, we perform pericardiocentesis and reverse anticoagulation. POSTPROCEDURAL ANTICOAGULATION The approach to anticoagulation within the first 24 hours after a successful procedure is determined in large part by preprocedural anticoagulant approach (see 'Preprocedural issues' above). There have been no studies comparing one approach to another. In the absence of any related bleeding, we suggest the following approach: For those previously taking warfarin, and for whom the management of the international normalized ratio was not problematic, we suggest continuing warfarin. The first postprocedural dose should be the day after the procedure, assuming a dose was given the morning of the procedure. (See 'Patients taking long-term vitamin K antagonist' above.) For patients taking warfarin whose procedure was done with a subtherapeutic international normalized ratio, we restart intravenous heparin without a bolus six hours after sheath pull and start low molecular weight heparin the morning after the procedure. Low molecular weight heparin is continued until the international normalized ratio is therapeutic. When low molecular weight heparin is used, some of our experts give the first dose at 50 percent. For patients previously taking a direct oral anticoagulant (DOAC; also referred to as non- vitamin K oral anticoagulants [NOAC]), DOAC may be restarted four to six hours after sheath pull. Alternatively, some experts delay restarting these newer agents until the morning after the procedure. If the DOAC is restarted the morning after the procedure, we give either intravenous unfractionated heparin (no bolus; drip at 1000 to 1200 units per hour starting six hours after sheath pull and continued until the morning after the procedure) or low https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 8/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate molecular weight heparin (enoxaparin 0.5 mg/kg; typically a single dose administered six hours after sheath pull). For patients previously not taking any oral agent, we suggest starting either a DOAC or warfarin. A first dose of either agent can be given six hours after an uncomplicated procedure. Patients started on warfarin will need to receive bridging treatment for a few days with low molecular weight heparin, as described directly above. LONG-TERM ANTICOAGULATION We continue oral therapy with the previously prescribed oral anticoagulant [44] for at least two months to ensure that the increased risk of embolization associated with the procedure, which lasts for about four weeks, has returned to a baseline risk and that there has been adequate time to document an absence of recurrence of atrial fibrillation (AF) for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [45]. (See 'Incidence, timing, and mechanism of embolism' above.) After this two-month period of mandatory oral anticoagulation, we generally restore the anticoagulant regimen in place prior to the procedure. For those patients without evidence of recurrent AF and whose risk for embolization is very low, such as those with a CHA DS -VASc 2 2 score of 0 ( table 1), we stop anticoagulation. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) Some experts are comfortable stopping anticoagulation in patients with a CHA DS -VASc score 2 2 of 1 ( table 1) after sufficient documentation of the absence of recurrent episodes of AF. We believe this approach has not been adequately tested. Therefore, we tell patients and referring physicians that the desire to stop long-term anticoagulation is not an indication for catheter ablation (CA) by itself. For all patients with a CHA DS -VASc score of >1 ( table 1) after CA, irrespective of whether or 2 2 not recurrence has been documented, we maintain the patient on long-term oral anticoagulation [46,47]. The optimal approach to chronic anticoagulation after successful CA, defined as no evidence of recurrence, is uncertain [48]. It is known that late recurrent AF occurs in 20 to 30 percent of patients, but the methods used in some studies likely underestimate the incidence [49-52]. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 9/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate In a 2019 meta-analysis of five studies with nearly 4000 patients that evaluated safety and efficacy of long-term oral anticoagulation (OAC) compared with no OAC, the following was found during a mean follow-up of nearly 40 months [53]: In patients with a CHA DS -VASc score 2, OAC continuation was associated with a 2 2 decrease in the risk of thromboembolic events (risk ratio [RR] 0.41, 95% CI 0.21-0.82) but an increased risk of intracranial hemorrhage (ICH; RR 5.78, 95% CI 1.33-25.08). The absolute risk decrease in thromboembolic risk was 1.14 percent, while the increase in ICH was 0.7 percent. In patients with a CHA DS -VASc score of 0 or 1, the risk of ICH from OAC exceeded any 2 2 potential decrease in thromboembolic risk. The issue of the role of long-term anticoagulation was indirectly addressed by at least three studies that found a lower incidence of stroke comparing successful CA to antiarrhythmic drug therapy [54-56]. In a retrospective study of 174 matched pairs of AF individuals with a CHA2DS2- VASc score 1 who were treated with either antiarrhythmic drug therapy or CA and treated for at least three months with warfarin, the rate of stroke/transient ischemic attack was lower with the CA group (0.59 versus 2.21 percent per year) [54]. In those individuals treated with CA and in whom there was no AF recurrence, the stroke rate was very low compared to those with recurrence (0.8 versus 5.4 percent) after a mean follow-up period of 47 months. In addition, it is not known if asymptomatic recurrences result in a persistent thromboembolic risk in patients who have undergone CA. A low risk of stroke was reported in a series of 755 patients with longstanding persistent AF who underwent CA or a tailored approach [57]. In this cohort, anticoagulation was discontinued three months after the procedure in the majority of the 522 patients who did not have evidence of recurrent AF. During a median follow-up of 25 months, none of the patients who stopped anticoagulation had a stroke. Although these results are encouraging, the study cohort had a low baseline thromboembolic risk, with most having a CHADS2-VASc score of 0 to 2 ( table 1). Some of these patients, such as those with lone AF, would not require chronic oral anticoagulation whether or not they had a successful CA procedure. The following recommendations were made in the 2019 update of the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline [58,59]: Systemic anticoagulation was recommended for at least two months in all patients following CA. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 10/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate After two months, the decision to continue anticoagulation should be based on the patient s risk factors for stroke and risk of bleeding, and not on the type of AF. The guideline acknowledges that recurrent episodes of AF, which may be asymptomatic, occur. The 2012 focused update of the European Society of Cardiology AF guideline recommends long- term oral anticoagulation CHA DS -VASc score of 2 [60]. The 2015 position document on 2 2 antithrombotic management in patients undergoing electrophysiological procedures states " the decision for oral anticoagulation depends on the patient s stroke risk profile and not the perceived success or failure of ablation " [43]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Catheter ablation of atrial fibrillation".) SUMMARY AND RECOMMENDATIONS The risk of stroke, transient ischemic attack, or other significant manifestation of embolization is increased, compared to baseline risk, at the time of catheter ablation (CA) for atrial fibrillation. (See 'Incidence, timing, and mechanism of embolism' above.) We perform a preprocedural transesophageal echocardiogram in most patients undergoing CA. The finding of intracardiac thrombus is a contraindication to the procedure. (See 'Role of transesophageal echocardiography' above.) Most patients scheduled to undergo CA who have been receiving long-term oral anticoagulation should continue to do so until the procedure. For those low-risk patients who have not been receiving long-term anticoagulation, including those in sinus rhythm at the time of the procedure, we suggest at least three weeks of effective anticoagulation prior to CA rather than no preprocedural anticoagulation (Grade 2C). An alternate approach is presented above. (See 'Preprocedural issues' above.) All patients should receive intraprocedural anticoagulation with intravenous heparin, irrespective of the patient s baseline thromboembolic risk and whether or not the procedure is performed on uninterrupted warfarin. (See 'Periprocedural issues' above.) https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 11/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate For patients taking long-term oral anticoagulant with warfarin who present for CA, we recommend continuing such therapy rather than stopping and using a heparin bridge (Grade 1A). For patients taking long-term oral anticoagulant with a newer oral anticoagulant who present for CA, we suggest discontinuing such therapy before the procedure rather than continuing it (Grade 2B). (See 'Periprocedural issues' above.) For the uncommon patient who is at very high risk of a periprocedural stroke, it is reasonable to not discontinue direct oral anticoagulants (DOAC; also referred to as non- vitamin K oral anticoagulants [NOAC]). (See 'Patients taking DOACs' above.) DOAC may be restarted four to six hours after sheath pull. Alternatively, DOAC may be restarted the morning after the procedure in patients who are treated overnight with either intravenous unfractionated heparin (no bolus; drip at 1000 to 1200 units per hour starting six hours after sheath pull and continued until the morning after the procedure) or low molecular weight heparin (enoxaparin 0.5 mg/kg; typically a single dose at six hours after sheath pull). (See 'Patients taking DOACs' above.) Oral anticoagulation is continued for at least two months after the procedure in all patients. After two months, the decision to continue anticoagulation should be based on the patient s risk factors for stroke and risk of bleeding and not on the type of AF or outcome of the procedure. (See 'Long-term anticoagulation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 2. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 3. Page SP, Herring N, Hunter RJ, et al. Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin. J Cardiovasc Electrophysiol 2014; 25:585. 4. Kosiuk J, Kornej J, Bollmann A, et al. Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors. Heart Rhythm 2014; 11:1934. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 12/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 5. Michaud GF. Silent cerebral embolism during catheter ablation of atrial fibrillation: how concerned should we be? Circulation 2010; 122:1662. 6. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 7. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 8. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. Circ Arrhythm Electrophysiol 2013; 6:843. 9. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 10. Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. Pacing Clin Electrophysiol 2013; 36:1328. 11. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 12. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 13. Shah RR, Pillai A, Schafer P, et al. Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. Am J Cardiol 2017; 120:404. 14. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm 2013; 10:483. 15. Nin T, Sairaku A, Yoshida Y, et al. A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol 2013; 36:172. 16. Winkle RA, Mead RH, Engel G, et al. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2012; 23:264. 17. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 13/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 2013; 6:460. 18. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:861. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014; 63:982. 20. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhythm Electrophysiol 2014; 7:576. 21. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59:1168. 22. Provid ncia R, Albenque JP, Combes S, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart 2014; 100:324. 23. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013; 15:1412. 24. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013; 15:1407. 25. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016; 117:926. 26. Knight BP. Transesophageal echocardiography before atrial fibrillation ablation: looking before cooking. J Am Coll Cardiol 2009; 54:2040. 27. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 14/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thor 28. Rathi VK, Reddy ST, Anreddy S, et al. Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. Heart Rhythm 2013; 10:1021. 29. Chen J, Zhang H, Zhu D, et al. Cardiac MRI for detecting left atrial/left atrial appendage thrombus in patients with atrial fibrillation : Meta-analysis and systematic review. Herz 2019; 44:390. 30. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 31. Saksena S, Sra J, Jordaens L, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with
1. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 2. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 3. Page SP, Herring N, Hunter RJ, et al. Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin. J Cardiovasc Electrophysiol 2014; 25:585. 4. Kosiuk J, Kornej J, Bollmann A, et al. Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors. Heart Rhythm 2014; 11:1934. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 12/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 5. Michaud GF. Silent cerebral embolism during catheter ablation of atrial fibrillation: how concerned should we be? Circulation 2010; 122:1662. 6. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 7. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 8. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. Circ Arrhythm Electrophysiol 2013; 6:843. 9. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 10. Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. Pacing Clin Electrophysiol 2013; 36:1328. 11. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 12. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 13. Shah RR, Pillai A, Schafer P, et al. Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. Am J Cardiol 2017; 120:404. 14. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm 2013; 10:483. 15. Nin T, Sairaku A, Yoshida Y, et al. A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol 2013; 36:172. 16. Winkle RA, Mead RH, Engel G, et al. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2012; 23:264. 17. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 13/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 2013; 6:460. 18. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:861. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014; 63:982. 20. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhythm Electrophysiol 2014; 7:576. 21. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59:1168. 22. Provid ncia R, Albenque JP, Combes S, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart 2014; 100:324. 23. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013; 15:1412. 24. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013; 15:1407. 25. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016; 117:926. 26. Knight BP. Transesophageal echocardiography before atrial fibrillation ablation: looking before cooking. J Am Coll Cardiol 2009; 54:2040. 27. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 14/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thor 28. Rathi VK, Reddy ST, Anreddy S, et al. Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. Heart Rhythm 2013; 10:1021. 29. Chen J, Zhang H, Zhu D, et al. Cardiac MRI for detecting left atrial/left atrial appendage thrombus in patients with atrial fibrillation : Meta-analysis and systematic review. Herz 2019; 44:390. 30. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 31. Saksena S, Sra J, Jordaens L, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with atrial fibrillation: the intracardiac echocardiography guided cardioversion helps interventional procedures study. Circ Arrhythm Electrophysiol 2010; 3:571. 32. Martinez MW, Kirsch J, Williamson EE, et al. Utility of nongated multidetector computed tomography for detection of left atrial thrombus in patients undergoing catheter ablation of atrial fibrillation. JACC Cardiovasc Imaging 2009; 2:69. 33. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129:2638. 34. Santangeli P, Di Biase L, Horton R, et al. Ablation of atrial fibrillation under therapeutic warfarin reduces periprocedural complications: evidence from a meta-analysis. Circ Arrhythm Electrophysiol 2012; 5:302. 35. Kuwahara T, Takahashi A, Takahashi Y, et al. Prevention of periprocedural ischemic stroke and management of hemorrhagic complications in atrial fibrillation ablation under continuous warfarin administration. J Cardiovasc Electrophysiol 2013; 24:510. 36. Di Biase L, Gaita F, Toso E, et al. Does periprocedural anticoagulation management of atrial fibrillation affect the prevalence of silent thromboembolic lesion detected by diffusion cerebral magnetic resonance imaging in patients undergoing radiofrequency atrial https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 15/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate fibrillation ablation with open irrigated catheters? Results from a prospective multicenter study. Heart Rhythm 2014; 11:791. 37. Kim JS, Jongnarangsin K, Latchamsetty R, et al. The optimal range of international normalized ratio for radiofrequency catheter ablation of atrial fibrillation during therapeutic anticoagulation with warfarin. Circ Arrhythm Electrophysiol 2013; 6:302. 38. Yu HT, Shim J, Park J, et al. When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study. Eur Heart J 2019; 40:1531. 39. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017; 376:1627. 40. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805. 41. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40:3013. 42. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018; 39:2942. 43. Sticherling C, Marin F, Birnie D, et al. Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC Working Group Thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS). Europace 2015; 17:1197. 44. Eitel C, Koch J, Sommer P, et al. Novel oral anticoagulants in a real-world cohort of patients undergoing catheter ablation of atrial fibrillation. Europace 2013; 15:1587. 45. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long- term follow-up in nationwide cohort of Denmark. Eur Heart J 2015; 36:307. 46. Schreiber D, Rostock T, Fr hlich M, et al. Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success. Circ Arrhythm Electrophysiol 2015; 8:308. 47. Jacobs V, May HT, Bair TL, et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm 2015; 12:681. 48. Kaufman ES, Waldo AL. The impact of asymptomatic atrial fibrillation. J Am Coll Cardiol 2004; 43:53. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 16/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 49. Saad EB, Marrouche NF, Saad CP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med 2003; 138:634. 50. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001; 104:2539. 51. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 52. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 53. Romero J, Cerrud-Rodriguez RC, Diaz JC, et al. Oral anticoagulation after catheter ablation of atrial fibrillation and the associated risk of thromboembolic events and intracranial hemorrhage: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2019; 30:1250. 54. Lin YJ, Chao TF, Tsao HM, et al. Successful catheter ablation reduces the risk of cardiovascular events in atrial fibrillation patients with CHA2DS2-VASc risk score of 1 and higher. Europace 2013; 15:676. 55. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011; 22:839. 56. Hunter RJ, McCready J, Diab I, et al. Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death. Heart 2012; 98:48. 57. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006; 114:759. 58. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 59. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:104. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 17/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 60. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14:1385. Topic 94502 Version 27.0 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 18/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or aortic plaque) 1 5 7.2 Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 19/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 Actual rates of stroke in contemporary cohorts might vary from these estimates. . References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 20/21 7/5/23, 8:11 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 21/21
7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. INTRODUCTION For patients with atrial fibrillation (AF), the two principal goals of long-term therapy are to improve quality of life (eg, symptom control) and to prevent associated morbidity and mortality (principally the prevention of thromboembolism). (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF' and "Atrial fibrillation in adults: Use of oral anticoagulants".) In asymptomatic or minimally symptomatic patients with AF, there is often no need to pursue aggressive measures to maintain sinus rhythm. For those patients who might feel better in sinus rhythm, rate- and rhythm-control strategies improve symptoms, but neither has been conclusively shown to improve survival compared to the other. The factors determining the choice between these two strategies are discussed elsewhere. (See "Management of atrial fibrillation: Rhythm control versus rate control".) For those patients in whom a rhythm control strategy is chosen, catheter ablation or antiarrhythmic drugs are the two principle therapeutic options. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) This topic will compare the efficacy and safety of these two options for rhythm control and provide recommendations for choosing one or the other. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 1/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate CLASSIFICATION The following terms are used in the classification of patients with atrial fibrillation (AF). In the studies discussed in this topic, some, but not all, of these groups have been included (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'): Paroxysmal (ie, self-terminating or intermittent) AF Paroxysmal AF is defined as recurrent AF ( 2 episodes) that terminates spontaneously in seven days or less, usually less than 24 hours. (See "Paroxysmal atrial fibrillation".) Persistent AF Persistent AF is defined as AF that fails to self-terminate within seven days. Episodes often require pharmacologic or electrical cardioversion to restore sinus rhythm. While a patient who has had persistent AF can have later episodes of paroxysmal AF, AF is generally considered a progressive disease. In individuals with paroxysmal AF, progression to persistent and permanent AF occurs in >50 percent beyond 10 years despite antiarrhythmic therapy [1]. Long-standing persistent AF Long-standing persistent AF refers to persistent AF that has lasted for one year or more [2]. Permanent AF Permanent AF is a term used to identify individuals with persistent AF where a decision has been made to no longer pursue a rhythm control strategy. CATHETER ABLATION AND ANTIARRHYTHMIC DRUG THERAPY General considerations Catheter ablation uses either cryoablation (cryotherapy) or radiofrequency ablation (RFA). AF will recur in one year in approximately 20 to 40 percent of patients who have a catheter ablation, although overall AF burden is often markedly decreased [3]; a recurrence is defined as an AF episode >30 seconds in duration on routine monitoring. Important complications from catheter ablation include cardiac tamponade, pulmonary vein stenosis (<1 percent), phrenic nerve paralysis (about 3 percent with cryoballoon), and rare instances of stroke and atrioesophageal fistula [4,5]. These and other complications are described in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) A 2017 randomized comparison between cryoablation and RFA showed similar success rates, as did a meta-analysis of observational studies [6,7]. (See "Atrial fibrillation: Catheter ablation" and https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 2/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non- electrophysiologists".) Commonly employed drugs to maintain sinus rhythm are amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone. Approximately 25 to 50 percent of people who receive antiarrhythmic medications will have recurrent AF within one year. Important side effects of antiarrhythmics include proarrhythmia, bradyarrhythmia, and organ toxicity in the case of amiodarone. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Approach For patients with symptomatic paroxysmal AF, in whom rhythm rather than a rate control is pursued, we suggest catheter ablation as first-line therapy in some patients as an alternative to antiarrhythmic drugs (AADs); this is particularly true for younger patients or patients who are poor candidates for AAD therapy or are concerned about the potential complications of AADs. Other factors that may impact the safety and efficacy of catheter ablation also need to be considered when deciding between catheter ablation and AAD. For patients with symptomatic paroxysmal or persistent AF who have failed or become intolerant to one or more AADs, we recommend catheter ablation. For patients with symptomatic persistent or longstanding persistent AF who have failed or become intolerant of one or more AADs or who choose not to start antiarrhythmic therapy, we suggest catheter ablation. Initial treatment of paroxysmal AF with catheter cryoballoon ablation was associated with a lower incidence of persistent AF or recurrent atrial tachyarrhythmia over three years of follow-up than initial use of AADs. Three hundred and three patients were assigned to undergo initial rhythm-control therapy with catheter ablation or to receive antiarrhythmic therapy. Over 36 months of follow-up the following findings were noted: Patients assigned catheter ablation had less persistent AF compared with patients assigned to AADs (1.9 versus 7.4 percent; hazard ratio [HR] 0.25 95% CI 0.09-0.70). Patients assigned catheter ablation had less recurrent atrial tachyarrhythmia, which occurred in 87 patients in the ablation group (56.5 percent) and in 115 in the AAD group (77.2 percent; 56.5 versus 77.2 percent; HR 0.51 95% CI 0.38-0.67). Serious adverse events occurred in seven patients (4.5 percent) in the ablation group and in 15 (10.1 percent) in the AAD group. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 3/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate PATIENTS WITHOUT PRIOR ANTIARRHYTHMIC DRUG TREATMENT Some patients with paroxysmal or persistent atrial fibrillation (AF) (see 'Classification' above) prefer a rhythm as opposed to a rate control strategy in order to decrease symptoms (see "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'). For patients who have chosen rhythm control and who have not previously received antiarrhythmic drug (AAD) therapy, we usually start with AAD rather than CA. On occasion, initial treatment with CA may be appropriate. All patients need to be informed of the possibility of recurrence of symptoms and adverse events with both therapies. Recurrence rates and side effects are discussed in detail elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Atrial fibrillation: Catheter ablation", section on 'Complications' and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Drug-related arrhythmias and mortality'.) Prior to 2020, catheter ablation (CA) was generally not offered as first-line therapy given the complexity of the procedure and the potential for complications. It was typically offered to patients who had failed AAD therapy. However, evidence suggests that CA is superior to AAD for control of symptoms. While CA appears superior to AAD for the prevention of AF recurrence, there is no evidence that the rates of cardiovascular death, myocardial infarction, or stroke differ between the two interventions. In addition, in the studies demonstrating superiority of CA, the procedure was performed by highly expert electrophysiologists. Thus, for most patients, we start with AAD. CA by an experienced operator may be considered as first-line therapy for symptomatic patients who, after a full discussion of the benefits and risks of both approaches, prefer an invasive approach. In a meta-analysis of six studies in 1200 patients comparing CA with AAD as first-line treatment for paroxysmal AF, CA was associated with [8]: Lower rates of recurrent atrial arrhythmias (35 versus 53 percent; risk ratio [RR] 0.64, 95% CI 0.51-0.80) [8]. Similar risks of serious adverse events (18 versus 21 percent; RR 0.87, 95% CI 0.58-1.30). Adverse events were defined differently across studies and included stroke, tamponade, and death. Lower rates of symptomatic atrial arrhythmias. Lower healthcare resource utilization. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 4/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate Lower rates of crossover to alternative treatment (RR 0.21, 95% CI 0.13-0.32). Limitations of this study include a moderate degree of heterogeneity among the included studies; one study in particular accounted for most of the heterogeneity (the RAAFT 2 trial) [9]. PATIENTS WITH PRIOR ANTIARRHYTHMIC DRUG TREATMENT For patients with either paroxysmal or persistent (see 'Classification' above) AF who are interested in decreasing their symptom burden and have received treatment with at least one antiarrhythmic drug, either catheter ablation or long-term antiarrhythmic drug therapy is a reasonable approach. The patient's choice will be guided by advantages and burdens of each approach. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) This section will review the studies that have directly compared the two approaches. These studies suggest that although catheter ablation and antiarrhythmic drug therapy lead to similar rates of all-cause mortality and other serious morbidities, there may be a greater improvement in quality of life with the former. This topic is not intended to address management in patients who have failed rhythm control with two or more antiarrhythmic drugs or those who have already received catheter ablation. Failure of an antiarrhythmic drug is defined as a drug trial that results in a reduction in AF burden that is not satisfactory to the patient, or results in side effects that are intolerable to the patient, proarrhythmia, or organ toxicity. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Long-term issues'.) Three early meta-analyses of studies comparing catheter ablation and antiarrhythmic drug therapy found that recurrence of AF occurred less often in patients who received catheter ablation in the 12 months after initiation of therapy [10-12]. The following three randomized trials directly compared catheter ablation with antiarrhythmic drug therapy: The ThermoCool AF study randomly assigned 167 symptomatic patients with paroxysmal AF (no episodes lasting more than 30 days) who did not respond to at least one AAD and who experienced at least three episodes of paroxysmal AF within six months before randomization to either catheter ablation (with RFA) or AAD therapy in a 2:1 fashion [13]. Patients with significant left ventricular dysfunction, persistent AF, and advanced heart failure were excluded. Catheter ablation included pulmonary vein isolation with confirmation of entrance block, and AAD therapy included flecainide (36 percent), https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 5/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate propafenone (41 percent), dofetilide, sotalol, or quinidine at the investigator's discretion. After nine months, there were significantly fewer patients with documented symptomatic paroxysmal AF in the catheter ablation group (16 versus 66 percent; hazard ratio 0.30, 95% CI 0.19-0.47). In addition, major treatment-related adverse events occurred more often with AAD therapy (9 versus 5 percent) at 30 days. Mean quality-of-life scores improved significantly with catheter ablation compared to AAD therapy. The STOP AF trial randomly assigned 245 paroxysmal AF patients (in a 2:1 manner) to cryoballoon ablation or drug therapy [14]. Patients had previously failed drug therapy; paroxysmal and early persistent AF were present in 78 and 22 percent, respectively. Treatment success was defined as freedom from chronic treatment failure, as defined by the absence of: any detectable AF after the blanking period; use of a non-study antiarrhythmic drug; and any non-protocol intervention for AF. At 12 months, the primary end point was present in 69.9 and 7.3 percent of the two groups (p<0.001). Serious adverse procedure-related events occurred in 3.1 percent. Phrenic nerve palsy occurred in 11.2 percent, but resolved in the majority. The Catheter ABlation vs ANtiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial randomly assigned 2204 patients with paroxysmal (43 percent) or persistent AF (57 percent) to catheter ablation or antiarrhythmic drug therapy [15]. Patients were excluded if they had a prior catheter ablation or had failed two or more antiarrhythmic drugs. The following findings were noted: Among the patients who received antiarrhythmic drug therapy, 27.5 percent crossed over to the ablation group. The primary composite end point (death, disabling stroke, serous bleeding, or cardiac arrest) occurred in 8.0 and 9.2 percent of the two groups, respectively (hazard ratio [HR] 0.86, 95% CI 0.65-1.15), during a median follow-up of about four years. There was no difference in all-cause mortality (5.2 versus 6.1 percent; HR 0.85, 95% CI 0.60-1.21). The end point of death or cardiovascular hospitalization occurred less often with catheter ablation (51.7 versus 58.1 percent; HR 0.83, 95% CI 0.74-0.93), as did the rate for AF recurrence (49.9 versus 69.5 percent; HR 0.52, 95% CI 0.45-0.60). Both patient groups achieved significant improvement in quality-of-life scores, and the improvement in the catheter ablation group was significantly greater than in the drug therapy group. Using one quality-of-life tool, the mean score at baseline was approximately 63 points. At 12 months, the scores were 80.9 and 86.4 points, respectively [16]. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 6/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate The Catheter Ablation compared with optimized Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial randomly assigned 155 patients with symptomatic persistent or paroxysmal AF to catheter ablation or antiarrhythmic drug therapy [17]. The primary end point, SF-36 General Health score, improved more in the ablation group than the drug therapy group from baseline to 12 months (mean baseline score, 61.8 versus 62.7; mean change 11.9 versus 3.1, respectively; p = 0.003). Patients with heart failure Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment. This issue is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of catheter ablation are available in societal guidelines. The 2016 European Society of Cardiology guideline recommends catheter ablation for patients with symptomatic, paroxysmal, persistent, and probably long-standing persistent atrial fibrillation who have failed (or are intolerant to) treatment with at least one antiarrhythmic drug [18]. The 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation makes the following recommendations regarding catheter ablation (CA) to maintain sinus rhythm [19] CA is useful for symptomatic paroxysmal AF refractory or intolerant to at least one class I or III antiarrhythmic medication when a rhythm control strategy is desired. CA is reasonable for selected patients with symptomatic persistent AF refractory or intolerant to at least one class I or III antiarrhythmic medication. CA may be considered for symptomatic long-standing (>12 months) persistent AF refractory or intolerant to at least one class I or III antiarrhythmic medication, when a rhythm control strategy is desired. CA may be considered prior to initiation of antiarrhythmic drug therapy with a class I or III antiarrhythmic medication for symptomatic paroxysmal AF when a rhythm control strategy is desired. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 7/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS For most patients with new-onset symptomatic paroxysmal atrial fibrillation (AF) who have chosen a rhythm rather than a rate control strategy, we suggest antiarrhythmic drug (AAD) therapy rather than catheter ablation (CA) as initial therapy (Grade 2C). Patients who may reasonably prefer CA as initial therapy include those who are concerned about the potential complications of AAD or the higher rate of AF recurrence with it. (See 'Patients without prior antiarrhythmic drug treatment' above.) For patients with symptomatic paroxysmal or persistent AF and who have failed or become intolerant to one or more AAD, we recommend CA (Grade 1A). (See 'Patients with prior antiarrhythmic drug treatment' above.) For patients with symptomatic persistent or longstanding persistent AF who have failed or become intolerant of one or more AAD or who choose not to start antiarrhythmic therapy, we suggest CA (Grade 2B). (See 'Patients with prior antiarrhythmic drug treatment' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wilber DJ. Pursuing sinus rhythm in patients with persistent atrial fibrillation: when is it too late? J Am Coll Cardiol 2009; 54:796. 2. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 3. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial. Circulation 2019; 140:1779. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 8/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate 4. Teunissen C, Velthuis BK, Hassink RJ, et al. Incidence of Pulmonary Vein Stenosis After Radiofrequency Catheter Ablation of Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:589. 5. Samuel M, Almohammadi M, Tsadok MA, et al. Population-Based Evaluation of Major Adverse Events After Catheter Ablation for Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:1425. 6. Kuck KH, F rnkranz A, Chun KR, et al. Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of- life outcomes in the FIRE AND ICE trial. Eur Heart J 2016; 37:2858. 7. Buiatti A, von Olshausen G, Barthel P, et al. Cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: an updated meta-analysis of randomized and observational studies. Europace 2017; 19:378. 8. Imberti JF, Ding WY, Kotalczyk A, et al. Catheter ablation as first-line treatment for paroxysmal atrial fibrillation: a systematic review and meta-analysis. Heart 2021; 107:1630. 9. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014; 311:692. 10. Noheria A, Kumar A, Wylie JV Jr, Josephson ME. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a systematic review. Arch Intern Med 2008; 168:581. 11. Terasawa T, Balk EM, Chung M, et al. Systematic review: comparative effectiveness of radiofrequency catheter ablation for atrial fibrillation. Ann Intern Med 2009; 151:191. 12. Chen HS, Wen JM, Wu SN, Liu JP. Catheter ablation for paroxysmal and persistent atrial fibrillation. Cochrane Database Syst Rev 2012; :CD007101. 13. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010; 303:333. 14. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013; 61:1713. 15. Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1261. 16. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1275. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 9/10 7/5/23, 8:12 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate 17. Blomstr m-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA 2019; 321:1059. 18. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 19. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. Topic 93920 Version 30.0 Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 10/10
7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of catheter ablation of cardiac arrhythmias : Samuel L vy, MD : N A Mark Estes, III, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 14, 2022. INTRODUCTION Pharmacologic therapy of arrhythmias, while frequently effective, is limited by high failure rates, potential for proarrhythmia, and drug toxicity. Nonpharmacologic therapy for symptomatic and life-threatening cardiac arrhythmias includes the use of catheter ablation, the implantable cardioverter-defibrillator for ventricular arrhythmias, and, at times, cardiac surgery. The clinical role of catheter ablation in the treatment of arrhythmias will be reviewed here. A discussion of invasive cardiac electrophysiology studies and cardiac mapping, both precursors to catheter ablation, is presented separately. (See "Invasive diagnostic cardiac electrophysiology studies".) INDICATIONS AND CLINICAL USE Catheter ablation using radiofrequency or cryothermal energy has become an important therapy in the management of patients with various types of tachyarrhythmia ( table 1), including [1-3]: Atrioventricular reentrant tachycardia (AVRT) associated with the Wolff-Parkinson-White (WPW) syndrome or a concealed accessory pathway (see "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Treatment to prevent recurrent arrhythmias') AV nodal reentrant tachycardia (AVNRT) (see "Atrioventricular nodal reentrant tachycardia", section on 'Catheter ablation') https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 1/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Atrial tachycardia (see "Focal atrial tachycardia", section on 'Catheter ablation') Atrial flutter (see "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation') Atrial fibrillation, either in a curative attempt, or AV nodal ablation with pacemaker implantation (see "Atrial fibrillation: Catheter ablation") Frequent ventricular ectopy with refractory symptoms or associated cardiomyopathy (see "Arrhythmia-induced cardiomyopathy", section on 'Frequent ventricular ectopy') Ventricular tachycardia (VT), both idiopathic and in some patients with structural heart disease, particularly if there are recurrent implantable cardioverter-defibrillator therapies (see "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation' and "Ventricular tachycardia in the absence of apparent structural heart disease" and "Bundle branch reentrant ventricular tachycardia") Persistent, frequent, or incessant tachycardia with tachycardia-induced cardiomyopathy (see "Arrhythmia-induced cardiomyopathy") Triggering premature ventricular contractions (PVCs) in rare patients with polymorphic VT and ventricular fibrillation The indications for catheter ablation of a cardiac arrhythmia generally revolve around the treatment of a recurrent or persistent symptomatic arrhythmia which has been refractory to medical therapy or for which medical therapy is not tolerated or preferred. Atrial tachycardia may be unifocal or multifocal; some unifocal tachycardias originate in or around the sinus node. Unifocal (or ectopic) atrial tachycardia may have an automatic or reentrant mechanism, and a paroxysmal or incessant pattern ( waveform 1 and waveform 2). Most varieties of unifocal atrial tachycardia are amenable to catheter ablation. (See "Intraatrial reentrant tachycardia" and "Focal atrial tachycardia" and "Atrial fibrillation: Catheter ablation".) Sinoatrial node reentrant tachycardia (SNRT) is a specific type of unifocal atrial tachycardia in which sinoatrial (SA) nodal or peri-SA nodal tissue is part of the reentry circuit; this results in P waves during tachycardia which may be indistinguishable from normal sinus P waves [4,5]. (See "Sinoatrial nodal reentrant tachycardia (SANRT)".) https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 2/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Intraatrial reentrant tachycardia (IART) is a macroreentrant atrial tachycardia that does not utilize the cavotricuspid isthmus ( figure 1) as a critical pathway for the reentry to perpetuate. Catheter ablation, however, has relatively high success rates for the acute termination of IART and for the long-term prevention of recurrences. (See "Intraatrial reentrant tachycardia", section on 'Catheter ablation'.) Inappropriate sinus tachycardia (IST), also known as chronic nonparoxysmal sinus tachycardia, is a distinct syndrome in which the resting sinus rate is elevated and there is an exaggerated chronotropic response to exercise [6]. Although IST is most often treated with beta blockers or ivabradine, ablation may be considered in refractory patients. (See "Sinus tachycardia: Evaluation and management", section on 'Inappropriate sinus tachycardia'.) Occasionally, patients with more than one discrete ectopic atrial focus are candidates for curative ablation. Multifocal atrial tachycardia (MAT), however, is due to abnormal automaticity or triggered activity throughout the atria, and is therefore not curable with standard catheter techniques ( waveform 3). Refractory patients with MAT may benefit from complete atrioventricular junctional ablation and permanent pacemaker implantation or AV nodal modification [7]. (See "Multifocal atrial tachycardia".) In some select indications for arrhythmias known to have a high cure rate with ablation therapy (eg, atrial flutter, paroxysmal supraventricular tachycardia, WPW, idiopathic PVCs/VT), catheter ablation may be indicated as a first-line treatment (class I indication). Catheter ablation is considered preferable to medical therapy in patients with symptomatic WPW syndrome. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation' and "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Catheter ablation'.) CONTRAINDICATIONS The absolute contraindications to catheter ablation, performed as part of an invasive cardiac electrophysiology (EP) study, are generally similar to the contraindications of the EP study itself and include [8]: Unstable angina Bacteremia or septicemia Acute decompensated congestive heart failure not caused by the arrhythmia Major bleeding diathesis Acute lower extremity venous thrombosis if femoral vein cannulation is desired https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 3/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Intracardiac mass or thrombus PREPROCEDURE EVALUATION, PREPARATION, AND INTRAPROCEDURE MONITORING Because catheter ablation is performed as part of an invasive electrophysiology (EP) study, the preprocedure evaluation, preparation, and intraprocedure monitoring for patients undergoing catheter ablation is essentially identical to that for an invasive EP study. This information is discussed in detail separately. (See "Invasive diagnostic cardiac electrophysiology studies", section on 'Preprocedural evaluation' and "Invasive diagnostic cardiac electrophysiology studies", section on 'Preparation and monitoring'.) MAPPING AND LOCALIZATION OF THE ARRHYTHMIA Cardiac mapping refers to careful movement of a mapping or ablation catheter in the area of interest, probing for the site at which radiofrequency or cryothermal ablation will be successful at curing the arrhythmia. Cardiac mapping during electrophysiologic testing identifies the temporal and spatial distributions of electrical potentials generated by the myocardium during normal and abnormal rhythms. This process allows description of the spread of activation from its initiation to its completion within a region of interest and, in its usual application, is focused toward the identification of the site of origin or a critical site of conduction for an arrhythmia. Multiple techniques for mapping have been developed [9]. Electrogram recordings Recorded electrograms can provide two important pieces of information: The local activation time (ie, the time of activation of myocardium immediately) adjacent to the recording electrode relative to a reference. The complexity of myocardial activation within the "field of view" of the recording electrode. Recording electrodes may be either unipolar (one pole in contact with the tissue whose electrical activity is being recorded and the second, an indifferent electrode located on the same catheter far from the first electrode, or independent from the catheter altogether) or bipolar (two poles in contact with the tissue and adjacent to each other separated by a few millimeters). In actuality, both types of recordings are bipolar, except that the two poles are much more widely spaced in unipolar electrodes. Unipolar recordings more accurately represent the timing of local activation https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 4/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate but are fraught with the detection of far-field signals due to the wide separation of the two poles. Bipolar signals do not suffer from the problem of recording far-field signals, and that is why they are more widely employed in mapping. Since extracellular potential decreases inversely with the square of the distance from a point source [10], far-field events generate relatively low amplitude signals compared with electrogram components generated by near- field sources in unipolar recordings. Establishing electrogram criteria, which permits accurate determination of the moment of myocardial activation at the recording electrode, is critical for construction of an area map of the activation sequence. Unipolar recording For unipolar recording, the point of maximum amplitude, the zero crossing, the point of maximum slope (maximum first derivative), and the minimum second derivative of the electrogram have been proposed as indicators for underlying myocardial activation [11,12]. Most studies have suggested that local activation is best determined from the unipolar electrogram by the point with maximum slope (maximum change in potential, or dV/dt) [13,14]. Using this fiducial point, errors in determining the local activation time as compared with intracellular recordings have been typically less than 1 millisecond [12]. Bipolar recording Algorithms for detecting local activation time from bipolar electrograms have been more problematic, due in part to generation of the bipolar electrogram by two spatially separated recording poles. Among several options, the absolute maximum electrogram amplitude appears to most consistently correlate with local activation time determined by other means [12]. Equipment The necessary equipment for mapping includes special catheters and an appropriate recording device. A large number of multipolar electrode catheters have been developed to facilitate desired catheter positioning and to fulfill various recording requirements. These include, among others, bipolar or quadripolar electrode catheters, multipolar recording electrode catheters, "halo" catheters used for mapping, small caliber electrode catheters, circular/spiral electrode catheters, a "flower" catheter (which has 20 electrodes on five radiating spines in a branching configuration), basket electrodes which can conform to the size and shape of the chamber, and steerable catheters [15-19]. For digital recording systems, the sampling rate should be at least twice as fast as the highest frequency component of the signal in order to avoid aliasing (the Nyquist limit). For practical purposes of activation mapping, however, sampling rates of 1000 Hz are generally adequate. Endocardial mapping techniques The simplest form of mapping is achieved by moving the single electrode sequentially to various points of interest on the endocardium in order to https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 5/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate measure local activation. The success of roving single point mapping is predicated upon the sequential beat-by-beat stability of the activation sequence being mapped and the ability of the patient to tolerate the sustained arrhythmia. However, this situation may not be present in certain settings such as mapping of polymorphic ventricular tachycardia (VT) or a monomorphic VT that has a repetitive sequence of endocardial activation, but is hemodynamically too unstable to allow time for complete roving of the endocavitary catheter in the electrophysiology laboratory. Mapping simultaneously from as many sites as possible greatly enhances the precision, detail, and speed of identifying regions of interest. The more sites that are simultaneously mapped, the less roving of a single point is required. Other types of mapping are available for use depending on the clinical situation and type(s) of arrhythmias being investigated. These include activation sequence mapping, pace mapping ( waveform 4A-B), entrainment mapping ( waveform 5), voltage mapping, and use of the dominant frequency and fractionated local electrogram. A detailed discussion of these techniques is beyond the scope of this topic but is discussed elsewhere [20]. Limitations of endocardial mapping The site of origin of the tachycardia may not be reachable from the endocardial approach. As an example, animal and human studies have shown that approximately one-third of VTs due to ischemic heart disease are generated within midmyocardial, subepicardial, or intraseptal regions; critical sites of VT origin in patients with inferior infarction without aneurysms are more likely to be located in the subepicardium [21-24]. Another limitation is that focal and presumably nonreentrant mechanisms of VT are not infrequent, even in the setting of ischemic heart disease with aneurysms. Epicardial ventricular mapping In a subset of patients in whom an endocardial approach is unsuccessful, the critical portion of the arrhythmia circuit may be located epicardially [25-27]. VT that cannot be successfully mapped by an endocardial approach, suggesting an epicardial origin, appears to be more common in patients with a nonischemic dilated cardiomyopathy. Epicardial ventricular mapping can be performed with special recording catheters that can be steered in the branches of the coronary sinus. It may be particularly important in identifying right ventricular outflow tract VTs, which may be difficult to ablate with the endocardial approach only. Another epicardial mapping technique using a subxiphoid percutaneous approach for accessing the epicardial surface has been used to map ventricular arrhythmias [27,28]. Electroanatomical mapping Electroanatomical (or electromagnetic) mapping, which is available in many electrophysiology (EP) laboratories, is based upon the use of a special catheter with a locatable sensor tip, connected to a mapping and navigation system [29,30]. The system https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 6/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate can generate isochrones of electrical activity as color-coded static maps or animated dynamic maps of activation wavefront. These pictures can define reentrant circuits as well as the site of origin or breakthrough of an ectopic activity with centrifugal, monoregional, or asymmetric spread of electrical activity ( image 1A-C and image 2). A major advantage of three-dimensional electroanatomical mapping is its ability to allow the catheter to anatomically and accurately "revisit" a critically important recording site, identified previously during the study, even if the tachycardia is no longer present or inducible and map- guided catheter navigation is no longer possible. This accurate repositioning can allow pace mapping from or further application of radiofrequency current to critically important sites that otherwise cannot be performed with a high degree of accuracy and reproducibility. The electroanatomical map can be integrated with other imaging modalities. In order to reduce the need for point-by-point reconstruction of the cardiac anatomy, systems have been developed to import and merge a three-dimensional computed tomography (CT) or magnetic resonance (MR) image of the heart obtained pre-procedurally with the electroanatomical map generated during the procedure [31]. Future mapping systems will likely use real-time imaging to create an accurate dynamic chamber image during intracardiac mapping [32]. Noncontact mapping The noncontact catheter available for clinical use is a multielectrode array mounted on a balloon tipped catheter. The balloon can be filled with contrast dye, permitting it to be visualized fluoroscopically [18,19,33]. The location of any conventional mapping catheter with respect to this multielectrode array can be determined by passing a high frequency, low current locator signal by a process described and validated previously [33]. The multielectrode array has been deployed in all four cardiac chambers using a transvenous, transseptal, or retrograde transaortic approach in order to map atrial tachyarrhythmias and VT [19,34,35]. Systemic anticoagulation is critical to avoid thromboembolic complications. It has been argued that the biggest advantage of noncontact endocardial mapping is its ability to recreate the endocardial activation sequence from simultaneously acquired multiple data points over a few (theoretically one) tachycardia beats, obviating the need for prolonged tachycardia episodes that the patient may tolerate poorly. Anatomic localization Mapping of the arrhythmia prior to performing an ablation is not required for all arrhythmias. Anatomic approaches to ablation are used when the arrhythmia has a known anatomic course. As an example, in typical or common type I atrial flutter, the wave front must proceed through the isthmus of tissue between the tricuspid annulus (TA) and inferior vena cava (IVC). Thus, ablation is directed largely anatomically, with the goal of delivering a continuous series of RF lesions to create an ablation line of complete bidirectional https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 7/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate conduction block between the TA and IVC ( waveform 6A-B) [36]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) There are several approaches to ablation for management atrial fibrillation (AF). All of these approaches incorporate an understanding of left atrial anatomy, and some are entirely anatomically based. Ablation for AF focuses on the elimination of triggers for AF via electrical isolation of the pulmonary vein ostia from the body of the left atrium, and sometimes also includes additional lesions made in the body of the left atrium to modify arrhythmic substrate. Advanced imaging techniques (eg, intracardiac echo, electroanatomic mapping, and three- dimensional CT reconstructions) are generally used to facilitate this procedure. The approach to AF ablation is discussed in greater detail separately. (See "Atrial fibrillation: Catheter ablation".) ENERGY SOURCES USED FOR ABLATION DC energy DC energy, delivered during general anesthesia, was the initial energy source used for catheter ablation. However, DC shock ablation, or fulguration, never achieved widespread use because of a high incidence of complications related to the high energy discharge. The procedure has not been used for many years and is of only historical interest. RF energy Radiofrequency (RF) energy, low voltage high frequency electrical energy (30 KHz to 1.5 MHz), is generally delivered from the tip of a catheter to the endocardial surface. RF energy produces controlled focal tissue ablation, as compared with the more extensive damage caused by DC fulguration. Initially, the magnitude and duration of RF ablation were limited by progressive heating of the catheter, leading to the formation of an insulating coagulum of denatured tissue proteins on the catheter tip. In 1995, RF ablation was further refined by the use of saline irrigation to cool the RF catheter tip [37]. This technique prevents tissue coagulum formation and makes larger RF lesions feasible. Saline cooling increased the efficacy of RF ablation in subsequent clinical studies [38-41]. In selected cases, RF energy may be applied to the epicardial surface via a pericardial approach. Since RF energy does not directly stimulate nerves or myocardium, the procedure is usually relatively painless and general anesthesia is not necessary. Cryothermal energy Even though RF energy is vastly superior to and safer than DC energy, efforts continue to identify alternate energy sources for catheter ablation. Microwave energy has been tested in animal models [42]. Cryothermal ablation offers the potential benefit of reversible cold mapping; if mild cooling has the intended effect, more profound freezing can inflict permanent tissue damage [43-46]. If limited cooling has an untoward effect or no effect at all, the tissue is allowed to thaw without permanent damage. https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 8/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Pulsed field ablation A new ablation modality, pulsed field ablation (PFA) [47] holds promise for the treatment of AF [48] and perhaps other arrhythmias, such as VT. PFA uses a series of very brief, high-amplitude electrical pulses to desiccate tissue by electroporation of the sarcolemmal membrane without significantly heating the tissue. Moreover, this energy form seems to be specific to myocardial tissue, as other tissues seem to be resistant to this modality. PFA systems are approved for use in Europe (CE Mark), and are undergoing clinical trials in the United States. COMPLICATIONS The potential risks and benefits of the ablation procedure include those risks associated with an invasive electrophysiology study (EP study) alone ( table 2). Generally, risks are lower in experienced operators and centers that perform larger numbers of procedures. These risks are discussed in greater detail separately. (See "Invasive diagnostic cardiac electrophysiology studies", section on 'Complications of invasive cardiac electrophysiology studies'.) Incidence The overall incidence of peri-procedural complications following catheter ablation is approximately 3 percent [9,49-51]. This was shown in a systematic review and meta-analysis of 192 studies including 83,236 patients undergoing catheter ablation for atrial fibrillation (AF) between 2000 and 2012, in which the overall incidence of periprocedural complications was 2.9 percent [51]. The acute complication rate declined over time, dropping to 2.6 percent on ablations performed from 2007 to 2012 compared with 4.0 percent from 2000 to 2006 [51]. Major complication rates can vary significantly depending on the type of ablation procedure (0.8 percent for supraventricular tachycardia, 3.4 percent for idiopathic ventricular tachycardia (VT), 5.2 percent for AF, and 6 percent for VT with structural heart disease) [50]. The potential risks and approximate incidences are similar in younger and older patients and include [52-54]: Death (approximately 0.1 to 0.3 percent). Heart block requiring permanent pacemaker (1 to 2 percent). (See 'Heart block' below.) Thromboembolism, including stroke, systemic embolism, pulmonary embolism (<1 percent). Complications related to vascular access (2 to 4 percent), including bleeding, infection, hematoma, and vascular injury. (See "Peripheral venous access in adults", section on 'Complications'.) https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 9/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Cardiac trauma, including myocardial perforation, tamponade, infarction, coronary artery dissection or embolism, valvular damage (1 to 2 percent). (See 'Troponin I and BNP' below.) New arrhythmias. (See 'New arrhythmias' below.) Radiation exposure. (See 'Radiation exposure' below.) Pulmonary hypertension due to pulmonary vein stenosis following pulmonary vein isolation for AF. (See "Atrial fibrillation: Catheter ablation", section on 'Pulmonary vein stenosis'.) Phrenic nerve injury following sinus node modification for inappropriate sinus tachycardia (IST) or AF ablation, particularly cryoablation. Esophageal injury following catheter ablation for AF. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) Heart block Heart block requiring the placement of a permanent pacemaker is relatively rare, occurring in less than 1 to 2 percent of procedures [55,56]. Atrioventricular (AV) block may not be immediately observed but may progress following the procedure. However, this is extremely rare in patients who did not have transient AV block during the ablation. The use of cryothermal ablation of the slow pathway is an approach that may reduce the potential for AV block; the ability to test prospective ablation sites before permanent destruction can prevent this inadvertent complication [45]. Radiation exposure Because of the risks of radiation exposure, clinicians and staff should be vigilant to try and minimize radiation exposure to the patient as well as the staff [57]. Newer imaging and mapping techniques have reduced fluoroscopy times, particularly during complex ablations as for AF. Pulse fluoroscopy and optimization of fluoroscopy exposure parameters also reduces the risk of radiation injury. Radiation exposure and its potential effects and manifestations are discussed in detail separately. (See "Radiation-related risks of imaging" and "Radiation dose and risk of malignancy from cardiovascular imaging".) New arrhythmias New arrhythmias are a potential concern, since radiofrequency lesions themselves might serve as arrhythmogenic foci. While this is a possibility, this problem has been seen clinically in only a few settings. New AF has occurred in patients undergoing ablation for atrial flutter; it is possible, however, that this occurs primarily in patients predisposed to AF [58]. Incomplete ablation lines in patients treated for AF may lead to left atrial flutter, which in some cases can cause more severe symptoms than the original AF. https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 10/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate An inappropriate sinus tachycardia may be present in some patients after posteroseptal accessory pathway or AV nodal modification for AVNRT, suggesting disruption of the parasympathetic and/or sympathetic inputs into the sinus and AV nodes [59-61]. When this occurs, it is typically relatively mild and transient. Ventricular fibrillation has been reported in up to 6 percent of patients with chronic AF after AV nodal ablation when the pacing rate is 70 beats per minute [62]. This complication can be minimized by post-ablation pacing for three months at a higher rate (ie, 90 beats per minute). A possible mechanism for post-ablation ventricular arrhythmia is activation of the sympathetic nervous system and a prolongation in action potential duration; pacing at a rate of 90 beats per minute decreases sympathetic nervous system activity [63]. Troponin I and BNP The degree of myocardial injury is more accurately assessed by serum troponin levels than CK-MB [64,65]. Elevated troponin I, present in up to 68 percent of patients undergoing ablation, correlates with the number of radiofrequency lesions applied, the site of lesions (ventricular > atrial > annular), and the approach to the left side (transaortic > transseptal) [64]. The prognostic significance of asymptomatic elevations of troponin I remains unclear. As such, we do not routinely monitor cardiac enzymes following electrical cardioversion in asymptomatic patients. Similarly, mild elevations of brain natriuretic peptide (BNP), also of uncertain clinical significance, have been noted following ablation procedures. In a series of 36 patients undergoing ablation for supraventricular tachycardia, a transient rise in BNP was noted [66]. From a baseline of 11.3 pg/mL, BNP peaked three hours post-procedure at 40 pg/mL and approached baseline 24 hours post-procedure. This rise correlated closely with modest troponin I elevations, as well as with the duration of ventricular stimulation and total RF energy application. Iatrogenic atrial septal defect Some catheter ablation procedures require crossing the atrial septum with placement of sheaths/catheters. An iatrogenic atrial septal defect may persist in 5 to 20 percent of patients 9 to 12 months after the procedure [67,68]. It is possible but unproven that the use of an oral anticoagulant may reduce the risk of paradoxical embolism, particularly in those with a cardiac implantable electronic device (eg, pacemakers and implantable cardioverter defibrillators). INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 11/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Catheter ablation for the heart (The Basics)") Beyond the Basics topic (see "Patient education: Catheter ablation for abnormal heartbeats (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Catheter ablation either using radiofrequency or cryothermal energy has emerged as a major tool for the non-pharmacological management of the vast majority of arrhythmias that are refractory to antiarrhythmic drug therapy for arrhythmias that are symptomatic and/or may have an untoward effect on cardiac function. (See 'Introduction' above.) In most supraventricular tachycardias (atrioventricular reentrant tachycardia [AVRT] or AV nodal reentrant tachycardia [AVNRT], in atrial flutter, and in macroreentrant or focal atrial tachycardias) and in idiopathic ventricular ectopy/tachycardia, the success rates are high. Catheter ablation of atrial fibrillation is increasingly offered to drug-refractory symptomatic patients with paroxysmal tachycardia and selected patients with persistent atrial fibrillation with the aim of isolating the pulmonary vein where most ectopic foci are located and/or to modify the anatomic left atrial substrate ( table 1). (See 'Indications and clinical use' above.) For life-threatening ventricular tachyarrhythmias (ventricular tachycardias and ventricular fibrillation), the mainstay treatment is the implantable cardioverter-defibrillator (ICD) alone or in combination of pharmacological therapy for the prevention of arrhythmia episodes. Catheter ablation may be useful in reducing the frequency of appropriate ICD discharges and to improve patient quality of life or to treat the arrhythmia storm in patients with ICD. The potential risks and benefits of the ablation procedure include those risks associated with an invasive electrophysiology study (EP study) alone ( table 2). Generally, risks are https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 12/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate lower in experienced operators and centers that perform larger numbers of procedures. (See 'Complications' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Bradley Knight, MD, FACC, Mark Link, MD, Brian Olshansky, MD, and Leonard Ganz, MD, FHRS, FACC, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. 3. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2016; 67:e27. 4. Narula OS. Sinus node re-entry: a mechanism for supraventricular tachycardia. Circulation 1974; 50:1114. 5. Gomes JA, Mehta D, Langan MN. Sinus node reentrant tachycardia. Pacing Clin Electrophysiol 1995; 18:1045. 6. Krahn AD, Yee R, Klein GJ, Morillo C. Inappropriate sinus tachycardia: evaluation and therapy. J Cardiovasc Electrophysiol 1995; 6:1124. 7. Ueng KC, Lee SH, Wu DJ, et al. Radiofrequency catheter modification of atrioventricular junction in patients with COPD and medically refractory multifocal atrial tachycardia. Chest 2000; 117:52. 8. Tracy CM, Akhtar M, DiMarco JP, et al. American College of Cardiology/American Heart Association 2006 update of the clinical competence statement on invasive https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 13/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate electrophysiologystudies,catheterablation,andcardioversion: a report of the American College of Cardiology/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training developed in collaboration with the Heart Rhythm Society. J Am Coll Cardiol 2006; 48:1503. 9. Tanawuttiwat T, Nazarian S, Calkins H. The role of catheter ablation in the management of ventricular tachycardia. Eur Heart J 2016; 37:594. 10. Plonsey R. Bioelectric Phenomenon, McGraw-Hill, New York 1969. 11. Biermann M, Shenasa M, Borggrefe M, et al. The interpretation of cardiac electrograms. In: Cardiac mapping, Shenasa M, Borggrefe M, Breithardt G (Eds), Futura, Mount Kisco, NY 199 3. p.11. 12. Anderson KP, Walker R, Fuller M, et al. Criteria for local myocardial electrical activation: effects of electrogram characteristics. IEEE Trans Biomed Eng 1993; 40:169. 13. Damiano RJ Jr, Blanchard SM, Asano T, et al. Effects of distant potentials on unipolar electrograms in an animal model utilizing the right ventricular isolation procedure. J Am Coll Cardiol 1988; 11:1100. 14. Claydon FJ 3rd, Pilkington TC, Ideker RE. Classification of heart tissue from bipolar and unipolar intramural potentials. IEEE Trans Biomed Eng 1985; 32:513. 15. Ha ssaguerre M, Hocini M, Sanders P, et al. Localized sources maintaining atrial fibrillation organized by prior ablation. Circulation 2006; 113:616. 16. Rodriguez E, Man DC, Coyne RF, et al. Type I atrial flutter ablation guided by a basket catheter. J Cardiovasc Electrophysiol 1998; 9:761. 17. Schmitt C, Zrenner B, Schneider M, et al. Clinical experience with a novel multielectrode basket catheter in right atrial tachycardias. Circulation 1999; 99:2414. 18. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: comparison of contact and reconstructed electrograms during sinus rhythm. Circulation 1998; 98:887. 19. Schilling RJ, Peters NS, Davies DW. Feasibility of a noncontact catheter for endocardial mapping of human ventricular tachycardia. Circulation 1999; 99:2543. 20. Josephson ME. Catheter and surgical ablation in the therapy of arrhythmias. In: Clinical Card iac Electrophysiology, 4th, Lippincott, Philadelphia 2008. p.746. 21. Downar E, Harris L, Mickleborough LL, et al. Endocardial mapping of ventricular tachycardia in the intact human ventricle: evidence for reentrant mechanisms. J Am Coll Cardiol 1988; 11:783. https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 14/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate 22. Downar E, Kimber S, Harris L, et al. Endocardial mapping of ventricular tachycardia in the intact human heart. II. Evidence for multiuse reentry in a functional sheet of surviving myocardium. J Am Coll Cardiol 1992; 20:869. 23. Garan H, Fallon JT, Rosenthal S, Ruskin JN. Endocardial, intramural, and epicardial activation patterns during sustained monomorphic ventricular tachycardia in late canine myocardial infarction. Circ Res 1987; 60:879. 24. Kramer JB, Saffitz JE, Witkowski FX, Corr PB. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985; 56:736. 25. Sosa E, Scanavacca M. Epicardial mapping and ablation techniques to control ventricular tachycardia. J Cardiovasc Electrophysiol 2005; 16:449. 26. Desai AD, Burke MC, Hong TE, et al. Termination of epicardial left ventricular tachycardia by pacing without global capture. J Cardiovasc Electrophysiol 2005; 16:92. 27. Schweikert RA, Saliba WI, Tomassoni G, et al. Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations. Circulation 2003; 108:1329. 28. Sosa E, Scanavacca M, D'Avila A, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc Electrophysiol 1998; 9:229. 29. Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart. In vitro and in vivo accuracy results. Circulation 1997; 95:1611. 30. Ben-Haim SA, Osadchy D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and mapping
nodal reentrant tachycardia [AVNRT], in atrial flutter, and in macroreentrant or focal atrial tachycardias) and in idiopathic ventricular ectopy/tachycardia, the success rates are high. Catheter ablation of atrial fibrillation is increasingly offered to drug-refractory symptomatic patients with paroxysmal tachycardia and selected patients with persistent atrial fibrillation with the aim of isolating the pulmonary vein where most ectopic foci are located and/or to modify the anatomic left atrial substrate ( table 1). (See 'Indications and clinical use' above.) For life-threatening ventricular tachyarrhythmias (ventricular tachycardias and ventricular fibrillation), the mainstay treatment is the implantable cardioverter-defibrillator (ICD) alone or in combination of pharmacological therapy for the prevention of arrhythmia episodes. Catheter ablation may be useful in reducing the frequency of appropriate ICD discharges and to improve patient quality of life or to treat the arrhythmia storm in patients with ICD. The potential risks and benefits of the ablation procedure include those risks associated with an invasive electrophysiology study (EP study) alone ( table 2). Generally, risks are https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 12/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate lower in experienced operators and centers that perform larger numbers of procedures. (See 'Complications' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Bradley Knight, MD, FACC, Mark Link, MD, Brian Olshansky, MD, and Leonard Ganz, MD, FHRS, FACC, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. 3. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2016; 67:e27. 4. Narula OS. Sinus node re-entry: a mechanism for supraventricular tachycardia. Circulation 1974; 50:1114. 5. Gomes JA, Mehta D, Langan MN. Sinus node reentrant tachycardia. Pacing Clin Electrophysiol 1995; 18:1045. 6. Krahn AD, Yee R, Klein GJ, Morillo C. Inappropriate sinus tachycardia: evaluation and therapy. J Cardiovasc Electrophysiol 1995; 6:1124. 7. Ueng KC, Lee SH, Wu DJ, et al. Radiofrequency catheter modification of atrioventricular junction in patients with COPD and medically refractory multifocal atrial tachycardia. Chest 2000; 117:52. 8. Tracy CM, Akhtar M, DiMarco JP, et al. American College of Cardiology/American Heart Association 2006 update of the clinical competence statement on invasive https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 13/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate electrophysiologystudies,catheterablation,andcardioversion: a report of the American College of Cardiology/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training developed in collaboration with the Heart Rhythm Society. J Am Coll Cardiol 2006; 48:1503. 9. Tanawuttiwat T, Nazarian S, Calkins H. The role of catheter ablation in the management of ventricular tachycardia. Eur Heart J 2016; 37:594. 10. Plonsey R. Bioelectric Phenomenon, McGraw-Hill, New York 1969. 11. Biermann M, Shenasa M, Borggrefe M, et al. The interpretation of cardiac electrograms. In: Cardiac mapping, Shenasa M, Borggrefe M, Breithardt G (Eds), Futura, Mount Kisco, NY 199 3. p.11. 12. Anderson KP, Walker R, Fuller M, et al. Criteria for local myocardial electrical activation: effects of electrogram characteristics. IEEE Trans Biomed Eng 1993; 40:169. 13. Damiano RJ Jr, Blanchard SM, Asano T, et al. Effects of distant potentials on unipolar electrograms in an animal model utilizing the right ventricular isolation procedure. J Am Coll Cardiol 1988; 11:1100. 14. Claydon FJ 3rd, Pilkington TC, Ideker RE. Classification of heart tissue from bipolar and unipolar intramural potentials. IEEE Trans Biomed Eng 1985; 32:513. 15. Ha ssaguerre M, Hocini M, Sanders P, et al. Localized sources maintaining atrial fibrillation organized by prior ablation. Circulation 2006; 113:616. 16. Rodriguez E, Man DC, Coyne RF, et al. Type I atrial flutter ablation guided by a basket catheter. J Cardiovasc Electrophysiol 1998; 9:761. 17. Schmitt C, Zrenner B, Schneider M, et al. Clinical experience with a novel multielectrode basket catheter in right atrial tachycardias. Circulation 1999; 99:2414. 18. Schilling RJ, Peters NS, Davies DW. Simultaneous endocardial mapping in the human left ventricle using a noncontact catheter: comparison of contact and reconstructed electrograms during sinus rhythm. Circulation 1998; 98:887. 19. Schilling RJ, Peters NS, Davies DW. Feasibility of a noncontact catheter for endocardial mapping of human ventricular tachycardia. Circulation 1999; 99:2543. 20. Josephson ME. Catheter and surgical ablation in the therapy of arrhythmias. In: Clinical Card iac Electrophysiology, 4th, Lippincott, Philadelphia 2008. p.746. 21. Downar E, Harris L, Mickleborough LL, et al. Endocardial mapping of ventricular tachycardia in the intact human ventricle: evidence for reentrant mechanisms. J Am Coll Cardiol 1988; 11:783. https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 14/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate 22. Downar E, Kimber S, Harris L, et al. Endocardial mapping of ventricular tachycardia in the intact human heart. II. Evidence for multiuse reentry in a functional sheet of surviving myocardium. J Am Coll Cardiol 1992; 20:869. 23. Garan H, Fallon JT, Rosenthal S, Ruskin JN. Endocardial, intramural, and epicardial activation patterns during sustained monomorphic ventricular tachycardia in late canine myocardial infarction. Circ Res 1987; 60:879. 24. Kramer JB, Saffitz JE, Witkowski FX, Corr PB. Intramural reentry as a mechanism of ventricular tachycardia during evolving canine myocardial infarction. Circ Res 1985; 56:736. 25. Sosa E, Scanavacca M. Epicardial mapping and ablation techniques to control ventricular tachycardia. J Cardiovasc Electrophysiol 2005; 16:449. 26. Desai AD, Burke MC, Hong TE, et al. Termination of epicardial left ventricular tachycardia by pacing without global capture. J Cardiovasc Electrophysiol 2005; 16:92. 27. Schweikert RA, Saliba WI, Tomassoni G, et al. Percutaneous pericardial instrumentation for endo-epicardial mapping of previously failed ablations. Circulation 2003; 108:1329. 28. Sosa E, Scanavacca M, D'Avila A, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc Electrophysiol 1998; 9:229. 29. Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheter-based electroanatomical mapping of the heart. In vitro and in vivo accuracy results. Circulation 1997; 95:1611. 30. Ben-Haim SA, Osadchy D, Schuster I, et al. Nonfluoroscopic, in vivo navigation and mapping technology. Nat Med 1996; 2:1393. 31. P rez-Castellano N, Villacast n J, Moreno J, et al. Errors in pulmonary vein identification and ostia location in the absence of pulmonary vein imaging. Heart Rhythm 2005; 2:1082. 32. Packer DL. Evolution of mapping and anatomic imaging of cardiac arrhythmias. J Cardiovasc Electrophysiol 2004; 15:839. 33. Schilling RJ, Peters NS, Davies DW. Noncontact mapping of cardiac arrhythmias. J Electrocardiol 1999; 32 Suppl:13. 34. Schneider MA, Ndrepepa G, Zrenner B, et al. Noncontact mapping-guided catheter ablation of atrial fibrillation associated with left atrial ectopy. J Cardiovasc Electrophysiol 2000; 11:475. 35. Schilling RJ, Kadish AH, Peters NS, et al. Endocardial mapping of atrial fibrillation in the human right atrium using a non-contact catheter. Eur Heart J 2000; 21:550. https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 15/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate 36. Cosio FG, Arribas F, Lopez-Gil M, Gonzalez HD. Radiofrequency ablation of atrial flutter. J Cardiovasc Electrophysiol 1996; 7:60. 37. Ruffy R, Imran MA, Santel DJ, Wharton JM. Radiofrequency delivery through a cooled catheter tip allows the creation of larger endomyocardial lesions in the ovine heart. J Cardiovasc Electrophysiol 1995; 6:1089. 38. Ja s P, Shah DC, Ha ssaguerre M, et al. Prospective randomized comparison of irrigated-tip versus conventional-tip catheters for ablation of common flutter. Circulation 2000; 101:772. 39. Yamane T, Ja s P, Shah DC, et al. Efficacy and safety of an irrigated-tip catheter for the ablation of accessory pathways resistant to conventional radiofrequency ablation. Circulation 2000; 102:2565. 40. Calkins H, Epstein A, Packer D, et al. Catheter ablation of ventricular tachycardia in patients with structural heart disease using cooled radiofrequency energy: results of a prospective multicenter study. Cooled RF Multi Center Investigators Group. J Am Coll Cardiol 2000; 35:1905. 41. Soejima K, Delacretaz E, Suzuki M, et al. Saline-cooled versus standard radiofrequency catheter ablation for infarct-related ventricular tachycardias. Circulation 2001; 103:1858. 42. Jumrussirikul P, Chen JT, Jenkins M, et al. Prospective comparison of temperature guided microwave and radiofrequency catheter ablation in the swine heart. Pacing Clin Electrophysiol 1998; 21:1364. 43. Skanes AC, Klein G, Krahn A, Yee R. Cryoablation: potentials and pitfalls. J Cardiovasc Electrophysiol 2004; 15:S28. 44. Rodriguez LM, Leunissen J, Hoekstra A, et al. Transvenous cold mapping and cryoablation of the AV node in dogs: observations of chronic lesions and comparison to those obtained using radiofrequency ablation. J Cardiovasc Electrophysiol 1998; 9:1055. 45. Skanes AC, Dubuc M, Klein GJ, et al. Cryothermal ablation of the slow pathway for the elimination of atrioventricular nodal reentrant tachycardia. Circulation 2000; 102:2856. 46. Rodriguez LM, Geller JC, Tse HF, et al. Acute results of transvenous cryoablation of supraventricular tachycardia (atrial fibrillation, atrial flutter, Wolff-Parkinson-White syndrome, atrioventricular nodal reentry tachycardia). J Cardiovasc Electrophysiol 2002; 13:1082. 47. Bradley CJ, Haines DE. Pulsed field ablation for pulmonary vein isolation in the treatment of atrial fibrillation. J Cardiovasc Electrophysiol 2020; 31:2136. 48. Reddy VY, Dukkipati SR, Neuzil P, et al. Pulsed Field Ablation of Paroxysmal Atrial Fibrillation: 1-Year Outcomes of IMPULSE, PEFCAT, and PEFCAT II. JACC Clin Electrophysiol 2021; 7:614. https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 16/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate 49. Calkins H, Yong P, Miller JM, et al. Catheter ablation of accessory pathways, atrioventricular nodal reentrant tachycardia, and the atrioventricular junction: final results of a prospective, multicenter clinical trial. The Atakr Multicenter Investigators Group. Circulation 1999; 99:262. 50. Bohnen M, Stevenson WG, Tedrow UB, et al. Incidence and predictors of major complications from contemporary catheter ablation to treat cardiac arrhythmias. Heart Rhythm 2011; 8:1661. 51. Gupta A, Perera T, Ganesan A, et al. Complications of catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol 2013; 6:1082. 52. Kay GN, Epstein AE, Dailey SM, Plumb VJ. Role of radiofrequency ablation in the management of supraventricular arrhythmias: experience in 760 consecutive patients. J Cardiovasc Electrophysiol 1993; 4:371. 53. Chen SA, Chiang CE, Tai CT, et al. Complications of diagnostic electrophysiologic studies and radiofrequency catheter ablation in patients with tachyarrhythmias: an eight-year survey of 3,966 consecutive procedures in a tertiary referral center. Am J Cardiol 1996; 77:41. 54. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. 55. Katritsis DG, Zografos T, Siontis KC, et al. Endpoints for Successful Slow Pathway Catheter Ablation in Typical and Atypical Atrioventricular Nodal Re-Entrant Tachycardia: A Contemporary, Multicenter Study. J Am Coll Cardiol EP 2019; 5:113. 56. Chrispin J, Misra S, Marine JE, et al. Current management and clinical outcomes for catheter ablation of atrioventricular nodal re-entrant tachycardia. Europace 2018; 20:e51. 57. Heidbuchel H, Wittkampf FH, Vano E, et al. Practical ways to reduce radiation dose for patients and staff during device implantations and electrophysiological procedures. Europace 2014; 16:946. 58. Paydak H, Kall JG, Burke MC, et al. Atrial fibrillation after radiofrequency ablation of type I atrial flutter: time to onset, determinants, and clinical course. Circulation 1998; 98:315. 59. Kocovic DZ, Harada T, Shea JB, et al. Alterations of heart rate and of heart rate variability after radiofrequency catheter ablation of supraventricular tachycardia. Delineation of parasympathetic pathways in the human heart. Circulation 1993; 88:1671. 60. Psychari SN, Theodorakis GN, Koutelou M, et al. Cardiac denervation after radiofrequency ablation of supraventricular tachycardias. Am J Cardiol 1998; 81:725. 61. Hamdan MH, Page RL, Wasmund SL, et al. Selective parasympathetic denervation following posteroseptal ablation for either atrioventricular nodal reentrant tachycardia or accessory https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 17/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate pathways. Am J Cardiol 2000; 85:875. 62. Geelen P, Brugada J, Andries E, Brugada P. Ventricular fibrillation and sudden death after radiofrequency catheter ablation of the atrioventricular junction. Pacing Clin Electrophysiol 1997; 20:343. 63. Hamdan MH, Page RL, Sheehan CJ, et al. Increased sympathetic activity after atrioventricular junction ablation in patients with chronic atrial fibrillation. J Am Coll Cardiol 2000; 36:151. 64. Manolis AS, Vassilikos V, Maounis T, et al. Detection of myocardial injury during radiofrequency catheter ablation by measuring serum cardiac troponin I levels: procedural correlates. J Am Coll Cardiol 1999; 34:1099. 65. Katritsis D, Hossein-Nia M, Anastasakis A, et al. Use of troponin-T concentration and kinase isoforms for quantitation of myocardial injury induced by radiofrequency catheter ablation. Eur Heart J 1997; 18:1007. 66. Chen L, Wei T, Zeng C, et al. Effect of radiofrequency catheter ablation on plasma B-type natriuretic peptide. Pacing Clin Electrophysiol 2005; 28:200. 67. Anselmino M, Scaglione M, Battaglia A, et al. Iatrogenic atrial septal defects following atrial fibrillation transcatheter ablation: a relevant entity? Europace 2014; 16:1562. 68. Madhavan M, Yao X, Sangaralingham LR, et al. Ischemic Stroke or Systemic Embolism After Transseptal Ablation of Arrhythmias in Patients With Cardiac Implantable Electronic Devices. J Am Heart Assoc 2016; 5:e003163. Topic 1007 Version 36.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 18/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate GRAPHICS [1-3] Indications for catheter ablation of arrhythmias Class I Paroxysmal SVT Symptomatic or medical refractory typical atrial flutter Symptomatic WPW Symptomatic PAF refractory to at least one class I/III drug Symptomatic VPBs in the setting of structurally normal heart VPB-induced cardiomyopathy Idiopathic VF induced by unifocal VPBs Idiopathic VT Bundle-branch reentrant VT Recurrent VT in ischemic cardiomyopathy refractory to amiodarone Class IIa Asymptomatic WPW with high-risk features or high-risk occupation Symptomatic PAF prior to treatment with class I/III drug Symptomatic persistent AF refractory to at least one class I/III drug or prior to class I/III drug Recurrent VT in NICM refractory to antiarrhythmic therapy Recurrent VT in adult congenital heart disease refractory to antiarrhythmic therapy Recurrent VT in ARVC refractory to beta blocker Class IIb Long-standing symptomatic persistent AF Select asymptomatic AF Recurrent VT in ischemic cardiomyopathy as an alternative to pharmacologic therapy SVT: supraventricular tachycardia; WPW: Wolff-Parkinson-White syndrome; PAF: paroxysmal atrial fibrillation; VPB: ventricular premature beat; VF: ventricular fibrillation; VT: ventricular tachycardia; AF: https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 19/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate atrial fibrillation; NICM: nonischemic cardiomyopathy; ARVC: arrhythmogenic right ventricular cardiomyopathy. References: 1. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2017. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation. Heart Rhythm 2017; 14:e275. 3. Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2016; 67:e27. Graphic 117234 Version 1.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 20/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Electrocardiogram showing an ectopic atrial tachycardia originating from the tricuspid annulus Electrocardiographic tracing showing a narrow complex tachycardia with uniform P waves consistent with an ectopic atrial tachycardia originating from the tricuspid annulus. Prior to the final QRS complex, there is spontaneous return to normal sinus rhythm with P wave of a different morphology. Courtesy of Peter Kistler, MBBS, FRACP, PhD. Graphic 74611 Version 10.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 21/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Electrocardiogram (ECG) showing atrial tachycardia originating from the left superior pulmonary vein. Electrocardiographic tracing showing a narrow complex tachycardia with uniform P waves consistent with atrial tachycardia originating from the left superior pulmonary vein. The initial QRS complex shows a normal sinus beat, followed by the development of atrial tachycardia. Courtesy of Dr. Peter Kistler. Graphic 57390 Version 3.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 22/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Reentrant circuit of typical atrial flutter within the right atrium Schematic representation of reentrant circuit (red arrow) of typical (type 1) atrial flutter. The reentrant impulse rotates in a counterclockwise direction around the tricuspid annulus. The crista terminalis (CT) and eustacian ridge (ER) serve as lines of block, preventing the impulse from short-circuiting the annulus. Ablation is performed in the isthmus between the IVC and TA, which is an obligatory part of the circuit. SVC: superior vena cava; CS: coronary sinus; IVC: inferior vena cava; FO: foramen ovale Graphic 52904 Version 5.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 23/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Electrocardiogram single-lead multifocal atrial tachycardia Clinical features: Elderly patients Decompensation of pulmonary disease Postoperative Arrhythmia usually does not cause severe hemodynamic compromise High mortality ECG features: P waves have 3 forms Atrial rate is usually 100 to 200 bpm Atrial rate is irregular PR interval varies Isoelectric baseline between P waves May progress to atrial fibrillation ECG: electrocardiogram; bpm: beats per minute. Courtesy of Alfred Buxton, MD. Graphic 127222 Version 1.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 24/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate 12-lead electrocardiogram (ECG) during electrophysiologic study showing pace mapping of an idiopathic RVOT tachycardia Left panel: 12 lead ECG of spontaneous ventricular tachycardia (VT) in a patient with a structurally normal heart. The VT has a left bundle branch block (LBBB) and an inferior axis morphology, suggesting that the origin is in the right ventricular outflow tract (RVOT). Right panel: A mapping catheter has been positioned in the RVOT and pacing is performed from its tip during sinus rhythm. The "pace map" closely approximates the QRS morphology of the spontaneous VT in all 12 leads, suggesting that the mapping catheter is at or near the VT focus. S: pacing stimulus artifact. Graphic 68142 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 25/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate 12-lead ECG showing pace map of ventricular tachycardia The QRS complexes on the twelve-lead ECG, recorded during spontaneous VT provoked by isoproterenol, are identical in each lead to those recorded during ventricular pacing. ECG: electrocardiogram; VT: ventricular tachycardia. Graphic 79938 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 26/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Electrophysiology study (EPS) tracings showing concealed entrainment (A) Pacing from the distal electrode pair of the mapping/ablation catheter during mapping of sustained ventr tachycardia. On the left side of the figure are the last three stimuli during a train of pacing at a cycle length o milliseconds. Following pacing, the tachycardia (cycle length 430 milliseconds) resumes. The interval from the paced beat to resumption of tachycardia, measured in the distal ablation catheter (Abl d), is just 10 millisecon greater than the tachycardia cycle length. Note that the interval from the pacing stimulus to onset of the QRS is the same as the interval from the local electrogram to the QRS onset when VT resumes after pacing. Note a the paced VT morphology replicates the morphology of the spontaneous tachycardia. This is an example of "concealed entrainment" and implies the catheter is within a critical part of a reentrant circuit. (B) Same site on the ablation catheter (Abl d) during sinus rhythm as shown during VT in figure A. During sinu rhythm, a late potential is present. The vertical line denotes the end of the QRS complex. Delivery of radiofreq energy at this site resulted in termination of VT. The tachycardia was no longer inducible after ablation. Sites this displaying late potentials may be targeted during "substrate-guided ablation." VT: ventricular tachycardia. Graphic 107237 Version 2.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 27/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Electroanatomic voltage map from a normal subject The right ventricular (RV) voltage map in the right anterior oblique projection from a normal subject is obtained using electroanatomic mapping. The colors represent the amplitude of the local unipolar electrogram and blue and purple indicated normal unipolar voltage values ( 5 mV) throughout the RV. LA: left atrium; RA: right atrium. Reproduced with permission from: Boulos M, Lashevsky I, Reisner S, Gepstein L. J Am Coll Cardiol 2001; 38:2020. Copyright 2001 American College of Cardiology. http://www.elsevier.com/locate/jacc http://www.sciencedirect.com Graphic 63899 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 28/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Echocardiographic and electroanatomic mapping of the right ventricle in arrhythmogenic right ventricular dysplasia Two-dimensional echocardiographic apical view of a patient with arrhythmogenic right ventricular dysplasia shows severe enlargement of the right ventricle (RV) and right atrium (RA) (panel A). The RV unipolar voltage maps, generated by electroanatomic mapping, are seen in the anteroposterior (panel B) and left anterior oblique views (panel C). There is extensive area of low voltage (red indicates <2 mV) in the apex and anterolateral free wall of the RV, with the septum being spared (purple indicates >5 mV). LA: left atrium; RVOT: RV outflow tract. Reproduced with permission from: Boulos M, Lashevsky I, Reisner S, Gepstein L. J Am Coll Cardiol 2001; 38:2020. Copyright 2001 American College of Cardiology. http://www.elsevier.com/locate/jacc http://www.sciencedirect.com Graphic 54163 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 29/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Typical electroanatomic map of infarcted myocardium The electroanatomic map of a patient with a myocardial infarction shows large regions of abnormal electromechanical activity and reduced local shortening (red, abnormally contracting regions with values <4 percent). In contrast, a region in which function remains unhindered is a color-coded blue/purple, normal contractile function >12 percent. Reprinted with permission from: the American College of Cardiology (Journal of the American College of Cardiology, 2001, 37:1590-7). http://www.elsevier.com/locate/jacc http://www.sciencedirect.com Graphic 57238 Version 3.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 30/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Correlation between electroanatomic map and pathological sections of infarcted heart Panel A shows a section of the left ventricle in a patient with a subendocardial myocardial infarction (arrow). The superimposed colors in the reconstruction from an electroanatomic map (panel B) depict bipolar electrogram amplitude (BEA); purple indicates values >6.1 mV; red indicates values <2.1 mV. Beneath the reconstructed sections (panel C) are typical recordings of unipolar electrogram and derivatives, the unipolar electrogram amplitude (UEA) and slew rate (SR) and bipolar electrogram and amplitude from selected points at the core of the infarcted region (the distance between two white marks on the electrogram time scale denotes a 50-millisecond period). Reprinted with permission from the American College of Cardiology (Journal of the American College of Cardiology, 2001, 37:1590-7). http://www.elsevier.com/locate/jacc http://www.sciencedirect.com https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 31/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Graphic 81609 Version 3.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 32/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study and radiofrequency catheter ablation of typical atrial flutter Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the high right atrium (HRA), a mapping catheter in the isthmus between the tricuspid valve and inferior vena cava (TV-IVC) (HBE1-2), eight recordings from a catheter extending from the lateral right atrial wall through the TV-IVC isthmus and into the ostium of the coronary sinus (CS15-1 to CS1-2), and right ventricular apex (RVA3-4) in a patient with typical atrial flutter. The tip of the mapping catheter was initially positioned on the tricuspid annulus, and then dragged through the TV-IVC isthmus to the ostium of the IVC during RF application; atrial flutter terminated. Note that the atrial activation (A) blocks between CS7-8 and CS5-6, which on fluoroscopy corresponded to the position of the mapping catheter. Fl: flutter waves; V: ventricular electrogram. Graphic 69946 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 33/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Intracardiac and surface electrocardiogram (ECG) recordings during electrophysiologic study and radiofrequency catheter ablation of atrial flutter showing bidirectional isthmus block Shown are three surface ECG leads (I, aVF, V1) and intracardiac recordings from the high right atrium (HRA), eight recordings from a catheter extending from the lateral right atrial wall through the tricuspid valve-inferior vena cava (TV- IVC) isthmus and into the ostium of the coronary sinus (CS15-16 through CS1- 2), and right ventricular apex (RVA3-4) in a patient who has undergone ablation for atrial flutter. Left panel shows pacing (PA) from the lateral right atrial wall; the impulse is propagated down the lateral wall of the high right atrium, generating an atrial electrogram (A), to the lateral TV-IVC isthmus region (CS13- 14, CS11-12, CS9-10) where conduction is blocked. The medial aspect of the isthmus is not depolarized until a wavefront of activation comes down the interatrial septum or from the low left atrium; the distal poles of the catheter are therefore depolarized late and in the opposite direction, from the coronary sinus ostium back towards the medial TV-IVC isthmus (CS3-4, CS5-6, CS7-8). Right panel shows pacing from the coronary sinus ostium. In this case, the medial isthmus is depolarized promptly (CS3-4, CS5-6), but conduction is blocked within the isthmus (CS7-8). Thus, activation of the lateral wall of the right atrium is delayed until a wavefront travels up the septum and across the roof of the right atrium. Activation of the proximal poles of the catheter is therefore delayed and occurs from high to low (CS15-16, CS13-14, CS11-12, https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 34/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate CS9-10). Patients with bidirectional block across the TC-IVC isthmus have a low rate of atrial flutter recurrence. Graphic 60090 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 35/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Complications of invasive cardiac electrophysiology studies Associated with percutaneous catheterization of veins and arteries Pain Adverse drug reaction Infection/abscess at the catheterization site, sepsis Excessive bleeding, hematoma formation Thrombophlebitis Pulmonary thromboembolism Arterial damage, aortic dissection Systemic thromboembolism Transient ischemic attack/stroke Associated with intracardiac catheters and programmed cardiac stimulation Cardiac chamber or coronary sinus perforation Hemopericardium, cardiac tamponade Atrial fibrillation Ventricular tachycardia/ventricular fibrillation Myocardial infarction Right or left bundle branch block Associated with transcatheter ablation Complete heart block Thromboembolism Vascular access problems (bleeding, infection, hematoma, vascular injury) Cardiac trauma (myocardial perforation, tamponade, valvular damage) Coronary artery thrombosis/myocardial infarction Cardiac arrhythmias Pericarditis Pulmonary vein stenosis Phrenic nerve paralysis Radiation skin burns Possible late malignancy Atrioesophageal fistula https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 36/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Death resulting from one of the above complications Graphic 63157 Version 4.0 https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 37/38 7/5/23, 8:12 AM Overview of catheter ablation of cardiac arrhythmias - UpToDate Contributor Disclosures Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-catheter-ablation-of-cardiac-arrhythmias/print 38/38
7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Amiodarone: Adverse effects, potential toxicities, and approach to monitoring : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA, Rod Passman, MD, MSCE : Mark S Link, MD, Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 24, 2021. INTRODUCTION Amiodarone has multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. Its primary effect is to block the potassium channels, but it can also block sodium and calcium channels and the beta and alpha adrenergic receptors. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Long-term use of oral amiodarone has been associated with a relatively high incidence of adverse effects that can range in severity from mild to potentially lethal. While long-term contemporary use of amiodarone has generally been at lower doses (200 to 300 mg/day) than were historically used, even low doses may be associated with significant adverse effects, particularly pulmonary, thyroid, cardiac, skin, and ocular toxicities. Many of these effects are due to the tissue accumulation of amiodarone with long-term oral therapy and are not seen with short-term intravenous therapy. The major adverse effects of amiodarone, along with the approach to baseline testing and serial monitoring, will be reviewed here. The clinical uses of amiodarone, including recommendations for its use in the treatment of various arrhythmias, are discussed separately. (See "Amiodarone: Clinical uses" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Supportive data for advanced cardiac life support in adults with sudden cardiac arrest", section on 'Amiodarone'.) https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 1/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate WHY IS MONITORING NECESSARY? The long half-life of oral amiodarone (25 to 100 days) and the potential severity and irreversible nature of some the adverse effects make early recognition of any potential adverse effects important. As a result, baseline testing and careful monitoring of patients taking amiodarone is essential. The need for baseline testing and monitoring depends on the route of administration and anticipated dose and duration of therapy. Many of the adverse effects associated with oral amiodarone are due to tissue accumulation of the drug with long-term therapy and are not seen with short-term use of intravenous amiodarone [1]. If only short term use is anticipated (eg, to prevent perioperative atrial fibrillation in patient undergoing cardiac surgery, cardioversion in a critically ill patient), no serial monitoring is typically needed, whereas patients in whom long- term use is anticipated should undergo appropriate baseline testing and serial monitoring. Intravenous (IV) amiodarone is generally used in the management of life-threatening ventricular arrhythmias or in critically ill patients with atrial fibrillation. Patients receiving IV amiodarone are generally on continuous electrocardiographic (ECG) monitoring with frequent assessment of vital signs. Such monitoring is appropriate in all patients due to the potential for hypotension and arrhythmias. If only short-term IV use is anticipated without a plan for long-term oral therapy, no baseline testing is required. However, for patients in whom a transition to long-term oral amiodarone is anticipated, the usual baseline laboratories should be obtained ( table 1). (See "Amiodarone: Clinical uses".) ADVERSE EFFECTS OF ORAL AMIODARONE Adverse pulmonary effects Pulmonary toxicity is one of the more common adverse effects of long-term amiodarone and is responsible for most of the rare deaths associated with amiodarone therapy ( table 1). While this issue is discussed in detail separately, a brief overview will be presented here, along with recommendations for baseline testing and serial monitoring. (See "Amiodarone pulmonary toxicity".) Clinical presentation of pulmonary toxicity Initial reports in which patients were usually treated with amiodarone doses 400 mg/day noted a 5 to 15 percent incidence of pulmonary toxicity [2-4]. However, the incidence is closer to 2 percent with lower maintenance doses used in contemporary practice [3,5,6]. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 2/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Pulmonary toxicity generally correlates more closely with the total cumulative dose than with serum drug levels [6]. As a result, pulmonary toxicity usually occurs several months to as late as several years after the initiation of amiodarone therapy [6]. However, there are anecdotal cases of severe pulmonary toxicity developing within two to three weeks of therapy with low cumulative doses [7]. Chronic interstitial pneumonitis is the most common pulmonary toxicity associated with long- term amiodarone therapy. A nonproductive cough and dyspnea are present in 50 of 75 percent of affected individuals at presentation. Pleuritic pain, weight loss, fever (33 to 50 percent of cases), and malaise can also occur. The physical examination often reveals bilateral inspiratory crackles, while clubbing is not seen. (See "Amiodarone pulmonary toxicity", section on 'Clinical manifestations'.) Several other pulmonary toxicities, including eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome, alveolar hemorrhage, and pulmonary nodules, have been reported less frequently. (See "Amiodarone pulmonary toxicity".) Baseline pulmonary testing Recommended baseline testing for patients who are starting long-term therapy with amiodarone consists of only a chest radiograph. There are differing opinions, and no consensus, of obtaining formal pulmonary function tests (PFTs) with assessment of diffusion capacity (ie, diffusion capacity of the lungs for carbon monoxide [DLCO]) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs ( table 1). Serial pulmonary monitoring and symptomatic follow up We perform a yearly chest radiograph for asymptomatic patients as long as they are taking amiodarone; however, we do not perform serial PFTs for asymptomatic patients, as PFTs are not helpful for predicting pulmonary toxicity. However, any patient who develops dyspnea or other symptoms suggestive of possible pulmonary toxicity should have both a chest radiograph and formal PFTs (including DLCO) and, as indicated by abnormal PFT findings, chest computed tomography. (See "Amiodarone pulmonary toxicity", section on 'Evaluation'.) Although DLCO is often decreased in patients with pulmonary toxicity, there is usually no premonitory change in DLCO among asymptomatic patients in whom symptomatic disease subsequently develops. As a result, the DLCO is not useful as a predictive index [8,9]. In one report, for example, most asymptomatic patients with a fall in DLCO of more than 20 percent did not develop pulmonary toxicity over the next year despite continued amiodarone therapy [9]. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 3/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Treatment of pulmonary toxicity The treatment of amiodarone pulmonary toxicity typically involves discontinuing the medication and systemic glucocorticoids. Details regarding treatment are presented separately. (See "Amiodarone pulmonary toxicity", section on 'Treatment'.) Adverse thyroid effects Thyroid dysfunction (including both hypothyroidism and hyperthyroidism) is another common complication of amiodarone therapy ( table 1). While this issue is discussed in detail separately, a brief overview will be presented here along with recommendations for baseline testing and serial monitoring. (See "Amiodarone and thyroid dysfunction".) Clinical presentation of thyroid toxicity Although initial reports using higher doses noted hyperthyroidism or hypothyroidism in up to 20 percent of patients, the risk is lower (approximately 3 to 4 percent) when lower doses are used [5]. Underlying thyroid status and iodine intake appear to influence the incidence and type of thyroid dysfunction seen with amiodarone therapy [10]. The clinical manifestations of hypothyroidism (eg, fatigue, cold intolerance, constipation, weight gain, coarse hair and skin, etc) and hyperthyroidism (eg, restlessness, unexplained weight loss, low-grade fever, hypertension, tachycardia, etc) are similar to thyroid disease from any etiology, although the intrinsic beta blocking properties of amiodarone may mask some of the hyperthyroid symptoms. (See "Clinical manifestations of hypothyroidism" and "Overview of the clinical manifestations of hyperthyroidism in adults".) Baseline thyroid testing and serial monitoring Patients should undergo thyroid function testing prior to initiating treatment with amiodarone, again within three to four months of initiating amiodarone, and every 12 months during chronic amiodarone therapy ( table 1). Typically a thyroid-stimulating hormone (TSH) level can be ordered and, if normal, testing is complete. Follow-up for an abnormal TSH varies depending upon the direction of the TSH abnormality: Elevated TSH (suggesting hypothyroidism) free T4 level Decreased TSH (suggesting hyperthyroidism) free T4 level and total T3 level Consultation with an endocrinologist is often warranted to determine the optimal course of action following abnormal thyroid function testing. Treatment of thyroid dysfunction The treatment of amiodarone-induced thyroid dysfunction is reviewed briefly here but discussed in detail separately. (See "Amiodarone and thyroid dysfunction".) Patients with hypothyroidism can usually be treated with thyroid hormone replacement and maintained on amiodarone. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 4/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Patients with amiodarone-induced hyperthyroidism should be evaluated by, and treated in conjunction with, an endocrinologist. Such patients may benefit from discontinuing amiodarone if no life-threatening arrhythmias are present and other antiarrhythmic options are available. Adverse cardiac effects Clinical presentation of cardiac toxicity Multiple cardiac effects can be seen in patients taking chronic amiodarone therapy ( table 1). Sinus bradycardia is an expected result from amiodarone treatment, but excessive bradycardia or AV block often represents toxicity. Amiodarone does generally lead to prolongation of the QT interval, but this is rarely proarrhythmic. Finally, amiodarone can alter the defibrillation thresholds for patients with implantable cardioverter-defibrillators (ICDs). Bradycardia and AV block Amiodarone can directly cause both sinus bradycardia and AV nodal block, due primarily to its calcium channel blocking activity. The overall incidence of bradycardic events has been approximately 3 to 5 percent [11]. In the meta-analysis of chronic low-dose amiodarone (mean 150 to 330 mg/day), the incidence of bradycardic events was significantly greater than with placebo (3.3 versus 1.4 percent; odds ratio [OR] 2.2, 95% CI 1.1-4.3) [5]. Typically sinus bradycardia results in few or no symptoms, but patients with second or third degree AV block are usually symptomatic with one or more of lightheadedness, presyncope, syncope, dyspnea, or fatigue. QT prolongation and proarrhythmia As with most antiarrhythmic drugs, amiodarone can result in prolongation of the QT interval [12]. However, the incidence of proarrhythmia is lower with amiodarone than other class III drugs (eg, sotalol, ibutilide, and dofetilide), with an incidence of torsades de pointes below 1 percent; the exact electrophysiologic mechanisms responsible for the low proarrhythmic activity of amiodarone remain incompletely understood [4,5,13-15]. In the meta-analysis of low-dose therapy, there were no cases of torsades de pointes in the 738 patients treated with amiodarone for at least one year [5]. Several factors contribute to the rarity of torsades de pointes with amiodarone: lack of reverse use dependence; concurrent blockade of the L-type calcium channels; and less heterogeneity of ventricular repolarization (less QT dispersion). Torsades de pointes associated with amiodarone therapy is more likely to occur in women due to slightly longer average baseline QT intervals in women, and is much more likely to occur with other factors that can cause QT prolongation such as hypokalemia, hypomagnesemia, and concomitant use of other drugs that prolong the QT interval [16]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug- induced long QT syndrome'.) https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 5/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Interaction with ICDs Amiodarone may have important interactions with ICDs. It may slow the ventricular tachycardia rate, possibly precluding its recognition by the device by decreasing the rate of the VT below the VT detection zone, and its major metabolite desethylamiodarone increases the defibrillation threshold in a dose-dependent fashion; this effect is seen with monophasic and biphasic waveforms [17-20]. If amiodarone is initiated in a patient with known elevated defibrillation thresholds (DFTs) or risk factors for elevated DFTs, a noninvasive ICD evaluation should be performed to test for adverse drug- device interactions once loading is complete [11]. Baseline cardiac testing and serial monitoring All patients should have an ECG prior to starting amiodarone therapy and annually for the duration of therapy, or more frequently in response to a change in symptoms ( table 1). Patients with an ICD are followed in accordance with standard practice for device monitoring. (See "Cardiac implantable electronic devices: Patient follow-up".) Management of adverse cardiac effects The management of adverse cardiac effects related to amiodarone varies depending upon the adverse effect and may require dose reduction or discontinuation of amiodarone. Despite dose modification or cessation of amiodarone, cardiac adverse effects may persist due to the drug s long half-life. If the effects are clinically significant, then urgent treatment (eg, pacing) may be required as the amiodarone tissue concentrations decrease. Sinus bradycardia If sinus bradycardia occurs during therapy, amiodarone and other drugs with negative chronotropic effects should be discontinued or dose-reduced, if possible. If amiodarone therapy is necessary and sinus bradycardia persists after medications have been modified, placement of a permanent pacemaker capable of atrial pacing may be required. High grade AV block If high grade (second or third degree) AV block develops during therapy, options include reducing the dose of amiodarone or other medications that cause AV block. If AV block does not resolve despite medication changes, placement of a permanent pacemaker may be necessary. QT prolongation While amiodarone prolongs the QT interval, the authors and editors of this topic agree that amiodarone-induced arrythmias are rare and that amiodarone is generally safe despite mild prolongation of the QT interval. When the QT interval is above 550 milliseconds, we avoid concomitant use of medications that interact with amiodarone metabolism or intrinsically prolong the QT interval [21]. A detailed discussion of https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 6/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate amiodarone-induced arrhythmias can be found separately. (See "Amiodarone: Clinical uses", section on 'Electrophysiologic properties'.) Increased ICD defibrillation threshold If ongoing treatment with amiodarone is required and results in an unacceptably high defibrillation threshold, options include using a high- output device, reprogramming the shock waveform (eg, duration, amplitude), repositioning the lead, or adding a subcutaneous array. Adverse hepatic effects Clinical presentation of hepatotoxicity A transient rise in serum aminotransferase concentrations occurs in approximately 25 percent (range 15 to 50 percent) of patients soon after amiodarone is begun; most patients are asymptomatic with this [22]. Symptomatic hepatitis occurs in less than 3 percent of patients; potential complications include cirrhosis and hepatic failure [22,23]. Jaundice is an unusual adverse effect that may be due to intrahepatic cholestasis [24,25]. Serum bilirubin concentrations may first increase or continue to increase for a period of time after the drug is discontinued [24,25]. These findings are consistent with the long half-life of amiodarone (25 to 100 days). Both direct hepatotoxicity and metabolic idiosyncrasy are thought to contribute to amiodarone-induced hepatic injury [22,26]. Baseline hepatic function assessment and serial monitoring Prior to beginning chronic amiodarone therapy, baseline testing ( table 1) should include serum transaminase levels (ALT and AST). These tests should be repeated every 12 months for the duration of therapy for following the development of signs or symptoms suggesting liver disease [11]. Treatment of hepatic toxicity Although the relation of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity and, therefore, that maintenance doses should be kept as low as possible. In the meta- analysis of chronic low-dose amiodarone (mean 150 to 330 mg/day), the incidence of hepatotoxicity was low and not significantly different from placebo (1.2 versus 0.8 percent; OR 1.2, 95% CI 0.4-3.3) [5]. Amiodarone should be discontinued in most cases if there is more than a twofold elevation in serum transaminase levels from baseline, or in patients diagnosed with hepatitis [11]. Adverse ocular effects Corneal microdeposits are an expected finding in patients on chronic oral amiodarone, typically with minimal to no impact on vision. In contrast, rare cases of optic neuropathy have been reported, with the potential to progress to blindness if undiagnosed and untreated. All patients should have a baseline eye examination prior to (or shortly after) initiating chronic oral amiodarone therapy ( table 1). Annual eye examinations are https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 7/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate recommended but not required if patients remain asymptomatic while taking amiodarone; however, patients with visual symptoms while on amiodarone should be promptly referred for a repeat eye examination. Corneal microdeposits Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities [27-29]. The corneal microdeposits are caused by the secretion of amiodarone by the lacrimal gland with accumulation on the corneal surface. They are identifiable on ophthalmologic examination as a brownish whorl at the juncture of the lower one-third and upper two-thirds of the cornea and have been described as resembling a cat's whiskers [27]. The formation of microdeposits is dose-dependent; the changes are reversible within seven months after amiodarone is discontinued [28]. Corneal microdeposits do not reduce visual acuity. However, ocular symptoms occur in a small number of patients [27,28]. These include halo vision (colored rings around lights), particularly at night, photophobia, and blurred vision. The incidence has been reported as 1.5 percent in a meta-analysis of trials of chronic low-dose amiodarone (mean dose 150 to 330 mg/day), compared with 0.1 percent seen with placebo (OR 3.4, 95% CI 1.2-9.6) [5,28]. The presence of microdeposits is not considered a contraindication to continued amiodarone therapy, since visual acuity is rarely affected [27,28]. In any patient with visual symptoms who is taking amiodarone, other common factors (a change in refractive correction, progression of age- related cataract, or increased intraocular pressure) should be considered before attributing the change to the drug. Optic neuropathy Amiodarone has been reported to cause optic nerve injury, with unilateral or bilateral visual loss that can rarely progress to permanent blindness [27,30,31]. Whether the prevalence of this adverse effect increases with time is unclear, although some survey data have reported that the prevalence may increase over time [27]. In a report of 296 cases of optic neuropathy identified through the US Food and Drug Administration adverse event reporting system, the mean duration of amiodarone treatment prior to visual loss was nine months (ranging from 1 to 84 months); nearly one- third of cases were asymptomatic [32]. In a Taiwanese nationwide cohort study, which included 6175 patients who started treatment with amiodarone between 2005 and 2009 (along with 24,700 matched controls) and were followed for an average of 1.9 years, significantly more amiodarone-treated patients developed optic neuropathy (17 [0.3 percent] versus 30 [0.1 percent] of controls; adjusted hazard ratio 2.1, 95% CI 1.1-3.9) [31]. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 8/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate In a post hoc report from the SCD-HeFT trial in which patients were randomized to amiodarone (n = 837) or placebo (n = 832), there were no reported cases of bilateral vision loss over a relatively short duration of follow-up (median 45.5 months) [33]. Additional long-term data are needed to clarify the incidence of optic neuropathy and potential causation from amiodarone. However, given the potential for permanent visual loss, immediate cessation of amiodarone or dose reduction is recommended for patients who develop optic neuropathy unless the arrhythmia is life-threatening and an alternative antiarrhythmic drug is not available [27]. Other Long-term amiodarone therapy has several other potential toxicities. Adverse skin reactions Various skin reactions, previously more common when higher doses of amiodarone were used, were reported in 2.3 percent of patients (compared with 0.7 percent in placebo recipients; OR 2.5, 95% CI 1.1-6.2) in the meta-analysis of chronic low-dose amiodarone therapy (mean dose 150 to 300 mg/day) [5]. Types of skin reactions include: Photosensitivity, which can be treated with avoidance of sun exposure and the use of sunblock. Bluish-slate gray discoloration of the skin (so-called "blue man syndrome"), which is usually most prominent on the face ( picture 1). Other reported adverse effects include hyperpigmentation, pseudoporphyria, and bullous dermatitis [34]. The bluish-slate gray discoloration of the skin occurs in 1 to 3 percent of patients on chronic amiodarone therapy and appears to be due to the deposition of lipofuscin in the dermis [35-37]. There may be a tissue threshold for amiodarone in individual patients above which skin discoloration appears and below which it fades [38]. Thus, patients disturbed by skin pigmentation who are taking large doses (more than 400 mg/day) may notice improvement in skin discoloration by reducing the dose. There is no specific therapy for the skin discoloration, but affected patients are advised to avoid sun exposure. Complete resolution after cessation of amiodarone therapy may take one year or more [39]. Adverse gastrointestinal effects Gastrointestinal adverse effects associated with amiodarone therapy, which include nausea, vomiting, anorexia, diarrhea, and constipation, occur mostly during the initial loading phase of therapy [5,11]. While previously reported in up to 30 percent of patients, findings from the meta-analysis of chronic low-dose amiodarone therapy https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 9/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate suggest that gastrointestinal adverse effects are not significantly more frequent than with placebo (4.2 versus 3.3 percent) [5]. Taking the medication with food or reducing the dose when possible can reduce GI side effects. Adverse neurologic function Neurologic toxicity associated with amiodarone therapy may take many forms, including tremor, ataxia, peripheral neuropathy with paresthesias, and sleep disturbances; similar to other toxicities, these appear to be dose-related in patients requiring higher doses [5,11,40]. In the meta-analysis of chronic low-dose amiodarone therapy (mean dose 150 to 330 mg/day), neurologic side effects were much less common than what was reported in early studies that utilized higher doses of amiodarone, but still significantly more frequent than with placebo (4.6 versus 1.9 percent; OR 2.0, 95% CI 1.1-3.7) [5]. We recommend stopping amiodarone to see if symptoms resolve. Adverse drug interactions Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Additionally, amiodarone can interfere with the hepatic metabolism of several antiarrhythmic drugs (such as quinidine, procainamide, and digoxin), possibly leading to supratherapeutic plasma concentrations if the dose is not reduced. These interactions are particularly worrisome because they may persist for as long as three months after the cessation of therapy due to the long elimination half-life of amiodarone (25 to 100 days). See Lexicomp drug interactions for additional information including specific dose adjustments or limits and management suggestions. Digoxin Amiodarone can interfere with the metabolism of digoxin, raising the plasma digoxin concentration and potentially leading to digoxin toxicity. The dose of digoxin should be empirically reduced by 50 percent at the time of amiodarone initiation or the need for digoxin reevaluated altogether. Digoxin levels should be measured within three days after amiodarone initiation. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification", section on 'Dose adjustment with concomitant medications'.) Warfarin Amiodarone can also interfere with the metabolism of warfarin, which often necessitates approximately a 25 percent reduction in warfarin dose to prevent an elevation in the international normalized ratio (INR) and potential bleeding complications [41,42]. In a retrospective cohort study of 754 patients treated with chronic warfarin therapy in whom amiodarone was started, the average INR increased from 2.6 to 3.1, with an average reduction in warfarin dose of 24.6 percent [42]. The INR level should be checked more frequently in the one to two weeks after amiodarone is initiated. The interaction between amiodarone and warfarin is further complicated by the potential effects of amiodarone on thyroid function. The effect of warfarin is potentiated by https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 10/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate thyrotoxicosis and attenuated in hypothyroidism [43]. Thyroid function should be reassessed in any patient on a stable warfarin and amiodarone regimen if the INR changes unexpectedly. (See 'Adverse thyroid effects' above.) Simvastatin Amiodarone alters the metabolism of simvastatin, resulting in a significantly higher risk of rhabdomyolysis when both drugs are used concurrently. If amiodarone and simvastatin are required in the same patient, the dose of simvastatin should be no higher than 20 mg daily. Other drugs Amiodarone can increase the plasma concentration of other medications including sildenafil, cyclosporine, and other hepatically metabolized drugs including some antidepressants. SUMMARY AND RECOMMENDATIONS The long half-life of amiodarone (25 to 100 days) and the potential severity of some of the adverse effects make early recognition important. As a result, baseline testing and careful monitoring of patients taking amiodarone is essential. The recommended approach to baseline testing and monitoring is summarized in the table ( table 1). (See 'Why is monitoring necessary?' above.) Pulmonary toxicity is one of the more common adverse effects of long-term amiodarone and is responsible for the rare deaths associated with amiodarone therapy. Pulmonary toxicity generally correlates more closely with the total cumulative dose than with serum drug levels. Several different types of adverse pulmonary effects may result from chronic amiodarone use, including chronic interstitial pneumonitis, the most common. A nonproductive cough and dyspnea are present in the majority of affected individuals at presentation, and the physical examination often reveals bilateral inspiratory crackles. The diagnosis of amiodarone pulmonary toxicity is one of exclusion. Treatment consists primarily of stopping amiodarone, with corticosteroid therapy administered in patients with symptomatic pulmonary toxicity. (See 'Adverse pulmonary effects' above and "Amiodarone pulmonary toxicity".) Thyroid dysfunction (including both hypothyroidism and hyperthyroidism) is another common complication of amiodarone therapy, occurring in approximately 3 to 4 percent of patients when lower doses (<400 mg/day) are used. Underlying thyroid status and iodine intake appear to influence the incidence and type of thyroid dysfunction seen with amiodarone therapy. Patients with hypothyroidism can usually be treated with thyroid hormone replacement and maintained on amiodarone, while those with amiodarone- https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 11/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate induced hyperthyroidism should be evaluated by, and treated in conjunction with, an endocrinologist. (See 'Adverse thyroid effects' above and "Amiodarone and thyroid dysfunction".) Multiple cardiac effects can be seen in patients taking chronic amiodarone therapy. Sinus bradycardia is an expected result from amiodarone treatment, but excessive bradycardia or AV block often represents toxicity. Amiodarone does generally lead to mild prolongation of the QT interval, but this is rarely proarrhythmic. Finally, amiodarone can alter the defibrillation thresholds for patients with an implantable cardioverter-defibrillators (ICDs). Management varies depending upon the adverse effect. (See 'Adverse cardiac effects' above.) Symptomatic hepatitis occurs in less than 3 percent of patients on amiodarone, and potential complications such as cirrhosis and hepatic failure occur very infrequently. However, a transient asymptomatic rise in serum aminotransferase concentrations occurs in approximately 25 percent of patients soon after beginning amiodarone. Although the relation of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity. While patients are usually asymptomatic, the drug should be discontinued if there is more than a twofold elevation in serum aminotransferases. (See 'Adverse hepatic effects' above.) Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities. While corneal microdeposits do not reduce visual acuity, ocular symptoms may occur, including halo vision (colored rings around lights), photophobia, and blurred vision. The presence of microdeposits is not considered a contraindication to continued amiodarone therapy since visual acuity is rarely affected. (See 'Corneal microdeposits' above.) Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Additionally, amiodarone can interfere with the hepatic metabolism of several antiarrhythmic drugs (such as quinidine, procainamide, and digoxin), possibly leading to supratherapeutic plasma concentrations if the dose is not reduced. (See 'Adverse drug interactions' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 12/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 1. Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997; 127:294. 2. Mason JW. Amiodarone. N Engl J Med 1987; 316:455. 3. Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51. 4. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356:935. 5. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 6. Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I). Chest 1988; 93:1067. 7. Kharabsheh S, Abendroth CS, Kozak M. Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 2002; 89:896. 8. Mason JW. Prediction of amiodarone-induced pulmonary toxicity. Am J Med 1989; 86:2. 9. Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung function testing in patients treated with amiodarone: a prospective study. Am J Med 1989; 86:4. 10. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101:28. 11. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 12. Malfatto G, Zaza A, Facchini M. Different effects of antiarrhythmic drugs on the rate- dependency of QT interval: a study with amiodarone and flecainide. J Cardiovasc Pharmacol 2007; 50:535. 13. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 1994; 121:529. 14. Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol 1995; 6:920. 15. van Opstal JM, Schoenmakers M, Verduyn SC, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation 2001; 104:2722. 16. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 13/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 17. Goldschlager N, Epstein A, Friedman P, et al. Environmental and drug effects on patients with pacemakers and implantable cardioverter/defibrillators: a practical guide to patient treatment. Arch Intern Med 2001; 161:649. 18. Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672. 19. Pelosi F Jr, Oral H, Kim MH, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol 2000; 11:736. 20. Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol 2001; 88:446. 21. Brown MA, Smith WM, Lubbe WF, Norris RM. Amiodarone-induced torsades de pointes. Eur Heart J 1986; 7:234. 22. Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology 1989; 9:679. 23. Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother 1995; 29:582. 24. Chang CC, Petrelli M, Tomashefski JF Jr, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999; 123:251. 25. Macarri G, Feliciangeli G, Berdini V, et al. Canalicular cholestasis due to amiodarone toxicity. A definite diagnosis obtained by electron microscopy. Ital J Gastroenterol 1995; 27:436. 26. Somani P, Bandyopadhyay S, Klaunig JE, Gross SA. Amiodarone- and desethylamiodarone- induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes. Hepatology 1990; 11:81. 27. M ntyj rvi M, Tuppurainen K, Ik heimo K. Ocular side effects of amiodarone. Surv Ophthalmol 1998; 42:360. 28. Ingram DV. Ocular effects in long-term amiodarone therapy. Am Heart J 1983; 106:902. 29. Flach AJ, Dolan BJ. Progression of amiodarone induced cataracts. Doc Ophthalmol 1993; 83:323. 30. Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127:610. 31. Cheng HC, Yeh HJ, Huang N, et al. Amiodarone-Associated Optic Neuropathy: A Nationwide Study. Ophthalmology 2015; 122:2553. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 14/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 32. Passman RS, Bennett CL, Purpura JM, et al. Amiodarone-associated optic neuropathy: a critical review. Am J Med 2012; 125:447. 33. Mindel JS, Anderson J, Hellkamp A, et al. Absence of bilateral vision loss from amiodarone: a randomized trial. Am Heart J 2007; 153:837.
dysfunction".) Multiple cardiac effects can be seen in patients taking chronic amiodarone therapy. Sinus bradycardia is an expected result from amiodarone treatment, but excessive bradycardia or AV block often represents toxicity. Amiodarone does generally lead to mild prolongation of the QT interval, but this is rarely proarrhythmic. Finally, amiodarone can alter the defibrillation thresholds for patients with an implantable cardioverter-defibrillators (ICDs). Management varies depending upon the adverse effect. (See 'Adverse cardiac effects' above.) Symptomatic hepatitis occurs in less than 3 percent of patients on amiodarone, and potential complications such as cirrhosis and hepatic failure occur very infrequently. However, a transient asymptomatic rise in serum aminotransferase concentrations occurs in approximately 25 percent of patients soon after beginning amiodarone. Although the relation of hepatotoxicity to cumulative dose and duration of therapy is uncertain, it is likely that cumulative dose correlates with overall toxicity. While patients are usually asymptomatic, the drug should be discontinued if there is more than a twofold elevation in serum aminotransferases. (See 'Adverse hepatic effects' above.) Corneal microdeposits occur in most patients receiving long-term amiodarone therapy, while some patients also develop lenticular opacities. While corneal microdeposits do not reduce visual acuity, ocular symptoms may occur, including halo vision (colored rings around lights), photophobia, and blurred vision. The presence of microdeposits is not considered a contraindication to continued amiodarone therapy since visual acuity is rarely affected. (See 'Corneal microdeposits' above.) Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Additionally, amiodarone can interfere with the hepatic metabolism of several antiarrhythmic drugs (such as quinidine, procainamide, and digoxin), possibly leading to supratherapeutic plasma concentrations if the dose is not reduced. (See 'Adverse drug interactions' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 12/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 1. Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997; 127:294. 2. Mason JW. Amiodarone. N Engl J Med 1987; 316:455. 3. Dusman RE, Stanton MS, Miles WM, et al. Clinical features of amiodarone-induced pulmonary toxicity. Circulation 1990; 82:51. 4. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356:935. 5. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 6. Martin WJ 2nd, Rosenow EC 3rd. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I). Chest 1988; 93:1067. 7. Kharabsheh S, Abendroth CS, Kozak M. Fatal pulmonary toxicity occurring within two weeks of initiation of amiodarone. Am J Cardiol 2002; 89:896. 8. Mason JW. Prediction of amiodarone-induced pulmonary toxicity. Am J Med 1989; 86:2. 9. Gleadhill IC, Wise RA, Schonfeld SA, et al. Serial lung function testing in patients treated with amiodarone: a prospective study. Am J Med 1989; 86:4. 10. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101:28. 11. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 12. Malfatto G, Zaza A, Facchini M. Different effects of antiarrhythmic drugs on the rate- dependency of QT interval: a study with amiodarone and flecainide. J Cardiovasc Pharmacol 2007; 50:535. 13. Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 1994; 121:529. 14. Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmic drugs: definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol 1995; 6:920. 15. van Opstal JM, Schoenmakers M, Verduyn SC, et al. Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation 2001; 104:2722. 16. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 13/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 17. Goldschlager N, Epstein A, Friedman P, et al. Environmental and drug effects on patients with pacemakers and implantable cardioverter/defibrillators: a practical guide to patient treatment. Arch Intern Med 2001; 161:649. 18. Zhou L, Chen BP, Kluger J, et al. Effects of amiodarone and its active metabolite desethylamiodarone on the ventricular defibrillation threshold. J Am Coll Cardiol 1998; 31:1672. 19. Pelosi F Jr, Oral H, Kim MH, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol 2000; 11:736. 20. Nielsen TD, Hamdan MH, Kowal RC, et al. Effect of acute amiodarone loading on energy requirements for biphasic ventricular defibrillation. Am J Cardiol 2001; 88:446. 21. Brown MA, Smith WM, Lubbe WF, Norris RM. Amiodarone-induced torsades de pointes. Eur Heart J 1986; 7:234. 22. Lewis JH, Ranard RC, Caruso A, et al. Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients. Hepatology 1989; 9:679. 23. Richer M, Robert S. Fatal hepatotoxicity following oral administration of amiodarone. Ann Pharmacother 1995; 29:582. 24. Chang CC, Petrelli M, Tomashefski JF Jr, McCullough AJ. Severe intrahepatic cholestasis caused by amiodarone toxicity after withdrawal of the drug: a case report and review of the literature. Arch Pathol Lab Med 1999; 123:251. 25. Macarri G, Feliciangeli G, Berdini V, et al. Canalicular cholestasis due to amiodarone toxicity. A definite diagnosis obtained by electron microscopy. Ital J Gastroenterol 1995; 27:436. 26. Somani P, Bandyopadhyay S, Klaunig JE, Gross SA. Amiodarone- and desethylamiodarone- induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes. Hepatology 1990; 11:81. 27. M ntyj rvi M, Tuppurainen K, Ik heimo K. Ocular side effects of amiodarone. Surv Ophthalmol 1998; 42:360. 28. Ingram DV. Ocular effects in long-term amiodarone therapy. Am Heart J 1983; 106:902. 29. Flach AJ, Dolan BJ. Progression of amiodarone induced cataracts. Doc Ophthalmol 1993; 83:323. 30. Macaluso DC, Shults WT, Fraunfelder FT. Features of amiodarone-induced optic neuropathy. Am J Ophthalmol 1999; 127:610. 31. Cheng HC, Yeh HJ, Huang N, et al. Amiodarone-Associated Optic Neuropathy: A Nationwide Study. Ophthalmology 2015; 122:2553. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 14/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate 32. Passman RS, Bennett CL, Purpura JM, et al. Amiodarone-associated optic neuropathy: a critical review. Am J Med 2012; 125:447. 33. Mindel JS, Anderson J, Hellkamp A, et al. Absence of bilateral vision loss from amiodarone: a randomized trial. Am Heart J 2007; 153:837. 34. Jaworski K, Walecka I, Rudnicka L, et al. Cutaneous adverse reactions of amiodarone. Med Sci Monit 2014; 20:2369. 35. Enseleit F, Wyss CA, Duru F, et al. Images in cardiovascular medicine. The blue man: amiodarone-induced skin discoloration. Circulation 2006; 113:e63. 36. Alinovi A, Reverberi C, Melissari M, Gabrielli M. Cutaneous hyperpigmentation induced by amiodarone hydrochloride. J Am Acad Dermatol 1985; 12:563. 37. Delage C, Lagac R, Huard J. Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study. Can Med Assoc J 1975; 112:1205. 38. Kounis NG, Frangides C, Papadaki PJ, et al. Dose-dependent appearance and disappearance of amiodarone-induced skin pigmentation. Clin Cardiol 1996; 19:592. 39. Blackshear JL, Randle HW. Reversibility of blue-gray cutaneous discoloration from amiodarone. Mayo Clin Proc 1991; 66:721. 40. Orr CF, Ahlskog JE. Frequency, characteristics, and risk factors for amiodarone neurotoxicity. Arch Neurol 2009; 66:865. 41. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121:19. 42. Holm J, Lindh JD, Andersson ML, Mannheimer B. The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2017; 15:446. 43. Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004; 83:107. Topic 931 Version 36.0 https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 15/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate GRAPHICS Amiodarone baseline testing and monitoring for side effects Monitoring Area of interest for Possible adverse monitoring effect Baseline testing Follow-up testing Cardiac ECG (at baseline and during loading dose) Yearly QT prolongation; torsades de pointes After adding medications that interact with amiodarone or prolong Symptomatic sinoatrial or conduction system impairment the QT interval Implantable cardioverter- Defibrillation threshold testing (if clinically As needed for signs/symptoms Increased defibrillation threshold defibrillators indicated) Dermatologic Physical examination As needed for signs/symptoms Photosensitivity to UV light Blue-gray skin discoloration Endocrine TSH (with reflex testing if abnormal) 3 to 4 months after starting drug, then yearly Hyperthyroidism, hypothyroidism As needed for signs/symptoms Hepatic AST and ALT 6 months after starting drug, then yearly AST or ALT elevation 2 upper limit of reference range Ophthalmologic Eye examination Yearly Corneal microdeposits Optic neuropathy Pulmonary Chest radiograph, PFTs* Yearly for surveillance Pulmonary toxicity (cough, fever, dyspnea) Along with PFTs (including DLCO) and chest computed tomography for signs/symptoms Refer to UpToDate topics on pulmonary toxicity, thyroid toxicity, and clinical uses of amiodarone for additional information. https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 16/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate ECG: electrocardiogram; UV: ultraviolet; TSH: thyroid-stimulating hormone; AST: aspartate aminotransferase; ALT: alanine transaminase; PFTs: pulmonary function tests; DLCO: diffusing capacity of the lungs for carbon monoxide. There are differing opinions, and no concensus, of obtaining formal PFTs with assessment of diffusion capacity (ie, DLCO) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs. Graphic 126072 Version 4.0 https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 17/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Amiodarone-induced pigmentation Amiodarone causes a striking slate-gray pigmentation in a photodistribution of the face. The blue color (ceruloderma) is due to the deposition of melanin and lipofuscin contained in macrophages and endothelial cells in the dermis. The pigmentation is reversible, but it may take up to a year or more to complete resolution. Reproduced with permission from: Fitzpatrick TB, Johnson AB, Wol K, Suurmond D. Color Atlas and Synopsis of Clinical Dermatology: Common and Serious Diseases, 4th ed, McGraw-Hill, New York 2001. Copyright 2001 The McGraw-Hill Companies, Inc. Graphic 70419 Version 6.0 https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 18/19 7/5/23, 8:18 AM Amiodarone: Adverse effects, potential toxicities, and approach to monitoring - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring/print 19/19
7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Amiodarone and thyroid dysfunction : Douglas S Ross, MD : David S Cooper, MD : Jean E Mulder, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2022. INTRODUCTION Amiodarone, a class III antiarrhythmic drug, has multiple effects on myocardial depolarization and repolarization that make it an extremely effective antiarrhythmic drug. However, amiodarone is associated with a number of side effects, including thyroid dysfunction (both hypo- and hyperthyroidism), which is due to amiodarone's high iodine content and its direct toxic effect on the thyroid. This topic will review the major effects of amiodarone on thyroid function. The clinical use and other side effects of amiodarone are reviewed elsewhere. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) PHARMACOLOGY Amiodarone contains two iodine atoms. It is estimated that amiodarone metabolism in the liver releases approximately 3 mg of inorganic iodine into the systemic circulation per 100 mg of amiodarone ingested. The average iodine content in a typical American diet is approximately 0.3 mg/day. Thus, 6 mg of iodine associated with a 200 mg dose of amiodarone markedly increases the daily iodine load [1,2]. Amiodarone is very lipophilic and is concentrated in adipose tissue, cardiac and skeletal muscle, and the thyroid. Elimination from the body occurs with a half-life of approximately 100 days [3]. Amiodarone toxicity can therefore occur well after drug withdrawal [4]. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 1/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate The effects of amiodarone on thyroid function can be divided into those effects that are intrinsic properties of the drug and those effects that are due to iodine. Intrinsic drug effects Amiodarone inhibits outer ring 5'-monodeiodination of thyroxine (T4), thus decreasing triiodothyronine (T3) production; reverse T3 accumulates since it is not metabolized to T2 [5]. Amiodarone (and particularly the metabolite desethylamiodarone) blocks T3-receptor binding to nuclear receptors [6] and decreases expression of some thyroid hormone- related genes [7]. Amiodarone may have a direct toxic effect on thyroid follicular cells, which results in a destructive thyroiditis [8]. (See 'Type II' below.) Effects due to iodine Iodine is a substrate for thyroid hormone synthesis. It is actively transported into thyroid follicular cells and organified onto tyrosyl residues in thyroglobulin. The normal autoregulation of iodine prevents normal individuals from becoming hyperthyroid after exposure to an iodine load (eg, radiocontrast). When intrathyroidal iodine concentrations reach a critical high level, iodine transport and thyroid hormone synthesis are transiently inhibited until intrathyroidal iodine stores return to normal levels (the Wolff-Chaikoff effect). (See "Thyroid hormone synthesis and physiology" and "Iodine-induced thyroid dysfunction".) Patients with underlying thyroid disease, however, have defects in autoregulation of iodine: Patients with autoimmune thyroid disease "fail to escape" from the Wolff-Chaikoff effect. The result is the development of goiter and hypothyroidism in Hashimoto's disease [9] and amelioration of Graves' hyperthyroidism. Patients with areas of autonomous function within a nodular goiter do not autoregulate iodine and the addition of more substrate may result in excessive thyroid hormone synthesis and thyrotoxicosis (Jod-Basedow) [10]. RISK OF THYROID DYSFUNCTION Both hypo- and hyperthyroidism are complications of amiodarone therapy [1,11-14]. In a meta- analysis of four randomized trials involving 1465 euthyroid patients, the prevalence of clinical thyroid disease was higher in patients receiving amiodarone therapy (150 to 330 mg/day for a minimum of one year) when compared with placebo (3.7 versus 0.4 percent, respectively) [13]. In https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 2/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate other reviews and reports, the risk of amiodarone-induced thyroid dysfunction ranges from 2 to 30 percent, depending upon an individual's underlying thyroid status, dietary iodine intake, and whether cases of subclinical thyroid disorders (eg, slight rise in thyroid-stimulating hormone [TSH] without symptoms) are included [1,11,12,14-17]. Underlying thyroid function The clinical effects of amiodarone on thyroid function in any individual are dependent upon the underlying status of that individual's thyroid gland. Normal In normal, euthyroid individuals receiving amiodarone, acute changes in thyroid function tests include [1,18]: Serum T4 and free T4 concentrations rise by 20 to 40 percent during the first month of therapy. Serum T3 concentrations decrease by up to 30 percent within the first few weeks of therapy. Serum reverse T3 concentrations increase by 20 percent soon after the initiation of therapy. The serum TSH concentration usually rises slightly after the initiation of treatment and may exceed the upper limit of normal. After three to six months of therapy, a steady state is reached in most patients who were euthyroid at baseline: Serum TSH concentration normalizes Serum total T4, free T4 and reverse T3 concentrations remain slightly elevated or in the upper normal range Serum T3 concentrations remain in the low normal range Amiodarone may also cause a destructive thyroiditis in patients without underlying thyroid disease [8]. (See 'Type II' below.) Abnormal Patients with underlying autoimmune thyroid disease are more likely to develop amiodarone-induced hypothyroidism, presumably due to failure to escape from the Wolff- Chaikoff effect. (See 'Effects due to iodine' above and 'Hypothyroidism' below.) In patients with underlying multinodular goiter or latent Graves' disease, hyperthyroidism (increased synthesis of T4 and T3) may occur. The excess iodine from the amiodarone https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 3/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate provides increased substrate, resulting in enhanced thyroid hormone production [19]. (See 'Type I' below.) Dietary iodine intake Dietary iodine intake also affects an individual's risk of amiodarone- induced thyroid dysfunction: In iodine-sufficient areas, amiodarone-induced hypothyroidism appears to be more common than hyperthyroidism [15,20-22]. In contrast, amiodarone-induced hyperthyroidism is more common than hypothyroidism in iodine-deficient regions [12]. One study illustrates the importance of both the underlying thyroid status and dietary iodine intake in relation to the risk of developing amiodarone-induced thyroid dysfunction. In Worcester, Massachusetts, an area with iodine sufficiency and a high prevalence of autoimmune thyroid disease, amiodarone was associated with a 22 percent rate of hypothyroidism and a 2 percent rate of hyperthyroidism [15]. In contrast, in Pisa, Italy, an area of borderline iodine intake and a high prevalence of nodular goiter, amiodarone was associated with a 5 percent rate of hypothyroidism and a 9.6 percent rate of hyperthyroidism. HYPOTHYROIDISM Epidemiology As noted above, transient changes in thyroid function tests often occur in euthyroid individuals treated with amiodarone. However, most patients remain euthyroid during amiodarone therapy (89 percent in one study) [23]. In one trial, overt hypothyroidism (TSH >10 mU/L) developed in 5 percent of patients receiving amiodarone, but subclinical hypothyroidism (TSH 4.5 to 10 mU/L) developed in an additional 25 percent [14]. In a meta-analysis, 14 percent of patients receiving amiodarone became hypothyroid [24]. Patients with underlying Hashimoto's thyroiditis or positive antithyroid antibodies are more likely to develop persistent hypothyroidism [4,25]. This observation may explain the higher prevalence of amiodarone-induced hypothyroidism in women compared with men [12]. In iodine-sufficient areas, amiodarone-induced hypothyroidism is more common than hyperthyroidism [15,20-22] and may occur in up to 20 percent of patients treated with amiodarone [11]. In contrast, amiodarone-induced hyperthyroidism is more common than hypothyroidism in iodine-deficient regions [12]. (See 'Dietary iodine intake' above.) Pregnancy Transient hypothyroidism may occur in the infants of women treated with amiodarone during pregnancy. As an example, in a study of 64 pregnancies in which https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 4/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate amiodarone was given to the mother, 11 infants (17 percent) had transient hypothyroidism; 2 of the 11 had a goiter [26]. Hypothyroidism was transient in all cases, and only five infants were treated short term with thyroid hormones. Clinical manifestations The clinical manifestations and diagnosis of amiodarone-associated hypothyroidism are similar to those of hypothyroidism from any cause. Hypothyroidism and hypothyroid symptoms may develop as soon as two weeks or as late as 39 months after the initiation of amiodarone therapy [27,28]. (See "Clinical manifestations of hypothyroidism".) Diagnosis Patients should have thyroid function assessed several weeks after starting amiodarone and every few months thereafter for the development of overt hypothyroidism, especially those with evidence for autoimmunity prior to initiating amiodarone [9,25]. Hypothyroidism should be diagnosed on the basis of a screening serum TSH value before the patient has symptoms. Since small increases in serum TSH concentrations (10 to 20 mU/L) are seen in euthyroid patients for the first three to six months after amiodarone therapy is initiated, amiodarone-induced hypothyroidism should only be diagnosed when serum T4 concentrations are low-normal or low, or mild TSH elevation persists. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".) Treatment Thyroid function can be easily normalized by replacement with T4 (levothyroxine) while amiodarone is continued. The goal of therapy is to restore the serum TSH concentration to normal, keeping in mind that a larger than usual dose may be required because of the likely effects of amiodarone on intrapituitary T4 metabolism and T3 production and, possibly, thyroid hormone action [11]. The patient should be retested if amiodarone is withdrawn at a later date. (See "Treatment of primary hypothyroidism in adults".) Amiodarone is usually not discontinued, unless it fails to control the underlying arrhythmia. However, if amiodarone is stopped, hypothyroidism in patients with no apparent preexisting thyroid disease often resolves. In contrast, hypothyroidism may persist after withdrawal of amiodarone in patients who have underlying chronic autoimmune thyroiditis with high titers of antithyroid peroxidase (TPO) antibodies and goiter, and they therefore require permanent T4 therapy [1,4,11,12,25]. HYPERTHYROIDISM Types of hyperthyroidism There are two types of amiodarone-induced thyrotoxicosis (AIT). In type I, there is increased synthesis of thyroid hormone, whereas in type II, there is excess release of T4 and T3 due to a destructive thyroiditis. These types differ in their pathogenesis, management, and outcome [29]. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 5/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate Type I In type I AIT, there is hyperthyroidism with increased synthesis of T4 and T3. This type is typically seen in patients with preexisting multinodular goiter or latent Graves' disease; the excess iodine from amiodarone provides increased substrate, resulting in enhanced thyroid hormone production [19]. While most of these patients have underlying multinodular goiter, occasional patients have latent Graves' disease that becomes overt upon exposure to large amounts of iodine [30]. (See "Iodine-induced thyroid dysfunction".) Type II In type II AIT, the hyperthyroidism is a destructive thyroiditis that results in excess release of T4 and T3, without increased hormone synthesis. It typically occurs in patients without underlying thyroid disease and is caused by a direct toxic effect of amiodarone on thyroid follicular epithelial cells [31-33]. The hyperthyroid phase may last from several weeks to several months, and it is often followed by a hypothyroid phase with eventual recovery in most, but not all, patients. For unclear reasons, the toxic effects of the drug may take two to three years to become manifest. (See "Overview of thyroiditis".) In many cases, mixed forms of AIT exist, making both diagnosis and treatment challenging (see 'Diagnosis' above and 'Treatment' above). The risk of either type increases with higher cumulative doses [34]. Prevalence The prevalence of AIT, as well as the distribution by type (I or II), varies by geographical region. This is thought to be primarily due to differences in dietary iodine intake (see 'Dietary iodine intake' above): In the United States, 3 to 5 percent of patients treated with amiodarone become hyperthyroid, usually between four months and three years after the initiation of the drug [14,25]. The majority of cases are type II. In iodine-deficient regions, AIT is more common than in the United States, occurring in approximately 10 to 12 percent of patients with type I AIT usually predominating [11,12,15]. However, the distribution of cases by type may be changing, as illustrated in a report of 215 consecutive patients with AIT seen at a single institution in Italy over 26 years [35]. In 1980 compared with 2006, 2 of 6 (40 percent) versus 12 of 14 (86 percent) of new AIT cases were type II. Possible explanations for this observation include improved dietary iodine intake in the region and the avoidance of amiodarone in patients with known thyroid disease. Clinical manifestations The clinical manifestations of amiodarone-induced hyperthyroidism are often masked because its beta-blocking activity minimizes many of the adrenergic https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 6/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate manifestations of thyroid hormone excess and possibly because amiodarone metabolites may block binding of T3 to its nuclear receptor [7]. Common presenting symptoms and signs include the development or redevelopment of atrial arrhythmias; exacerbation of ischemic heart disease or heart failure; or unexplained weight loss, restlessness, or low-grade fever [1]. Patients with amiodarone-induced hyperthyroidism have a threefold higher rate of major adverse cardiovascular events (mostly ventricular arrhythmias) compared with euthyroid controls [36]. The presence of severe left ventricular dysfunction in patients with amiodarone- induced hyperthyroidism (type I or type II) may be associated with increased mortality [37]. Differentiating the two types The distinction between type I and type II is critical since therapy differs for the two types. However, the distinction may be difficult using clinical criteria, partly because some patients may have a mixture of both mechanisms [33]. Thyroid function tests are not helpful for differentiating type I from type II hyperthyroidism. Type I, when seen in the setting of an underlying autonomous nodule or goiter, tends to occur early after amiodarone treatment is started (at a median 3.5 months in one study), while type II occurs much later (median 30 months) [38]. When thyrotoxicosis initially occurs after amiodarone has been discontinued (19 percent of AIT in this study), it is much more likely to be type II (95 percent in this study) [38]. In patients not taking amiodarone, the radioiodine uptake is the primary test used to distinguish between destructive subacute thyroiditis and hyperthyroidism associated with de novo synthesis of thyroid hormone; the 24-hour radioiodine uptake is <1 percent in subacute thyroiditis and elevated or normal in toxic nodular goiter or Graves' disease. However, the daily ingestion of 6 mg or more of bioavailable iodine with amiodarone results in sufficiently high serum levels of iodine that compete with the tracer used to perform the uptake test. Therefore, the majority of patients with type I (as well as all patients with type II) has uptakes that are less than 1 percent [39]. In one European study, a significant percentage of patients with type I hyperthyroidism had measurable or even elevated uptakes [40]; however, this is an unusual finding in the United States. (See "Disorders that cause hyperthyroidism".) The criteria used to attempt to distinguish type I from type II hyperthyroidism are: If the 24-hour radioiodine uptake is detectable, it suggests type I AIT [40]. Patients with type I often have multinodular goiters or diffuse goiter, whereas those with type II usually have no goiter or a small diffuse goiter. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 7/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate In two studies, serum thyroglobulin concentrations were higher and serum interleukin-6 concentrations were lower in patients with type I hyperthyroidism [29,32]. In a third study, interleukin-6 concentrations were not useful for distinguishing type I from type II [41]. Two studies reported that color-flow Doppler sonography (CFDS) may distinguish type I (increased vascularity) from type II (absent vascularity) hyperthyroidism [41,42]; 80 percent of patients could be classified by CFDS. However, interpretations of CFDS in amiodarone-associated hyperthyroidism require an experienced sonographer. It is straightforward to separate patients into those with increased and low flow when a group of patients with amiodarone-associated hyperthyroidism are being scanned sequentially, but due to the lack of an accepted "gold standard," it may be difficult to interpret the CFDS of a single thyroid gland scanned during a typical day of multiorgan ultrasound examinations. Two reports utilized technetium-99m (99mTc)-sestamibi thyroid uptake and scintigraphy to distinguish type I (normal or increased) from type II (decreased) and found this to be more useful than CFDS [43,44]. The presence of thyrotropin receptor antibodies (TRAb) suggests Graves' disease. However, in patients suspected of having type I AIT, TRAb measurements to diagnose Graves' disease should be measured using a thyroid-stimulating immunoglobin (TSI) assay, if available, and not a thyrotropin-binding inhibitory immunoassay (TBII) assay. TBII assays cannot distinguish between type I and II AIT. As an example, in one study, 21 of 309 patients (7 percent) had positive TRAb when measured in a TBII [45]. Of these, 43 percent appeared to have type I AIT based on color- flow Doppler or response to methimazole, while 57 percent appeared to have type II AIT based on response to corticosteroids. TRAb, measured by a TSI assay, was positive in patients suspected of having type I AIT and negative in those suspected of having type II AIT. Treatment Should amiodarone be discontinued? There are few data that directly address this question. In a retrospective study from Italy of type II AIT, the median time to normalize thyroid function was similar whether amiodarone was continued (n = 8) or discontinued (n = 32) [46]. However, five of seven patients taking amiodarone had recurrent thyrotoxicosis compared with 3 of 32 patients in whom the amiodarone was discontinued. In a study from the Netherlands of type II AIT in which 36 patients were treated with prednisone, sodium perchlorate, or both, https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 8/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate therapy was effective in all patients receiving prednisone or perchlorate plus prednisone, despite continuation of amiodarone in all patients [47]. Recurrent thyrotoxicosis occurred in only three patients (8 percent). When deciding whether to discontinue amiodarone, the following should be considered: Amiodarone may be necessary to control a life-threatening arrhythmia. Since the half-life of elimination from the body is approximately 100 days, there is no immediate benefit to stopping amiodarone [48]. Amiodarone appears to ameliorate hyperthyroidism by blocking T4 to T3 conversion, beta- adrenergic receptors, and possibly T3 receptors. Stopping amiodarone might actually exacerbate hyperthyroid symptoms and signs. In patients who develop AIT in whom the amiodarone was prescribed for life-threatening ventricular arrhythmias (and is effective), we suggest continuing the amiodarone and simultaneously treating the hyperthyroidism. If the amiodarone was not prescribed for life- threatening ventricular arrhythmias (or is ineffective), we suggest discontinuing the drug in consultation with the patient's cardiologist if alternative antiarrhythmics can be used. For type I AIT, amiodarone should not be discontinued until hyperthyroid symptoms are well controlled with thionamides, since worsening hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is discontinued. Treatment of type I AIT Thionamides Patients with type I hyperthyroidism usually respond to a thionamide drug, although the response may be slow and large doses may be required, presumably because of very high intrathyroidal iodine stores [4,49]. The average initial dose is often 30 to 40 mg of methimazole daily, with careful monitoring for adverse effects such as skin rash, arthralgia, hepatotoxicity, and, rarely, bone marrow suppression. The risk of agranulocytosis in one study was higher in patients with amiodarone-induced thyrotoxicosis (8 of 593 [1.35 percent]), compared with patients with thyrotoxicosis unrelated to amiodarone (20 of 14,188 [0.14 percent]) [50]. (See "Thionamides in the treatment of Graves' disease", section on 'Initiation of therapy' and "Thionamides: Side effects and toxicities", section on 'Agranulocytosis'.) The addition of perchlorate, which blocks further iodine uptake by the thyroid, may be of benefit [51], but chronic use has been associated (rarely) with aplastic anemia, and perchlorate is not currently available in the United States. The addition of lithium carbonate to the antithyroid drug has also been reported to speed recovery when the hyperthyroidism is severe [52]. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 9/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate Thionamides are usually tapered to a low maintenance dose in patients with hyperthyroidism. In amiodarone-associated type I hyperthyroidism, care must be taken not to reduce the dose of thionamide too quickly, or patients might develop recurrent and prolonged hyperthyroidism. An alternative strategy is to continue high-dose thionamides and add T4 after patients become hypothyroid. If amiodarone is stopped (eg, if there is evidence of toxicity in other organs or if it is ineffective as an antiarrhythmic), depending upon the clinical setting one might add beta-adrenergic blocking drugs and iopanoic acid to block T4 to T3 conversion. However, neither iopanoic acid nor ipodate are available in the United States. It is unclear when, or even whether, they will ever again be marketed in the United States. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".) Patients with iodine-induced hyperthyroidism who are continuing amiodarone will need to continue thionamides. If amiodarone is subsequently discontinued, the thionamide should be continued until measurement of urine iodine returns to normal. This may take 6 to 18 months, after which one could cautiously attempt to taper antithyroid therapy. In one study, when amiodarone was reintroduced in patients with a history of AIT type I who were not taking a thionamide, 8 of 11 patients (73 percent) developed recurrent AIT [53]. Radioiodine If the radioiodine uptake is high enough, one could treat the patient with radioiodine. In one series of 14 patients in whom amiodarone had been discontinued due to hyperthyroidism, subsequent radioiodine ablation of the thyroid allowed reintroduction of amiodarone (and control of recurrent tachyarrhythmias) in 12 of the 14 subjects [54]. However, radioiodine ablation is usually not an option due to low radioiodine uptake in these patients. Surgery Patients who are refractory to antithyroid drug therapy should be treated by thyroidectomy. This recommendation is consistent with the European Thyroid Association guidelines for the management of amiodarone-associated thyroid dysfunction [55]. When balancing the risk of a surgical procedure during careful cardiovascular monitoring with the risk of several months of unmonitored and uncontrolled thyrotoxicosis, the advantages of surgery in this setting become compelling [56-58]. In one study of 207 patients, 51 of whom had surgery and 156 of whom were treated medically, overall and cardiovascular mortality was lower in the surgery group due to reduced mortality among patients with moderate to severe reductions in left ventricular ejection fraction (under 40 percent) [59]. (See "Surgical management of hyperthyroidism".) Treatment of type II AIT https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 10/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate Glucocorticoids Patients with type II hyperthyroidism respond well to moderately large doses of corticosteroids (eg, prednisone 40 to 60 mg/day) [29,60], even if the amiodarone is continued [39,61]. We typically start with prednisone (40 to 60 mg/day) and continue therapy for one to three months before tapering (to avoid exacerbations of hyperthyroidism). Some improvement is usually seen as early as one week [29]. In one study of 66 patients, 60 percent were euthyroid within one month and 16 percent remained hyperthyroid for more than three months [62]. Prolonged hyperthyroidism was associated with higher serum free T4 levels and goiter. Glucocorticoid therapy is more effective than iopanoic acid. In a prospective, randomized trial, both glucocorticoids and iopanoic acid were effective in type II hyperthyroidism, but thyroid function returned to normal more rapidly after steroid administration [63]. (See "Iodinated radiocontrast agents in the treatment of hyperthyroidism".) In a randomized, clinical trial, the addition of perchlorate to prednisone added no benefit [47]. Patients with type II AIT may develop transient (or sometimes permanent) hypothyroidism when the hyperthyroidism resolves [8] and benefit from T4 replacement. (See "Overview of thyroiditis".) Surgery Patients who are refractory to glucocorticoids should be treated with thyroidectomy. In the study of 207 patients with AIT described above, 64 percent of patients who had surgery for amiodarone-induced thyrotoxicosis had type II AIT [59]. (See 'Surgery' above.) Treatment if mechanism unknown Some patients may have a "mixed" form of thyrotoxicosis or the underlying cause (type I or type II) may be uncertain. In such cases, a combination of prednisone (40 mg/day) and methimazole (40 mg/day) is prudent initial therapy. A rapid response suggests type II hyperthyroidism; the methimazole can then be tapered or stopped and, if indicated, iopanoic acid can be added (if available). A poor response initially argues for type I hyperthyroidism. If so, steroids can be tapered and, depending upon the subsequent course, perchlorate, lithium, and/or surgery may be necessary. MONITORING Since thyroid dysfunction is relatively common with amiodarone therapy, all patients should have thyroid function tests checked before starting therapy and at three- to four-month intervals during treatment [12]. Thyroid dysfunction may occur after amiodarone withdrawal, and therefore, thyroid function should be assessed for at least one year after the drug is discontinued, and longer in patients with high cumulative doses or a history of hypothyroidism https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 11/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate during treatment. In a study of 71 patients followed after stopping amiodarone, five (7 percent) developed type II amiodarone-induced thyrotoxicosis (AIT) between 7 and 16 months after withdrawal [64]. Compared with patients who did not develop AIT, they had been on amiodarone longer (mean 76 versus 16 months) and had been more likely to have had hypothyroidism during amiodarone therapy. PATIENTS ON WARFARIN In patients taking amiodarone who are also being treated with warfarin, the consequences of amiodarone-induced thyroid dysfunction include a significant influence on warfarin response. The effect of warfarin is potentiated by thyrotoxicosis and attenuated in hypothyroidism [65]. In addition, amiodarone itself has effects on warfarin pharmacokinetics, which may be important if the amiodarone is discontinued because of thyroid dysfunction. In any patient with amiodarone- induced thyroid dysfunction who is also taking warfarin, the International Normalized Ratio (INR) should be monitored closely and appropriate adjustments in warfarin dosing made. (See "Warfarin and other VKAs: Dosing and adverse effects".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism" and "Society guideline links: Hypothyroidism".) SUMMARY AND RECOMMENDATIONS Thyroid dysfunction (both hypo- and hyperthyroidism) is a common complication of amiodarone therapy due to direct effects of the drug on the thyroid, as well as its high iodine content. (See 'Introduction' above.) Direct effects of amiodarone on the thyroid include: inhibition of outer ring 5'- monodeiodination of thyroxine (T4), thus decreasing triiodothyronine (T3) production; blocking T3-receptor binding to nuclear receptors; decreased expression of some thyroid hormone-related genes; and a direct toxic effect on the thyroid (destructive thyroiditis). (See 'Intrinsic drug effects' above.) Other effects on the thyroid are due to the extremely high iodine content of amiodarone. (See 'Effects due to iodine' above.) https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 12/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate Transient changes in thyroid function tests often occur in euthyroid individuals treated with amiodarone. While most patients remain euthyroid during amiodarone therapy, the clinical effects of amiodarone on thyroid function in any individual are dependent upon underlying thyroid status and dietary iodine intake: Patients with underlying autoimmune thyroid disease are at highest risk for amiodarone-induced hypothyroidism (due to failure to escape from the Wolff-Chaikoff effect). (See 'Abnormal' above.) Patients with nodular goiter are at increased risk of type I amiodarone-induced thyrotoxicosis (AIT). The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone synthesis and hyperthyroidism. (See 'Type I' above.) Destructive thyroiditis (type II AIT) typically occurs in patients with no underlying thyroid disease. (See 'Type II' above.) In iodine-sufficient areas, amiodarone-induced hypothyroidism appears to be more common than hyperthyroidism. In contrast, amiodarone-induced hyperthyroidism (usually type I AIT) is more common than hypothyroidism in iodine-deficient regions. (See 'Dietary iodine intake' above.) We suggest continuing amiodarone therapy in patients who develop amiodarone-induced hypothyroidism (Grade 2C). (See 'Treatment' above.) The diagnosis and treatment of amiodarone-induced hypothyroidism is the same as for other patients with primary hypothyroidism. Euthyroidism should be restored by replacement with thyroid hormone. Thyroid hormone, in doses larger than normal, is often required. (See 'Treatment' above.) Amiodarone should only be discontinued if it fails to control the underlying arrhythmia. If amiodarone is discontinued in a patient without preexisting autoimmune thyroid disease, the hypothyroidism often resolves. (See 'Treatment' above.) There are two types of AIT. In type I, there is increased synthesis of thyroid hormone (excess iodine provides the increased substrate), whereas in type II, there is excess release of T4 and T3 due to a destructive thyroiditis (direct toxic effect of amiodarone on the thyroid gland). For patients with type II AIT, the hyperthyroid phase may last from several weeks to several months and is often followed by a hypothyroid phase and then recovery. (See 'Types of hyperthyroidism' above.) https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 13/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate It is often difficult to distinguish between the two types, and some patients may have elements of both. The 24-hour radioiodine uptake is typically not able to distinguish between types I and II AIT, because the high levels of ingested iodine with amiodarone results in 24-hour uptakes of less than 1 percent in most patients with either type I or type II AIT. Technetium-99m (99mTc)-sestamibi imaging, where available, or color-flow Doppler sonography (CFDS) may be the best ways of distinguishing between the two types of AIT. (See 'Differentiating the two types' above.) In patients who develop AIT in whom the amiodarone was prescribed for life-threatening ventricular arrhythmias (and is effective), we suggest continuing the amiodarone and simultaneously treating the hyperthyroidism (Grade 2C). (See 'Should amiodarone be discontinued?' above.) In patients who develop AIT in whom the amiodarone was not prescribed for life- threatening ventricular arrhythmias (or is ineffective), we suggest discontinuing the drug (Grade 2C). This should only be done in consultation with the patient's cardiologist if alternative antiarrhythmics can be used. For type I AIT, amiodarone should not be discontinued until hyperthyroid symptoms are well controlled with thionamides, since worsening hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is discontinued. (See 'Should amiodarone be discontinued?' above.) For the treatment of type I AIT, we suggest thionamides as our first choice of therapy (whether amiodarone is continued or discontinued) (Grade 2B) (see 'Thionamides' above). Although radioiodine ablation has been reported to have been used (in rare patients with high enough radioiodine uptake), this is usually not an option due to low radioiodine uptake in the majority of type I patients. (See 'Radioiodine' above.) Higher than average initial doses of thionamides are usually needed (30 to 40 mg of methimazole or 450 to 600 mg propylthiouracil [PTU] daily). Perchlorate or lithium are sometimes added to speed recovery, however, perchlorate is not available in the United States. In addition, perchlorate has been associated, albeit rarely, with aplastic anemia. (See 'Thionamides' above.) For the treatment of type II AIT, we suggest glucocorticoid therapy as our first-line drug (whether amiodarone is continued or discontinued) (Grade 2B). We typically start with prednisone (40 to 60 mg/day) and continue therapy for one to two months before tapering (to avoid exacerbations of hyperthyroidism). (See 'Glucocorticoids' above.) Patients with type I or type II AIT who are refractory to medical therapy should be treated by thyroidectomy. When balancing the risk of a surgical procedure during careful https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 14/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate cardiovascular monitoring with the risk of several months of unmonitored and uncontrolled thyrotoxicosis, the advantages of surgery in this setting become compelling. (See 'Surgery' above and 'Surgery' above.) If the mechanism of the hyperthyroidism is uncertain or the patient appears to have "mixed" type I and type II AIT, a combination of prednisone (40 mg/day) and methimazole (40 mg/day) is reasonable initial therapy. A rapid response suggests type II AIT; the methimazole can then be tapered or stopped. A poor or slow initial response argues for type I AIT. (See 'Treatment if mechanism unknown' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005; 118:706. 2. Kennedy RL, Griffiths H, Gray TA. Amiodarone and the thyroid. Clin Chem 1989; 35:1882. 3. Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet 1984; 9:136. 4. Martino E, Aghini-Lombardi F, Mariotti S, et al. Amiodarone: a common source of iodine- induced thyrotoxicosis. Horm Res 1987; 26:158. 5. Rao RH, McCready VR, Spathis GS. Iodine kinetic studies during amiodarone treatment. J Clin Endocrinol Metab 1986; 62:563. 6. Franklyn JA, Davis JR, Gammage MD, et al. Amiodarone and thyroid hormone action. Clin Endocrinol (Oxf) 1985; 22:257. 7. van Beeren HC, Bakker O, Wiersinga WM. Structure-function relationship of the inhibition of the 3,5,3'-triiodothyronine binding to the alpha1- and beta1-thyroid hormone receptor by amiodarone analogs. Endocrinology 1996; 137:2807. 8. Roti E, Minelli R, Gardini E, et al. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone. A possible consequence of a destructive process in the thyroid. Arch Intern Med 1993; 153:886. 9. Braverman LE, Ingbar SH, Vagenakis AG, et al. Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 1971; 32:515. 10. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998; 8:83. 11. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 15/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate 12. Trip MD, Wiersinga W, Plomp TA. Incidence, predictability, and pathogenesis of amiodarone- induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91:507. 13. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 14. Batcher EL, Tang XC, Singh BN, et al. Thyroid function abnormalities during amiodarone therapy for persistent atrial fibrillation. Am J Med 2007; 120:880. 15. Martino E, Safran M, Aghini-Lombardi F, et al. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984; 101:28. 16. Tsadok MA, Jackevicius CA, Rahme E, et al. Amiodarone-induced thyroid dysfunction: brand- name versus generic formulations. CMAJ 2011; 183:E817.
thyrotoxicosis (AIT). The excess iodine from the amiodarone provides increased substrate, resulting in enhanced thyroid hormone synthesis and hyperthyroidism. (See 'Type I' above.) Destructive thyroiditis (type II AIT) typically occurs in patients with no underlying thyroid disease. (See 'Type II' above.) In iodine-sufficient areas, amiodarone-induced hypothyroidism appears to be more common than hyperthyroidism. In contrast, amiodarone-induced hyperthyroidism (usually type I AIT) is more common than hypothyroidism in iodine-deficient regions. (See 'Dietary iodine intake' above.) We suggest continuing amiodarone therapy in patients who develop amiodarone-induced hypothyroidism (Grade 2C). (See 'Treatment' above.) The diagnosis and treatment of amiodarone-induced hypothyroidism is the same as for other patients with primary hypothyroidism. Euthyroidism should be restored by replacement with thyroid hormone. Thyroid hormone, in doses larger than normal, is often required. (See 'Treatment' above.) Amiodarone should only be discontinued if it fails to control the underlying arrhythmia. If amiodarone is discontinued in a patient without preexisting autoimmune thyroid disease, the hypothyroidism often resolves. (See 'Treatment' above.) There are two types of AIT. In type I, there is increased synthesis of thyroid hormone (excess iodine provides the increased substrate), whereas in type II, there is excess release of T4 and T3 due to a destructive thyroiditis (direct toxic effect of amiodarone on the thyroid gland). For patients with type II AIT, the hyperthyroid phase may last from several weeks to several months and is often followed by a hypothyroid phase and then recovery. (See 'Types of hyperthyroidism' above.) https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 13/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate It is often difficult to distinguish between the two types, and some patients may have elements of both. The 24-hour radioiodine uptake is typically not able to distinguish between types I and II AIT, because the high levels of ingested iodine with amiodarone results in 24-hour uptakes of less than 1 percent in most patients with either type I or type II AIT. Technetium-99m (99mTc)-sestamibi imaging, where available, or color-flow Doppler sonography (CFDS) may be the best ways of distinguishing between the two types of AIT. (See 'Differentiating the two types' above.) In patients who develop AIT in whom the amiodarone was prescribed for life-threatening ventricular arrhythmias (and is effective), we suggest continuing the amiodarone and simultaneously treating the hyperthyroidism (Grade 2C). (See 'Should amiodarone be discontinued?' above.) In patients who develop AIT in whom the amiodarone was not prescribed for life- threatening ventricular arrhythmias (or is ineffective), we suggest discontinuing the drug (Grade 2C). This should only be done in consultation with the patient's cardiologist if alternative antiarrhythmics can be used. For type I AIT, amiodarone should not be discontinued until hyperthyroid symptoms are well controlled with thionamides, since worsening hyperthyroid symptoms due to increased T3 levels may occur when the amiodarone is discontinued. (See 'Should amiodarone be discontinued?' above.) For the treatment of type I AIT, we suggest thionamides as our first choice of therapy (whether amiodarone is continued or discontinued) (Grade 2B) (see 'Thionamides' above). Although radioiodine ablation has been reported to have been used (in rare patients with high enough radioiodine uptake), this is usually not an option due to low radioiodine uptake in the majority of type I patients. (See 'Radioiodine' above.) Higher than average initial doses of thionamides are usually needed (30 to 40 mg of methimazole or 450 to 600 mg propylthiouracil [PTU] daily). Perchlorate or lithium are sometimes added to speed recovery, however, perchlorate is not available in the United States. In addition, perchlorate has been associated, albeit rarely, with aplastic anemia. (See 'Thionamides' above.) For the treatment of type II AIT, we suggest glucocorticoid therapy as our first-line drug (whether amiodarone is continued or discontinued) (Grade 2B). We typically start with prednisone (40 to 60 mg/day) and continue therapy for one to two months before tapering (to avoid exacerbations of hyperthyroidism). (See 'Glucocorticoids' above.) Patients with type I or type II AIT who are refractory to medical therapy should be treated by thyroidectomy. When balancing the risk of a surgical procedure during careful https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 14/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate cardiovascular monitoring with the risk of several months of unmonitored and uncontrolled thyrotoxicosis, the advantages of surgery in this setting become compelling. (See 'Surgery' above and 'Surgery' above.) If the mechanism of the hyperthyroidism is uncertain or the patient appears to have "mixed" type I and type II AIT, a combination of prednisone (40 mg/day) and methimazole (40 mg/day) is reasonable initial therapy. A rapid response suggests type II AIT; the methimazole can then be tapered or stopped. A poor or slow initial response argues for type I AIT. (See 'Treatment if mechanism unknown' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005; 118:706. 2. Kennedy RL, Griffiths H, Gray TA. Amiodarone and the thyroid. Clin Chem 1989; 35:1882. 3. Latini R, Tognoni G, Kates RE. Clinical pharmacokinetics of amiodarone. Clin Pharmacokinet 1984; 9:136. 4. Martino E, Aghini-Lombardi F, Mariotti S, et al. Amiodarone: a common source of iodine- induced thyrotoxicosis. Horm Res 1987; 26:158. 5. Rao RH, McCready VR, Spathis GS. Iodine kinetic studies during amiodarone treatment. J Clin Endocrinol Metab 1986; 62:563. 6. Franklyn JA, Davis JR, Gammage MD, et al. Amiodarone and thyroid hormone action. Clin Endocrinol (Oxf) 1985; 22:257. 7. van Beeren HC, Bakker O, Wiersinga WM. Structure-function relationship of the inhibition of the 3,5,3'-triiodothyronine binding to the alpha1- and beta1-thyroid hormone receptor by amiodarone analogs. Endocrinology 1996; 137:2807. 8. Roti E, Minelli R, Gardini E, et al. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone. A possible consequence of a destructive process in the thyroid. Arch Intern Med 1993; 153:886. 9. Braverman LE, Ingbar SH, Vagenakis AG, et al. Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 1971; 32:515. 10. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid 1998; 8:83. 11. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997; 126:63. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 15/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate 12. Trip MD, Wiersinga W, Plomp TA. Incidence, predictability, and pathogenesis of amiodarone- induced thyrotoxicosis and hypothyroidism. Am J Med 1991; 91:507. 13. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. 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Effects of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment. J Endocrinol Invest 2001; 24:116. 27. Nademanee K, Piwonka RW, Singh BN, Hershman JM. Amiodarone and thyroid function. Prog Cardiovasc Dis 1989; 31:427. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 16/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate 28. Christidis G, Lammert F, Krawczyk M. Amiodarone and hypothyroidism. Lancet 2021; 397:704. 29. Bartalena L, Brogioni S, Grasso L, et al. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996; 81:2930. 30. Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev 2001; 22:240. 31. Lambert M, Unger J, De Nayer P, et al. Amiodarone-induced thyrotoxicosis suggestive of thyroid damage. J Endocrinol Invest 1990; 13:527. 32. Bartalena L, Grasso L, Brogioni S, et al. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994; 78:423. 33. Brennan MD, Erickson DZ, Carney JA, Bahn RS. Nongoitrous (type I) amiodarone-associated thyrotoxicosis: evidence of follicular disruption in vitro and in vivo. Thyroid 1995; 5:177. 34. Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Amiodarone-induced thyroid dysfunction associated with cumulative dose. Pharmacoepidemiol Drug Saf 2002; 11:601. 35. Bogazzi F, Bartalena L, Dell'Unto E, et al. Proportion of type 1 and type 2 amiodarone- induced thyrotoxicosis has changed over a 27-year period in Italy. Clin Endocrinol (Oxf) 2007; 67:533. 36. Yiu KH, Jim MH, Siu CW, et al. Amiodarone-induced thyrotoxicosis is a predictor of adverse cardiovascular outcome. J Clin Endocrinol Metab 2009; 94:109. 37. O'Sullivan AJ, Lewis M, Diamond T. Amiodarone-induced thyrotoxicosis: left ventricular dysfunction is associated with increased mortality. Eur J Endocrinol 2006; 154:533. 38. Tomisti L, Rossi G, Bartalena L, et al. The onset time of amiodarone-induced thyrotoxicosis (AIT) depends on AIT type. Eur J Endocrinol 2014; 171:363. 39. Daniels GH. Amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2001; 86:3. 40. Martino E, Bartalena L, Mariotti S, et al. Radioactive iodine thyroid uptake in patients with amiodarone-iodine-induced thyroid dysfunction. Acta Endocrinol (Copenh) 1988; 119:167. 41. Eaton SE, Euinton HA, Newman CM, et al. Clinical experience of amiodarone-induced thyrotoxicosis over a 3-year period: role of colour-flow Doppler sonography. Clin Endocrinol (Oxf) 2002; 56:33. 42. Bogazzi F, Martino E, Dell'Unto E, et al. Thyroid color flow doppler sonography and radioiodine uptake in 55 consecutive patients with amiodarone-induced thyrotoxicosis. J Endocrinol Invest 2003; 26:635. 43. Piga M, Cocco MC, Serra A, et al. The usefulness of 99mTc-sestaMIBI thyroid scan in the differential diagnosis and management of amiodarone-induced thyrotoxicosis. Eur J https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 17/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate Endocrinol 2008; 159:423. 44. Wang J, Zhang R. Evaluation of 99mTc-MIBI in thyroid gland imaging for the diagnosis of amiodarone-induced thyrotoxicosis. Br J Radiol 2017; 90:20160836. 45. Cappellani D, De Marco G, Ferrarini E, et al. Identification of Two Different Phenotypes of Patients with Amiodarone-Induced Thyrotoxicosis and Positive Thyrotropin Receptor Antibody Tests. Thyroid 2021; 31:1463. 46. Bogazzi F, Bartalena L, Tomisti L, et al. Continuation of amiodarone delays restoration of euthyroidism in patients with type 2 amiodarone-induced thyrotoxicosis treated with prednisone: a pilot study. J Clin Endocrinol Metab 2011; 96:3374. 47. Eskes SA, Endert E, Fliers E, et al. Treatment of amiodarone-induced thyrotoxicosis type 2: a randomized clinical trial. J Clin Endocrinol Metab 2012; 97:499. 48. Osman F, Franklyn JA, Sheppard MC, Gammage MD. Successful treatment of amiodarone- induced thyrotoxicosis. Circulation 2002; 105:1275. 49. Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 2010; 95:2529. 50. Gershinsky M, Saliba W, Lavi I, et al. Increased Risk of Antithyroid Drug Agranulocytosis Associated with Amiodarone-Induced Thyrotoxicosis: A Population-Based Cohort Study. Thyroid 2019; 29:193. 51. Martino E, Aghini-Lombardi F, Mariotti S, et al. Treatment of amiodarone associated thyrotoxicosis by simultaneous administration of potassium perchlorate and methimazole. J Endocrinol Invest 1986; 9:201. 52. Dickstein G, Shechner C, Adawi F, et al. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med 1997; 102:454. 53. Maqdasy S, Batisse-Lignier M, Auclair C, et al. Amiodarone-Induced Thyrotoxicosis Recurrence After Amiodarone Reintroduction. Am J Cardiol 2016; 117:1112. 54. Hermida JS, Jarry G, Tcheng E, et al. Radioiodine ablation of the thyroid to allow the reintroduction of amiodarone treatment in patients with a prior history of amiodarone- induced thyrotoxicosis. Am J Med 2004; 116:345. 55. Bartalena L, Bogazzi F, Chiovato L, et al. 2018 European Thyroid Association (ETA) Guidelines for the Management of Amiodarone-Associated Thyroid Dysfunction. Eur Thyroid J 2018; 7:55. 56. Bogazzi F, Miccoli P, Berti P, et al. Preparation with iopanoic acid rapidly controls thyrotoxicosis in patients with amiodarone-induced thyrotoxicosis before thyroidectomy. Surgery 2002; 132:1114. https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 18/19 7/5/23, 8:17 AM Amiodarone and thyroid dysfunction - UpToDate 57. Houghton SG, Farley DR, Brennan MD, et al. Surgical management of amiodarone- associated thyrotoxicosis: Mayo Clinic experience. World J Surg 2004; 28:1083. 58. Tomisti L, Materazzi G, Bartalena L, et al. Total thyroidectomy in patients with amiodarone- induced thyrotoxicosis and severe left ventricular systolic dysfunction. J Clin Endocrinol Metab 2012; 97:3515. 59. Cappellani D, Papini P, Pingitore A, et al. Comparison Between Total Thyroidectomy and Medical Therapy for Amiodarone-Induced Thyrotoxicosis. J Clin Endocrinol Metab 2020; 105. 60. Bogazzi F, Tomisti L, Rossi G, et al. Glucocorticoids are preferable to thionamides as first-line treatment for amiodarone-induced thyrotoxicosis due to destructive thyroiditis: a matched retrospective cohort study. J Clin Endocrinol Metab 2009; 94:3757. 61. Uzan L, Guignat L, Meune C, et al. Continuation of amiodarone therapy despite type II amiodarone-induced thyrotoxicosis. Drug Saf 2006; 29:231. 62. Bogazzi F, Bartalena L, Tomisti L, et al. Glucocorticoid response in amiodarone-induced thyrotoxicosis resulting from destructive thyroiditis is predicted by thyroid volume and serum free thyroid hormone concentrations. J Clin Endocrinol Metab 2007; 92:556. 63. Bogazzi F, Bartalena L, Cosci C, et al. Treatment of type II amiodarone-induced thyrotoxicosis by either iopanoic acid or glucocorticoids: a prospective, randomized study. J Clin Endocrinol Metab 2003; 88:1999. 64. Yagishita A, Hachiya H, Kawabata M, et al. Amiodarone-induced thyrotoxicosis late after amiodarone withdrawal. Circ J 2013; 77:2898. 65. Kurnik D, Loebstein R, Farfel Z, et al. Complex drug-drug-disease interactions between amiodarone, warfarin, and the thyroid gland. Medicine (Baltimore) 2004; 83:107. Topic 7834 Version 22.0 Contributor Disclosures Douglas S Ross, MD Consultant/Advisory Boards: Medullary Thyroid Cancer Registry Consortium [Thyroid cancer]. All of the relevant financial relationships listed have been mitigated. David S Cooper, MD No relevant financial relationship(s) with ineligible companies to disclose. Jean E Mulder, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-and-thyroid-dysfunction/print 19/19
7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Amiodarone: Clinical uses : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA, Rod Passman, MD, MSCE : Samuel L vy, MD, Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 30, 2022. INTRODUCTION Amiodarone is an iodinated benzofuran derivative that was synthesized and tested as an antianginal agent in the 1960s but was later discovered to have antiarrhythmic properties. Amiodarone is widely prescribed, largely due to its efficacy in the management of both supraventricular and ventricular arrhythmias. In addition to the superior efficacy compared with most other antiarrhythmic drugs, amiodarone has very little negative inotropic activity and a low rate of ventricular proarrhythmia, making it advantageous for use in patients with heart failure [1]. Despite these advantages, the use of amiodarone is associated with a relatively high incidence of side effects, making it a complicated drug to use safely. This topic will review the electrophysiologic properties of amiodarone, clinical indications, and dosing recommendations for oral and intravenous amiodarone. The side effects of amiodarone are discussed in detail elsewhere. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Amiodarone and thyroid dysfunction".) PHARMACOKINETICS Slow and wide distribution of amiodarone to tissue (fat, muscle, highly perfused organs) results in a requirement of long loading periods in an effort to accelerate the onset of drug activity. Oral amiodarone is markedly lipophilic, resulting in a very large volume of distribution (average approximately 66 L/kg) and a prolonged time to reach stable plasma levels [1]. It is incompletely absorbed (approximately 30 to 70 percent) after oral administration and is taken up very https://www.uptodate.com/contents/amiodarone-clinical-uses/print 1/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate extensively by tissue, with marked interindividual variation [2]. Because of these characteristics, even with loading, arrhythmia recurrence during the first months of therapy does not necessarily predict long-term efficacy. Conversely, intravenous (IV) amiodarone begins to act within one hour, with rapid onset of action within minutes following an IV bolus. Estimates of the elimination half-life of amiodarone vary, depending on how the half-life has been measured and the route of amiodarone administration. After long-term oral therapy, amiodarone has a true elimination half-life between 60 and 142 days [2,3]. The relatively short half-life for disappearance of amiodarone from plasma after a single- dose or short-term IV administration is likely a measure of drug redistribution from vascular space into tissue and not true body elimination. There is little correlation between the plasma concentration of amiodarone or its major active metabolite, desethylamiodarone, and drug efficacy or toxicity [1]. ELECTROPHYSIOLOGIC PROPERTIES The electrophysiologic properties of amiodarone are complex and incompletely understood. Though classified as a Vaughan-Williams class III antiarrhythmic agent due to its inhibition of outward potassium channels, the drug also has class I sodium channel blocking effects, class II antiadrenergic effects, and class IV calcium channel blocking effects ( table 1). The oral and intravenous (IV) forms of amiodarone have important electrophysiologic differences that have an impact on their clinical use ( table 2). Oral amiodarone Oral amiodarone is classified as a class III antiarrhythmic agent since it prolongs the duration of the action potential and the refractory period of both atrial and ventricular tissue ( figure 1). This effect is primarily mediated by blockade of the rapid component of the delayed rectifier current (IKr) that is responsible for phase 3 repolarization of the action potential ( figure 2). (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Like other class III agents (sotalol, dofetilide, ibutilide, dronedarone), amiodarone prolongs the QT interval. However, by contrast to most other class III agents, amiodarone has very little proarrhythmic activity. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 2/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Oral amiodarone has several other effects that may contribute to its therapeutic efficacy: It inhibits inactivated (phase 0) sodium channels, an effect that is primarily seen at rapid heart rates It has some class II antiarrhythmic drug activity, inhibiting sympathetic activity, primarily by causing noncompetitive beta receptor blockade It also has some class IV antiarrhythmic drug activity by blocking L-type (slow) calcium channels Intravenous amiodarone IV amiodarone has a number of important electrophysiologic differences from chronically administered oral amiodarone [4,5]: IV amiodarone produces a much smaller increase in the action potential duration in atrial and ventricular myocardium and a minimal increase in the atrial and ventricular refractory periods. As a result, there is little or no increase in QRS duration or the QT interval, respectively. IV amiodarone has little effect on sinus cycle length. It has vasodilator activity that triggers an increase in sympathetic activity, and as a result, there is little or no slowing of the sinus rate. IV amiodarone may have more potent and more rapid antiadrenergic activity. Like oral amiodarone, IV amiodarone inhibits inactivated sodium channels, though to a lesser degree than the oral form [4]. This property may account for the efficacy of the agent in the suppression of ventricular tachyarrhythmias [6]. IV amiodarone also prolongs atrioventricular (AV) nodal conduction and refractoriness and may be effective in slowing the ventricular rate in critically ill patients with atrial tachyarrhythmias [7]. Effects on the ECG The multiple actions of chronically administered oral amiodarone therapy can produce a variety of changes in the electrocardiogram (ECG). These include: Slowing of the sinus rate. Both calcium channel blockade and beta blockade may contribute to this effect, which can lead to sinus bradycardia [5]. Prolongation of the PR interval and the AV nodal refractory period. Thus, AV conduction block may occur, an effect that may also be related to calcium channel blockade since the AV node is a "slow response" tissue that relies on an inward calcium current for depolarization. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs", section on 'Action potential in slow response tissues'.) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 3/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Widening of the QRS complex (typically less than 10 percent), as conduction is slowed in ventricular muscle by the blocking effect on the inactivated sodium channel, thereby slowing phase 0 depolarization ( figure 1) [8]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Prolongation of the QT interval (typically less than 10 percent) due to blockade of IKr, the delayed rectifier potassium current that is responsible for phase 3 depolarization of the action potential ( figure 1) [8,9]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects'.) ORAL AMIODARONE FOR THE TREATMENT OF ATRIAL ARRHYTHMIAS Amiodarone can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. It is commonly used for several reasons: Amiodarone is the most effective medical therapy available for maintaining sinus rhythm There is a low risk of ventricular proarrhythmia based on the electrophysiologic properties of amiodarone Amiodarone does not increase mortality in heart failure patients Therapy can be easily initiated on an outpatient basis In addition, if AF recurs, amiodarone usually slows the ventricular response at rest and with exercise. It also may reduce symptoms associated with rapid ventricular response to AF, though amiodarone is not recommended solely as a rate-controlling agent. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.) Amiodarone can be used to treat other atrial arrhythmias such as atrial flutter or atrial tachycardia, but the availability of other antiarrhythmic drugs with lower toxicity rates, and the high success rates of ablative approaches to atrial flutter or atrial tachycardia, often favors these alternatives. The major limiting factor in the use of oral amiodarone for the treatment of AF and other atrial arrhythmias is long-term organ toxicity (eg, thyroid, lung, etc) ( table 3). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Prevention of recurrent paroxysmal atrial fibrillation The decision to pursue a strategy of rhythm control in any patient with AF is complex and depends on: https://www.uptodate.com/contents/amiodarone-clinical-uses/print 4/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate The presence or absence of symptoms Potential adverse effects of persistent AF (ie, uncontrolled ventricular rate) Adverse effects of alternative therapies for AF The choice of which antiarrhythmic drug to use for paroxysmal AF is also complex and based on a variety of factors, most notably the presence and type of structural heart disease. Unlike many other antiarrhythmic drugs, amiodarone has a low risk of ventricular proarrhythmia and does not increase mortality when administered to patients with coronary disease, left ventricular (LV) hypertrophy, LV dysfunction, or congestive heart failure. While there is no universally accepted dosing regimen, oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used ( table 4) [10]. Gastrointestinal side effects may limit loading doses. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can sometimes be as low as 100 mg daily. Doses up to 400 mg/day may also be used but are not recommended for routine maintenance given the higher risk of adverse events. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Pharmacologic cardioversion of atrial fibrillation Amiodarone is not a first-line therapy for pharmacologic cardioversion given its limited efficacy and long onset of action. If amiodarone is used in this setting, American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines recommend oral loading and maintenance doses to be the same as those described for amiodarone use to prevent recurrence and maintain sinus rhythm in patients with paroxysmal AF. (See 'Prevention of recurrent paroxysmal atrial fibrillation' above.) Oral amiodarone can result in pharmacologic cardioversion of AF in approximately 25 percent of patients with high ventricular rates from either acute or recent-onset AF [10-12]. Because of the potential for cardioversion following administration of amiodarone, standard precautions need to be considered to prevent thromboembolic events. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Amiodarone and other pharmacologic agents for cardioversion are reviewed separately. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) Pretreatment before elective cardioversion or catheter ablation for persistent atrial fibrillation In patients who did not remain in sinus rhythm following cardioversion or in patients at high risk for recurrent AF after planned cardioversion, we often pretreat with an antiarrhythmic drug, including amiodarone [13]. Given the prolonged half-life of oral https://www.uptodate.com/contents/amiodarone-clinical-uses/print 5/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate amiodarone, the loading time is extended, so the drug should be started two to six weeks prior to elective cardioversion to reduce the risk of recurrence. Dosing regimens vary ( table 4) but generally aim for an oral load of 6 to 10 grams over a period of two to six weeks prior to cardioversion, with a decrease in dose to maintenance levels (usually 100 to 200 mg daily) following cardioversion or shortly thereafter. Given the unique pharmacologic properties of amiodarone, AF recurrences in the first two to three months following cardioversion do not necessarily predict long-term failure of the drug. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.) Oral amiodarone has also been investigated in patients undergoing catheter ablation for persistent AF. In the AMIO-CAT trial, in which 212 patients undergoing AF ablation were randomized to begin therapy with amiodarone or placebo for eight weeks following catheter ablation, there was a nonsignificant trend toward fewer recurrences of AF in the amiodarone group (39 versus 48 percent), but significantly fewer patients receiving amiodarone required hospitalization or cardioversion for recurrent AF [14]. In the SPECULATE trial, in which 112 patients with long-standing persistent AF were randomized to discontinuation of chronic amiodarone therapy four months prior to ablation or continuation of therapy and then followed for an average of 32 months, significantly more patients who continued amiodarone had successful termination of AF at the time of ablation (79 versus 57 percent); however, late AF recurrence was significantly greater in the group who continued amiodarone [15]. Further investigation is needed to determine the optimal role for amiodarone in patients undergoing AF ablation. Prophylaxis against atrial fibrillation following cardiac surgery Amiodarone lowers the incidence of postoperative AF in patients undergoing cardiac surgery [10]. Various dosing regimens for oral amiodarone have been used in clinical trials [16,17]. In general, however, we recommend beta blockers rather than amiodarone; however, for patients who cannot take beta blockers, amiodarone may be used. The approach to prevention of AF following cardiac surgery is discussed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Amiodarone'.) INTRAVENOUS AMIODARONE FOR THE TREATMENT OF ATRIAL ARRHYTHMIAS https://www.uptodate.com/contents/amiodarone-clinical-uses/print 6/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Intravenous (IV) amiodarone is primarily used for the treatment of atrial arrhythmias in two settings: Restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable atrial fibrillation (AF). Rate control in critically ill patients with AF with rapid ventricular response in whom the tachycardia is contributing to hemodynamic compromise. The administration of IV amiodarone requires attention to a specific dosing schedule to minimize side effects, which are largely different from those seen with chronic oral therapy. In addition, there is substantial interindividual variability in response time; as a result, careful patient observation and dose adjustment are recommended as necessary. Amiodarone should be mixed in a 5 percent dextrose solution and the amiodarone concentration kept below 2 mg/mL if given through a peripheral vein to minimize the development of local phlebitis. Higher drug concentrations must be delivered through an indwelling catheter in a central vein. Amiodarone is physically incompatible with a number of drugs, including heparin, which should not be given in the same solution. (See 'Side effects with IV administration' below.) Restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable atrial fibrillation AF is common in critically ill patients and may contribute to hemodynamic instability. IV amiodarone can be used in this situation but has not been sufficiently studied in this population to allow for specific recommendations. When administered ( table 4), an initial IV loading dose of 150 mg is given over a minimum of 10 minutes. More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter [1]. This regimen delivers 1050 mg of amiodarone in the first 24 hours. In general, the reported efficacy of IV amiodarone in restoring and maintaining sinus rhythm is inconsistent, though professional society guidelines list IV amiodarone as an option for pharmacologic cardioversion [10]. (See "Atrial fibrillation: Cardioversion", section on 'Indications'.) Several meta-analyses have been published evaluating the efficacy of IV amiodarone in restoration of normal sinus rhythm in critically ill patients [18-20]. The meta-analyses have included studies with widely varying methodologies, leading to some conflicting results. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 7/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate The largest meta-analysis included studies comparing amiodarone with other antiarrhythmic drugs or placebo [19]. IV amiodarone was as efficacious as other antiarrhythmic drugs and more effective than placebo, but amiodarone was associated with a higher rate of adverse events compared with placebo. Another meta-analysis, which included only studies comparing amiodarone with placebo or class Ic antiarrhythmic drugs, determined that conversion from AF to sinus rhythm was greater at 8 and 24 hours, but not at one or two hours [20]. Conversion rates from AF to sinus rhythm following IV amiodarone are higher when the bolus (3 to 7 mg/kg) is followed by continuous infusion (900 to 3000 mg daily) [18]. Ventricular rate control in critically ill patients with atrial fibrillation and rapid ventricular response IV amiodarone may be used as a rate-controlling agent in critically ill individuals with hemodynamically destabilizing AF who cannot be maintained in sinus rhythm and in whom standard rate-controlling therapies have been either unsuccessful or are contraindicated due to hypotension. An initial IV loading dose of 150 mg is given over a minimum of 10 minutes ( table 4). More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter [1]. This regimen delivers 1050 mg of amiodarone in the first 24 hours. Repeated 150 mg boluses can be given over 10 to 30 minutes, but no more than six to eight additional boluses should be administered in any 24-hour period. AF with rapid ventricular response may contribute to hemodynamic compromise. Furthermore, ventricular rates >120 beats/minute for prolonged periods of time may contribute to left ventricular dysfunction. In a retrospective study, intensive care unit patients with hemodynamically destabilizing AF or atrial flutter resistant to conventional therapy experienced a significant 37 beat/minute decrease in ventricular rate and an increase in systolic blood pressure of 24 mmHg with no associated adverse effects [7]. IV amiodarone may also be used for rate control in patients with congestive heart failure [10]. AMIODARONE FOR VENTRICULAR ARRHYTHMIAS Amiodarone is useful in a variety of ventricular arrhythmias including ventricular premature beats (VPBs), nonsustained ventricular tachycardia (VT), and sustained VT or ventricular fibrillation (VF). Most commonly, amiodarone is used for the secondary prevention of recurrent ventricular arrhythmias in patients with an implantable cardioverter-defibrillator (ICD) to reduce the frequency of ICD shocks. Typically, a beta blocker is co-administered with amiodarone. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 8/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Treatment of ventricular arrhythmias Amiodarone suppresses VPBs and episodes of nonsustained VT. This is clearly demonstrated in several of the primary prevention trials of amiodarone in post-myocardial infarction (MI) and congestive heart failure patients in whom baseline and follow-up 24-hour ambulatory ECGs were performed. As examples: The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) pilot study enrolled patients with frequent or repetitive asymptomatic ventricular premature depolarizations (VPDs) [21]. When compared with placebo, patients receiving amiodarone had much greater suppression of VPDs and nonsustained VT (86 compared with 50 percent of placebo patients). The CHF-STAT trial compared amiodarone versus placebo in patients with heart failure, left ventricular (LV) ejection fraction of 40 percent or less, and frequent VPBs (more than 10/hour) [22]. Following two weeks of treatment, significantly fewer patients on amiodarone had VT on Holter monitor (33 versus 76 percent). Despite the reduction in ventricular arrhythmias and ectopy, amiodarone did not reduce mortality. Additional trials are reviewed in detail elsewhere. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Amiodarone is also one of the few antiarrhythmic drugs that does not increase mortality when given to patients with moderate to severe LV dysfunction. The apparent efficacy and safety of amiodarone for the treatment of ventricular tachyarrhythmias in patients with structural heart disease have led to several studies evaluating the impact of amiodarone on survival in patients at high risk of arrhythmic death. Primary prevention of sudden cardiac death Amiodarone for primary prevention of sudden cardiac death (SCD) is generally considered only for patients with LV dysfunction who are not candidates for, or refuse to have, ICD implantation [23]. When administered ( table 4), the recommended loading dose for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [1]. Higher loading dose regimens have been evaluated but do not appear to provide greater efficacy. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. Ventricular arrhythmias are responsible for a large proportion of SCDs, especially in those individuals with underlying structural heart disease. The ability of amiodarone to suppress ventricular arrhythmias led to several trials designed to assess its effect on patients deemed high risk for ventricular arrhythmias either because they have already survived a sustained ventricular tachyarrhythmia or were believed to be at high risk of developing such arrhythmias due to the presence of LV dysfunction. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 9/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Earlier studies comparing amiodarone with standard medical therapy generally enrolled patients with either recent MI or congestive heart failure [2]. A 2015 Cochrane systematic review and meta-analysis (based on low to moderate quality evidence) concluded that, compared with placebo or no intervention, amiodarone reduced SCD (risk ratio [RR] 0.76, 95% CI 0.66-0.88), total cardiac death (RR 0.86, 95% CI 0.77-0.96), and all-cause mortality (RR 0.88, 95% CI 0.78-1.00) [24]. In trials comparing amiodarone with ICD therapy, ICD therapy was superior in the primary prevention of SCD [25,26]. Because of this, amiodarone for primary prevention of SCD is rarely used without concurrent use of an ICD. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Secondary prevention of sudden cardiac death In view of the superiority of ICD compared with antiarrhythmic drugs, including amiodarone, for the secondary prevention of SCD, amiodarone should not be used alone for secondary prevention except in those who do not meet ICD criteria, or in those who meet criteria but cannot receive a device or refuse device implantation. When administered ( table 4), the recommended loading dose for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams [1]. Higher loading dose regimens have been evaluated but do not appear to provide greater efficacy. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. Survivors of SCD due to arrhythmia carry a high risk of recurrence. With the possible exception of amiodarone, attempts to significantly reduce SCD rates by using antiarrhythmic drugs have yielded disappointing results, most likely related to the proarrhythmic effects of many antiarrhythmic drugs. The recognition of the limitations of antiarrhythmic drugs for secondary prevention was paralleled by the development of smaller, transvenous ICDs with tiered therapies, bradycardia pacing, and success rates of >95 percent in terminating VT and VF. Several randomized trials and meta-analyses have compared ICDs with antiarrhythmic drugs for secondary prevention of SCD in patients with resuscitated VF, sustained VT with syncope, or sustained VT with ejection fraction 40 percent, and evidence of hemodynamic compromise. All showed superior efficacy of ICD compared with antiarrhythmic drugs. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) Prevention of ventricular arrhythmias in patients with ICDs Shocks delivered by an ICD, especially when repetitive, can be painful and impact quality of life [27]. Amiodarone may be used to decrease the risk of ICD shocks. When administered ( table 4), the recommended loading dose for the prevention of ICD shocks is 400 to 1200 mg/day (usually in divided doses) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 10/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate for a total of 6 to 10 grams [23,28]. Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) Study evaluated amiodarone plus beta blocker, sotalol alone, and beta blocker alone for the prevention of ICD shocks in 412 patients [29]. Amiodarone plus beta blocker significantly reduced the risk of shock compared with beta blocker alone (hazard ratio [HR] 0.27, 95% CI 0.14- 0.52) or sotalol alone (HR 0.43, 95% CI 0.22-0.85). In the SURVIVE-VT trial, patients with ischemic cardiomyopathy and appropriate ICD shocks who were randomly assigned antiarrhythmic drugs, including amiodarone, were more likely to experience the composite endpoint (including cardiovascular death, appropriate ICD shock, heart failure hospitalization, or severe treatment- related complications), compared with those treated with ablation (HR 0.52, 95%CI 0.30-0.90). (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Antiarrhythmic drugs'.) When using amiodarone in patients with ICDs, reassessment of defibrillation threshold may be necessary in those individuals with marginally acceptable defibrillation threshold prior to drug initiation [30]. Additionally, care must be taken in device programming as amiodarone may slow the rate of VT such that the cycle length of spontaneous VT falls outside of the programmed limits (heart rate or cycle length) for detection of VT. (See "Cardiac implantable electronic devices: Long-term complications", section on 'Increased defibrillation threshold'.) IV amiodarone for the treatment of electrical storm and incessant ventricular tachycardia The use of IV amiodarone in the treatment of electrical storm and incessant VT is discussed separately. (See "Electrical storm and incessant ventricular tachycardia".) IV amiodarone during resuscitation from cardiac arrest The administration of IV amiodarone as part of the advanced cardiac life support protocol for resuscitation of cardiac arrest is discussed separately. (See "Advanced cardiac life support (ACLS) in adults".) SPECIAL CONSIDERATIONS Side effects with IV administration A major problem noted with the intravenous (IV) preparation is hypotension, which occurs in as many as 26 percent of patients and has been attributed to faster loading rates as well as the solvents used in the preparation [6,31]. Hypotension does not appear to occur with a preparation of amiodarone that employs an aqueous base [32]. Patients who develop hypotension may benefit from a decrease in the infusion rate, while additional IV boluses may be beneficial in patients with recurrent arrhythmias during the early phase of therapy [1,7]. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 11/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Proarrhythmia has been noted in 2 to 3 percent of patients treated with intravenous amiodarone; it usually manifests as torsades de pointes, but ventricular fibrillation can occur [4,6]. In a multicenter study in which 6 of 342 patients developed proarrhythmia, all had an exacerbating factor such as acute ischemia or an electrolyte imbalance [6]. Other cardiac side effects (bradycardia, asystole, heart failure, and shock), nausea, vomiting, and abnormal liver function tests occurred in 1 to 5 percent of patients each [4,6]. When given through peripheral intravenous lines, amiodarone may cause local phlebitis [33,34]. The risk of amiodarone-induced phlebitis increases with higher infusion rates and higher concentrations (eg, >2 mg/mL). The risk of phlebitis can be reduced by using lower infusion rates (when possible), lower concentrations (<2 mg/mL), or an in-line filter [35]. Transition from IV to oral therapy The bioavailability of oral compared with intravenous amiodarone ranges from 30 to 70 percent and is increased in the presence of food. Additionally, an increase in plasma levels may not be seen for four to five hours after the ingestion of oral amiodarone. We suggest the following approach to converting IV to oral amiodarone dosing: Patients who have been on IV therapy for more than two weeks can be started on maintenance oral amiodarone at a dose of 200 to 400 mg/day. Patients who have been on IV therapy for one to two weeks can be started on an intermediate amiodarone dose of 400 to 800 mg/day. This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. Patients who have been on IV therapy for one week or less should probably receive the usual oral amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function. Dose adjustment Amiodarone is metabolized in the liver. The major metabolite is desethylamiodarone, which is active and has a longer elimination half-life than amiodarone [1]. Dose reduction is probably necessary in patients with significant hepatic disease. By comparison, there is minimal elimination of both amiodarone and desethylamiodarone by the kidneys due both to the large volume of distribution and extensive protein binding; the latter effect also minimizes drug removal by dialysis. As a result, the dose of amiodarone does not have to be reduced in patients with renal disease or in patients undergoing dialysis. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 12/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Drug interactions Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Interactions with other drugs, such as digoxin and warfarin, must be considered. A few key drug interactions are discussed separately in UpToDate. Additionally, specific interactions of amiodarone with other medications may be determined using the Lexicomp drug interactions tool. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.) Use in children The overall safety and efficacy of amiodarone in children have not been fully established. Use of amiodarone in the treatment of tachyarrhythmias in children has been reported in several small series and one small clinical trial [36]. Although amiodarone is effective for number of arrhythmias, its use in children is often limited by toxicities. Adverse events are common with IV amiodarone use in children and may be severe. Consultation with a pediatric cardiologist is advised. Severe adverse effects may include cardiovascular collapse, hypotension, bradycardia, and AV block. Nausea and vomiting are also common. ECG and blood pressure monitoring should be performed during administration of IV amiodarone. Amiodarone appears to be effective in the following circumstances: Supraventricular tachycardia (SVT) In children with refractory SVT, IV amiodarone is an option as second-line therapy for conversion to sinus rhythm. Use of IV amiodarone in this setting is generally limited to treatment of SVT that is refractory to other agents (adenosine, procainamide), and oral amiodarone is a second-line therapy for the prevention of recurrent arrhythmia. In children with frequent or symptomatic SVT episodes, oral amiodarone is sometimes used for chronic management if there is a poor response to first- and second-line agents (eg, beta blockers, digoxin, and sotalol). (See "Management of supraventricular tachycardia (SVT) in children".) Wide QRS complex tachycardia IV amiodarone has also been used, alone or in combination with other antiarrhythmic drugs, in infants and children with resistant, life- threatening ventricular tachyarrhythmias [37,38]. (See "Management and evaluation of wide QRS complex tachycardia in children", section on 'Shock-resistant tachyarrhythmia'.) Optimal dosing of amiodarone in children is not well established. For oral therapy, dosing is based upon body weight or, in children less than one year of age, upon body surface area. The loading dose, which can be given in one or two divided 2 doses per day, is 10 to 15 mg/kg per day or 600 to 800 mg/1.73 m per day for 4 to 14 days or until adequate control of the arrhythmia is attained or prominent adverse effects occur. 2 The dose should then be reduced to 5 mg/kg per day or 200 to 400 mg/1.73 m per day https://www.uptodate.com/contents/amiodarone-clinical-uses/print 13/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate once daily for several weeks. If the arrhythmia does not recur, the lowest effective dose should be used for maintenance. The usual minimal dose is 2.5 mg/kg per day. For IV therapy in critically ill children with tachyarrhythmias who have not responded to standard therapy, a variety of regimens have been used. We typically give a slow bolus infusion of 5 mg/kg (maximum dose 300 mg) IV over 20 to 60 minutes. If the patient does not convert to sinus rhythm, additional bolus doses of 1 to 5 mg/kg (up to a total of 15 mg/kg) can be given if there are no signs of toxicity (eg, hypotension, prolonged QT interval). This can be followed, if necessary, by a continuous infusion at a rate of 5 to 10 mcg/kg per minute. Use in pregnancy Amiodarone has unique characteristics that mandate cautious use in pregnancy. The complications that can occur with the use of amiodarone during pregnancy are: Hypothyroidism or hyperthyroidism in the mother or fetus because of the iodine in amiodarone Fetal bradycardia Fetal QT interval prolongation Premature labor Low birth weight In addition, amiodarone is found in fetal tissue and breast milk. For these reasons, the use of amiodarone in pregnancy should be reserved for maternal and fetal arrhythmias not responding to agents with known safety. Concomitant beta-blocker therapy should be avoided. Breast feeding is not recommended when the mother is taking amiodarone. (See "Supraventricular arrhythmias during pregnancy" and "Maternal conduction disorders and bradycardia during pregnancy".) Neonates of mothers taking amiodarone should have complete thyroid function tests and developmental follow-up. (See "Clinical features and detection of congenital hypothyroidism".) SIDE EFFECTS While amiodarone does have many potential benefits, side effects are a serious concern. Of greatest concern are potential toxicities involving the lungs, thyroid, liver, eyes, and skin ( table 3). The potential side effects related to amiodarone use are discussed in detail separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 14/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Electrocardiographic actions Amiodarone has various electrophysiologic properties that are favorable in the treatment of tachyarrhythmias. There are important differences in these properties between the oral and intravenous (IV) preparations. (See 'Electrophysiologic properties' above.) Amiodarone can slow the sinus heart rate, prolong the PR interval, widen the QRS complex, and prolong the QT interval on surface electrocardiogram. (See 'Effects on the ECG' above.) Treatment of atrial arrythmias Oral amiodarone This can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. While there is no universally accepted dosing regimen ( table 4), oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can
usual oral amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day. Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function. Dose adjustment Amiodarone is metabolized in the liver. The major metabolite is desethylamiodarone, which is active and has a longer elimination half-life than amiodarone [1]. Dose reduction is probably necessary in patients with significant hepatic disease. By comparison, there is minimal elimination of both amiodarone and desethylamiodarone by the kidneys due both to the large volume of distribution and extensive protein binding; the latter effect also minimizes drug removal by dialysis. As a result, the dose of amiodarone does not have to be reduced in patients with renal disease or in patients undergoing dialysis. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 12/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Drug interactions Amiodarone is highly bound to plasma proteins (>96 percent) and can alter the plasma concentration of other highly bound drugs. Interactions with other drugs, such as digoxin and warfarin, must be considered. A few key drug interactions are discussed separately in UpToDate. Additionally, specific interactions of amiodarone with other medications may be determined using the Lexicomp drug interactions tool. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse drug interactions'.) Use in children The overall safety and efficacy of amiodarone in children have not been fully established. Use of amiodarone in the treatment of tachyarrhythmias in children has been reported in several small series and one small clinical trial [36]. Although amiodarone is effective for number of arrhythmias, its use in children is often limited by toxicities. Adverse events are common with IV amiodarone use in children and may be severe. Consultation with a pediatric cardiologist is advised. Severe adverse effects may include cardiovascular collapse, hypotension, bradycardia, and AV block. Nausea and vomiting are also common. ECG and blood pressure monitoring should be performed during administration of IV amiodarone. Amiodarone appears to be effective in the following circumstances: Supraventricular tachycardia (SVT) In children with refractory SVT, IV amiodarone is an option as second-line therapy for conversion to sinus rhythm. Use of IV amiodarone in this setting is generally limited to treatment of SVT that is refractory to other agents (adenosine, procainamide), and oral amiodarone is a second-line therapy for the prevention of recurrent arrhythmia. In children with frequent or symptomatic SVT episodes, oral amiodarone is sometimes used for chronic management if there is a poor response to first- and second-line agents (eg, beta blockers, digoxin, and sotalol). (See "Management of supraventricular tachycardia (SVT) in children".) Wide QRS complex tachycardia IV amiodarone has also been used, alone or in combination with other antiarrhythmic drugs, in infants and children with resistant, life- threatening ventricular tachyarrhythmias [37,38]. (See "Management and evaluation of wide QRS complex tachycardia in children", section on 'Shock-resistant tachyarrhythmia'.) Optimal dosing of amiodarone in children is not well established. For oral therapy, dosing is based upon body weight or, in children less than one year of age, upon body surface area. The loading dose, which can be given in one or two divided 2 doses per day, is 10 to 15 mg/kg per day or 600 to 800 mg/1.73 m per day for 4 to 14 days or until adequate control of the arrhythmia is attained or prominent adverse effects occur. 2 The dose should then be reduced to 5 mg/kg per day or 200 to 400 mg/1.73 m per day https://www.uptodate.com/contents/amiodarone-clinical-uses/print 13/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate once daily for several weeks. If the arrhythmia does not recur, the lowest effective dose should be used for maintenance. The usual minimal dose is 2.5 mg/kg per day. For IV therapy in critically ill children with tachyarrhythmias who have not responded to standard therapy, a variety of regimens have been used. We typically give a slow bolus infusion of 5 mg/kg (maximum dose 300 mg) IV over 20 to 60 minutes. If the patient does not convert to sinus rhythm, additional bolus doses of 1 to 5 mg/kg (up to a total of 15 mg/kg) can be given if there are no signs of toxicity (eg, hypotension, prolonged QT interval). This can be followed, if necessary, by a continuous infusion at a rate of 5 to 10 mcg/kg per minute. Use in pregnancy Amiodarone has unique characteristics that mandate cautious use in pregnancy. The complications that can occur with the use of amiodarone during pregnancy are: Hypothyroidism or hyperthyroidism in the mother or fetus because of the iodine in amiodarone Fetal bradycardia Fetal QT interval prolongation Premature labor Low birth weight In addition, amiodarone is found in fetal tissue and breast milk. For these reasons, the use of amiodarone in pregnancy should be reserved for maternal and fetal arrhythmias not responding to agents with known safety. Concomitant beta-blocker therapy should be avoided. Breast feeding is not recommended when the mother is taking amiodarone. (See "Supraventricular arrhythmias during pregnancy" and "Maternal conduction disorders and bradycardia during pregnancy".) Neonates of mothers taking amiodarone should have complete thyroid function tests and developmental follow-up. (See "Clinical features and detection of congenital hypothyroidism".) SIDE EFFECTS While amiodarone does have many potential benefits, side effects are a serious concern. Of greatest concern are potential toxicities involving the lungs, thyroid, liver, eyes, and skin ( table 3). The potential side effects related to amiodarone use are discussed in detail separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 14/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Electrocardiographic actions Amiodarone has various electrophysiologic properties that are favorable in the treatment of tachyarrhythmias. There are important differences in these properties between the oral and intravenous (IV) preparations. (See 'Electrophysiologic properties' above.) Amiodarone can slow the sinus heart rate, prolong the PR interval, widen the QRS complex, and prolong the QT interval on surface electrocardiogram. (See 'Effects on the ECG' above.) Treatment of atrial arrythmias Oral amiodarone This can be used to treat most types of atrial arrhythmias but is used primarily to maintain normal sinus rhythm in patients with atrial fibrillation (AF). However, oral amiodarone is not FDA approved in the United States for rhythm control in AF, despite common usage for this indication. While there is no universally accepted dosing regimen ( table 4), oral loading doses of 400 to 1200 mg/day in divided doses (up to a total loading dose of 6 to 10 grams) can be used. The usual maintenance dose should be the lowest effective dose, which for AF is usually 200 mg daily but can sometimes be as low as 100 mg daily. (See 'Oral amiodarone for the treatment of atrial arrhythmias' above.) IV amiodarone This is primarily used for the treatment of atrial arrhythmias in two settings: restoration and maintenance of sinus rhythm in critically ill patients with hemodynamically unstable AF, and rate control in critically ill patients with AF with rapid ventricular response in whom the tachycardia is contributing to hemodynamic compromise. An initial IV loading dose of 150 mg is given over a minimum of 10 minutes ( table 4). More rapid infusion increases the risk of hypotension. The loading dose should be followed by a continuous infusion of 1 mg/minute for six hours and 0.5 mg/minute thereafter. (See 'Intravenous amiodarone for the treatment of atrial arrhythmias' above.) https://www.uptodate.com/contents/amiodarone-clinical-uses/print 15/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Treatment of ventricular arrythmias Amiodarone is useful in a variety of ventricular arrhythmias but is most commonly used for the secondary prevention of recurrent ventricular arrhythmias in patients, including patients with an implantable cardioverter- defibrillator (ICD) to reduce the frequency of ICD shocks. The recommended loading dose ( table 4) for the prevention of ventricular arrhythmias is 400 to 1200 mg/day (usually in divided doses) for a total of 6 to 10 grams (except for secondary prevention of ICD shocks, when the loading dose is typically 8 to 10 grams). Maintenance doses range from 200 to 400 mg/day, with the lower doses carrying less risk of adverse side effects. (See 'Amiodarone for ventricular arrhythmias' above.) In the context of implantable cardioverter-defibrillators Despite its effectiveness in reducing ventricular tachyarrhythmias, amiodarone has been shown to be inferior to ICDs in reducing mortality in both primary and secondary prevention studies of patients at high risk for sudden cardiac death. Thus, the use of amiodarone in this setting should be reserved for patients who are candidates for an ICD but who cannot or refuse to have an ICD implanted. (See 'Primary prevention of sudden cardiac death' above and 'Secondary prevention of sudden cardiac death' above.) Transition from IV to oral dosing The dosing of amiodarone following conversion from IV to oral administration varies according to the duration of IV treatment prior to conversion. (See 'Transition from IV to oral therapy' above.) Drug interactions and side effects Amiodarone has the potential for numerous drug interactions and side effects ( table 3) that require monitoring. (See 'Drug interactions' above and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007; 4:1250. 2. Connolly SJ. Evidence-based analysis of amiodarone efficacy and safety. Circulation 1999; 100:2025. 3. Vassallo P, Trohman RG. Prescribing amiodarone: an evidence-based review of clinical indications. JAMA 2007; 298:1312. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 16/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate 4. Desai AD, Chun S, Sung RJ. The role of intravenous amiodarone in the management of cardiac arrhythmias. Ann Intern Med 1997; 127:294. 5. Gomes JA, Kang PS, Hariman RJ, et al. Electrophysiologic effects and mechanisms of termination of supraventricular tachycardia by intravenous amiodarone. Am Heart J 1984; 107:214. 6. Scheinman MM, Levine JH, Cannom DS, et al. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. The Intravenous Amiodarone Multicenter Investigators Group. Circulation 1995; 92:3264. 7. Clemo HF, Wood MA, Gilligan DM, Ellenbogen KA. Intravenous amiodarone for acute heart rate control in the critically ill patient with atrial tachyarrhythmias. Am J Cardiol 1998; 81:594. 8. Aiba T, Shimizu W, Inagaki M, et al. Excessive increase in QT interval and dispersion of repolarization predict recurrent ventricular tachyarrhythmia after amiodarone. Pacing Clin Electrophysiol 2004; 27:901. 9. Kamiya K, Nishiyama A, Yasui K, et al. Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K(+) current. Circulation 2001; 103:1317. 10. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 11. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 12. Lei LY, Chew DS, Lee W, et al. Pharmacological Cardioversion of Atrial Tachyarrhythmias Using Single High-Dose Oral Amiodarone: A Systematic Review and Meta-Analysis. Circ Arrhythm Electrophysiol 2021; 14:e010321. 13. Um KJ, McIntyre WF, Mendoza PA, et al. Pre-treatment with antiarrhythmic drugs for elective electrical cardioversion of atrial fibrillation: a systematic review and network meta-analysis. Europace 2022; 24:1548. 14. Darkner S, Chen X, Hansen J, et al. Recurrence of arrhythmia following short-term oral AMIOdarone after CATheter ablation for atrial fibrillation: a double-blind, randomized, placebo-controlled study (AMIO-CAT trial). Eur Heart J 2014; 35:3356. 15. Mohanty S, Di Biase L, Mohanty P, et al. Effect of periprocedural amiodarone on procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm 2015; 12:477. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 17/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate 16. Daoud EG, Strickberger SA, Man KC, et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997; 337:1785. 17. Giri S, White CM, Dunn AB, et al. Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo- controlled trial. Lancet 2001; 357:830. 18. Khan IA, Mehta NJ, Gowda RM. Amiodarone for pharmacological cardioversion of recent- onset atrial fibrillation. Int J Cardiol 2003; 89:239. 19. Hilleman DE, Spinler SA. Conversion of recent-onset atrial fibrillation with intravenous amiodarone: a meta-analysis of randomized controlled trials. Pharmacotherapy 2002; 22:66. 20. Chevalier P, Durand-Dubief A, Burri H, et al. Amiodarone versus placebo and class Ic drugs for cardioversion of recent-onset atrial fibrillation: a meta-analysis. J Am Coll Cardiol 2003; 41:255. 21. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet 1997; 349:675. 22. Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med 1995; 333:77. 23. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018; 72:e91. 24. Claro JC, Candia R, Rada G, et al. Amiodarone versus other pharmacological interventions for prevention of sudden cardiac death. Cochrane Database Syst Rev 2015; :CD008093. 25. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996; 335:1933. 26. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999; 341:1882. 27. Passman R, Subacius H, Ruo B, et al. Implantable cardioverter defibrillators and quality of life: results from the defibrillators in nonischemic cardiomyopathy treatment evaluation study. Arch Intern Med 2007; 167:2226. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 18/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate 28. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 29. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta- blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study: a randomized trial. JAMA 2006; 295:165. 30. Hohnloser SH, Dorian P, Roberts R, et al. Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial. Circulation 2006; 114:104. 31. Podrid PJ. Amiodarone: reevaluation of an old drug. Ann Intern Med 1995; 122:689. 32. Gallik DM, Singer I, Meissner MD, et al. Hemodynamic and surface electrocardiographic effects of a new aqueous formulation of intravenous amiodarone. Am J Cardiol 2002; 90:964. 33. Boyce BA, Yee BH. Incidence and severity of phlebitis in patients receiving peripherally infused amiodarone. Crit Care Nurse 2012; 32:27. 34. Norton L, Ottoboni LK, Varady A, et al. Phlebitis in amiodarone administration: incidence, contributing factors, and clinical implications. Am J Crit Care 2013; 22:498. 35. Oragano CA, Patton D, Moore Z. Phlebitis in Intravenous Amiodarone Administration: Incidence and Contributing Factors. Crit Care Nurse 2019; 39:e1. 36. Saul JP, Scott WA, Brown S, et al. Intravenous amiodarone for incessant tachyarrhythmias in children: a randomized, double-blind, antiarrhythmic drug trial. Circulation 2005; 112:3470. 37. Perry JC, Fenrich AL, Hulse JE, et al. Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol. J Am Coll Cardiol 1996; 27:1246. 38. Figa FH, Gow RM, Hamilton RM, Freedom RM. Clinical efficacy and safety of intravenous Amiodarone in infants and children. Am J Cardiol 1994; 74:573. Topic 926 Version 43.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 19/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/amiodarone-clinical-uses/print 20/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 21/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Oral versus intravenous amiodarone Effect Variable Oral Intravenous amiodarone amiodarone Prolongation of action potential duration in atrial and ventricular myocardium +++ + Blockage of inactivated sodium channels +++ ++ Slowing of phase 4 depolarization in the sinus node +++ + Calcium channel blockade +++ +++ Noncompetetive blockade of alpha and beta adrenoreceptors + + (faster) AV node effective refractory period Ventricular effective refractory period / Heart rate QRS interval / QTc duration A-H interval H-V interval Block conversion of thyroxine to trilodothyronine +++ AV: atrioventricular; A-H interval: time from initial rapid deflection of the atrial wave to the initial rapid deflection of the His bundle potential; H-V interval: time from initial deflection of the His bundle potential to the onset of ventricular activity; +: yes or present; -: no or absent; : increase; : decrease. Comparison of the electropharmacologic effects of oral and intravenous amiodarone. Compared with oral amiodarone, the intravenous preparation produces a much lesser increase in the action potential duration in atrial and ventricular myocardium and a minimal increase in the atrial and ventricular refractory periods. As a result, there is little or no increase in QRS duration and the QT interval, respectively. Intravenous amiodarone also has little effect on sinus cycle length and has vasodilator activity that triggers an increase in sympathetic activity; both of these effects result in little or no slowing of the sinus rate. Lastly, the intravenous preparation may have more potent and more rapid antiadrenergic activity. Data from: Desai AD, Chun S, Sung RJ. Ann Intern Med 1997; 127:294. Graphic 79689 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 22/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Relationship between fast sodium-mediated myocardial action potential and surface electrocardiogram Each phase of the myocardial action potential (numbers, upper panel) corresponds to a deflection or interval on the surface ECG (lower panel). Phase 4, the resting membrane potential, is responsible for the TQ segment; this segment has a prominent role in the ECG manifestations of ischemia during exercise testing. ECG: electrocardiogram. Graphic 64133 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 23/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 24/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Amiodarone baseline testing and monitoring for side effects Monitoring Area of interest for monitoring Possible adverse effect Baseline testing Follow-up testing Cardiac ECG (at baseline and during loading dose) Yearly QT prolongation; torsades de pointes After adding medications that Symptomatic sinoatrial interact with amiodarone or prolong or conduction system impairment the QT interval Implantable Defibrillation threshold As needed for Increased defibrillation cardioverter- testing (if clinically signs/symptoms threshold defibrillators indicated) Dermatologic Physical examination As needed for Photosensitivity to UV signs/symptoms light Blue-gray skin discoloration Endocrine TSH (with reflex testing if abnormal) 3 to 4 months after starting drug, then Hyperthyroidism, hypothyroidism yearly As needed for signs/symptoms Hepatic AST and ALT 6 months after starting AST or ALT elevation 2 upper limit of reference range drug, then yearly Ophthalmologic Eye examination Yearly Corneal microdeposits Optic neuropathy Pulmonary Chest radiograph, Yearly for surveillance Pulmonary toxicity PFTs* (cough, fever, dyspnea) Along with PFTs (including DLCO) and chest computed tomography for signs/symptoms Refer to UpToDate topics on pulmonary toxicity, thyroid toxicity, and clinical uses of amiodarone for additional information. https://www.uptodate.com/contents/amiodarone-clinical-uses/print 25/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate ECG: electrocardiogram; UV: ultraviolet; TSH: thyroid-stimulating hormone; AST: aspartate aminotransferase; ALT: alanine transaminase; PFTs: pulmonary function tests; DLCO: diffusing capacity of the lungs for carbon monoxide. There are differing opinions, and no concensus, of obtaining formal PFTs with assessment of diffusion capacity (ie, DLCO) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs. Graphic 126072 Version 4.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 26/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Amiodarone dosing in adults by indication Indications Loading dose Maintenance dose Atrial arrhythmias Prevention of recurrent Total loading dose: 6 to 10 Lowest effective dose, PAF grams usually 100 to 200 mg orally once per day Pharmacologic Outpatient: Given as 400 to cardioversion of PAF 600 mg orally per day in divided doses with meals Maximum 200 mg orally per day Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals Pretreatment before Total loading dose: 6 to 10 Lowest effective dose, elective cardioversion or catheter ablation of AF grams orally over 2 to 6 weeks usually 100 to 200 mg orally once per day Given as 400 to 1200 mg orally per day in divided Maximum 400 mg orally per day in most circumstances doses Restoration and maintenance of NSR in Total IV loading dose: 1050 mg critically ill patients with AF Given as 150 mg IV bolus over 10 to 30 minutes, Ventricular rate control in critically ill patients with followed by continuous IV infusion at 1 mg per minute AF and rapid ventricular response for 6 hours, then 0.5 mg per minute for 18 hours* IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy If amiodarone will be used chronically: Following IV infusion, give 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams; consider overlapping IV and oral amiodarone for 24 to 48 hours Ventricular arrhythmias https://www.uptodate.com/contents/amiodarone-clinical-uses/print 27/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Primary and secondary Total oral loading dose: 6 to Maximum 400 mg orally per prevention of SCD in patients with LV 10 grams day in most circumstances Outpatient: 400 to 600 mg Lowest effective dose, ideally dysfunction who are not candidates for or refuse orally per day in divided doses with meal 200 mg or less orally once per day or in divided doses ICD implantation Inpatient: 400 to 1200 mg orally per day in divided doses with meals for 1 to 2 weeks Prevention of ventricular arrhythmias in patients Total loading dose: 6 to 10 grams Maximum 400 mg orally per day in most circumstances with ICDs to decrease risk Outpatient: Given as 400 to 600 mg orally per day in Lowest effective dose, ideally 200 mg or less orally per day of shocks divided doses with meals Inpatient: Given as 400 to 1200 mg orally per day in divided doses with meals until desired dose is achieved Cardiac arrest associated 300 mg IV or IO rapid bolus with VF or pulseless VT with a repeat dose of 150 mg as indicated Upon return of spontaneous circulation follow with an infusion of 1 mg per minute for 6 hours and then 0.5 mg per minute for 18 hours* Electrical (VT) storm and incessant VT in Total IV loading dose: 1050 mg If amiodarone is used chronically: Lowest effective hemodynamically stable patients dose, ideally 200 mg or less orally per day; maximum 400 150 mg IV bolus over 10 minutes, followed by mg orally per day in most continuous IV infusion at 1 mg per minute for 6 hours, circumstances then 0.5 mg per minute for 18 hours IV infusion (0.5 mg per minute) may need to be extended past 24 hours if unable to transition to oral therapy Additional 150 mg boluses may be given if VT storm recurs https://www.uptodate.com/contents/amiodarone-clinical-uses/print 28/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate If amiodarone will be used chronically: Following IV infusion 400 to 1200 mg orally per day in divided doses to complete a total (IV plus oral) loading dose of 10 grams. Consider overlapping IV and oral amiodarone for 24-48 hours PAF: paroxysmal atrial fibrillation; AF: atrial fibrillation; NSR: normal sinus rhythm; IV: intravenous; SCD: sudden cardiac death; LV: left ventricular; ICD: implantable cardioverter-defibrillator; VF: ventricular fibrillation; VT: ventricular tachycardia; IO: intraosseous. When administered to critically ill patients with atrial fibrillation and rapid ventricular response, repeated 150 mg boluses can be given over 10 to 30 minutes if needed, but no more than six to eight additional boluses should be administered in any 24-hour period. Typically, patients are given 1 or 2 doses of oral amiodarone prior to discontinuation of the IV infusion. Graphic 117524 Version 5.0 https://www.uptodate.com/contents/amiodarone-clinical-uses/print 29/30 7/5/23, 8:18 AM Amiodarone: Clinical uses - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-clinical-uses/print 30/30
7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Amiodarone pulmonary toxicity : Edward D Chan, MD, Talmadge E King, Jr, MD : Kevin R Flaherty, MD, MS : Paul Dieffenbach, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 30, 2021. INTRODUCTION Amiodarone is an iodinated benzofuran derivative that is used to suppress ventricular and supraventricular tachyarrhythmias. (See "Amiodarone: Clinical uses".) Pulmonary toxicity is among the most serious adverse effects of amiodarone [1]. Several forms of pulmonary disease occur among patients treated with amiodarone, including interstitial pneumonitis, eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH), pulmonary nodules and solitary masses, and also (rarely) pleural effusion. Other adverse effects from amiodarone include photosensitivity, blue-gray discoloration of the skin, thyroid dysfunction, corneal deposits, abnormal liver function tests, and bone marrow suppression [2]. The types, pathogenesis, risk factors, diagnosis, and treatment of amiodarone pulmonary toxicity will be reviewed here. The other major side effects of amiodarone are discussed separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) INTERSTITIAL PNEUMONITIS Interstitial pneumonitis is the most common presentation of amiodarone-induced pulmonary disease. Interstitial pneumonitis usually presents after two or more months of therapy, especially in patients in whom the dose of amiodarone exceeds 400 mg per day [3]. The incidence of pulmonary toxicity from amiodarone is not precisely known; it is estimated to be 1 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 1/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate to 5 percent, depending on the dose of amiodarone [4-7]. The rate increases at higher doses of amiodarone, particularly long-term use of doses over 500 mg daily. Pathogenesis The mechanisms involved in amiodarone-induced interstitial pneumonitis are incompletely understood. Two major hypotheses have been suggested, a direct toxic injury to lung cells and an indirect immunologic reaction [8]. Genetic susceptibility of certain individuals may play an additional role in determining the type of injury that ensues. Whether these processes pertain to other forms of amiodarone-induced lung toxicity is not known. Cytotoxicity A direct toxic reaction in the lung is supported by the following findings: Amiodarone has a long half-life and a high tissue affinity for the lung. In addition, an active metabolite of amiodarone, monodesethylamiodarone (DEA), exhibits cytotoxic activity and tends to accumulate in the lungs even more than amiodarone [9]. Drug-phospholipid complexes accumulate in lung cells (eg, macrophages, interstitial cells) and interfere with normal cellular metabolic pathways, which ultimately leads to direct cell injury and death. Both apoptotic and necrotic cell death have been implicated [10]. The role of autophagy in the pathogenesis of amiodarone-induced lung injury is controversial. On one hand, induction of autophagy is considered to be a host- protective response to amiodarone-induced cellular toxicity [11]. On the other hand, amiodarone was found to induce autophagy-dependent apoptosis of type II alveolar epithelial cells [12]. The cellular injury is thought to cause chronic inflammation, which can ultimately lead to fibrosis. Amiodarone alters the phospholipid bilayer, which in turn disrupts cellular and organelle membrane function. Toxic oxygen species resulting in tissue injury are generated by amiodarone [8]. Based on evidence from experimental animal models, stimulation of the angiotensin enzyme system may contribute to the pathogenesis of amiodarone-induced lung cell apoptosis, airway epithelial cell injury, mononuclear cell infiltration of the lamina propria, and interalveolar septal thickening [13]. Furthermore, concomitant administration of the angiotensin receptor blocker, olmesartan, in the amiodarone- exposed animals attenuated these histopathologic abnormalities [13]. In addition, retrospective analyses found that the prevalence of amiodarone-related lung disease was greater in patients not on an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), although this potential effect has not been sufficiently studied to guide their use to prevent amiodarone lung toxicity [13,14]. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 2/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Another study implicates elevated levels of angiotensin II as increasing the risk for amiodarone-induced lung toxicity because repeated episodes of heart failure, which are associated with increased angiotensin II, appear to be a risk factor. Hypersensitivity An immunologic reaction is suggested by several patients who presented with histopathologic features of a hypersensitivity pneumonitis: Lymphocytic infiltration, often with "intraalveolar buds" (organizing pneumonia-like reaction) CD8 T-cell lymphocytosis [15] Positive IgG immunofluorescence in the lung Risk factors Risk factors for amiodarone pulmonary toxicity are uncertain but may include a high cumulative dose, a daily dose greater than 400 mg/day, a duration of therapy exceeding two months, increased patient age, preexisting lung disease, thoracic or nonthoracic surgery, and pulmonary angiography. In a retrospective analysis of over 200 patients with amiodarone lung toxicity, patients over 60 years old and those on amiodarone for 6 to 12 months had the highest risk of toxicity [16]. Cumulative dose Pulmonary toxicity correlates more closely with the total cumulative dose than with serum drug levels. Consistent with this observation, pulmonary toxicity usually occurs several months to several years after the initiation of amiodarone therapy [3,17,18]. However, there exist anecdotal cases of severe pulmonary toxicity developing within two to three weeks of therapy with low cumulative doses [19,20]. Daily dose Early reports (when patients were usually treated with amiodarone doses 400 mg/day) noted a 5 to 15 percent incidence of pulmonary toxicity [2,21]. The incidence appears to be lower (1 to 5 percent) with smaller maintenance doses [3,21,22]. As an example, one study of 573 patients demonstrated that patients who developed pulmonary toxicity took higher daily doses than those who did not develop pulmonary disease (517 versus 409 mg/day) [21]. In this study, there were no cases of pulmonary toxicity when the maintenance dose was below 305 mg/day [21]. Although the likelihood of pulmonary toxicity may be less in patients receiving smaller daily doses, pulmonary toxicity may still occur at low doses, albeit infrequently. In a meta- analysis of four trials (1465 patients) that randomly assigned patients to receive a low-dose amiodarone (150 to 330 mg/day) or placebo for a minimum of one year, the incidence of pulmonary toxicity with amiodarone was not statistically different from placebo (1.9 versus 0.7 percent) [22]. In a subsequent, eight-year retrospective study of over 6000 amiodarone users in Quebec, Canada, there was independent association of either lower dose https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 3/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate amiodarone ( 200 mg/day) or higher dose amiodarone (>200 mg/day) with alveolar and interstitial lung disease [4]. Similarly, a retrospective series of 500 Japanese patients found that daily doses as low as approximately 140 mg per day were associated with a cumulative incidence of amiodarone lung toxicity of approximately 4 to 11 percent at one to five years, respectively [23]. Older age and higher maintenance dose of amiodarone were risk factors for lung toxicity, while pre-existing lung disease (eg, COPD, sarcoidosis), baseline diffusing capacity, and loading dose of amiodarone were not. Preexisting lung disease An association between preexisting lung disease and the development of amiodarone pulmonary toxicity has been reported in some series. However, it is possible that these patients had limited pulmonary reserve and thus become symptomatic earlier in their course than other individuals. The following two studies illustrate the conflicting literature: One randomized trial of 519 patients with heart failure found no accelerated loss of diffusing capacity among patients with chronic obstructive pulmonary disease who received amiodarone, compared with those who received placebo [24]. In contrast, a separate randomized trial demonstrated that patients with preexisting pulmonary disease had an increased risk of amiodarone pulmonary toxicity [25]. However, amiodarone use did not increase pulmonary death or all-cause mortality. Clinical manifestations Interstitial pneumonitis due to amiodarone toxicity is characterized by the insidious onset of nonproductive cough and/or dyspnea, which are present in 50 to 75 percent at presentation [3,7]. Fever is present in 33 to 50 percent; and other symptoms, such as pleuritic pain, weight loss, and malaise, may also be reported [3]. The onset of symptoms is usually within 6 to 12 months of starting amiodarone, but may occur within two months or after several years of treatment [7]. The physical examination often reveals bilateral inspiratory crackles, while clubbing is not seen. Peripheral blood findings are nonspecific but include elevations of the white blood cell count, serum lactate dehydrogenase (LDH) level, C-reactive protein, and erythrocyte sedimentation rate [3]. Eosinophilia and antinuclear antibodies are not typically seen. Amiodarone levels are usually within the normal range [3]. Evaluation Amiodarone-induced interstitial pneumonitis is generally suspected on the basis of new onset of dyspnea and/or cough in a patient who is taking or has recently discontinued taking amiodarone. The purpose of the evaluation is to narrow the diagnostic possibilities, exclude alternate diagnoses, and assess the severity of respiratory impairment. A careful history of medication use, symptoms suggestive of rheumatic disease, and occupational and https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 4/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate environmental exposures is an important component of the evaluation, as with any interstitial lung disease. Similarly, the physical examination should include a search for exacerbation of cardiovascular disease and the presence of rheumatic disease with a potential pulmonary component. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".) Laboratory studies A white blood cell count with differential and plasma brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) levels are obtained to evaluate for infection and heart failure. While the erythrocyte sedimentation rate and C-reactive protein levels are often elevated, these tests do not differentiate well among the diagnostic possibilities, and we do not usually obtain them. Serologic studies such as an antinuclear antibody test and rheumatoid factor are obtained based on the degree of suspicion for amiodarone lung toxicity versus rheumatic disease. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests'.) Amiodarone levels are not predictive or diagnostic of pulmonary toxicity. Measurement of serum concentrations of KL-6, a mucin-like high molecular weight glycoprotein secreted by proliferating type II pneumocytes, is a sensitive marker of disease activity in various interstitial lung diseases. Serum KL-6 has been proposed as a marker of amiodarone pulmonary toxicity, but lack of specificity limits its utility [23,26-28]. Chest imaging The chest radiograph in interstitial pneumonitis due to amiodarone typically shows new, diffuse or localized, reticular, consolidative, or mixed opacities [29]. These changes may be migratory and can occur in the absence of symptoms ( image 1) [30]. Pleural effusions are rare. (See 'Pleural disease' below.) High-resolution computed tomography (HRCT) is obtained to clarify the radiographic pattern and distribution of abnormalities. Supine and prone HRCT images should be compared to exclude dependent changes, given the possibility of heart failure in these patients [18,31,32]. HRCT in patients with amiodarone-induced interstitial pneumonitis may show areas of high attenuation in the lungs, as well as the liver and spleen, due to the accumulation of iodinated amiodarone in tissue macrophages ( image 2) [33]. Although this finding is specific for amiodarone use, it is not necessary to the diagnosis of amiodarone pneumonitis and may be seen in the absence of lung toxicity. Other HRCT findings related to amiodarone-induced interstitial pneumonitis include diffuse (usually bilateral) ground glass opacities and septal thickening; honeycombing and traction bronchiectasis can also be seen [18,34,35]. While gallium scans showing increased lung uptake are a sensitive marker for the presence of amiodarone pneumonitis, gallium scans are generally not performed in patients with suspected https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 5/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate amiodarone toxicity due to lack of specificity. Furthermore, gallium uptake in the lungs may remain elevated despite discontinuation of amiodarone and resolution of clinical disease [36]. Pulmonary function testing Pulmonary function tests, including spirometry, lung volumes, DLCO, and pulse oxygen saturation (SpO ) at rest and with exertion, are typically obtained to 2 evaluate patients with dyspnea and cough. While amiodarone-induced pulmonary toxicity is often associated with a restrictive pattern (reduced forced vital capacity and total lung capacity) and a reduction in diffusing capacity, these findings are nonspecific. However, a documented decline in the DLCO of greater than 20 percent is useful in suggesting the need for closer monitoring or further diagnostic testing with chest imaging [7]. Bronchoalveolar lavage Flexible bronchoscopy with bronchoalveolar lavage (BAL) is performed when the clinical diagnosis of amiodarone-induced interstitial pneumonitis is uncertain and is more helpful in the exclusion of alternative diagnoses (eg, infection, hemorrhage, malignancy) than in securing a diagnosis of amiodarone lung toxicity. Lavage samples should be sent for cell counts, microbial stains, culture, and cytologic evaluation. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and 'Diffuse alveolar hemorrhage' below.) The BAL pattern in amiodarone pneumonitis is highly variable, and no particular BAL cellular pattern appears predictive of outcome. The presence of "foam" cells (due to the accumulation of phospholipids in alveolar macrophages) is not pathognomonic of pulmonary toxicity because up to 50 percent of exposed patients without signs or symptoms of toxicity may have these findings. The absence of foam cells, however, makes the diagnosis of amiodarone pulmonary toxicity unlikely [3]. (See 'Histopathology' below.) Reported findings in BAL fluid from patients with amiodarone pneumonitis include [37-39]: Lymphocytosis Neutrophilia Eosinophilia Normal BAL cellular counts Among patients presenting with more acute forms of amiodarone-related respiratory disease, BAL may reveal alveolar hemorrhage with sequentially more hemorrhagic lavage returns and/or a high concentration of hemosiderin-laden macrophages [40]. (See 'Diffuse alveolar hemorrhage' below.) Lung biopsy Lung biopsy is usually not necessary to prove amiodarone pulmonary toxicity in patients with new-onset respiratory symptoms and compatible pulmonary function test and https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 6/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate radiographic changes. Due to concerns regarding the development of acute respiratory distress syndrome (ARDS) following surgical procedures in patients taking amiodarone, open or thoracoscopic lung biopsies are usually reserved for patients in whom other efforts to diagnose the illness have been unsuccessful, including a trial of drug withdrawal and perhaps also systemic glucocorticoid administration, and those in whom an alternate diagnosis is suspected. Occasionally, when amiodarone is felt to be essential to the management of a patient's dysrhythmias and the diagnosis of amiodarone toxicity is uncertain, a biopsy may be indicated for confirmation. (See 'Acute respiratory distress syndrome' below.) For patients who require a lung biopsy, biopsies obtained via video-assisted thoracoscopic surgery (VATS) or open thoracotomy are preferred over transbronchial biopsies as the latter are generally insufficient to make definitive diagnosis of amiodarone toxicity. On the other hand, it may be reasonable to obtain a transbronchial lung biopsy at the time of flexible bronchoscopy to help rule out infection or malignancy. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy'.) Histopathology The histopathologic findings of amiodarone-induced interstitial pneumonitis include a nonspecific interstitial pneumonitis (with a mononuclear cell infiltrate), type II cell hyperplasia, interstitial edema, fibrosis, and lipid-laden alveolar macrophages [41]. The presence of numerous lipid-laden, "foamy" macrophages in the air spaces is a characteristic finding in all patients exposed to amiodarone ( picture 1). The "foamy" appearance is due to amiodarone-phospholipid complexes ( image 3) and is also seen in patients without lung toxicity who are taking amiodarone. Amiodarone can cause an accumulation of phospholipids within lysosomes in other lung cells, although this is less common [2,41]. Ultrastructural studies show myelinoid (lamellated) inclusion bodies in the affected tissue. Various forms of lymphocytic infiltration have been described in amiodarone interstitial pneumonitis, including diffuse lymphoid hyperplasia, follicular bronchiolitis, and lymphoid interstitial pneumonia [42]. Occasionally, a component of organizing pneumonia is seen within the larger overall appearance of interstitial pneumonia [18]. Diagnosis and differential diagnosis The diagnosis of amiodarone-induced lung disease (interstitial pneumonitis and other types) is essentially a diagnosis of exclusion. While a lung biopsy showing the characteristic histopathologic changes is the gold standard for the diagnosis of interstitial pneumonitis due to amiodarone (see 'Histopathology' above), a clinical diagnosis can often be made when the clinical features and evaluation are consistent, other possibilities https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 7/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate have been excluded, and the patient improves with drug cessation with or without a trial of glucocorticoid therapy [7,43]. Key features that support a clinical diagnosis of amiodarone-induced interstitial pneumonitis include the following: New or worsening dyspnea, cough, and weight loss in a patient taking 200 mg of amiodarone a day, particularly 6 to 12 months into therapy New ground glass or reticular opacities on chest radiograph and confirmatory findings on HRCT Negative evaluation for heart failure (eg, normal plasma brain natriuretic peptide, normal ventricular ejection fraction, absent or incomplete improvement with diuresis) or at least improving cardiac function despite worsening lung function Exclusion of lung infection Exclusion of other interstitial lung diseases (eg, hypersensitivity pneumonitis, occupational, rheumatic) Presence of foamy macrophages in the BAL (although not diagnostic, their absence makes the diagnosis unlikely) (see 'Bronchoalveolar lavage' above) Improvement in symptoms and radiographic manifestations following withdrawal of amiodarone (with or without glucocorticoid therapy) The differential diagnosis of interstitial pneumonia due to amiodarone includes processes that can present similarly, such as heart failure, infectious pneumonia, intercurrent interstitial lung disease, and lung toxicity from another drug, as well as other types of pulmonary toxicity due to amiodarone described below. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Pulmonary disease induced by cardiovascular drugs" and "Nitrofurantoin-induced pulmonary injury".) Screening There are no adequate predictors of pulmonary toxicity due to amiodarone. Guidelines suggest obtaining a baseline and annual chest radiograph and baseline pulmonary function tests (including a DLCO) [43,44]. However, serial pulmonary function tests are not helpful because changes in DLCO are not specific for toxicity [45,46]. One study prospectively evaluated the usefulness of serial DLCO and spirometry measurements in 91 patients who were receiving amiodarone therapy for refractory arrhythmias [46]. Most of the asymptomatic https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 8/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate patients whose DLCO decreased more than 20 percent did not develop pulmonary toxicity over the next year despite continued amiodarone therapy. Treatment Treatment of amiodarone interstitial pneumonitis consists primarily of stopping amiodarone and, in more symptomatic patients, initiating systemic glucocorticoids. Patients with mild symptoms and normal oxygenation can be observed off amiodarone without glucocorticoids. Due to the accumulation of amiodarone in fatty tissues and its long elimination half-life (approximately 45 days), pulmonary toxicity may progress initially despite drug discontinuation. For the majority of patients with more than mild symptoms (eg, dyspnea on mild to moderate exertion) and evidence of respiratory impairment, we initiate systemic glucocorticoid therapy (eg, prednisone 40 to 60 mg per day). In a number of case reports, glucocorticoid therapy has been associated with dramatic improvement even in patients with severe disease [7,35]. After a clinical response is evident, glucocorticoid therapy is tapered slowly, as tolerated, over two to six months. If symptoms and signs recur, the glucocorticoid dose is returned to the last effective dose and further tapering is slower, over approximately 12 months. Recurrent pulmonary toxicity during tapering of glucocorticoids may be due to greater body stores of amiodarone associated with greater body mass indices and/or amounts of body fat [47]. We suggest NOT resuming amiodarone in patients who have recovered from amiodarone- induced pulmonary toxicity due to the risk of recurrent disease and progressive pulmonary fibrosis. Alternative medications and procedures are available to treat supraventricular arrhythmias, and the implantable cardioverter-defibrillator may be an alternative for potentially life-threatening ventricular arrhythmias. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) Dronedarone, an antiarrhythmic with similar structure to amiodarone, appears to have lower risk of lung toxicity than amiodarone, but its use in patients with prior amiodarone toxicity has not been formally examined. There have been three case reports in which dronedarone was implicated as the cause of lung toxicity one with diffuse alveolar damage and two with organizing pneumonia [48-50]. The association of dronedarone with increased mortality in patients with advanced heart failure will likely limit its use [51]. (See "Clinical uses of dronedarone".) While preliminary studies suggest a protective effect of ACEi and ARB [14], the use of these agents solely for the reduction of amiodarone lung toxicity cannot be recommended without additional studies. (See 'Pathogenesis' above.) https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 9/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Prognosis The prognosis of amiodarone interstitial pneumonitis is generally favorable. In one study, for example, three-fourths of patients stabilized or improved after withdrawal of the drug with or without glucocorticoid treatment [38]. Death attributable to amiodarone pneumonitis occurred in 10 percent of cases reported in the literature, although the actual mortality in clinical practice is probably less [18]. EOSINOPHILIC PNEUMONIA A few cases of eosinophilic pneumonia have been reported in association with amiodarone [42]. Presentations consistent with acute or chronic eosinophilic pneumonia have been described, although the acute presentation appears more common. Clinical features Acute eosinophilic pneumonia typically presents with less than one month and often less than one week of fever, nonproductive cough, and dyspnea, while chronic eosinophilic pneumonia presents as a subacute illness with more than a month of cough, fever, progressive breathlessness, weight loss, wheezing, and night sweats. (See "Idiopathic acute eosinophilic pneumonia", section on 'Clinical features' and "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.) Peripheral blood eosinophilia may be present in both acute and chronic eosinophilic pneumonia. Chest computed tomography (CT) findings include ground glass opacities, diffuse reticular changes, and masses; in the chronic form, the radiographic changes may have a peripheral distribution [42]. (See "Overview of pulmonary eosinophilia", section on 'Idiopathic acute eosinophilic pneumonia' and "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.) Diagnosis In both acute and chronic eosinophilic pneumonia due to amiodarone, the diagnosis is supported by bronchoalveolar lavage (BAL) fluid showing abundant eosinophils, often >25 percent, and abundant foamy macrophages [42,52-54], but requires exclusion of other causes of eosinophilic pneumonia. The differential diagnosis of eosinophilic pneumonia includes fungal and parasitic infection, vasculitis, and eosinophilic pneumonia induced by other drugs. These processes must be excluded by appropriate history (eg, medication use, travel or residence in areas with endemic fungi or parasites) and serologic studies (eg, antineutrophil cytoplasmic antibody, rheumatoid factor, enzyme- linked immunoassays for specific coccidioidal IgM and IgG). (See "Overview of pulmonary eosinophilia", section on 'Diagnostic approach'.) Treatment In addition to cessation of amiodarone, the majority of patients with eosinophilic pneumonia associated with amiodarone are treated with systemic https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 10/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate glucocorticoids, following the approaches for idiopathic acute and chronic eosinophilic pneumonias, depending on which presentation the individual patient displays. (See "Idiopathic acute eosinophilic pneumonia", section on 'Treatment' and "Chronic eosinophilic pneumonia", section on 'Treatment'.) ORGANIZING PNEUMONIA Organizing pneumonia (OP), formerly called bronchiolitis obliterans organizing pneumonia or BOOP, occurs in approximately 25 percent of cases of amiodarone pulmonary toxicity [29,55-57]. (See "Cryptogenic organizing pneumonia".) The typical pathologic findings in OP include excessive proliferation of granulation tissue, consisting of loose collagen-embedded fibroblasts and myofibroblasts, and involving alveolar ducts and alveoli, with or without bronchiolar intraluminal polyps. In addition to these findings, lymphoid hyperplasia can rarely be seen on lung biopsies obtained from patients with OP associated with amiodarone [42]. In eight of these patients, lymphoid hyperplasia manifested as diffuse lymphoid hyperplasia, follicular bronchiolitis, lymphoid interstitial pneumonia, or lymphocytic perivascular cuffing [42]. Clinical features The presentation of OP due to amiodarone is typically more acute in onset than that of chronic interstitial pneumonitis and occurs over a few weeks to months. It is characterized by a nonproductive cough, pleuritic chest pain, fever, and dyspnea, which often mimic an infectious pneumonitis [58]. (See "Cryptogenic organizing pneumonia", section on 'Clinical features'.) Pulmonary auscultation typically reveals crackles, which may be focal, and sometimes a pleural rub. The chest radiograph usually demonstrates patchy areas of consolidation, sometimes with an air bronchogram. High-resolution computed tomography (HRCT) usually confirms patchy and sometimes nodular areas of consolidative opacity. When patients have a prominence of lymphoid hyperplasia, additional chest computed tomography (CT) findings include septal thickening, ground glass nodules, and masses [42]. Diagnosis As the clinical presentation may initially suggest infection, the diagnosis of OP is often suspected after a lack of response to antibiotics administered for suspected bacterial pneumonia. In the majority of patients, a biopsy demonstrating organizing pneumonia is needed to secure a diagnosis. In order to have enough tissue for the pathologist to exclude other processes, we prefer to obtain a lung biopsy via video-assisted https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 11/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate thoracoscopic surgery (VATS) or open thoracotomy rather than transbronchial biopsy. The histopathologic features of organizing pneumonia are described separately. (See "Cryptogenic organizing pneumonia", section on 'Diagnosis' and "Cryptogenic organizing pneumonia", section on 'Histopathologic diagnosis of organizing pneumonia'.) Treatment Treatment of OP in the context of amiodarone therapy requires cessation of amiodarone and generally also a course of systemic glucocorticoid therapy [59]. Similar to the treatment of cryptogenic OP, the decision to implement glucocorticoid therapy, the choice of initial dose, and length of the tapered dose regimen depend on the severity of respiratory involvement. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.) ACUTE RESPIRATORY DISTRESS SYNDROME Acute respiratory distress syndrome (ARDS) is a rare but potentially fatal form of amiodarone pulmonary toxicity and is usually characterized by diffuse alveolar damage with hyaline membranes ( picture 2) [29]. Rarely, a histopathologic pattern of diffuse alveolar damage plus eosinophilic infiltration has been attributed to amiodarone lung toxicity [42]. (See 'Eosinophilic pneumonia' above.) Clinical presentation Amiodarone-associated ARDS has been reported in patients who have undergone thoracic surgery or pulmonary angiography; such incidences have occurred during chronic treatment with amiodarone or when the amiodarone was initiated in the peri-procedural period [60-63]. However, the role of amiodarone in acute periprocedural ARDS is controversial, and a review of amiodarone pulmonary toxicity cites evidence against such an association [62,64-66]. In reports describing surgical patients, ARDS developed within one to four days after extubation [60,61]. In comparison, the report of two patients with fatal ARDS following pulmonary angiography described respiratory deterioration within 30 minutes of the procedure [62]. While some surgical literature suggests that use of amiodarone is safe after lung resection [64,66,67], others have voiced concern about lung toxicity in such circumstances and call for clinical studies to determine the true risks and benefits of peri-operative amiodarone [65]. Diagnosis The diagnosis of ARDS is based on clinical criteria: acute onset of symptoms ( 1 week), bilateral opacities consistent with pulmonary edema on chest computed tomography (CT), absence of cardiac failure or fluid overload, and a moderate to severe impairment of oxygenation. The differential diagnosis of ARDS includes cardiogenic pulmonary edema, diffuse alveolar hemorrhage (see below), acute interstitial pneumonia, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 12/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate acute eosinophilic pneumonia, and cancer. Usually, when ARDS is suspected, bronchoalveolar lavage (BAL) is performed to exclude lung infection, hemorrhage, eosinophilic pneumonia, and malignancy. Once these processes have been excluded, other causes of ARDS, such as sepsis, aspiration, transfusion, and drug toxicity (other than amiodarone), need to be excluded. (See 'Diffuse alveolar hemorrhage' below and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults" and "Basic principles and technique of bronchoalveolar lavage".) Acute fibrinous and organizing pneumonia (AFOP) is a separate process that is in the differential diagnosis of ARDS as it presents similarly. At least one case of AFOP associated with amiodarone has been reported [68]. AFOP has a different histopathologic pattern from ARDS, characterized by the presence of intra-alveolar fibrin (fibrin "balls") and organizing pneumonia, but without the hyaline membranes associated with ARDS. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.) Treatment Management of ARDS associated with amiodarone toxicity should include cessation of amiodarone, implementation of supportive care for the critically ill patient, and use of mechanical ventilation with strategies to minimize supplemental oxygen and also reduce barotrauma and volutrauma. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Ventilator management strategies for adults with acute respiratory distress syndrome".) While systemic glucocorticoids are not part of routine care in ARDS and have not been formally evaluated in ARDS associated with amiodarone, most patients with amiodarone- associated ARDS are treated empirically with systemic glucocorticoids (eg, methylprednisolone 500 to 1000 mg/day intravenously, followed by prednisone 0.5 mg/kg daily) after infection has been excluded [7,69]. This practice is based on the response to glucocorticoids observed in other forms of amiodarone lung toxicity and in a small number of patients with amiodarone-associated ARDS [7,69]. Often, patients will need to be treated empirically for more than one possibility (eg, infection and drug-induced lung toxicity) while studies are pending. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.) In one patient with life-threatening amiodarone lung toxicity manifested by diffuse radiographic opacities and respiratory failure that were unresponsive to glucocorticoids, hemoperfusion with a polymyxin B-immobilized fiber column dramatically improved https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 13/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate oxygenation with concomitant reduction in serum amiodarone and desethylamiodarone levels [70]. Further study is needed to determine the efficacy of this treatment. Patients in whom ARDS develops due to amiodarone have a mortality rate of approximately 50 percent [71]. Prevention Given the apparent association of amiodarone-associated ARDS with surgery or medical procedures, it has been hypothesized that amiodarone may sensitize patients to high concentrations of inspired oxygen or to iodinated contrast media. Some experts advise close monitoring of the pulse oxygen saturation (SpO ) and/or partial pressure of 2 arterial oxygen (PaO ) to minimize supplemental oxygen, although data to support this 2 practice are lacking. While caution should be used when considering patients on amiodarone for surgery, especially in the setting of preoperative pulmonary dysfunction, the concerns about performing surgery on such patients must be weighed against the alternative concern that withdrawal of amiodarone before surgery may delay the operation for several weeks (because amiodarone has a very long half-life) and put the patient at increased risk of malignant dysrhythmias. DIFFUSE ALVEOLAR HEMORRHAGE Diffuse alveolar hemorrhage (DAH) is a rare complication of amiodarone [40,72-75]. It may occur abruptly in the first few days or months (average six months) after initiation of the drug [29,73,74,76-78]. Clinical features The patients commonly present with an acute onset of cough, shortness of breath, fever, and sometimes hemoptysis. Many of the patients have pre- existing chronic lung disease [74]. Laboratory studies often show a decrease in hemoglobin. Imaging studies show bilateral diffuse ground glass opacities and/or consolidation. Diagnosis The diagnosis of DAH due to amiodarone is usually suspected based on the clinical presentation (eg, acute onset, hemoptysis) and imaging studies (diffuse opacities). Confirmation is usually obtained by sequential bronchoalveolar lavages (BALs) in an area of radiographic opacities that reveal progressively more hemorrhagic returns [40]. Hemosiderin-laden macrophages, which may be demonstrated by Prussian blue staining, are also characteristic of DAH. While hemosiderin-laden macrophages can be seen in cardiogenic pulmonary edema, they are typically present in lower numbers than in pulmonary hemorrhage due to amiodarone. A lung biopsy is generally not indicated. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.) https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 14/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Differential diagnosis The differential diagnosis of DAH includes pulmonary edema (cardiogenic and noncardiogenic), systemic lupus, vasculitis, and hemorrhage due to another drug (eg, cocaine, propylthiouracil) or due to therapy with anticoagulants or platelet glycoprotein IIB/IIIA inhibitors. These possibilities can be narrowed by studies, such as a platelet count, coagulation tests, urinalysis, drug screening for cocaine, plasma brain natriuretic peptide (BNP), serologic tests for antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA) and antiglomerular basement membrane antibodies, and an echocardiogram. (See 'Acute respiratory distress syndrome' above and "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.) Treatment As with other forms of amiodarone toxicity, prompt discontinuation of the medication is indicated. Most patients are treated with systemic glucocorticoids following
in the peri-procedural period [60-63]. However, the role of amiodarone in acute periprocedural ARDS is controversial, and a review of amiodarone pulmonary toxicity cites evidence against such an association [62,64-66]. In reports describing surgical patients, ARDS developed within one to four days after extubation [60,61]. In comparison, the report of two patients with fatal ARDS following pulmonary angiography described respiratory deterioration within 30 minutes of the procedure [62]. While some surgical literature suggests that use of amiodarone is safe after lung resection [64,66,67], others have voiced concern about lung toxicity in such circumstances and call for clinical studies to determine the true risks and benefits of peri-operative amiodarone [65]. Diagnosis The diagnosis of ARDS is based on clinical criteria: acute onset of symptoms ( 1 week), bilateral opacities consistent with pulmonary edema on chest computed tomography (CT), absence of cardiac failure or fluid overload, and a moderate to severe impairment of oxygenation. The differential diagnosis of ARDS includes cardiogenic pulmonary edema, diffuse alveolar hemorrhage (see below), acute interstitial pneumonia, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 12/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate acute eosinophilic pneumonia, and cancer. Usually, when ARDS is suspected, bronchoalveolar lavage (BAL) is performed to exclude lung infection, hemorrhage, eosinophilic pneumonia, and malignancy. Once these processes have been excluded, other causes of ARDS, such as sepsis, aspiration, transfusion, and drug toxicity (other than amiodarone), need to be excluded. (See 'Diffuse alveolar hemorrhage' below and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults" and "Basic principles and technique of bronchoalveolar lavage".) Acute fibrinous and organizing pneumonia (AFOP) is a separate process that is in the differential diagnosis of ARDS as it presents similarly. At least one case of AFOP associated with amiodarone has been reported [68]. AFOP has a different histopathologic pattern from ARDS, characterized by the presence of intra-alveolar fibrin (fibrin "balls") and organizing pneumonia, but without the hyaline membranes associated with ARDS. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.) Treatment Management of ARDS associated with amiodarone toxicity should include cessation of amiodarone, implementation of supportive care for the critically ill patient, and use of mechanical ventilation with strategies to minimize supplemental oxygen and also reduce barotrauma and volutrauma. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Ventilator management strategies for adults with acute respiratory distress syndrome".) While systemic glucocorticoids are not part of routine care in ARDS and have not been formally evaluated in ARDS associated with amiodarone, most patients with amiodarone- associated ARDS are treated empirically with systemic glucocorticoids (eg, methylprednisolone 500 to 1000 mg/day intravenously, followed by prednisone 0.5 mg/kg daily) after infection has been excluded [7,69]. This practice is based on the response to glucocorticoids observed in other forms of amiodarone lung toxicity and in a small number of patients with amiodarone-associated ARDS [7,69]. Often, patients will need to be treated empirically for more than one possibility (eg, infection and drug-induced lung toxicity) while studies are pending. (See "Cryptogenic organizing pneumonia", section on 'Treatment'.) In one patient with life-threatening amiodarone lung toxicity manifested by diffuse radiographic opacities and respiratory failure that were unresponsive to glucocorticoids, hemoperfusion with a polymyxin B-immobilized fiber column dramatically improved https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 13/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate oxygenation with concomitant reduction in serum amiodarone and desethylamiodarone levels [70]. Further study is needed to determine the efficacy of this treatment. Patients in whom ARDS develops due to amiodarone have a mortality rate of approximately 50 percent [71]. Prevention Given the apparent association of amiodarone-associated ARDS with surgery or medical procedures, it has been hypothesized that amiodarone may sensitize patients to high concentrations of inspired oxygen or to iodinated contrast media. Some experts advise close monitoring of the pulse oxygen saturation (SpO ) and/or partial pressure of 2 arterial oxygen (PaO ) to minimize supplemental oxygen, although data to support this 2 practice are lacking. While caution should be used when considering patients on amiodarone for surgery, especially in the setting of preoperative pulmonary dysfunction, the concerns about performing surgery on such patients must be weighed against the alternative concern that withdrawal of amiodarone before surgery may delay the operation for several weeks (because amiodarone has a very long half-life) and put the patient at increased risk of malignant dysrhythmias. DIFFUSE ALVEOLAR HEMORRHAGE Diffuse alveolar hemorrhage (DAH) is a rare complication of amiodarone [40,72-75]. It may occur abruptly in the first few days or months (average six months) after initiation of the drug [29,73,74,76-78]. Clinical features The patients commonly present with an acute onset of cough, shortness of breath, fever, and sometimes hemoptysis. Many of the patients have pre- existing chronic lung disease [74]. Laboratory studies often show a decrease in hemoglobin. Imaging studies show bilateral diffuse ground glass opacities and/or consolidation. Diagnosis The diagnosis of DAH due to amiodarone is usually suspected based on the clinical presentation (eg, acute onset, hemoptysis) and imaging studies (diffuse opacities). Confirmation is usually obtained by sequential bronchoalveolar lavages (BALs) in an area of radiographic opacities that reveal progressively more hemorrhagic returns [40]. Hemosiderin-laden macrophages, which may be demonstrated by Prussian blue staining, are also characteristic of DAH. While hemosiderin-laden macrophages can be seen in cardiogenic pulmonary edema, they are typically present in lower numbers than in pulmonary hemorrhage due to amiodarone. A lung biopsy is generally not indicated. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.) https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 14/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Differential diagnosis The differential diagnosis of DAH includes pulmonary edema (cardiogenic and noncardiogenic), systemic lupus, vasculitis, and hemorrhage due to another drug (eg, cocaine, propylthiouracil) or due to therapy with anticoagulants or platelet glycoprotein IIB/IIIA inhibitors. These possibilities can be narrowed by studies, such as a platelet count, coagulation tests, urinalysis, drug screening for cocaine, plasma brain natriuretic peptide (BNP), serologic tests for antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA) and antiglomerular basement membrane antibodies, and an echocardiogram. (See 'Acute respiratory distress syndrome' above and "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.) Treatment As with other forms of amiodarone toxicity, prompt discontinuation of the medication is indicated. Most patients are treated with systemic glucocorticoids following the treatment approach for other causes of DAH, although the value and dosing in this setting are uncertain. A reasonable initial dose of glucocorticoids, is the equivalent of methylprednisolone 500 to 1000 mg intravenously in divided doses, daily for up to five days followed by gradual tapering and then maintenance for weeks to months on an oral preparation. (See "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.) One patient, who required continuation of amiodarone to prevent life-threatening arrhythmias, was successfully treated with glucocorticoids and a reduction in the dose of amiodarone to half of the prior dose [74]. PULMONARY NODULES OR MASS Solitary and multiple pulmonary nodules and masses have been attributed to amiodarone toxicity in a number of case reports and case series [79,80]. Among four such patients who had histopathologic evaluation, one had a single mass with a background of increased reticular markings, while the others had two or more nodules [80]. Increased F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake was noted in two patients. Pathologic examination revealed areas of necrosis within solid inflammation [80]. Surrounding the necrosis were sheets of vacuolated histiocytes and aggregates of neutrophils. Patches of organizing pneumonia were noted peripheral to some nodules. The appearance was somewhat similar to granulomatosis with polyangiitis, but palisading histiocytes, vasculitis, and granulomatous inflammation were not present. The patient with multiple nodules had improvement in symptoms and resolution of the nodules after cessation of amiodarone; the others had excisions of the lesions due to suspicion for malignancy. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 15/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate In a separate report, a solitary pulmonary mass simulating a pulmonary malignancy and associated with additional smaller, peripheral nodules was described as a complication of amiodarone therapy [79]. Increased uptake was noted on FDG-PET scan in support of possible malignancy. However, needle aspirates yielded foamy macrophages and type II cells, and no evidence of malignancy. With cessation of amiodarone and treatment with prednisone, the lung abnormalities resolved over 12 months. Dual energy computed tomography (CT) demonstrated high iodine content in a mass-like lung consolidation of a patient treated with amiodarone, which was confirmed to be due to amiodarone by lung biopsy [81]. PLEURAL DISEASE A few case reports have described exudative pleural effusions associated with amiodarone therapy either isolated or in combination with pneumonitis [82-85]. In at least one case, the patient presented with features of drug-induced lupus [84]. (See "Drug-induced lupus".) Pleuroparenchymal fibroelastosis was described in one patient after five years of amiodarone therapy [86]; no other cause of PPFE was identified. SUMMARY AND RECOMMENDATIONS Amiodarone is associated with several forms of pulmonary toxicity including interstitial pneumonitis (the most common presentation), eosinophilic pneumonia, organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH), pulmonary nodules and masses, and rarely pleural effusions. The incidence of pulmonary toxicity from amiodarone is not precisely known; it is estimated to be 1 to 5 percent, depending on the dose of amiodarone. (See 'Introduction' above and 'Interstitial pneumonitis' above.) Risk factors for amiodarone-induced pulmonary toxicity include a daily dose 400 mg/day, duration of therapy exceeding two months, patient age >60 years, preexisting lung disease, surgery, and pulmonary angiography. Pulmonary toxicity can also occur at lower daily doses. (See 'Risk factors' above.) Permanent discontinuation of amiodarone is the primary therapy for amiodarone pulmonary toxicity. (See 'Treatment' above.) Interstitial pneumonitis Interstitial pneumonitis due to amiodarone toxicity is characterized by the insidious onset of nonproductive cough and/or dyspnea. Fever, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 16/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate pleuritic pain, weight loss, and malaise can also occur. The onset of symptoms is usually 6 to 12 months of amiodarone therapy, but may occur within two months or after several years of treatment. (See 'Clinical manifestations' above.) The chest radiograph typically reveals new focal or diffuse reticular or ground glass opacities. High-resolution computed tomography (HRCT) of the chest and upper abdomen usually shows ground glass and reticular opacities and also increased attenuation in the lungs, liver, and spleen. Pulmonary function tests typically show restriction and a reduced diffusing capacity (DLCO). (See 'Laboratory studies' above.) Flexible bronchoscopy with bronchoalveolar lavage (BAL) is performed to exclude alternative diagnoses (eg, infection, hemorrhage, malignancy). Samples should be sent for cell counts, culture, and cytologic evaluation. The presence of "foam" cells (alveolar macrophages full of amiodarone-phospholipid complexes) is a characteristic of, but not pathognomonic for, pulmonary toxicity ( picture 1). (See 'Bronchoalveolar lavage' above and 'Histopathology' above.) A clinical diagnosis of amiodarone-induced interstitial pneumonitis can often be made when the clinical features are consistent; other possibilities (eg, infection, heart failure) have been excluded; and the patient improves with drug cessation and, possibly, a trial of glucocorticoid therapy. Lung biopsy is usually deferred unless the diagnosis remains uncertain after a trial of drug cessation. (See 'Diagnosis and differential diagnosis' above.) In addition to cessation of amiodarone, for the majority of patients with more than mild symptoms of interstitial pneumonitis due to amiodarone, we suggest initiation of systemic glucocorticoid therapy (Grade 2C). The usual dose is the equivalent of oral prednisone 40 to 60 mg/day. Due to the long elimination half-life (approximately 45 days) of amiodarone, pulmonary toxicity may initially progress despite drug discontinuation and may recur upon glucocorticoid withdrawal. (See 'Treatment' above.) For screening, guidelines suggest a baseline and annual chest radiograph and baseline pulmonary function tests for patients on long-term amiodarone therapy. However, serial pulmonary function tests are not helpful in predicting amiodarone toxicity. (See 'Screening' above.) Eosinophilic pneumonia Acute and chronic eosinophilic pneumonia are rarely associated with amiodarone. Chest computed tomography (CT) features include ground glass opacities, diffuse reticular changes, and masses. Peripheral blood eosinophilia may be present. In both acute and chronic eosinophilic pneumonia, the diagnosis is supported by https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 17/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate BAL fluid that often contains >25 percent eosinophils. Other causes of pulmonary eosinophilia (eg, fungal or parasitic infection, pulmonary eosinophilia due to another drug, vasculitis) must be excluded. (See 'Eosinophilic pneumonia' above and "Overview of pulmonary eosinophilia".) Treatment includes cessation of amiodarone and administration of systemic glucocorticoids, following the approaches for acute or chronic eosinophilic pneumonia, depending on the pattern manifested by the individual patient. (See "Idiopathic acute eosinophilic pneumonia", section on 'Treatment' and "Chronic eosinophilic pneumonia", section on 'Treatment'.) Organizing pneumonia Organizing pneumonia (such as that seen in cryptogenic organizing pneumonia) is present in approximately 25 percent of cases of amiodarone pulmonary toxicity. Suggestive features include a subacute or acute onset mimicking an infectious pneumonia, patchy or nodular consolidative opacities on imaging, and no response to antimicrobial therapy. A lung biopsy is needed for diagnosis. Treatment requires cessation of amiodarone; addition of systemic glucocorticoids is based on severity of disease and follows that for cryptogenic organizing pneumonia. (See 'Organizing pneumonia' above and "Cryptogenic organizing pneumonia".) Acute respiratory distress syndrome ARDS is a rare but potentially fatal form of amiodarone pulmonary toxicity that typically occurs shortly after a pulmonary angiogram or surgery. (See 'Acute respiratory distress syndrome' above.) Patients present with rapidly progressive respiratory failure, impaired oxygenation, and diffuse ground glass opacities on radiographic imaging. BAL is performed promptly to exclude infection, hemorrhage, and eosinophilic pneumonia. Other common causes of ARDS (eg, sepsis, aspiration) are also investigated. Management includes amiodarone cessation, supportive care, and mechanical ventilation. In addition, we suggest systemic glucocorticoid therapy (Grade 2C). A reasonable dose (after the exclusion of infection) is methylprednisolone 500 to 1000 mg/day intravenously, followed by prednisone 0.25 to 0.5 mg/kg daily. (See 'Acute respiratory distress syndrome' above.) Diffuse alveolar hemorrhage DAH due to amiodarone has an acute presentation of dyspnea, cough, and sometimes hemoptysis. Imaging shows diffuse or patchy ground glass or consolidative opacities. The diagnosis is usually made by sequential BAL sampling that shows progressively more hemorrhagic effluent; other causes of DAH must be excluded. In addition to cessation of amiodarone, we suggest systemic glucocorticoid https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 18/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate therapy (Grade 2C). A reasonable dose (after the exclusion of infection) is methylprednisolone 500 to 1000 mg/day, intravenously in divided doses for up to five days, followed by gradual tapering. (See 'Diffuse alveolar hemorrhage' above and "The diffuse alveolar hemorrhage syndromes", section on 'Glucocorticoids'.) Pulmonary nodules and masses Solitary and multiple pulmonary nodules and masses due to amiodarone toxicity can mimic pulmonary malignancy in radiographic appearance and F-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake. A pathologic diagnosis is needed to exclude malignancy. (See 'Pulmonary nodules or mass' above.) Pleural effusion Exudative pleural effusions are a rare manifestation of amiodarone toxicity; they may be isolated or occur in association with interstitial pneumonitis. (See 'Pleural disease' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ruzieh M, Moroi MK, Aboujamous NM, et al. Meta-Analysis Comparing the Relative Risk of Adverse Events for Amiodarone Versus Placebo. Am J Cardiol 2019; 124:1889. 2. Mason JW. Amiodarone. N Engl J Med 1987; 316:455. 3. Martin WJ 2nd, Rosenow EC 3rd. 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Arch Bronconeumol (Engl Ed) 2020; 56:55. https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 24/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Topic 4364 Version 22.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 25/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate GRAPHICS Amiodarone pulmonary toxicity Chest radiographs from a patient treated with amiodarone demonstrate left upper lobe consolidation (A) and six months later right upper lobe consolidation with residual scar in left upper lobe (B). Courtesy of Paul Stark, MD. Graphic 50428 Version 3.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 26/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Amiodarone pulmonary toxicity Computed tomographic scan obtained without intravenous contrast material reveals a high-attenuation right upper lobe consolidation (upper panel). Images from the upper abdomen (lower panel) demonstrate increased attenuation of the liver parenchyma. The attenuation of this lesion is the result of iodine deposition from chronic amiodarone therapy. Courtesy of Paul Stark, MD. Graphic 58121 Version 3.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 27/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate BAL in amiodarone pulmonary toxicity Bronchoalveolar lavage (BAL) cytopreparation smear with normal differential and marked foamy appearance of alveolar macrophages. Courtesy of Talmadge E King Jr, MD. Graphic 53653 Version 2.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 28/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Amiodarone toxicity Electron micrograph shows an alveolar macrophage with intracytoplasmic lamellar bodies typical of amiodarone toxicity. These phospholipid inclusions account for the foamy appearance of histiocytes and epithelial cells in patients taking amiodarone and can be identified even in patients who lack radiographic or clinical evidence of lung disease. Courtesy of Je rey L Myers, MD. Graphic 64923 Version 2.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 29/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Amiodarone toxicity Amiodarone lung biopsy photomicrograph shows diffuse alveolar damage in a patient with amiodarone toxicity. Alveolar spaces contain histiocytes with finely vacuolated cytoplasm (arrow). Chronic interstitial pneumonia with fibrosis and organizing pneumonia have also been described in patients with amiodarone toxicity. Courtesy of Je rey L Myers, MD. Graphic 78032 Version 3.0 Normal lung High-power photomicrograph shows alveoli containing capillaries within a narrow interstitium. The alveoli are lined with thin, https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 30/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate elongated type I pneumocytes (arrow) and smaller numbers of cuboidal type II pneumocytes (dashed arrow). Courtesy of Steven E Weinberger, MD. Graphic 80140 Version 3.0 https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 31/32 7/5/23, 8:17 AM Amiodarone pulmonary toxicity - UpToDate Contributor Disclosures Edward D Chan, MD No relevant financial relationship(s) with ineligible companies to disclose. Talmadge E King, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kevin R Flaherty, MD, MS Grant/Research/Clinical Trial Support: Boehringer Ingelheim [IPF]. Consultant/Advisory Boards: Arrowhead [Interstitial lung disease]; AstraZeneca [Interstitial lung disease]; Bellerophon [Interstitial lung disease]; CSL Behring [Interstitial lung disease]; Daewong Pharmaceuticals [Interstitial lung disease]; DevPro [Interstitial lung disease]; Dispersol [Interstitial lung disease]; Fibrogen [Interstitial lung disease]; Horizon [Interstitial lung disease]; Immunmet [Interstitial lung disease]; Insilco [Interstitial lung disease]; Lupin [Interstitial lung disease]; NeRRe Therapeutics [Interstitial lung disease]; Pliant [Interstitial lung disease]; Polarean [Interstitial lung disease]; PureHealth [Interstitial lung disease]; PureTech [Interstitial lung disease]; Respivant [Interstitial lung disease]; Roche/Genentech [Interstitial lung disease]; Shionogi [Interstitial lung disease]; Sun Pharmaceuticals [Interstitial lung disease]; Trevi Pharmaceuticals [Interstitial lung disease]; United Therapeutics [Interstitial lung disease]; Vicore [Interstitial lung disease]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/amiodarone-pulmonary-toxicity/print 32/32
7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials : Kapil Kumar, MD, Peter J Zimetbaum, MD : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2023. INTRODUCTION Long-term outcomes, such as survival or rate of thromboembolism, are similar with either rhythm or rate control strategies in patients with atrial fibrillation (AF) ( figure 1A-B). In addition, anticoagulation is required with both in most patients [1,2]. Thus, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes [3,4]. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1) [3,5]. Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia [6-8]. Most patients for whom rhythm control is chosen will require rate control, both prior to its initiation and after, as many patients will have breakthrough episodes of AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) The studies describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs used to maintain sinus rhythm in patients with AF will be reviewed here. Recommendations concerning the use of pharmacologic therapy, the choice between a rhythm and a rate control strategy, and the role of alternative methods to maintain sinus rhythm in selected patients who are refractory to conventional therapy, including surgery and radiofrequency ablation, are discussed separately. (See "Antiarrhythmic drugs to maintain sinus https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 1/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate rhythm in patients with atrial fibrillation: Recommendations" and "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) This topic will also address the issue of whether other medications are associated with a decreased frequency of recurrent AF. (See 'Other therapies' below.) META-ANALYSIS The safety and efficacy of a number of antiarrhythmic drugs was assessed in a 2019 meta- analysis, which included 59 trials (n = 20,981) in which an antiarrhythmic drug for the treatment of atrial fibrillation (AF) was compared against a placebo, another antiarrhythmic, or untreated controls [9]. The following findings were noted: Compared with controls, disopyramide, quinidine, flecainide, propafenone, amiodarone, dofetilide, dronedarone, and sotalol lowered the recurrence rate of AF (risk ratios [RR] 0.77, 0.83, 0.65, 0.67, 0.52, 0.72, 0.85, and 0.83, respectively). Metoprolol also lowered the risk (RR 0.83). All-cause mortality was increased (compared with controls) with sotalol (2.23, 95% CI 1.03- 4.81). Mortality may be increased with other antiarrhythmic drugs, but the evidence was of moderate certainty or weak. These data support the general observation (as summarized in the following sections) that antiarrhythmics can reduce AF recurrences, but their overall value is limited by adverse effects. All of the antiarrhythmic drugs used to maintain sinus rhythm in AF have the potential to provoke ventricular arrhythmias. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Drugs'.) CLASS IA ANTIARRHYTHMIC DRUGS Quinidine, disopyramide, and procainamide are class IA antiarrhythmic drugs ( table 2). These drugs act by modifying the sodium channel and inhibiting the outward potassium current resulting in QT prolongation. They also have important vagolytic effects. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Quinidine is the most widely studied class IA agent for the maintenance of sinus rhythm in AF [10,11]. Although studies have shown that quinidine can reduce the rate of recurrent AF https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 2/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate compared to placebo, it is associated with an increase in mortality, particularly in patients with heart failure [7,8,12,13]. The use of quinidine for the maintenance of sinus rhythm has declined largely because other drugs are both more effective and safer. Disopyramide also seems to have some benefit in the prevention of recurrent AF [14], although it must be used with caution since it can significantly worsen underlying heart failure. The efficacy of oral procainamide has been evaluated in older and poorly controlled trials or in patients who recently underwent coronary artery bypass surgery [15-17]. Oral procainamide is not readily available in the US. CLASS IC ANTIARRHYTHMIC DRUGS Flecainide and propafenone are classified as class IC antiarrhythmic agents, although they are known to have significantly different electrophysiologic and other properties. The following observations have been made regarding their efficacy: Compared to placebo, both are more effective in maintaining sinus rhythm at six months and in prolonging the time to atrial fibrillation (AF) recurrence [18-26]. Flecainide and propafenone appear to have equal efficacy [27,28]. In a randomized, open- label study of 200 patients, for example, the probability of a safe and effective response (maintenance of sinus rhythm or fewer episodes of paroxysmal AF) at one year was 77 and 75 percent with flecainide and propafenone, respectively [27]. A meta-analysis evaluated trials of patients with AF resistant to class I drugs or sotalol who were treated with flecainide or amiodarone after cardioversion [29]. Maintenance of sinus rhythm at 12 months was significantly more likely with amiodarone (60 versus 34 percent with flecainide). Despite the apparent benefit for the prevention of recurrent AF, the toxicity associated with these drugs has restricted their use. The cardiac complications of the class IC drugs include worsening of heart failure, bradycardia, and presumably drug-induced atrial and ventricular arrhythmias in 7 to 27 percent of cases. In up to 13 percent of patients AF recurs as, or converts to, persistent atrial flutter [30]. Radiofrequency ablation of the atrial flutter, with continuation of the antiarrhythmic agent, is an effective approach for reducing arrhythmia recurrence and duration [30,31]. (See 'Hybrid therapy in patients who develop atrial flutter' below and "Atrial flutter: Maintenance of sinus rhythm".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 3/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The use of flecainide is restricted to those patients who have no structural heart disease, particularly coronary heart disease. The concern about the use of the class IC agents is primarily the result of the Cardiac Arrhythmia Suppression Trial (CAST), which showed that flecainide increased the number of deaths among patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction ( figure 2) [32]. It is not known if these findings can be extrapolated to other types of heart disease. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Class I agents'.) Propafenone has some mild beta-blocking activity in addition to its effects on the sodium channel. Thus, its toxicity may not be identical to that of flecainide and, in patients with ventricular arrhythmia, propafenone appears to be less proarrhythmic. In a study of 480 patients with supraventricular arrhythmia treated with propafenone for 14 months, 59 percent of patients experienced at least one side effect; the drug was discontinued due to an adverse reaction in only 15 percent, while 17 percent required a reduction in dose [33]. Arrhythmia aggravation occurred in 2 percent of patients; the incidence was higher in those with structural heart disease compared to those without (3 versus 1 percent). CLASS III ANTIARRHYTHMIC AGENTS Amiodarone, dronedarone, sotalol, dofetilide, and ibutilide are classified as class III antiarrhythmic agents. There are, however, many dissimilarities among these drugs, and they should be considered separately. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Amiodarone Amiodarone is the most effective antiarrhythmic drug for the prevention of atrial fibrillation (AF), as demonstrated in the following randomized trials [34-39]: The Canadian Trial of Atrial Fibrillation (CTAF) randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3). There was no difference among the three therapies in mortality, but there was an almost significant trend toward an increased incidence of side effects resulting in drug discontinuation with amiodarone (18 versus 11 percent for sotalol or propafenone). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Similar relative efficacies were noted in a substudy from the AFFIRM trial [37]. Patients in the rhythm control arm were randomly assigned to amiodarone or sotalol (256 patients), https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 4/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate amiodarone or a class I drug (222 patients), or sotalol and a class I drug (183 patients). The one-year endpoint was defined as the patient being alive, being in sinus rhythm at follow- up visits, still taking the drug (ie, no discontinuation for episodes of highly symptomatic AF), and needing no electrical or pharmacologic cardioversions. The likelihood of achieving the endpoint was significantly higher with amiodarone compared to sotalol (60 versus 38 percent) or a class I drug (62 versus 23 percent). In comparison to CTAF, amiodarone was not associated with a higher risk than sotalol of cessation of therapy for adverse effects (13 versus 16 percent). The SAFE-T trial compared amiodarone, sotalol, and placebo in patients with persistent AF for both conversion to sinus rhythm and maintenance of sinus rhythm [35]. The rate of maintenance of sinus rhythm was significantly higher at one year with amiodarone than sotalol or placebo and with sotalol than placebo (52 versus 32 and 13 percent on intention to treat analysis and 65 versus 40 and 18 percent on treatment received analysis). The primary endpoint, the median time to recurrence beginning after day 28, was 487, 74, and 6 days in the three groups. However, among the approximately 25 percent of patients with ischemic heart disease, the median time to recurrence with amiodarone was not significantly different from sotalol (569 versus 428 days). There was no difference among the study groups in terms of adverse effects except for a small increase in minor bleeding among patients treated with amiodarone. The mortality rate was not significantly higher with amiodarone and sotalol combined compared to placebo (4.36 versus 2.84 per 100 person-years), but trials of patients with heart failure or myocardial infarction have not shown an increase in mortality with amiodarone [40,41]. Nonrandomized studies of patients with chronic or paroxysmal AF refractory to most other antiarrhythmic agents have shown that amiodarone maintained sinus rhythm in 53 to 79 percent of cases during a 15 to 27 month follow-up [42-45]. Amiodarone is less effective in patients who have AF for over one year or who have an enlarged LA. However, even in this group, the success rate with amiodarone may be as high as 50 to 60 percent [42,43]. Amiodarone has also been evaluated as a prophylactic therapy to prevent AF after cardiac surgery. This issue is discussed separately. (See "Early noncardiac complications of coronary artery bypass graft surgery".) Sotalol Sotalol is not very effective in converting AF to sinus rhythm, but is useful in preventing recurrent episodes [46-48]. As an example, one study randomly assigned 253 patients with AF or atrial flutter to placebo or three doses of sotalol (80, 120, or 160 mg BID); the recurrence rate at one year was 72, 70, 60, and 55 percent, respectively, and the median times to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 5/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recurrence were 27, 106, 119, and 175 days, respectively [48]. As noted with other drugs, predictors of AF recurrence were the presence of coronary disease, duration of AF >2 months before reversion, LA size >60 mm, and older age. A number of studies have compared the efficacy of sotalol to other antiarrhythmic drugs for preventing recurrent AF. As noted above, randomized controlled trials and a substudy analysis from AFFIRM demonstrated that sotalol was less effective than amiodarone [34-37]. After a mean follow- up of 16 months in CTAF, for example, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3) [34]. Similar findings were noted in SAFE-T [35]. (See 'Amiodarone' above.) Sotalol appears to have equal efficacy to propafenone [34,49,50]. The best data come from CTAF, which randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, the proportion of patients free from recurrent AF was 37 percent with both sotalol and propafenone ( figure 3). (See 'Amiodarone' above.) Dofetilide Dofetilide is a class III antiarrhythmic drug ( table 2). The SAFIRE-D trial evaluated 204 patients with AF who were successfully cardioverted electrically or pharmacologically with dofetilide and maintained on a dose of 125, 250, or 500 g twice daily or placebo [51]. The probability of remaining in sinus rhythm at one year was significantly greater for dofetilide compared to placebo (40, 37, and 58 versus 25 percent). The all-cause mortality was the same in the four groups. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) The results were similar in the EMERALD trial, which randomly assigned patients who were pharmacologically or electrically cardioverted to therapy with one of three doses of dofetilide (125, 250, or 500 g twice daily), sotalol (80 mg twice daily), or placebo [52]. After 12 months of therapy, AF recurred in 79 percent of placebo patients, 34 percent of those receiving the highest dose of dofetilide, and between 48 and 60 percent in the other groups. (See "Clinical use of dofetilide".) It is of concern that nonfatal torsades de pointes (TdP) or sudden death occurred in four patients in the high-dose dofetilide group [52]. However, a pooled analysis of 1346 patients receiving dofetilide and 677 treated with placebo in randomized clinical trials of the treatment of supraventricular arrhythmias found that dofetilide was not associated with an increase in mortality (adjusted hazard ratio 1.1) [53]. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 6/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The lack of an increase in mortality with dofetilide is reassuring. However, because drug-induced TdP is relatively rare and can be treated if it occurs in a monitored setting, the impact of this complication may not be seen in analyses limited to overall survival. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Dronedarone Dronedarone is a derivative of amiodarone. In patients with AF, randomized trials with up to 12 months of follow-up have found that dronedarone prevents recurrent AF and was safe (including no increased risk of serious arrhythmias) [54-56]. However, in the ANDROMEDA trial in patients with advanced heart failure from LV systolic dysfunction, there was an increased risk of death with dronedarone and the trial was stopped early [57]. As a result, dronedarone is contraindicated in this population of patients. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) In the ATHENA trial 4628 patients with AF were randomly assigned to either dronedarone or placebo [58]. Patients with New York Heart Association (NYHA) class II or III heart failure comprised 21 percent of the study population, but patients with NYHA class IV heart failure were excluded. After a mean follow-up period of 21 months, dronedarone significantly reduced the primary outcome of death or cardiovascular hospitalization (31.9 versus 39.4 percent, hazard ratio 0.76, 95% CI 0.69-0.84) and the secondary outcome of cardiovascular death (2.7 versus 3.9 percent, hazard ratio 0.71, 95% CI 0.51-0.98). Dronedarone is the only antiarrhythmic drug that has shown a salutary effect on mortality. Maintenance of sinus rhythm was not one of the endpoints in ATHENA. The DIONYSOS study was a short-term (median duration of seven months) comparison between amiodarone and dronedarone to assess the differences in drug tolerability and AF recurrence in 504 patients [59]. Sixty percent of the patients had persistent AF. The authors found that the composite primary endpoint of AF recurrence or premature study drug discontinuation occurred in 75.5 percent of patients taking dronedarone, but only 58.8 percent of patients taking amiodarone. This endpoint was primarily driven by AF recurrence on dronedarone compared to amiodarone (63.5 versus 42.0 percent, respectively). Drug discontinuation and the main safety endpoints of extra-cardiac toxicity only tended to be less with dronedarone, but did not reach statistical significance. It is possibly that with longer follow-up periods there would have been a greater difference in noncardiac side effects, since the toxicity with amiodarone is typically manifest after several months to years of use. In a meta-analysis of dronedarone trials prior to the DIONYSOS study, where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, a similar conclusion was reached [60]. Amiodarone was found to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 7/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events. The PALLAS trial, which was stopped early due to an increase in adverse events in patients taking dronedarone, evaluated the potential use of dronedarone to improve cardiovascular outcomes in patients with permanent AF. This trial is discussed elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone'.) Ibutilide Ibutilide is only available for intravenous use and therefore is useful for the acute reversion of AF, not for long-term prevention [61]. (See "Atrial fibrillation: Cardioversion".) Vernakalant Vernakalant is considered a relatively atrially-selective antiarrhythmic agent since one of its main actions is to inhibit the ultrarapid potassium current (IKur) and the acetylcholine potassium current (IKAch), both of which are predominantly found in the atria. Vernakalant also mildly inhibits other potassium channels and, to a much lesser extent, the sodium current. The program for vernakalant drug development in the US has been terminated. The drug is available in an intravenous form to terminate AF in Europe. BETA BLOCKERS There is no evidence to support the use of beta blockers (aside for sotalol), in the absence of other antiarrhythmic drugs, for the prevention of atrial fibrillation (AF). In patients with heart failure (HF) due to systolic dysfunction, chronic treatment with certain beta blockers reduces mortality. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) There is evidence that beta blockers may also reduce the likelihood of the development of AF in patients with HF. A systematic review including seven randomized trials of 11,952 patients evaluated the efficacy of beta blockers for this purpose [62]. Among patients who were in sinus rhythm at baseline and were followed for six months to two years, the incidence of new onset AF was significantly lower in patients treated with beta blockers than those assigned to placebo (28 versus 39 per 1000 patient years). (See "The management of atrial fibrillation in patients with heart failure".) A separate issue is whether beta blockers, which are felt to have some antiarrhythmic properties ( table 2), are effective for preventing recurrent atrial fibrillation in patients with no heart disease. The evidence to support their use for this purpose is scant, and any reduction in the https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 8/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate reported frequency of AF may be attributable to improved rate control that may render recurrent AF silent. VERAPAMIL The calcium channel blocking agents verapamil and diltiazem impair conduction and prolong refractoriness in the AV node. They have been used both acutely and chronically to slow the ventricular response in atrial fibrillation (AF). Verapamil has also been investigated for its effectiveness in maintaining sinus rhythm after cardioversion. The rationale for this approach is the observation that the electrical remodeling that occurs during AF is thought to be due, at least in part, to abnormal calcium loading during rapid atrial rates. In studies in animals and humans, verapamil has been shown to prevent electrical remodeling [63,64]. (See "Mechanisms of atrial fibrillation", section on 'Electrical remodeling'.) Verapamil as a single agent was not effective in preventing AF recurrence in the VERDICT trial, in which 97 patients with persistent AF were randomly assigned to either verapamil or digoxin [65]. There was no difference in AF recurrence rates at one month. It was suggested that verapamil may be effective only when given with a sodium or potassium channel blocking agent [66]. Verapamil with another agent Based upon the observations cited above, several studies evaluated the benefit of verapamil with another agent in preventing recurrences of AF. In the small VEPARAF trial, the addition of verapamil to either amiodarone or flecainide significantly reduced the incidence of recurrent AF within three months of cardioversion compared with either agent alone [67]. The larger PAFAC and SOPAT trials found the combination of verapamil and quinidine to be comparable to sotalol, and superior to placebo, in preventing AF recurrence. In PAFAC, 848 patients with persistent AF were cardioverted and then randomly assigned to sotalol, quinidine and verapamil, or placebo [68]. Patients used an event recorder to record and transmit at least one ECG daily during a mean of nine months of follow-up. The incidence of death or any AF recurrence was significantly lower for both sotalol and for quinidine plus verapamil than for placebo (67 and 65 versus 83 percent). Serious adverse events were not more common with quinidine plus verapamil than with sotalol, and the only episodes of torsades de pointes occurred with sotalol. In the SOPAT trial, 1033 patients with recurrent symptomatic paroxysmal AF were randomly assigned to placebo, sotalol, or one of two dose combinations of quinidine plus verapamil [69]. As in the PAFAC trial, patients recorded and transmitted at least one ECG daily with an event https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 9/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recorder. The mean time to first AF recurrence was prolonged significantly in all three active treatment groups compared to placebo. At a mean of eight months of follow-up, the number of days of symptomatic AF was reduced significantly for all three active treatment arms compared to placebo. There was no difference between the sotalol and the two quinidine plus verapamil treatment groups in either of these efficacy endpoints or in the incidence of serious adverse side effects. OTHER THERAPIES In addition to conventional antiarrhythmic drugs, a number of other agents have been investigated for the purpose of suppressing atrial fibrillation (AF). ACE inhibitors, angiotensin II receptor blockers Both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) reduce the incidence of atrial fibrillation in selected patient populations. In a recent meta-analysis of 26 randomized trials that evaluated the effect of ACE inhibitors and ARBs on the prevention of AF, it was demonstrated that both classes of drugs had a similar beneficial effect on AF [70]. The effect was more potent for recurrent AF compared to primary prevention of AF (OR 0.45 versus 0.80, respectively). ACE inhibitor or ARB effect on AF was additive to that of amiodarone when used concurrently and endured even in patients with depressive LV function. This issue is discussed in further detail separately. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".) Magnesium Although not a primary antiarrhythmic agent, magnesium affects atrial electrophysiologic properties. Some studies, particularly those in patients undergoing coronary artery bypass surgery, have found that magnesium deficiency is associated with AF and that magnesium supplementation reduces its incidence. (See "Significance of hypomagnesemia in cardiovascular disease" and "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The role of oral magnesium therapy in the prevention of recurrent AF after cardioversion was evaluated in one study of 301 patients who were followed for at least six months after the restoration of sinus rhythm; magnesium therapy alone or in combination with sotalol was ineffective for preventing recurrent AF [71]. Statins There is some evidence that statins may prevent recurrences in patients with lone AF [72,73], ischemic heart disease [73,74] and after cardiac bypass surgery [73,75]. Aldosterone Blockers These drugs have been useful in the treatment of heart failure. Spironolactone and eplerenone have effects on atrial electrophysiologic properties in https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 10/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate experimental animals, but no studies in patients with AF have been done. DRUG-REFRACTORY ATRIAL FIBRILLATION Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. There are limited data to support the use of combination antiarrhythmic drug therapy, and this approach may expose the patient to a greater risk of proarrhythmia and other side effects. As a result, combination therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy of atrial fibrillation (AF). These options include: Radiofrequency catheter ablation (RFA), which is the most common of these approaches. (See "Atrial fibrillation: Catheter ablation".) Surgical procedures such as the maze operation, particularly for patients undergoing cardiac surgery for another indication. Some centers also offer mini-maze operations using limited bilateral thoracotomies as standalone procedures as well. (See "Atrial fibrillation: Surgical ablation".) HYBRID THERAPY IN PATIENTS WHO DEVELOP ATRIAL FLUTTER Atrial flutter can occur after the initiation of antiarrhythmic drug therapy in patients with atrial fibrillation (AF), especially with the use of class IC agents or amiodarone. One approach to managing this situation has been a hybrid approach that involves ablation of atrial flutter by creating a block across the cavotricuspid isthmus and then continuation of the antiarrhythmic drug. Although this approach may be helpful in maintaining sinus rhythm in the short term, data (articles below) suggest that in the long term, there is a high recurrence of AF [76,77]. Therefore, the development of atrial flutter on an antiarrhythmic drug may be considered failure of therapy. SUMMARY Recommendations for the use drug therapy to maintain sinus rhythm in patients with atrial fibrillation (AF) are found elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 11/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The following are the important points made in this topic: The main goal of drug therapy to maintain sinus rhythm is to reduce symptoms by decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 12/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. 6. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 7. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 8. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 9. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9:CD005049. 10. S dermark T, Jonsson B, Olsson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J 1975; 37:486. 11. Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J 1984; 65:367. 12. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality. Am Heart J 1992; 124:924. 13. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 14. Karlson BW, Torstensson I, Abj rn C, et al. Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J 1988; 9:284. 15. Szekely P, Sideris DA, Batson GA. Maintenance of sinus rhythm after atrial defibrillation. Br Heart J 1970; 32:741. 16. Madrid AH, Moro C, Mar n-Huerta E, et al. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 1993; 14:1127. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 13/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 17. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 18. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64:1317. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80:1557. 20. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med 1991; 114:539. 21. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. UK Propafenone PSVT Study Group. Circulation 1995; 92:2550. 22. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 23. Antman EM, Beamer AD, Cantillon C, et al. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990; 15:698. 24. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87:172. 25. Meinertz T, Lip GY, Lombardi F, et al. Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study). Am J Cardiol 2002; 90:1300. 26. Pritchett EL, Page RL, Carlson M, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92:941. 27. Chimienti M, Cullen MT Jr, Casadei G. Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: report from the Flecainide and Propafenone Italian Study Investigators. Am J Cardiol 1996; 77:60A. 28. Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77:66A.
decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 12/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. 6. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 7. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 8. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 9. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9:CD005049. 10. S dermark T, Jonsson B, Olsson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J 1975; 37:486. 11. Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J 1984; 65:367. 12. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality. Am Heart J 1992; 124:924. 13. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 14. Karlson BW, Torstensson I, Abj rn C, et al. Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J 1988; 9:284. 15. Szekely P, Sideris DA, Batson GA. Maintenance of sinus rhythm after atrial defibrillation. Br Heart J 1970; 32:741. 16. Madrid AH, Moro C, Mar n-Huerta E, et al. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 1993; 14:1127. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 13/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 17. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 18. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64:1317. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80:1557. 20. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med 1991; 114:539. 21. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. UK Propafenone PSVT Study Group. Circulation 1995; 92:2550. 22. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 23. Antman EM, Beamer AD, Cantillon C, et al. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990; 15:698. 24. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87:172. 25. Meinertz T, Lip GY, Lombardi F, et al. Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study). Am J Cardiol 2002; 90:1300. 26. Pritchett EL, Page RL, Carlson M, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92:941. 27. Chimienti M, Cullen MT Jr, Casadei G. Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: report from the Flecainide and Propafenone Italian Study Investigators. Am J Cardiol 1996; 77:60A. 28. Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77:66A. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 14/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 29. Zarembski DG, Nolan PE Jr, Slack MK, Caruso AC. Treatment of resistant atrial fibrillation. A meta-analysis comparing amiodarone and flecainide. Arch Intern Med 1995; 155:1885. 30. Schumacher B, Jung W, Lewalter T, et al. Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation. Am J Cardiol 1999; 83:710. 31. Nabar A, Rodriguez LM, Timmermans C, et al. Radiofrequency ablation of "class IC atrial flutter" in patients with resistant atrial fibrillation. Am J Cardiol 1999; 83:785. 32. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 33. Podrid PJ, Anderson JL. Safety and tolerability of long-term propafenone therapy for supraventricular tachyarrhythmias. The Propafenone Multicenter Study Group. Am J Cardiol 1996; 78:430. 34. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. 35. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 36. Kochiadakis GE, Igoumenidis NE, Marketou ME, et al. Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. Heart 2000; 84:251. 37. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 38. Dorian P, Mangat I. Restoring sinus rhythm in atrial fibrillation: a Pyrrhic victory? J Am Coll Cardiol 2003; 42:30. 39. Zimetbaum P. Amiodarone for atrial fibrillation. N Engl J Med 2007; 356:935. 40. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Amiodarone Trials Meta-Analysis Investigators. Lancet 1997; 350:1417. 41. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352:225. 42. Brodsky MA, Allen BJ, Walker CJ 3rd, et al. Amiodarone for maintenance of sinus rhythm after conversion of atrial fibrillation in the setting of a dilated left atrium. Am J Cardiol 1987; 60:572. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 15/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 43. Gold RL, Haffajee CI, Charos G, et al. Amiodarone for refractory atrial fibrillation. Am J Cardiol 1986; 57:124. 44. Horowitz LN, Spielman SR, Greenspan AM, et al. Use of amiodarone in the treatment of persistent and paroxysmal atrial fibrillation resistant to quinidine therapy. J Am Coll Cardiol 1985; 6:1402. 45. Skoularigis J, R thlisberger C, Skudicky D, et al. Effectiveness of amiodarone and electrical cardioversion for chronic rheumatic atrial fibrillation after mitral valve surgery. Am J Cardiol 1993; 72:423. 46. Gallik DM, Kim SG, Ferrick KJ, et al. Efficacy and safety of sotalol in patients with refractory atrial fibrillation or flutter. Am Heart J 1997; 134:155. 47. Alt E, Ammer R, Lehmann G, et al. Patient characteristics and underlying heart disease as predictors of recurrent atrial fibrillation after internal and external cardioversion in patients treated with oral sotalol. Am Heart J 1997; 134:419. 48. Benditt DG, Williams JH, Jin J, et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1999; 84:270. 49. Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1993; 71:558. 50. Bellandi F, Simonetti I, Leoncini M, et al. Long-term efficacy and safety of propafenone and sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation. Am J Cardiol 2001; 88:640. 51. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 52. Ferguson JJ. Meeting highlights. Highlights of the 71st scientific sessions of the American Heart Association. Circulation 1999; 99:2486. 53. Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138:994. 54. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 55. Kathofer S, Thomas D, Karle CA. The novel antiarrhythmic drug dronedarone: comparison with amiodarone. Cardiovasc Drug Rev 2005; 23:217. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 16/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 56. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 57. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 58. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 59. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 60. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 61. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. 62. Nasr IA, Bouzamondo A, Hulot JS, et al. Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis. Eur Heart J 2007; 28:457. 63. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. 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Eur Heart J 2004; 25:1385. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 17/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 69. Patten M, Maas R, Bauer P, et al. Suppression of paroxysmal atrial tachyarrhythmias results of the SOPAT trial. Eur Heart J 2004; 25:1395. 70. Zhang Y, Zhang P, Mu Y, et al. The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Pharmacol Ther 2010; 88:521. 71. Frick M, Darp B, Ostergren J, Rosenqvist M. The effect of oral magnesium, alone or as an adjuvant to sotalol, after cardioversion in patients with persistent atrial fibrillation. Eur Heart J 2000; 21:1177. 72. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003; 92:1343. 73. Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect of statin therapy and atrial fibrillation a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2008; 51:828. 74. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 2003; 92:1379. 75. Dotani MI, Elnicki DM, Jain AC, Gibson CM. Effect of preoperative statin therapy and cardiac outcomes after coronary artery bypass grafting. Am J Cardiol 2000; 86:1128. 76. Garc a Seara J, Raposeiras Roubin S, Gude Sampedro F, et al. Failure of hybrid therapy for the prevention of long-term recurrence of atrial fibrillation. Int J Cardiol 2014; 176:74. 77. Anastasio N, Frankel DS, Deyell MW, et al. Nearly uniform failure of atrial flutter ablation and continuation of antiarrhythmic agents (hybrid therapy) for the long-term control of atrial fibrillation. J Interv Card Electrophysiol 2012; 35:57. Topic 1038 Version 37.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 18/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate GRAPHICS Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 19/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 20/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate ACC/AHA/ESC guideline summary: Maintenance of sinus rhythm in atrial fibrillation (AF) Class I - There is evidence and/or general agreement that the following approach is effective for the maintenance of sinus rhythm in patients with AF Treatment of precipitating or reversible causes of AF before initiating therapy with antiarrhythmic drugs. Class IIa - The weight of evidence or opinion is in favor of the usefulness of the following approaches for the maintenance of sinus rhythm in patients with AF Antiarrhythmic drug therapy to maintain sinus rhythm and prevent tachycardia-induced cardiomyopathy. Infrequent, well tolerated recurrent episodes of recurrent AF is reasonable as a successful outcome of antiarrhythmic drug therapy. Outpatient initiation of therapy in patients with no associated heart disease when the antiarrhythmic drug is well tolerated. In patients with lone AF and no structural heart disease, outpatient initiation of propafenone or flecainide therapy in patients with paroxysmal AF who are in sinus rhythm at the time of drug initiation. Sotalol in outpatients in sinus rhythm who have little or no heart disease, are prone to paroxysmal AF, a baseline uncorrected QT interval less than 460 msec, normal serum electrolytes, and no risk factors for class III drug-related proarrhythmia. Catheter ablation as an alternative to antiarrhythmic drug therapy to prevent recurrent AF in symptomatic patients with little or no left atrial enlargement. Class III - There is evidence and/or general agreement that the following approaches are not useful or may be harmful for the maintenance of sinus rhythm in patients with AF Use of a particular antiarrhythmic drug is not recommended in patients with well-defined risk factors for proarrhythmia with that drug. Antiarrhythmic drug therapy is not recommended in patients with advanced sinus node disease or atrioventricular node dysfunction unless they have a functioning electronic cardiac pacemaker. Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 78424 Version 2.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 21/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Maintenance of sinus rhythm Therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Drugs are listed alphabetically and not in order of suggested use. The seriousness of heart disease progresses from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present. LVH: left ventricular hypertrophy. Reproduced from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011; 57:223. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 83173 Version 2.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 22/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 23/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 24/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 25/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 26/27 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 27/27
7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations : Kapil Kumar, MD : Peter J Zimetbaum, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 24, 2021. INTRODUCTION For patients with atrial fibrillation (AF), there are two main strategies to manage the irregular rhythm and its impact on symptoms: rhythm control (restoration followed by maintenance of sinus rhythm with either antiarrhythmic drugs or catheter ablation); and rate control with atrioventricular (AV) nodal blockers. (See 'Initial management decisions' below.) For those patients in whom a rhythm control strategy is chosen, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes as well as the symptoms during recurrences [1,2]. As antiarrhythmic drugs are associated with a potential for serious adverse side effects, particularly the induction of proarrhythmia, they should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risks associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' below.) Rhythm control can be achieved with either antiarrhythmic drug therapy or nonpharmacologic methods. This topic provides recommendations for the former. The clinical trials describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Nonpharmacologic methods to maintain sinus rhythm (including surgery and radiofrequency ablation or cryoballoon ablation) in selected patients who are refractory to conventional therapy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 1/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) INDICATIONS There are three settings in which a rhythm control strategy for the maintenance of sinus rhythm should be considered [3]: Persistent symptoms (palpitations, dyspnea, lightheadedness, angina, syncope, and heart failure) despite adequate rate control. An inability to attain adequate rate control (to prevent tachycardia-mediated cardiomyopathy). (See "Arrhythmia-induced cardiomyopathy".) Patient preference. Some patients will strongly prefer to avoid either paroxysmal or persistent AF. We consider cardioversion to sinus rhythm in most patients, particularly younger patients, with a first-detected episode of atrial fibrillation (AF) in whom the arrhythmia is of recent onset and the risk for recurrence appears to be low. Maintenance antiarrhythmic drug therapy is not routinely used after cardioversion in patients with newly detected AF [3]. These issues are discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) INITIAL MANAGEMENT DECISIONS Prior to selecting and initiating antiarrhythmic drug therapy, the following issues should be considered. Rhythm versus rate control: The choice between a rhythm- or a rate-control strategy is determined by many factors, including patient age, the degree to which symptoms interfere with the quality of life, and concerns about antiarrhythmic drug therapy or catheter ablation. There is no evidence that long-term outcomes, such as rates of survival or thromboembolism, are improved by rhythm control ( figure 1 and figure 2) [4,5]. Our recommendations for the use of these two strategies are found elsewhere. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 2/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Precipitating factors: Before initiating a rhythm control strategy, any risk factors for atrial fibrillation (AF) should be addressed. Examples include hyperthyroidism, hypertension, heart failure, sleep apnea, and excess alcohol intake. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations'.) Maintenance antiarrhythmic drug therapy is not recommended after cardioversion in a patient with a transient or reversible cause (such as cardiac surgery, pericarditis, or pulmonary embolism). An option in such patients is beta blocker therapy after restoration of sinus rhythm, which may provide modest protection against recurrent AF [6]. However, short-term antiarrhythmic therapy can be considered in this situation as the underlying cause is treated in patients who are highly symptomatic. Anticoagulation: The proper use of anticoagulation in the period surrounding conversion to sinus rhythm is discussed separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Rate control: An atrioventricular (AV) nodal blocker, such as a beta blocker or a rate- slowing calcium channel blocker, is usually started before, or simultaneously with, antiarrhythmic drug therapy in patients who have demonstrated a moderate to rapid ventricular rate ( 110 beats per minute) during AF. Slowing of the rate generally improves symptoms prior to the restoration of sinus rhythm. This therapy is continued while the patient is in sinus rhythm to protect against a rapid ventricular rate should AF recur. This issue is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) Restoration of sinus rhythm: Many patients with AF in whom a rhythm control strategy is chosen will need sinus rhythm restored prior to the initiation of long-term antiarrhythmic drug therapy. The restoration of sinus rhythm is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion".) Some patients with relatively infrequent episodes of paroxysmal atrial fibrillation can be managed with antiarrhythmic therapy given only at the time of the episode. This form of outpatient "pill-in-the-pocket" therapy for recurrent AF is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) SELECTING AN ANTIARRHYTHMIC DRUG https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 3/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Once the issues discussed above have been addressed, an antiarrhythmic agent can be chosen. The choice of drug is significantly influenced both by drug and patient characteristics. As with all therapeutic interventions, the choice of agent should take into account the benefit to risk ratio of the therapy chosen. (See 'Proarrhythmia' below.) Amiodarone, dofetilide, flecainide, propafenone, sotalol, and less commonly dronedarone are the drugs we recommend to maintain sinus rhythm. (See 'Concerns about dronedarone' below.) For additional information regarding the therapeutic use of these drugs, including information regarding dosing and side effects, the reader is referred to individual UpToDate topics on these drugs or to the individual drug monographs in our drug database. The following points regarding antiarrhythmic drugs should be kept in mind in choosing therapy: Compared to other agents, amiodarone is associated with the greatest likelihood of maintaining sinus rhythm, but also with the highest risk of long-term complications [7,8]. In addition, a 2014 report raises the possibility that amiodarone use in patients taking warfarin is associated with an increased risk of stroke compared to those not taking the drug [9]. In this study, there was a lower time in the therapeutic range (of the international normalized ratio) in patients receiving amiodarone. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Quinidine, procainamide, and disopyramide are no longer recommended for patients with AF, except perhaps in patients with vagally mediated atrial fibrillation (AF), as there are more effective drugs and due to extracardiac side effects as well as the concern about proarrhythmia [10]. (See 'Proarrhythmia' below.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia [6,11,12]. Of course beta blockers may have already been initiated to slow the ventricular rate in AF. (See 'Proarrhythmia' below and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Beta blockers'.) The following patient characteristics may influence decision making: The clinical features of the patient, such as presence or absence of clinical heart disease. We believe it is prudent to obtain a two-dimensional echocardiogram to screen for structural heart disease (eg, left ventricular systolic dysfunction, left ventricular https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 4/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate hypertrophy, or valvular heart disease). An exercise or nuclear stress imaging test may be used to screen for coronary heart disease and is typically done before starting a class IC agent. (See 'Atrial fibrillation without structural heart disease' below and 'Atrial fibrillation associated with structural heart disease' below.) The presence of paroxysmal compared to persistent AF [1,13]. As examples, our experts rarely use dofetilide for paroxysmal AF and infrequently choose dronedarone for persistent AF due to reduced efficacy compared with amiodarone. The presence of vagally-mediated AF [14,15]. The 2016 European Society of Cardiology AF guideline suggest that, because of its long-lasting anticholinergic activity, disopyramide may be considered in patients with vagally-induced AF (eg, occurring most often in athletic young men with slow heart rates during rest or sleep), as long as the patient does not have prostatism or glaucoma [13,16]. The combination of disopyramide and either a beta blocker or a calcium channel blocker must be used cautiously because of the additive negative inotropic effects. If disopyramide cannot be given or is not tolerated, flecainide and amiodarone represent the sequential alternatives. Our experts use disopyramide cautiously due to concern for proarrhythmia. For patients with adrenergically-mediated AF (eg, occurring during exercise or other activity), we suggest beta blockers as first-line therapy, followed by sotalol and amiodarone. Antiarrhythmic drugs are associated with a potential for serious adverse side effects, particularly the induction of proarrhythmia. Thus, they should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risk associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' below.) As the expectation of antiarrhythmic therapy is to reduce the frequency and duration of episodes, improve quality of life, and prevent hospitalization, a recurrence of AF does not necessarily denote a failure of the medication or mandate a change to a different antiarrhythmic drug. Atrial fibrillation without structural heart disease Patients without structural heart disease include those with hypertension who do not have left ventricular hypertrophy. The author and reviewers of this topic generally select flecainide or propafenone as the first antiarrhythmic drug for these patients due to its relatively good side effect profile, efficacy, and ease of use. The use of these drugs in patients >70 years of age should be considered more cautiously, given the higher likelihood of underlying coronary artery disease. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 5/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate In these patients, flecainide, propafenone, amiodarone, dronedarone, sotalol, and dofetilide are superior to placebo for maintaining sinus rhythm. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) For those patients in whom flecainide or propafenone will not be used as the preferred agent, the following points can influence the choice of antiarrhythmic drug in patients without structural heart disease: In the Canadian Trial of Atrial fibrillation, AFFIRM, and the SAFE-T randomized trials, amiodarone was more effective than flecainide, propafenone, or sotalol (which have nearly equivalent efficacy to each other), but has a significantly higher rate of adverse side effects. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.) In a meta-analysis of trials where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, amiodarone was found to be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events [17]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Both amiodarone and dronedarone are associated with significant side effects. We suggest carefully discussing these with the patient prior to initiating therapy. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of dronedarone".)In the EMERALD trial, Dofetilide had a somewhat better efficacy than sotalol. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dofetilide'.) Some cardiologists prefer to use low-dose amiodarone (100 to 200 mg per day), particularly in older patients, in preference to flecainide, sotalol, or dronedarone for two principal reasons: greater efficacy than sotalol and dronedarone ( figure 3) [18-20], and a very low incidence of torsades de pointes [21,22]. In addition, since amiodarone has beta blocking and calcium channel blocking activity, the ventricular rate is usually slower and better tolerated if AF does recur. If amiodarone is used for rhythm control, the need for additional medications to control rate (eg, beta blockers or calcium channel blockers) may be decreased. Despite these advantages, low-dose amiodarone still has appreciable toxicity, including thyroid disease, hepatic dysfunction, lung disease, neurologic abnormalities, and bradycardia [21,22]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 6/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Atrial fibrillation associated with structural heart disease Amiodarone, sotalol, and dofetilide are the most commonly recommended first-line drugs in patients with structural heart disease ( algorithm 1) [13]. Our authors and reviewers prefer either dronedarone or sotalol to amiodarone and dofetilide. Dronedarone is easier to use than sotalol (continuous monitoring of initiation required), but is less efficacious. (See "Clinical uses of sotalol".) These drugs (with the exception of dronedarone) were used for initial therapy in almost 70 percent of patients in AFFIRM, 88 percent of whom had organic heart disease and/or hypertension [4]. Amiodarone was significantly more effective than sotalol in the CTAF, AFFIRM, and SAFE-T trials [18-20]. However, in SAFE-T, sotalol was as effective as amiodarone in the subgroup of patients with coronary heart disease [19]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Coronary heart disease In patients with coronary heart disease who do not have heart failure, sotalol, dronedarone, dofetilide, and amiodarone are acceptable choices ( table 1 and algorithm 1) [13,23,24]. We prefer sotalol due to its better extracardiac side effect profiles. Flecainide and propafenone are contraindicated in this population. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Major side effects of class I antiarrhythmic drugs".) In the Cardiac Arrhythmia Suppression Trial (CAST) of patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction, flecainide increased mortality compared to placebo ( figure 4) [25]. Although propafenone was not used in CAST and may not have the same potential for proarrhythmia as flecainide and encainide [26], it cannot be recommended in patients with underlying heart disease [27]. The extension of this concern to structural heart disease other than coronary artery disease stems in part from the flecainide clinical and safety database, which was used in a retrospective study demonstrating that the presence of structural heart disease including valvular heart disease, congenital heart disease, and cardiomyopathies lead to an alarming increase in proarrhythmia and death [28]. Heart failure Amiodarone and dofetilide, are used in patients with AF and heart failure (HF) or those with a left ventricular ejection fraction less than 35 percent. Our authors and reviewers are more comfortable using dofetilide in this setting with an implantable defibrillator in place or in younger patients with less severe impairment of left ventricular systolic function. This issue is discussed in detail elsewhere. (See "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 7/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Sotalol, propafenone, dronedarone, and flecainide should not be used in patients with heart failure, due to studies showing an increase in mortality with these agents. (See "Clinical uses of sotalol" and "Amiodarone: Clinical uses" and "Major side effects of class I antiarrhythmic drugs".) Left ventricular hypertrophy Patients with significant left ventricular hypertrophy (defined as left ventricular wall thickness greater 1.4 cm for the purposes of this discussion) due to hypertension, hypertrophic cardiomyopathy, or aortic stenosis have underlying subendocardial ischemia and electrophysiologic abnormalities. These increase the risk for proarrhythmia with antiarrhythmic agents. (See "Left ventricular hypertrophy and arrhythmia" and 'Proarrhythmia' below and "Left ventricular hypertrophy: Clinical findings and ECG diagnosis".) Sotalol, flecainide and propafenone are thought to have a significant arrhythmic risk in patients with left ventricular hypertrophy (LVH). Dronedarone has been evaluated in patients with LVH and is thought to be relatively safe [24], although our experts rarely use it. Amiodarone is another therapeutic option. (See "Clinical uses of dronedarone".) Drug-resistant atrial fibrillation Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. Although some have suggested that combination antiarrhythmic drug therapy (eg, a class IC agent with sotalol or amiodarone, often in lower doses, or the combination of dronedarone plus ranolazine) may be an alternative, there are limited data to support such an approach and the patient may be exposed to a greater risk of proarrhythmia and other side effects [29]. As a result, combination antiarrhythmic drug therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy to prevent recurrent AF including surgery (such as the maze operation) or catheter ablation (such as pulmonary vein isolation). (See "Atrial fibrillation: Catheter ablation" and "The role of pacemakers in the prevention of atrial fibrillation" and "Atrial fibrillation: Surgical ablation".) INPATIENT VERSUS OUTPATIENT INITIATION Many patients begun on antiarrhythmic drug therapy should be hospitalized for continuous electrocardiographic monitoring due to a 10 to 15 percent incidence of adverse cardiac events during the initiation of therapy [30]. (See 'Proarrhythmia' below and "Arrhythmia management for the primary care clinician", section on 'Antiarrhythmic drugs'.) The two complications of greatest concern are bradycardia and proarrhythmia. Other adverse cardiac events can include significant QT prolongation, heart failure, rapid ventricular rate, https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 8/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate conduction abnormalities, hypotension, and stroke. The risk is greatest in the first 24 hours and in patients with a prior myocardial infarction. Outpatient initiation of antiarrhythmic drug therapy with the following agents may be considered: Flecainide or propafenone in patients in sinus rhythm who have no underlying structural heart disease, normal baseline QT intervals, and no profound bradycardia or suspected sinus or atrioventricular (AV) node dysfunction [13]. Amiodarone or dronedarone in selected patients who have no other risk factors for torsades de pointes (eg, hypokalemia, hypomagnesemia) or sinus node dysfunction or AV conduction disease. Dronedarone and amiodarone are the only two drugs that can be initiated in outpatients while in atrial fibrillation. Patients with an implantable cardioverter-defibrillator (ICD) represent another group in which outpatient initiation of therapy can be tried, since the ICD provides protection against the risks associated with bradyarrhythmias and tachyarrhythmias. However, one should be cognizant of the potential effects of antiarrhythmic drugs on ventricular defibrillation threshold and ventricular tachycardia cycle length, which could influence the efficacy of ICD therapy. The initiation of antiarrhythmic drugs in patients with paroxysmal AF while they are in sinus rhythm is also associated with some risk. In a review of 409 outpatient initiation trials for a history of recurrent AF or atrial flutter, adverse cardiac events occurred in 17 (4.5 percent); these included three deaths, three permanent pacemakers for bradycardia, and 11 dose reductions for bradycardia [31]. Inpatient initiation with continuous telemetry of higher-risk drugs such as dofetilide and sotalol is typically done over a course of three days, which encompasses five half-lives allowing for achievement of steady-state plasma concentrations. In highly selected patients (eg, normal renal function, no bradycardia, and normal QT interval), sotalol can be loaded as outpatient with event monitor and closely following electrocardiogram for QT interval while in sinus rhythm. LONG-TERM ISSUES AF recurrence Recurrent atrial fibrillation (AF) should not necessarily be labeled as treatment failure. Some patients will elect to continue drug therapy (and, in some cases, occasional cardioversion) because the arrhythmia burden has been substantially reduced as evidenced by episodes that are less frequent, shorter, or associated with milder symptoms. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 9/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nonpharmacologic therapies are another option in such patients. (See "Atrial fibrillation: Atrioventricular node ablation" and "Atrial fibrillation: Catheter ablation".) If a patient has unacceptable recurrent AF on one antiarrhythmic drug, the drug is discontinued and another (and on rare occasion a third) agent is tried. Dosing The starting and maintenance doses for amiodarone, dronedarone, propafenone, flecainide, sotalol, disopyramide, and dofetilide are found in respective LexiComp drug monographs available in UpToDate. Many factors including age, sex, weight, renal or hepatic function, and characteristics on the electrocardiogram influence the starting dose for many of these. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Drug-related arrhythmias and mortality The use of antiarrhythmic drugs is associated with possible life-threatening side effects. The greatest concerns with these agents are proarrhythmia (and consequent tachyarrhythmia) and bradycardia. Patients should be instructed to report symptoms suggestive of the development of drug related arrhythmias, such as syncope, lightheadedness or dizzy spells, or worsening exercise intolerance. (See "Arrhythmia management for the primary care clinician", section on 'Antiarrhythmic drugs' and "Arrhythmia management for the primary care clinician", section on 'Symptoms'.) A 2012 meta-analysis of 56 studies (20,771 patients) compared one or more antiarrhythmic drugs to control or to each other [32]. Compared to controls, the use of the class IA antiarrhythmics quinidine and disopyramide (odds ratio 2.39, 95% CI 1.03-5.59) or sotalol (2.47, 95% CI 1.2-5.05) was associated with increased all-cause mortality, whereas the use of amiodarone, dronedarone, and dofetilide was not (odds ratios were not calculated for flecainide or propafenone). All antiarrhythmics studied showed increased pro-arrhythmic effects (counting both bradyarrhythmias and tachyarrhythmias attributable to treatment), with the exceptions of amiodarone, dronedarone, and propafenone. Proarrhythmia All of the antiarrhythmic drugs used to maintain sinus rhythm have the potential to increase ectopy or induce or aggravate monomorphic ventricular tachycardia (VT), torsades de pointes, or ventricular fibrillation (VF); this is referred to as proarrhythmia ( table 1). In addition to its baseline potential to predispose the patient to proarrhythmia, a drug that is initially safe may become proarrhythmic when the patient develops coronary heart disease or heart failure or is treated with other medications that in combination may be arrhythmogenic. Thus, the patient should be alerted to the potential significance of symptoms such as syncope https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 10/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate and dyspnea and warned about the use of noncardiac drugs that can prolong the QT interval ( table 2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) We agree with the following recommendations made according to drug class in the American College of Cardiology/American Heart Association/European Society of Cardiology guideline [13]: With type IC drugs, QRS widening should not be permitted to exceed 150 percent of the baseline QRS duration. Exercise testing may detect QRS widening that occurs only at rapid heart rates (use-dependent conduction slowing). Exercise testing is also a useful way to screen for exercise-induced proarrhythmia and is typically performed one to two weeks after drug initiation. For type IA or type III drugs ( table 3), with the possible exception of amiodarone, the corrected QT interval in sinus rhythm should remain below 520 milliseconds. More specific and conservative recommendations are available for dofetilide in the package insert. During follow-up, serum creatinine, potassium, and magnesium concentrations should be monitored periodically because proarrhythmia is increased by renal insufficiency, which can lead to drug accumulation, hyperkalemia, and hypermagnesemia. The presence of renal insufficiency warrants dose reduction or cessation of sotalol and dofetilide. In comparison, amiodarone is metabolized in the liver and dose adjustment is probably necessary in patients with hepatic dysfunction. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse hepatic effects'.) Bradyarrhythmia Amiodarone and dronedarone can cause both sinus bradycardia and AV nodal block, with an overall incidence of bradycardic events of about 5 percent. Sotalol, like other beta blockers, can also cause bradycardia. In some cases, permanent pacemaker placement is necessary to permit continued use of these agents. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol".) Ambulatory monitoring Our authors and reviewers have differing thresholds for the use of ambulatory monitoring to screen for proarrhythmia and bradycardia, ranging from screening in the highest risk cases only to screening in everyone. Some experts suggest screening all patients with an ambulatory event monitor for at least two weeks after initiation of therapy, looking for QT interval prolongation or bradyarrhythmias. The basis for this recommendation is that many events occur after three days [31]. For those experts who are more selective based on patient risk, high-risk is defined as baseline bradycardia or borderline QT prolongation, heart failure, or systolic left ventricular dysfunction. Others perform routine monitoring when sotalol, flecainide, or propafenone are chosen. Dofetilide must be initiated in a setting with continuous monitoring. (See "Clinical use of dofetilide".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 11/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate For those patients who are not referred for ambulatory monitoring, we suggest that a 12-lead electrocardiogram be obtained after the initiation of antiarrhythmic drug therapy. Short- versus long-term therapy Based on concerns about drug related arrhythmias and the observation that the atrial action potential normalizes after two to four weeks of sinus rhythm (after AF), the concept that short-term therapy might be as effective and safer than long-term therapy has been proposed. This concept was tested in the Flec-SL non-inferiority trial, which randomly assigned 554 patients with persistent AF and who were intended to undergo cardioversion to either four weeks or six months of flecainide (200 to 300 mg per day) [33]. All patients had successful restoration of sinus rhythm and were then followed with daily telemetric electrocardiography (and Holter monitoring whenever AF was noted on two ECGs) for six months. The primary outcome of time to persistent AF or death occurred in 46 and 39 percent of patients, respectively, which did not meet the criteria of non-inferiority. In addition, a post-hoc analysis of patients who had not reached the primary endpoint in the first month found long- term therapy to be superior (Kaplan-Meier estimate of difference 14.3 percent; hazard ratio 0.3; p = 0.0001). We do not consider short-term therapy appropriate for most patients with persistent AF. Concerns about dronedarone Patients with severe heart failure (HF) (generally those with NYHA class III or IV HF, or those who have been hospitalized with HF in the past four weeks) or those with an ejection fraction of <35 percent should not receive dronedarone. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) The Permanent Atrial fibriLLAtion outcome Study (PALLAS) was designed to test the hypothesis that dronedarone would improve major outcomes in 10,000 patients with permanent AF, over 70 percent of whom had New York Heart Association heart failure class I to III or left ventricular systolic dysfunction at baseline. The rationale was that patients with permanent AF, which affects up to 50 percent of patients with AF, have an increased risk of adverse cardiovascular outcomes including death and myocardial infarction as well as systemic embolization. The ATHENA trial showed a significant reduction in cardiovascular events with dronedarone in patients with paroxysmal or persistent AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled), after a significantly increased risk (Hazard Ratio 2.29, 95% CI 1.34-3.94) of cardiovascular events https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 12/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [34]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. (See 'Summary and recommendations' below.) The European Medicines Agency and the United States Food and Drug Agency (USFDA) have advised against the use of dronedarone in patients with permanent AF [35,36]. In addition, the USFDA now recommends that people taking the drug should have an electrocardiogram every three months to make sure that AF has not become permanent. For patients taking dronedarone, routine monitoring of lung and liver function is not mandated by the USFDA; however, periodic monitoring may be reasonable [37]. (See "Clinical uses of dronedarone", section on 'Maintenance of sinus rhythm'.) Follow-up We consider the following approach to follow-up reasonable: We perform an ECG one week after initiation of any antiarrhythmic drug. We typically see patients within three months of initiating a new antiarrhythmic drug to assess efficacy and side effects. This is in addition to commonly performing ambulatory monitoring after drug initiation. Patients are typically seen every 6 to 12 months unless there are particular concerns regarding QT interval prolongation, bradycardia, or other issues identified on the ECG. Specific follow-up recommendations for individual drugs are presented separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol", section on 'Major side effects' and "Clinical use of dofetilide", section on 'Safety' and "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide' and "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) RECOMMENDATIONS OF OTHERS Our recommendations for the use of antiarrhythmic drugs to maintain sinus rhythm in patients with AF are generally in agreement with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society (2014) and its 2019 focused update, as well as the European Society of Cardiology (2016) [15,38-40]. (See 'Summary and recommendations' below.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 13/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS For those patients with atrial fibrillation (AF) in whom a rhythm-control strategy is chosen, the principal goal is to reduce symptoms by decreasing the frequency and duration of episodes [1,2]. (See 'Initial management decisions' above.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia. (See 'Selecting an antiarrhythmic drug' above.) Compared to placebo, amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective for the maintenance of sinus rhythm, but maintenance rates at one year are significantly less than 75 percent. Amiodarone is consistently more effective than the other antiarrhythmic drugs. (See 'Selecting an antiarrhythmic drug' above.)
electrocardiogram be obtained after the initiation of antiarrhythmic drug therapy. Short- versus long-term therapy Based on concerns about drug related arrhythmias and the observation that the atrial action potential normalizes after two to four weeks of sinus rhythm (after AF), the concept that short-term therapy might be as effective and safer than long-term therapy has been proposed. This concept was tested in the Flec-SL non-inferiority trial, which randomly assigned 554 patients with persistent AF and who were intended to undergo cardioversion to either four weeks or six months of flecainide (200 to 300 mg per day) [33]. All patients had successful restoration of sinus rhythm and were then followed with daily telemetric electrocardiography (and Holter monitoring whenever AF was noted on two ECGs) for six months. The primary outcome of time to persistent AF or death occurred in 46 and 39 percent of patients, respectively, which did not meet the criteria of non-inferiority. In addition, a post-hoc analysis of patients who had not reached the primary endpoint in the first month found long- term therapy to be superior (Kaplan-Meier estimate of difference 14.3 percent; hazard ratio 0.3; p = 0.0001). We do not consider short-term therapy appropriate for most patients with persistent AF. Concerns about dronedarone Patients with severe heart failure (HF) (generally those with NYHA class III or IV HF, or those who have been hospitalized with HF in the past four weeks) or those with an ejection fraction of <35 percent should not receive dronedarone. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) The Permanent Atrial fibriLLAtion outcome Study (PALLAS) was designed to test the hypothesis that dronedarone would improve major outcomes in 10,000 patients with permanent AF, over 70 percent of whom had New York Heart Association heart failure class I to III or left ventricular systolic dysfunction at baseline. The rationale was that patients with permanent AF, which affects up to 50 percent of patients with AF, have an increased risk of adverse cardiovascular outcomes including death and myocardial infarction as well as systemic embolization. The ATHENA trial showed a significant reduction in cardiovascular events with dronedarone in patients with paroxysmal or persistent AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled), after a significantly increased risk (Hazard Ratio 2.29, 95% CI 1.34-3.94) of cardiovascular events https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 12/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [34]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. (See 'Summary and recommendations' below.) The European Medicines Agency and the United States Food and Drug Agency (USFDA) have advised against the use of dronedarone in patients with permanent AF [35,36]. In addition, the USFDA now recommends that people taking the drug should have an electrocardiogram every three months to make sure that AF has not become permanent. For patients taking dronedarone, routine monitoring of lung and liver function is not mandated by the USFDA; however, periodic monitoring may be reasonable [37]. (See "Clinical uses of dronedarone", section on 'Maintenance of sinus rhythm'.) Follow-up We consider the following approach to follow-up reasonable: We perform an ECG one week after initiation of any antiarrhythmic drug. We typically see patients within three months of initiating a new antiarrhythmic drug to assess efficacy and side effects. This is in addition to commonly performing ambulatory monitoring after drug initiation. Patients are typically seen every 6 to 12 months unless there are particular concerns regarding QT interval prolongation, bradycardia, or other issues identified on the ECG. Specific follow-up recommendations for individual drugs are presented separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol", section on 'Major side effects' and "Clinical use of dofetilide", section on 'Safety' and "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide' and "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) RECOMMENDATIONS OF OTHERS Our recommendations for the use of antiarrhythmic drugs to maintain sinus rhythm in patients with AF are generally in agreement with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society (2014) and its 2019 focused update, as well as the European Society of Cardiology (2016) [15,38-40]. (See 'Summary and recommendations' below.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 13/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS For those patients with atrial fibrillation (AF) in whom a rhythm-control strategy is chosen, the principal goal is to reduce symptoms by decreasing the frequency and duration of episodes [1,2]. (See 'Initial management decisions' above.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia. (See 'Selecting an antiarrhythmic drug' above.) Compared to placebo, amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective for the maintenance of sinus rhythm, but maintenance rates at one year are significantly less than 75 percent. Amiodarone is consistently more effective than the other antiarrhythmic drugs. (See 'Selecting an antiarrhythmic drug' above.) In addition to less-than-optimal efficacy, serious drug-related adverse side effects limit the use of these drugs. Antiarrhythmic drug therapy should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risks https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 14/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' above.) Based upon the potential for drug toxicity in the form of induced bradycardia or tachycardia, many patients will need to be hospitalized for continuous electrocardiographic monitoring. Dofetilide must be initiated in a setting with continuous monitoring. (See 'Inpatient versus outpatient initiation' above.) For patients with no structural heart disease and no apparent risk for drug-induced bradycardia or tachycardia, we suggest flecainide or propafenone as the preferred antiarrhythmic drug (Grade 2B). Amiodarone, dofetilide, dronedarone, or sotalol may be used, with sotalol chosen more often by our authors and reviewers. Practitioners should choose only those agents with which they have significant familiarity. (See 'Atrial fibrillation without structural heart disease' above.) For patients with coronary artery disease who do not have advanced heart failure, we suggest dronedarone or sotalol in preference to amiodarone (Grade 2B). Amiodarone is a reasonable choice in patients who prefer its greater efficacy despite its worse extracardiac side-effect profile. (See 'Coronary heart disease' above.) For patients with heart failure, we suggest amiodarone in preference to dofetilide (Grade 2B). Flecainide, propafenone, dronedarone, and sotalol are contraindicated in these patients. (See 'Heart failure' above.) For patients with left ventricular hypertrophy, either amiodarone or dronedarone is generally preferred to other antiarrhythmic agents. Our authors and reviewers have differing approaches, with some choosing amiodarone more often and others choosing dronedarone more often. (See 'Left ventricular hypertrophy' above.) After the initiation of antiarrhythmic drug therapy, screening for drug-associated arrhythmia with ambulatory monitoring should be considered, particularly for patients at high risk of drug-induced arrhythmia. This includes those with baseline bradycardia or borderline QT prolongation, heart failure, or systolic left ventricular dysfunction. (See 'Ambulatory monitoring' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 15/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 2. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. 3. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003; 139:1009. 4. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 5. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 6. K hlkamp V, Schirdewan A, Stangl K, et al. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2000; 36:139. 7. McNamara RL, Tamariz LJ, Segal JB, Bass EB. 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Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 18. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. 19. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 20. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 21. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 22. Vorperian VR, Havighurst TC, Miller S, January CT. 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Podrid PJ, Anderson JL. Safety and tolerability of long-term propafenone therapy for supraventricular tachyarrhythmias. The Propafenone Multicenter Study Group. Am J Cardiol 1996; 78:430. 27. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 28. Morganroth J, Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol 1986; 8:607. 29. Reiffel JA, Camm AJ, Belardinelli L, et al. The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism. Circ Arrhythm Electrophysiol 2015; 8:1048. 30. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 31. Hauser TH, Pinto DS, Josephson ME, Zimetbaum P. Safety and feasibility of a clinical pathway for the outpatient initiation of antiarrhythmic medications in patients with atrial fibrillation or atrial flutter. Am J Cardiol 2003; 91:1437. 32. Lafuente-Lafuente C, Longas-Tejero MA, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2012; :CD005049. 33. Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open- label, blinded endpoint assessment trial. Lancet 2012; 380:238. 34. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 35. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/09/new s_detail_001344.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac0 58004d5c1. 36. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPro ducts/ucm264204.htm. 37. http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm. 38. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 18/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 39. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 40. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1035 Version 60.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 19/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate GRAPHICS Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 20/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 21/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 22/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 23/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Types of proarrhythmia during treatment with antiarrhythmic drugs (AADs) for atrial fibrillation or atrial flutter according to the Vaughan Williams Classification Ventricular proarrhythmia Torsade de pointes (Vaughan Williams class IA and type III drugs) Sustained monomorphic ventricular tachycardia (usually class IC drugs) Sustained polymorphic ventricular tachycardia/ventricular fibrillation without long QT interval (class IA, IC, and III drugs) Atrial proarrhythmia Provocation of recurrence (probably class IA, IC, and III drugs) Conversion of atrial fibrillation (AF) to atrial flutter (usually class IC drugs) with 1:1 conduction Increase of defibrillation threshold (a potential problem with class IC drugs) Abnormalities of conduction or impulse formation Accelerate ventricular rate during AF (class IA and type IC drugs) Accelerate conduction over accessory pathway (digoxin, type IV drugs) Sinus node dysfunction, atrioventricular block (almost all drugs) Vaughan Williams classification of AADs used for the treatment of atrial fibrillation or flutter Class IA - Disopyramide, procainamide, quinidine Class IC - Flecainide, propafenone Class III - Amiodarone, dofetilide, ibutilide, sotalol Class IV - Nondihydropyridine calcium channel blockers (diltiazem and verapamil) Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 66133 Version 4.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 24/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 25/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, especially with Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia prominent T-wave Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 26/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine antimoniate Clarithromycin Flecainide Sparfloxacin Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil (systemic) Terbutaline Nilotinib Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate Dasatinib Vemurafenib oral) dimeglumine Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 27/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 28/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 29/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 30/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 31/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 28/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 29/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 30/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 31/32 7/5/23, 8:19 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 32/32
7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Calcium channel blockers in the treatment of cardiac arrhythmias : Christopher Madias, MD : Mark S Link, MD : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Dec 06, 2021. INTRODUCTION Calcium channel blockers (CCBs) are useful antiarrhythmic agents in the management of certain arrhythmias, primarily supraventricular tachyarrhythmias [1-3]. They have diverse electrophysiologic properties and are therefore of variable antiarrhythmic efficacy. The primary settings in which they are useful can be best appreciated from an understanding of their mechanism of action. This topic will review the electrophysiological properties of CCBs and their clinical indications in a variety of arrhythmias. More detailed discussions of the use of CCBs in specific arrhythmias, CCBs for nonarrhythmic conditions, and other treatment options for arrhythmias are presented separately. (See "Calcium channel blockers in the management of chronic coronary syndrome".) (See "Calcium channel blockers in heart failure with reduced ejection fraction".) (See "Choice of drug therapy in primary (essential) hypertension".) (See "Atrioventricular nodal reentrant tachycardia".) (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome".) (See "Wide QRS complex tachycardias: Approach to management".) (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) (See "Control of ventricular rate in atrial flutter".) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 1/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate ELECTROPHYSIOLOGIC PROPERTIES CCBs, considered class IV antiarrhythmic drugs ( table 1), preferentially affect myocardial tissue with a slow action potential that is mediated by calcium currents. The sinoatrial and atrioventricular nodes depend on calcium currents to generate slowly propagating action potentials. In contrast, fast response myocardial tissues (the atria, specialized infranodal conducting system, the ventricles, and accessory pathways) depend on sodium channel currents. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) CCBs block the slow calcium channel in a dose-dependent fashion, resulting in the following direct effects [3,4]: Slowing of phase 4 depolarization and the conduction velocity of the sinoatrial (SA) and atrioventricular (AV) nodes Lengthening the antegrade and retrograde refractory periods of the AV node Slowing of the sinus rate and increased PR interval on the electrocardiogram (ECG) via the slowing of conduction through the AV node Similar to sodium channel blockers, CCBs with antiarrhythmic activity (ie, verapamil and diltiazem) exhibit "use-dependence." This phenomenon is characterized by an increase in the extent of calcium channel blockade as the frequency of impulse generation and ventricular activation increases. CCBs can also cause significant peripheral vasodilation, an effect which can induce reflex activation of the sympathetic nervous system. As a result, the observed electropharmacologic and pharmacodynamic properties of CCBs represent a combination of direct effects and indirect sympathetic reflex actions. This is particularly important with dihydropyridines (ie, nifedipine), which are potent vasodilators and sympathetic activators. The serum concentration of dihydropyridine CCBs necessary to achieve electrophysiologic activity in humans is much higher than the concentration needed to induce potent vasodilation. Therefore, at prescribed doses, these agents do not exert measurable electrophysiologic effects and appear to be devoid of antiarrhythmic activity. In addition, the reflex activation of the sympathetic nervous system offsets any direct effect of the dihydropyridine CCBs on the sinoatrial and AV nodes. Among nondihydropyridine CCBs, the effect on vasodilation is more apparent with diltiazem than verapamil, which results in verapamil having a more pronounced effect on the SA and AV nodes as its action is not offset by vasodilatory activation of sympathetic activity. https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 2/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate CLINICAL USE Because verapamil and diltiazem primarily affect slow response tissues in the SA and AV nodes, these medications are primarily used for the management of supraventricular tachycardias dependent on conduction through the AV node (ie, atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia) and for ventricular rate control in atrial fibrillation (AF), atrial flutter, and atrial tachycardia. They are largely ineffective for the direct prevention of most ventricular arrhythmias; however, there are some exceptions, such as the utility of verapamil for the treatment of idiopathic fascicular ventricular tachycardia. (See 'Ventricular arrhythmia' below.) The antiarrhythmic effect of verapamil appears to be similar in adults and children, although less experience is available in children [1,2,5]. Verapamil and to a lesser degree diltiazem may be harmful in patients with hypotension or impaired ventricular function (especially those with a history of heart failure [HF]), and in general should not be used in patients with these conditions. In addition, CCBs should be used cautiously in patients already taking a beta blocker because of the combined negative inotropic and chronotropic effects of both classes of medications [5]. A brief review of these issues is provided here; the use of CCBs in the treatment of specific arrhythmias is discussed in detail elsewhere. Supraventricular tachycardia Both diltiazem and verapamil are accepted as treatments of choice for the termination of supraventricular tachycardias (SVT), such as AV nodal reentrant tachycardia and atrioventricular reciprocating tachycardia due to an accessory pathway. An important exception to the first-line use of these agents occurs in unstable patients with hemodynamic compromise. In an unstable patient with SVT, the preferred treatment is direct electrical cardioversion or intravenous adenosine, a very short-acting AV nodal blocking agent that rarely produces additional hypotension. (See "Atrioventricular nodal reentrant tachycardia".) Another situation in which CCBs should be avoided or used with caution is in the presence of a wide QRS complex tachycardia. If there is no doubt that a wide QRS complex tachycardia is supraventricular in origin, therapy directed at the AV node and the SVT may be given. In such cases, management is similar to that described above for SVT with a normal QRS duration. However, with a wide QRS complex tachycardia that is potentially ventricular tachycardia, CCBs blockers should be avoided, as there is a risk for hemodynamic deterioration following the administration of these medications. (See "Wide QRS complex tachycardias: Approach to management".) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 3/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate CCBs appear to be of limited value in other forms of reentrant and automatic SVT [2,3,5,6]. Limited data exist concerning their role in SA nodal reentrant tachycardia or in atrial tachycardia due to an ectopic focus or intraatrial reentry (except for rate control by AV nodal blockade). However, oral verapamil may convert paroxysmal atrial tachycardia with block to sinus rhythm under certain circumstances, such as digoxin toxicity. Multifocal atrial tachycardia Either a non-dihydropyridine calcium channel blocker (ie, verapamil and diltiazem) or a beta blocker is usually the treatment of choice for multifocal atrial tachycardia. These drugs impair AV nodal conduction and will therefore slow the ventricular rate in this disorder; they do not usually reverse or prevent this arrhythmia. (See "Multifocal atrial tachycardia".) Atrial fibrillation and flutter Verapamil and diltiazem are used both acutely (via the intravenous route) and chronically (via the oral route) to slow the ventricular response in AF and atrial flutter. Their efficacy for rate control is due to their direct action to slow conduction and prolonged refractoriness in the AV node. Verapamil and diltiazem reduce both the resting and the exercise-induced increases in heart rate, whereas the major effect of digoxin (which works on the AV node via enhancing vagal tone) is on the resting rate. Therefore, verapamil and diltiazem are generally preferred to digoxin as monotherapy (in the absence of underlying HF) [7]. However, for patients with inadequate ventricular rate control with monotherapy, the concurrent use of digoxin or a beta blocker with verapamil or diltiazem has an additive depressant effect on the AV node. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter".) AV nodal blocking medications that are normally used to control the ventricular rate during AF (most importantly) or atrial flutter, including the CCBs verapamil and diltiazem, are contraindicated in patients with an accessory pathway and preexcitation. This is discussed in further detail in another topic. (See "Treatment of arrhythmias associated with the Wolff- Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.) CCBs also have a propensity to convert atrial flutter to fibrillation in a small number of patients, presumably due to a shortening of the atrial effective refractory period [8]. CCBs have been regarded as having little value in the termination and prevention of AF. However, verapamil may prevent the atrial electrical remodeling that occurs in AF, and the combination of verapamil with another agent has been shown to be effective in preventing AF recurrence [9]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Verapamil'.) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 4/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Ventricular arrhythmia The role of CCBs in ventricular arrhythmias is less well defined [10- 15]. CCBs inadequately suppress ventricular premature beats in patients with structurally normal or abnormal hearts. They also have no significant effect on arrhythmia frequency or arrhythmic mortality in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, or mitral valve prolapse [1,2,16]. As a class, CCBs have a limited role in the treatment of ventricular tachycardia (VT) or ventricular fibrillation (VF) in the setting of organic heart disease. They do not suppress nonsustained VT, nor do they prevent the inducibility of VT/VF after programmed electrical stimulation. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".) However, calcium blockers may have a role in the following clinical settings: They are often effective when ventricular tachycardia or fibrillation is due to transient coronary artery spasm [17]. (See "Vasospastic angina".) They may have a role for polymorphic VT in the structurally normal heart or in those with familial catecholaminergic polymorphic VT that is due to a RyR2 or calsequestrin gene mutation [18]. (See "Catecholaminergic polymorphic ventricular tachycardia".) Exercise-triggered VT (called repetitive monomorphic VT) having the morphologic pattern of left bundle branch block and an inferiorly directed axis deviation (right ventricular outflow tract tachycardia) or a pattern of right bundle branch block and rightward axis (left ventricular outflow tract tachycardia) may respond predictably and promptly to intravenous verapamil. Such an arrhythmia may occur in patients without identifiable cardiac disease [12,19,20]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) A relatively rare, sustained VT that occurs in patients without evidence of structural heart disease has the morphologic pattern of right bundle branch block with left axis deviation [21-23]. This arrhythmia, which is called an idiopathic fascicular ventricular tachycardia (primarily of the left posterior fascicle), verapamil sensitive tachycardia, or Belhassen tachycardia, appears to be a distinct clinical entity and, in most cases, responds to intravenous verapamil [21,24]. (See "Ventricular tachycardia in the absence of apparent structural heart disease".) Arrhythmia mortality after myocardial infarction Routine treatment of the post-MI patient with a calcium channel blocker is not justified. It is possible that CCBs might benefit selected https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 5/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate patients after MI, particularly those with a non-Q wave infarct, without HF, and who are unable to take a beta blocker [25-27]. However, the level of benefit, if present, is small. Additionally, there are subsets of patients in whom certain CCBs may increase mortality (see "Overview of the nonacute management of ST-elevation myocardial infarction" and "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Calcium channel blockers' and "Major side effects and safety of calcium channel blockers" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction" and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Calcium channel blockers'). CCBs reverse coronary vasospasm and attenuate myocardial ischemic damage following experimental coronary occlusion [28]. These observations led to clinical studies assessing if these drugs might increase survival in patients with acute myocardial infarction (MI). Numerous randomized controlled trials of CCBs (diltiazem, verapamil, and nifedipine) have been analyzed [29,30]. No agent was found to unequivocally and decisively decrease mortality; in fact, pooled data for five CCBs suggested an unfavorable trend in total mortality, particularly with the short-acting dihydropyridines ( figure 1). This is in contrast to the clear benefit associated with other drugs such as beta blockers, statins, aspirin, and angiotensin converting enzyme inhibitors. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS In addition to adenosine, the calcium channel blockers (CCBs) diltiazem and verapamil are treatments of choice for the termination of supraventricular tachycardia. (See 'Supraventricular tachycardia' above and "Atrioventricular nodal reentrant tachycardia".) Diltiazem and verapamil can be used both acutely (via the intravenous route) and chronically (via the oral route) to slow the ventricular response in atrial fibrillation (AF), atrial tachycardia, and atrial flutter. (See 'Atrial fibrillation and flutter' above.) https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 6/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate In patients with hypotension or impaired ventricular function, especially those with a history of heart failure, diltiazem and verapamil may be harmful, and are relatively contraindicated. (See 'Clinical use' above.) CCBs should be used cautiously in patients already taking a beta blocker because of the combined negative inotropic and chronotropic effects of both classes of medications. (See 'Clinical use' above.) In a patient with a wide QRS complex tachycardia that is potentially ventricular tachycardia, CCBs should be avoided, as there is a risk for hemodynamic deterioration following the administration of these medications. (See 'Supraventricular tachycardia' above and "Wide QRS complex tachycardias: Approach to management".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Haines DE, DiMarco JP. Current therapy for supraventricular tachycardia. Curr Probl Cardiol 1992; 17:411. 2. Singh BN, Ellrodt G, Peter CT. Verapamil: a review of its pharmacological properties and therapeutic use. Drugs 1978; 15:169. 3. Singh BN, Hecht HS, Nademanee K, Chew CY. Electrophysiologic and hemodynamic effects of slow-channel blocking drugs. Prog Cardiovasc Dis 1982; 25:103. 4. Cranefield PF, Aronson RS, Wit AL. Effect of verapamil on the noraml action potential and on a calcium-dependent slow response of canine cardiac Purkinje fibers. Circ Res 1974; 34:204. 5. Singh BN, Nademanee K, Baky SH. Calcium antagonists. Clinical use in the treatment of arrhythmias. Drugs 1983; 25:125. 6. Boriani G, Bertaglia E, Carboni A, et al. A controlled study on the effect of verapamil on atrial tachycaarrhythmias in patients with brady-tachy syndrome implanted with a DDDR pacemaker. Int J Cardiol 2005; 104:73. 7. Tsuneda T, Yamashita T, Fukunami M, et al. Rate control and quality of life in patients with permanent atrial fibrillation: the Quality of Life and Atrial Fibrillation (QOLAF) Study. Circ J 2006; 70:965. 8. Singh BN. Control of cardiac arrhythmias by modulation of the slow myocardial channel. In: Calcium channels, their properties, functions, regulation, and clinical relevance, Horowitz L, Partridge LD, Leach JK (Eds), CRC Press, Boca Raton 1991. p.327. https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 7/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate 9. De Simone A, De Pasquale M, De Matteis C, et al. VErapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24:1425. 10. Belhassen B, Horowitz LN. Use of intravenous verapamil for ventricular tachycardia. Am J Cardiol 1984; 54:1131. 11. Wellens HJ, B r FW, Lie KI, et al. Effect of procainamide, propranolol and verapamil on mechanism of tachycardia in patients with chronic recurrent ventricular tachycardia. Am J Cardiol 1977; 40:579. 12. Gill JS, Blaszyk K, Ward DE, Camm AJ. Verapamil for the suppression of idiopathic ventricular tachycardia of left bundle branch block-like morphology. Am Heart J 1993; 126:1126. 13. Sung RJ, Shapiro WA, Shen EN, et al. Effects of verapamil on ventricular tachycardias possibly caused by reentry, automaticity, and triggered activity. J Clin Invest 1983; 72:350. 14. Sclarovsky S, Strasberg B, Fuchs J, et al. Multiform accelerated idioventricular rhythm in acute myocardial infarction: electrocardiographic characteristics and response to verapamil. Am J Cardiol 1983; 52:43. 15. Grenadier E, Alpan G, Maor N, et al. Polymorphous ventricular tachycardia in acute myocardial infarction. Am J Cardiol 1984; 53:1280. 16. McKenna, WJ, Harris, et al. Hypertrophic cardiomyopathy: Comparison of verapamil and amiodarone in the treatment of arrhythmia. Br Heart J 1980; 45:354. 17. Kimura E, Tanaka K, Mizuno K, et al. Suppression of repeatedly occurring ventricular fibrillation with nifedipine in variant form of angina pectoris. Jpn Heart J 1977; 18:736. 18. Swan H, Laitinen P, Kontula K, Toivonen L. Calcium channel antagonism reduces exercise- induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations. J Cardiovasc Electrophysiol 2005; 16:162. 19. Palileo EV, Ashley WW, Swiryn S, et al. Exercise provocable right ventricular outflow tract tachycardia. Am Heart J 1982; 104:185. 20. Wu D, Kou HC, Hung JS. Exercise-triggered paroxysmal ventricular tachycardia. A repetitive rhythmic activity possibly related to afterdepolarization. Ann Intern Med 1981; 95:410. 21. Lin FC, Finley CD, Rahimtoola SH, Wu D. Idiopathic paroxysmal ventricular tachycardia with a QRS pattern of right bundle branch block and left axis deviation: a unique clinical entity with specific properties. Am J Cardiol 1983; 52:95. 22. German LD, Packer DL, Bardy GH, Gallagher JJ. Ventricular tachycardia induced by atrial stimulation in patients without symptomatic cardiac disease. Am J Cardiol 1983; 52:1202. https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 8/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate 23. Belhassen B, Shapira I, Pelleg A, et al. Idiopathic recurrent sustained ventricular tachycardia responsive to verapamil: an ECG-electrophysiologic entity. Am Heart J 1984; 108:1034. 24. Nogami A. Idiopathic left ventricular tachycardia: assessment and treatment. Card Electrophysiol Rev 2002; 6:448. 25. Verapamil in acute myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction. Eur Heart J 1984; 5:516. 26. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II DAVIT II). Am J Cardiol 1990; 66:779. 27. Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988; 319:385. 28. Singh BN, Nayler WG. The role of calcium antagonists in acute myocardial infarction. In: Earl y interventions in acute myocardial infarction, Rapaport E (Ed), Kluwer Academic Publication s, Boston 1989. p.123. 29. Held PH, Yusuf S. Impact of calcium channel blockers on mortality. In: Cardiovascular pharm acology and therapeutics, Singh BN, Dzau VJ, Vanhoutte PM, Woosley RL (Eds), Churchill Livi ngtion, New York 1993. p.525. 30. Yusuf S, Held P, Furberg C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardiol 1991; 67:1295. Topic 951 Version 26.0 https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 9/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 10/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 11/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Calcium channel blockers do not change mortality after acute myocardial infarction (MI) A meta-analysis of controlled trials of calcium channel blockers in post-myocardial infarction patients failed to show any effect on mortality. However, the agents that reduce heart rate, particularly verapamil, showed a trend toward an improved survival while nifedipine, which increases heart rate, showed a trend toward an increased mortality. Data from Held PH, Yusuf S. In: Cardiovascular Pharmacology and Therapeutics, Singh BN, Dzau V, Vanhoutte PM, Woosley RL (Eds), Churchill Livingstone, New York, 1993, p. 525. Graphic 74199 Version 3.0 https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 12/13 7/5/23, 8:20 AM Calcium channel blockers in the treatment of cardiac arrhythmias - UpToDate Contributor Disclosures Christopher Madias, MD No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/calcium-channel-blockers-in-the-treatment-of-cardiac-arrhythmias/print 13/13
7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs : Jonathan C Makielski, MD, FACC, L Lee L Eckhardt, MD, FHRS : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 29, 2021. INTRODUCTION The myocardial action potential refers to the "all or nothing" depolarization followed by repolarization of the cell membrane, which results from a complex interaction of voltage and time dependent ion channels and carriers in the cellular membrane. When abnormalities arise in the normal process of cardiac excitability, patients may develop tachyarrhythmias by a variety of mechanisms. This topic will review the normal cardiac excitation process and the generation of the myocardial action potential, along with mechanisms of arrhythmia and the classes of antiarrhythmic medications and their impact on cardiac excitability. The treatment of specific tachyarrhythmias is discussed elsewhere. (See "Overview of the acute management of tachyarrhythmias".) CARDIAC EXCITABILITY Cardiac excitability refers to the ease with which cardiac cells undergo a series of events characterized by sequential depolarization and repolarization, communication with adjacent cells, and propagation of the electrical activity. The normal heartbeat arises from an organized flow of ionic currents across the cell membrane, through the myoplasm and between cells and the extracellular space [1,2]. Excitable membranes containing specialized ion-specific channels, cell-to-cell connecting proteins, and intracellular components transmit the action potential and lead to excitation-contraction coupling. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 1/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Understanding cardiac electrophysiology requires knowing the types and regulation pathways of ion channels, electrogenic exchange transporters, gap junctions, and the proportional contribution of each mechanism. Abnormalities of these elements, both inherited and acquired, can lead to arrhythmia. Acquired abnormalities occurring in the setting of cardiac disease such as cardiomyopathy are called electrical remodeling. Inherited abnormalities arise from mutations in genes encoding the subunits and associated proteins of these channels, and have been associated with familial arrhythmic syndromes and sudden cardiac death. Examples include the congenital long QT syndrome (mainly sodium and potassium current), the Brugada syndrome (mainly sodium current), and congenital heart block (sodium current). (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Brugada syndrome: Epidemiology and pathogenesis" and "Etiology of atrioventricular block", section on 'Familial disease'.) + + Cardiac ion channels and currents Ions (sodium [Na ], potassium [K ], chloride [Cl ], and 2+ calcium [Ca ]) flow through cardiac membrane channels with pores formed by proteins, with these ion channels encoded by specific genes [3]. The pore-forming protein is called the alpha subunit, which also contains the voltage-dependent sensors and gates. For many ion channels, one or more secondary regulatory subunit proteins are present (usually named beta, gamma, delta, and so on) in association with the alpha subunit, and many ion channel proteins have subunit isoforms adding to their complexity. The encoding genes, amino acid sequences, and structure-function relationships for many ion channels have been described and are now reasonably well understood ( figure 1) [4]. Ion channels are grouped and currents are named in one of three ways: by the ionic charge species to which the channel is permeant, the distinguishing kinetics, or pharmacology ( figure 1). For example, the voltage-dependent sodium current (I ) flows through the protein Na NaV1.5 encoded by the gene SCN5A and similarly for other ion channels. The dominant channel + 2+ types in heart cells are Na channels (I ), L-type and T-type Ca channels (I , I Ca-L Ca-T ), and Na + several K channels (I , I , I , I , I ). The sodium-potassium pump and the sodium-calcium K1 to1 to2 Kr Ks exchanger are not considered channels because they require energy to drive ions across the membrane against their gradients, however they do generate currents ( figure 1). Resting membrane potential The resting cardiac cell membrane potential is normally polarized between -80 and -95 mV, with the cell interior negative relative to the extracellular 2+ space. The resting membrane potential is determined by the balance of inward (Na and Ca ) + + and outward (K ) currents and the corresponding equilibrium potentials of these currents. In https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 2/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate turn, the equilibrium potential for a given ion is determined by the concentrations of that ion inside and outside the cell. Using these concentrations, the equilibrium potential is calculated by the Nernst equation. As an example, potassium ion concentrations are higher inside than outside the cell, and the potassium equilibrium potential is between -80 and -95 mV. When potassium channels open, potassium ions flow down their gradient as an outward current, carrying positive ions outside the cell and taking the cell toward more negative potentials. In the heart, the resting membrane potential is generated by the inward rectifier current (I ), K1 which is the predominant open channel at rest. Potassium current flowing through these channels continues until the interior negative potential is at the same magnitude as the equilibrium potential for potassium. Only small amounts of actual potassium flow are required to maintain this potential. The equilibrium potentials for sodium and calcium are positive (approximately +40 mV and approximately +80 mV, respectively) so that when these channels are open, they tend to depolarize the membrane. Voltage-sensitive sodium, calcium, and potassium channels play only a small role in the resting state since most of these channels are closed [5,6]. The Na-K-ATPase pump maintains the potassium and sodium gradients by pumping potassium into and sodium out of the cells. The Na-Ca exchanger uses the power of the Na gradient to pump Ca out of the cell. These and other pumps maintain the ion channel gradient that is important for both excitability and contraction. Action potential in fast response tissues Tissues that depend upon the opening of voltage- sensitive, kinetically rapid (opening in less than a millisecond) sodium channels to initiate depolarization are called fast response tissues [7]. Fast response tissues include the atria, the specialized infranodal conducting system (bundle of His, fascicles and bundle branches, and terminal Purkinje fibers), and the ventricles ( figure 2), while the sinoatrial (SA) and atrioventricular (AV) nodes represent slow response tissues. It is important to recognize that accessory AV pathways (ie, bypass tracts) associated with Wolff-Parkinson-White syndrome are derived from the atria and are thus also fast response tissues dependent upon sodium current for depolarization. (See "Wolff-Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis".) The following is a simplified description of the steps involved in the generation of an action potential in the heart ( figure 1 and figure 3 and movie 1) [8]. The particular shape and duration of the individual action potential varies for atria, nodal tissue, specialized conduction tissue, and the ventricles ( figure 4), depending upon differences in the density of ion channels in these tissues. The shape and duration of the action potentials also vary in the right and left ventricle, and transmurally across the wall of the heart [9], again depending upon differences in ion channel and current densities. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 3/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Phase 0 Rapid depolarization (phase 0) occurs when the resting cell is brought to threshold, leading sequentially to activation or opening of voltage-dependent sodium channels, rapid sodium entry into the cells down a favorable concentration gradient, and a cell interior positive potential that can approach +45 mV. The marked depolarization initiates voltage-dependent inactivation of the sodium channels. Calcium channels also open during depolarization, but the inward calcium flux is much slower. Phase 1 Phase 1 repolarization often inscribes a "notch" and is primarily caused by activation of the transient outward potassium currents (I ) combined with a corresponding to rapid decay of the sodium current. The degree of repolarization in phase 1 is dependent on the density of I and varies between cardiac chambers and regions within chambers. to Phase 2 Following initial repolarization in phase 1, phase 2 represents a plateau that lasts for hundreds of milliseconds and distinguishes the cardiac action potential from nerve and skeletal muscle action potentials, which are significantly shorter. Late inactivating depolarizing calcium and sodium currents are balanced by activating repolarizing potassium currents to maintain the plateau, which is often down-sloping as repolarizing currents begin to dominate. Phases 3 and 4 The final rapid repolarizing phase 3 is driven by the decay of the calcium current and progressive activation of repolarizing potassium currents (I , I Kr Ks ). Terminal repolarization toward the potassium equilibrium potential is dominated in phase 3 by I , K1 which then maintains the resting membrane potential (phase 4). During one cycle of depolarization and repolarization, the voltage-dependent channels cycle through three different kinetic or gating states: Resting. Open, as the channels open during phase 0 depolarization. Inactivated, which occurs at positive potentials (end of phase 0) and during sustained depolarization (as during the phase 2 plateau). During recovery in diastole, the channel returns to the resting state. The resting and inactivated states are different physiologically, even though the channel is effectively nonconducting in both settings. In the resting state, the channels can be opened positive to the threshold potential. In comparison, the inactivated channel cannot be activated until it cycles or "recovers" to the resting state. These different states are important clinically, since, for example, some antiarrhythmic drugs (such as the class I antiarrhythmic drugs) preferentially bind to open and inactivated sodium channels. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 4/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Action potential in slow response tissues The SA and AV nodes represent slow response tissues, which have different properties from the fast response tissues ( table 1). Phase 0 depolarization depends on an inward calcium (not sodium) current via L-type calcium channels [10]. These channels are selective for calcium, have a slower conduction velocity than the sodium channels, and take longer to reactivate. In some cases, as with tissue damage or changes in the extracellular milieu, fast response tissues can be converted to slow response tissues. In this setting, sodium channels become inactivated and depolarization is dependent upon the slow calcium channels. Impulse propagation When an action potential forms in a patch of membrane (the source), current flows from this patch to neighboring patches (the sink). Gap junctions are the low resistance structures that allow ions to flow from one cell to another and, if the current flow is sufficient, to cause sequential depolarization from cell to cell. The gap junctions are actually active, opening and closing in response to changes in pH, calcium, and, at times, voltage. In addition to ion flow and gap junction resistance, impulse propagation can also be affected by the orientation of fibers and of the collagen matrix in which the fibers reside. "Fast" tissues may conduct very slowly (declining from meters/second to millimeters/second) in a number of circumstances, resulting in prolongation of the QRS and QT intervals on the surface electrocardiogram (ECG). These include inactivation of sodium channels induced by hyperkalemia or ischemia-induced acidosis, direct damage to the cells, or the effect of drugs, particularly antiarrhythmic drugs. (See 'Action of antiarrhythmic drugs' below.) MECHANISMS OF TACHYARRHYTHMIA FORMATION While the term "arrhythmia" also includes bradyarrhythmias caused by a failure of impulse generation, this section will focus on the cellular and tissue mechanisms of tachyarrhythmias. Three distinct mechanisms underlie tachyarrhythmia induction: enhanced automaticity, reentry, and triggered activity ( figure 5). Enhanced automaticity Enhanced automaticity refers to abnormal phase 4 diastolic depolarization, and occurs when spontaneous depolarization develops during diastole ( figure 5). While this is a normal phenomenon in nodal cells, and with subsidiary pacemakers at slower rates in all myocardial cells, enhanced or abnormal automaticity may lead to tachyarrhythmia. A typical example is automatic (ie, focal) atrial tachycardia. Common automaticity stimulants include excess catecholamine or situations causing hypoxia, acidosis, or ischemic related metabolites. (See "Focal atrial tachycardia" and "Enhanced cardiac automaticity".) https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 5/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Reentry Reentry is the most commonly encountered arrhythmia mechanism and refers to any arrhythmia dependent on an electrical circuit within the heart ( figure 5). Critical components for reentry include both of the following: The presence of fast and slow conduction with varying refractory/recovery periods A fixed or functional core about which the circuit moves Initiation of reentry requires a unidirectional block within the reentrant path, such that one arm of the circuit conducts the approaching electrical wave front and the blocks it in the other arm. Reentry can travel around a fixed or anatomical circuit such as myocardial scar, or a functional circuit such as an area of tissue that is depolarized or refractory and does not support conduction. A common example of a reentry-based arrhythmia is AV reciprocating tachycardia (AVRT) related to an accessory pathway (ie, bypass tract) as part of the Wolff-Parkinson-White syndrome. In AVRT, the fast conducting limb (for either antegrade or retrograde AVRT) is the accessory + pathway, which uses Na channels to support rapid conduction, while the slow conducting limb is the normal AV node. An example of fixed reentry arrhythmia is ventricular tachycardia with a fixed myocardial scar and variable conduction in the surrounding myocardium. Interventions to terminate reentrant arrhythmias differ from other mechanisms and are + 2+ generally geared to modify the critical components of the reentrant circuit. Blocking Na or Ca + channels can slow or block conduction, while blocking K channels prolongs the action potential and therefore increases refractoriness. Another approach is to improve functional properties such as ischemia in an area of functional block that can terminate the arrhythmia. Interventions that electrically interrupt the reentrant loop include delivering a small electrical impulse to depolarize or block a small part of the reentrant loop (ie, anti-tachycardia pacing), delivering a large electrical shock to depolarize most or all the reentrant loop (ie, cardioversion), or ablating tissue critical to the reentrant loop. (See "Ventricular arrhythmias during acute myocardial infarction: Incidence, mechanisms, and clinical features".) Triggered activity Triggered activity refers to a depolarization that occurs after the initial depolarization wavefront and comes in two forms, either early or late. Secondary depolarizations that occur before the action potential has fully repolarized are early afterdepolarizations (EADs) ( figure 5). Those that occur after the action potential has fully repolarized are delayed afterdepolarizations (DADs) ( figure 5). Both EADs and DADs depend on the previous action potential to trigger them, hence an afterdepolarization is said to be a triggered arrhythmia. However, it is important to understand that DADs and EADs differ in mechanism. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 6/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate EADs EADs are triggered during prolonged action potentials. A prolonged action 2+ potential allows a longer window for reopening of L-type Ca channels during phase 2 (or 2+ occasionally phase 3) of the action potential. L-type Ca current depolarizes the membrane 2+ before repolarization, triggering an afterdepolarization. Due to L-type Ca channel time and voltage dependence, EADs occur at slow stimulation rates or after a ventricular pause when action potential duration (phase 2) is prolonged and they are suppressed with faster heart rates. EADs are thought to initiate the polymorphic ventricular arrhythmias torsades de pointes (TdP) found in inherited and acquired long QT syndrome (LQTS), for example drug-induced LQTS. A point of distinction to be made here is that triggered activity can initiate TdP, but TdP may be a re-entrant mechanism at the organ level with a functional (spiral reentry) rather than fixed anatomical core. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) 2+ DADs DADs, which result from intracellular Ca overload, are triggered after the action 2+ 2+ potential is fully repolarized. Under conditions of Ca overload, Ca taken back up by the sarcoplasmic reticulum is then transiently re-released into the cytoplasm. This in turn 2+ causes a transient rise in cytoplasmic Ca activating Ca -dependent depolarizing 2+ + 2+ + membrane current mostly through the Na -Ca exchanger. The exchange of three Na for 2+ one Ca produces a net inward and transient depolarization or a DAD. If the DAD reaches 2+ threshold voltage, it can initiate an action potential. Conditions which enhance cellular Ca loading, such as rapid heart rates, enhance DAD susceptibility. DADs may be important in myocardial ischemia, digoxin toxicity, and in some inherited arrhythmia syndromes such as catecholaminergic polymorphic ventricular tachycardia. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Mechanisms of cardiac toxicity' and "Catecholaminergic polymorphic ventricular tachycardia".) ACTION OF ANTIARRHYTHMIC DRUGS Classification of antiarrhythmic drugs The different antiarrhythmic drugs often have several effects on action potential generation and propagation and may also affect the autonomic nervous system. The classification of antiarrhythmic drugs according to the Harrison modification of the Vaughan Williams classification was originally based upon their effects on the action potential, but later modification and enhancements included the molecular targets such as specific ion channels and beta adrenergic receptors [8,11]. The most recent modification ( table 2 and table 3) adds additional classes and subclasses to the four traditional classes based on targets, some of which have clinically available drugs (eg, Class 0 pacemaker channel blocker ivabradine), and others that are experimental or theoretical targets (eg, Class VI gap https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 7/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate junction blockers) [11]. This scheme differs slightly from a classification endorsed by international societies [4]. Further modifications are to be expected. All these classification schemes assume that individual drugs have a predominant mechanism of action. This distinction remains useful, even though it does not account for the complicated electrophysiologic and autonomic interactions that are present, with some drugs having actions on more than one target. The modified Vaughan Williams classification has proven surprisingly useful even though it represents an oversimplification of the electrophysiologic events that occur. The classification appears to work because the multiple factors that influence cardiac excitability are sufficiently coordinated to produce predictable outcomes, rather than unpredictably complex behavior [12,13]. There is an electrophysiologic matrix or substrate of interacting active (ion channels) and passive (lipid bilayer of the cell membrane, myoplasm, and gap junctions) cellular properties that determine normal cardiac excitability. The normal substrate is altered by arrhythmogenic influences that affect one or more determinants of excitability. The ensuing proarrhythmic state can result in reentrant, automatic, or triggered arrhythmias. (See "Reentry and the development of cardiac arrhythmias" and "Enhanced cardiac automaticity".) The substrate that is deformed by arrhythmogenic factors interacts with antiarrhythmic drugs. Depending upon the substrate encountered, the resulting substrate may be antiarrhythmic, antifibrillatory, or proarrhythmic. Certain arrhythmogenic substrates are common, such as those induced by ischemia or infarction. In this setting, a certain effect of a drug becomes predominant and predictable, as with class I activity in ischemia, and a drug classification appears accurate. However, the major drug effect may be quite different if a different proarrhythmic substrate exists. Consider, for example, the differences in digitalis action in hypokalemia and hyperkalemia. Class 0 Drugs in the newly proposed Class 0 modulate the pacemaker channel HCN4, affecting the pacemaker current I [11]. The blocker ivabradine slows heart rate. f Class I The class I drugs act by modulating or blocking the sodium channels, thereby inhibiting phase 0 depolarization. They are all at least in part positively charged and presumably interact with specific amino acid residues in the internal pore of the sodium channel. Three different subgroups ( table 2 and table 3) have been identified because their mechanism or https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 8/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate duration of action is somewhat different due to variable rates of drug binding to and dissociation from the channel receptor [14]: The class Ic agents have the slowest binding and dissociation from the binding site. The class Ib agents have the most rapid binding and dissociation from the binding site. The class Ia agents are intermediate in terms of the speed of binding and dissociation from the binding site. During faster heart rates, less time exists for the drug to dissociate from the receptor, resulting in an increased number of blocked channels and enhanced blockade. These pharmacologic effects may cause a progressive decrease in impulse conduction velocity and a widening of the QRS complex. This property is known as "use-dependence" and is seen most frequently with the class Ic agents, less frequently with the class Ia drugs, and rarely with the class Ib agents [15]. Class Ia drugs (quinidine, procainamide, and disopyramide) depress phase 0 (sodium- dependent) depolarization, thereby slowing conduction. They also have moderate potassium channel blocking activity (which tends to slow the rate of repolarization and prolong action potential duration [APD]), and quinidine in particular also blocks potassium current I , which is useful for suppressing certain ventricular arrhythmias such as those To found in the Brugada syndrome. Class Ia agents also have anticholinergic activity and tend to depress myocardial contractility. At slower heart rates, when use-dependent blockade of the sodium current is not significant, potassium channel blockade may become predominant (reverse use-dependence), leading to prolongation of the APD and QT interval and increased automaticity. One difference between the drugs is that quinidine and procainamide generally decrease vascular resistance, whereas disopyramide increases vascular resistance. In addition, N- acetyl-procainamide (NAPA), a metabolite of procainamide, has little sodium current blocking activity, while retaining potassium current blocking activity. Thus, NAPA behaves like a class III drug. (See 'Class III' below.) The class Ib drugs (lidocaine and mexiletine) have less prominent sodium channel blocking activity at rest, but effectively block the sodium channel in depolarized tissues. They tend to bind in the inactivated state (which is induced by depolarization) and dissociate from the sodium channel more rapidly than other class I drugs. As a result, they are more effective with tachyarrhythmias than with slow arrhythmias. Class Ic drugs (flecainide and propafenone) primarily block open sodium channels and slow conduction. They dissociate slowly from the sodium channels during diastole, resulting in https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 9/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate increased effect at a more rapid rate (use-dependence). This characteristic is the basis for their antiarrhythmic efficacy, especially against supraventricular arrhythmias. Use- dependence may also contribute to the proarrhythmic activity of these drugs, especially in the diseased myocardium, resulting in incessant ventricular tachycardia. Flecainide and propafenone also have potassium channel blocking activity and can increase the APD in ventricular myocytes. Propafenone has significant beta blocking activity. Another recognized target for antiarrhythmic action is the late sodium current, which is enhanced in both acquired and inherited arrhythmias. When enhanced, it lengthens the APD and can create a substrate for arrhythmia by reentry and triggered activity (both early and delayed afterdepolarizations). Some class I drugs such as mexiletine and flecainide and class III drugs such as amiodarone preferentially block the late sodium current. The most selective late sodium current blocking drug is ranolazine, a drug approved for the treatment of chronic angina, but which may have antiarrhythmic activity [16]. This target has been proposed as a new sub-classification, Id [11]. Class II Class II drugs act by inhibiting sympathetic activity, primarily by causing beta blockade. They may also have a mild inhibitory effect on the sodium channels. Sympathetic stimulation has the following potential proarrhythmic actions [17]: An increase in automaticity due to enhancement of phase 4 spontaneous depolarization (see "Enhanced cardiac automaticity"). An increase in membrane excitability due to shortening in refractoriness (phases 2 and 3 of the action potential). An increase in the rate of impulse conduction through the myocardial membrane, resulting from acceleration of phase 0 upstroke velocity or the rate of membrane depolarization. An increase in delayed afterpotentials, especially when the cell is calcium loaded, such as in digoxin toxicity. By blocking catecholamine and sympathetically mediated actions, beta blockers slow the rate of discharge of the sinus and ectopic pacemakers, and increase the effective refractory period of the AV node. They also slow both antegrade and retrograde conduction in anomalous pathways [18]. Carvedilol is a beta-blocker with unique additional properties. In addition to beta- and alpha- adrenergic blockade, carvedilol can also block potassium (KCNH2, formerly HERG), calcium, and sodium currents and modestly prolong APD. However, when administered chronically, carvedilol https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 10/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate increases the number of these channels, which is probably a favorable effect in diseased hearts [19]. The most recent classification ( table 2 and table 3) expands the definition of class II to include "autonomic inhibitors and activators," with subclass IIa as beta adrenergic blockers such as those mentioned above, IIb as adrenergic activators such as isoproterenol, IIc as muscarinic inhibitors such as atropine, IId as muscarinic activators such as carbachol and digoxin, and IIe as adenosine receptor activators [11]. Adrenergic activators and muscarinic inhibitors augment, and muscarinic activators and adenosine activators decrease, heart rate by actions on the electrophysiology of the sinoatrial (SA) node and AV node. These additional classifications bring drugs that were previously outside the Vaughan Williams classification into the scheme. Class III The class III drugs (eg, amiodarone, dronedarone, ibutilide, dofetilide, sotalol, vernakalant) block the potassium channels to inhibit I , I , I , and I , thereby prolonging Kr Ks K1 KUR repolarization, the APD, and the refractory period. The relative potency of these drugs for specific potassium currents may account for atrial selectivity, for example I is only known to KUR be in the atria [19]. Blockage of ventricular potassium currents is manifested on the surface ECG by prolongation of the QT interval, providing the substrate for torsades de pointes, a polymorphic ventricular tachycardia. Amiodarone and dronedarone are exceptions with very little proarrhythmic activity, perhaps because of a balance of offsetting actions. Additionally, there are more atrial-specific agents such as vernakalant that block primarily I . KUR These drugs also have other antiarrhythmic effects: Sotalol has beta blocking activity. (See "Clinical uses of sotalol".) Amiodarone and dronedarone block sodium channels in depolarized tissues (a Class Ib effect) and also block calcium channels, potassium channels, and adrenergic receptors. Amiodarone also has thyroid effects that dronedarone, an amiodarone derivative without the iodine moiety, lacks. (See "Amiodarone: Clinical uses" and "Clinical uses of dronedarone" and "Amiodarone and thyroid dysfunction".) Ibutilide, which is available in intravenous form, is approved for the acute termination of atrial flutter and atrial fibrillation, and it prolongs the QT interval by enhancing the slow, delayed inward sodium current as well as blocking potassium channels during repolarization. (See "Therapeutic use of ibutilide".) Some of the class III agents, such as sotalol, dofetilide, and ibutilide, exhibit reverse use- dependent effects on repolarization [20]. This pharmacologic property is characterized by a dynamic increase in the repolarization time and the refractory period during slower heart rates. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 11/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Clinically, this property manifests as an increased QT interval at slower heart rates, which can increase the risk of torsades de pointes [20]. The new classification scheme ( table 2 and table 3) adds subclass IIIb and IIIc agents. + Subclass IIIb agents (metabolically dependent K channel openers, eg, pinacidil) may shorten the action potential but do not have antiarrhythmic activity [11]. Subclass IIIc agents (transmitter-dependent K-channel blockers, such as acetylcholine) activate potassium channels, but there are no clinically available drugs in this subclass. Class IV The class IV drugs are calcium channel blockers. Verapamil has a more pronounced inhibitory effect on the slow response SA and AV nodes than diltiazem. In comparison, the dihydropyridines, such as nifedipine, have little electrophysiologic effect on the heart. Verapamil and diltiazem can slow the sinus rate (usually in the presence of sinus node dysfunction or beta blockade), increase the refractoriness of and prolong conduction through the AV node, occasionally prolong the PR interval, and depress LV function. The newer classification scheme ( table 2 and table 3) calls this class "Ca handling modulators" and divides it into five subclassifications of targets, of which Class IVa is the classic Vaughan Williams surface channel blockers [11]. The additional classes IVb through IVe for the most part do not yet contain clinically available drugs, but this scheme does serve as a template for further research. An exception to this are the Class I drugs flecainide and propafenone, which qualify as class IVd ryanodine receptor blockers and are active against catecholaminergic polymorphic ventricular tachycardia. Additional proposed classes include Class V (mechanosensitive channel blockers) and Class VI (gap junction blockers), which have drugs under investigation. Class VII (upstream target modulators) includes angiotensin converting enzyme inhibitors and angiotensin receptor blockers that may have antiarrhythmic action by their effects on cardiac remodeling. A position paper on antiarrhythmic drugs produced by international societies provides additional detail [4]. SUMMARY AND RECOMMENDATIONS Antiarrhythmic drugs target ion channels and receptors in the heart, generally blocking or inhibiting function. (See 'Cardiac excitability' above.) Classification of antiarrhythmic drugs is generally done by their predominant action and target ( table 2 and table 3). Note that nearly all clinically used drugs act on multiple https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 12/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate targets. (See 'Classification of antiarrhythmic drugs' above.) The multiple electrophysiologic actions of antiarrhythmic drugs interacting with the variable underlying substrate present in each patient determine whether the clinical effect will be proarrhythmic or antiarrhythmic. (See 'Classification of antiarrhythmic drugs' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arnsdorf MF. The cellular basis of cardiac arrhythmias. A matrical perspective. Ann N Y Acad Sci 1990; 601:263. 2. Fozzard HA, Arnsdor MF. Cardiac electrophysiology. In: The Heart and Cardiovascular Syste m, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.63. 3. Grant AO. Cardiac Ion Channels. Circ Arrythm Electrophysiol 2009; 2:185. 4. Dan GA, Martinez-Rubio A, Agewall S, et al. Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). Europace 2018; 20:731. 5. Catterall WA. Structure and function of voltage-sensitive ion channels. Science 1988; 242:50. 6. St hmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 1989; 339:597. 7. Fozzard HA, Danck DA. Sodium channels. In: The Heart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.1091. 8. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991; 84:1831. 9. Liu DW, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 1993; 72:671. 10. Pelzer D, Pelzer S, McDonald TF. Calcium channels in heart. In: The Heart and Cardiovascular System,, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York1 991. p.1049. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 13/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate 11. Lei M, Wu L, Terrar DA, Huang CL. Modernized Classification of Cardiac Antiarrhythmic Drugs. Circulation 2018; 138:1879. 12. Arnsdorf MF. Arnsdorf's paradox. J Cardiovasc Electrophysiol 1990; 1:42. 13. Arnsdorf MF. Cardiac excitability, the electrophysiologic matrix and electrically induced ventricular arrhythmias: order and reproducibility in seeming electrophysiologic chaos. J Am Coll Cardiol 1991; 17:139. 14. Snyders DJ, Hondeghem LM, Bennett PB. Mechanisms of drug-channel interaction. In: The H eart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, N ew York 1991. p.2165. 15. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984; 24:387. 16. Antzelevitch C, Nesterenko V, Shryock JC, et al. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol 2014; 221:137. 17. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82:I103. 18. Frishman W, Silverman R. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 2. Physiologic and metabolic effects. Am Heart J 1979; 97:797. 19. Naccarelli GV, Lukas MA. Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. Clin Cardiol 2005; 28:165. 20. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. Topic 895 Version 30.0
dronedarone" and "Amiodarone and thyroid dysfunction".) Ibutilide, which is available in intravenous form, is approved for the acute termination of atrial flutter and atrial fibrillation, and it prolongs the QT interval by enhancing the slow, delayed inward sodium current as well as blocking potassium channels during repolarization. (See "Therapeutic use of ibutilide".) Some of the class III agents, such as sotalol, dofetilide, and ibutilide, exhibit reverse use- dependent effects on repolarization [20]. This pharmacologic property is characterized by a dynamic increase in the repolarization time and the refractory period during slower heart rates. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 11/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Clinically, this property manifests as an increased QT interval at slower heart rates, which can increase the risk of torsades de pointes [20]. The new classification scheme ( table 2 and table 3) adds subclass IIIb and IIIc agents. + Subclass IIIb agents (metabolically dependent K channel openers, eg, pinacidil) may shorten the action potential but do not have antiarrhythmic activity [11]. Subclass IIIc agents (transmitter-dependent K-channel blockers, such as acetylcholine) activate potassium channels, but there are no clinically available drugs in this subclass. Class IV The class IV drugs are calcium channel blockers. Verapamil has a more pronounced inhibitory effect on the slow response SA and AV nodes than diltiazem. In comparison, the dihydropyridines, such as nifedipine, have little electrophysiologic effect on the heart. Verapamil and diltiazem can slow the sinus rate (usually in the presence of sinus node dysfunction or beta blockade), increase the refractoriness of and prolong conduction through the AV node, occasionally prolong the PR interval, and depress LV function. The newer classification scheme ( table 2 and table 3) calls this class "Ca handling modulators" and divides it into five subclassifications of targets, of which Class IVa is the classic Vaughan Williams surface channel blockers [11]. The additional classes IVb through IVe for the most part do not yet contain clinically available drugs, but this scheme does serve as a template for further research. An exception to this are the Class I drugs flecainide and propafenone, which qualify as class IVd ryanodine receptor blockers and are active against catecholaminergic polymorphic ventricular tachycardia. Additional proposed classes include Class V (mechanosensitive channel blockers) and Class VI (gap junction blockers), which have drugs under investigation. Class VII (upstream target modulators) includes angiotensin converting enzyme inhibitors and angiotensin receptor blockers that may have antiarrhythmic action by their effects on cardiac remodeling. A position paper on antiarrhythmic drugs produced by international societies provides additional detail [4]. SUMMARY AND RECOMMENDATIONS Antiarrhythmic drugs target ion channels and receptors in the heart, generally blocking or inhibiting function. (See 'Cardiac excitability' above.) Classification of antiarrhythmic drugs is generally done by their predominant action and target ( table 2 and table 3). Note that nearly all clinically used drugs act on multiple https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 12/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate targets. (See 'Classification of antiarrhythmic drugs' above.) The multiple electrophysiologic actions of antiarrhythmic drugs interacting with the variable underlying substrate present in each patient determine whether the clinical effect will be proarrhythmic or antiarrhythmic. (See 'Classification of antiarrhythmic drugs' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Arnsdorf MF. The cellular basis of cardiac arrhythmias. A matrical perspective. Ann N Y Acad Sci 1990; 601:263. 2. Fozzard HA, Arnsdor MF. Cardiac electrophysiology. In: The Heart and Cardiovascular Syste m, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.63. 3. Grant AO. Cardiac Ion Channels. Circ Arrythm Electrophysiol 2009; 2:185. 4. Dan GA, Martinez-Rubio A, Agewall S, et al. Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). Europace 2018; 20:731. 5. Catterall WA. Structure and function of voltage-sensitive ion channels. Science 1988; 242:50. 6. St hmer W, Conti F, Suzuki H, et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 1989; 339:597. 7. Fozzard HA, Danck DA. Sodium channels. In: The Heart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York 1991. p.1091. 8. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation 1991; 84:1831. 9. Liu DW, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 1993; 72:671. 10. Pelzer D, Pelzer S, McDonald TF. Calcium channels in heart. In: The Heart and Cardiovascular System,, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, New York1 991. p.1049. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 13/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate 11. Lei M, Wu L, Terrar DA, Huang CL. Modernized Classification of Cardiac Antiarrhythmic Drugs. Circulation 2018; 138:1879. 12. Arnsdorf MF. Arnsdorf's paradox. J Cardiovasc Electrophysiol 1990; 1:42. 13. Arnsdorf MF. Cardiac excitability, the electrophysiologic matrix and electrically induced ventricular arrhythmias: order and reproducibility in seeming electrophysiologic chaos. J Am Coll Cardiol 1991; 17:139. 14. Snyders DJ, Hondeghem LM, Bennett PB. Mechanisms of drug-channel interaction. In: The H eart and Cardiovascular System, Fozzard HA, Haber E, Jennings A, et al (Eds), Raven Press, N ew York 1991. p.2165. 15. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984; 24:387. 16. Antzelevitch C, Nesterenko V, Shryock JC, et al. The role of late I Na in development of cardiac arrhythmias. Handb Exp Pharmacol 2014; 221:137. 17. Podrid PJ, Fuchs T, Candinas R. Role of the sympathetic nervous system in the genesis of ventricular arrhythmia. Circulation 1990; 82:I103. 18. Frishman W, Silverman R. Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 2. Physiologic and metabolic effects. Am Heart J 1979; 97:797. 19. Naccarelli GV, Lukas MA. Carvedilol's antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. Clin Cardiol 2005; 28:165. 20. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. Topic 895 Version 30.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 14/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate GRAPHICS Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 15/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Normal conduction system Schematic representation of the normal intraventricular conduction system (His- Purkinje system). The Bundle of His divides into the left bundle branch and right bundle branch. The left bundle branch divides into anterior, posterior, and, in some cases, median fascicles. AV: atrioventricular; RA: right atrium; LA: left atrium; RV: right ventricle; LV: left ventricle. Graphic 63340 Version 6.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 16/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Myocardial action potential Representation of a ventricular action potential. There are 5 phases of the action potential beginning with phase 0, rapid depolarization by sodium influx. Phase 1 is a rapid repolarization via potassium efflux followed by phase 2 or the plateau phase. The plateau phase results from entry of calcium into the cell and potassium efflux. Phase 3 repolarization is dominated by potassium currents which polarize the cell and potassium inward rectifier maintains the resting potential or phase 4. See text for full description. Graphic 71390 Version 4.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 17/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Action potentials generated by different parts of conduction system The sinoatrial (SA) and atrioventricular (AV) nodes generate a slow action potential, mediated by calcium ions. In comparison, the tissues of the atria, ventricles, and the His-Purkinje system generate a fast action potential mediated by sodium ions. Sequential activation of these structures results in the characteristic waveforms visible on the surface electrocardiogram (ECG). The AV node and bundle of His are small structures; as a result, no electrical activity is recorded on the surface ECG during their activation. Graphic 61989 Version 4.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 18/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Fast versus slow response cardiac tissues Properties Fast response tissues Slow response tissues Atria, specialized infranodal SA and AV nodes, depolarized fast Location conducting system, ventricles, AV bypass tracts response tissues in which phase 0 depends upon calcium current Passive cellular properties Normal resting 80 to -95 mV 40 to -65 mV potential Active cellular properties Phase 0 current Sodium Primarily calcium Phase 0 channel kinetics Fast Slow activation; inactivation depends upon voltage and cell calcium concentration Peak overshoot +20 to +40 mV 5 to + 20 mV Action potential amplitude 90 to 135 mV 30 to 70 mV Properties dependent upon active and passive properties Threshold voltage 60 to -75 mV 40 to -60 mV Conduction 0.5 to 5 m/second 0.01 to 0.1 m/second velocity Conducive to reentry Only with inactivation of sodium channels with marked slowing of conduction velocity Present in normal tissue Yes Yes Automaticity Comparison of the major electrophysiologic characteristics of "fast" and "slow" response tissues. AV: atrioventricular; SA: sinoatrial. Graphic 71831 Version 3.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 19/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Mechanisms of tachyarrhythmias (A) Enhanced automaticity: nodal action potentials with normal automaticity (solid orange line) compared wit (dotted blue line) as would be seen with increased pacemaker current (I ) and/or decreased inward rectifier c enhanced automaticity arrhythmia, atrial tachycardia, is shown in the figure. f (B) Reentry: a schematic of a reentrant circuit with fast and slow conduction adjacent to a fixed core. An exam of ventricular tachycardia is shown below the figure. (C) Triggered activity, DADs: DADs with the first DAD (solid orange line) not reaching threshold to trigger an a subsequent DADs reaching threshold (dotted blue line). Bidirectional ventricular tachycardia from a catechola ventricular tachycardia patient is depicted and thought to initiate with DADs. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 20/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate (D) Triggered activity, EADs: reverence action potentials (solid black line) with a prolonged action potential an a long interval, which sets up conditions for a single EAD (dotted blue line) or oscillatory EADs. Typical short-l torsade de pointes in a patient with drug-induced long QT syndrome. AP: action potential; DAD: delayed afterdepolarization; EAD: early afterdepolarization. Courtesy of Lee Eckhardt, MD. Graphic 120258 Version 2.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 21/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs Pharmacological Electrophysiological Examples of Class Subclass targets effects drugs HCN channel blockers 0 HCN channel- mediated Inhibition of I reducing SAN phase 4 pacemaker Ivabradine f pacemaker current (I ) block depolarization rate, thereby reducing heart f rate; possible decreased AVN and Purkinje cell automaticity; increase in RR intervals + Voltage-gated Na channel blockers https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 22/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate I Ia Nav1.5 open state; intermediate (Tau 1 to 10 seconds) dissociation kinetics; Reduction in peak I AP generation, and , Quinidine, ajmaline, Na (dV/dt) increased excitation with disopyramide max often concomitant K channel block threshold; slowing of AP conduction in atria, + ventricles, and specialized ventricular conduction pathways; concomitant I block increasing APD and ERP; K increase in QT intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 23/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Ib Nav1.5 open state; rapid dissociation (Tau 0.1 to 1 second); I Reduction in peak I AP generation and , Lidocaine, mexiletine Na (dV/dt) increased excitation with max ; window Na current threshold; slowing of AP conduction in atria, ventricles, and specialized ventricular conduction pathways; shortening of APD and ERP in normal ventricular and Purkinje myocytes; prolongation of ERP and postrepolarization refractoriness with reduced window current in ischemic, partially depolarized cells Relatively little electrocardiographic effect; slight QTc shortening Ic Nav1.5 inactivated state; slow dissociation (Tau >10 Reduction in peak I AP generation and (dV/dt) , Propafenone, flecainide Na with max seconds) increased excitation threshold; slowing of AP conduction in atria, ventricles, and specialized ventricular conduction pathways; reduced overall excitability; prolongation of APD at high heart rates; increase in QRS duration https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 24/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate + Id Nav1.5 late current Reduction in late Na Ranolazine current (I NaL AP recovery, ), affecting refractoriness, repolarization reserve, and QT interval Autonomic inhibitors and activators https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 25/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate II IIa Nonselective beta- and selective beta1- Inhibition of adrenergically induced Nonselective beta inhibitors: adrenergic receptor inhibitors G protein-mediated effects of increased carvedilol, propranolol, s adenylyl kinase activity and [cAMP] with effects i including slowed SAN nadolol Selective beta1- adrenergic receptor pacemaker rate caused by reduced I and I ; f CaL inhibitors: increased AVN conduction time and atenolol, bisoprolol, betaxolol, refractoriness, and decreased SAN pacing celiprolol, and triggered activity esmolol, metoprolol resulting from reduced ; and reduced RyR2- I CaL mediated SR Ca release and triggered activity; increase in RR and PR intervals 2+ https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 26/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 27/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate IIb Nonselective beta- adrenergic receptor Activation of adrenergically induced Isoproterenol activators G -protein effects of increasing adenylyl s kinase activity and [cAMP] (refer to entry i above); decrease in RR and PR intervals IIc Muscarinic M receptor inhibitors Inhibition of supraventricular (SAN, atrial, AVN) muscarinic M cholinergic receptors (refer to entry below); Atropine, anisodamine, hyoscine, scopolamine 2 2 decreased RR and PR intervals IId Muscarinic M Activation of Carbachol, 2 receptor activators supraventricular (SAN, atrial, AVN) muscarinic M cholinergic receptors channels, activates K ACh hyperpolarizing the SAN pilocarpine, methacholine, digoxin 2 and shortening APDs in atrial and AVN tissue, and reduces [cAMP] and therefore I i and SAN CaL I ; inhibitory effects on f adenylyl cyclase and cAMP activation, reducing its stimulatory effects on I , I , CaL Ks Cl , I and I in adrenergically activated ventricular ti tissue; increased RR and PR intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 28/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate IIe Adenosine A receptor activators Activation of adenosine A receptors in Adenosine, ATP; aminophylline 1 1 supraventricular tissue (SAN, atrial, AVN) acts as an adenosine activates G protein- coupled inward receptor inhibitor + rectifying K channels and I hyperpolarizing the SAN current, KAdo and shortening APDs in atrial and AVN tissue, and reduces [cAMP] and therefore I i and SAN CaL I ; inhibitory effects on f adenylyl cyclase and cAMP activation, reducing its stimulatory effects on I and I in adrenergically activated ventricular tissue; increased RR and increased PR intervals , I , CaL Ks Cl , I ti + K channel blockers and openers III + + Voltage dependent K channel blockers IIIa Nonselective K channel blockers Block of multiple K channel targets resulting in prolonged atrial, Purkinje, and/or ventricular myocyte AP recovery, increased ERP, Ambasilide, amiodarone, dronedarone + and reduced repolarization reserve; prolonged QT intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 29/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Kv11.1 (HERG) Prolonged atrial, Dofetilide, channel-mediated rapid K current (I Purkinje, and ventricular myocyte AP recovery, ibutilide, sotalol + ) Kr blockers increased ERP, and reduced repolarization reserve; prolonged QT intervals Kv7.1 channel- Prolonged atrial, No clinically + mediated, slow K current (I Purkinje, and ventricular myocyte AP recovery, approved drugs in use ) blockers Ks increased ERP, and reduced repolarization reserve; prolonged QT intervals https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 30/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Kv1.5 channel- mediated, ultrarapid Prolonged atrial AP recovery, increased ERP, Vernakalant + K current (I blockers ) and reduced repolarization reserve Kur Kv1.4 and Kv4.2 Prolonged atrial, Blocker under channel-mediated transient outward Purkinje, and ventricular myocyte AP recovery, regulatory review for the acute + K current (I ) increased ERP, and conversion of to1 blockers reduced repolarization reserve, particularly in subepicardial as atrial fibrillation: tedisamil opposed to subendocardial ventricular cardiomyocytes Metabolically + dependent K channel IIIb Kir6.2 (I ) openers Opening of ATP- Nicorandil, pinacidil KATP + sensitive K channels ), shortening AP (I KATP openers recovery, refractoriness, and repolarization reserve in all cardiomyocytes apart from SAN cells; shortened QT intervals Transmitter dependent K channel blockers IIIc GIRK1 and GIRK4 (I Inhibition of direct or G protein -subunit- mediated activation of , particularly in I Blocker under regulatory review for management of atrial i + ) blockers KACh KACh SAN, AVN, and atrial cells, prolonging APD fibrillation: BMS 914392 and ERP and decreasing repolarization reserve 2+ Ca handling modulators IV 2+ Surface IVa Nonselective surface Block of Ca current Bepridil 2+ membrane membrane Ca (I ), resulting in Ca 2+ Ca channel blockers channel blockers inhibition of SAN pacing, inhibition of AVN conduction, prolonged ERP, increased AP https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 31/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate recovery time, increased refractory period, diminished repolarization reserve, and suppression of intracellular Ca 2+ signaling; increased PR intervals 2+ Ca 1.2 and Ca 1.3 channel mediated L- Block of Ca current ), resulting in (I Phenylalkylamines (eg, verapamil), v v Ca 2+ type Ca current ) blockers (I inhibition of SAN pacing, inhibition of AVN benzothiazepines (eg, diltiazem) CaL conduction, prolonged ERP, increased AP recovery time, increased refractory period, diminished repolarization reserve, and suppression of intracellular Ca signaling; increased PR intervals 2+ Ca 3.1 channel mediated T-type Ca current (I blockers Inhibition of SAN pacing, prolonged His- Purkinje phase 4 repolarization, absent No clinically approved drugs in use v 2+ ) CaT from ventricular cells 2+ 2+ Intracellular Ca channel blockers IVb SR RyR2-Ca channel blockers Reduced SR Ca release: reduced 2+ cytosolic and SR [Ca ] Flecainide, propafenone 2+ 2+ IP R-Ca channel blockers 2+ Reduced atrial SR Ca release; reduced No clinically approved drugs in 3 2+ cytosolic and SR [Ca ] use 2+ Sarcoplasmic 2+ reticular Ca - ATPase IVc Sarcoplasmic 2+ Increased Ca -ATPase No clinically reticular Ca pump activators activity, increased SR 2+ [Ca ] approved drugs in use activators + 2+ Surface IVd Surface membrane Reduced Na Ca No clinically membrane ion exchange ion exchanger (eg, SLC8A) inhibitors exchange reduces depolarization approved drugs in use inhibitors associated with rises in 2+ subsarcolemmal [Ca ] https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 32/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Phosphokinase and IVe Increased/decreased phosphorylation Includes CaMKII modulators: altered No clinically approved drugs in 2+ phosphorylase inhibitors levels of cytosolic Ca handling intracellular Ca signaling use 2+ proteins Mechanosensitive channel blockers 2+ V Transient receptor Intracellular Ca Blocker under potential channel (TRPC3/TRPC6) signaling investigation: N (p-amylcinnamoyl) blockers anthranilic acid Gap junction channel blockers VI Cx (Cx40, Cx43, Cx45) blockers Reduced cell-cell coupling and AP Blocker under investigation: propagation; Cx40: atria, AVN, ventricular conduction system; carbenoxolone Cx43: atria and ventricles, distal conduction system; Cx45: SAN, AVN, conducting bundles Upstream target modulators https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 33/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate VII Angiotensin- converting enzyme Electrophysiological and structural (fibrotic, Captopril, enalapril, delapril, inhibitors hypertrophic, or inflammatory) ramipril, quinapril perindopril, remodeling lisinopril, benazepril, imidapril, trandolapril, cilazapril Angiotensin receptor blockers Electrophysiological and structural (fibrotic, Losartan, candesartan, hypertrophic, or eprosartan, inflammatory) remodeling telmisartan, irbesartan, olmesartan, valsartan, saprisartan Omega-3 fatty acids Electrophysiological and Omega-3 fatty structural (fibrotic, hypertrophic, or inflammatory) remodeling acids: eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid Statins Electrophysiological and structural (fibrotic, hypertrophic, or Statins inflammatory) remodeling HCN: hyperpolarization-activated cyclic nucleotide-gated; SAN: sino-atrial node; AVN: atrioventricular node; AP: action potential; APD: action potential duration; ERP: effective refractory period; SQTS: short-QT syndrome; DAD: delayed afterdepolarization; EAD: early afterdepolarization; RyR2: ryanodine receptor 2; SR: sarcoplasmic reticulum; CaMKII: calcium/calmodulin kinase II. https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 34/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate From: Lei M, Wu L, Terrar DA, et al. Modernized classi cation of cardiac antiarrhythmic drugs. Circulation 2018; 138:1879. Available at: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.118.035455 (Accessed on January 29, 2019). Reproduced under the terms of the Creative Commons Attribution License. Graphic 120226 Version 2.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 35/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 36/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 37/38 7/5/23, 8:20 AM Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs - UpToDate Contributor Disclosures Jonathan C Makielski, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. L Lee L Eckhardt, MD, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs/print 38/38
7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical use of dofetilide : Rod Passman, MD, MSCE, Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 14, 2023. INTRODUCTION Dofetilide is a class III antiarrhythmic agent ( table 1) available for the acute termination of atrial fibrillation or flutter, as well as prevention of atrial fibrillation or flutter recurrence. Dofetilide has also been used in an off-label manner to treat paroxysmal supraventricular tachycardias. Some investigators have studied the efficacy of dofetilide in the treatment of life- threatening ventricular arrhythmias, although the drug is not approved for this indication. In contrast to some other antiarrhythmic medications, dofetilide appears to be hemodynamically safe for use in patients with heart failure or a prior myocardial infarction [1]. Because of a relatively high risk of torsades de pointes as an adverse effect of dofetilide, it has extensive contraindications for its use and rigorous dosing guidelines. The basic pharmacologic properties of dofetilide, its clinical uses, and its safety profile are discussed in detail here. Alternative treatment approaches for supraventricular and ventricular arrhythmias are discussed separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrioventricular nodal reentrant tachycardia", section on 'Initial management' and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis".) ELECTROPHYSIOLOGY https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 1/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Dofetilide is a class III antiarrhythmic agent that blocks the delayed rectifier cardiac potassium channel and prolongs repolarization ( table 1). Dofetilide has relative selectivity for blocking the rapidly-activating component of the delayed rectifier potassium current (IKr) at concentrations of 10 to 30 nanomol/L [2,3]. At these concentrations, it does not block the slow component of the delayed rectifier potassium current (IKs) or the inward rectifier (IKi) and does not affect calcium currents. Evidence from one study shows that dofetilide and several other drugs known to cause torsades de pointes (d-sotalol, thioridazine, and erythromycin) increase the late sodium current (I ) in cardiac cells, an action (IC = 0.1 micromol/L) that could 50 NaL contribute to their arrhythmogenic potential [4]. As a result of its electrophysiologic actions on I and possibly I , dofetilide has a selective Kr NaL effect on the QT interval of the surface ECG. In clinical electrophysiologic studies, it prolongs the QT interval with little, if any, effect on QT dispersion [5]. Purkinje fibers from female dogs are more sensitive to dofetilide than fibers from male dogs, which is consistent with the threefold greater incidence of torsades de pointes in women and the observation that women are more likely to require dose reduction or discontinuation than men [6,7]. Like other class III agents, dofetilide exhibits reverse use dependency (greater prolongation of repolarization and the refractory period during slower heart rates). The drug prolongs the effective refractory period of atrial and ventricular myocardium and accessory pathways, but it has no effect on conduction parameters, sinus cycle length, or sinus node recovery [8,9]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) PHARMACOLOGIC DATA/PHARMACOKINETICS The oral doses of dofetilide that have been used in clinical trials range from 125 to 500 mcg twice daily. Peak plasma concentrations are seen two to three hours after oral dosing when fasting. Dofetilide is completely absorbed after oral administration, and bioavailability ranges from 75 to 100 percent [10]. Elimination is predominantly renal (80 percent), with only 20 percent hepatic conversion to inactive metabolites [11]. The elimination half-life is approximately ten hours after intravenous or oral administration. Clearance has been estimated to be 0.35 L/hour/kg [12]. There is a very linear relationship between the dose administered, plasma concentration of dofetilide, and its effect on the QT interval after both oral and intravenous administration [12]. This observation indicates that it is unlikely that there are important effects of the metabolites on potassium channels and supports earlier work examining the activities of the metabolites in vitro. https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 2/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Although some safety and efficacy trials with intravenous dofetilide have been performed, dofetilide is not available for intravenous administration in the United States [13-17]. METABOLISM AND DRUG INTERACTIONS Dofetilide, like most other potassium channel blockers, is metabolized predominantly by the CYP3A4 family of enzymes in the liver and gastrointestinal tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such as erythromycin, clarithromycin, or ketoconazole, resulting in higher and potentially toxic levels of dofetilide [18]. The QT-prolonging effects and the risk of torsades de pointes can be increased by coadministration of dofetilide with other drugs that also prolong the QT interval or drugs that interfere with renal elimination of dofetilide (eg, cimetidine, verapamil, trimethoprim, alone or in combination with sulfamethoxazole, prochlorperazine, hydrochlorothiazide, alone or in combination with triamterene, megestrol, dolutegravir, or ketoconazole). Additional information can also be found using the Lexicomp drug interactions tool. Dofetilide has been studied in experiments that examine concomitant administration of QT-prolonging drugs. Some examples have shown nearly additive effects on QT interval and action potential duration, while others have shown inhibitory effects dependent on the order in which the drugs were administered [19-21]. As a result, while caution is appropriate to avoid additive or synergistic effects, resulting in QT prolongation and increased risk of torsades de pointes, the presence of inhibitory effects of certain drug-drug combinations indicates the need for additional research to gain a better understanding of drug-drug interaction on the QT interval and action potential duration. There is frequent use of diuretics among those requiring dofetilide. The concomitant use of hydrochlorothiazide almost doubles the degree of heart-rate corrected QT interval prolongation related to decreased dofetilide clearance and diuretic-induced hypokalemia [22]. DRUG APPROVAL AND RESTRICTIONS The US Food and Drug Administration (FDA) approved the use of dofetilide for the cardioversion of atrial fibrillation (AF) and atrial flutter (AFl) to normal sinus rhythm and for maintenance of normal sinus rhythm in symptomatic patients with AF/AFl. Several other countries worldwide have also approved its use; however, widespread approval and usage have been somewhat limited due to safety concerns. Because of the risk of torsades de pointes, the FDA recommends that patients initiating or reinitiating dofetilide must be placed in a facility for a minimum of three days that can provide dosing based on estimated creatinine clearance, cardiac monitoring, and cardiac resuscitation. The majority (ie, 75 percent) of episodes of torsades de pointes have https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 3/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate occurred within the three-day period of initial dosing and at the time of peak increase in the QT interval [23]. However, late occurrence is possible and has been reported. PROTOCOL FOR ADMINISTRATION In an effort to optimize efficacy and safety, the initiation or reinitiation of dofetilide should occur in a controlled fashion according to the FDA-recommended dose protocol ( figure 1). Deviation from the FDA-recommended protocol is required in up to 45 percent of cases, often due to adverse events [24]. When patients require reinitiation of therapy or dose increase, experience suggests that the recommended protocol and hospital admission should be implemented [25]. SPECIFIC INDICATIONS Because dofetilide can cause life-threatening ventricular arrhythmias, it is recommended that it should be reserved for patients in whom atrial fibrillation/atrial flutter (AF/AFl) is highly symptomatic or has resulted in heart failure. Although not approved for use, it has been evaluated in small studies in patients with other supraventricular arrhythmias and ventricular tachycardia. Oral dofetilide for atrial fibrillation/atrial flutter termination and prevention Dofetilide is indicated for the conversion of atrial fibrillation/atrial flutter (AF/AFl) and maintenance of normal sinus rhythm (delay in time to recurrence of AF/AFl) in patients whose arrhythmia is of greater than one-week duration and who have been converted to normal sinus rhythm. Oral dofetilide has been evaluated for the cardioversion of atrial fibrillation (AF) or atrial flutter (AFl) to normal sinus rhythm and for the prevention of recurrent AF or atrial flutter. To evaluate the efficacy of dofetilide in termination of atrial arrhythmias, the SAFIRE-D study randomly assigned 325 patients with AF (n = 277) or AFl (n = 48) to 125, 250, and 500 mcg of dofetilide twice daily or placebo [26]. Overall conversion rates were 6, 10, and 30 percent, respectively, versus 1.2 percent for placebo. At a dose of 500 mcg twice daily, the conversion rates for AF and atrial flutter were 22 and 67 percent, respectively. For those patients who responded to dofetilide, conversion to sinus rhythm occurred within 24 hours in 70 percent and within 36 hours in 91 percent. (See "Atrial fibrillation: Cardioversion".) The SAFIRE-D trial also evaluated the long-term efficacy of dofetilide for maintenance of sinus rhythm in 204 patients with AF who were successfully cardioverted electrically or https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 4/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate pharmacologically with dofetilide and maintained on a dofetilide dose of 125, 250, or 500 mcg twice daily or placebo [26]. The probability of remaining in sinus rhythm at one year was 40, 37, and 58 percent versus 25 percent for placebo. The all-cause mortality was the same in the four groups. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Acute conversion versus long-term arrhythmia free survival In retrospective studies of patients who initiated dofetilide during persistent AF/AFl, between 45 and 56 percent have converted to sinus rhythm during dofetilide loading [27,28]. Female gender, history of AFl, greater number of prior catheter ablations, shorter duration of current AF/AFl, and presentation in AFl were all associated with acute pharmacologic conversion (p = 0.001, 0.05, 0.001, 0.003, and 0.003, respectively) [27]. Pharmacologic conversion was not significantly associated with time to AF/AFl recurrence (HR = 0.79, 95% CI 0.57-1.10, p = 0.2). Acute pharmacologic conversion of persistent AF/AFl to sinus rhythm frequently occurs during dofetilide loading but does not predict long-term arrhythmia control, which was moderate at best. Comparative efficacy In an observational study of 5952 consecutive patients with AF who were prescribed amiodarone (n = 2266), dronedarone (n = 488), dofetilide (n = 539), sotalol (n = 1718), or class 1C agents (n = 941) and followed for a median of 18 months, amiodarone, class 1C agents, and sotalol were associated with less AF recurrence than dofetilide or dronedarone [29]. Another observational study suggests that when properly initiated and monitored, dofetilide's ef cacy and safety are comparable to that of amiodarone. The study assessed rhythm control with dofetilide in 657 patients with AF and/or atrial utter and AF. Dofetilide was successfully initiated in 87 percent of patients, including 89 percent with persistent AF and 11 percent with paroxysmal AF. During a mean follow-up of 19 7 months, sinus rhythm was maintained in 63 percent of 573 dofetilide-treated patients. At 12 months, dofetilide patients had a similar likelihood of experiencing recurrent atrial arrhythmias compared with 2476 patients on amiodarone for rhythm control (37 versus 39 percent). The ef cacy of dofetilide and amiodarone was similar in subgroups, including patients >75 years of age, low ventricular ejection fraction, obesity, renal insuf ciency, and prior catheter ablation for AF [30]. Rapid conversion of patients who were refractory or intolerant of amiodarone to dofetilide therapy was successful in 66 percent of 179 patients who had an ICD in place and for whom amiodarone had been discontinued for seven days [31]. https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 5/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Dofetilide for preventing recurrence of paroxysmal supraventricular tachycardia Dofetilide (500 mcg twice daily) was compared with propafenone (150 mg three times daily) and placebo for the prevention of recurrent paroxysmal supraventricular tachycardia (PSVT) in a trial of 122 patients [32]. After six months of therapy, freedom from episodes of PSVT was the same with dofetilide and propafenone (50 and 54 versus 6 percent for placebo); the median number of episodes of PSVT in those with recurrences was also the same with these two agents (1 and 0.5 versus 5 for placebo). Ventricular tachyarrhythmias Animal studies have suggested that dofetilide reduces the incidence of sustained ventricular tachyarrhythmias during acute myocardial ischemia [33]. However, comprehensive studies of dofetilide in patients with life-threatening ventricular tachyarrhythmias are limited. Oral dofetilide (500 mcg twice daily) was compared with oral sotalol (160 mg twice daily) in a randomized, crossover comparative trial of 135 patients with ischemic heart disease and ventricular tachycardia (VT) induced during electrophysiologic testing [34]. Patients underwent repeat electrophysiologic testing after three to five days of therapy and then crossed over to the alternate drug. The response rate was the same with dofetilide and sotalol (36 versus 34 percent), but only 18 percent responded to both drugs. Drug-related adverse effects were significantly less frequent with dofetilide. Oral dofetilide has also been evaluated patients with an ICD, yielding mixed results. Among one cohort of 174 patients with an implantable cardioverter-defibrillator (ICD), dofetilide did not reduce the incidence of ICD interventions for ventricular tachycardia or ventricular fibrillation (VF) compared with placebo; however, the incidence of pause-dependent torsades de pointes was significantly higher with dofetilide (17 versus 6 percent for placebo) [35]. However, in a smaller cohort of 30 patients with ICDs for secondary prevention who were treated with dofetilide and followed for an average of 32 months, dofetilide led to significant reductions in VT and VF as well as ICD therapies delivered [36]. Pending the completion of additional prospective studies of dofetilide, we do not suggest its routine use as a first-line antiarrhythmic drug for the treatment of ventricular tachyarrhythmias. Heart failure Both animal and human studies have shown that dofetilide does not have a negative inotropic effect on left ventricular contractility [37,38]. In a clinical study of patients with class II or III heart failure, intravenous dofetilide (8 mcg/kg), which is not available in all countries, did not alter left ventricular contractility or ventricular volumes [38]. In addition, because of the limited number of antiarrhythmic medications available for use in patients with heart failure or reduced left ventricular systolic function, there is interest in developing https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 6/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate additional antiarrhythmic medications for use in this population. Despite this potential interest, there remain limited data with mixed outcomes regarding the safety and efficacy of dofetilide use in such patients, particularly in those with advanced heart failure. There are limited post-approval data and safety outcomes with dofetilide use in patients with reduced left ventricular ejection fraction. In a retrospective review from a single center, dofetilide as an initial antiarrhythmic strategy for atrial fibrillation in left ventricular ejection fraction 35 percent was associated with improvement in left ventricular ejection fraction >35 percent in 73 percent of patients, precluding the need for primary prevention implantable cardioverter defibrillator in most patients [39]. The DIAMOND-CHF trial evaluated the safety of dofetilide compared with placebo in 1518 patients with symptomatic heart failure and left ventricular dysfunction (left ventricular ejection fraction 35 percent), including 391 with AF at baseline [23]. After one month of therapy, 12 percent of patients with AF at baseline had sinus rhythm restored compared with only 1 percent receiving placebo. After a mean follow-up of 18 months, there was no overall difference in mortality between the two groups (41 versus 42 percent). In a subsequent analysis, a difference in mortality was noted according to baseline corrected QT (QTc) interval [40]. In those with a QTc interval <429 milliseconds, dofetilide was associated with a significant reduction in mortality (risk ratio 0.4, 95% CI 0.3 to 0.8), while it tended to increase mortality in those with a QTc interval >479 milliseconds (risk ratio 1.3, 95% CI 0.8 to 1.9). In these same patients, the incidence of torsades de pointes was 3.3 percent; three-quarters of these episodes occurred within the first three days while the patient was in the hospital. (See "The management of atrial fibrillation in patients with heart failure".) Postmyocardial infarction Dofetilide has been evaluated and appears safe for use in patients with a history of myocardial infarction (MI). The DIAMOND-MI trial enrolled 1510 patients with an acute MI and a left ventricular ejection fraction 35 percent. Patients were randomly assigned to dofetilide (500 mcg twice per day) or placebo within seven days of the MI [41]. The one year mortality was 31 percent, and the incidence of arrhythmic deaths was 17 percent. Total mortality, cardiac mortality, arrhythmic mortality, and the combined end point of cardiac death and resuscitation were the same in both groups. In addition, there was evidence of antiarrhythmic efficacy of dofetilide. Among patients receiving dofetilide, there was a lower incidence of new atrial fibrillation and a higher rate of conversion of atrial fibrillation to sinus rhythm (42.4 versus 12.5 percent for placebo). Torsades de pointes developed in 0.9 percent of patients treated with dofetilide, most of which occurred within the first four days of treatment. However, the patients in this trial were https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 7/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate scrutinized carefully to exclude those with known risk factors for torsade, which may explain why the incidence of torsade was lower than in some other studies noted above. Use of dofetilide in patients with left ventricular hypertrophy United States guidelines recommend avoiding pure class III antiarrhythmics such as dofetilide in patients with significant left ventricular hypertrophy (LVH) due to concerns for increased risk of death. However, in a propensity-matched cohort of 718 patients with AF and LVH, dofetilide was not associated with increased mortality at three years (the primary outcome). Patients ( 18 years of age with AF and LVH 1.4) were treated with dofetilide, and a control group of patients without a history of antiarrhythmic drug use were propensity matched. Total all- cause hospitalizations were higher in the control group, but hospitalizations for AF were no different. Given the current options available, these preliminary findings suggest that further studies of dofetilide in patients with LVH are reasonable for managing symptomatic AF [42]. SAFETY There is concern about the safety of dofetilide, which like other class III antiarrhythmic agents ( figure 1) is associated with a risk of torsades de pointes [43,44]. Torsades de pointes has been reported in up to 3 percent of patients receiving dofetilide [15,45]. In a pooled analysis from the dofetilide treated patients in the DIAMOND-HF and DIAMOND-MI trials (where the incidence of torsades de pointes was 2.1 percent), the risk of torsades de pointes was greater in women than in men (OR 2.2), and in patients with NYHA class III or IV heart failure (OR 3.2) [46]. Despite the increased risk of torsade de pointes, a pooled analysis of 1346 patients receiving dofetilide and 677 treated with placebo in randomized clinical trials did not show an increase in mortality with dofetilide use (adjusted hazard ratio 1.1) [47]. To evaluate the incidence and risk factors for in-hospital adverse events as well as the long-term safety of continued use of dofetilide, one study conducted a retrospective chart review of a cohort of 1404 patients initially receiving loading doses for AF suppression between 2008 and 2012 [48]. Of the 17 patients (1.2 percent) who developed torsades de pointes during loading, 10 had a cardiac arrest requiring resuscitation (with one death), five had syncope/presyncope, and two were asymptomatic. Dofetilide loading doses were stopped for 105 patients (7.5 percent) due to excessive QTc prolongation or torsades de pointes. Variables that correlated with torsades de pointes were female gender, 500 mcg dose, reduced ejection fraction, and increase in QTc from baseline. One-year all-cause mortality was higher in patients who continued https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 8/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate dofetilide compared with those who discontinued use (HR 2.48, 95% CI 1.08 to 5.71, p = 0.03). Those patients who experienced a torsades de pointes event had higher one-year all-cause mortality than those who did not (17.6 versus 3 percent at one year, p<0.001). Because excessive QT prolongation is assumed to be a critical component of torsades de pointes, orally administered magnesium citrate has been used to shorten dofetilide-induced QT prolongation [49]. Intravenous magnesium may also increase the chemical cardioversion rate and lower the incidence of torsades de pointes [50]. (See 'Oral dofetilide for atrial fibrillation/atrial flutter termination and prevention' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Electrophysiology Dofetilide is a class III antiarrhythmic agent ( table 1) that blocks the delayed rectifier cardiac potassium channel and increases the late sodium current, both actions that prolong repolarization. (See 'Electrophysiology' above.) Ventricular tachyarrhythmias For patients who are candidates for other antiarrhythmic drugs (ie, amiodarone, sotalol, etc), we do not suggest the routine use of dofetilide as a first-line antiarrhythmic drug for the treatment of ventricular tachyarrhythmias. This is based on the lack of prospective efficacy data showing improvement in outcomes over other medications when dofetilide is used for the treatment of ventricular tachyarrhythmias. (See 'Ventricular tachyarrhythmias' above.) Protocol for administration In an effort to optimize efficacy and safety, the initiation or reinitiation of dofetilide should occur in a controlled fashion according to the US Food and Drug Administration (FDA)-recommended dose protocol ( figure 1). Drug approval and restrictions The use of dofetilide is approved by FDA and several countries worldwide. Its use in the US is contingent upon the following restrictions (see 'Drug approval and restrictions' above): Patients must be hospitalized for a minimum of three days for dofetilide initiation to monitor creatinine clearance, QT interval, and cardiac rhythm ( figure 1). Most https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 9/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate episodes of torsades de pointes occur within this three day period, the time of peak increase in the QT interval, but rarely torsades de pointes can occur later. Hospitalization with monitoring is recommended when therapy has been interrupted and is to be reinitiated or when dose increase is considered necessary. Dofetilide is contraindicated in patients with congenital long QT syndrome, a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities), severe renal insufficiency (CCr <20 mL/min), known hypersensitivity, and in patients taking drugs known to slow its renal elimination (eg, cimetidine, verapamil, trimethoprim, alone or in combination with sulfamethoxazole, prochlorperazine, hydrochlorothiazide, alone or in combination with triamterene, megestrol, dolutegravir, and ketoconazole). Specific indications Dofetilide appears to be safe for use in patients with a history of heart failure or prior myocardial infarction. In patients with heart failure, however, there is a suggestion of increased mortality in patients with a baseline corrected QT (QTc) interval >479 milliseconds. (See 'Heart failure' above and 'Postmyocardial infarction' above.) Safety Like other class III antiarrhythmic agents, dofetilide is associated with dose- dependent prolongation of the QT interval and a risk of torsades de pointes, which has been reported in up to 3 percent of patients receiving dofetilide. This risk may be attenuated with concomitant magnesium therapy, careful attention to modifiable risk factors, and participation of clinical pharmacists to help manage the treatment initiation protocol required by the FDA. (See 'Safety' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Raymond Woosley, MD, PhD, who contributed to an earlier version of this topic review. 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Pacing Clin Electrophysiol 2017; 40:667. https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 12/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate 29. Qin D, Leef G, Alam MB, et al. Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation. J Cardiol 2016; 67:471. 30. Shantha G, Chugh A, Crawford T, et al. Comparative Efficacy of Dofetilide Versus Amiodarone in Patients With Atrial Fibrillation. JACC Clin Electrophysiol 2021; 7:642. 31. Sharma SP, Turagam M, Atkins D, et al. Safety of rapid switching from amiodarone to dofetilide in atrial fibrillation patients with an implantable cardioverter-defibrillator. Heart Rhythm 2019; 16:990. 32. Tendera M, Wnuk-Wojnar AM, Kulakowski P, et al. Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo. Am Heart J 2001; 142:93. 33. Andersen HR, Wiggers H, Knudsen LL, et al. Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs. Cardiovasc Res 1994; 28:1635. 34. Boriani G, Lubinski A, Capucci A, et al. A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease. Eur Heart J 2001; 22:2180. 35. Mazur A, Anderson ME, Bonney S, Roden DM. Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide: a placebo-controlled, implantable cardioverter-defibrillator-based evaluation. J Am Coll Cardiol 2001; 37:1100. 36. Baquero GA, Banchs JE, Depalma S, et al. Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies. J Cardiovasc Electrophysiol 2012; 23:296. 37. Wallace AA, Stupienski RF 3rd, Brookes LM, et al. Cardiac electrophysiologic and inotropic actions of new and potent methanesulfonanilide class III antiarrhythmic agents in anesthetized dogs. J Cardiovasc Pharmacol 1991; 18:687. 38. Rousseau MF, Massart PE, van Eyll C, et al. Cardiac and hemodynamic effects of intravenous dofetilide in patients with heart failure. Am J Cardiol 2001; 87:1250. 39. Koene RJ, Menon V, Cantillon DJ, et al. Clinical Outcomes and Characteristics With Dofetilide in Atrial Fibrillation Patients Considered for Implantable Cardioverter-Defibrillator. Circ Arrhythm Electrophysiol 2020; 13:e008168. 40. Brendorp B, Elming H, Jun L, et al. Qtc interval as a guide to select those patients with congestive heart failure and reduced left ventricular systolic function who will benefit from antiarrhythmic treatment with dofetilide. Circulation 2001; 103:1422. https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 13/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate 41. K ber L, Bloch Thomsen PE, M ller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet 2000; 356:2052. 42. Wann DG, Medoff BS, Mehdi NA, et al. Dofetilide use is not associated with increased mortality in patients with left ventricular hypertrophy and atrial fibrillation. J Cardiovasc Electrophysiol 2023; 34:447. 43. Naksuk N, Sugrue AM, Padmanabhan D, et al. Potentially modifiable factors of dofetilide- associated risk of torsades de pointes among hospitalized patients with atrial fibrillation. J Interv Card Electrophysiol 2019; 54:189. 44. Ko EYJ, Carpenter CM, Gagnon DJ, Andrle AM. Pharmacist-Managed Inpatient Dofetilide Initiation Program: Description and Adherence Rate Post-Root Cause Analysis. J Pharm Pract 2020; 33:784. 45. Ferguson JJ. Meeting highlights. Highlights of the 71st scientific sessions of the American Heart Association. Circulation 1999; 99:2486. 46. Pedersen HS, Elming H, Seibaek M, et al. Risk factors and predictors of Torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving Dofetilide. Am J Cardiol 2007; 100:876. 47. Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138:994. 48. Abraham JM, Saliba WI, Vekstein C, et al. Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. Circ Arrhythm Electrophysiol 2015; 8:772. 49. McBride BF, Min B, Kluger J, et al. An evaluation of the impact of oral magnesium lactate on the corrected QT interval of patients receiving sotalol or dofetilide to prevent atrial or ventricular tachyarrhythmia recurrence. Ann Noninvasive Electrocardiol 2006; 11:163. 50. Coleman CI, Sood N, Chawla D, et al. Intravenous magnesium sulfate enhances the ability of dofetilide to successfully cardiovert atrial fibrillation or flutter: results of the Dofetilide and Intravenous Magnesium Evaluation. Europace 2009; 11:892. Topic 1033 Version 28.0 https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 14/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 15/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications
23. Torp-Pedersen C, M ller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857. 24. Turagam MK, Afzal MR, Reddy M, et al. Practice variation in the re-initiation of dofetilide: An observational study. Int J Cardiol 2017; 236:221. 25. Cho JH, Youn SJ, Moore JC, et al. Safety of Oral Dofetilide Reloading for Treatment of Atrial Arrhythmias. Circ Arrhythm Electrophysiol 2017; 10. 26. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 27. Khurshid S, Akerman S, Man JP, et al. Acute conversion of persistent atrial fibrillation during dofetilide loading does not predict long-term atrial fibrillation-free survival. J Interv Card Electrophysiol 2015; 42:117. 28. Steinberg JS, Shah Y, Szepietowska B. Pharmacologic Conversion during Dofetilide Treatment for Persistent Atrial Fibrillation. Pacing Clin Electrophysiol 2017; 40:667. https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 12/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate 29. Qin D, Leef G, Alam MB, et al. Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation. J Cardiol 2016; 67:471. 30. Shantha G, Chugh A, Crawford T, et al. Comparative Efficacy of Dofetilide Versus Amiodarone in Patients With Atrial Fibrillation. JACC Clin Electrophysiol 2021; 7:642. 31. Sharma SP, Turagam M, Atkins D, et al. Safety of rapid switching from amiodarone to dofetilide in atrial fibrillation patients with an implantable cardioverter-defibrillator. Heart Rhythm 2019; 16:990. 32. Tendera M, Wnuk-Wojnar AM, Kulakowski P, et al. Efficacy and safety of dofetilide in the prevention of symptomatic episodes of paroxysmal supraventricular tachycardia: a 6-month double-blind comparison with propafenone and placebo. Am Heart J 2001; 142:93. 33. Andersen HR, Wiggers H, Knudsen LL, et al. Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs. Cardiovasc Res 1994; 28:1635. 34. Boriani G, Lubinski A, Capucci A, et al. A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease. Eur Heart J 2001; 22:2180. 35. Mazur A, Anderson ME, Bonney S, Roden DM. Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide: a placebo-controlled, implantable cardioverter-defibrillator-based evaluation. J Am Coll Cardiol 2001; 37:1100. 36. Baquero GA, Banchs JE, Depalma S, et al. Dofetilide reduces the frequency of ventricular arrhythmias and implantable cardioverter defibrillator therapies. J Cardiovasc Electrophysiol 2012; 23:296. 37. Wallace AA, Stupienski RF 3rd, Brookes LM, et al. Cardiac electrophysiologic and inotropic actions of new and potent methanesulfonanilide class III antiarrhythmic agents in anesthetized dogs. J Cardiovasc Pharmacol 1991; 18:687. 38. Rousseau MF, Massart PE, van Eyll C, et al. Cardiac and hemodynamic effects of intravenous dofetilide in patients with heart failure. Am J Cardiol 2001; 87:1250. 39. Koene RJ, Menon V, Cantillon DJ, et al. Clinical Outcomes and Characteristics With Dofetilide in Atrial Fibrillation Patients Considered for Implantable Cardioverter-Defibrillator. Circ Arrhythm Electrophysiol 2020; 13:e008168. 40. Brendorp B, Elming H, Jun L, et al. Qtc interval as a guide to select those patients with congestive heart failure and reduced left ventricular systolic function who will benefit from antiarrhythmic treatment with dofetilide. Circulation 2001; 103:1422. https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 13/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate 41. K ber L, Bloch Thomsen PE, M ller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet 2000; 356:2052. 42. Wann DG, Medoff BS, Mehdi NA, et al. Dofetilide use is not associated with increased mortality in patients with left ventricular hypertrophy and atrial fibrillation. J Cardiovasc Electrophysiol 2023; 34:447. 43. Naksuk N, Sugrue AM, Padmanabhan D, et al. Potentially modifiable factors of dofetilide- associated risk of torsades de pointes among hospitalized patients with atrial fibrillation. J Interv Card Electrophysiol 2019; 54:189. 44. Ko EYJ, Carpenter CM, Gagnon DJ, Andrle AM. Pharmacist-Managed Inpatient Dofetilide Initiation Program: Description and Adherence Rate Post-Root Cause Analysis. J Pharm Pract 2020; 33:784. 45. Ferguson JJ. Meeting highlights. Highlights of the 71st scientific sessions of the American Heart Association. Circulation 1999; 99:2486. 46. Pedersen HS, Elming H, Seibaek M, et al. Risk factors and predictors of Torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving Dofetilide. Am J Cardiol 2007; 100:876. 47. Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138:994. 48. Abraham JM, Saliba WI, Vekstein C, et al. Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. Circ Arrhythm Electrophysiol 2015; 8:772. 49. McBride BF, Min B, Kluger J, et al. An evaluation of the impact of oral magnesium lactate on the corrected QT interval of patients receiving sotalol or dofetilide to prevent atrial or ventricular tachyarrhythmia recurrence. Ann Noninvasive Electrocardiol 2006; 11:163. 50. Coleman CI, Sood N, Chawla D, et al. Intravenous magnesium sulfate enhances the ability of dofetilide to successfully cardiovert atrial fibrillation or flutter: results of the Dofetilide and Intravenous Magnesium Evaluation. Europace 2009; 11:892. Topic 1033 Version 28.0 https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 14/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 15/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 16/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Dofetilide dosing The QT prolonging effects and the risk of torsades de pointes can be increased by coadministration of dofetilide with verapamil, other drugs that also prolong the QT, or drugs that interfere with renal elimination of dofetilide (eg, cimetidine, verapamil, trimethoprim, alone or in combination with sulfamethoxazole, prochlorperazine, https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 17/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate hydrochlorothiazide, alone or in combination with triamterene, megestrol, and ketoconazole). Courtesy of Dr. Raymond L. Woosley. Graphic 64845 Version 2.0 https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 18/19 7/5/23, 8:20 AM Clinical use of dofetilide - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-use-of-dofetilide/print 19/19
7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical uses of dronedarone : Rod Passman, MD, MSCE, Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2023. INTRODUCTION Dronedarone, a noniodinated congener of amiodarone, was developed as an antiarrhythmic agent for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Because of the molecular and structural differences between dronedarone and amiodarone, in particular the deletion of the iodine molecules which are present in amiodarone, researchers have hypothesized that dronedarone will have fewer thyroid and pulmonary effects than amiodarone. Clinical trials have shown the clinical use and short-term safety (up to 21 months) of dronedarone for the maintenance of sinus rhythm following cardioversion in patients with AF [1]. The efficacy and tolerability of dronedarone in children and adolescents aged <18 years have not been established. A review of the pharmacology of dronedarone, its clinical uses, adverse effects, and drug interactions will be presented here. The clinical uses and toxicities of amiodarone and the choice of antiarrhythmic agents in the management of AF are discussed separately. (See "Amiodarone: Clinical uses".) (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 1/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate ELECTROPHYSIOLOGY AND MECHANISMS OF ACTION Dronedarone is a class III antiarrhythmic agent ( table 1) and a potent blocker of multiple intracardiac ion channels with many electrophysiological properties in common with amiodarone [2]. Like amiodarone, dronedarone has antiadrenergic (ie, beta blocking) properties and inhibits multiple transmembrane potassium currents, including the delayed rectifier current, the ultra-rapid delayed rectifier current, the inward rectifier current, and the transient outward current. In addition, dronedarone blocks inward depolarizing sodium and L-type calcium currents. PHARMACOLOGIC DATA/PHARMACOKINETICS Limited pharmacokinetic data are available for dronedarone and are derived primarily from data in the US Food and Drug Administration (FDA) prescribing information and from data in the FDA briefing document [3]. Dronedarone is approximately 70 to 94 percent absorbed after oral administration, but its absolute bioavailability is only approximately 15 percent due to significant first pass metabolism. Peak plasma concentrations are achieved within three to six hours. However, there is a significant food effect which increases plasma dronedarone concentrations between two- and threefold when the drug is taken with food [3]. Following the initiation of dronedarone 400 mg twice daily, steady-state plasma concentrations are reached within four to eight days [4]. The clearance of dronedarone is principally nonrenal, with a terminal half-life of approximately 24 hours [3]. This is markedly shorter than the half-life of amiodarone, which has an effective half-life of up to 50 days. Dronedarone is highly bound to plasma proteins and is not associated with significant tissue accumulation. Therefore, it has been postulated that systemic side effects secondary to long-term usage of the drug, such as liver toxicity, pulmonary fibrosis, or thyroid dysfunction will be minimized in comparison to amiodarone. However, long-term toxicity data are not yet available. Dronedarone has been shown to increase serum creatinine by 10 to 15 percent, a change which appears to resolve once the drug is discontinued [5]. A phase I trial of dronedarone (400 mg twice daily for seven days) in 12 healthy males reported a decrease in creatinine clearance of 18 percent (compared with placebo) without adverse effects on glomerular filtration rate or renal plasma flow [5]. Partial inhibition of tubular organic cation transporters has been suggested as a mechanism to explain the decrease in creatinine clearance. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 2/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial, with some suggestion that this cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms [6]. In a report of patient samples from the ATHENA trial, dronedarone exerted direct inhibitory effects on parameters of hemostasis and platelet reactivity at plasma concentrations typically achieved after routine clinical dosing [7]. These actions appear to be independent of the drug's antiarrhythmic properties and suggest a previously unknown pleiotropic effect. The active metabolite of dronedarone, SR35021A, demonstrates direct anticoagulant and antiplatelet effects in vitro at plasma concentrations typically achieved during conventional therapeutic dosing. These antithrombotic effects are likely to have contributed to the reported beneficial effects of dronedarone on ischemic events in patients with paroxysmal AF [6]. Further studies are needed to better understand the mechanisms involved and to gauge the magnitude of these pleiotropic effects of dronedarone in patients. METABOLISM AND DRUG INTERACTIONS Oral dronedarone 400 mg twice daily (taken with morning and evening meals) is approved for the maintenance of normal sinus rhythm in patients with a history of atrial fibrillation or atrial flutter. Dronedarone is metabolized by the CYP3A4 system in the liver and has many potential drug interactions Additional information can also be found using the Lexicomp drug interactions tool. As dronedarone primarily undergoes hepatic metabolism, its clearance may also be altered in patients with hepatic impairment. No dose adjustment is required in patients with renal insufficiency. The pharmacokinetics of dronedarone in patients with severe hepatic impairment have not been assessed; however, administration of dronedarone to patients with severe hepatic impairment is contraindicated [3]. Currently, there are no dose adjustment recommendations for patients with moderate hepatic impairment; however, data provided from the manufacturer indicate that patients with moderate hepatic impairment achieve higher dronedarone values with the potential to rise to supra-therapeutic concentrations [3]. (See "Drugs and the liver: Metabolism and mechanisms of injury".) Several drugs or classes of medications deserve special mention, as the risks associated with concomitant administration of dronedarone are potentially significant [3]: Ketoconazole and other potent CYP3A inhibitors Repeated doses of ketoconazole, a strong CYP3A4 inhibitor, result in a 17-fold increase in dronedarone exposure and a ninefold increase in the peak concentration (C ). Concomitant use of ketoconazole as max https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 3/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate well as other potent CYP3A inhibitors ( table 2) such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated. Dronedarone is also a CYP2D6 inhibitor and causes a modest increase in bioavailability of metoprolol in CYP2D6 extensive metabolizers [8]. (See "Drugs and the liver: Metabolism and mechanisms of injury".) QT prolonging medications Coadministration of drugs with the potential to prolong the QT interval (such as some phenothiazines, tricyclic antidepressants, some macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated due to the risk of inducing torsade de pointes-type ventricular tachycardia. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia'.) Digoxin Concomitant administration of dronedarone and digoxin results in higher serum digoxin levels, likely due to a P-glycoprotein-mediated interaction in the kidney, and may be associated with a greater risk of death [4,9]. Studies have shown that when compared with placebo, concurrent digoxin and dronedarone administration was associated with an approximately 40 percent increase in digoxin levels [9,10]. Additionally, among 1070 patients from the PALLAS trial who were taking digoxin and randomized to dronedarone (544 patients) or placebo (526 patients), there were 15 cardiovascular deaths in patients receiving dronedarone (compared with two deaths in patients receiving placebo; adjusted hazard ratio [HR] 7.3, 95% CI 1.7-32.2) [9]. (See "Digitalis (cardiac glycoside) poisoning".) When dronedarone and digoxin are co-administered, a 50 percent digoxin dose reduction is recommended because of increased digoxin exposure [11-13]. Digoxin levels should be monitored closely to maintain serum concentrations of 0.5 to 0.8 ng/mL, with additional digoxin dose reductions as needed. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".) Oral anticoagulants Dronedarone increases serum warfarin exposure by 1.2-fold and does not cause clinically significant prolongation of INR values. Clinical trials have not identified a clinically significant interaction between dronedarone and warfarin [14,15]. A small, single-center crossover trial evaluating the competitive thrombin inhibitor dabigatran in 16 healthy volunteers demonstrated that dabigatran levels were increased when it was administered with dronedarone (1.7- to 2.0-fold greater than dabigatran alone) [16]. The increase was within the range seen with other dabigatran-drug combinations, and no dose adjustment has been recommended. Rivaroxaban levels can also increase when given concurrently with dronedarone, particularly in patients with decreased renal function [3]. The same is true for apixaban, and while no specific dose adjustments are required, patients should be routinely evaluated for signs and symptoms of blood loss. A study from a United States Claims Database showed a modest increased risk of gastrointestinal https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 4/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate bleeding when dronedarone was used with dabigatran (HR 1.40; 95% CI 1.01-1.93) or rivaroxaban (HR 1.31; 95% CI 1.01-1.69) [17]. There was no increased risk of intracranial hemorrhage associated with combined use of dronedarone and any nonvitamin K oral anticoagulant. Metoprolol Dronedarone increases the bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect [8]. These effects are modest when taking dronedarone 400 mg twice daily, and no dose adjustment is necessary. Neither higher doses of dronedarone nor metoprolol combinations have been evaluated; however, the potential for more marked effects on left ventricular function could be expected with higher doses [8]. In addition, while other beta blockers have not been reported, it is likely that a similar negative inotropic effect could result. Statins Dronedarone increases simvastatin, rosuvastatin, and atorvastatin exposure by 1.4- to 4-fold, which increases the potential for statin-induced myopathy [3]. (See "Statin muscle-related adverse events".) Grapefruit juice Grapefruit juice is a moderate inhibitor of CYP3A and results in a threefold increase in dronedarone exposure and a 2.5 increase in C . Therefore, patients max should avoid beverages containing grapefruit juice when using dronedarone [3]. Calcium channel blockers Verapamil, diltiazem, and nifedipine are moderate CYP3A inhibitors and increase dronedarone exposure by approximately 1.4 to 1.7-fold [3]. DRUG APPROVAL AND RESTRICTIONS Dronedarone is approved for maintenance of sinus rhythm in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation. Dronedarone is contraindicated in patients with permanent atrial fibrillation who will not or cannot be cardioverted to normal sinus rhythm. The use of dronedarone in these patients has resulted in increases in death, stroke, and heart failure hospitalizations when compared with placebo [18]. Other contraindications to dronedarone include: Concomitant use of strong CYP3A inhibitors. NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization. Severe hepatic disease. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 5/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate History of amiodarone-induced lung toxicity. Bradycardia <50 beats per minute, advanced AV block (second or third degree), or sick sinus syndrome, except when used in conjunction with a pacemaker. Use caution when administering dronedarone to Asian patients. Pharmacokinetic studies show Asian males (Japanese) have an approximate twofold higher dronedarone exposure than White males. DOSING AND MONITORING The adult and geriatric dose of dronedarone is 400 mg PO twice daily. Safety and efficacy in adolescents, children, and infants have not been established. Dose adjustments are not needed in mild to moderate liver impairment. Dronedarone use is contraindicated in severe liver impairment. Discontinue Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong CYP3A4 inhibitors (eg, ketoconazole) prior to initiating dronedarone therapy. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' below.) INDICATIONS/CLINICAL USES Overview Dronedarone is primarily used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter ( algorithm 1) and no evidence of moderate to severe heart failure due to left ventricular systolic function [19]. Although spontaneous cardioversion occasionally occurs following the initiation of dronedarone, its efficacy is low for chemical cardioversion, and other drugs should be used. Dronedarone should not be used exclusively as a rate control medication given the greater likelihood of adverse cardiovascular events (based on the PALLAS trial preliminary results) and the availability of other agents for this purpose [19]. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 6/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Dronedarone has been reported to significantly increase mortality in patients with recently decompensated NYHA class III and IV heart failure and, as such, is contraindicated in this population. Little evidence has been published indicating that dronedarone has any efficacy in the treatment of ventricular arrhythmias. Because of this, there is no role for dronedarone in the treatment of ventricular tachyarrhythmias. Maintenance of sinus rhythm For the maintenance of sinus rhythm in patients with AF, dronedarone has been consistently shown to be more effective than placebo. In the ADONIS, EURIDIS, and DAFNE trials, patients treated with dronedarone compared with placebo had significantly longer times to first recurrence of AF and significantly greater chances of remaining in sinus rhythm at 6 and 12 months [1,20]. As an example, the following significant benefits from dronedarone therapy were noted in the ADONIS and EURIDIS trials [1,21]: A longer time to first recurrence of AF compared with placebo (96 versus 41 days in EURIDIS, 158 versus 59 days in ADONIS, and 116 versus 53 days on pooled analysis). A significantly higher percentage of patients remaining in sinus rhythm at 12 months (36 versus 25 percent receiving placebo). A significantly reduced risk of recurrent AF in patients who had previously failed another antiarrhythmic drug, with the greatest reduction among patients who failed therapy with a class Ic agent ( table 1) [21]. Compared with placebo, post-ablation patients treated with dronedarone in the ATHENA study had a reduced risk of recurrent AF (57 versus 71 percent) and a prolonged median time to first AF/AFL recurrence (561 days versus 180 days). There was no difference in the risk of first CV hospitalization/all-cause mortality [22]. At 12 months post-ablation, patients treated with dronedarone compared with sotalol had lower risks of hospitalization (HR 0.70; 95% CI 0.66-0.93) and proarrhythmia (HR 0.83; 95% CI 0.73-0.94) [23]. These findings were predominantly attributable to lower rates of atrial- tachyarrhythmia-related hospitalizations and lower rates of bradycardic proarrhythmia and need for pacemaker implantation. One trial directly compared dronedarone with amiodarone, which has long been considered to be the most effective antiarrhythmic drug for the maintenance of sinus rhythm following cardioversion for AF or atrial flutter. The DIONYSOS trial was a double-blind trial of 504 patients with AF that randomly assigned patients to dronedarone or amiodarone [24]. Patients were followed for at least six months, with a primary composite endpoint of recurrence of AF https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 7/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate (including unsuccessful electrical cardioversion, no spontaneous conversion, and no electrical cardioversion) or premature study drug discontinuation for intolerance or lack of efficacy. After 12 months of treatment, the primary composite endpoint was significantly more likely to have occurred in patients receiving dronedarone (75 versus and 59 percent in the amiodarone group, respectively; hazard ratio [HR] 1.59; 95% CI 1.28-1.98). This result was mainly driven by a more frequent recurrence of AF in the dronedarone group (64 versus 42 percent with amiodarone). However, there was a trend toward less frequent study drug discontinuation for intolerance in the dronedarone group (10 versus 12 percent in the amiodarone group). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Based upon the DIONYSOS study, dronedarone is less effective than amiodarone for the maintenance of sinus rhythm in patients with AF. While short-term toxicities appear to be less common among patients taking dronedarone, there are limited data regarding long-term toxicities. Our recommendations regarding the role of dronedarone in the maintenance of sinus rhythm are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) Chemical cardioversion of AF Dronedarone is only rarely effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients) [20]. As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Ventricular rate control in AF Dronedarone slows the resting ventricular heart rate by approximately 10 to 15 beats per minute in patients who develop recurrent AF and has been shown to reduce the maximum heart rate with exercise by up to 25 beats per minute [1,10,25]. However, dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. (See 'Effect on cardiovascular mortality' below and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Changing to another antiarrhythmic drug In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 8/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, clinical trial data describe three approaches: In the ADONIS and EURIDIS trials, dronedarone was initiated immediately upon discontinuation of amiodarone [1]. In the ERATO trial, patients underwent a two-month washout from amiodarone prior to initiation of dronedarone [10]. In the ATHENA trial, patients discontinued amiodarone one month prior to initiating dronedarone [6]. In general, dronedarone can be started promptly after amiodarone discontinuation, except in cases of clinically significant bradycardia or QT prolongation. SAFETY CONCERNS Effect on cardiovascular mortality There has never been any clear evidence of an overall mortality benefit with class I or class III antiarrhythmic medications ( table 1), including dronedarone, when used for the maintenance of sinus rhythm. Early post-hoc analyses of dronedarone trials suggested that patients receiving dronedarone may have reduced cardiovascular mortality and stroke risk. However, a preliminary analysis of the PALLAS trial showed increased mortality when dronedarone was used solely as a rate controlling agent in patients with chronic AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) A post-hoc analysis of the EURIDIS and ADONIS trials described above reported reduced rates of hospitalization or death in patients taking dronedarone [1]. In the ATHENA trial, the largest trial of dronedarone to evaluate cardiovascular hospitalization and mortality, 4628 patients with AF who were thought to be at high risk of cardiovascular events were randomly assigned to receive dronedarone or placebo; patients with NYHA class IV heart failure were excluded [6]. When compared with placebo, dronedarone was associated with a significant reduction in cardiovascular mortality (2.7 versus 3.9 percent, HR 0.71, 95% CI 0.51-0.98) that was mostly due to a reduction in arrhythmic mortality. Additionally, a post-hoc analysis of 1405 patients (followed for 2.5 years) from the ATHENA trial with paroxysmal or persistent AF and established coronary heart disease (CHD) demonstrated significantly lower rates of death or cardiovascular https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 9/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate hospitalization in those taking dronedarone (38 percent versus 47 percent with placebo; HR 0.73; 95% CI 0.62-0.86) [26]. Based upon the results of the ATHENA trial, the PALLAS trial was designed to test the hypothesis that dronedarone would improve major cardiovascular outcomes in patients with permanent rather than paroxysmal AF. Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled) after a significantly increased risk (HR 2.29, 95% CI 1.34-3.94) of cardiovascular events (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [27]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. While patients enrolled in the PALLAS trial were older, had a higher prevalence of baseline comorbidities including heart failure compared with those enrolled in ATHENA, and were in chronic AF with no plans for rhythm control, we are concerned about these findings which further underscore the potential toxicities of AADs. When used in routine clinical practice according to the appropriate guidelines and restrictions, dronedarone appears to be as safe as, or safer than, other antiarrhythmic drugs. In an analysis of nearly 175,000 Swedish patients with a diagnosis of AF between 2010 and 2012 (4856 received dronedarone, while 170,139 who did not served as the control population, mean follow-up 1.6 years) that used multivariable adjustment and propensity score matching to address baseline differences in the populations, patients who received dronedarone had significantly lower mortality compared with controls who did not receive dronedarone (1.31 versus 2.73 percent following adjustment and propensity score matching; HR 0.41; 95% CI 0.33-0.51) [28]. Patients receiving dronedarone also had lower mortality when compared with the general population. Our recommendations regarding the use of dronedarone for the maintenance of the sinus rhythm are discussed in detail separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone' and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Long-term follow-up'.) Patients with moderate to severe heart failure Because of the increase in mortality in patients with moderate to severe heart failure, dronedarone should NOT be used for the treatment of AF in such patients. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 10/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate The ANDROMEDA trial was a randomized, double-blind trial comparing dronedarone with placebo in 627 patients with a history of AF or atrial flutter hospitalized with symptomatic heart failure (NYHA III and IV) and a left ventricular ejection fraction 35 percent [29]. The primary endpoint was death from any cause or hospitalization for worsening heart failure. The trial was stopped prematurely because of significantly increased mortality in the dronedarone arm (8 versus 4 percent in the placebo arm, HR 2.13, 95% CI 1.07-4.25). The excess mortality in the dronedarone arm was primarily due to heart failure, with the risk being highest in those with the most severely reduced left ventricular systolic function. There were no significant differences with respect to arrhythmic or sudden death and other nonfatal adverse events (except for higher serum creatinine levels in the dronedarone arm). In a 2012 meta-analysis of seven randomized controlled trials (10,676 patients) involving dronedarone (six trials used placebo, and one trial used amiodarone as the comparator), dronedarone use was associated with a non-significant trend toward higher cardiovascular and 2 all-cause mortality but with significant heterogeneity in the outcomes (I of 75 and 53 percent respectively), with ATHENA identified as the source of the heterogeneity [30]. When the data 2 were reanalyzed following exclusion of the ATHENA data, the outcomes were homogeneous (I of 0), with the risk of both cardiovascular (relative risk [RR] 2.33, 95% CI 1.49-3.64) and all-cause (RR 1.75, 95% CI 1.15-2.66) mortality significantly increased in users of dronedarone. In the above-mentioned analysis of nearly 175,000 Swedish patients, dronedarone patients with a diagnosis of heart failure were reported to have lower mortality compared with other heart failure patients (HR 0.40; 95% CI 0.30-0.53) and compared with the general population [28]. While these data do not supplant the results of the prior randomized trials and meta-analysis, they are reassuring that dronedarone, when used according to prescribing guidelines and restrictions, appears to be as safe as, or safer than, other antiarrhythmic drugs. In contrast to those with moderate to severe congestive heart failure due to left ventricular dysfunction, a post-hoc analysis of 221 patients in the ATHENA trial found that dronedarone was associated with a reduction in the risk of death or cardiovascular hospitalization (HR 0.76; 95% CI, 0.69-0.84); results were similar in subgroups of patients with persistent atrial fibrillation or atrial flutter, heart failure with preserved ejection fraction, and heart failure with mildly reduced ejection fraction [31]. Ventricular arrhythmia/ICDs Other than a case report describing complete suppression of ventricular tachycardia that was resistant to multiple antiarrhythmic drugs and endocardial ablation, there are no clinical data evaluating the use of dronedarone for the treatment of ventricular tachyarrhythmias or for the prevention of appropriate ICD shocks for ventricular tachycardia or ventricular fibrillation [32]. Pending further evidence of benefit, dronedarone https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 11/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate should not be prescribed for the treatment of ventricular arrhythmias. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Antiarrhythmic drugs'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Background Dronedarone is a class III antiarrhythmic agent that may be considered for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Dronedarone has many electrophysiological properties in common with amiodarone, including its antiadrenergic (ie, beta blocking) properties and the ability to inhibit multiple transmembrane potassium, sodium, and calcium currents. (See 'Electrophysiology and mechanisms of action' above and "Amiodarone: Clinical uses".) Metabolism and drug interactions Because of its hepatic metabolism, there are numerous potential drug interactions with dronedarone. Concomitant use of dronedarone with some medications (eg, ketoconazole, class I antiarrhythmic drugs) is contraindicated, while its use with other medications (eg, digoxin, warfarin, statins) may require dose adjustment. (See 'Metabolism and drug interactions' above.) Maintenance of sinus rhythm Dronedarone (400 mg twice daily) is used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter and no evidence of heart failure or left ventricular systolic dysfunction who have spontaneously reverted to sinus rhythm or in whom cardioversion is planned. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' above.) Not as a rate control medication Dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. Dronedarone is only rarely https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 12/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients). As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See 'Ventricular rate control in AF' above and 'Effect on cardiovascular mortality' above and 'Chemical cardioversion of AF' above.) Changing to another medication In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, dronedarone can usually be started immediately after amiodarone discontinuation unless there is clinically significant bradycardia or QT prolongation. (See 'Changing to another antiarrhythmic drug' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 2. Varr A, Tak cs J, N meth M, et al. Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol 2001; 133:625. 3. MULTAQ Dronedarone tablets prescribing information products.sanofi.us/Multaq/Multaq.p df (Accessed on June 16, 2011). 4. Hoy SM, Keam SJ. Dronedarone. Drugs 2009; 69:1647. 5. Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol 2007; 64:785. 6. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 7. Zafar MU, Santos-Gallego CG, Smith DA, et al. Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions. Atherosclerosis 2017; https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 13/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate 266:81. 8. Damy T, Pousset F, Caplain H, et al. Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin Pharmacol 2004; 18:113. 9. Hohnloser SH, Halperin JL, Camm AJ, et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol 2014; 7:1019. 10. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J 2008; 156:527.e1. 11. Vallakati A, Chandra PA, Pednekar M, et al. Dronedarone-induced digoxin toxicity: new drug, new interactions. Am J Ther 2013; 20:e717. 12. Dorian P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 2010; 15:15S. 13. Dronedarone tablets. European Medicines Agency (EMA) Summary of product characteristic s. Last updated October 29, 2014. European Medicines Agency. www.ema.europa.eu/ema/in dex.jsp. 14. Shirolkar SC, Fiuzat M, Becker RC. Dronedarone and vitamin K antagonists: a review of drug- drug interactions. Am Heart J 2010; 160:577. 15. Patel C, Yan GX, Kowey PR. Dronedarone. Circulation 2009; 120:636. 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 17. Gandhi SK, Reiffel JA, Boiron R, Wieloch M. Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database). Am J Cardiol 2021; 159:79. 18. Multaq [package insert]. Bridgewater, NJ: Sanofi-aventis; 2014. 19. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 20. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 21. Guerra F, Hohnloser SH, Kowey PR, et al. Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents. Clin Cardiol 2014; 37:717. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 14/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate 22. Vamos M, Calkins H, Kowey PR, et al. Efficacy and safety of dronedarone in patients with a prior ablation for atrial fibrillation/flutter: Insights from the ATHENA study. Clin Cardiol 2020; 43:291. 23. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 24. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 25. Page RL, Connolly SJ, Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol 2011; 107:1019. 26. Pisters R, Hohnloser SH, Connolly SJ, et al. Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial. Europace 2014; 16:174. 27. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 28. Friberg L. Safety of dronedarone in routine clinical care. J Am Coll Cardiol 2014; 63:2376. 29. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 30. Chatterjee S, Ghosh J, Lichstein E, et al. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. Am J Cardiol 2012; 110:607.
Maintenance of sinus rhythm Dronedarone (400 mg twice daily) is used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter and no evidence of heart failure or left ventricular systolic dysfunction who have spontaneously reverted to sinus rhythm or in whom cardioversion is planned. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' above.) Not as a rate control medication Dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. Dronedarone is only rarely https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 12/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients). As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See 'Ventricular rate control in AF' above and 'Effect on cardiovascular mortality' above and 'Chemical cardioversion of AF' above.) Changing to another medication In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, dronedarone can usually be started immediately after amiodarone discontinuation unless there is clinically significant bradycardia or QT prolongation. (See 'Changing to another antiarrhythmic drug' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 2. Varr A, Tak cs J, N meth M, et al. Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol 2001; 133:625. 3. MULTAQ Dronedarone tablets prescribing information products.sanofi.us/Multaq/Multaq.p df (Accessed on June 16, 2011). 4. Hoy SM, Keam SJ. Dronedarone. Drugs 2009; 69:1647. 5. Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol 2007; 64:785. 6. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 7. Zafar MU, Santos-Gallego CG, Smith DA, et al. Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions. Atherosclerosis 2017; https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 13/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate 266:81. 8. Damy T, Pousset F, Caplain H, et al. Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin Pharmacol 2004; 18:113. 9. Hohnloser SH, Halperin JL, Camm AJ, et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol 2014; 7:1019. 10. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J 2008; 156:527.e1. 11. Vallakati A, Chandra PA, Pednekar M, et al. Dronedarone-induced digoxin toxicity: new drug, new interactions. Am J Ther 2013; 20:e717. 12. Dorian P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 2010; 15:15S. 13. Dronedarone tablets. European Medicines Agency (EMA) Summary of product characteristic s. Last updated October 29, 2014. European Medicines Agency. www.ema.europa.eu/ema/in dex.jsp. 14. Shirolkar SC, Fiuzat M, Becker RC. Dronedarone and vitamin K antagonists: a review of drug- drug interactions. Am Heart J 2010; 160:577. 15. Patel C, Yan GX, Kowey PR. Dronedarone. Circulation 2009; 120:636. 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 17. Gandhi SK, Reiffel JA, Boiron R, Wieloch M. Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database). Am J Cardiol 2021; 159:79. 18. Multaq [package insert]. Bridgewater, NJ: Sanofi-aventis; 2014. 19. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 20. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 21. Guerra F, Hohnloser SH, Kowey PR, et al. Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents. Clin Cardiol 2014; 37:717. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 14/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate 22. Vamos M, Calkins H, Kowey PR, et al. Efficacy and safety of dronedarone in patients with a prior ablation for atrial fibrillation/flutter: Insights from the ATHENA study. Clin Cardiol 2020; 43:291. 23. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 24. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 25. Page RL, Connolly SJ, Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol 2011; 107:1019. 26. Pisters R, Hohnloser SH, Connolly SJ, et al. Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial. Europace 2014; 16:174. 27. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 28. Friberg L. Safety of dronedarone in routine clinical care. J Am Coll Cardiol 2014; 63:2376. 29. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 30. Chatterjee S, Ghosh J, Lichstein E, et al. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. Am J Cardiol 2012; 110:607. 31. Vaduganathan M, Piccini JP, Camm AJ, et al. Dronedarone for the treatment of atrial fibrillation with concomitant heart failure with preserved and mildly reduced ejection fraction: a post-hoc analysis of the ATHENA trial. Eur J Heart Fail 2022; 24:1094. 32. Shaaraoui M, Freudenberger R, Levin V, Marchlinski FE. Suppression of ventricular tachycardia with dronedarone: a case report. J Cardiovasc Electrophysiol 2011; 22:201. Topic 16216 Version 31.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 15/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 16/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 17/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- containing coformulations Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, and norethindrone therapy pack Darunavir Phenobarbital Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- Mifepristone* Pexidartinib palonosetron Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- ritonavir plus dasabuvir Netupitant Nilotinib Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 18/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified [1,2] Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 19/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 20/21 7/5/23, 8:22 AM Clinical uses of dronedarone - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 21/21
7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical uses of sotalol : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA, Rod Passman, MD, MSCE : Mark S Link, MD, Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 14, 2023. INTRODUCTION Sotalol, a methanesulfonanilide, is a class III antiarrhythmic drug ( table 1) that is used for the treatment of both atrial and ventricular arrhythmias. Sotalol was originally approved by the FDA (tradename Betapace) for the treatment of life-threatening ventricular arrhythmias. The present commercial product (tradename Betapace AF) is intended for use in atrial fibrillation (AF), with the caveat that sotalol is not effective for conversion of AF to sinus rhythm, but it may be used to prevent AF. Although both commercial presentations contain sotalol, Betapace should not be substituted for Betapace AF because of significant differences in the labeling sections on indications, dosing, administration, and safety profile. Additionally, an injectable form of sotalol was approved by the FDA in July 2009. The package inserts for Betapace and Betapace AF contain black box warnings regarding potential for QT prolongation and ventricular arrhythmias [1]. (See 'Cardiac toxicity' below.) This topic will review the electrophysiology and mechanisms of action of sotalol, and will discuss dosing, the different settings in which sotalol has been used as an antiarrhythmic drug, and major side effects. Recommendations for the role of sotalol in the treatment of atrial and ventricular arrhythmias are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Choice of pharmacologic therapy'.) ELECTROPHYSIOLOGY AND MECHANISM OF ACTION https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 1/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Sotalol consists of a racemic mixture of d and l isomers in an approximate ratio of 1:1; this mixture is often called dl-sotalol. D- and l-stereoisomers of sotalol have been studied individually, but only dl-sotalol is commercially available. The two isomers contribute to the unique antiarrhythmic properties of sotalol [2-5]: The d isomer prolongs repolarization by blocking IKr ( figure 1), the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization of the action potential ( figure 2) [6,7]. This represents a class III effect. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) The l isomer has two actions: it prolongs repolarization and it has beta blocking activity. The beta blocker effect is dose-dependent, is not cardioselective, and is not associated with membrane stabilizing activity or intrinsic sympathomimetic activity. Class III activity The antiarrhythmic activity of sotalol is primarily mediated by its class III property ( table 1), which results in prolongation of the monophasic action potential duration as well as lengthening of the effective refractory period (ERP) in the atria, atrioventricular (AV) node (as reflected by the AH interval), ventricles, and antegrade and retrograde bypass tracts (when present) [4,8-10]. The class III effect results from blockade of the rapid component of the delayed rectifier potassium current (IKr) that is responsible for phase 3 repolarization of the action potential ( figure 2) [6,7].The prolongation of cardiac action potential duration does not appear to be related to concurrent beta blockade, since d-sotalol, which has little beta blocking activity, produces a similar delay in repolarization as l-sotalol [2]. The effect of sotalol on the action potential duration shows reverse use dependence, which is seen with other class III antiarrhythmic drugs except for amiodarone. Reverse use dependence is defined as an inverse correlation between the heart rate and the QT interval [11]. As a result, the QT interval is prolonged as the heart rate slows, which could explain the association between bradycardia and antiarrhythmic drug-induced torsades de pointes and the possible decrease in drug efficacy at higher heart rates. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology' and 'Proarrhythmia' below.) The clinical manifestations of sotalol-induced beta blockade include an increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness (prolonged PR interval) [4]. Effects on the ECG The combined actions of sotalol produce a variety of changes in the electrocardiogram (ECG) [4,12,13]: https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 2/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Because of its beta blocking activity, sotalol slows the sinus rate by approximately 25 percent and slightly prolongs the PR interval. The QRS duration is not altered, since ventricular conduction at normal sinus rates is unchanged [12,13]. This is thought to reflect a lack of effect of sotalol on the His-Purkinje (HV) interval [4,9,14]. The QT interval is prolonged in a dose-dependent fashion [15]. Since the QRS duration is not prolonged, the increase in QT interval results solely from delayed repolarization (ie, the JT interval) [12,13]. In a review of 114 patients given chronic oral sotalol therapy, the average increase in QT interval was 80 and 91 msec with 320 and 640 mg/day [12]. However, the increase in QTc, which is corrected for heart rate, was less prominent (21 and 30 msec, respectively). (See "Congenital long QT syndrome: Diagnosis", section on 'QT rate correction'.) PHARMACOKINETICS Sotalol is, essentially, completely absorbed and not metabolized. Consequently, bioavailability is close to 100 percent. Age and food have slight but unimportant effects on bioavailability. The maximum concentration of sotalol is achieved within 2 to 3 hours with a half-life between 7 and 15 hours. Excretion of sotalol is primarily through the kidneys, with no metabolism by liver and no first-pass effect. Therefore, sotalol plasma levels and half-life are directly related to creatinine clearance and glomerular filtration rate. Appropriate dose adjustments must be made for patients with impaired renal function or increased renal blood flow, as in pregnancy. The beta- adrenoceptor antagonistic effects of sotalol are directly related to plasma levels, which, in turn, are directly related to dose. However, the beta-adrenoceptor antagonism half-life is longer than the sotalol plasma half-life [16]. DOSING The dose of sotalol should be individualized on the basis of therapeutic response and tolerance. Because of its beta blocking activity, sotalol should not be used in patients with uncontrolled asthma, sinus bradycardia, Mobitz II second degree AV block or third degree AV block (unless the patient is treated with a pacemaker), cardiogenic shock, or uncontrolled heart failure [5]. In addition, because sotalol prolongs the QT interval, it should not be used in patients with congenital or acquired long QT syndrome, and should be used with caution in patients taking other medications known to prolong the QT interval ( table 2). (See 'Proarrhythmia' below.) https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 3/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Initiation of therapy Bradycardic and proarrhythmic events can occur after the initiation of sotalol therapy and with each upward dosing adjustment [17,18]. As a result, sotalol should be initiated in a hospital with facilities for cardiac rhythm monitoring and assessment. The package insert for sotalol contains a black box warning regarding initiation of the drug in a center with QT monitoring and cardiac resuscitation capabilities. However, some providers have initiated sotalol (or uptitrated doses) in an off-label manner in the outpatient setting in patients felt to be at low risk of QT prolongation or polymorphic VT. Before beginning sotalol, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of two to three half-lives, if clinically possible. (See 'Proarrhythmia' below.) The recommended initial dose of oral sotalol in adults is 80 mg twice daily whether used for the treatment of ventricular arrhythmias or atrial fibrillation. If necessary, the initial dose can be increased gradually to a maximum daily of 240 mg or 320 mg. Dose adjustments should be made at three day intervals so that steady-state plasma concentrations can be attained and the QT interval monitored. In a retrospective analysis, this standard approach was compared with initiating sotalol at 120 to 160 mg orally twice per day [19]. The accelerated dosing regimen neither shortened hospitalization nor had any effect on treatment efficacy. Due to the marginally increased risk of cardiac and non-cardiac side effects with an accelerated regimen, we favor the traditional starting dose of 80 mg twice daily. As of March 2020, intravenous sotalol has an updated FDA-approved dosing regimen for in- hospital initiation and reinitiation of patients on sotalol therapy. The key change is that with the use of intravenous sotalol, patients can now be initiated (titrated to steady-state blood levels) on sotalol therapy in the hospital in one day (versus three days). In addition, with intravenous sotalol (unlike with oral sotalol), patients can be initiated at either 80 or 120 mg. In other words, with intravenous sotalol, patients may be initiated at 120 mg without titrating up from 80 mg. Dose adjustment with chronic kidney disease Oral sotalol is primarily excreted unchanged in the urine, since it is not appreciably metabolized in the liver [3]. As a result, the elimination half-life is prolonged in patients with renal insufficiency. When sotalol is given for the treatment of ventricular arrhythmias, the dosing interval should be modified based upon the reduction in creatinine clearance: >60 mL/min 12 hours 30 to 60 mL/min 24 hours 10 to 29 mL/min 36 to 48 hours <10 mL/min should be individualized https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 4/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Patients with severe renal disease are at risk for potentially life-threatening ventricular arrhythmia even if low doses are used [20,21]. When used for the treatment of atrial fibrillation, sotalol is considered contraindicated when the creatinine clearance is less than 40 mL/min. Intravenous sotalol Intravenous sotalol has primarily been used to terminate supraventricular tachyarrhythmias [22-24]. It has also been used to terminate spontaneous sustained ventricular tachycardia (VT) and to suppress inducible ventricular tachyarrhythmia during electrophysiology study [25,26]. Several reports have described the value and limitations of intravenous sotalol to convert arial fibrillation to sinus rhythm. A review concerning the effectiveness of antiarrhythmic drugs administered intravenously indicates that sotalol has a modest success on cardioversion of AF to sinus rhythm approximating 30 percent; it is less effective than class I agents or ibutilide [27]. In particular, high-dose ibutilide showed a greater conversion rate than intravenous sotalol [23]. A meta-analysis concluded that intravenous and oral sotalol for conversion of AF of varied duration are as effective as class IA or class IC agents, and as effective as amiodarone for pharmacological conversion of AF [28]. Another report found sotalol less efficient than flecainide, propafenone, or ibutilide and likely as effective as intravenous amiodarone [29]. A prospective study from Australia compared intravenous administration of digoxin, amiodarone, and sotalol [30]. The results at 24 hours revealed conversion to sinus rhythm was 50 percent for digoxin, 69 percent for amiodarone, and 80 percent for sotalol. In addition, the conversion at 48 hours was 58 percent for digoxin, 77 percent for amiodarone, and 88 percent for sotalol. Monitoring After the sotalol loading dose is complete, generally the patient is asked to return for an electrocardiogram (ECG) within one and two weeks, looking for QT interval prolongation and bradyarrhythmia. Patients should typically have an ECG performed every six months while taking sotalol, and whenever any additional QT prolonging medications are newly prescribed. Routine laboratory studies are not needed to monitor sotalol levels or for potential toxicities. CLINICAL INDICATIONS https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 5/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Oral sotalol is used for the treatment of documented ventricular arrhythmias (ie, sustained ventricular tachycardia [VT]) that, in the judgment of the clinician are life-threatening, and for the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation (AF) and atrial flutter who are currently in sinus rhythm. What follows is a brief review of the major settings in which sotalol is given with links to the topic reviews in which the role of sotalol therapy is discussed in detail. Ventricular arrhythmias Sotalol is used to prevent recurrence of sustained VT or ventricular fibrillation (VF) [12,31- 33]. The main setting in which sotalol is used for VT/VF is as adjunctive therapy to an ICD to reduce the frequency of appropriate shocks or of inappropriate shocks due to supraventricular arrhythmias. However, sotalol may be used as primary therapy in patients who do not want or are not candidates for an ICD (eg, due to marked comorbidities or end- stage heart failure that make death likely). Although sotalol reduces both recurrent arrhythmia and the frequency of ICD shocks [34], sotalol is typically second-line therapy to empiric amiodarone. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Antiarrhythmic drugs' and "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Choice of pharmacologic therapy'.) Sotalol is effective in patients with arrhythmogenic right ventricular cardiomyopathy who have either inducible or noninducible non-life-threatening VT; in contrast, other antiarrhythmic drugs have little efficacy [35]. Thus, initial therapy with sotalol is a reasonable option for many such patients. For those that do not respond to sotalol, response to other drugs is unlikely, and consideration should be given to nonpharmacologic therapy such as radiofrequency catheter ablation. (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis", section on 'Antiarrhythmic drugs'.) A preparation containing only the d isomer has been developed as a "pure" class III drug [36,37]. However, in the Survival with Oral D-sotalol (SWORD) trial of patients with a reduced left ventricular ejection fraction and either a recent myocardial infarction (MI) or symptomatic heart failure and a remote MI, d-sotalol therapy, compared with placebo, was associated with a significant increase in mortality that was largely due to an increase in presumed arrhythmic deaths [37]. This observation suggests an important contribution from the beta blocking activity that is seen with dl-sotalol. Atrial arrhythmias Both the class III and beta blocking activity of dl-sotalol contribute to its use in the treatment of atrial arrhythmias, mostly atrial fibrillation (AF). https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 6/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Sotalol promotes maintenance of sinus rhythm after cardioversion in patients with AF. The main indication for sotalol, if a rhythm control strategy is chosen, is in patients with underlying coronary heart disease ( algorithm 1). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) In comparison, oral sotalol has limited efficacy for pharmacologic cardioversion of AF to sinus rhythm [38] and, where available, intravenous sotalol is less effective than other drugs [23,24]. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) Sotalol appears to be effective for the prevention of AF after cardiac surgery (eg, coronary artery bypass graft or valve surgery) [39]. In a meta-analysis of 15 studies involving sotalol for the prevention of AF after cardiac surgery, sotalol was significantly more effective in preventing AF than no treatment, placebo, or beta blockers, and it was equally as effective as amiodarone [40]. Recommendations about the choice of a particular agent for the prevention of AF after cardiac surgery are presented separately. (See "Atrial fibrillation and flutter after cardiac surgery".) The safety of sotalol was compared with dronedarone after AF ablation. Propensity-score matching resulted in 1815 patients receiving dronedarone matched 1:1 to patients receiving sotalol. Patients on dronedarone had lower risk of cardiovascular hospitalization compared with patients treated with sotalol, predominantly attributable to lower rates of ATA-related hospitalization. In addition, dronedarone-treated patients had a better safety profile after ablation compared with sotalol patients because of lower rates of combined proarrhythmia, predominantly driven by lower rates of bradycardic proarrhythmia and need for pacemaker implantation [41]. The DASH-AF study compared the safety and feasibility of intravenous sotalol compared with the traditional five-dose inpatient titration of oral sotalol for the treatment of atrial arrhythmias. The nonrandomized study compared QT interval changes, safety outcomes, and cost in 120 patients receiving inpatient oral loading with 120 patients receiving intravenous sotalol at a loading dose of 125 mg for all patients with a CrCL >60 m/min for an intended maintenance regimen of 120 mg twice daily and 82.5 mg for CrCL >60 mL/min for an intended maintenance dose of 80 mg twice daily; oral sotalol was started four hours after the intravenous sotalol infusion. The majority (60 percent) of oral loading was at the 120 mg twice-daily dose. Patients were matched on AF type and CrCL. There was no significant change in QTc in both groups, and the risk of adverse events was also similar. The estimated cost savings with intravenous sotalol was $3,500.68 per admission. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 7/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Fetal arrhythmias Fetal tachycardia is a serious condition for which treatment should be initiated, especially in the presence of hydrops fetalis. The management of fetal arrhythmias is discussed in detail separately. (See "Fetal arrhythmias".) MAJOR SIDE EFFECTS Sotalol is generally well tolerated. It has been estimated that sotalol is discontinued because of side effects in approximately 15 percent of patients [4,42]. The major causes for cessation of therapy are fatigue (4 percent), bradycardia, dyspnea, proarrhythmia (each 3 percent), and dizziness and asthenia (each 2 percent) [4]. However, some of these side effects, such as dizziness, fatigue, and anxiety, may not be more common than with placebo [34]. The potential for cardiac toxicity is clearly of greatest concern. Bradycardic and proarrhythmic events can occur after the initiation of sotalol therapy and with each upward dosing adjustment. As a result, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. (See 'Initiation of therapy' above.) Cardiac toxicity The two major cardiac side effects of sotalol are proarrhythmia, most often torsades de pointes, and bradycardia. In addition, the beta blocking activity of sotalol can cause new or worsened heart failure. The arrhythmic and bradycardic complications often occur within the first three days after the initiation of sotalol therapy and with each upward dosing adjustment [17,18]. As a result, sotalol should generally be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. (See 'Initiation of therapy' above.) Proarrhythmia Sotalol, like other class III drugs, has the potential to be arrhythmogenic due to marked prolongation of the duration of the action potential that is manifested on the surface electrocardiogram (ECG) by prolongation of the QT interval [3,43]. This effect is mediated by blockade of IKr ( figure 1), the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization of the action potential ( figure 2) [6,7]. (See 'Class III activity' above.) At standard doses between 160 and 320 mg/day, sotalol increases by QT interval by 40 to 100 msec [3]. However, the amount of change in the QT interval is highly variable and difficult to predict in an individual patient. In a cohort of 541 patients starting sotalol, the average change in corrected QT interval (QTc using the Bazett formula) was 3 42 milliseconds at two hours and 11 37 milliseconds at 48 hours following the initial dose [44]. The maximum recommended QTc interval on sotalol is 500 to 520 msec [3,4,45]. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 8/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate The effect of sotalol on the action potential duration shows reverse use dependence, which is seen with other class III antiarrhythmic drugs except for amiodarone. Reverse use dependence is defined as an inverse correlation between the heart rate and the QT interval [11]. As a result, the QT interval is prolonged as the heart rate slows, which could explain the association between bradycardia and antiarrhythmic drug-induced torsades de pointes. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology'.) The most important clinical manifestation of sotalol-induced proarrhythmia is torsades de pointes, characterized by a "twisting" of the peaks of the QRS complexes around the isoelectric line of the ECG ( waveform 1). Triggered activity caused by early afterdepolarizations is thought to be responsible for the induction of this arrhythmia, which is most likely to occur in patients with prolongation of the QT interval. The reported risk of torsades de pointes has varied from 1 to 4 percent [34,42,46]. The incidence of and risk factors for torsades de pointes were described in a 1996 review of 3135 patients who were treated with sotalol for sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (41 percent) or non-life-threatening arrhythmias such as ventricular premature beats, atrial fibrillation (AF), nonsustained VT, or paroxysmal supraventricular tachycardia (59 percent) [46]. The overall rate of torsades de pointes was 2.5 percent at a median follow-up of 164 days. However, a number of groups at significantly increased risk were identified: Sotalol dose above 320 mg/day (3.7 versus 1.8 and 0.1 percent at doses of 161 to 320 mg/day and 160 mg/day, respectively). Serum creatinine above 1.4 mg/dL [124 micromol/L] in women and 1.6 mg/dL [141 micromol/L] in men (5.1 versus 2.2 percent). Sustained VT/VT as the presenting arrhythmia (4.5 versus 1.1 percent with other arrhythmias such as atrial fibrillation). History of heart failure (5.0 versus 1.7 percent without heart failure) or coronary heart disease (3.1 versus 1.9 percent). Female gender (4.1 versus 1.9 percent in men). The gender difference was independent of dose-related bradycardic responses and was similar in women greater than 50 and 50 years of age, which suggests that estrogen may not be responsible for the increased risk in women. An increase in risk in females has also been noted with torsades de pointes due to other antiarrhythmic drugs, noncardiac drugs, and the congenital long QT syndrome [47-49]. In each of these settings, females constitute approximately 70 percent of affected patients. Compared https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 9/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate with males, females have a longer corrected QT interval and a greater response to drugs that block IKr, potentiating the development of torsades de pointes [50]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Risk factors for drug-induced long QT syndrome'.) There are also general predisposing factors such as bradycardia, which is thought to result from reverse use dependence in which the QT interval is prolonged as the heart rate slows, and other factors that prolong the baseline QT interval such as hypokalemia, hypomagnesemia, and the concomitant use of other drugs that prolong the QT interval, including antiarrhythmic drugs such as procainamide, quinidine, and the other class III agents (amiodarone, dofetilide, ibutilide) ( table 2). All of these drugs predispose to torsades de pointes except for amiodarone. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse cardiac effects' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Bradycardia Sotalol has the potential to cause all of the rhythm effects induced by beta blockade, including sinus bradycardia and atrioventricular (AV) block. Bradyarrhythmias, mostly sinus bradycardia, occur in approximately 10 to 15 percent of patients [3,4,17,18,34,42]. By comparison, sinus node arrest and second or third degree heart block occur in 1 percent [4,42]. Heart failure Many patients treated with sotalol, particularly for ventricular arrhythmias, have underlying cardiac disease. Fortunately, impairment of myocardial contractility in patients treated with sotalol is less than might be expected with a beta blocker. Most patients have no significant decrease in left ventricular ejection fraction [3], and it has been estimated that clinically significant heart failure aggravation occurs in only 1.5 to 3 percent of patients [42,45,51]. The risk is greater in patients with a prior history of heart failure, particularly those with a baseline ejection fraction of <30 percent [4,5,42,46]. In the review of 3135 patients cited above, the incidence to torsades de pointes was much higher in patients with heart failure (5.0 versus 1.7 percent without heart failure) [46]. Because of the concern related to the safety of sotalol in patients with heart failure, amiodarone is generally preferred for the treatment of ventricular arrhythmias and for maintenance of sinus rhythm in atrial fibrillation when pharmacologic therapy is given. However, sotalol safely reduces the frequency of recurrent arrhythmia and appropriate shocks in patients with an implantable cardioverter-defibrillator (ICD) [34]. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 10/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Contraindications Sotalol should not be used in patients with uncontrolled asthma, sinus bradycardia, Mobitz II second degree AV block and third degree AV block, congenital long QT syndrome, acquired long QT syndrome ( table 2), cardiogenic shock, or uncontrolled heart failure. In addition, it should be used with caution in patients with reduced renal function, since decreased clearance can result in drug accumulation and possible proarrhythmia [46]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Introduction Sotalol consists of a racemic mixture of d and l isomers in an approximate ratio of 1:1. The two isomers contribute to the unique antiarrhythmic properties of sotalol, with d isomer prolonging repolarization by blocking the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization of the action potential, while the l isomer both prolongs repolarization and has beta blocking activity. (See 'Electrophysiology and mechanism of action' above.) Mechanism The effect of sotalol on the action potential duration shows reverse use dependence, which is seen with other class III antiarrhythmic drugs, except for amiodarone. Reverse use dependence is defined as an inverse correlation between the heart rate and the QT interval. As a result, the QT interval is prolonged as the heart rate slows, with an associated risk of drug-induced torsades de pointes and a possible decrease in drug efficacy at higher heart rates. (See 'Class III activity' above.) Dosing Bradycardic and proarrhythmic events occur in up to 20 percent of patients after the initiation of sotalol therapy and with each upward dosing adjustment. As a result, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. (See 'Dosing' above.) The recommended initial dose of oral sotalol in adults is 80 mg twice daily whether used for the treatment of ventricular arrhythmias or atrial fibrillation (AF). If necessary, the initial dose can be increased gradually to a total daily dose of 240 mg or 320 mg. Dose adjustments should be made at three day intervals so that steady-state plasma https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 11/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate concentrations can be attained and the QT interval monitored. The dosing interval requires modification in patients with impaired renal function and reduced creatinine clearance. (See 'Dosing' above.) Proarrhythmia Sotalol should not be given to patients with congenital or acquired long QT syndrome unless the cause can be reversed because of the risk of further QT interval prolongation and proarrhythmia, particularly torsades de pointes ( table 2). (See 'Proarrhythmia' above.) Clinical indications Oral sotalol is used for the treatment of ventricular arrhythmias (ie, sustained VT) that are potentially life-threatening and for the maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation and atrial flutter who are currently in sinus rhythm. (See 'Clinical indications' above.) Side effects Sotalol is generally well tolerated, being discontinued because of side effects in approximately 15 percent of patients. The major causes for intolerance are fatigue, bradycardia, dyspnea, proarrhythmia, dizziness and asthenia. (See 'Major side effects' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019865s021lbl.pdf. 2. Kato R, Ikeda N, Yabek SM, et al. Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics. J Am Coll Cardiol 1986; 7:116. 3. Hohnloser SH, Woosley RL. Sotalol. N Engl J Med 1994; 331:31. 4. Anderson JL, Prystowsky EN. Sotalol: An important new antiarrhythmic. Am Heart J 1999; 137:388. 5. Singh BN. Sotalol: Current Status and Expanding Indications. J Cardiovasc Pharmacol Ther 1999; 4:49. 6. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res 2000; 87:1012. 7. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 1990; 96:195. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 12/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 8. Brodsky M, Saini R, Bellinger R, et al. Comparative effects of the combination of digoxin and dl-sotalol therapy versus digoxin monotherapy for control of ventricular response in chronic atrial fibrillation. dl-Sotalol Atrial Fibrillation Study Group. Am Heart J 1994; 127:572. 9. Nademanee K, Feld G, Hendrickson J, et al. Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias. Circulation 1985; 72:555. 10. Mitchell LB, Wyse DG, Duff HJ. Electropharmacology of sotalol in patients with Wolff- Parkinson-White syndrome. Circulation 1987; 76:810. 11. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. 12. Anastasiou-Nana MI, Gilbert EM, Miller RH, et al. Usefulness of d, I sotalol for suppression of chronic ventricular arrhythmias. Am J Cardiol 1991; 67:511. 13. Creamer JE, Nathan AW, Shennan A, Camm AJ. Acute and chronic effects of sotalol and propranolol on ventricular repolarization using constant-rate pacing. Am J Cardiol 1986; 57:1092. 14. Touboul P, Atallah G, Kirkorian G, et al. Clinical electrophysiology of intravenous sotalol, a beta-blocking drug with class III antiarrhythmic properties. Am Heart J 1984; 107:888. 15. Wang T, Bergstrand RH, Thompson KA, et al. Concentration-dependent pharmacologic properties of sotalol. Am J Cardiol 1986; 57:1160. 16. Antonaccio MJ, Gomoll A. Pharmacology, pharmacodynamics and pharmacokinetics of sotalol. Am J Cardiol 1990; 65:12A. 17. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 18. Chung MK, Schweikert RA, Wilkoff BL, et al. Is hospital admission for initiation of antiarrhythmic therapy with sotalol for atrial arrhythmias required? Yield of in-hospital monitoring and prediction of risk for significant arrhythmia complications. J Am Coll Cardiol 1998; 32:169. 19. Kim RJ, Juriansz GJ, Jones DR, et al. Comparison of a standard versus accelerated dosing regimen for D,L-sotalol for the treatment of atrial and ventricular dysrhythmias. Pacing Clin Electrophysiol 2006; 29:1219. 20. Rizza C, Valderrabano M, Singh BN. Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease. J Cardiovasc Pharmacol Ther 1999; 4:129. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 13/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 21. Reiffel JA, Appel G. Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy. J Cardiovasc Pharmacol Ther 2001; 6:111. 22. Sung RJ, Tan HL, Karagounis L, et al. Intravenous sotalol for the termination of supraventricular tachycardia and atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled study. Sotalol Multicenter Study Group. Am Heart J 1995; 129:739. 23. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 24. Reisinger J, Gatterer E, Heinze G, et al. Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol 1998; 81:1450. 25. Ho DS, Zecchin RP, Richards DA, et al. Double-blind trial of lignocaine versus sotalol for acute termination of spontaneous sustained ventricular tachycardia. Lancet 1994; 344:18. 26. Singh BN, Kehoe R, Woosley RL, et al. Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group. Am Heart J 1995; 129:87. 27. L vy S. Cardioversion of recent-onset atrial fibrillation using intravenous antiarrhythmics: A European perspective. J Cardiovasc Electrophysiol 2021; 32:3259. 28. Milan DJ, Saul JP, Somberg JC, Molnar J. Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis. Cardiology 2017; 136:52. 29. Kpaeyeh JA Jr, Wharton JM. Sotalol. Card Electrophysiol Clin 2016; 8:437. 30. Joseph AP, Ward MR. A prospective, randomized controlled trial comparing the efficacy and safety of sotalol, amiodarone, and digoxin for the reversion of new-onset atrial fibrillation. Ann Emerg Med 2000; 36:1. 31. Roden DM. Usefulness of sotalol for life-threatening ventricular arrhythmias. Am J Cardiol 1993; 72:51A. 32. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:452. 33. Haverkamp W, Martinez-Rubio A, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30:487. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 14/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 34. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855. 35. Wichter T, Borggrefe M, Haverkamp W, et al. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation 1992; 86:29. 36. Hohnloser SH, Meinertz T, Stubbs P, et al. Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group. Circulation 1995; 92:1517. 37. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348:7. 38. Ferreira E, Sunderji R, Gin K. Is oral sotalol effective in converting atrial fibrillation to sinus rhythm? Pharmacotherapy 1997; 17:1233. 39. Crystal E, Connolly SJ, Sleik K, et al. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002; 106:75. 40. Kerin NZ, Jacob S. The efficacy of sotalol in preventing postoperative atrial fibrillation: a meta-analysis. Am J Med 2011; 124:875.e1. 41. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 42. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol 1990; 65:74A. 43. Multicentre randomized trial of sotalol vs amiodarone for chronic malignant ventricular
4. Anderson JL, Prystowsky EN. Sotalol: An important new antiarrhythmic. Am Heart J 1999; 137:388. 5. Singh BN. Sotalol: Current Status and Expanding Indications. J Cardiovasc Pharmacol Ther 1999; 4:49. 6. Numaguchi H, Mullins FM, Johnson JP Jr, et al. Probing the interaction between inactivation gating and Dd-sotalol block of HERG. Circ Res 2000; 87:1012. 7. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 1990; 96:195. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 12/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 8. Brodsky M, Saini R, Bellinger R, et al. Comparative effects of the combination of digoxin and dl-sotalol therapy versus digoxin monotherapy for control of ventricular response in chronic atrial fibrillation. dl-Sotalol Atrial Fibrillation Study Group. Am Heart J 1994; 127:572. 9. Nademanee K, Feld G, Hendrickson J, et al. Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias. Circulation 1985; 72:555. 10. Mitchell LB, Wyse DG, Duff HJ. Electropharmacology of sotalol in patients with Wolff- Parkinson-White syndrome. Circulation 1987; 76:810. 11. Hondeghem LM, Snyders DJ. Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 1990; 81:686. 12. Anastasiou-Nana MI, Gilbert EM, Miller RH, et al. Usefulness of d, I sotalol for suppression of chronic ventricular arrhythmias. Am J Cardiol 1991; 67:511. 13. Creamer JE, Nathan AW, Shennan A, Camm AJ. Acute and chronic effects of sotalol and propranolol on ventricular repolarization using constant-rate pacing. Am J Cardiol 1986; 57:1092. 14. Touboul P, Atallah G, Kirkorian G, et al. Clinical electrophysiology of intravenous sotalol, a beta-blocking drug with class III antiarrhythmic properties. Am Heart J 1984; 107:888. 15. Wang T, Bergstrand RH, Thompson KA, et al. Concentration-dependent pharmacologic properties of sotalol. Am J Cardiol 1986; 57:1160. 16. Antonaccio MJ, Gomoll A. Pharmacology, pharmacodynamics and pharmacokinetics of sotalol. Am J Cardiol 1990; 65:12A. 17. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 18. Chung MK, Schweikert RA, Wilkoff BL, et al. Is hospital admission for initiation of antiarrhythmic therapy with sotalol for atrial arrhythmias required? Yield of in-hospital monitoring and prediction of risk for significant arrhythmia complications. J Am Coll Cardiol 1998; 32:169. 19. Kim RJ, Juriansz GJ, Jones DR, et al. Comparison of a standard versus accelerated dosing regimen for D,L-sotalol for the treatment of atrial and ventricular dysrhythmias. Pacing Clin Electrophysiol 2006; 29:1219. 20. Rizza C, Valderrabano M, Singh BN. Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease. J Cardiovasc Pharmacol Ther 1999; 4:129. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 13/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 21. Reiffel JA, Appel G. Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy. J Cardiovasc Pharmacol Ther 2001; 6:111. 22. Sung RJ, Tan HL, Karagounis L, et al. Intravenous sotalol for the termination of supraventricular tachycardia and atrial fibrillation and flutter: a multicenter, randomized, double-blind, placebo-controlled study. Sotalol Multicenter Study Group. Am Heart J 1995; 129:739. 23. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 24. Reisinger J, Gatterer E, Heinze G, et al. Prospective comparison of flecainide versus sotalol for immediate cardioversion of atrial fibrillation. Am J Cardiol 1998; 81:1450. 25. Ho DS, Zecchin RP, Richards DA, et al. Double-blind trial of lignocaine versus sotalol for acute termination of spontaneous sustained ventricular tachycardia. Lancet 1994; 344:18. 26. Singh BN, Kehoe R, Woosley RL, et al. Multicenter trial of sotalol compared with procainamide in the suppression of inducible ventricular tachycardia: a double-blind, randomized parallel evaluation. Sotalol Multicenter Study Group. Am Heart J 1995; 129:87. 27. L vy S. Cardioversion of recent-onset atrial fibrillation using intravenous antiarrhythmics: A European perspective. J Cardiovasc Electrophysiol 2021; 32:3259. 28. Milan DJ, Saul JP, Somberg JC, Molnar J. Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis. Cardiology 2017; 136:52. 29. Kpaeyeh JA Jr, Wharton JM. Sotalol. Card Electrophysiol Clin 2016; 8:437. 30. Joseph AP, Ward MR. A prospective, randomized controlled trial comparing the efficacy and safety of sotalol, amiodarone, and digoxin for the reversion of new-onset atrial fibrillation. Ann Emerg Med 2000; 36:1. 31. Roden DM. Usefulness of sotalol for life-threatening ventricular arrhythmias. Am J Cardiol 1993; 72:51A. 32. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993; 329:452. 33. Haverkamp W, Martinez-Rubio A, Hief C, et al. Efficacy and safety of d,l-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol 1997; 30:487. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 14/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 34. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. d,l-Sotalol Implantable Cardioverter-Defibrillator Study Group. N Engl J Med 1999; 340:1855. 35. Wichter T, Borggrefe M, Haverkamp W, et al. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disease. Results in patients with inducible and noninducible ventricular tachycardia. Circulation 1992; 86:29. 36. Hohnloser SH, Meinertz T, Stubbs P, et al. Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group. Circulation 1995; 92:1517. 37. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 1996; 348:7. 38. Ferreira E, Sunderji R, Gin K. Is oral sotalol effective in converting atrial fibrillation to sinus rhythm? Pharmacotherapy 1997; 17:1233. 39. Crystal E, Connolly SJ, Sleik K, et al. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation 2002; 106:75. 40. Kerin NZ, Jacob S. The efficacy of sotalol in preventing postoperative atrial fibrillation: a meta-analysis. Am J Med 2011; 124:875.e1. 41. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 42. Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol 1990; 65:74A. 43. Multicentre randomized trial of sotalol vs amiodarone for chronic malignant ventricular tachyarrhythmias. Amiodarone vs Sotalol Study Group. Eur Heart J 1989; 10:685. 44. Weeke P, Delaney J, Mosley JD, et al. QT variability during initial exposure to sotalol: experience based on a large electronic medical record. Europace 2013; 15:1791. 45. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 46. Lehmann MH, Hardy S, Archibald D, et al. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation 1996; 94:2535. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 15/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate 47. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 1993; 270:2590. 48. Zeltser D, Justo D, Halkin A, et al. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore) 2003; 82:282. 49. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998; 97:2237. 50. Drici MD, Cl ment N. Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf 2001; 24:575. 51. Kehoe RF, Zheutlin TA, Dunnington CS, et al. Safety and efficacy of sotalol in patients with drug-refractory sustained ventricular tachyarrhythmias. Am J Cardiol 1990; 65:58A. Topic 925 Version 33.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 16/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 17/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 18/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Action potential currents Major cardiac ion currents and channels responsible for a ventricular action potential are shown with their common name, abbreviation, and the gene and protein for the alpha subunit that forms the pore or transporter. The diagram on the left shows the time course of amplitude of each current during the action potential, but does not accurately reflect amplitudes relative to each of the other currents. This summary represents a ventricular myocyte, and lists only the major ion channels. The currents and their molecular nature vary within regions of the ventricles, and in atria, and other specialized cells such as nodal and Purkinje. Ion channels exist as part of multi-molecular complexes including beta subunits and other associated regulatory proteins which are also not shown. Courtesy of Jonathan C Makielski, MD, FACC. Graphic 70771 Version 4.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 19/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Myocardial action potential Representation of a ventricular action potential. There are 5 phases of the action potential beginning with phase 0, rapid depolarization by sodium influx. Phase 1 is a rapid repolarization via potassium efflux followed by phase 2 or the plateau phase. The plateau phase results from entry of calcium into the cell and potassium efflux. Phase 3 repolarization is dominated by potassium currents which polarize the cell and potassium inward rectifier maintains the resting potential or phase 4. See text for full description. Graphic 71390 Version 4.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 20/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or infarction, especially with prominent T-wave inversions GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga (ibogaine), licorice extract in overuse via electrolyte disturbances Intracranial disease Hypothyroidism Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate insecticides AV block: Second or third degree Medications* High risk Adagrasib Cisaparide (restricted Lenvatinib Selpercatinib Ajmaline Levoketoconazole Sertindole availability) Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab ozogamacin Propafenone Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 21/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Certinib Escitalopram Levofloxacin (systemic) Risperidone Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole (systemic) Romidepsin Anagrelide Foscarnet Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- lumefantrine Glasdegib Mizolastine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine (rare reports) Nortriptyline Benperidol Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus (systemic) Olodaterol Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 22/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide overdose in Eliglustat Primaquine Vorinostat Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list [1,2] . The use of other classification criteria may lead to some agents being classified differently by other sources. Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 23/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 24/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 25/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Single lead electrocardiogram (ECG) showing polymorphic ventricular tachycardia (VT) This is an atypical, rapid, and bizarre form of ventricular tachycardia that is characterized by a continuously changing axis of polymorphic QRS morphologies. Graphic 53891 Version 5.0 https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 26/27 7/5/23, 8:23 AM Clinical uses of sotalol - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-uses-of-sotalol/print 27/27
7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Major side effects of beta blockers : Philip J Podrid, MD, FACC : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 15, 2023. INTRODUCTION Most of the major adverse effects of beta blocking drugs result from beta-adrenoreceptor blockade. Many signs and symptoms can therefore be induced because the beta receptors affect multiple metabolic and physiologic functions. Other reactions apparently unrelated to beta blockade can occur, but they are uncommon. The major side effects associated with the use of beta blockers will be reviewed here. Beta blocker intoxication (overdose) and the clinical use of these drugs for the treatment of arrhythmias, hypertension, myocardial infarction, and heart failure are discussed separately. (See "Beta blocker poisoning" and "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker' and "Choice of drug therapy in primary (essential) hypertension".) ADVERSE CARDIAC EFFECTS Major cardiac effects caused by beta blockade include the precipitation or worsening of congestive heart failure, and significant negative chronotropy. Heart failure Beta blockers are an important component of long-term therapy for patients with chronic heart failure and reduced left ventricular systolic function, as these drugs reduce the detrimental effects of excess chronic catecholamine stimulation and downregulation of the beta receptor due to excessive sympathetic stimulation. With beta blockade, the beta receptors become upregulated and are therefore more responsive to sympathetic stimulation, an https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 1/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate important concern in patient with reduced left ventricular function and chronic heart failure. However, beta blockers may exacerbate symptoms in patients with acute decompensated heart failure or in those with preexisting myocardial dysfunction and borderline compensation, since the maintenance of cardiac output in such patients depends in part upon sympathetic drive. Hence, beta blockers should not be administered as new therapy until after heart failure is compensated. However, patients already receiving beta blockers can be continued on this therapy if there is decompensated heart failure. (See "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action", section on 'Beta blockers'.) Increased peripheral vascular resistance (and hence increase in afterload) induced by nonselective beta blockers, also may contribute to the decline in myocardial function in this setting. On the other hand, drugs with intrinsic sympathetic activity (ISA), such as pindolol or acebutolol, may be less likely to impair myocardial function [1]. Despite these concerns, only a minority of patients with stable heart failure deteriorate after the initiation of beta blocker therapy. As an example, worsening of heart failure was observed in only 6 percent of patients with chronic heart failure who were being treated with carvedilol [2]. Furthermore, long-term therapy with beta blockers is often beneficial in such patients, improving survival in patients with systolic heart failure and improving diastolic function in patients with diastolic heart failure. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Another concern about beta blockers in patients with HF is the occurrence of other symptoms, including dizziness due to hypotension and bradycardia. One study that reviewed data from HF trials reported between 1966 and 2002 found that, although beta blockers were associated with these side effects, the absolute increase in symptoms was small and did not necessitate withdrawal of drug therapy [3]. Negative chronotropic effects Slowing of the resting heart rate and the development of sinus bradycardia is a normal response to treatment with a beta blocker. This effect is less prominent with drugs with ISA. Nevertheless, all beta blockers are relatively contraindicated in patients with symptomatic bradycardia that may be associated with sinus node dysfunction, especially if there is a further reduction in rate, unless an artificial pacemaker is present. Beta blockers also depress conduction through the atrioventricular (AV) node, potentially causing heart block. Use of a beta blocking drug can therefore lead to a serious bradyarrhythmia in patients with an underlying complete or partial AV conduction defect (ie, second- or third-degree AV block), especially if the patient is also receiving another agent that https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 2/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate impairs AV nodal conduction such as digoxin or a calcium channel blocker (ie, verapamil or diltiazem). Compounds with ISA may cause less impairment of AV conduction [4]. Beta blocker withdrawal Acute withdrawal of a beta blocker can lead to substantial morbidity and even mortality [5]. The most important concern with beta blocker withdrawal is the exacerbation of ischemic symptoms, including the precipitation of an acute myocardial infarction, in patients with known coronary artery disease. In some cases there may be the precipitation of serious ventricular tachyarrhythmia, including sudden cardiac death [6-8]. This can occur even in patients who have no previous history of coronary symptoms [8]. These withdrawal symptoms are due to increased sympathetic activity, which is a probable reflection of adrenergic receptor upregulation during the period of sympathetic blockade [9]. Upregulation of beta receptors results in an increase in beta receptor responsiveness to circulating catecholamines. The degree to which this will occur depends upon the relationship between the rate at which beta blockade wears off and the rate at which the receptors downregulate (the latter has a half-life of 24 to 36 hours) [10]. Thus, a hyperadrenergic state is most likely with short-acting drugs (such as propranolol), since receptor upregulation will persist after the antihypertensive effect has disappeared [5,10]. Gradual tapering of the propranolol dose will diminish the risk of withdrawal [7]. In comparison, withdrawal syndromes are relatively unusual with longer-acting agents (such as atenolol or nadolol) [5,10]. Although data about the timing of beta blocker withdrawal are not available, we use the following approach in patients who must stop taking a beta blocker: For beta blockers with shorter half-lives which require administration two or more times per day (eg, propranolol, short acting metoprolol, carvedilol), we have patients take their usual dose once daily for one week, then every other day for one week, then stop the medication. For beta blockers with longer half-lives that are administered once daily (eg, atenolol, long acting metoprolol, nadolol), we have patient take one-half their usual dose once daily for one week, then one-half their usual dose every other day for a week, then stop the medication. However, beta blocker withdrawal can be accomplished in less time if necessary, usually by taking one-half the usual dose every other day for a week. ADVERSE NONCARDIAC EFFECTS DUE TO BETA BLOCKADE The lungs, peripheral blood vessels, glucose metabolism, and central nervous system are all affected by beta blockade although the clinical magnitude of the last three effects seems less https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 3/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate pronounced than originally thought. Increased airways resistance Beta blockade with nonselective agents prevents bronchodilation due to bronchial beta-2 receptors [11]. This can lead to increased airways resistance in patients with bronchospastic disease, a problem that is less likely to occur with compounds with ISA or beta-1 selectivity [12-14]. Beta-1 selectivity is not absolute, however, and may diminish at higher doses. It has also been suggested that combined beta and alpha blockade with labetalol or carvedilol may be better tolerated than nonselective agents in patients with chronic lung disease [15]. All beta blockers should be avoided in patients with severe or decompensated bronchospastic disease; nonselective beta blockers should generally be avoided in susceptible patients with mild to moderate bronchospastic disease, while the selective beta blockers or possibly combined alpha and beta blockers appear to be safe and should be used with caution. Therapeutic doses of beta-1 selective beta blockers are generally well tolerated, although some patients who are using inhaled beta agonists may require an increase inhaler requirement [16]. This issue of beta blocker therapy in patients with chronic obstructive disease is discussed more fully elsewhere. (See "Management of the patient with COPD and cardiovascular disease", section on 'Treatment of CVD in patients with COPD'.) Exacerbation of peripheral artery disease Initial studies with nonselective beta blockers (eg, propranolol) in patients with severe peripheral artery disease described a variety of complications including worsening claudication, cold extremities, absent pulses, and, in some cases, cyanosis and impending gangrene [17]. Raynaud's phenomenon can also be a manifestation of nonselective beta blockade [18,19]. It was thought that both the reduction in cardiac output and blockade of beta-2-receptor-mediated vasodilation of vessels within skeletal muscle contribute to the vascular insufficiency [20]. Beta blockers with beta-1 selectivity or ISA do not affect the peripheral vessels to the same degree as the nonselective drugs. A meta-analysis of published studies in patients with mild to moderate peripheral artery disease found no exacerbation of symptoms with beta blockers [21]. Thus, the concern may be overstated, particularly in patients with mild to moderate disease treated with a beta-1 selective agent [22]. Although selective agents can also be used in patients with severe disease, they should be used cautiously [23]. (See "Management of claudication due to peripheral artery disease".) Facilitation of hypoglycemia Epinephrine, acting via the beta-adrenergic receptors, has important effects on glucose metabolism. It increases glucose production by stimulating both glycogenolysis and gluconeogenesis from amino acids, glycerol, and pyruvate. It also increases https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 4/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate the delivery of these gluconeogenic substrates from the peripheral tissue, inhibits glucose utilization by several tissues, and, via the alpha-2-receptors, inhibits insulin secretion. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".) All of these actions help to protect against the development of hypoglycemia. In addition, epinephrine induces early warning symptoms of neuroglycopenia, such as sweating and anxiety. Studies published in the 1960s showed that nonselective beta blockers can retard recovery from insulin-induced hypoglycemia [24] and that the reactions are more likely to be severe [25,26]. The latter effect is presumably due to diminished or absent early warning signs [27,28]. However, later studies showed that the effects on glucose metabolism may be less prominent with beta-1 selective drugs and those with ISA [29,30] and that an increased risk of serious hypoglycemia among patients with diabetes mellitus was hard to demonstrate [30]. Furthermore, carvedilol appears to promote glucose utilization and lower insulin levels in patients with type 2 diabetes [31]. Hyperkalemia Catecholamines have potentially important clinical effects on potassium balance, primarily by influencing the distribution of potassium between the extracellular fluid and the cells. In particular, stimulation of the beta-2-receptors by epinephrine promotes the movement of extracellular potassium into the cells, thereby lowering the plasma potassium concentration. (See "Causes of hypokalemia in adults", section on 'Elevated beta-adrenergic activity'.) These effects on potassium balance can be reversed by beta-adrenergic blockers, which will tend to impair potassium entry into the cells, thereby raising the plasma potassium concentration after a potassium load. This is most likely to occur with the nonselective beta blockers (such as propranolol or labetalol); in contrast, the beta-1 selective agents such as atenolol or metoprolol have little effect, since the beta-2 receptors remain intact [32,33]. In most cases, the administration of beta blockers is associated with only a minor elevation in the plasma potassium concentration of less than 0.5 meq/L, as the potassium that cannot enter the cells is excreted in the urine. True hyperkalemia is rare unless associated with a superimposed problem such as a marked potassium load, marked exercise (which is associated with the release of potassium from the cells into the extracellular fluid), hypoaldosteronism, heart failure exacerbation (with the potential for renal insufficiency due to a decreased cardiac output and reduced renal perfusion), or end-stage kidney disease [34-36]. Hyperkalemia has also been reported in renal transplant recipients treated with labetalol [37]. (See "Causes and evaluation of hyperkalemia in adults", section on 'Beta blockers'.) https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 5/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Depression, fatigue, sexual dysfunction Depression, fatigue, and sexual dysfunction are commonly cited side effects of beta blockers, and may be one reason why use of beta blockers is lower than desired for some approved indications [38]. However, these associations are primarily based upon case series and randomized trials with methodologic flaws. The best available data on this issue come from a systematic review of randomized trials, which found no increased risk of depression with beta blocker therapy, and only small increases in fatigue and sexual dysfunction [39]. The review included 15 randomized, placebo-controlled trials involving more than 35,000 patients who were followed for a minimum of six months. Both patient reported symptoms and withdrawal of therapy were investigated. The following findings were reported: There was a small significant increase in risk of fatigue (18 per 1000 patients, 95% CI 5-30). This is equivalent to one additional report of fatigue for every 57 patients treated per year. There was a small significant increase in risk of sexual dysfunction (5 per 1000 patients, 95% CI 2-8). This is equivalent to one additional report of sexual dysfunction for every 199 patients treated per year. There was no significant annual increase in risk of reported depressive symptoms. It has been hypothesized that lipophilic drugs (eg, propranolol, metoprolol) ( table 1) are associated with a higher incidence of central nervous system effects such as fatigue and depression because of their ability to penetrate the central nervous system. However, lipid solubility of the beta blockers did not affect the risk of adverse effects in this review. In trials testing early generation beta blockers (propranolol, timolol), the risk of fatigue, but not depression or sexual dysfunction, was higher (relative risk 1.78, 95% CI 1.08-2.93) when compared with later generation beta blockers. However, the number of trials was small and the confidence intervals were wide. One small study of 96 patients treated with atenolol suggested that erectile dysfunction was possibly related to knowledge about this as a side effect and the anxiety provoked rather than as a direct consequence of the drug [40]. In addition, among those who developed erectile dysfunction, sildenafil and placebo were equally effective as therapy. Thus, although beta blockers appear to cause small increases in the risk of fatigue and sexual dysfunction, the risk is much lower than previously thought, and beta blockers should not be withheld based upon concerns about developing these adverse effects. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 6/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Lipid metabolism Beta blockers interfere with lipid metabolism and are associated with alteration of serum triglyceride and HDL-cholesterol concentrations. The effect varies based on the receptor selectivity and pharmacologic profile of each individual agent. This is discussed in greater detail separately. (See "Antihypertensive drugs and lipids", section on 'Beta blockers'.) Weight gain A systematic review of eight randomized trials of beta blockers versus placebo in hypertensive patients revealed a median increase in body weight in the beta blocker group of 1.2 kg (range -0.4 to 3.5 kg) [41,42]. Most of this weight gain occurred within the first few months. ADVERSE EFFECTS UNRELATED TO BETA BLOCKADE The major side effects unrelated to beta blockade are drug interactions and severe toxicity. The latter condition is most commonly associated with suicide attempts and accidental overdosing. Drug interactions The combined use of beta blockers and other agents can result in a number of adverse interactions ( table 2). Drugs that depress myocardial function or pacemaker activity, including calcium channel blockers and some antiarrhythmic agents which have negative inotropic effects (ie, disopyramide, propafenone, flecainide), are of particular concern when used in combination therapy with a beta blocker. These combinations are common in patients with ischemic heart disease and arrhythmias, who often have underlying abnormalities of myocardial function as well as depressed sinus and AV node activity. Additional information can also be found using the Lexicomp drug interactions tool. Antinuclear antibodies Beta blockers have also been associated with the development of antinuclear antibodies [43]. A cross-sectional study of 1500 hypertensive patients found a prevalence of antinuclear antibodies of more than 10 percent in those receiving atenolol, labetalol, and acebutolol [44]. However, rheumatic symptoms (generally persistent arthralgias and myalgias) are infrequent. ANA titers and symptoms resolve after the cessation of therapy. OVERDOSE Attempted suicide or accidental overdose with beta blockers can result in bradycardia, hypotension, low cardiac output, cardiac failure, and cardiogenic shock [45,46]. Bronchospasm and respiratory depression may also occur due perhaps to severe circulatory impairment or a central drug effect. The myocardium in severe intoxications may become relatively refractory to pharmacologic and electrical stimulation, resulting in asystolic death. Changes in mental status, convulsions, and coma have also been described. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 7/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Sotalol intoxication differs from that seen with other beta blockers as this agent also has class III antiarrhythmic effects and can prolong time for membrane repolarization and refractoriness. This results in prolongation of the QT interval and may contribute to ventricular tachyarrhythmias, typically a type of polymorphic VT known as torsades de pointes. Intoxicated patients should be managed with intensive supportive care in facilities equipped for continuous cardiac monitoring and ventilatory support. (See "Beta blocker poisoning" and "Clinical uses of sotalol", section on 'Major side effects'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Side effects from medicines (The Basics)") Basics topic (see "Patient education: Side effects from medicines (The Basics)") SUMMARY AND RECOMMENDATIONS Major cardiac effects caused by beta blockade include the precipitation or worsening of congestive heart failure, and significant negative chronotropy. Adverse cardiac effects Heart failure Beta blockers may exacerbate heart failure (HF) in patients with decompensated HF. Beta blockers may also precipitate HF in those with preexisting myocardial dysfunction and borderline compensation since the maintenance of cardiac output in such patients depends in part upon sympathetic drive. Increased peripheral https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 8/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate vascular resistance, induced by nonselective beta blockers, also may contribute to the decline in myocardial function in this setting. (See 'Heart failure' above.) Negative chronotropic effects Beta blockers are relatively contraindicated in patients with symptomatic bradycardia that may be associated with a sinus node dysfunction, especially if there is a further reduction in rate. Beta blockers also depress conduction through the AV node, potentially leading to a serious bradyarrhythmia in patients with an underlying complete or partial AV conduction defect (ie, second or third degree AV block). This is especially true if the patient is also receiving another agent that impairs AV nodal conduction such as digoxin or a calcium channel blocker (ie, verapamil or diltiazem). (See 'Negative chronotropic effects' above.) Beta blocker withdrawal Acute withdrawal of a beta blocker can lead to increased sympathetic activity (most likely with short-acting drugs). This hyperadrenergic state may lead to accelerated angina, myocardial infarction, or even sudden death. Although no data are available, we use the following approach in patients who must stop taking a beta blocker (see 'Beta blocker withdrawal' above): For beta blockers with shorter half-lives which require twice daily administration (eg, propranolol, short acting metoprolol, carvedilol), we have patients take their usual dose once daily for one week, then every other day for one week, then stop the medication. For beta blockers with longer half-lives that are administered once daily (eg, atenolol, long acting metoprolol, nadolol), we have patient take one-half their usual dose once daily for one week, then one-half their usual dose every other day for a week, then stop the medication. However, beta blocker withdrawal can be accomplished in less time if necessary, usually by taking one-half the usual dose every other day for a week. Adverse noncardiac effects While beta blockers have many noncardiac effects, their effects on the lungs, energy levels, and sexual function are the most common and may be significant. Increased airway resistance Beta blockade with nonselective agents prevents bronchodilation due to bronchial beta-2 receptors, leading to increased airway resistance in patients with bronchospastic disease. While therapeutic doses of beta-1 selective beta blockers are generally well tolerated and can be safely used in most patients, the risks and benefits should be considered prior to initiating treatment in https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 9/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate patients with severe or decompensated bronchospastic airway disease. (See 'Increased airways resistance' above.) Depression, fatigue, and sexual dysfunction are commonly cited side effects of beta blockers. However, a systematic review of randomized trials found no increased risk of depression with beta blocker therapy, and only small increases in fatigue and sexual dysfunction. As such, while the occasional patient may need to discontinue a beta blocker because of one of these side effects, beta blockers should not be initially withheld based upon concerns about developing these adverse effects. (See 'Depression, fatigue, sexual dysfunction' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Taylor SH, Silke B, Lee PS. Intravenous beta-blockade in coronary heart disease: is cardioselectivity or intrinsic sympathomimetic activity hemodynamically useful? N Engl J Med 1982; 306:631. 2. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334:1349. 3. Ko DT, Hebert PR, Coffey CS, et al. Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials. Arch Intern Med 2004; 164:1389. 4. Frishman WH. Drug therapy. Pindolol: a new beta-adrenoceptor antagonist with partial agonist activity. N Engl J Med 1983; 308:940. 5. Houston MC. Abrupt cessation of treatment in hypertension: consideration of clinical features, mechanisms, prevention and management of the discontinuation syndrome. Am Heart J 1981; 102:415. 6. Miller RR, Olson HG, Amsterdam EA, Mason DT. Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 1975; 293:416. 7. Rangno RE, Nattel S, Lutterodt A. Prevention of propranolol withdrawal mechanism by prolonged small dose propranolol schedule. Am J Cardiol 1982; 49:828. 8. Psaty BM, Koepsell TD, Wagner EH, et al. The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers. JAMA 1990; 263:1653. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 10/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate 9. Lefkowitz RJ, Caron MG, Stiles GL. Mechanisms of membrane-receptor regulation. Biochemical, physiological, and clinical insights derived from studies of the adrenergic receptors. N Engl J Med 1984; 310:1570. 10. Krukemyer JJ, Boudoulas H, Binkley PF, Lima JJ. Comparison of hypersensitivity to adrenergic stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences. Am Heart J 1990; 120:572. 11. Dunlop D, Shanks RG. Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother 1968; 32:201. 12. Beumer, HM, Hardonk, HJ . Effects of beta-adrenergic blocking drugs on ventilatory function in asthmatics. Eur J Clin Pharmacol 1972; 5:77. 13. Singh BN, Whitlock RM, Comber RH, et al. Effects of cardioselective beta adrenoceptor blockade on specific airways resistance in normal subjects and in patients with bronchial asthma. Clin Pharmacol Ther 1976; 19:493. 14. Skinner C, Gaddie J, Palmer KN. Comparison of effects of metoprolol and propranolol on asthmatic airway obstruction. Br Med J 1976; 1:504. 15. Sirak TE, Jelic S, Le Jemtel TH. Therapeutic update: non-selective beta- and alpha-adrenergic blockade in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol 2004; 44:497. 16. Khosla S, Kunjummen B, Khaleel R, et al. Safety of therapeutic beta-blockade in patients with coexisting bronchospastic airway disease and coronary artery disease. Am J Ther 2003; 10:48. 17. Frohlich ED, Tarazi RC, Dustan HP. Peripheral arterial insufficiency. A complication of beta- adrenergic blocking therapy. JAMA 1969; 208:2471. 18. Simpson FO. Beta-adrenergic receptor blocking drugs in hypertension. Drugs 1974; 7:85. 19. Zacharias FJ, Cowen KJ, Prestt J, et al. Propranolol in hypertension: a study of long-term therapy, 1964-1970. Am Heart J 1972; 83:755. 20. Lundvall J, J rhult J. Beta adrenergic dilator component of the sympathetic vascular response in skeletal muscle. Influence on the micro-circulation and on transcapillary exchange. Acta Physiol Scand 1976; 96:180. 21. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med 1991; 151:1769. 22. Thadani U, Whitsett TL. Beta-adrenergic blockers and intermittent claudication. Time for reappraisal. Arch Intern Med 1991; 151:1705. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 11/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate 23. Heintzen MP, Strauer BE. Peripheral vascular effects of beta-blockers. Eur Heart J 1994; 15 Suppl C:2. 24. Antonis A, Clark ML, Hodge RL, et al. Receptor mechanisms in the hyperglycaemic response to adrenaline in man. Lancet 1967; 1:1135. 25. Abramson EA, Arky RA, Woeber KA. Effects of propranolol on the hormonal and metabolic responses to insulin-induced hypoglycaemia. Lancet 1966; 2:1386. 26. Reveno WS, Rosenbaum H. Propranolol and hypoglycaemia. Lancet 1968; 1:920. 27. Lloyd-Mostyn RH, Oram S. Modification by propranolol of cardiovascular effects of induced hypoglycaemia. Lancet 1975; 1:1213. 28. Hirsch IB, Boyle PJ, Craft S, Cryer PE. Higher glycemic thresholds for symptoms during beta- adrenergic blockade in IDDM. Diabetes 1991; 40:1177. 29. Deacon SP, Barnett D. Comparison of atenolol and propranolol during insulin-induced hypoglycaemia. Br Med J 1976; 2:272. 30. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA 1997; 278:40. 31. Giugliano D, Acampora R, Marfella R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med 1997; 126:955. 32. Reid JL, Whyte KF, Struthers AD. Epinephrine-induced hypokalemia: the role of beta adrenoceptors. Am J Cardiol 1986; 57:23F. 33. Castellino P, Bia MJ, DeFronzo RA. Adrenergic modulation of potassium metabolism in uremia. Kidney Int 1990; 37:793. 34. Lim M, Linton RA, Wolff CB, Band DM. Propranolol, exercise, and arterial plasma potassium. Lancet 1981; 2:591. 35. Arthur S, Greenberg A. Hyperkalemia associated with intravenous labetalol therapy for acute hypertension in renal transplant recipients. Clin Nephrol 1990; 33:269. 36. Nowicki M, Miszczak-Kuban J. Nonselective Beta-adrenergic blockade augments fasting hyperkalemia in hemodialysis patients. Nephron 2002; 91:222. 37. McCauley J, Murray J, Jordan M, et al. Labetalol-induced hyperkalemia in renal transplant recipients. Am J Nephrol 2002; 22:347. 38. Gheorghiade M, Eichhorn EJ. Practical aspects of using beta-adrenergic blockade in systolic heart failure. Am J Med 2001; 110 Suppl 7A:68S. 39. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 12/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate fatigue, and sexual dysfunction. JAMA 2002; 288:351. 40. Silvestri A, Galetta P, Cerquetani E, et al. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo. Eur Heart J 2003; 24:1928. 41. Sharma AM, Pischon T, Hardt S, et al. Hypothesis: Beta-adrenergic receptor blockers and weight gain: A systematic analysis. Hypertension 2001; 37:250. 42. Leslie WS, Hankey CR, Lean ME. Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM 2007; 100:395. 43. Stephen SA. Unwanted effects of propranolol. Am J Cardiol 1966; 18:463. 44. Booth RJ, Wilson JD, Bullock JY. Beta-adrenergic-receptor blockers and antinuclear antibodies in hypertension. Clin Pharmacol Ther 1982; 31:555. 45. Self-poisoning with beta-blockers. Br Med J 1978; 1:1010. 46. Frishman W, Jacob H, Eisenberg E, Ribner H. Clinical pharmacology of the new beta- adrenergic blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J 1979; 98:798. Topic 967 Version 30.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 13/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate GRAPHICS Beta blocker properties Alpha Beta-1 Half l Drug ISA MSA Lipophilicity Usual dose* blockade selectivity hour Acebutolol No Yes Yes Yes Low 100 to 400 mg 3 to 4 twice per day Atenolol No Yes No No Low 50 to 200 mg once daily 6 to 9 Betaxolol No Yes No Yes Low 10 to 20 mg once daily 14 to 22 Bisoprolol No Yes No No Moderate 2.5 to 20 mg once daily 9 to 12 Carteolol No No Yes No Low 2.5 to 5 mg once daily 6 Carvedilol Yes No No Yes High 3.125 to 25 mg twice per day 7 to 10 Esmolol No Yes No No Low IV only 250 to 500 9 minut micrograms/kg over one minute then 25 to 50 micrograms/kg per minute as IV infusion; titrate incrementally up to maximum of 300 microgram/kg per minute https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 14/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Labetalol Yes No Yes (Beta ) 2 Low Moderate IV 20 mg 3 to 4 Orally 100-400 mg two or three times per day Metoprolol tartrate No Yes No Low Moderate IV 1.25 to 5 mg 3 to 4 (7 to 9 h in poor Orally 25 to 100 mg two metabo times per day Metoprolol succinate No Yes No Low Moderate Orally 50 to 400 mg once Apparen half-life (extended daily prolong release) continu osmotic release ~20 hou Nadolol No No No No Low 40 to 160 mg 20 to 24 once daily Nebivolol No Yes No No High 5 to 40 mg once daily 10 to 12 (19 to 32 poor metabo Oxprenolol No No Yes Yes Moderate 40 to 80 mg three times per day 1.5 Penbutolol No No Yes No High 10 to 40 mg once daily 5 Pindolol No No Yes Low Moderate 5 to 30 mg 3 to 4 twice per day Propranolol No No No Yes High IV 1 to 5 mg 3 to 4 Orally 10 to 80 mg two to four times daily Sotalol No No No No Low 80 to 160 mg 12 twice per day Timolol No No No No Moderate 10 to 30 mg 4 to 5 twice per day https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 15/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate ISA: intrinsic sympathomimetic activity; MSA: membrane stabilizing activity; IV: intravenous. Range of usual, oral, anti-hypertensive dose, unless "IV" noted. Duration of hypotensive effect, in general, is longer than may be predicted by serum half-life. Usual initial IV dose. Subsequent dosing generally needed. See drug monograph for detail. Not available in US. Sotalol has independent class III antiarrhythmic activity. Prepared with data from: 1. Frishman WH, Alwarshetty M. -Adrenergic blockers in systemic hypertension pharmacokinetic considerations related to current guidelines. Clin Pharmacokinet 2002; 41:505. 2. Brubacher JR. -Adrenergic Antagonists. In: Goldfrank's Toxicologic Emergencies, 9th ed, Nelson LS (Ed), McGraw-Hill, New York 2010. Graphic 82571 Version 11.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 16/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Major drug interactions with beta blockers Drug Possible effects Precautions Aluminum hydroxide gel Decreased beta-blocker Avoid beta-blocker-aluminum adsorption and therapeutic effect hydroxide combination Aminophylline Mutual inhibition Observe patient's response Amiodarone May induce cardiac arrest Combination should be used with extreme caution Antidiabetic agents Enhanced hypoglycemia; Monitor for altered diabetic response hypertension Calcium channel inhibitors Potentiation of bradycardia, Avoid use, although few patients show (verapamil, diltiazem) myocardial depression, and hypotension ill effects Cimetidine Prolongs half-life of Combination should be used with propranolol caution Clonidine Hypertension during clonidine withdrawal Monitor for hypertensive response; withdraw beta blocker before withdrawing clonidine Digitalis glycosides Potentiation of bradycardia Observe patient's response; interactions may benefit angina patients with abnormal ventricular function Epinephrine Hypertension; bradycardia Administer epinephrine cautiously; cardioselective beta blocker may be safer Ergot alkaloids Excessive vasoconstriction Observe patient's response; few patients show ill effects Glucagon Inhibition of hyperglycemic Monitor for reduced response effect Halofenate Reduced beta-blocking activity; induction of Observe for impaired response to beta blockade propranolol withdrawal rebound Indomethacin Inhibition of antihypertensive Observe patient's response response to beta blockade Isoproterenol Mutual inhibition Avoid concurrent use or choose cardiac-selective beta blocker https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 17/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Levodopa Antagonism of levodopa's hypotensive and positive Monitor for altered response; interaction may have favorable results inotropic effects Lidocaine Propranolol pretreatment increases lidocaine levels with Combination should be used with caution; use lower doses of lidocaine potential toxicity Methyldopa Hypertension during stress Monitor for hypertensive episodes MAO inhibitors Uncertain, theoretical Manufacturer of propranolol considers concurrent use contraindicated Phenothazines Additive hypotensive effects Monitor for altered response, especially with high doses of phenothiazines Phenylpropranolamine Severe hypertensive reaction Phenytoin Additive cardiac depressant effects Administer IV phenytoin with great caution Quinidine Additive cardiac depressant Observe patient's response; few effects patients show ill effects Reserpine Excessive sympathetic Observe patient's response blockade Rifampin Increased metabolism of beta blockers Observe patient's response Smoking Increased metabolism of beta blockers Observe patient's response Tricyclic antidepressants Inhibits negative inotropic and chronotropic effects of beta blockers
hyperkalemia in hemodialysis patients. Nephron 2002; 91:222. 37. McCauley J, Murray J, Jordan M, et al. Labetalol-induced hyperkalemia in renal transplant recipients. Am J Nephrol 2002; 22:347. 38. Gheorghiade M, Eichhorn EJ. Practical aspects of using beta-adrenergic blockade in systolic heart failure. Am J Med 2001; 110 Suppl 7A:68S. 39. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 12/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate fatigue, and sexual dysfunction. JAMA 2002; 288:351. 40. Silvestri A, Galetta P, Cerquetani E, et al. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo. Eur Heart J 2003; 24:1928. 41. Sharma AM, Pischon T, Hardt S, et al. Hypothesis: Beta-adrenergic receptor blockers and weight gain: A systematic analysis. Hypertension 2001; 37:250. 42. Leslie WS, Hankey CR, Lean ME. Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM 2007; 100:395. 43. Stephen SA. Unwanted effects of propranolol. Am J Cardiol 1966; 18:463. 44. Booth RJ, Wilson JD, Bullock JY. Beta-adrenergic-receptor blockers and antinuclear antibodies in hypertension. Clin Pharmacol Ther 1982; 31:555. 45. Self-poisoning with beta-blockers. Br Med J 1978; 1:1010. 46. Frishman W, Jacob H, Eisenberg E, Ribner H. Clinical pharmacology of the new beta- adrenergic blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J 1979; 98:798. Topic 967 Version 30.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 13/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate GRAPHICS Beta blocker properties Alpha Beta-1 Half l Drug ISA MSA Lipophilicity Usual dose* blockade selectivity hour Acebutolol No Yes Yes Yes Low 100 to 400 mg 3 to 4 twice per day Atenolol No Yes No No Low 50 to 200 mg once daily 6 to 9 Betaxolol No Yes No Yes Low 10 to 20 mg once daily 14 to 22 Bisoprolol No Yes No No Moderate 2.5 to 20 mg once daily 9 to 12 Carteolol No No Yes No Low 2.5 to 5 mg once daily 6 Carvedilol Yes No No Yes High 3.125 to 25 mg twice per day 7 to 10 Esmolol No Yes No No Low IV only 250 to 500 9 minut micrograms/kg over one minute then 25 to 50 micrograms/kg per minute as IV infusion; titrate incrementally up to maximum of 300 microgram/kg per minute https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 14/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Labetalol Yes No Yes (Beta ) 2 Low Moderate IV 20 mg 3 to 4 Orally 100-400 mg two or three times per day Metoprolol tartrate No Yes No Low Moderate IV 1.25 to 5 mg 3 to 4 (7 to 9 h in poor Orally 25 to 100 mg two metabo times per day Metoprolol succinate No Yes No Low Moderate Orally 50 to 400 mg once Apparen half-life (extended daily prolong release) continu osmotic release ~20 hou Nadolol No No No No Low 40 to 160 mg 20 to 24 once daily Nebivolol No Yes No No High 5 to 40 mg once daily 10 to 12 (19 to 32 poor metabo Oxprenolol No No Yes Yes Moderate 40 to 80 mg three times per day 1.5 Penbutolol No No Yes No High 10 to 40 mg once daily 5 Pindolol No No Yes Low Moderate 5 to 30 mg 3 to 4 twice per day Propranolol No No No Yes High IV 1 to 5 mg 3 to 4 Orally 10 to 80 mg two to four times daily Sotalol No No No No Low 80 to 160 mg 12 twice per day Timolol No No No No Moderate 10 to 30 mg 4 to 5 twice per day https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 15/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate ISA: intrinsic sympathomimetic activity; MSA: membrane stabilizing activity; IV: intravenous. Range of usual, oral, anti-hypertensive dose, unless "IV" noted. Duration of hypotensive effect, in general, is longer than may be predicted by serum half-life. Usual initial IV dose. Subsequent dosing generally needed. See drug monograph for detail. Not available in US. Sotalol has independent class III antiarrhythmic activity. Prepared with data from: 1. Frishman WH, Alwarshetty M. -Adrenergic blockers in systemic hypertension pharmacokinetic considerations related to current guidelines. Clin Pharmacokinet 2002; 41:505. 2. Brubacher JR. -Adrenergic Antagonists. In: Goldfrank's Toxicologic Emergencies, 9th ed, Nelson LS (Ed), McGraw-Hill, New York 2010. Graphic 82571 Version 11.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 16/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Major drug interactions with beta blockers Drug Possible effects Precautions Aluminum hydroxide gel Decreased beta-blocker Avoid beta-blocker-aluminum adsorption and therapeutic effect hydroxide combination Aminophylline Mutual inhibition Observe patient's response Amiodarone May induce cardiac arrest Combination should be used with extreme caution Antidiabetic agents Enhanced hypoglycemia; Monitor for altered diabetic response hypertension Calcium channel inhibitors Potentiation of bradycardia, Avoid use, although few patients show (verapamil, diltiazem) myocardial depression, and hypotension ill effects Cimetidine Prolongs half-life of Combination should be used with propranolol caution Clonidine Hypertension during clonidine withdrawal Monitor for hypertensive response; withdraw beta blocker before withdrawing clonidine Digitalis glycosides Potentiation of bradycardia Observe patient's response; interactions may benefit angina patients with abnormal ventricular function Epinephrine Hypertension; bradycardia Administer epinephrine cautiously; cardioselective beta blocker may be safer Ergot alkaloids Excessive vasoconstriction Observe patient's response; few patients show ill effects Glucagon Inhibition of hyperglycemic Monitor for reduced response effect Halofenate Reduced beta-blocking activity; induction of Observe for impaired response to beta blockade propranolol withdrawal rebound Indomethacin Inhibition of antihypertensive Observe patient's response response to beta blockade Isoproterenol Mutual inhibition Avoid concurrent use or choose cardiac-selective beta blocker https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 17/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Levodopa Antagonism of levodopa's hypotensive and positive Monitor for altered response; interaction may have favorable results inotropic effects Lidocaine Propranolol pretreatment increases lidocaine levels with Combination should be used with caution; use lower doses of lidocaine potential toxicity Methyldopa Hypertension during stress Monitor for hypertensive episodes MAO inhibitors Uncertain, theoretical Manufacturer of propranolol considers concurrent use contraindicated Phenothazines Additive hypotensive effects Monitor for altered response, especially with high doses of phenothiazines Phenylpropranolamine Severe hypertensive reaction Phenytoin Additive cardiac depressant effects Administer IV phenytoin with great caution Quinidine Additive cardiac depressant Observe patient's response; few effects patients show ill effects Reserpine Excessive sympathetic Observe patient's response blockade Rifampin Increased metabolism of beta blockers Observe patient's response Smoking Increased metabolism of beta blockers Observe patient's response Tricyclic antidepressants Inhibits negative inotropic and chronotropic effects of beta blockers Observe patient's response Tubocurarine Enhanced neuromuscular blockade Observe response in surgical patients, especially after high doses of propranolol IV: intravenous. Graphic 77171 Version 3.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 18/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Contributor Disclosures Philip J Podrid, MD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 19/19
7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Major side effects of class I antiarrhythmic drugs : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 10, 2022. INTRODUCTION Quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide, and propafenone are all class I antiarrhythmic drugs ( table 1) used for the treatment of various atrial and ventricular arrhythmias. This topic will review the major side effects of the various drugs. Recommendations for the clinical role of these drugs in the treatment of atrial and ventricular arrhythmias are presented separately. (See "Overview of the acute management of tachyarrhythmias".) WHEN TO MEASURE DRUG CONCENTRATIONS Monitored drug concentrations are useful for patient care in several situations: Acutely, when increasing or decreasing the dose, if there is concern about either an inadequate therapeutic effect or possible toxic effect To confirm a stable dose in a medication with narrow therapeutic window and significant potential toxicities If you suspect unpredictable metabolism and/or elimination, caused by changes in electrolytes, kidney or liver disease (depending on the major route of elimination of the drug), older age category or congestive heart failure, all of which could result in higher than predicted concentrations resulting in drug toxicity. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 1/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate More detailed information regarding recommendations for measuring drug concentrations and target drug concentrations for specific medications is available in the Lexicomp drug database. QUINIDINE Quinidine is a class Ia antiarrhythmic agent ( table 1) that can be used to treat both atrial and ventricular arrhythmias. It is no longer as commonly used as some antiarrhythmic agents, primarily due to concern about side effects ( table 2), particularly proarrhythmia and sudden death [1]. Cardiovascular toxicity There are a variety of potential cardiac toxicities related to the administration of quinidine, including proarrhythmia, conduction disturbances, hypotension, and congestive heart failure. Proarrhythmia and ventricular arrhythmias Ventricular arrhythmias, including isolated ventricular premature beats, couplets, bigeminy, and ventricular tachycardia, can be induced by quinidine [2]. As an example, "quinidine syncope," which is probably due to self-terminating torsades de pointes (a form of polymorphic ventricular tachycardia), has been reported to occur in 1.5 percent of patients per year [3]. Thus, the induction of arrhythmias appears to reflect the proarrhythmic effect of quinidine, rather than true toxicity. Furthermore, there is suggestive evidence that these arrhythmias may be fatal, leading to lower survival rates in patients treated with quinidine. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Class IA antiarrhythmic drugs'.) Quinidine syncope and torsades de pointes are frequently associated with significant QT prolongation [3,4] precipitated or aggravated by hypokalemia, hypomagnesemia, and bradycardia, and concurrent therapy with digitalis [3-5]. Other antiarrhythmic drugs that prolong the QT interval (such as procainamide, disopyramide, amiodarone, and sotalol) should be avoided. Electrophysiologically-guided class 1A antiarrhythmic drug treatment with quinidine appears to have a place for patients with Brugada syndrome. The results of small, nonrandomized studies in patients with Brugada syndrome with various clinical presentations and who had inducible VF have shown an excellent protective effect of quinidine during electrophysiological testing and an excellent clinical outcome in drug-treated patients. [6]. (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) Treatment of torsades de pointes Treatment of torsades de pointes requires immediate discontinuation of quinidine and any other drug that prolongs the QT interval [7]. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 2/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Torsades de pointes appears to be induced by triggered activity resulting from early afterdepolarizations associated with QT prolongation [8,9]. The approach to the treatment of torsades de pointes is presented separately. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) Prevention Alkalinization with sodium bicarbonate or sodium lactate (lactate is rapidly metabolized to bicarbonate) may diminish the proarrhythmic effect of quinidine [1,10]. At the level of the sodium channel, which is blocked by quinidine in part via a charge effect of this cationic drug, alkalosis will enhance recovery of the sodium channel by at least two mechanisms [11]: It will hyperpolarize the cell by decreasing the extracellular potassium concentration. (See "Potassium balance in acid-base disorders".) It will drive the reaction + Qud + OH < > QudOH to the right, thereby decreasing the availability of the active charged form of the drug. It has also been hypothesized that administration of a sodium containing solution directly reverses the sodium channel blockade. Sex differences Females are more susceptible to QT interval prolongation and torsades de pointes after the administration of quinidine and drugs that delay cardiac repolarization. This effect appears to be independent of serum drug concentrations. In a study of 45 healthy volunteers (21 females) which compared serum quinidine concentrations and changes in QRS and QT intervals between males and females, there were no sex differences in the plasma concentrations or pharmacokinetic variables, but demonstrated a significantly greater increase in QTc and in QRS duration when compared with men [12,13]. Thus, the disparity in prolongation of cardiac repolarization is due to a pharmacodynamic difference, and appears to involve sex- specific effects on both depolarization and repolarization. Conduction disturbances The cardiac toxicity associated with quinidine may be initially manifested by slowed sinus or AV nodal conduction, causing sinus node conduction abnormalities or AV block [14,15]. Higher plasma concentrations may lead to marked QRS widening. Hypotension Hypotension, requiring either slowing or cessation of intravenous therapy, occurs in approximately 25 percent of patients. Some reports have demonstrated a good response to 500 mL of isotonic saline, a regimen that can be tolerated even in patients with significant HF. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 3/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Quinidine can induce hypotension, particularly if large doses are administered rapidly and intravenously. The fall in blood pressure is due both to direct vasodilation and to inhibition of alpha-adrenergic mediated vasoconstriction in arteries and veins [16]. The hemodynamic effects of oral quinidine are similar but less pronounced. Increased ventricular response during atrial fibrillation or flutter Quinidine can significantly increase the ventricular rate in patients with uncontrolled atrial fibrillation or flutter [1]. Two factors contribute to this response. By slowing the atrial fibrillation or atrial flutter rate, quinidine increases the likelihood that a given impulse will pass through the AV node. This tendency is enhanced by the direct vagolytic action of quinidine. Thus, conduction through the AV node must be slowed and the ventricular response controlled (using -blockers, calcium channel blockers, or digitalis) before therapy with quinidine is initiated in these disorders. (See "Atrial fibrillation: Cardioversion".) Central nervous system toxicity Central nervous system toxicity is associated with high- dose therapy and subsequent high plasma quinidine concentrations. The constellation of symptoms that may be seen is called cinchonism and includes tinnitus, hearing loss, confusion, delirium, disturbances in vision, and psychosis. (See 'When to measure drug concentrations' above.) Gastrointestinal symptoms The most frequent adverse effects with oral quinidine are gastrointestinal, including nausea, diarrhea, and abdominal bloating and discomfort [1]. These symptoms may be less severe with the gluconate preparation. Immune-mediated reactions A number of immune-mediated reactions may be induced by quinidine therapy, such as rash, fever, hemolytic anemia, thrombocytopenia, leukopenia, hepatotoxicity, and anaphylaxis [1]. Thrombocytopenia, for example, results from antibodies to quinidine-platelet complexes, which cause platelets to agglutinate and lyse [17]. A lupus-like syndrome, similar to that induced by procainamide, is a rare problem [18]. (See "Drug-induced lupus".) Interaction with other drugs and with grapefruit juice Quinidine is metabolized by the cytochrome P450 system and it is a substrate of the CYP3A4 enzyme. Since CYP3A4 activity can be affected by grapefruit juice and a large number of other medications ( table 3), providers must be alert for potential quinidine toxicity when used in combination with CYP3A4 inhibitors and other cardiac drugs after grapefruit juice ingestion. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Phase I reactions'.) DISOPYRAMIDE https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 4/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Anticholinergic symptoms are the most common side effect profile of disopyramide, but cardiac toxicity is of greatest concern. In particular, the negative inotropic activity and proarrhythmic potential of disopyramide limits its use in settings in which it might otherwise be effective. Anticholinergic side effects The administration of disopyramide is associated with a anticholinergic symptoms including dry mouth (32 percent), urinary hesitancy (14 percent), and constipation (11 percent). As a result, disopyramide should not be used in patients with underlying conditions that may be exacerbated by decreased cholinergic activity including glaucoma, myasthenia gravis, and urinary retention. The anticholinergic effects can be diminished by the coadministration of drugs that increase cholinergic activity such as physostigmine, pyridostigmine, or bethanechol [19]. These agents selectively reduce anticholinergic symptoms without affecting the electrophysiologic or antiarrhythmic properties of disopyramide [19,20]. Disopyramide concentration and its metabolite, mono-N-dealkyldisopyramide, concentration should be monitored in patients whose renal function is decreased to prevent anticholinergic side effects associated with disopyramide. When serum mono-N-dealkyldisopyramide concentration is over approximately 1 microg/mL, the dose should be decreased or discontinued [21]. (See 'When to measure drug concentrations' above.) Cardiac toxicity Disopyramide has substantial negative inotropic activity in humans, resulting in reductions in cardiac contractility and cardiac output, and a reflex increase in systemic vascular resistance [22]. These changes can lead to overt heart failure (HF). HF usually occurs within the first three weeks of therapy; however, it can be seen as soon as 48 hours after initiation or several months later. This complication is most likely to occur with preexisting HF, affecting 55 percent of such patients versus only 5 percent without a prior history of heart disease. Intravenous disopyramide administration and concurrent renal failure are other risk factors for a significant decline in myocardial function. Patients with known significant chronic kidney disease should have serum drug concentrations measured at steady state in an effort to minimize toxicity. (See 'When to measure drug concentrations' above.) The decline in contractility generally resolves rapidly after discontinuation of disopyramide. There may, however, be an acute requirement for therapy with diuretics, inotropic agents, or afterload reducing drugs. Other suggestions to enhance the safety of disopyramide in patients with underlying myocardial dysfunction include avoidance of loading doses or intravenous administration, and careful dose titration. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 5/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Electrocardiographic and proarrhythmic effects Significant widening of the QRS interval occurs in a minority of patients treated with disopyramide. This is most likely to occur at high circulating drug concentrations, but may be seen with values in the therapeutic range. Therapy should be discontinued until the plasma disopyramide concentration is determined. Like other class IA antiarrhythmic drugs, disopyramide can prolong the QT interval, possibly leading to increased ventricular ectopy, torsades de pointes (a form of polymorphic ventricular tachycardia), or syncope [23]. Concurrent use of other class I or class III agents (such as amiodarone or sotalol) can produce an additive increase in both the QRS and QT intervals. A similar effect can be induced by the administration of erythromycin or clarithromycin, drugs that inhibit the metabolism of disopyramide by inhibiting CYP3A4 ( table 3) [24-26]. Azithromycin may be safer [27], but potentially fatal ventricular arrhythmias can be induced when used in combination with disopyramide [28]. Disopyramide should be discontinued if the QT interval increases by more than 25 percent or ventricular ectopy is exacerbated. (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) The proarrhythmic potential for disopyramide (6 percent) is less than that for the other class IA drugs, quinidine (15 percent) and procainamide (9 percent) [29]. With each of these drugs, the likelihood of proarrhythmia is increased by hypokalemia, hypomagnesemia, and bradyarrhythmias [30,31]. Intravenous magnesium sulfate has been useful in patients with QT prolongation and torsades de pointes [32,33]. Magnesium may act by suppressing afterdepolarizations. Increased ventricular response during atrial fibrillation or flutter Like other class IA antiarrhythmic drugs, disopyramide can increase the ventricular rate in patients with uncontrolled atrial fibrillation or flutter. Two factors contribute to this response: disopyramide slows the fibrillation or flutter rate, thereby making it more likely that a given impulse will pass through the AV node; and the direct anticholinergic effect of disopyramide enhances AV nodal conduction. Thus, the AV node must be slowed and the ventricular rate controlled (with - blockers, calcium channel blockers, or digoxin) before therapy with disopyramide is begun. (See "Atrial fibrillation: Cardioversion".) Safety of disopyramide in obstructive hypertrophic cardiomyopathy At the typical doses used in modern practice, disopyramide does not appear to induce proarrhythmia in patients with hypertrophic cardiomyopathy (HCM) with symptomatic left ventricular outflow tract obstruction. This is discussed in greater detail separately. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction", section on 'Disopyramide'.) https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 6/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate PROCAINAMIDE Procainamide is an effective antiarrhythmic drug; however, its use may be limited by a lupus-like syndrome and, an infrequent but potentially severe adverse effect of bone marrow toxicity. Lupus-like syndrome Chronic administration of procainamide is associated with a positive antinuclear antibody titer in patients, particularly in those who are slow acetylators. Symptoms similar to those seen in lupus (eg, arthritis, arthralgias, and pleuritis) develop in 15 to 20 percent of patients. The clinical manifestations typically remit when therapy is discontinued or changed to N-acetylprocainamide, the major active metabolite of procainamide [34]. The inability of N- acetylprocainamide to induce the lupus-like syndrome suggests an important pathogenetic role for the aromatic amino group on procainamide [35]. (See "Drug-induced lupus".) Blood dyscrasia Pancytopenia or agranulocytosis is a rare but potentially life-threatening complication that may be mediated by allergic, hypersensitivity, or immunologic mechanisms [36,37]. These complications are rare, with an estimated incidence of 0.22 percent, and usually develop within three months after the initiation of therapy [36,37]. Drug withdrawal is indicated in all cases; however, there is a variable degree of recovery of the white blood cell count. Cardiac toxicity Although some cardiac side effects of procainamide can be seen at therapeutic concentrations, a variety of more serious and potentially lethal effects are more common at toxic plasma concentrations (above 30 mg/L for procainamide plus its major metabolite N-acetylprocainamide versus a therapeutic range of 4 to 12 mg/L for procainamide alone). Since procainamide is largely metabolized by the liver and eliminated by the kidneys, changes in liver and kidney function could account for changes in the therapeutic concentration in adults. (See 'When to measure drug concentrations' above.) Among the changes that can occur are: Conduction delay, manifested by progressive PR prolongation or widening of the QRS interval Prolonged refractoriness, leading to prolongation of the QT interval in proportion to the plasma procainamide concentration Arrhythmias, such as ventricular premature contractions and ventricular tachycardia Severe left ventricular function depression https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 7/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Effects on ECG intervals The electrocardiogram can be used to monitor both the therapeutic and toxic effects of procainamide on the heart. These effects are due to both a direct influence on electrophysiologic properties and the indirect impact of autonomic modulation (vagolytic properties). PR interval When atrioventricular (AV) conduction is normal, procainamide has little effect on the PR interval, if however, there is preexisting slowing of AV conduction, then procainamide can depress conduction further, leading to higher degrees of AV block even at therapeutic drug concentrations. The risk of heart block in this setting is heightened since procainamide also reduces ventricular automaticity. QRS duration Normal procainamide concentrations widen the QRS complex due to slowing of conduction in the Purkinje system and ventricular muscle. The drug should be discontinued if the QRS duration increases by more than 35 to 50 percent to avoid serious toxicity. Toxic plasma concentrations can cause intraventricular conduction disturbances and reentry, resulting in ventricular arrhythmias. QT interval Procainamide prolongs the QT interval, usually in proportion to the plasma procainamide concentration. Marked prolongation occurring in conjunction with hypokalemia can cause early afterdepolarizations and triggered activity leading to ventricular tachycardia. Other medications that prolong the QT interval, such as fluoroquinolones and certain antihistamines ( table 4), should be avoided in patients with known prolongation of the QT interval, and patients receiving procainamide [38]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Increased ventricular response during atrial fibrillation or flutter Procainamide, like quinidine and disopyramide, can significantly increase the ventricular rate in patients with uncontrolled atrial fibrillation or flutter. Two factors contribute to this response: By slowing the atrial rate of atrial fibrillation or atrial flutter, procainamide increases the likelihood that a given impulse will pass through the AV node, thereby potentially increasing the ventricular rate. Procainamide has a direct vagolytic action on the AV node, increasing conduction through the AV node. Therefore, when administering procainamide for chemical cardioversion of atrial fibrillation, conduction through the AV node must be slowed and the ventricular response controlled (using -blockers, calcium channel blockers, or digitalis) before therapy with procainamide is initiated in these disorders [39]. (See "Atrial fibrillation: Cardioversion".) https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 8/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate LIDOCAINE (INTRAVENOUS) Lidocaine, administered intravenously in the treatment of ventricular arrhythmias, is generally well tolerated. The major side effects primarily involve the central nervous system, the cardiovascular system, and the gastrointestinal tract. Neurologic toxicity The most common adverse effect of intravenous lidocaine is central nervous system (CNS) toxicity [40-43]. The symptoms are usually mild, dose-dependent, and resolve with a decrease in the infusion rate or discontinuation of the drug. These side effects may be particularly frequent in older adults or those with HF, and in patients with significant liver impairment in whom the metabolism of lidocaine is reduced. Tremor is a useful bedside sign of toxicity. Other neurologic side effects include insomnia or drowsiness, lightheadedness, dysarthria and slurred speech, ataxia, depression, agitation, change in sensorium, a change in personality, nystagmus, hallucinations, memory impairment, and emotional lability. High plasma concentrations of lidocaine can also provoke seizures that are usually generalized [44]. This can also occur at lower drug concentrations if lidocaine is given to patients congeners of lidocaine, such as oral tocainide or mexiletine. (See 'When to measure drug concentrations' above.) Cardiovascular toxicity Cardiac side effects are an infrequent complication of intravenous lidocaine therapy even among patients with significant underlying heart disease. The primary cardiovascular side effects include sinus slowing, asystole, hypotension, and shock. These are most often associated with overdosing or with rapid administration of lidocaine. Individuals who are older than 60 years and those with significant preexisting heart disease are at greatest risk [45,46]. MEXILETINE The side effects of mexiletine are generally dose- and concentration-dependent. The most common adverse effects are related to the gastrointestinal and central nervous systems [47,48]. Common digestive complaints include nausea, vomiting, or heartburn. These symptoms are reversible and can be reduced by food or antacid administration. The most frequent central nervous system complaints are dizziness, lightheadedness, tremor, nervousness, difficulty with coordination, change in sleep habits, paresthesias, and numbness [47,48]. More serious noncardiac side effects are rare. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 9/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cardiac complications There are two potential cardiac complications associated with mexiletine: proarrhythmia; and impaired hemodynamics. Proarrhythmia Mexiletine has a proarrhythmic effect that is of greatest concern in patients with life-threatening arrhythmias such as sustained ventricular tachycardia [49,50]. Exacerbation of arrhythmia after mexiletine occurs in 10 to 15 percent of patients [29]. Mexiletine also has a depressant effect on sinus node function and can result in sinus bradycardia or prolonged sinus node recovery time in patients with preexisting sinus node dysfunction or following administration of high doses [29,49]. Hemodynamics Mexiletine is usually well tolerated hemodynamically, lacking the potent negative inotropic effects seen with disopyramide, flecainide, and -blockers. Nevertheless, in patients with severe congestive HF, mexiletine should be used with caution because it can aggravate the HF or cause hypotension [51-53]. Cardiodepressant effects may be more evident in patients with severe left ventricular dysfunction. Furthermore, hepatic metabolism may be impaired in HF, resulting in prolongation of the elimination half-life of mexiletine to 25 hours. Mexiletine-induced hypersensitivity syndrome Mexiletine-induced hypersensitivity syndrome occurs most frequently in Japanese males and is manifested by fever, rash, peripheral blood eosinophilia, and elevation of liver transaminase enzymes [54,55]. Although the mechanism for the immunogenicity is not clear, a role of reactive drug metabolites in initiating an immune response via hapten formation has been suggested. The involvement of viral infection has been explored suggesting a relationship between human herpes virus 6 and the development of systemic immune responses [56]. Inhibitor of CYP1A2 Mexiletine is a potent CYP1A2 inhibitor and co-administration of mexiletine increases plasma concentrations of substrates for cytochrome P450 (CYP) 1A2 such as theophylline [57], caffeine [57,58], and tizanidine (a new antispastic agent) [59]. Mexiletine, approved for managing pain, painful neuropathies, and headache when used in conjunction with tizanidine may cause unpredictable changes in plasma concentrations and pharmacodynamic effects and should be used with care as it is with other substrates for CYP1A2 [60]. FLECAINIDE Flecainide is an effective agent against both ventricular and supraventricular arrhythmias. However, its use is limited by concern about toxicity, particularly its proarrhythmic effects. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 10/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cardiac toxicity Proarrhythmia Flecainide was one of two class IC antiarrhythmic medications included in the CAST trial, which evaluated patients with asymptomatic, non-life-threatening ventricular arrhythmias who were six days to two years after an acute myocardial infarction (MI) [61]. Flecainide had an apparent proarrhythmic effect with a significantly increased incidence of mortality plus nonfatal cardiac arrest (6.1 percent versus 2.3 percent in the placebo group). It has been proposed that the increase in malignant arrhythmias was due to the use of flecainide in the setting of ischemia and/or cardiac structural abnormalities (eg scar from the prior infarction). This hypothesis is supported by the following observations: All patients in the CAST trial had prior MI. A case series of three patients without CHD who developed ventricular arrhythmias after flecainide use for atrial fibrillation included one patient with a prosthetic mitral valve, one patient with hypertrophic cardiomyopathy, and one patient without known cardiac structural abnormalities [62]. Flecainide did not increase mortality when used for the treatment of supraventricular arrhythmias in structurally normal hearts [63]. Conduction abnormalities Due to its significant effect on sodium channels, flecainide prolongs depolarization and can slow conduction in the AV node, the His-Purkinje system, and below. These changes can lead to prolongation of the PR interval, increased QRS duration, and first- and second-degree heart block. In addition, profound sinus bradycardia can be induced in patients with preexisting sinus node disease [64]. In contrast, flecainide does not affect repolarization and therefore has little effect on the QT interval [65]. The cardiac safety profile of flecainide was assessed in 227 outpatients with paroxysmal atrial fibrillation (PAF) [66]. Patients were treated with 200 mg daily for 24 weeks. The following results were reported: Mean QRS duration increase was 11.4 percent, and 19 percent of patients had 25 percent increase in QRS duration. Significant left ventricular ejection fraction (LVEF) reduction occurred in 1.4 percent of patients. Bradycardia (13.2 percent) and ventricular extrasystoles (10.6 percent) were the most frequently identified proarrhythmic effects. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 11/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Other adverse cardiac events included atrioventricular block (4.0 percent), supraventricular tachycardia (2.2 percent), bundle branch block (1.8 percent) and atrial fibrillation (1.3 percent). Extracardiac effects Flecainide can induce a variety of noncardiac side effects, including dizziness, blurred vision or difficulty in focusing, headache, and nausea, each of which occurs in 10 to 20 percent of patients [67]. Renal dysfunction Flecainide accumulates in patients with renal failure; close monitoring of concentrations is needed. Although the absorption and volume of distribution of flecainide are unaffected by renal failure, the plasma elimination half-life is prolonged in mild to moderate renal impairment (10 to 30 h) compared with normal renal function (6 to 15 h). Moreover, the half-life increases further in patients with stage 5 chronic kidney disease (up to 40 h) [68]. Since flecainide is not removed efficiently by dialysis there is a potential for toxicity in patients undergoing dialysis. (See 'When to measure drug concentrations' above.) Renal failure may predispose to toxicity at lower serum flecainide concentrations and cause severe neurotoxicity [69-71]. While dizziness and visual disturbances, including diplopia, are not unusual, severe neurologic complications are rare. However, they include paranoid psychosis, dysarthria, visual hallucinations, generalized seizures and cerebello-myoclonic syndrome. CYP2D6 inhibitors Flecainide is a substrate of the hepatic enzyme system CYP2D6, which is inhibited by the selective serotonin-reuptake inhibitors (SSRIs), fluoxetine and paroxetine. Thus, these CYP2D6 inhibitors also have the potential to cause central nervous system toxicity with flecainide ( table 5) [72,73]. PROPAFENONE Patients with known structural heart disease should not receive propafenone. Propafenone should be discontinued in patients who develop sustained VT. Approximately 15 to 20 percent of patients taking propafenone will have side effects that require drug discontinuation [74-76]. The most common adverse reactions involve the gastrointestinal, central nervous, and cardiovascular systems. Most of these complications are dose-dependent, particularly central nervous system side effects such as dizziness, nausea, unusual taste, and blurred vision, which are often ameliorated if the propafenone dose is reduced [74]. Potential side effects involving the cardiovascular system are most concerning, as the cardiac side effects are the most life-threatening. The risk of cardiovascular toxicity is greater in patients with https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 12/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate structural heart disease and in those treated for ventricular rather than supraventricular arrhythmias [74,75]. The relation between propafenone dose, concentration, clinical response, and toxicity is complex. The main metabolic route of propafenone is via the cytochrome P450 2D6 isoenzyme. This metabolic pathway, known to have genetic polymorphisms, is functionally absent in approximately 7 percent of White and African Americans. In these "slow metabolizers," the extent of first-pass hepatic metabolism is much less than in "extensive metabolizers," and increased plasma concentration may be more likely to cause side effects. Moreover, because the oxidative elimination of propafenone is saturable, small dose increases may cause a rapid and disproportionate increase in plasma concentrations, thus augmenting its potential for causing toxicity. (See 'When to measure drug concentrations' above.) Cardiovascular effects Inotropic effects In patients with a normal or minimally decreased LVEF ( 40 percent), oral propafenone can decrease the ejection fraction without causing symptoms of HF [77]. However, overt HF may be induced in patients with preexisting ventricular systolic dysfunction [78]. The negative inotropic effect of propafenone is associated with significant increases in pulmonary capillary wedge pressure and in systemic and pulmonary vascular resistance and a decline in cardiac output. Propafenone should therefore be avoided in patients with overt HF. However, propafenone can be administered cautiously to patients with mildly reduced LVEF who have no clinical signs or symptoms of HF, with close monitoring over one to two weeks for the development of HF symptoms following the initiation of therapy. Chronotropic effects Propafenone has a variety of effects that can lead to bradycardia including its Class IC activity and its beta-blocker and calcium channel blocker properties. As a result, patients with known sinus node dysfunction, including the sinus node dysfunction, should not receive propafenone in the absence of a permanent pacemaker [79]. Alternatively, because potential variations in propafenone metabolism may exist and remain undetected in everyday practice, some authors have suggested a heart rate challenge, such as exercise testing, for patients using chronic propafenone [80]. Conduction disturbances Propafenone slows atrioventricular conduction and causes prolongation of the PR and QRS intervals. Prolongation of the PR interval ranges from 15 to 25 percent; it is a common finding and is not necessarily regarded as a sign of toxicity. However, on rare occasions propafenone has been associated with the development of atrioventricular block. Patients on propafenone who develop second or third degree AV block should have their dose of propafenone reduced or discontinued. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 13/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Propafenone has been associated with QRS prolongation, new left bundle branch block, and new right bundle branch block [81,82]. These conduction disturbances usually occur in patients with underlying heart disease and appear to be dose-dependent. No specific dose adjustments are required in this setting. Proarrhythmia Like other antiarrhythmic agents, propafenone has a proarrhythmic effect that can trigger sustained ventricular tachycardia (VT) [29]. The proarrhythmic effect of propafenone may be somewhat reduced by its beta-blocking activity. The potential for proarrhythmia is greater with the class IC agents, such as flecainide or propafenone, compared with the IA or IB drugs ( table 1) [83]. The two most powerful predictors of proarrhythmia are previous VT and decreased LVEF. CNS side effects A variety of adverse central nervous system (CNS) effects have been reported in association with propafenone, with dizziness being the most common along with nausea, unusual taste, and blurred vision. Ataxia caused by propafenone has also been reported [84]. Although the side effects of the drug are usually dose-related, the precise mechanism is not fully understood. Blockade of beta-adrenergic receptors may be partly responsible, because this action can in itself cause CNS symptoms including sleep disturbance, depression, drowsiness, fatigue, lethargy, hallucination, delirium, paranoia, and amnesia. In patients who develop CNS effects from propafenone, it is reasonable to consider lowering the dose in an effort to reduce side effects. If CNS side effects persist, propafenone should be discontinued. Gastrointestinal side effects Gastrointestinal side effects from propafenone, usually mild in nature, are among the most commonly reported adverse effects. Up to 20 percent of patients receiving propafenone report an unusual taste , and up to 10 percent develop nausea. The frequency of side effects may be reduced when medication is taken with food. Propafenone intoxication HF, conduction disturbances, and seizures are major clinical signs of intoxication. While adverse reactions to propafenone are relatively common, reports of death secondary to propafenone intoxication are comparatively rare [85]. Propafenone intoxication is associated with ingested doses from 1800 to 9000 mg and serum concentrations as high as 12,000 ng/mL have been reported (normal therapeutic and toxic ranges for propafenone are 400 to 1100 ng/mL and 1100 to 2000 ng/mL, respectively) [85,86]. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 14/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Treatment for propafenone intoxication centers on hemodynamic support and includes intravenous glucagon (to reverse any toxicity due to the beta blocker effects), hypertonic sodium bicarbonate, hypertonic saline, and inotropic agents [86]. A temporary pacemaker may be required for patients with high-degree AV block related to the overdose. Routine blood testing for propafenone concentrations should be performed in patients following resuscitation, particularly in patients undergoing treatment for arrhythmias. (See "General approach to drug poisoning in adults", section on 'Poisoning management'.) SUMMARY AND RECOMMENDATIONS Quinidine side effects Gastrointestinal These are the most frequent adverse effects with oral quinidine. Nausea, diarrhea, and abdominal bloating and discomfort can occur. Central nervous system toxicity This is associated with high-dose therapy and subsequent high plasma quinidine concentrations. The constellation of symptoms is called cinchonism and includes tinnitus, hearing loss, confusion, delirium, disturbances in vision, and psychosis. Cardiac toxicities These include proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia), slowed atrioventricular (AV) nodal conduction (potentially leading to heart block), and hypotension. (See 'Quinidine' above.) Disopyramide side effects Anticholinergic symptoms These include dry mouth, urinary hesitancy, and constipation. Cardiac effects These include negative inotropic activity (potentially resulting in heart failure) and proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia). (See 'Disopyramide' above.) Procainamide side effects Gastrointestinal disturbances. Central nervous system dysfunction. Fever, rash, and myalgias.
are the most life-threatening. The risk of cardiovascular toxicity is greater in patients with https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 12/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate structural heart disease and in those treated for ventricular rather than supraventricular arrhythmias [74,75]. The relation between propafenone dose, concentration, clinical response, and toxicity is complex. The main metabolic route of propafenone is via the cytochrome P450 2D6 isoenzyme. This metabolic pathway, known to have genetic polymorphisms, is functionally absent in approximately 7 percent of White and African Americans. In these "slow metabolizers," the extent of first-pass hepatic metabolism is much less than in "extensive metabolizers," and increased plasma concentration may be more likely to cause side effects. Moreover, because the oxidative elimination of propafenone is saturable, small dose increases may cause a rapid and disproportionate increase in plasma concentrations, thus augmenting its potential for causing toxicity. (See 'When to measure drug concentrations' above.) Cardiovascular effects Inotropic effects In patients with a normal or minimally decreased LVEF ( 40 percent), oral propafenone can decrease the ejection fraction without causing symptoms of HF [77]. However, overt HF may be induced in patients with preexisting ventricular systolic dysfunction [78]. The negative inotropic effect of propafenone is associated with significant increases in pulmonary capillary wedge pressure and in systemic and pulmonary vascular resistance and a decline in cardiac output. Propafenone should therefore be avoided in patients with overt HF. However, propafenone can be administered cautiously to patients with mildly reduced LVEF who have no clinical signs or symptoms of HF, with close monitoring over one to two weeks for the development of HF symptoms following the initiation of therapy. Chronotropic effects Propafenone has a variety of effects that can lead to bradycardia including its Class IC activity and its beta-blocker and calcium channel blocker properties. As a result, patients with known sinus node dysfunction, including the sinus node dysfunction, should not receive propafenone in the absence of a permanent pacemaker [79]. Alternatively, because potential variations in propafenone metabolism may exist and remain undetected in everyday practice, some authors have suggested a heart rate challenge, such as exercise testing, for patients using chronic propafenone [80]. Conduction disturbances Propafenone slows atrioventricular conduction and causes prolongation of the PR and QRS intervals. Prolongation of the PR interval ranges from 15 to 25 percent; it is a common finding and is not necessarily regarded as a sign of toxicity. However, on rare occasions propafenone has been associated with the development of atrioventricular block. Patients on propafenone who develop second or third degree AV block should have their dose of propafenone reduced or discontinued. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 13/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Propafenone has been associated with QRS prolongation, new left bundle branch block, and new right bundle branch block [81,82]. These conduction disturbances usually occur in patients with underlying heart disease and appear to be dose-dependent. No specific dose adjustments are required in this setting. Proarrhythmia Like other antiarrhythmic agents, propafenone has a proarrhythmic effect that can trigger sustained ventricular tachycardia (VT) [29]. The proarrhythmic effect of propafenone may be somewhat reduced by its beta-blocking activity. The potential for proarrhythmia is greater with the class IC agents, such as flecainide or propafenone, compared with the IA or IB drugs ( table 1) [83]. The two most powerful predictors of proarrhythmia are previous VT and decreased LVEF. CNS side effects A variety of adverse central nervous system (CNS) effects have been reported in association with propafenone, with dizziness being the most common along with nausea, unusual taste, and blurred vision. Ataxia caused by propafenone has also been reported [84]. Although the side effects of the drug are usually dose-related, the precise mechanism is not fully understood. Blockade of beta-adrenergic receptors may be partly responsible, because this action can in itself cause CNS symptoms including sleep disturbance, depression, drowsiness, fatigue, lethargy, hallucination, delirium, paranoia, and amnesia. In patients who develop CNS effects from propafenone, it is reasonable to consider lowering the dose in an effort to reduce side effects. If CNS side effects persist, propafenone should be discontinued. Gastrointestinal side effects Gastrointestinal side effects from propafenone, usually mild in nature, are among the most commonly reported adverse effects. Up to 20 percent of patients receiving propafenone report an unusual taste , and up to 10 percent develop nausea. The frequency of side effects may be reduced when medication is taken with food. Propafenone intoxication HF, conduction disturbances, and seizures are major clinical signs of intoxication. While adverse reactions to propafenone are relatively common, reports of death secondary to propafenone intoxication are comparatively rare [85]. Propafenone intoxication is associated with ingested doses from 1800 to 9000 mg and serum concentrations as high as 12,000 ng/mL have been reported (normal therapeutic and toxic ranges for propafenone are 400 to 1100 ng/mL and 1100 to 2000 ng/mL, respectively) [85,86]. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 14/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Treatment for propafenone intoxication centers on hemodynamic support and includes intravenous glucagon (to reverse any toxicity due to the beta blocker effects), hypertonic sodium bicarbonate, hypertonic saline, and inotropic agents [86]. A temporary pacemaker may be required for patients with high-degree AV block related to the overdose. Routine blood testing for propafenone concentrations should be performed in patients following resuscitation, particularly in patients undergoing treatment for arrhythmias. (See "General approach to drug poisoning in adults", section on 'Poisoning management'.) SUMMARY AND RECOMMENDATIONS Quinidine side effects Gastrointestinal These are the most frequent adverse effects with oral quinidine. Nausea, diarrhea, and abdominal bloating and discomfort can occur. Central nervous system toxicity This is associated with high-dose therapy and subsequent high plasma quinidine concentrations. The constellation of symptoms is called cinchonism and includes tinnitus, hearing loss, confusion, delirium, disturbances in vision, and psychosis. Cardiac toxicities These include proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia), slowed atrioventricular (AV) nodal conduction (potentially leading to heart block), and hypotension. (See 'Quinidine' above.) Disopyramide side effects Anticholinergic symptoms These include dry mouth, urinary hesitancy, and constipation. Cardiac effects These include negative inotropic activity (potentially resulting in heart failure) and proarrhythmia with lengthening of the QT interval (potentially resulting in polymorphic ventricular tachycardia). (See 'Disopyramide' above.) Procainamide side effects Gastrointestinal disturbances. Central nervous system dysfunction. Fever, rash, and myalgias. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 15/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Positive antinuclear antibody titer This is seen in almost all patients with chronic administration of procainamide. This is particularly seen in slow acetylators, with symptoms similar to those in systemic lupus erythematosus (eg, arthritis, arthralgias, and pleuritis) in 15 to 20 percent of patients. Serious and potentially lethal cardiac effects These are more common at toxic plasma concentrations (above 30 mg/L for procainamide plus its major metabolite N- acetylprocainamide versus a therapeutic range of 4 to 12 mg/L for procainamide alone), including conduction delay (with PR prolongation or QRS widening), QT prolongation, ventricular tachyarrhythmias, increased AV nodal conduction, and depressed left ventricular function. (See 'Procainamide' above.) Lidocaine side effects When administered intravenously in the treatment of ventricular arrhythmias, lidocaine is generally well tolerated. Central nervous system These include tremor, insomnia or drowsiness, lightheadedness, ataxia, and agitation. Gastrointestinal These include nausea, vomiting, and anorexia. Cardiovascular system These include sinus node slowing, asystole, hypotension, and shock. (See 'Lidocaine (intravenous)' above.) Mexiletine side effects The side effects of mexiletine are generally dose and concentration dependent. Gastrointestinal tract These are the most common adverse effects and include nausea, vomiting, or heartburn. Central nervous system These include dizziness, lightheadedness, tremor, nervousness, difficulty with coordination, change in sleep habits, paresthesias, and numbness. Cardiac A proarrhythmic effect can contribute to ventricular tachyarrhythmias. (See 'Mexiletine' above.) Flecainide side effects This is generally well tolerated, though it can induce a variety of generally mild and tolerable side effects. Noncardiac These include dizziness, blurred vision or difficulty in focusing, headache, and nausea, each of which occurs in 10 to 20 percent of patients. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 16/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cardiac Proarrhythmia and the potential for fatal ventricular arrhythmias can occur in persons with structural heart disease. Conversely, flecainide does not appear to increase mortality when used for the treatment of supraventricular arrhythmias in persons with structurally normal hearts. (See 'Flecainide' above.) Propafenone side effects Approximately 15 to 20 percent of patients taking propafenone will have side effects that require drug discontinuation. Gastrointestinal These are the most common and include nausea and an unusual taste sensation. Central nervous system Most commonly, dizziness occurs. 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Topic 86747 Version 24.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 23/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 24/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 25/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Side effects induced by quinidine Side effect Relative frequency Cardiovascular Proarrhythmia +++ Torsades de pointes +++ Prolonged QT interval ++ Hypotension ++ Sinus arrest + Heart failure + AV block Gastrointestinal Diarrhea +++ Nausea, abdominal pain ++ Hepatotoxicity + Central nervous system Cinchonism ++ Psychosis ++ Depression + Blurred vision + Hematologic Thrombocytopenia +++ Agranulocytosis + Hemolytic anemia + Hypoprothrombinemia Other Fever + Lupus-like syndrome + Major side effects induced by quinidine and their relative frequency. Graphic 65568 Version 1.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 26/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and Conivaptan Lumacaftor Dexamethasone cobicistat- Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, and norethindrone Darunavir Phenobarbital Duvelisib Idelalisib therapy pack Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin Fedratinib Ketoconazole (rifampicin) Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium St. John's wort Ombitasvir- paritaprevir- sulfate) Lefamulin ritonavir Letermovir Ombitasvir- Netupitant paritaprevir- Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 27/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may use a different classification system resulting in some agents being classified differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 28/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, especially with Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga Intracranial disease Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances Bradyarrhythmias HIV infection Sinus node Hypothermia dysfunction Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 29/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 30/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 31/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews.
Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 28/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, especially with Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia prominent T-wave inversions Anorexia nervosa Herbs Liquid protein diets Cinchona (contains quinine), iboga Intracranial disease Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances Bradyarrhythmias HIV infection Sinus node Hypothermia dysfunction Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine Vandetanib Dofetilide (intracoronary) Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 29/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine Clarithromycin Flecainide Sparfloxacin antimoniate Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil Terbutaline Nilotinib (systemic) Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate dimeglumine Dasatinib Vemurafenib oral) Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 30/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 31/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 32/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Cytochrome P450 2D6 (CYP2D6) inhibitors Strong inhibitors Moderate inhibitors Bupropion Abiraterone Dacomitinib Adagrasib Fluoxetine Cinacalcet Paroxetine Darifenacin Quinidine Darunavir Tipranavir Duloxetine Givosiran Lorcaserin Mirabegron Perhexiline* Rolapitant Terbinafine (systemic) Thioridazine This table lists strong and moderate CYP450 2D6 inhibitors; there are no known clinically relevant inducers of CYP2D6. Inhibitors of CYP2D6 metabolism listed above can alter serum concentrations of other drugs that are dependent on CYP2D6 liver enzymes for activation or elimination: Codeine, tamoxifen, and tramadol are examples of drugs that require transformation by CYP2D6 to their active metabolite(s). The presence of CYP2D6 inhibitors can decrease efficacy of these drugs. Amitriptyline, clozapine, desipramine, flecainide, haloperidol, nortriptyline, risperidone, and valbenazine are examples of drugs that are eliminated by CYP2D6 metabolism. The presence of CYP2D6 inhibitors can increase levels of these drugs. The specific effect of CYP2D6 inhibition on CYP2D6 substrate blood levels varies widely among individual patients because of variability in CYP2D6 function (ie, genetic polymorphism). Poor, intermediate, extensive, and ultrarapid CYP2D6 function types have been well characterized. These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may use a different classification system resulting in some agents being classified differently. For additional information on CYP2D6 drug metabolism, refer to the UpToDate topic review of pharmacogenomics, section on CYP2D6 variants, and clinical topic reviews of the use of these agents and their drug interactions. Specific drug interactions and management suggestions may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate topics on specific agents and indications for further details. CYP2D6: cytochrome P450 2D6. https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 33/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Not available in United States. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 116164 Version 23.0 https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 34/35 7/5/23, 8:23 AM Major side effects of class I antiarrhythmic drugs - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs/print 35/35
7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Pulmonary disease induced by cardiovascular drugs : Edward D Chan, MD, Talmadge E King, Jr, MD : Kevin R Flaherty, MD, MS : Paul Dieffenbach, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 16, 2021. INTRODUCTION A number of cardiovascular drugs have the potential to cause respiratory impairment, although diffuse parenchymal lung disease is quite rare ( table 1A-B). Several different respiratory adverse effects have been identified: upper airway angioedema or hematoma, bronchoconstriction, cough, interstitial pneumonitis, organizing pneumonia, eosinophilic pneumonia, drug-induced lupus, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pleuritis, pleural effusion, methemoglobinemia, and solitary lung mass. This topic review will provide an overview of the lung diseases induced by various cardiovascular drugs. The clinical manifestations, diagnosis, and management of pulmonary toxicity due to amiodarone and an approach to the diagnosis of interstitial lung disease are discussed separately. (See "Amiodarone pulmonary toxicity" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".) AMIODARONE Pulmonary toxicity is a well-known adverse effect of the antiarrhythmic agent amiodarone. Several forms of pulmonary disease have been described, including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome (ARDS), diffuse alveolar hemorrhage (DAH), eosinophilic pneumonia, pulmonary nodules, solitary masses, and also (rarely) pleural https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 1/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate effusion. The clinical presentation, pathogenesis, diagnosis, and treatment of amiodarone pulmonary toxicity are discussed separately. (See "Amiodarone pulmonary toxicity".) ANGIOTENSIN CONVERTING ENZYME INHIBITORS Angiotensin converting enzyme (ACE) inhibitors are associated with cough, angioedema, and, rarely, pneumonitis. Cough All of the ACE inhibitors can induce a dry, persistent, and often nocturnal cough (in 5 to 20 percent of patients). The cough may develop within hours of the first dose or weeks to months later. It is more common in women, non-smokers, and persons of Chinese origin. The cough typically resolves one to four weeks after discontinuation of the ACE inhibitor but in a subgroup of coughers, resolution may take several months [1]. One important caveat is that cough may be a symptom of heart failure, and a thorough history and physical examination are needed to ascertain whether the cough is truly related to the ACE inhibitor therapy. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers" and "Causes and epidemiology of subacute and chronic cough in adults".) Angioedema Angioedema, particularly of the oropharynx and larynx, complicates ACE inhibitor therapy in approximately 0.1 to 0.7 percent of recipients. Since ACE inhibitor- associated angioedema typically causes swelling of the mouth, lips, tongue, larynx, pharynx, and subglottic tissues, upper airway compromise may be the presenting sign. Pruritus and urticaria are typically absent. Unlike classical hereditary angioedema, C1 inhibitor level and function and thus the C4 levels are normal in ACE inhibitor-associated angioedema. (See "An overview of angioedema: Pathogenesis and causes", section on 'ACE inhibitors' and "ACE inhibitor-induced angioedema", section on 'Pathophysiology'.) Interstitial pneumonitis Captopril and perindopril have rarely been associated with the development of diffuse interstitial pneumonitis. An eosinophilic pneumonia was found in most cases, but an acute hypersensitivity pneumonitis with lymphocytic infiltration has been described [2-6]. The radiographic appearance is nonspecific, with bilateral patchy ground glass or consolidative opacities being the most frequent finding. The diagnosis is usually made on the basis of peripheral blood or bronchoalveolar lavage eosinophilia, exclusion of infection, and/or response to empiric drug discontinuation. Occasionally, a lung biopsy is needed. Therapy consists of drug withdrawal; occasionally systemic glucocorticoids have been used for patients with more severe respiratory impairment [5,6]. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".) https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 2/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate ANGIOTENSIN RECEPTOR BLOCKERS The incidence of cough appears not to be increased with use of the angiotensin receptor blockers (ARB). Angiotensin receptor blockers (ARB) are associated with a low rate of angioedema (0.1 to 0.2 percent in large trials). However, the cross-reactivity with angiotensin converting enzyme (ACE) inhibitors is difficult to ascertain because of the phenomenon that patients with ACE inhibitor induced angioedema may continue to have episodes for weeks to months following discontinuation of the ACE inhibitor, which may overlap with initiation of the ARB. In a systematic review and meta-analysis of 11 randomized trials evaluating ARB in patients intolerant to ACE inhibitors, ARB had cough and angioedema incidences similar to placebo [7]. ANTICOAGULANT MEDICATIONS Use of anticoagulant and anti-platelet medications (vitamin K antagonists, glycoprotein IIB/IIIA antagonists) and thrombolytic agents in patients with coronary artery disease have been associated with diffuse alveolar hemorrhage (DAH) [8-23]. DAH has a similar presentation to pulmonary edema, so a high index of suspicion is needed, particularly when a patient with presumed pulmonary edema does not respond promptly to diuresis. The diagnosis and management of DAH are discussed separately. (See "The diffuse alveolar hemorrhage syndromes".) Rarely, spontaneous pharyngeal and laryngeal hematomas associated with warfarin anticoagulation have caused airway obstruction [24-26]. A few cases have been reported of interstitial pneumonitis due to ticlopidine and clopidogrel [27-30]. ASPIRIN In patients with aspirin-exacerbated respiratory disease (AERD) such as that seen with Samter's triad (asthma, nasal polyposis, and acute bronchoconstriction secondary to aspirin ingestion), ingestion of aspirin can result in acute bronchoconstriction. Some patients are able to tolerate 81 mg, but develop symptoms at 162 or 325 mg. Thus, AERD should be suspected in patients who develop dyspnea within three hours of initiation of aspirin therapy or an increase in the dose. Most patients will experience a combination of nasal congestion, rhinorrhea, wheezing, and dyspnea. Additional symptoms may include facial flushing/erythema, laryngospasm, abdominal cramps, epigastric pain, and hypotension. Bronchoconstriction is typically reversible https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 3/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate with an inhaled bronchodilator, which should be given promptly. Aspirin desensitization is an option for patients with AERD who require aspirin therapy; in addition, such protocolized desensitization has been shown to improve nasal-sinus and asthma symptoms in those with suboptimal control of their asthma [31]. When undertaking desensitization, premedication with a leukotriene-modifying agent such as montelukast is recommended. The protocol for aspirin desensitization is discussed separately. (See "Aspirin-exacerbated respiratory disease" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization", section on 'Challenge protocols and procedures'.) BETA BLOCKERS Beta blockers can exacerbate diseases of the airways (eg, chronic obstructive lung disease [COPD] and asthma) and the pulmonary vasculature (eg, portopulmonary hypertension). However, only rarely have they been associated with pleural or pulmonary parenchymal diseases, such as drug-induced lupus and interstitial pneumonitis. Asthma and COPD Beta-blocking medications are commonly used to treat hypertension, heart failure, and symptomatic coronary artery disease. However, beta-blocking medications that act on beta2 receptors can also cause bronchoconstriction. Since beta-adrenergic receptors of large and small airway smooth muscle are primarily the beta2 subtype, nonselective beta1/beta2 blockers (eg, propranolol) are more likely to cause bronchoconstriction in susceptible individuals [32]. In contrast, selective beta1-blockers (eg, atenolol, metoprolol) have a 20-fold greater affinity for beta1 adrenergic receptors than beta2 adrenergic receptors and, therefore, are less likely to induce bronchoconstriction. Studies of selective beta1-blockers are reassuring regarding their safety in patients with COPD, including those with a reversible component. In a meta-analysis that examined the effect of cardioselective beta-blockers given as a single dose or for longer duration, the beta1-blockers did not reduce the forced expiratory volume in one second (FEV ) or increase respiratory 1 symptoms compared with placebo, and beta1-blocker treatment did not reduce the improvement in FEV following inhaled beta2-agonists [33]. A subgroup analysis revealed no 1 change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component. The benefits of using beta blockers, like any other drug, must be weighed on a case-by-case basis against the risk of side effects. Nonselective beta-blockers should be avoided in patients with asthma and used with caution in patients with an exacerbation of COPD. The use of selective beta1-blockers in patients who have COPD and a cardiovascular indication is discussed https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 4/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate separately. (See "Management of the patient with COPD and cardiovascular disease", section on 'Treatment of CVD in patients with COPD' and "Arrhythmias in COPD", section on 'Multifocal atrial tachycardia' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".) Portopulmonary hypertension Beta-blockers are used prophylactically to prevent variceal hemorrhage in patients with cirrhosis complicated by portal hypertension. However, in patients with cirrhosis and portopulmonary hypertension, beta blockers can cause worsening exercise capacity and increased pulmonary vascular resistance. (See "Primary prevention of bleeding from esophageal varices in patients with cirrhosis", section on 'Preventive strategies' and "Portopulmonary hypertension" and "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis".) Drug-induced lupus The development of anti-nuclear antibodies is not uncommon with beta- blocker use, but the incidence of a symptomatic lupus syndrome attributed to a beta-blocker is distinctly less common ( table 2) [34]. Beta-blocker induced lupus syndrome with pleuritis and pneumonitis has rarely been reported [35]. (See "Drug-induced lupus".) Interstitial lung disease Organizing pneumonia and eosinophilic pneumonia have rarely been reported with beta-blocking agents, such as sotalol and acebutolol [36-38]. As an example, migratory radiographic opacities were described in a patient on sotalol [36]. On lung biopsy, features of both organizing pneumonia and eosinophilic pneumonia were seen. Partial improvement was noted with addition of systemic glucocorticoids; complete recovery was seen only after sotalol was stopped. (See "Cryptogenic organizing pneumonia" and "Idiopathic acute eosinophilic pneumonia".) HYDRALAZINE Hydralazine, a vasodilating agent, is associated with drug-induced lupus (pleural and pericardial effusions), antineutrophil cytoplasmic antibody positive-pulmonary vasculitis, and diffuse alveolar hemorrhage [39]. (See "Drug-induced lupus", section on 'Causative drugs' and "Drug- induced lupus", section on 'Clinical spectrum of drug-induced lupus'.) MINOXIDIL Minoxidil is uncommonly used, mainly to treat recalcitrant hypertension. Fluid retention is a potential adverse effect of the drug. Minoxidil has been associated with the development of pericardial and pleural effusions, which may be exudative [40,41]. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 5/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate NITRATES Overdoses of nitrate medications, such as intravenous infusions of nitroglycerin or nitroprusside, can cause methemoglobinemia. The clinical presentation may include dyspnea, respiratory depression, cyanosis, lethargy, altered consciousness, hypotension, and seizures. Measurement of oxygen saturation by a pulse oximeter may be inaccurate for assessing oxygen saturation as severe methemoglobinemia causes the SpO to trend towards 85 percent and thus 2 may either overestimate or underestimate the true arterial oxygen saturation (SaO ) as 2 measured by arterial blood gas analysis [42]. Methemoglobinemia is suspected when the arterial tension of oxygen (PaO ) is normal despite clinical cyanosis. The diagnosis is based upon 2 laboratory measurement of methemoglobin. (See "Methemoglobinemia", section on 'Evaluation and diagnosis (acquired/toxic)'.) PACLITAXEL-ELUTING STENTS Paclitaxel is an antineoplastic agent that can cause an interstitial pneumonitis when used to treat cancer. Paclitaxel has also been used to prevent restenosis after placement of coronary artery drug-eluting stents (DES), and case reports have described interstitial pneumonitis associated with these stents [43,44]. The onset of dyspnea, fever, and progressive respiratory insufficiency occurred within days of stent placement. Chest radiographs showed bilateral diffuse opacities. Due to the rarity of these events, the optimal management is not known. The three reported patients succumbed to progressive respiratory failure despite systemic glucocorticoid therapy [43,44]. Paclitaxel DES are rarely used due to the better performance of newer generation DES. (See "Taxane-induced pulmonary toxicity" and "Intracoronary stents: Stent types", section on 'Early-generation drug-eluting stents' and "Periprocedural complications of percutaneous coronary intervention", section on 'Hypersensitivity reactions'.) PROCAINAMIDE The antiarrhythmic agent procainamide is associated with drug-induced lupus, antiphospholipid antibody syndrome, interstitial pneumonitis, and respiratory muscle weakness. A number of extrapulmonary adverse effects are also associated with use of procainamide, including nonspecific systemic symptoms, blood dyscrasias, and cardiac toxicity. (See "Major side effects of class I antiarrhythmic drugs".) Use of procainamide is obviously decreasing with availability of more effective antiarrhythmics such as amiodarone. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 6/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Drug-induced lupus Procainamide can cause a syndrome of drug-induced lupus with protean clinical manifestations, including fever, arthralgia, rashes, myositis, vasculitis, serositis, and Raynaud phenomenon ( table 2) [45,46]. Respiratory system involvement includes pleuritis (pleural effusions and pleurisy) and, less commonly, diffuse parenchymal lung disease. (See "Drug-induced lupus".) Among patients with procainamide-induced lupus, pleuritis occurs in approximately half. While a high pleural fluid antinuclear antibody (ANA) may be seen in drug-induced lupus pleuritis, it lacks specificity and does not differentiate systemic lupus erythematosus (SLE) from drug-induced lupus. There are, however, a number of features that help to distinguish drug-induced lupus from SLE, including the general absence of renal and central nervous system disease with drug-induced lupus and the presence of anti-double stranded DNA antibodies and hypocomplementemia with SLE ( table 2). The clinical manifestations and diagnosis of drug-induced lupus are discussed separately. (See "Drug-induced lupus", section on 'Diagnostic approach' and "Pleural fluid analysis in adults with a pleural effusion".) One sensitive serologic indicator of drug-induced lupus is the presence of antibodies directed against the histone complex H2A-H2B [47]; the absence of this autoantibody essentially rules out drug-induced lupus. However, approximately 60 to 80 percent of patients with active spontaneous SLE also have this antibody. Thus, the presence of anti- histone antibodies does not discriminate between idiopathic SLE and drug-induced lupus. (See "Drug-induced lupus".) Antiphospholipid antibodies Antiphospholipid antibodies are also associated with procainamide, although the antiphospholipid antibody syndrome due to procainamide is rare [48,49]. Respiratory muscle weakness Procainamide may rarely have adverse effects on respiratory muscles by several mechanisms [50]. First, it can competitively block the acetylcholine receptor, thereby impairing neuromuscular transmission and causing postoperative apnea and/or a myasthenia gravis-like syndrome. Second, myositis has also been reported in association with drug-induced lupus and can impair respiratory muscle function. Lastly, procainamide may induce a myasthenic crisis in patients with underlying autoimmune myasthenia gravis [51]. QUINIDINE https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 7/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate The antiarrhythmic agent quinidine has been associated with drug-induced lupus, respiratory muscle weakness, acute pneumonitis, and diffuse alveolar hemorrhage (DAH) in case reports [50,52,53]. The incidence of drug-induced lupus is much lower than with procainamide, which may be explained by quinidine's lack of an amine group [54]. Similar to procainamide, the pulmonary manifestations associated with quinidine-induced lupus are primarily related to pleuritis [54]. (See 'Drug-induced lupus' above.) Quinidine can rarely cause a myasthenia gravis-like syndrome and has been shown to exacerbate autoimmune myasthenia gravis [50]. Two cases of DAH have been reported in patients with quinidine sulfate-induced thrombocytopenia [52,55]. STATINS Various statins have been associated with interstitial lung disease (fibrotic, eosinophilic, nonspecific) in case reports [56-58]. Onset of lung disease was 1 week to 10 years after initiation of statin therapy. Radiographic findings included ground glass, consolidative, and reticular opacities. While a case control study of patients with idiopathic pulmonary fibrosis (IPF) did not find an increased risk of IPF associated with statin use [59], this observation does not exclude the possibility of a drug-induced pneumonitis due to a statin medication. Conversely, a post hoc analysis of 624 patients randomized to placebo in three trials of pirfenidone in the treatment of IPF suggest that statins may have a beneficial effect on clinical outcomes in IPF [60]. Similarly, a potential beneficial effect on clinical outcomes has been found for patients taking a statin in trials of nintedanib for IPF [61]. A meta-analysis of randomized trials determining the clinical impacts of statin therapy on patients with pulmonary hypertension secondary to lung diseases (group 3) has suggested that statins might be safe and beneficial for patients with pulmonary arterial hypertension due to chronic lung diseases [62,63]. No prospective clinical trials have been performed to validate these findings. TOCAINIDE The anti-arrhythmic agent tocainide (no longer sold in the United States, limited availability elsewhere) has uncommonly been associated with an interstitial pneumonitis that develops after a few months of therapy [64-66]. Computed tomography (CT) typically shows septal thickening https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 8/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate and consolidative opacities [65]. The lung disease may be characterized initially by a neutrophilic alveolitis with organizing pneumonia; irreversible fibrosis may develop with continuing inflammation. In most cases, symptoms remit with discontinuation of therapy. However, progressive respiratory failure has been described in patients with advanced fibrosis despite discontinuation of tocainide [64]. Systemic glucocorticoids may hasten recovery in more severe disease. SUMMARY AND RECOMMENDATIONS A number of cardiovascular drugs have the potential to cause dyspnea, cough, and radiographic abnormalities, although the incidence of diffuse parenchymal lung disease associated with cardiovascular drugs is quite rare. Several different respiratory adverse effects have been identified: upper airway angioedema or hematoma, bronchoconstriction, cough, interstitial pneumonitis, organizing pneumonia, eosinophilic pneumonia, drug- induced lupus, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pleuritis, pleural effusion, and solitary lung mass ( table 1A-B). (See 'Introduction' above.) Angiotensin converting enzyme (ACE) inhibitors are associated with cough, angioedema, and, rarely, pneumonitis. The cough is typically nonproductive, persistent, and often nocturnal (in 5 to 20 percent of patients) and frequently requires cessation of therapy. (See 'Angiotensin converting enzyme inhibitors' above and "Major side effects of angiotensin- converting enzyme inhibitors and angiotensin II receptor blockers".) Treatment of coronary artery disease with anticoagulant and anti-platelet medications (vitamin K antagonists, glycoprotein IIB/IIIA antagonists) and thrombolytic agents has been associated with diffuse alveolar hemorrhage (DAH). Rare cases of upper airway obstruction due to retropharyngeal or glottic hematoma have been reported. Clopidogrel and ticlopidine have infrequently been associated with interstitial pneumonitis. (See 'Anticoagulant medications' above.) Aspirin causes acute bronchoconstriction in patients with aspirin-exacerbated respiratory disease (triad of asthma, nasal polyps, acute bronchoconstriction due to aspirin). The dose of aspirin that provokes a reaction varies among patients; some patients are able to tolerate 81 mg, but develop symptoms at 162 or 325 mg. Aspirin desensitization, a protocol that may also help improve asthma symptoms, is an option for patients with AERD who require aspirin therapy. (See 'Aspirin' above and "Aspirin-exacerbated respiratory disease" and "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".) https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 9/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Nonselective beta1/beta2 blockers (eg, propranolol) can cause bronchoconstriction in susceptible individuals, but this effect is substantially less likely to occur with selective beta1 blockers (eg, atenolol, metoprolol). (See 'Beta blockers' above and "Management of the patient with COPD and cardiovascular disease".) Eosinophilic pneumonitis has rarely been found in patients taking ACE inhibitors, beta- blocker medications, and statins. Organizing pneumonia has been reported in association with amiodarone, beta-blocker medications, and tocainide. (See 'Amiodarone' above and 'Angiotensin converting enzyme inhibitors' above and 'Beta blockers' above and 'Statins' above and 'Tocainide' above.) Drug-induced lupus has been reported with beta-blocker medications, hydralazine, procainamide, and quinidine. The diagnosis of drug-induced lupus is based on the combination of clinical manifestations (eg, pleuropericarditis), serologic evaluation, and response to discontinuation of the implicated medication. Features that help to differentiate drug-induced lupus from systemic lupus erythematosus (SLE) are listed in the table ( table 2). The presence of anti-histone antibodies in the absence of other autoantibodies (eg, anti-double stranded DNA, anti-ribonucleoprotein, anti-Smith) strongly favors drug-induced lupus. (See 'Drug-induced lupus' above and 'Hydralazine' above and 'Procainamide' above and 'Quinidine' above and "Drug-induced lupus".) Procainamide and quinidine can cause respiratory muscle weakness by unmasking or exacerbating underlying myasthenia gravis. Rarely, a drug-induced myopathy has been reported; this effect is likely a manifestation of drug-induced lupus ( table 2). (See 'Procainamide' above and 'Quinidine' above.) Minoxidil is rarely associated with development of pleural and pericardial effusions. Overdoses of nitrates can cause methemoglobinemia. Statins, paclitaxel-eluting stents, and tocainide have been associated with pneumonitis in case reports. (See 'Minoxidil' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitor-induced cough: ACCP evidence- based clinical practice guidelines. Chest 2006; 129:169S. 2. Benard A, Melloni B, Gosselin B, et al. Perindopril-associated pneumonitis. 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Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis. Thorax 2017; 72:148. 61. Kreuter M, Costabel U, Richeldi L, et al. Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis. Respiration 2018; 95:317. 62. Zhang MZ, Qian DH, Xu JC, et al. Statins may be beneficial for patients with pulmonary hypertension secondary to lung diseases. J Thorac Dis 2017; 9:2437. 63. Faraj R, Paine D, Black SM, Wang T. Anti-inflammatory Effects of Statins in Lung Vascular Pathology: From Basic Science to Clinical Trials. Adv Exp Med Biol 2021; 1303:33. 64. Feinberg L, Travis WD, Ferrans V, et al. Pulmonary fibrosis associated with tocainide: report of a case with literature review. Am Rev Respir Dis 1990; 141:505. 65. Stein MG, Demarco T, Gamsu G, et al. Computed tomography: pathologic correlation in lung disease due to tocainide. Am Rev Respir Dis 1988; 137:458. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 14/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 66. Van Natta B, Lazarus M, Li C. Irreversible interstitial pneumonitis associated with tocainide therapy. West J Med 1988; 149:91. Topic 4345 Version 23.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 15/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate GRAPHICS Pulmonary complications of cardiovascular drugs Agent Syndrome Frequency Potential mechanism Procainamide SLE-like syndrome 50 to 90 percent of patients have positive Autoantibodies against histone H2A-H2B complex, potentially ANA test; 10 to 20 percent become symptomatic; pleuritis, pleural effusion, and parenchymal infiltrates are common induced by interaction of drug metabolites with DNA, or drug- induced alteration in T-cell DNA methylation Quinidine SLE-like syndrome Rare; pleuritis and pleural Autoantibodies against histone effusions are most common pulmonary signs; parenchymal infiltrates uncommon H2A-H2B complex, potentially induced by interaction of drug metabolites with DNA, or drug- induced alteration in T-cell DNA methylation Tocainide Pneumonitis/fibrosis Incidence is about 0.3 percent Unknown Flecainide Pneumonitis/fibrosis Rare Unknown Mexiletine Pneumonitis/fibrosis Rare Unknown; interferes with theophylline metabolism and can cause toxic elevations in theophylline levels in serum ACE inhibitors Cough Incidence is 5 to 15 percent; occurs with all Decreased degradation of irritant and bronchoconstrictive ACE inhibitors; whether these agents precipitate bronchospasm in patients with asthma is controversial mediators (bradykinin and substance P); direct increase in sensitivity to irritant-induced cough; genetic predisposition (based on differences in ACE gene). Angioneurotic Rare; can lead to Unknown edema respiratory failure Sotalol Bronchospasm Occurs in 2 percent of Direct blockage of 2-receptors patients Adenosine Bronchospasm Occurs with rapid Induction of mast cell mediator infusion in 5 to 10 percent of patients; may release https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 16/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate trigger acute bronchospasm in patients with asthma or COPD. Reversible with aminophylline Redrawn from Zitnik, RJ, J Respir Dis 1996; 17:254; and Zitnik, RJ, J Respir Dis 1996; 17:293. Graphic 54967 Version 1.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 17/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Pulmonary complications of cardiovascular drugs Potential mechanism Agent Syndrome Frequency Beta blockers Cough or bronchospasm Common; usually occurs in patients with asthma or COPD; 1-selective agents, labetalol, esmolol, and pindolol are better tolerated than nonselective agents Direct antagonism of 2 receptor-mediated bronchodilation
95:326. 36. Faller M, Quoix E, Popin E, et al. Migratory pulmonary infiltrates in a patient treated with sotalol. Eur Respir J 1997; 10:2159. 37. Camus P, Lombard JN, Perrichon M, et al. Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone. Thorax 1989; 44:711. 38. Markou N, Antzoulatos N, Haniotou A, et al. A case of drug-induced pneumonitis caused by carvedilol. Respiration 2004; 71:650. 39. Espinosa MC, Ding B, Choi K, et al. A simultaneous presentation of drug-induced lupus with drug-induced ANCA vasculitis secondary to hydralazine use in a patient with sarcoidosis. Proc (Bayl Univ Med Cent) 2019; 32:231. 40. Webb DB, Whale RJ. Pleuropericardial effusion associated with minoxidil administration. Postgrad Med J 1982; 58:319. 41. Siddiqui A, Ansari M, Shakil J, Chemitiganti R. Minoxidil-associated exudative pleural effusion. South Med J 2010; 103:458. 42. Chan ED, Chan MM, Chan MM. Pulse oximetry: understanding its basic principles facilitates appreciation of its limitations. Respir Med 2013; 107:789. 43. Kato K, Fukuda S, Fujimaki T, et al. Paclitaxel-induced interstitial pneumonia after drug- eluting stent implantation: report of a fatal case. Intern Med 2009; 48:911. 44. Fujimaki T, Kato K, Fukuda S, et al. Acute interstitial pneumonitis after implantation of paclitaxel-eluting stents: a report of two fatal cases. Int J Cardiol 2011; 148:e21. 45. Zitnik, RJ. Drug-induced lung disease: Antiarrhythmic agents. J Respir Dis 1996; 17:254. 46. Arnaud L, Mertz P, Gavand PE, et al. Drug-induced systemic lupus: revisiting the ever- changing spectrum of the disease using the WHO pharmacovigilance database. Ann Rheum Dis 2019; 78:504. 47. Totoritis MC, Tan EM, McNally EM, Rubin RL. Association of antibody to histone complex H2A-H2B with symptomatic procainamide-induced lupus. N Engl J Med 1988; 318:1431. 48. Merrill JT, Shen C, Gugnani M, et al. High prevalence of antiphospholipid antibodies in patients taking procainamide. J Rheumatol 1997; 24:1083. 49. Asherson RA, Zulman J, Hughes GR. Pulmonary thromboembolism associated with procainamide induced lupus syndrome and anticardiolipin antibodies. Ann Rheum Dis 1989; 48:232. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 13/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 50. Aldrich TK, Prezant DJ. Adverse effects of drugs on the respiratory muscles. Clin Chest Med 1990; 11:177. 51. Godley PJ, Morton TA, Karboski JA, Tami JA. Procainamide-induced myasthenic crisis. Ther Drug Monit 1990; 12:411. 52. Alperin JB, deGroot WJ, Cimo PL. Quinidine-induced thrombocytopenia with pulmonary hemorrhage. Arch Intern Med 1980; 140:266. 53. Poukkula A, P kk P. Quinidine-induced reversible pneumonitis. Chest 1994; 106:304. 54. McCormack GD, Barth WF. Quinidine induced lupus syndrome. Semin Arthritis Rheum 1985; 15:73. 55. LeBlanc KE. A second case of quinidine-induced thrombocytopenia with pulmonary hemorrhage. Arch Intern Med 1980; 140:1250. 56. Fern ndez AB, Karas RH, Alsheikh-Ali AA, Thompson PD. Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports. Chest 2008; 134:824. 57. Liebhaber MI, Wright RS, Gelberg HJ, et al. Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten cases. Chest 1999; 115:886. 58. Lisco t-Loheac N, Andr N, Couturaud F, et al. [Hypersensitivity pneumonitis in a patient taking pravastatin]. Rev Mal Respir 2001; 18:426. 59. Ponnuswamy A, Manikandan R, Sabetpour A, et al. Association between ischaemic heart disease and interstitial lung disease: a case-control study. Respir Med 2009; 103:503. 60. Kreuter M, Bonella F, Maher TM, et al. Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis. Thorax 2017; 72:148. 61. Kreuter M, Costabel U, Richeldi L, et al. Statin Therapy and Outcomes in Trials of Nintedanib in Idiopathic Pulmonary Fibrosis. Respiration 2018; 95:317. 62. Zhang MZ, Qian DH, Xu JC, et al. Statins may be beneficial for patients with pulmonary hypertension secondary to lung diseases. J Thorac Dis 2017; 9:2437. 63. Faraj R, Paine D, Black SM, Wang T. Anti-inflammatory Effects of Statins in Lung Vascular Pathology: From Basic Science to Clinical Trials. Adv Exp Med Biol 2021; 1303:33. 64. Feinberg L, Travis WD, Ferrans V, et al. Pulmonary fibrosis associated with tocainide: report of a case with literature review. Am Rev Respir Dis 1990; 141:505. 65. Stein MG, Demarco T, Gamsu G, et al. Computed tomography: pathologic correlation in lung disease due to tocainide. Am Rev Respir Dis 1988; 137:458. https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 14/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate 66. Van Natta B, Lazarus M, Li C. Irreversible interstitial pneumonitis associated with tocainide therapy. West J Med 1988; 149:91. Topic 4345 Version 23.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 15/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate GRAPHICS Pulmonary complications of cardiovascular drugs Agent Syndrome Frequency Potential mechanism Procainamide SLE-like syndrome 50 to 90 percent of patients have positive Autoantibodies against histone H2A-H2B complex, potentially ANA test; 10 to 20 percent become symptomatic; pleuritis, pleural effusion, and parenchymal infiltrates are common induced by interaction of drug metabolites with DNA, or drug- induced alteration in T-cell DNA methylation Quinidine SLE-like syndrome Rare; pleuritis and pleural Autoantibodies against histone effusions are most common pulmonary signs; parenchymal infiltrates uncommon H2A-H2B complex, potentially induced by interaction of drug metabolites with DNA, or drug- induced alteration in T-cell DNA methylation Tocainide Pneumonitis/fibrosis Incidence is about 0.3 percent Unknown Flecainide Pneumonitis/fibrosis Rare Unknown Mexiletine Pneumonitis/fibrosis Rare Unknown; interferes with theophylline metabolism and can cause toxic elevations in theophylline levels in serum ACE inhibitors Cough Incidence is 5 to 15 percent; occurs with all Decreased degradation of irritant and bronchoconstrictive ACE inhibitors; whether these agents precipitate bronchospasm in patients with asthma is controversial mediators (bradykinin and substance P); direct increase in sensitivity to irritant-induced cough; genetic predisposition (based on differences in ACE gene). Angioneurotic Rare; can lead to Unknown edema respiratory failure Sotalol Bronchospasm Occurs in 2 percent of Direct blockage of 2-receptors patients Adenosine Bronchospasm Occurs with rapid Induction of mast cell mediator infusion in 5 to 10 percent of patients; may release https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 16/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate trigger acute bronchospasm in patients with asthma or COPD. Reversible with aminophylline Redrawn from Zitnik, RJ, J Respir Dis 1996; 17:254; and Zitnik, RJ, J Respir Dis 1996; 17:293. Graphic 54967 Version 1.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 17/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Pulmonary complications of cardiovascular drugs Potential mechanism Agent Syndrome Frequency Beta blockers Cough or bronchospasm Common; usually occurs in patients with asthma or COPD; 1-selective agents, labetalol, esmolol, and pindolol are better tolerated than nonselective agents Direct antagonism of 2 receptor-mediated bronchodilation Pulmonary fibrosis Rare Unknown Lupus-like syndrome Rare Unknown Hydralazine Lupus-like syndrome Renal disease more common than in other drug-induced lupus-like Unknown; slow acetylation may be a risk syndromes factor Dipyridamole Bronchospasm Occurs in about 0.15 percent of Induction of mast cell (IV form only) patients during infusion for stress testing mediator release Protamine Anaphylaxis, uritcaria, angioedema, bronchospasm Occurs in 0.2 percent of patients Unknown Pulmonary hypertension Mild pulmonary hypertension and systemic hypotension in up to 5 percent of patients; severe Antiprotamine antibodies; activated neutrophils; reaction rare thromboxane A2 generation Redrawn from Zitnik, RJ, J Respir Dis 1996; 17:254; and Zitnik, RJ, J Respir Dis 1996; 17:293. Graphic 69778 Version 1.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 18/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Features of spontaneous and drug-induced lupus Clinical feature Idiopathic SLE Drug-induced lupus Gender predisposition (F:M) 9:1 1:1 Acetylation type Slow = Fast Slow (described for hydralazine and procainamide) Symptom onset Gradual Abrupt Usual age 20 to 40 Drug-dependent, tends to be older population than idiopathic (>50)* Race All Less likely to occur in black patients Fever/malaise 40 to 85 percent 40 to 50 percent Arthralgias/arthritis 75 to 95 percent 80 to 95 percent Rash (all) 50 to 70 percent 10 to 30 percent Rash (discoid) 20 percent Rare Rash (malar/acute cutaneous) 42 percent 2 percent Raynaud's 35 to 50 percent <25 percent Pleuritis/pleural effusion 16 to 60 percent 10 to 50 percent (procainamide) Pulmonary infiltrates 0 to 10 percent 5 to 40 percent (procainamide) Pericarditis 6 to 45 percent 2 to 18 percent Hepatomegaly/splenomegaly 10 to 45 percent 5 to 25 percent Renal involvement 30 to 50 percent 0 to 5 percent CNS/neurologic involvement 25 to 70 percent 0 to 2 percent Hematologic Common Unusual Laboratory feature Idiopathic SLE Drug-induced lupus ANA 95 to 98 percent 95 to 100 percent Anti-dsDNA 50 to 80 percent <5 percent (rare) Anti-Smith 20 to 30 percent <5 percent (rare) Anti-RNP 40 to 50 percent 20 percent Anti-Ro/SS-A 30 to 40 percent Uncertain Anti-histone 60 to 80 percent 90 to 95 percent Low complement levels 40 to 65 percent Rare https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 19/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Anemia 30 to 90 percent 0 to 46 percent Leukopenia 35 to 66 percent 2 to 33 percent Positive Coombs' test 18 to 65 percent 0 to 33 percent CNS: central nervous system; ANA: anti-nuclear antibody; LE: lupus erythematosus; RNP: ribonucleoprotein; dsDNA: double-stranded deoxyribonucleic acid. Minocycline-induced disease tends to occur in young females, consistent with greater use of the medication than other groups. Case reports of drug-induced discoid lupus with anti-TNF drug exposure. Insufficient data are available to provide an accurate estimate for (systemic) drug-induced lupus. The antibodies are present in 70 to 90 percent of patients with drug-induced subacute cutaneous lupus. Overall presence of anti-histone antibodies in drug-induced lupus; prevalence varies markedly between implicated drugs (may be less with minocycline or tumor necrosis factor inhibitors, and data are lacking for many agents). (Merola JF. Lupus-like syndromes related to drugs. In: Lupus Erythematosus: Clinical Evaluation and Treatment, Schur PH, Massarotti E. (Eds), Springer, New York, pp. 211-221). Most common with methyldopa exposure. Graphic 69467 Version 7.0 https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 20/21 7/5/23, 8:24 AM Pulmonary disease induced by cardiovascular drugs - UpToDate Contributor Disclosures Edward D Chan, MD No relevant financial relationship(s) with ineligible companies to disclose. Talmadge E King, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kevin R Flaherty, MD, MS Grant/Research/Clinical Trial Support: Boehringer Ingelheim [IPF]. Consultant/Advisory Boards: Arrowhead [Interstitial lung disease]; AstraZeneca [Interstitial lung disease]; Bellerophon [Interstitial lung disease]; CSL Behring [Interstitial lung disease]; Daewong Pharmaceuticals [Interstitial lung disease]; DevPro [Interstitial lung disease]; Dispersol [Interstitial lung disease]; Fibrogen [Interstitial lung disease]; Horizon [Interstitial lung disease]; Immunmet [Interstitial lung disease]; Insilco [Interstitial lung disease]; Lupin [Interstitial lung disease]; NeRRe Therapeutics [Interstitial lung disease]; Pliant [Interstitial lung disease]; Polarean [Interstitial lung disease]; PureHealth [Interstitial lung disease]; PureTech [Interstitial lung disease]; Respivant [Interstitial lung disease]; Roche/Genentech [Interstitial lung disease]; Shionogi [Interstitial lung disease]; Sun Pharmaceuticals [Interstitial lung disease]; Trevi Pharmaceuticals [Interstitial lung disease]; United Therapeutics [Interstitial lung disease]; Vicore [Interstitial lung disease]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/pulmonary-disease-induced-by-cardiovascular-drugs/print 21/21
7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Therapeutic use of ibutilide : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 19, 2022. INTRODUCTION Ibutilide is a class III antiarrhythmic drug available only for intravenous use for the termination of atrial arrhythmias. An oral form is not available because of extensive first-pass metabolism [1]. The physiology and pharmacology of ibutilide use and the side effects that can occur will be reviewed here. The pharmacokinetics of ibutilide, drug interactions, and the various clinical settings in which ibutilide might be used are discussed in detail separately. MECHANISMS OF ACTION Cellular mechanisms Like other class III antiarrhythmic agents ( table 1), ibutilide prolongs repolarization in atrial and ventricular myocardium [1,2]. The class III drugs block IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period [1]. Ibutilide increases the refractoriness of atrial and ventricular myocardium, the atrioventricular node, His-Purkinje system, and accessory pathway [3]. In addition, ibutilide activates a slow, delayed inward sodium current that occurs early during repolarization [1,4]. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs" and 'Major side effects' below.) Effects on the ECG Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 1/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate prolongation of the QT interval. There is no effect on the PR interval or QRS duration. The degree of QT prolongation associated with ibutilide is related to the dose, the rate of infusion, and the serum concentration [5]. Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. The QT interval returns to baseline within two to four hours after stopping the infusion. (See 'Proarrhythmia' below and 'Discontinuing ibutilide infusion' below.) Mechanism of proarrhythmic effect Like other drugs that prolong the QT interval and cause torsades de pointes, ibutilide blocks IKr, the rapid component of the delayed rectifier potassium current that is responsible for phase 3 repolarization [6]. IKr results from a heteromeric complex formed by a tetrameric potassium channel encoded by the KCNH2 gene (formerly called HERG gene) in complex with an accessory subunit encoded by the MirP1 gene (KCNE2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Pathophysiology'.) Ibutilide exhibits "reverse use dependence", which is defined as an inverse correlation between the heart rate and QT interval. As a result, the QT interval decreases as the heart rate increases and lengthens as the heart rate slows. This explains why drug-induced polymorphic ventricular tachycardia (VT) is more commonly seen with bradycardia. The effect of heart rate may be mediated by changes in the local extracellular potassium concentration [7]. Lower heart rates result in less potassium moving out of the cell during repolarization (before subsequent reuptake by the Na-K-ATPase pump), since there are fewer repolarizations. The associated reduction in extracellular potassium concentration enhances the degree of drug-induced inhibition of IKr, increasing the QT interval. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) PHARMACOKINETICS Ibutilide has a half-life of 2 to 12 hours. It is extensively metabolized by the liver to eight metabolites. Only one metabolite exhibits antiarrhythmic activity, but its level is only approximately 10 percent of the parent drug level. As a result, this metabolite plays no role in the efficacy of ibutilide. Although almost 90 percent of the drug or its metabolites are detected in the urine, only 7 percent is excreted as the native, active drug. CLINICAL USES https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 2/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate Ibutilide is approved for the acute termination of atrial fibrillation and atrial flutter of recent onset. Since there is no oral preparation of ibutilide, it has no role in the long-term prevention of these arrhythmias. Ibutilide is not approved for the treatment of ventricular arrhythmias, and its efficacy for these arrhythmias is unknown. Atrial fibrillation Intravenous ibutilide is useful and effective for the pharmacologic cardioversion of recent-onset atrial fibrillation [8]. As with other antiarrhythmic drugs, the efficacy of ibutilide is greatest when the atrial fibrillation is of short duration ( figure 1) [9]. While it is of clear benefit in atrial fibrillation that has been present for seven days or less, the evidence is less robust but also suggests efficacy for atrial fibrillation of more than seven days duration. Most patients studied had arrhythmia for less than 90 days [9-11]. Similar efficacy has not been demonstrated with arrhythmia duration exceeding 90 days [12]. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) The indications for pharmacologic cardioversion of atrial fibrillation and the settings in which ibutilide might be used are discussed separately. (See "Atrial fibrillation: Cardioversion".) In addition to the general use of ibutilide for cardioversion of atrial fibrillation, it has also been used in specific settings: As pretreatment before electrical cardioversion. (See "Atrial fibrillation: Cardioversion", section on 'Preprocedural antiarrhythmic drugs'.) To convert atrial fibrillation to sinus rhythm in patients with Wolff-Parkinson-White syndrome. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Atrial fibrillation with preexcitation'.) To convert atrial fibrillation to sinus rhythm after cardiac surgery or cardiac transplantation [13,14]. (See "Atrial fibrillation and flutter after cardiac surgery".) Ibutilide also appears to be a safe and effective antiarrhythmic agent for cardioversion of recent- onset atrial fibrillation and flutter in elderly patients. In a study of 32 patients (mean age 76 years) with recent-onset atrial fibrillation (19 patients) or atrial flutter (13 patients), the overall rate of successful conversion was 59 percent with a mean conversion time was 33 minutes [15]. Ibutilide-induced lengthening of the QTc interval was 17 21 milliseconds. Atrial flutter Ibutilide is effective for the cardioversion of atrial flutter [9-11,16], including atrial flutter that occurs after cardiac surgery [13]. (See "Restoration of sinus rhythm in atrial flutter" and "Atrial fibrillation and flutter after cardiac surgery".) https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 3/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate Ibutilide in children and in patients with congenital heart disease The safety and efficacy of ibutilide for cardioversion of atrial flutter and atrial fibrillation in children and in patients with congenital heart disease was reviewed in a report of 19 patients, age 6 months to 34 years (median 16 years) [17]. Ibutilide successfully restored sinus rhythm in 71 percent of arrhythmia episodes, with success during the first administration in 12 of 19 (63 percent). Fourteen episodes in six patients required electrical cardioversion after ibutilide failed. There were no episodes of symptomatic bradycardia, and only one episode each of polymorphic and monomorphic ventricular tachycardia. With careful monitoring, ibutilide can be effective for children and young patients with congenital heart disease for cardioversion of atrial arrhythmias. Chemical cardioversion of atrial fibrillation or flutter with ibutilide and other antiarrhythmic drugs Similar to ibutilide, intravenous esmolol has a short half-life, which makes it appealing for use in the acute conversion of atrial fibrillation. A randomized, prospective study comparing the combination of intravenous esmolol plus ibutilide with ibutilide monotherapy for conversion of recent-onset atrial fibrillation with a rapid ventricular rate showed improvement in the rate of conversion to sinus rhythm in the combined ibutilide/esmolol group (67 percent with the combination versus 46 percent for ibutilide monotherapy) [18]. The slower the ventricular rate at the time of ibutilide administration, the greater was the probability of conversion to sinus rhythm. In addition, there was a marked reduction in the incidence of immediate atrial fibrillation recurrence in the group receiving both esmolol and ibutilide. The ibutilide/esmolol combination was also associated with a lower risk of torsade de pointes. Patients receiving amiodarone Combination therapy may be a useful cardioversion method for chronic atrial fibrillation or flutter for patients on amiodarone who are treated with ibutilide. The efficacy and safety of cardioversion with combination amiodarone and ibutilide was evaluated in patients on long-term oral amiodarone and referred for elective cardioversion of atrial fibrillation (81 percent) or atrial flutter (19 percent) [12]. Patients, who were in the arrhythmia for a mean of 196 before cardioversion and were taking amiodarone for a mean of 153 days, were administered 2 mg intravenous ibutilide. Within 30 minutes of infusion, ibutilide converted 54 percent with atrial flutter and 39 percent with atrial fibrillation. One episode of torsade de pointes occurred although QT-interval prolongation after ibutilide was noted. Thirty- five (90 percent) of 39 patients who did not convert with ibutilide underwent successful electrical cardioversion. Patients receiving propafenone In a trial using combination therapy, concurrent administration of propafenone plus ibutilide for pharmacological cardioversion of persistent atrial fibrillations was found safe and more effective than ibutilide alone [19]. Among 100 consecutive patients (66 men, mean age 65 years) with persistent atrial fibrillation (mean https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 4/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate duration 99 days) who were admitted for elective pharmacological cardioversion and were randomly assigned to either intravenous ibutilide (1 mg plus an additional 1 mg, if required) or oral propafenone (600 mg) plus intravenous ibutilide, successful cardioversion occurred in 41 percent with ibutilide alone, compared with 71 percent with propafenone plus ibutilide. A comparable increase in the QTc interval was observed in both groups, but one case of sustained torsade de pointes, requiring electrical cardioversion, was observed in the propafenone plus ibutilide group. Patients undergoing catheter ablation for atrial fibrillation In patients with persistent atrial fibrillation undergoing catheter ablation, ibutilide administration was not shown to increase procedural efficacy and long-term freedom from atrial arrythmias [20]. In patients with persistent atrial fibrillation who are undergoing a catheter-based ablation, incorporation of electroanatomic mapping allows for the detection and targeting of complex fractionated atrial electrograms (CFAEs). Since ibutilide reduces CFAEs, it was hypothesized that ibutilide administration prior to CFAE ablation would identify sites critical for persistent atrial fibrillation maintenance, allowing for improved procedural efficacy and long-term freedom from atrial arrhythmias. In the MAGIC-AF trial, 200 patients undergoing a first-ever persistent atrial fibrillation catheter ablation procedure were randomly assigned to 0.25 mg of intravenous ibutilide or saline placebo upon completion of pulmonary vein isolation. CFAE sites were then targeted with ablation. The study found that despite a reduction in CFAE area and greater atrial fibrillation termination during CFAE ablation, procedure efficacy was not statistically higher when CFAE ablation was guided by ibutilide administration versus placebo (56 versus 49 percent) [20]. (See "Atrial fibrillation: Catheter ablation" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists".) ADMINISTRATION Dosing The recommended dose of ibutilide varies with patient size: For patients weighing less than 60 kg, the dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate within 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) may be given. For patients weighing more than 60 kg, the dose is 1 mg over 10 minutes. Again, if the arrhythmia does not terminate within 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes may be given. Role of magnesium Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter, and it can attenuate the QT interval https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 5/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate prolongation associated with ibutilide therapy. Two cohort studies have shown that the concurrent administration of magnesium (doses of four to five grams administered intravenously) with ibutilide is associated with a greater chance of successful chemical conversion [21,22]. One of the two studies also reported a significantly lower rate of polymorphic ventricular tachycardia in patients who received the magnesium/ibutilide combination compared with patients who received only ibutilide [22]. MAJOR SIDE EFFECTS Side effects with the use of ibutilide are infrequent and typically transient. In one report, the only noncardiac side effects that occurred more frequently than with placebo were nausea (1.9 percent), headache (3.6 percent), and renal failure (0.3 percent) [9]. The most serious side effects are those involving the cardiovascular system. As a result, ibutilide should not be used in patients with severe structural cardiac disease, prolonged QT interval, or underlying sinus node disease. Additional information about potential drug interactions can be found using the Lexicomp drug interactions tool. Proarrhythmia Proarrhythmia, particularly nonsustained or sustained polymorphic (torsades de pointes) or monomorphic ventricular tachycardia (VT), is the most important toxic reaction. Because of the risk of ventricular tachycardia, particularly torsades de pointes, patients treated with ibutilide should be observed with continuous ECG monitoring for at least four hours after the infusion is finished and longer if needed until the QTc interval has returned to baseline. In several large series, polymorphic VT was seen in between four and eight percent of patients [10,11,16,23]. Sustained episodes requiring cardioversion were seen in approximately two percent of patients. In addition to polymorphic VT, nonsustained monomorphic VT occurred in three to four percent of patients [10,11]. The majority of episodes of sustained polymorphic VT occurred within ten minutes of the first dose (before the second dose would be given, if necessary). Torsades de pointes may be more common in women, occurring in six percent of women in one series (versus three percent of men) [23]. In addition, the risk was increased in patients with heart failure (eleven percent versus four percent in those without heart failure) [16]. Class IC antiarrhythmic drugs, which slow conduction by blocking sodium channels, also have the potential for proarrhythmia. However, since class IC drugs do not cause QT prolongation, it has also been suggested these drugs can be used safely with ibutilide. In two reports including a total of 175 patients with atrial fibrillation or atrial flutter, 150 were treated with propafenone and 25 were treated with flecainide [24,25]. All were treated with ibutilide up to 2 mg, which was https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 6/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate successful in restoring sinus rhythm in 62 percent. Only two patients developed nonsustained polymorphic VT with one developing sustained polymorphic VT (two percent of patients), a rate consistent with that seen in patients not taking a class IC antiarrhythmic drug. The potential for polymorphic VT is increased in patients who are being treated with another drug that prolongs the QT interval. However, the risk of proarrhythmia does not appear to be increased when ibutilide is given with amiodarone [12]. Other cardiac toxicities Ibutilide has been associated with a number of cardiac side effects other than proarrhythmia [26]: Hypotension 2 percent. Usually the degree of hypotension is mild and responds to fluid resuscitation. Sinus tachycardia or supraventricular tachycardia 2.7 percent. Sinus bradycardia 1.2 percent. Atrioventricular block 1.5 percent. Bundle branch block 1.9 percent. All of the above arrhythmias and conduction changes have been reported transient with minimal or no associated symptoms. Hemodynamic effects Ibutilide produces no clinically significant changes in left ventricular function or hemodynamics, including mean pulmonary artery pressure or pulmonary capillary wedge pressure, even in patients with reduced left ventricular ejection fraction [27]. Discontinuing ibutilide infusion In most patients who respond to ibutilide, arrhythmia termination is seen within 40 to 60 minutes after beginning the infusion (mean 27 to 33 minutes in two studies) [11,16]. The infusion should be stopped for the following reasons: The presenting arrhythmia is terminated. The patient develops ventricular tachycardia (sustained or nonsustained). The patient develops marked prolongation of the QT interval (to a corrected QT interval >500 msec with narrow QRS, or corrected QT >550 msec in patients with bundle branch block). SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 7/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Mechanism and pharmacokinetics Ibutilide, a class III antiarrhythmic drug, blocks IKr, the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization, increased action potential duration, and lengthening of the refractory period. (See 'Mechanisms of action' above.) Effects on electrocardiogram Ibutilide has two major effects on the electrocardiogram (ECG): it produces mild slowing of the sinus rate and, as with other class III antiarrhythmic drugs, prolongation of the QT interval. There is no effect on the PR interval or QRS duration. Prolongation of the QT interval provides the substrate for torsades de pointes (TdP), a polymorphic ventricular tachycardia. (See 'Mechanisms of action' above.) Clinical uses Ibutilide is approved for the acute termination of atrial fibrillation and atrial flutter and is most useful and effective for the pharmacologic cardioversion of atrial fibrillation less than or equal to seven days duration. (See 'Atrial fibrillation' above and 'Atrial flutter' above and "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) Side effects Proarrhythmia, particularly nonsustained or sustained polymorphic ventricular tachycardia (VT) (torsades de pointes) or monomorphic VT, is the most important toxicity associated with ibutilide. Because of the risk of VT, particularly torsades de pointes, patients treated with ibutilide should be observed with continuous ECG monitoring for at least four hours after the infusion is finished, or until the QTc interval has returned to baseline. (See 'Proarrhythmia' above.) The ibutilide infusion should be stopped for the following reasons (see 'Discontinuing ibutilide infusion' above): The presenting arrhythmia is terminated. The patient develops VT (sustained or nonsustained). The patient develops marked prolongation of the QT interval. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 8/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate 1. Murray KT. Ibutilide. Circulation 1998; 97:493. 2. Cimini MG, Brunden MN, Gibson JK. Effects of ibutilide fumarate, a novel antiarrhythmic agent, and its enantiomers on isolated rabbit myocardium. Eur J Pharmacol 1992; 222:93. 3. Glatter KA, Dorostkar PC, Yang Y, et al. Electrophysiological effects of ibutilide in patients with accessory pathways. Circulation 2001; 104:1933. 4. Lee KS. Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na+ current in guinea pig ventricular cells. J Pharmacol Exp Ther 1992; 262:99. 5. Buchanan LV, Kabell G, Brunden MN, Gibson JK. Comparative assessment of ibutilide, D- sotalol, clofilium, E-4031, and UK-68,798 in a rabbit model of proarrhythmia. J Cardiovasc Pharmacol 1993; 22:540. 6. Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation 1995; 91:1799. 7. Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 1996; 93:407. 8. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 9. Vos MA, Golitsyn SR, Stangl K, et al. Superiority of ibutilide (a new class III agent) over DL- sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group. Heart 1998; 79:568. 10. Ellenbogen KA, Stambler BS, Wood MA, et al. Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study. J Am Coll Cardiol 1996; 28:130. 11. Abi-Mansour P, Carberry PA, McCowan RJ, et al. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Study Investigators. Am Heart J 1998; 136:632. 12. Glatter K, Yang Y, Chatterjee K, et al. Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy. Circulation 2001; 103:253. 13. VanderLugt JT, Mattioni T, Denker S, et al. Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery. Circulation 1999; 100:369. 14. Tallaj JA, Franco V, Rayburn BK, et al. Safety and efficacy of ibutilide in heart transplant recipients. J Heart Lung Transplant 2009; 28:505. https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 9/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate 15. Gowda RM, Khan IA, Punukollu G, et al. Use of ibutilide for cardioversion of recent-onset atrial fibrillation and flutter in elderly. Am J Ther 2004; 11:95. 16. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. 17. Hoyer AW, Balaji S. The safety and efficacy of ibutilide in children and in patients with congenital heart disease. Pacing Clin Electrophysiol 2007; 30:1003. 18. Fragakis N, Bikias A, Delithanasis I, et al. Acute beta-adrenoceptor blockade improves efficacy of ibutilide in conversion of atrial fibrillation with a rapid ventricular rate. Europace 2009; 11:70. 19. Korantzopoulos P, Kolettis TM, Papathanasiou A, et al. Propafenone added to ibutilide increases conversion rates of persistent atrial fibrillation. Heart 2006; 92:631. 20. Singh SM, d'Avila A, Kim YH, et al. The modified stepwise ablation guided by low-dose ibutilide in chronic atrial fibrillation trial (The MAGIC-AF Study). Eur Heart J 2016; 37:1614. 21. Tercius AJ, Kluger J, Coleman CI, White CM. Intravenous magnesium sulfate enhances the ability of intravenous ibutilide to successfully convert atrial fibrillation or flutter. Pacing Clin Electrophysiol 2007; 30:1331. 22. Patsilinakos S, Christou A, Kafkas N, et al. Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. Am J Cardiol 2010; 106:673. 23. Gowda RM, Khan IA, Punukollu G, et al. Female preponderance in ibutilide-induced torsade de pointes. Int J Cardiol 2004; 95:219. 24. Chiladakis JA, Kalogeropoulos A, Patsouras N, Manolis AS. Ibutilide added to propafenone for the conversion of atrial fibrillation and atrial flutter. J Am Coll Cardiol 2004; 44:859. 25. Hongo RH, Themistoclakis S, Raviele A, et al. Use of ibutilide in cardioversion of patients with atrial fibrillation or atrial flutter treated with class IC agents. J Am Coll Cardiol 2004; 44:864. 26. http://www.bionichepharmausa.com/pdf/Ibutilide_Fumarate_PI.pdf. 27. Stambler BS, Beckman KJ, Kadish AH, et al. Acute hemodynamic effects of intravenous ibutilide in patients with or without reduced left ventricular function. Am J Cardiol 1997; 80:458. Topic 924 Version 31.0 https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 10/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 11/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 12/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate Reversion of AF with antiarrhythmic drugs is related to arrhythmia duration In a study comparing two doses of intravenous ibutilide with intravenous sotalol for acute reversion of atrial fibrillation, the rate of successful reversion was inversely related to the duration of the arrhythmia prior to therapy. Data from: Vos MA, Golitsyn SR, Stangl K, et al for the Ibutilide/Sotalol Comparator Study Group, Heart 1998; 79:568. Graphic 62459 Version 2.0 https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 13/14 7/5/23, 8:24 AM Therapeutic use of ibutilide - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/therapeutic-use-of-ibutilide/print 14/14
7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment with digoxin: Initial dosing, monitoring, and dose modification : Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Brian Olshansky, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 16, 2022. INTRODUCTION Cardiac glycosides have important positive inotropic, neurohormonal, and electrophysiologic actions, which are the basis for its use in two clinical situations: heart failure due to systolic dysfunction, and in certain supraventricular tachyarrhythmias. The ability of digoxin to reduce sympathetic activation has also been recognized. For maximal early benefits in treating tachyarrhythmias, digoxin requires loading doses, which can be administered intravenously or orally. While two cardiac glycosides (digoxin and digitoxin) were previously used, digitoxin has not been widely available since the 1980s. As digoxin is now the only cardiac glycoside available in most countries, the method of initiating therapy with digoxin for patients with atrial fibrillation is presented here. Recommendations regarding the use of digoxin in the management of heart failure or arrhythmias are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) INITIATION OF THERAPY The electrolyte and renal status of each patient should be ascertained prior to initiating treatment and periodically thereafter. Hypokalemia or hypomagnesemia, for example, may https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 1/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate promote the development of digoxin-induced arrhythmias, while impaired renal function may result in higher than anticipated serum drug levels. (See 'Dose adjustments' below.) The initiation of digoxin therapy has been divided into rapid and slow digitalization followed by the maintenance digoxin dose, and the proposed regimens vary considerably. The following principles should be viewed as a general guide to the use of digoxin for its inotropic or electrophysiologic effects, which must be modified according to clinical circumstances. Patients receiving digoxin for ventricular rate control in atrial fibrillation or flutter will usually require more rapid loading than those treated with digoxin for heart failure, in whom a loading dose is typically not required. The use of digoxin primarily for heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Slow digoxin loading Slow oral digitalization, generally preferred for most patients, can be achieved by starting a maintenance dose of 0.125 to 0.25 mg daily. A steady state will be achieved after five cycles of the drug half-life (T1/2 ), which is approximately 7 to 10 days in the average subject. Rapid digoxin loading Rapid intravenous and oral digitalization can be used to control the ventricular response in atrial fibrillation and flutter. However, other drugs may be more effective and/or have a more rapid onset of action on the ventricular response in these arrhythmias; therefore, rapid digitalization is rarely needed unless alternative drugs are contraindicated or have not been effective. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Control of ventricular rate in atrial flutter", section on 'Rate control with drugs'.) The total loading dose with digoxin varies from patient to patient but is usually between 0.75 to 1.5 mg with intravenous administration and 1 to 1.5 mg with oral administration. (See 'Dose adjustment in kidney disease' below and 'Patients with low body weight' below.) Intravenous loading For ventricular rate control in atrial fibrillation and flutter, the most rapid means of digitalization is the intravenous route. An initial intravenous dose of 0.25 to 0.5 mg of digoxin is given over several minutes, followed by 0.25 mg every 6 hours for a total loading dose of 0.75 to 1.5 mg (10 to 12 mcg/kg lean body weight) (calculator 1 and calculator 2). Intravenous digoxin begins to act in 15 to 30 minutes with a peak effect in 1 to 5 hours. Oral loading Rapid oral digitalization can be accomplished by giving 0.5 mg initially followed by 0.25 mg every six hours for a total loading dose of 0.75 to 1.5 mg. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 2/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Loading dose adjustments Patients who are hypokalemic, hypomagnesemic, hypercalcemic, hypoxic, or with hypothyroidism are more sensitive to the effects of digoxin. If these issues persist at the time of digoxin loading, an initial loading dose in the lower range (eg, 0.75 mg or less) should be considered. Digoxin distributes widely to skeletal muscle, cardiac, and other lean tissue and has a large volume of distribution (ie, 4 to 7 L/kg) in normal subjects, which is decreased in patients who are older, have low skeletal muscle mass, or severe renal impairment. Digoxin serum concentrations relative to the administered loading dose may be proportionally increased among persons with low muscle mass and/or renal impairment, and a reduced loading dose should be considered. Renal impairment The digoxin loading dose should be reduced by approximately one-third to one-half (or more) in the setting of severe chronic renal insufficiency [1-3]. For most patients with chronic renal insufficiency not on dialysis, the reduced loading dose may be supplemented after six hours if clinical response is inadequate, in absence of toxicity. For patients with stage 5 chronic kidney disease (glomerular filtration rate [GFR] <15 mL/minute), or for those on hemodialysis, chronic ambulatory peritoneal dialysis, or continuous renal replacement therapy, alternative agents (eg, beta blockers or nondihydropyridine calcium channel blockers) may be preferred for heart rate control; however, if digoxin will be used, a reduced loading dose of 3 to 5 mcg/kg (0.25 to 0.375 mg) is recommended, followed by a maintenance dose of 0.0625 mg every 48 hours. (See 'Dose adjustment in kidney disease' below.) Lean body weight In general, it is reasonable to select an initial loading dose in the lower range (ie, 0.75 to 1 mg) for patients of low to average lean body weight (eg, 45 to 70 kg) and in the upper part of the dose range (ie, 1 to 1.5 mg) for patients of average to above average lean body weight (eg, 71 to 90 kg) (calculator 1 and calculator 2). Patients with low body weight Patients with body weight of less than 45 kg should receive 50 percent of the normal loading dose. Patients who are obese Compared with normal weight subjects, neither volume of distribution nor clearance of digoxin are consistently altered by changes in body composition associated with obesity [4-6]. Therefore, normal (non-weight based) loading doses should be used. However, if a weight based dose is used, it should be based upon estimated lean body weight (calculator 1 and calculator 2). Maintenance digoxin dosing For most patients, the maintenance dose of digoxin will be between 0.125 mg and 0.25 mg daily. The daily maintenance dose will vary depending on the indication for digoxin therapy, with patients receiving digoxin for heart failure often requiring lower doses than those who are taking digoxin for ventricular rate control. Additionally, the https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 3/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate maintenance dose is affected by renal function, body weight, and the presence or absence of other medications which are known to alter the metabolism of digoxin [7]. (See 'Dose adjustments' below.) Ventricular rate control For patients taking digoxin for ventricular rate control in the setting of atrial arrhythmias, the typical maintenance dose is between 0.125 and 0.25 mg daily. In contrast to digoxin use for heart failure, there is no particular serum digoxin level which is targeted, as the medication should be adjusted to maintain optimal ventricular rate control. However, serum digoxin levels higher than 1 ng/mL (1.3 nmol/L) should be avoided to reduce the risk of digoxin toxicity. Heart failure The approach to maintenance digoxin dosing in patients with heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Dose adjustments Bioavailability is between 70 and 80 percent for conventional digoxin tablets and between 75 and 85 percent for digoxin elixir, and the T1/2 of digoxin ranges from 33 to 50 hours when renal function is normal. Unlike certain other drugs (eg, furosemide), the bioavailability of the oral dose forms of digoxin does not appear to be affected by heart failure. Dose adjustments of digoxin are necessary in patients with renal dysfunction, patients with low body weight, and with the concomitant use of certain medications. The effect of digoxin in patients with heart failure and the need for dose adjustments in such patients are discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Dose adjustment in kidney disease Approximately 70 to 80 percent of digoxin is eliminated unchanged in the urine, leading to prolongation of the half-life in patients with renal insufficiency. Renal insufficiency also decreases the extravascular volume of distribution of digoxin, another effect that can elevate plasma drug levels. As a result, both the initial loading dose and the maintenance dose must be reduced in patients with underlying kidney disease. In end-stage kidney disease, for example, the loading dose should be one-half to two-thirds normal. The adjustment of the digoxin loading dose is discussed above. (See 'Renal impairment' above.) The initial maintenance dose (for congestive heart failure) adjusted for ideal body weight and renal function (except stage 5 chronic kidney disease or receiving renal replacement therapy) is presented in the table ( table 1). (See 'Patients requiring hemodialysis' below https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 4/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate and "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Patients requiring hemodialysis For patients on intermittent hemodialysis (IHD), chronic ambulatory peritoneal dialysis (CAPD), and continuous renal replacement therapy (CRRT), the dosing recommendation is 0.0625 mg every 48 hours, or approximately 10 to 25 percent of the usual dose for patients with normal renal function given every 48 hours [8,9]. No supplemental dose for dialysis is required because renal replacement therapies (eg, IHD, CAPD, CRRT) remove only insignificant amounts of digoxin from the body due to digoxin's large volume of distribution. Serum digoxin concentrations should be monitored. The same dose recommendation is used for stage 5 chronic kidney disease patients (GFR <15 mL/minute) who are not currently receiving dialysis. (See 'Monitoring serum digoxin' below.) Dose adjustment with hepatic disease Hepatic disease has little influence on digoxin metabolism or clearance; therefore, no dose adjustment is necessary. Dose adjustment with concomitant medications There are a number of important drug interactions with digoxin. Some examples are provided below; in addition, specific interactions of digoxin with medications may be determined using the Lexicomp drug interactions program included within UpToDate (Lexicomp drug interactions). Inhibitors of P-glycoprotein efflux transporters (eg, amiodarone, dronedarone, propafenone, quinidine, and verapamil) can increase serum digoxin levels. With concurrent dronedarone administration, for example, the digoxin dose should be reduced by one-half if digoxin cannot be discontinued [10-12] (see "Clinical uses of dronedarone", section on 'Metabolism and drug interactions'). A list of medicines that inhibit P-glycoprotein is provided separately ( table 2). Inducers of P-glycoprotein (eg, phenytoin, rifampin, etc), on the other hand, can decrease serum digoxin levels. A list of medicines that induce P-glycoprotein is provided separately ( table 2). Cholestyramine and antacids can decrease the intestinal absorption of digoxin by 20 to 35 percent, necessitating an increase in the daily dose. To avoid these interactions, digoxin should be dosed one hour before or two to three hours after the administration of the antacids or cholestyramine. Bupropion, an antidepressant that is also frequently prescribed to aid in smoking cessation, can decrease digoxin levels by 60 percent; monitor serum digoxin levels and clinical status [13-15]. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 5/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Diuretics may increase digitalis toxicity as a result of a decrease in the glomerular filtration rate and the development of electrolyte abnormalities, especially hypokalemia. Tetracycline and erythromycin can interfere with the sequential hydrolysis pathway of digoxin metabolism (which begins in the stomach and is responsible for less than 15 percent of the metabolism in most patients but which can be significantly more active in a minority of patients). As such, these drugs increase digoxin levels in approximately 10 percent of patients in whom this pathway is a significant component of the drug's metabolism. High doses of biotin (vitamin B7) can increase the measured serum concentration of digoxin by as much as 0.25 ng/mL (0.3 nmol/L) when measured using the luminescent oxygen channeling immunoassay (LOCI) [16]. This does not represent a true increase in serum digoxin concentration but an interaction between biotin and the measurement assay, resulting in the artificial appearance of increased serum digoxin levels. Digoxin in pregnancy Digoxin crosses the placenta and has been used for both fetal and maternal cardiac indications without report of fetal harm or teratogenicity [17]. As such, there is no contraindication for using digoxin during pregnancy or during lactation. Digoxin in patients with amyloidosis The inotropic effects of digoxin are not generally beneficial in patients with amyloidosis. Moreover, because digoxin binds avidly to amyloid fibrils, patients with amyloidosis who take digoxin may be at an increased risk of digoxin toxicity [18]. Additionally, as a result of the binding of digoxin to myocardial amyloid fibrils, cardiac digoxin concentration may be higher than serum digoxin concentration, leading to toxicity in the setting of "therapeutic" serum digoxin levels. However, in a patient with atrial fibrillation with a rapid ventricular response, careful digoxin administration is usually safe and effective for reducing the ventricular rate [19]. (See "Amyloid cardiomyopathy: Treatment and prognosis".) MONITORING SERUM DIGOXIN Monitoring Given the relatively narrow therapeutic window of digoxin, with substantial overlap between so-called therapeutic and toxic levels, patients taking digoxin require monitoring of the serum digoxin concentration, with the "optimal" level varying with the clinical setting. Monitoring the serum digoxin level is particularly important in persons with chronic renal dysfunction or rapidly changing renal function, as significantly decreased renal function can lead to accumulation of digoxin and its metabolites and predispose to digoxin toxicity. Additionally, patients with electrolyte disturbances, particularly hypokalemia and hypomagnesemia, which may be related to diuretic therapy or other medications, are at https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 6/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate increased risk for digoxin-associated arrhythmias and should undergo monitoring of the serum digoxin level until serum potassium level and magnesium concentration return to the normal range [20]. (See 'Dose adjustments' above and "Cardiac arrhythmias due to digoxin toxicity", section on 'Plasma digoxin levels associated with toxicity'.) Monitoring the serum digoxin concentration is most important when digoxin is used in the treatment of heart failure with systolic dysfunction, whereas levels are only checked when used in patients with atrial fibrillation if toxicity is suspected. Blood samples should be obtained at least 6 hours, but optimally 12 hours, after administration of digoxin to ensure completion of distribution from the blood to the tissues. In patients with advanced kidney disease or who are on hemodialysis, the digoxin level should be checked at least 12 to 24 hours after the prior dose. Serum digoxin concentrations measured prior to these times may be falsely elevated. Adjusting the digoxin dose Assuming that the digoxin level was drawn at the correct time, at steady state, and under conditions of stable renal function, there is a linear relationship between digoxin dose and serum concentration. As an example, a steady state concentration is measured and returns at 1.6 ng/mL (2.05 nmol/L) in a patient taking a daily maintenance dose (for this example, 0.25 mg daily). Assuming the desired serum concentration is 0.8 ng/mL (1.0 nmol/L), the dose should be reduced by 50 percent (to 0.125 mg daily in this example). The same linear relationship is true for patients whose serum concentration is lower than desired in whom a dose increase is needed. Heart failure The monitoring of serum digoxin levels in patients with heart failure is discussed separately. (See "Secondary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Digoxin'.) Atrial fibrillation Digoxin is generally less effective for rate control of atrial fibrillation (AF) than beta blockers or calcium channel blockers, is less likely to control the ventricular rate during exercise (when vagal tone is low and sympathetic tone is high), has little or no ability to terminate the arrhythmia, and often does not slow the heart rate with recurrent AF. Thus, patients frequently require the addition of a beta blocker or calcium channel blocker for optimal rate control. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should be monitored periodically, although the drug concentration often does not correlate with ventricular rate control and is used more as a guide to toxicity than to therapy. Junctional escape beats (as detected by the equality of all the longest observed R-R intervals on the electrocardiogram) are common when digitalis has successfully slowed the ventricular rate. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 7/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Giving more digoxin in this setting will increase the degree of AV nodal block and produce periods of regular junctional rhythm. The change from single junctional escapes to periodic junctional rhythm usually signifies the development of digoxin toxicity. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Junctional rhythm, tachycardia, and bradycardia'.) Relation to digoxin toxicity Digoxin-related cardiac arrhythmias and extracardiac symptoms can occur when the serum digoxin concentration is in the therapeutic or even subtherapeutic range; as a result, the presence of digoxin toxicity or excess is often a clinical diagnosis irrespective of circulating levels (unless of course the value is zero). (See "Cardiac arrhythmias due to digoxin toxicity".) SUMMARY AND RECOMMENDATIONS Indications Cardiac glycosides such as digoxin have positive inotropic, neurohormonal, and electrophysiologic actions which are the basis for its use in two clinical situations: heart failure with reduced ejection fraction, and in certain supraventricular tachyarrhythmias, primarily atrial fibrillation (AF) and atrial flutter. (See 'Introduction' above.) Slow digoxin loading This approach is preferred for most patients. A slow digoxin load is achieved by starting a maintenance oral dose of 0.125 to 0.25 mg daily, which results in a steady state serum level of drug in approximately 7 to 10 days in the average subject. (See 'Slow digoxin loading' above.) Rapid digoxin loading This approach can be used to control the ventricular response in AF and atrial flutter (see 'Rapid digoxin loading' above): Initial intravenous doses of 0.25 to 0.5 mg of digoxin are given over several minutes, followed by 0.25 mg every six hours for a total dose of 0.75 to 1.5 mg with appropriate dosing adjustments for kidney disease and the concomitant use of certain medications. (See 'Dose adjustment in kidney disease' above and 'Dose adjustment with concomitant medications' above.) Rapid oral digoxin loading can be accomplished by giving 0.5 mg initially followed by 0.25 mg every six hours for a total loading dose of 0.75 to 1.5 mg. Monitoring considerations Narrow therapeutic window Given the relatively narrow therapeutic window of digoxin and substantial overlap between therapeutic and toxic levels, patients taking https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 8/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate digoxin require monitoring of the serum digoxin concentration. The optimal level of digoxin varies according to clinical setting. Monitoring the serum digoxin level is particularly important in persons with chronic kidney disease, rapidly changing kidney function, or electrolyte disturbances (eg, hypokalemia, hypomagnesemia). (See 'Monitoring serum digoxin' above.) Dose adjustments Assuming that the digoxin level was drawn at the correct time, at steady state, and under conditions of stable kidney function, there is a linear relationship between digoxin dose and serum concentration that should be followed for any necessary dose adjustments. (See 'Adjusting the digoxin dose' above.) When digoxin is used strictly for ventricular rate control in AF, serum digoxin levels should be monitored periodically, although the drug concentration often does not correlate with ventricular rate control and is used more as a guide to toxicity than to therapy. (See 'Atrial fibrillation' above.) Patients with kidney disease Approximately 70 to 80 percent of digoxin is eliminated in the urine; thus, the half-life of digoxin is prolonged in patients with kidney disease. Kidney disease also decreases the extravascular volume of distribution of digoxin, another effect that can elevate plasma drug levels. As a result, we reduce both the initial loading dose and the maintenance dose in patients with kidney disease ( table 1). (See 'Dose adjustment in kidney disease' above.) Patients with concomitant medications Quinidine, verapamil, and amiodarone (medications that inhibit P-glycoprotein efflux transporters) can increase serum digoxin levels, thereby requiring a reduction in the daily digoxin dose ( table 2). Inducers of P- glycoprotein (eg, phenytoin, rifampin, etc), on the other hand, can decrease serum digoxin levels. Cholestyramine and antacids can decrease the intestinal absorption of digoxin. This necessitates spacing of the doses or an increase in the daily digoxin dose. Specific interactions of digoxin with other medications may be determined using the Lexicomp drug interactions program (Lexicomp drug interactions) included within UpToDate. (See 'Dose adjustment with concomitant medications' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 9/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate The UpToDate editorial staff acknowledges Lynne Sylvia, PharmD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Aronson JK. Clinical pharmacokinetics of cardiac glycosides in patients with renal dysfunction. Clin Pharmacokinet 1983; 8:155. 2. Cheng JW, Charland SL, Shaw LM, et al. Is the volume of distribution of digoxin reduced in patients with renal dysfunction? Determining digoxin pharmacokinetics by fluorescence polarization immunoassay. Pharmacotherapy 1997; 17:584. 3. Matzke GR, Frye RF. Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity. Drug Saf 1997; 16:205. 4. Ewy GA, Groves BM, Ball MF, et al. Digoxin metabolism in obesity. Circulation 1971; 44:810. 5. Abernethy DR, Greenblatt DJ. Drug disposition in obese humans. An update. Clin Pharmacokinet 1986; 11:199. 6. Erstad BL. Dosing of medications in morbidly obese patients in the intensive care unit setting. Intensive Care Med 2004; 30:18. 7. DiDomenico RJ, Bress AP, Na-Thalang K, et al. Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy 2014; 34:1121. 8. Caroline Ashley and Aileen Dunleavy. Digoxin. In: The Renal Drug Handbook: The Ultimate P rescribing Guide for Renal Practitioners, 5th edition, CRC Press, Boca Raton 2018. p.330. 9. Mooradian AD. Digitalis. An update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations. Clin Pharmacokinet 1988; 15:165. 10. Vallakati A, Chandra PA, Pednekar M, et al. Dronedarone-induced digoxin toxicity: new drug, new interactions. Am J Ther 2013; 20:e717. 11. Dorian P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 2010; 15:15S. 12. Dronedarone tablet. US Food & Drug Administration (FDA) approved product information. R evised March, 2014. US National Library of Medicine. Available online at http://www.dailyme d.nlm.nih.gov/. 13. Kirby BJ, Collier AC, Kharasch ED, et al. Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 10/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate rifampin, or bupropion. Drug Metab Dispos 2012; 40:610. 14. He J, Yu Y, Prasad B, et al. Mechanism of an unusual, but clinically significant, digoxin- bupropion drug interaction. Biopharm Drug Dispos 2014; 35:253. 15. Bupropion US prescribing information (revision May 10, 2017) https://www.accessdata.fda.g ov/drugsatfda_docs/label/2017/020711s045s046s047lbl.pdf. 16. Rodriguez JJ, Acosta F, Bourgeois L, Dasgupta A. Biotin at High Concentration Interferes with the LOCI Digoxin Assay but the PETINIA Phenytoin Assay Is Not Affected. Ann Clin Lab Sci 2018; 48:164. 17. Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99:1265. 18. Rubinow A, Skinner M, Cohen AS. Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981; 63:1285. 19. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005; 112:2047. 20. Broeren MA, Geerdink EA, Vader HL, van den Wall Bake AW. Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med 2009; 151:755. Topic 1051 Version 50.0 https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 11/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate GRAPHICS Initial digoxin maintenance dose for adult patients with heart failure targeting a serum concentration of 0.5 to 0.9 nmol/L Creatinine clearance (mL/minute) Digoxin oral dose per day (mg) Ideal body weight (kg)* 45 to 50 15 to 60 0.0625 >60 0.125 51 to 60 15 to 45 0.0625 46 to 110 0.125 >110 0.25 61 to 70 15 to 35 0.0625 36 to 110 0.125 >110 0.25 20 71 to 80 0.0625 21 to 80 0.125 >80 0.25 81 to 90 15 to 70 0.125 >70 0.25 This table provides initial dose recommendations based upon a nomogram tested at a single center in nondialysis patients. Dose adjustment(s) according to clinical response and serum digoxin concentration(s) at steady state (ie, after 7 to 10 days of therapy) may be necessary. NOTE: This nomogram is not for use in patients with stage 5 chronic kidney disease and/or receiving renal replacement therapy . Dosing recommendations are provided separately in the clinical topic discussion. Alternative renal dose adjustment recommendations are available in the Lexicomp digoxin drug monograph included in UpToDate. A calculator to determine ideal body weight is available in UpToDate. A calculator to estimate creatinine clearance according to Cockcroft and Gault equation is available in UpToDate. 0.0625 mg daily dose can alternatively be given as 0.125 mg every other day. Patients with unstable renal function or stage 5 renal disease requiring renal replacement therapy, pregnant patients, and patients who were receiving medications known to significantly interact with https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 12/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate digoxin (eg, amiodarone, quinidine, verapamil, or macrolide antibiotics) were excluded from the population in which this nomogram was validated. Adapted from DiDomenico RJ, Bress AP, Na-Thalang K, et al. Use of a simpli ed nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy 2014. Graphic 90157 Version 15.0 https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 13/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- containing coformulations Neratinib Lorlatinib Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- Tamoxifen* ivacaftor Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole (isavuconazonium sulfate) Verapamil Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 14/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. These classifications are based upon US FDA guidance. [1,2] Other sources may use a different classification system resulting in some agents being classified differently. Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 15/16 7/5/23, 8:24 AM Treatment with digoxin: Initial dosing, monitoring, and dose modification - UpToDate Contributor Disclosures Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/treatment-with-digoxin-initial-dosing-monitoring-and-dose-modification/print 16/16
7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation : E Kevin Heist, MD, PhD : Samuel L vy, MD, Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. INTRODUCTION Initial studies suggested that angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and (possibly) aldosterone antagonists might either prevent new onset and recurrent atrial fibrillation (AF) or reduce the rate of major adverse cardiovascular outcomes in these patients. However, the available data do not support the use of these drugs solely for these purposes. In this topic, ACE inhibitors and ARBs collectively will be referred to as "angiotensin inhibition." POSSIBLE MECHANISMS Mechanisms proposed to explain the benefit of angiotensin blockade found in the early studies included the direct effects of angiotensin blockade on the structural and electrical properties of the atria, as well as the indirect influence of improved control of heart failure and hypertension (in patients with these conditions), both of which are known risk factors for atrial fibrillation (AF) [1]. (See "The electrocardiogram in atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'.) The following observations supported the proposed mechanisms: https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 1/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Reduction in atrial stretch Atrial stretch, due to increased left atrial (LA) pressure, is associated with changes in the refractory period and conduction properties of atrial myocardium. These abnormalities provide both potential triggers and the substrate for the initiation and perpetuation of AF. The hemodynamic effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) result in improved ventricular function and also reductions in LA pressure and wall stress [2]. Prevention of atrial fibrosis Fibrosis in the atrial myocardium may be an important component of the substrate necessary for AF. Atrial fibrosis is stimulated by elevated levels of angiotensin-II [3] and reduced by treatment with ACE inhibitors [4,5]. Prevention of electrical remodeling and direct antiarrhythmic effects Direct effects of angiotensin blockade on ion channels and electrophysiologic properties have been suggested [6], but data from both animal and human studies have been conflicting and inconclusive. Canine work has suggested direct inhibition of triggering of atrial arrhythmias by ACE inhibitors and ARBs [7]. PREVENTION OF NEW ONSET AF Post-hoc analyses of randomized trials and observations from nonrandomized studies have suggested that angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) reduce the incidence of new atrial fibrillation (AF) in a variety of settings including the treatment of left ventricular dysfunction or hypertension, and after coronary artery bypass graft surgery (CABG). The following findings were noted in a 2010 meta-analysis of data from 26 randomized trials [8]: ACE inhibitors and ARBs significantly reduced the risk of the development of AF (Odds Ratio [OR] 0.65, 95% CI 0.55-0.76); the benefit was equivalent with the two classes of drugs. The benefit of ACE inhibitors and ARBs appeared large in patients with systolic heart failure (OR 0.50), but the result was not statistically significant (95% CI 0.19-1.16). The effect of ACE inhibitors and ARBs was greater in preventing recurrent AF (OR 0.45, 95% CI 0.31-0.65) compared to new-onset AF (OR 0.80, 95% CI 0.70-0.92) However, the strength of the conclusions from the meta-analysis is weakened due the inclusion of post hoc analyses of randomized trials performed for reasons other than prevention of AF (eg, heart failure, post-myocardial infarction [MI], or hypertension), heterogeneity, and the likely presence of publication or ascertainment bias. https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 2/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Left ventricular dysfunction or heart failure In the TRACE trial of patients with left ventricular dysfunction and sinus rhythm after an acute myocardial infarction, trandolapril therapy was associated with a significantly reduced incidence of subsequent AF at two- to four- year follow-up (2.8 versus 5.3 percent with placebo) [9]. Similar findings were noted in retrospective analyses from the randomized trials SOLVD and Val- HeFT, which enrolled patients with chronic left ventricular dysfunction, almost all of whom had ischemic heart disease [10,11]. In the SOLVD trial, enalapril significantly reduced the incidence of subsequent AF at a mean follow-up of 2.9 years (5.4 versus 24 percent with placebo, hazard ratio 0.22). (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials" and "Management and prognosis of asymptomatic left ventricular systolic dysfunction", section on 'ACE inhibitors'.) A smaller reduction in the incidence of new AF with the ARB candesartan was noted in the CHARM trials [12]. Among 7601 patients enrolled in the three trials, 6379 patients did not have AF at baseline. At a median follow-up of 38 months, candesartan produced a reduction in the incidence of new AF (5.6 versus 6.7 percent, adjusted P value 0.039). Hypertension Some [13-17], but not all [18-20], studies comparing ACE inhibitors or ARBs to other classes of drugs in patients with hypertension have shown a lowering of the risk of development AF. A 2010 meta-analysis of trials with substantial heterogeneity found no significant reduction in the risk for AF [21]. The role of angiotensin blockade in the treatment of hypertension is discussed separately. (See "Choice of drug therapy in primary (essential) hypertension".) Patients with other risk factors for atrial fibrillation The issue of whether these therapies might prevent the development of AF in patients with risk factors other than left ventricular dysfunction, heart failure, or hypertension, such as diabetes or coronary artery disease, has not been well studied. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) Coronary artery bypass graft The possible role of these therapies for the prevention of AF in patients undergoing cardiac surgery is discussed elsewhere. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) PREVENTION OF RECURRENT AF Multiple small studies have demonstrated reduction in recurrent atrial fibrillation (AF) with use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), but https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 3/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate these findings have not been confirmed in larger, better powered studies. In small trials that enrolled fewer than 200 patients, ACE inhibitors or ARBs in combination with amiodarone reduced the rate of recurrent AF compared with amiodarone alone [22-26]. A small study of ramipril versus placebo in hypertensive patients demonstrated reduced AF recurrence with ramipril [26] and a small randomized study comparing telmisartan to carvedilol in hypertensive patients with prior AF demonstrated less recurrence of AF in patients treated with telmisartan, despite similar blood pressure reduction between the two agents [27]. However, these results from smaller studies were not confirmed in the GISSI-AF trial, which randomly assigned 1442 patients with a history of symptomatic AF and in sinus rhythm to receive either valsartan or placebo [28]. All patients had underlying cardiovascular disease, diabetes, or left atrial enlargement. GISSI-AF found that valsartan did NOT prevent recurrent AF. At one-year follow-up, there was no significant difference between valsartan or placebo in the proportion of patients who had more than one episode of AF (51 versus 52 percent, adjusted hazard ratio 0.97, 95% CI 0.83-1.14) or in the median time from randomization to the first recurrence of AF (295 versus 291 days). Although 57 percent of patients were taking an ACE inhibitor and 70 percent were taking antiarrhythmic drugs at baseline that were continued throughout the trial and might have confounded the results, the outcomes in subgroup analysis were similar in the patients who were or were not being treated with such agents. Another possible contributor to the lack of benefit in GISSI-AF was a low prevalence of heart failure/left ventricular dysfunction (8 percent), since the meta-analysis cited above found that the benefit was greatest in patients with these conditions [29]. Prevention of recurrent AF with irbesartan was also analyzed in the ACTIVE I study, which randomized 9016 patients with a history of AF, stroke risk factors and a systolic blood pressure of at least 110 mm Hg to either irbesartan 300 mg once daily or placebo. Patients who received irbesartan in ACTIVE I were not significantly more likely to be in sinus rhythm at subsequent follow-up, regardless of whether they were initially in AF at baseline or in sinus rhythm at baseline (RR 0.97, p = 0.61). Similarly, the ANTIPAF study, a randomized study of placebo versus olmesartan in patients with documented paroxysmal AF, demonstrated no benefit in regard to recurrent AF episodes in patients randomized to olmesartan [30]. Aldosterone inhibition and atrial fibrillation There are data from animal and human studies to suggest that spironolactone, an aldosterone antagonist, may reduce the risk of recurrent AF [31,32]. Supportive studies of specific drugs are summarized as follows: https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 4/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Eplerenone A newer aldosterone antagonist, eplerenone, was shown in the randomized EMPHASIS-HF study to reduce new onset AF in patients with systolic heart failure and mild heart failure symptoms [33]. Eplerenone was also shown in a small study to decrease AF recurrence after catheter ablation for long-standing persistent AF [34]. Spironolactone In the TOPCAT randomized trial of spironolactone in patients with heart failure with preserved ejection fraction, spironolactone did not reduce the incidence of AF [35] (see "Treatment and prognosis of heart failure with preserved ejection fraction" and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Mineralocorticoid receptor antagonists'). A 2016 meta-analysis did suggest reduced AF in patients treated with aldosterone antagonists based on three randomized controlled trials and two observations studies, although this effect was evident for eplerenone but not spironolactone [36]. Finerenone In a secondary analysis of the randomized FIDELIO-DKD trial of patients with chronic kidney disease and type 2 diabetes, those assigned the mineralocorticoid receptor antagonist finerenone resulted in a lower incidence of new-onset atrial fibrillation or flutter compared with placebo (hazard ratio 0.71; 95% CI 0.53-0.94) [37]. Meta analysis of aldosterone-antagonists A 2019 meta-analysis of 24 studies (representing both randomized and observational studies, with a total of 7914 patients) demonstrated a significant reduction in AF occurrence in aldosterone-antagonist-treated patients compared with control patients (odds ratio 0.55; 95% CI 0.44-0.70), with significant AF reduction demonstrated in randomized and observational studies, and regardless of the particular aldosterone antagonist used [38]. Although there appears to be potential benefit to the use of aldosterone inhibitors in heart failure patients, we do not recommend aldosterone inhibitors specifically for prevention of new or recurrent AF. The details of mineralocorticoid receptor antagonists in heart failure are presented separately. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Primary components of therapy'.) Catheter ablation of atrial fibrillation The data are mixed as to whether ACE inhibitors/ARBs reduce AF after radiofrequency catheter ablation procedures: A significant benefit was seen in some [39], but not other [40,41] studies. (See "Atrial fibrillation: Catheter ablation".) PREVENTION OF CARDIOVASCULAR EVENTS https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 5/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate As discussed in the sections on prevention above, the benefit of either angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB) therapy for the prevention of new or recurrent atrial fibrillation (AF) is uncertain. The issue of whether ARB therapy can reduce the rate of major adverse cardiovascular events in patients with AF was addressed in the ACTIVE I trial, which enrolled individuals with either permanent AF or at least two episodes of intermittent AF (in the previous six months) from the ACTIVE A and ACTIVE W trials [42]. (See 'Prevention of recurrent AF' above and "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Introduction'.) Mean reductions in systolic and diastolic blood pressures were 2.9 and 1.9 mmHg greater in the irbesartan group. At a mean follow-up of 4.1 years, there was no significant difference in the rates of the first combined coprimary outcome of stroke, myocardial infarction, or death from vascular causes for the irbesartan compared with placebo groups (5.4 percent per 100 person- years in both groups), and there was no significant difference in the rates of the second combined coprimary outcome, which included the components of the first coprimary outcome plus the rate of hospitalization for heart failure (7.3 and 7.7 percent per 100 person-years in the two groups, respectively). A Swedish registry study of patients followed after acute myocardial infarction showed that use of ACE inhibitors and ARBs did reduce all-cause mortality, but did not reduce the incidence of new-onset AF [43]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Prevention of atrial fibrillation For patients at risk for atrial fibrillation (AF) but without another indication for angiotensin blockade, we recommend not initiating therapy with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker solely to prevent new onset AF (Grade 1B). (See 'Prevention of new onset AF' above.) Prevention of AF recurrence In patients with a history of AF, we recommend NOT treating with an ACE inhibitor or ARB for the sole purpose of preventing recurrent AF (Grade 1B). (See 'Prevention of recurrent AF' above.) https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 6/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ehrlich JR, Hohnloser SH, Nattel S. Role of angiotensin system and effects of its inhibition in atrial fibrillation: clinical and experimental evidence. Eur Heart J 2006; 27:512. 2. Webster MW, Fitzpatrick MA, Nicholls MG, et al. Effect of enalapril on ventricular arrhythmias in congestive heart failure. Am J Cardiol 1985; 56:566. 3. McEwan PE, Gray GA, Sherry L, et al. Differential effects of angiotensin II on cardiac cell proliferation and intramyocardial perivascular fibrosis in vivo. Circulation 1998; 98:2765. 4. Li D, Shinagawa K, Pang L, et al. Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001; 104:2608. 5. Sakabe M, Fujiki A, Nishida K, et al. Enalapril prevents perpetuation of atrial fibrillation by suppressing atrial fibrosis and over-expression of connexin43 in a canine model of atrial pacing-induced left ventricular dysfunction. J Cardiovasc Pharmacol 2004; 43:851. 6. Nakashima H, Kumagai K, Urata H, et al. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000; 101:2612. 7. Sicouri S, Cordeiro JM, Talarico M, Antzelevitch C. Antiarrhythmic effects of losartan and enalapril in canine pulmonary vein sleeve preparations. J Cardiovasc Electrophysiol 2011; 22:698. 8. Zhang Y, Zhang P, Mu Y, et al. The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Pharmacol Ther 2010; 88:521. 9. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999; 100:376. 10. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation 2003; 107:2926. 11. Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J 2005; 149:548. 12. Ducharme A, Swedberg K, Pfeffer MA, et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 7/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J 2006; 152:86. 13. Schaer BA, Schneider C, Jick SS, et al. Risk for incident atrial fibrillation in patients who receive antihypertensive drugs: a nested case-control study. Ann Intern Med 2010; 152:78. 14. L'Allier PL, Ducharme A, Keller PF, et al. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol 2004; 44:159. 15. Dahl f B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:995. 16. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol 2005; 45:712. 17. Heckbert SR, Wiggins KL, Glazer NL, et al. Antihypertensive treatment with ACE inhibitors or beta-blockers and risk of incident atrial fibrillation in a general hypertensive population. Am J Hypertens 2009; 22:538. 18. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353:611. 19. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354:1751. 20. Yamashita T, Inoue H, Okumura K, et al. Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study). Europace 2011; 13:473. 21. Schneider MP, Hua TA, B hm M, et al. Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis. J Am Coll Cardiol 2010; 55:2299. 22. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002; 106:331. 23. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus rhythm maintenance after external cardioversion of long-standing persistent atrial fibrillation. Results of a prospective and controlled study. Eur Heart J 2003; 24:2090. https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 8/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate 24. Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation. Eur Heart J 2006; 27:1841. 25. Fogari R, Mugellini A, Destro M, et al. Losartan and prevention of atrial fibrillation recurrence in hypertensive patients. J Cardiovasc Pharmacol 2006; 47:46. 26. Belluzzi F, Sernesi L, Preti P, et al. Prevention of recurrent lone atrial fibrillation by the angiotensin-II converting enzyme inhibitor ramipril in normotensive patients. J Am Coll Cardiol 2009; 53:24. 27. Galzerano D, Di Michele S, Paolisso G, et al. A multicentre, randomized study of telmisartan versus carvedilol for prevention of atrial fibrillation recurrence in hypertensive patients. J Renin Angiotensin Aldosterone Syst 2012; 13:496. 28. GISSI-AF Investigators, Disertori M, Latini R, et al. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009; 360:1606. 29. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin- converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005; 45:1832. 30. Goette A, Sch n N, Kirchhof P, et al. Angiotensin II-antagonist in paroxysmal atrial fibrillation (ANTIPAF) trial. Circ Arrhythm Electrophysiol 2012; 5:43. 31. Zhao J, Li J, Li W, et al. Effects of spironolactone on atrial structural remodelling in a canine model of atrial fibrillation produced by prolonged atrial pacing. Br J Pharmacol 2010; 159:1584. 32. Dabrowski R, Borowiec A, Smolis-Bak E, et al. Effect of combined spironolactone- -blocker enalapril treatment on occurrence of symptomatic atrial fibrillation episodes in patients with a history of paroxysmal atrial fibrillation (SPIR-AF study). Am J Cardiol 2010; 106:1609. 33. Swedberg K, Zannad F, McMurray JJ, et al. Eplerenone and atrial fibrillation in mild systolic heart failure: results from the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. J Am Coll Cardiol 2012; 59:1598. 34. Ito Y, Yamasaki H, Naruse Y, et al. Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation. Am J Cardiol 2013; 111:1012. 35. Cikes M, Claggett B, Shah AM, et al. Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial. JACC Heart Fail 2018; 6:689. https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 9/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate 36. Liu T, Korantzopoulos P, Shao Q, et al. Mineralocorticoid receptor antagonists and atrial fibrillation: a meta-analysis. Europace 2016; 18:672. 37. Filippatos G, Bakris GL, Pitt B, et al. Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes. J Am Coll Cardiol 2021; 78:142. 38. Alexandre J, Dolladille C, Douesnel L, et al. Effects of Mineralocorticoid Receptor Antagonists on Atrial Fibrillation Occurrence: A Systematic Review, Meta-Analysis, and Meta-Regression to Identify Modifying Factors. J Am Heart Assoc 2019; 8:e013267. 39. Klemm HU, Heitzer T, Ruprecht U, et al. Impact of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the long-term outcome after pulmonary vein isolation for paroxysmal atrial fibrillation. Cardiology 2010; 117:14. 40. Richter B, Derntl M, Marx M, et al. Therapy with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and statins: no effect on ablation outcome after ablation of atrial fibrillation. Am Heart J 2007; 153:113. 41. Al Chekakie MO, Akar JG, Wang F, et al. The effects of statins and renin-angiotensin system blockers on atrial fibrillation recurrence following antral pulmonary vein isolation. J Cardiovasc Electrophysiol 2007; 18:942. 42. ACTIVE I Investigators, Yusuf S, Healey JS, et al. Irbesartan in patients with atrial fibrillation. N Engl J Med 2011; 364:928. 43. Batra G, Lindhagen L, Andell P, et al. Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Are Associated With Improved Outcome but Do Not Prevent New-Onset Atrial Fibrillation After Acute Myocardial Infarction. J Am Heart Assoc 2017; 6. Topic 935 Version 27.0 Contributor Disclosures E Kevin Heist, MD, PhD Equity Ownership/Stock Options: Oracle Health [Device diagnostics]. Consultant/Advisory Boards: Biotronik [Cardiac resynchronization therapy and atrial fibrillation]; Boston Scientific [Cardiac resynchronization therapy and atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 10/11 7/5/23, 9:02 AM ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation - UpToDate Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/ace-inhibitors-angiotensin-receptor-blockers-and-atrial-fibrillation/print 11/11
7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials : Kapil Kumar, MD, Peter J Zimetbaum, MD : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2023. INTRODUCTION Long-term outcomes, such as survival or rate of thromboembolism, are similar with either rhythm or rate control strategies in patients with atrial fibrillation (AF) ( figure 1A-B). In addition, anticoagulation is required with both in most patients [1,2]. Thus, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes [3,4]. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1) [3,5]. Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia [6-8]. Most patients for whom rhythm control is chosen will require rate control, both prior to its initiation and after, as many patients will have breakthrough episodes of AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) The studies describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs used to maintain sinus rhythm in patients with AF will be reviewed here. Recommendations concerning the use of pharmacologic therapy, the choice between a rhythm and a rate control strategy, and the role of alternative methods to maintain sinus rhythm in selected patients who are refractory to conventional therapy, including surgery and radiofrequency ablation, are discussed separately. (See "Antiarrhythmic drugs to maintain sinus https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 1/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate rhythm in patients with atrial fibrillation: Recommendations" and "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) This topic will also address the issue of whether other medications are associated with a decreased frequency of recurrent AF. (See 'Other therapies' below.) META-ANALYSIS The safety and efficacy of a number of antiarrhythmic drugs was assessed in a 2019 meta- analysis, which included 59 trials (n = 20,981) in which an antiarrhythmic drug for the treatment of atrial fibrillation (AF) was compared against a placebo, another antiarrhythmic, or untreated controls [9]. The following findings were noted: Compared with controls, disopyramide, quinidine, flecainide, propafenone, amiodarone, dofetilide, dronedarone, and sotalol lowered the recurrence rate of AF (risk ratios [RR] 0.77, 0.83, 0.65, 0.67, 0.52, 0.72, 0.85, and 0.83, respectively). Metoprolol also lowered the risk (RR 0.83). All-cause mortality was increased (compared with controls) with sotalol (2.23, 95% CI 1.03- 4.81). Mortality may be increased with other antiarrhythmic drugs, but the evidence was of moderate certainty or weak. These data support the general observation (as summarized in the following sections) that antiarrhythmics can reduce AF recurrences, but their overall value is limited by adverse effects. All of the antiarrhythmic drugs used to maintain sinus rhythm in AF have the potential to provoke ventricular arrhythmias. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Drugs'.) CLASS IA ANTIARRHYTHMIC DRUGS Quinidine, disopyramide, and procainamide are class IA antiarrhythmic drugs ( table 2). These drugs act by modifying the sodium channel and inhibiting the outward potassium current resulting in QT prolongation. They also have important vagolytic effects. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Quinidine is the most widely studied class IA agent for the maintenance of sinus rhythm in AF [10,11]. Although studies have shown that quinidine can reduce the rate of recurrent AF https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 2/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate compared to placebo, it is associated with an increase in mortality, particularly in patients with heart failure [7,8,12,13]. The use of quinidine for the maintenance of sinus rhythm has declined largely because other drugs are both more effective and safer. Disopyramide also seems to have some benefit in the prevention of recurrent AF [14], although it must be used with caution since it can significantly worsen underlying heart failure. The efficacy of oral procainamide has been evaluated in older and poorly controlled trials or in patients who recently underwent coronary artery bypass surgery [15-17]. Oral procainamide is not readily available in the US. CLASS IC ANTIARRHYTHMIC DRUGS Flecainide and propafenone are classified as class IC antiarrhythmic agents, although they are known to have significantly different electrophysiologic and other properties. The following observations have been made regarding their efficacy: Compared to placebo, both are more effective in maintaining sinus rhythm at six months and in prolonging the time to atrial fibrillation (AF) recurrence [18-26]. Flecainide and propafenone appear to have equal efficacy [27,28]. In a randomized, open- label study of 200 patients, for example, the probability of a safe and effective response (maintenance of sinus rhythm or fewer episodes of paroxysmal AF) at one year was 77 and 75 percent with flecainide and propafenone, respectively [27]. A meta-analysis evaluated trials of patients with AF resistant to class I drugs or sotalol who were treated with flecainide or amiodarone after cardioversion [29]. Maintenance of sinus rhythm at 12 months was significantly more likely with amiodarone (60 versus 34 percent with flecainide). Despite the apparent benefit for the prevention of recurrent AF, the toxicity associated with these drugs has restricted their use. The cardiac complications of the class IC drugs include worsening of heart failure, bradycardia, and presumably drug-induced atrial and ventricular arrhythmias in 7 to 27 percent of cases. In up to 13 percent of patients AF recurs as, or converts to, persistent atrial flutter [30]. Radiofrequency ablation of the atrial flutter, with continuation of the antiarrhythmic agent, is an effective approach for reducing arrhythmia recurrence and duration [30,31]. (See 'Hybrid therapy in patients who develop atrial flutter' below and "Atrial flutter: Maintenance of sinus rhythm".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 3/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The use of flecainide is restricted to those patients who have no structural heart disease, particularly coronary heart disease. The concern about the use of the class IC agents is primarily the result of the Cardiac Arrhythmia Suppression Trial (CAST), which showed that flecainide increased the number of deaths among patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction ( figure 2) [32]. It is not known if these findings can be extrapolated to other types of heart disease. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Class I agents'.) Propafenone has some mild beta-blocking activity in addition to its effects on the sodium channel. Thus, its toxicity may not be identical to that of flecainide and, in patients with ventricular arrhythmia, propafenone appears to be less proarrhythmic. In a study of 480 patients with supraventricular arrhythmia treated with propafenone for 14 months, 59 percent of patients experienced at least one side effect; the drug was discontinued due to an adverse reaction in only 15 percent, while 17 percent required a reduction in dose [33]. Arrhythmia aggravation occurred in 2 percent of patients; the incidence was higher in those with structural heart disease compared to those without (3 versus 1 percent). CLASS III ANTIARRHYTHMIC AGENTS Amiodarone, dronedarone, sotalol, dofetilide, and ibutilide are classified as class III antiarrhythmic agents. There are, however, many dissimilarities among these drugs, and they should be considered separately. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Amiodarone Amiodarone is the most effective antiarrhythmic drug for the prevention of atrial fibrillation (AF), as demonstrated in the following randomized trials [34-39]: The Canadian Trial of Atrial Fibrillation (CTAF) randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3). There was no difference among the three therapies in mortality, but there was an almost significant trend toward an increased incidence of side effects resulting in drug discontinuation with amiodarone (18 versus 11 percent for sotalol or propafenone). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Similar relative efficacies were noted in a substudy from the AFFIRM trial [37]. Patients in the rhythm control arm were randomly assigned to amiodarone or sotalol (256 patients), https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 4/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate amiodarone or a class I drug (222 patients), or sotalol and a class I drug (183 patients). The one-year endpoint was defined as the patient being alive, being in sinus rhythm at follow- up visits, still taking the drug (ie, no discontinuation for episodes of highly symptomatic AF), and needing no electrical or pharmacologic cardioversions. The likelihood of achieving the endpoint was significantly higher with amiodarone compared to sotalol (60 versus 38 percent) or a class I drug (62 versus 23 percent). In comparison to CTAF, amiodarone was not associated with a higher risk than sotalol of cessation of therapy for adverse effects (13 versus 16 percent). The SAFE-T trial compared amiodarone, sotalol, and placebo in patients with persistent AF for both conversion to sinus rhythm and maintenance of sinus rhythm [35]. The rate of maintenance of sinus rhythm was significantly higher at one year with amiodarone than sotalol or placebo and with sotalol than placebo (52 versus 32 and 13 percent on intention to treat analysis and 65 versus 40 and 18 percent on treatment received analysis). The primary endpoint, the median time to recurrence beginning after day 28, was 487, 74, and 6 days in the three groups. However, among the approximately 25 percent of patients with ischemic heart disease, the median time to recurrence with amiodarone was not significantly different from sotalol (569 versus 428 days). There was no difference among the study groups in terms of adverse effects except for a small increase in minor bleeding among patients treated with amiodarone. The mortality rate was not significantly higher with amiodarone and sotalol combined compared to placebo (4.36 versus 2.84 per 100 person-years), but trials of patients with heart failure or myocardial infarction have not shown an increase in mortality with amiodarone [40,41]. Nonrandomized studies of patients with chronic or paroxysmal AF refractory to most other antiarrhythmic agents have shown that amiodarone maintained sinus rhythm in 53 to 79 percent of cases during a 15 to 27 month follow-up [42-45]. Amiodarone is less effective in patients who have AF for over one year or who have an enlarged LA. However, even in this group, the success rate with amiodarone may be as high as 50 to 60 percent [42,43]. Amiodarone has also been evaluated as a prophylactic therapy to prevent AF after cardiac surgery. This issue is discussed separately. (See "Early noncardiac complications of coronary artery bypass graft surgery".) Sotalol Sotalol is not very effective in converting AF to sinus rhythm, but is useful in preventing recurrent episodes [46-48]. As an example, one study randomly assigned 253 patients with AF or atrial flutter to placebo or three doses of sotalol (80, 120, or 160 mg BID); the recurrence rate at one year was 72, 70, 60, and 55 percent, respectively, and the median times to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 5/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recurrence were 27, 106, 119, and 175 days, respectively [48]. As noted with other drugs, predictors of AF recurrence were the presence of coronary disease, duration of AF >2 months before reversion, LA size >60 mm, and older age. A number of studies have compared the efficacy of sotalol to other antiarrhythmic drugs for preventing recurrent AF. As noted above, randomized controlled trials and a substudy analysis from AFFIRM demonstrated that sotalol was less effective than amiodarone [34-37]. After a mean follow- up of 16 months in CTAF, for example, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3) [34]. Similar findings were noted in SAFE-T [35]. (See 'Amiodarone' above.) Sotalol appears to have equal efficacy to propafenone [34,49,50]. The best data come from CTAF, which randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, the proportion of patients free from recurrent AF was 37 percent with both sotalol and propafenone ( figure 3). (See 'Amiodarone' above.) Dofetilide Dofetilide is a class III antiarrhythmic drug ( table 2). The SAFIRE-D trial evaluated 204 patients with AF who were successfully cardioverted electrically or pharmacologically with dofetilide and maintained on a dose of 125, 250, or 500 g twice daily or placebo [51]. The probability of remaining in sinus rhythm at one year was significantly greater for dofetilide compared to placebo (40, 37, and 58 versus 25 percent). The all-cause mortality was the same in the four groups. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) The results were similar in the EMERALD trial, which randomly assigned patients who were pharmacologically or electrically cardioverted to therapy with one of three doses of dofetilide (125, 250, or 500 g twice daily), sotalol (80 mg twice daily), or placebo [52]. After 12 months of therapy, AF recurred in 79 percent of placebo patients, 34 percent of those receiving the highest dose of dofetilide, and between 48 and 60 percent in the other groups. (See "Clinical use of dofetilide".) It is of concern that nonfatal torsades de pointes (TdP) or sudden death occurred in four patients in the high-dose dofetilide group [52]. However, a pooled analysis of 1346 patients receiving dofetilide and 677 treated with placebo in randomized clinical trials of the treatment of supraventricular arrhythmias found that dofetilide was not associated with an increase in mortality (adjusted hazard ratio 1.1) [53]. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 6/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The lack of an increase in mortality with dofetilide is reassuring. However, because drug-induced TdP is relatively rare and can be treated if it occurs in a monitored setting, the impact of this complication may not be seen in analyses limited to overall survival. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Dronedarone Dronedarone is a derivative of amiodarone. In patients with AF, randomized trials with up to 12 months of follow-up have found that dronedarone prevents recurrent AF and was safe (including no increased risk of serious arrhythmias) [54-56]. However, in the ANDROMEDA trial in patients with advanced heart failure from LV systolic dysfunction, there was an increased risk of death with dronedarone and the trial was stopped early [57]. As a result, dronedarone is contraindicated in this population of patients. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) In the ATHENA trial 4628 patients with AF were randomly assigned to either dronedarone or placebo [58]. Patients with New York Heart Association (NYHA) class II or III heart failure comprised 21 percent of the study population, but patients with NYHA class IV heart failure were excluded. After a mean follow-up period of 21 months, dronedarone significantly reduced the primary outcome of death or cardiovascular hospitalization (31.9 versus 39.4 percent, hazard ratio 0.76, 95% CI 0.69-0.84) and the secondary outcome of cardiovascular death (2.7 versus 3.9 percent, hazard ratio 0.71, 95% CI 0.51-0.98). Dronedarone is the only antiarrhythmic drug that has shown a salutary effect on mortality. Maintenance of sinus rhythm was not one of the endpoints in ATHENA. The DIONYSOS study was a short-term (median duration of seven months) comparison between amiodarone and dronedarone to assess the differences in drug tolerability and AF recurrence in 504 patients [59]. Sixty percent of the patients had persistent AF. The authors found that the composite primary endpoint of AF recurrence or premature study drug discontinuation occurred in 75.5 percent of patients taking dronedarone, but only 58.8 percent of patients taking amiodarone. This endpoint was primarily driven by AF recurrence on dronedarone compared to amiodarone (63.5 versus 42.0 percent, respectively). Drug discontinuation and the main safety endpoints of extra-cardiac toxicity only tended to be less with dronedarone, but did not reach statistical significance. It is possibly that with longer follow-up periods there would have been a greater difference in noncardiac side effects, since the toxicity with amiodarone is typically manifest after several months to years of use. In a meta-analysis of dronedarone trials prior to the DIONYSOS study, where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, a similar conclusion was reached [60]. Amiodarone was found to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 7/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events. The PALLAS trial, which was stopped early due to an increase in adverse events in patients taking dronedarone, evaluated the potential use of dronedarone to improve cardiovascular outcomes in patients with permanent AF. This trial is discussed elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone'.) Ibutilide Ibutilide is only available for intravenous use and therefore is useful for the acute reversion of AF, not for long-term prevention [61]. (See "Atrial fibrillation: Cardioversion".) Vernakalant Vernakalant is considered a relatively atrially-selective antiarrhythmic agent since one of its main actions is to inhibit the ultrarapid potassium current (IKur) and the acetylcholine potassium current (IKAch), both of which are predominantly found in the atria. Vernakalant also mildly inhibits other potassium channels and, to a much lesser extent, the sodium current. The program for vernakalant drug development in the US has been terminated. The drug is available in an intravenous form to terminate AF in Europe. BETA BLOCKERS There is no evidence to support the use of beta blockers (aside for sotalol), in the absence of other antiarrhythmic drugs, for the prevention of atrial fibrillation (AF). In patients with heart failure (HF) due to systolic dysfunction, chronic treatment with certain beta blockers reduces mortality. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) There is evidence that beta blockers may also reduce the likelihood of the development of AF in patients with HF. A systematic review including seven randomized trials of 11,952 patients evaluated the efficacy of beta blockers for this purpose [62]. Among patients who were in sinus rhythm at baseline and were followed for six months to two years, the incidence of new onset AF was significantly lower in patients treated with beta blockers than those assigned to placebo (28 versus 39 per 1000 patient years). (See "The management of atrial fibrillation in patients with heart failure".) A separate issue is whether beta blockers, which are felt to have some antiarrhythmic properties ( table 2), are effective for preventing recurrent atrial fibrillation in patients with no heart disease. The evidence to support their use for this purpose is scant, and any reduction in the https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 8/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate reported frequency of AF may be attributable to improved rate control that may render recurrent AF silent. VERAPAMIL The calcium channel blocking agents verapamil and diltiazem impair conduction and prolong refractoriness in the AV node. They have been used both acutely and chronically to slow the ventricular response in atrial fibrillation (AF). Verapamil has also been investigated for its effectiveness in maintaining sinus rhythm after cardioversion. The rationale for this approach is the observation that the electrical remodeling that occurs during AF is thought to be due, at least in part, to abnormal calcium loading during rapid atrial rates. In studies in animals and humans, verapamil has been shown to prevent electrical remodeling [63,64]. (See "Mechanisms of atrial fibrillation", section on 'Electrical remodeling'.) Verapamil as a single agent was not effective in preventing AF recurrence in the VERDICT trial, in which 97 patients with persistent AF were randomly assigned to either verapamil or digoxin [65]. There was no difference in AF recurrence rates at one month. It was suggested that verapamil may be effective only when given with a sodium or potassium channel blocking agent [66]. Verapamil with another agent Based upon the observations cited above, several studies evaluated the benefit of verapamil with another agent in preventing recurrences of AF. In the small VEPARAF trial, the addition of verapamil to either amiodarone or flecainide significantly reduced the incidence of recurrent AF within three months of cardioversion compared with either agent alone [67]. The larger PAFAC and SOPAT trials found the combination of verapamil and quinidine to be comparable to sotalol, and superior to placebo, in preventing AF recurrence. In PAFAC, 848 patients with persistent AF were cardioverted and then randomly assigned to sotalol, quinidine and verapamil, or placebo [68]. Patients used an event recorder to record and transmit at least one ECG daily during a mean of nine months of follow-up. The incidence of death or any AF recurrence was significantly lower for both sotalol and for quinidine plus verapamil than for placebo (67 and 65 versus 83 percent). Serious adverse events were not more common with quinidine plus verapamil than with sotalol, and the only episodes of torsades de pointes occurred with sotalol. In the SOPAT trial, 1033 patients with recurrent symptomatic paroxysmal AF were randomly assigned to placebo, sotalol, or one of two dose combinations of quinidine plus verapamil [69]. As in the PAFAC trial, patients recorded and transmitted at least one ECG daily with an event https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 9/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recorder. The mean time to first AF recurrence was prolonged significantly in all three active treatment groups compared to placebo. At a mean of eight months of follow-up, the number of days of symptomatic AF was reduced significantly for all three active treatment arms compared to placebo. There was no difference between the sotalol and the two quinidine plus verapamil treatment groups in either of these efficacy endpoints or in the incidence of serious adverse side effects. OTHER THERAPIES In addition to conventional antiarrhythmic drugs, a number of other agents have been investigated for the purpose of suppressing atrial fibrillation (AF). ACE inhibitors, angiotensin II receptor blockers Both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) reduce the incidence of atrial fibrillation in selected patient populations. In a recent meta-analysis of 26 randomized trials that evaluated the effect of ACE inhibitors and ARBs on the prevention of AF, it was demonstrated that both classes of drugs had a similar beneficial effect on AF [70]. The effect was more potent for recurrent AF compared to primary prevention of AF (OR 0.45 versus 0.80, respectively). ACE inhibitor or ARB effect on AF was additive to that of amiodarone when used concurrently and endured even in patients with depressive LV function. This issue is discussed in further detail separately. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".) Magnesium Although not a primary antiarrhythmic agent, magnesium affects atrial electrophysiologic properties. Some studies, particularly those in patients undergoing coronary artery bypass surgery, have found that magnesium deficiency is associated with AF and that magnesium supplementation reduces its incidence. (See "Significance of hypomagnesemia in cardiovascular disease" and "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The role of oral magnesium therapy in the prevention of recurrent AF after cardioversion was evaluated in one study of 301 patients who were followed for at least six months after the restoration of sinus rhythm; magnesium therapy alone or in combination with sotalol was ineffective for preventing recurrent AF [71]. Statins There is some evidence that statins may prevent recurrences in patients with lone AF [72,73], ischemic heart disease [73,74] and after cardiac bypass surgery [73,75]. Aldosterone Blockers These drugs have been useful in the treatment of heart failure. Spironolactone and eplerenone have effects on atrial electrophysiologic properties in https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 10/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate experimental animals, but no studies in patients with AF have been done. DRUG-REFRACTORY ATRIAL FIBRILLATION Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. There are limited data to support the use of combination antiarrhythmic drug therapy, and this approach may expose the patient to a greater risk of proarrhythmia and other side effects. As a result, combination therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy of atrial fibrillation (AF). These options include: Radiofrequency catheter ablation (RFA), which is the most common of these approaches. (See "Atrial fibrillation: Catheter ablation".) Surgical procedures such as the maze operation, particularly for patients undergoing cardiac surgery for another indication. Some centers also offer mini-maze operations using limited bilateral thoracotomies as standalone procedures as well. (See "Atrial fibrillation: Surgical ablation".) HYBRID THERAPY IN PATIENTS WHO DEVELOP ATRIAL FLUTTER Atrial flutter can occur after the initiation of antiarrhythmic drug therapy in patients with atrial fibrillation (AF), especially with the use of class IC agents or amiodarone. One approach to managing this situation has been a hybrid approach that involves ablation of atrial flutter by creating a block across the cavotricuspid isthmus and then continuation of the antiarrhythmic drug. Although this approach may be helpful in maintaining sinus rhythm in the short term, data (articles below) suggest that in the long term, there is a high recurrence of AF [76,77]. Therefore, the development of atrial flutter on an antiarrhythmic drug may be considered failure of therapy. SUMMARY Recommendations for the use drug therapy to maintain sinus rhythm in patients with atrial fibrillation (AF) are found elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 11/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The following are the important points made in this topic: The main goal of drug therapy to maintain sinus rhythm is to reduce symptoms by decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 12/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. 6. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 7. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 8. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 9. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9:CD005049. 10. S dermark T, Jonsson B, Olsson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J 1975; 37:486. 11. Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J 1984; 65:367. 12. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality. Am Heart J 1992; 124:924. 13. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 14. Karlson BW, Torstensson I, Abj rn C, et al. Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J 1988; 9:284. 15. Szekely P, Sideris DA, Batson GA. Maintenance of sinus rhythm after atrial defibrillation. Br Heart J 1970; 32:741. 16. Madrid AH, Moro C, Mar n-Huerta E, et al. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 1993; 14:1127. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 13/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 17. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 18. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64:1317. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80:1557. 20. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med 1991; 114:539. 21. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. UK Propafenone PSVT Study Group. Circulation 1995; 92:2550. 22. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 23. Antman EM, Beamer AD, Cantillon C, et al. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990; 15:698. 24. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87:172. 25. Meinertz T, Lip GY, Lombardi F, et al. Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study). Am J Cardiol 2002; 90:1300. 26. Pritchett EL, Page RL, Carlson M, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92:941. 27. Chimienti M, Cullen MT Jr, Casadei G. Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: report from the Flecainide and Propafenone Italian Study Investigators. Am J Cardiol 1996; 77:60A. 28. Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77:66A.
decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 12/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 5. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. 6. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 7. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 8. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992; 20:527. 9. Valembois L, Audureau E, Takeda A, et al. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2019; 9:CD005049. 10. S dermark T, Jonsson B, Olsson A, et al. Effect of quinidine on maintaining sinus rhythm after conversion of atrial fibrillation or flutter. A multicentre study from Stockholm. Br Heart J 1975; 37:486. 11. Lloyd EA, Gersh BJ, Forman R. The efficacy of quinidine and disopyramide in the maintenance of sinus rhythm after electroconversion from atrial fibrillation. A double-blind study comparing quinidine, disopyramide and placebo. S Afr Med J 1984; 65:367. 12. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of the efficacy and safety of antiarrhythmic therapy for chronic atrial fibrillation: observations on the role of trial design and implications of drug-related mortality. Am Heart J 1992; 124:924. 13. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 14. Karlson BW, Torstensson I, Abj rn C, et al. Disopyramide in the maintenance of sinus rhythm after electroconversion of atrial fibrillation. A placebo-controlled one-year follow-up study. Eur Heart J 1988; 9:284. 15. Szekely P, Sideris DA, Batson GA. Maintenance of sinus rhythm after atrial defibrillation. Br Heart J 1970; 32:741. 16. Madrid AH, Moro C, Mar n-Huerta E, et al. Comparison of flecainide and procainamide in cardioversion of atrial fibrillation. Eur Heart J 1993; 14:1127. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 13/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 17. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 18. Van Gelder IC, Crijns HJ, Van Gilst WH, et al. Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. Am J Cardiol 1989; 64:1317. 19. Anderson JL, Gilbert EM, Alpert BL, et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. Circulation 1989; 80:1557. 20. Pritchett EL, McCarthy EA, Wilkinson WE. Propafenone treatment of symptomatic paroxysmal supraventricular arrhythmias. A randomized, placebo-controlled, crossover trial in patients tolerating oral therapy. Ann Intern Med 1991; 114:539. 21. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. UK Propafenone PSVT Study Group. Circulation 1995; 92:2550. 22. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol 1997; 79:418. 23. Antman EM, Beamer AD, Cantillon C, et al. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol 1990; 15:698. 24. Geller JC, Geller M, Carlson MD, Waldo AL. Efficacy and safety of moricizine in the maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Am J Cardiol 2001; 87:172. 25. Meinertz T, Lip GY, Lombardi F, et al. Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study). Am J Cardiol 2002; 90:1300. 26. Pritchett EL, Page RL, Carlson M, et al. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol 2003; 92:941. 27. Chimienti M, Cullen MT Jr, Casadei G. Safety of long-term flecainide and propafenone in the management of patients with symptomatic paroxysmal atrial fibrillation: report from the Flecainide and Propafenone Italian Study Investigators. Am J Cardiol 1996; 77:60A. 28. Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide versus propafenone in hospital out-patients with symptomatic paroxysmal atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996; 77:66A. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 14/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 29. Zarembski DG, Nolan PE Jr, Slack MK, Caruso AC. Treatment of resistant atrial fibrillation. A meta-analysis comparing amiodarone and flecainide. Arch Intern Med 1995; 155:1885. 30. Schumacher B, Jung W, Lewalter T, et al. Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation. Am J Cardiol 1999; 83:710. 31. Nabar A, Rodriguez LM, Timmermans C, et al. Radiofrequency ablation of "class IC atrial flutter" in patients with resistant atrial fibrillation. Am J Cardiol 1999; 83:785. 32. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 33. Podrid PJ, Anderson JL. Safety and tolerability of long-term propafenone therapy for supraventricular tachyarrhythmias. The Propafenone Multicenter Study Group. Am J Cardiol 1996; 78:430. 34. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. 35. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 36. Kochiadakis GE, Igoumenidis NE, Marketou ME, et al. 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Gallik DM, Kim SG, Ferrick KJ, et al. Efficacy and safety of sotalol in patients with refractory atrial fibrillation or flutter. Am Heart J 1997; 134:155. 47. Alt E, Ammer R, Lehmann G, et al. Patient characteristics and underlying heart disease as predictors of recurrent atrial fibrillation after internal and external cardioversion in patients treated with oral sotalol. Am Heart J 1997; 134:419. 48. Benditt DG, Williams JH, Jin J, et al. Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1999; 84:270. 49. Reimold SC, Cantillon CO, Friedman PL, Antman EM. Propafenone versus sotalol for suppression of recurrent symptomatic atrial fibrillation. Am J Cardiol 1993; 71:558. 50. Bellandi F, Simonetti I, Leoncini M, et al. Long-term efficacy and safety of propafenone and sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation. Am J Cardiol 2001; 88:640. 51. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000; 102:2385. 52. Ferguson JJ. Meeting highlights. Highlights of the 71st scientific sessions of the American Heart Association. Circulation 1999; 99:2486. 53. Pritchett EL, Wilkinson WE. Effect of dofetilide on survival in patients with supraventricular arrhythmias. Am Heart J 1999; 138:994. 54. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 55. Kathofer S, Thomas D, Karle CA. The novel antiarrhythmic drug dronedarone: comparison with amiodarone. Cardiovasc Drug Rev 2005; 23:217. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 16/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 56. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 57. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 58. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 59. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 60. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 61. Stambler BS, Wood MA, Ellenbogen KA, et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation 1996; 94:1613. 62. Nasr IA, Bouzamondo A, Hulot JS, et al. Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis. Eur Heart J 2007; 28:457. 63. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997; 95:1945. 64. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans. Circulation 1997; 96:1542. 65. Van Noord T, Van Gelder IC, Tieleman RG, et al. VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2001; 12:766. 66. Knight BP. Calcium channel blockade for prevention of recurrent atrial fibrillation: have we reached a VERDICT? J Cardiovasc Electrophysiol 2001; 12:770. 67. De Simone A, De Pasquale M, De Matteis C, et al. VErapamil plus antiarrhythmic drugs reduce atrial fibrillation recurrences after an electrical cardioversion (VEPARAF Study). Eur Heart J 2003; 24:1425. 68. Fetsch T, Bauer P, Engberding R, et al. Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. Eur Heart J 2004; 25:1385. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 17/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate 69. Patten M, Maas R, Bauer P, et al. Suppression of paroxysmal atrial tachyarrhythmias results of the SOPAT trial. Eur Heart J 2004; 25:1395. 70. Zhang Y, Zhang P, Mu Y, et al. The role of renin-angiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Pharmacol Ther 2010; 88:521. 71. Frick M, Darp B, Ostergren J, Rosenqvist M. The effect of oral magnesium, alone or as an adjuvant to sotalol, after cardioversion in patients with persistent atrial fibrillation. Eur Heart J 2000; 21:1177. 72. Siu CW, Lau CP, Tse HF. Prevention of atrial fibrillation recurrence by statin therapy in patients with lone atrial fibrillation after successful cardioversion. Am J Cardiol 2003; 92:1343. 73. Fauchier L, Pierre B, de Labriolle A, et al. Antiarrhythmic effect of statin therapy and atrial fibrillation a meta-analysis of randomized controlled trials. J Am Coll Cardiol 2008; 51:828. 74. Young-Xu Y, Jabbour S, Goldberg R, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol 2003; 92:1379. 75. Dotani MI, Elnicki DM, Jain AC, Gibson CM. Effect of preoperative statin therapy and cardiac outcomes after coronary artery bypass grafting. Am J Cardiol 2000; 86:1128. 76. Garc a Seara J, Raposeiras Roubin S, Gude Sampedro F, et al. Failure of hybrid therapy for the prevention of long-term recurrence of atrial fibrillation. Int J Cardiol 2014; 176:74. 77. Anastasio N, Frankel DS, Deyell MW, et al. Nearly uniform failure of atrial flutter ablation and continuation of antiarrhythmic agents (hybrid therapy) for the long-term control of atrial fibrillation. J Interv Card Electrophysiol 2012; 35:57. Topic 1038 Version 37.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 18/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate GRAPHICS Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 19/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 20/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate ACC/AHA/ESC guideline summary: Maintenance of sinus rhythm in atrial fibrillation (AF) Class I - There is evidence and/or general agreement that the following approach is effective for the maintenance of sinus rhythm in patients with AF Treatment of precipitating or reversible causes of AF before initiating therapy with antiarrhythmic drugs. Class IIa - The weight of evidence or opinion is in favor of the usefulness of the following approaches for the maintenance of sinus rhythm in patients with AF Antiarrhythmic drug therapy to maintain sinus rhythm and prevent tachycardia-induced cardiomyopathy. Infrequent, well tolerated recurrent episodes of recurrent AF is reasonable as a successful outcome of antiarrhythmic drug therapy. Outpatient initiation of therapy in patients with no associated heart disease when the antiarrhythmic drug is well tolerated. In patients with lone AF and no structural heart disease, outpatient initiation of propafenone or flecainide therapy in patients with paroxysmal AF who are in sinus rhythm at the time of drug initiation. Sotalol in outpatients in sinus rhythm who have little or no heart disease, are prone to paroxysmal AF, a baseline uncorrected QT interval less than 460 msec, normal serum electrolytes, and no risk factors for class III drug-related proarrhythmia. Catheter ablation as an alternative to antiarrhythmic drug therapy to prevent recurrent AF in symptomatic patients with little or no left atrial enlargement. Class III - There is evidence and/or general agreement that the following approaches are not useful or may be harmful for the maintenance of sinus rhythm in patients with AF Use of a particular antiarrhythmic drug is not recommended in patients with well-defined risk factors for proarrhythmia with that drug. Antiarrhythmic drug therapy is not recommended in patients with advanced sinus node disease or atrioventricular node dysfunction unless they have a functioning electronic cardiac pacemaker. Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 78424 Version 2.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 21/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Maintenance of sinus rhythm Therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Drugs are listed alphabetically and not in order of suggested use. The seriousness of heart disease progresses from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present. LVH: left ventricular hypertrophy. Reproduced from: Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial brillation: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol 2011; 57:223. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 83173 Version 2.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 22/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 23/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 24/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 25/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 26/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 27/27
7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations : Kapil Kumar, MD : Peter J Zimetbaum, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 24, 2021. INTRODUCTION For patients with atrial fibrillation (AF), there are two main strategies to manage the irregular rhythm and its impact on symptoms: rhythm control (restoration followed by maintenance of sinus rhythm with either antiarrhythmic drugs or catheter ablation); and rate control with atrioventricular (AV) nodal blockers. (See 'Initial management decisions' below.) For those patients in whom a rhythm control strategy is chosen, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes as well as the symptoms during recurrences [1,2]. As antiarrhythmic drugs are associated with a potential for serious adverse side effects, particularly the induction of proarrhythmia, they should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risks associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' below.) Rhythm control can be achieved with either antiarrhythmic drug therapy or nonpharmacologic methods. This topic provides recommendations for the former. The clinical trials describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Nonpharmacologic methods to maintain sinus rhythm (including surgery and radiofrequency ablation or cryoballoon ablation) in selected patients who are refractory to conventional therapy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 1/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) INDICATIONS There are three settings in which a rhythm control strategy for the maintenance of sinus rhythm should be considered [3]: Persistent symptoms (palpitations, dyspnea, lightheadedness, angina, syncope, and heart failure) despite adequate rate control. An inability to attain adequate rate control (to prevent tachycardia-mediated cardiomyopathy). (See "Arrhythmia-induced cardiomyopathy".) Patient preference. Some patients will strongly prefer to avoid either paroxysmal or persistent AF. We consider cardioversion to sinus rhythm in most patients, particularly younger patients, with a first-detected episode of atrial fibrillation (AF) in whom the arrhythmia is of recent onset and the risk for recurrence appears to be low. Maintenance antiarrhythmic drug therapy is not routinely used after cardioversion in patients with newly detected AF [3]. These issues are discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) INITIAL MANAGEMENT DECISIONS Prior to selecting and initiating antiarrhythmic drug therapy, the following issues should be considered. Rhythm versus rate control: The choice between a rhythm- or a rate-control strategy is determined by many factors, including patient age, the degree to which symptoms interfere with the quality of life, and concerns about antiarrhythmic drug therapy or catheter ablation. There is no evidence that long-term outcomes, such as rates of survival or thromboembolism, are improved by rhythm control ( figure 1 and figure 2) [4,5]. Our recommendations for the use of these two strategies are found elsewhere. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 2/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Precipitating factors: Before initiating a rhythm control strategy, any risk factors for atrial fibrillation (AF) should be addressed. Examples include hyperthyroidism, hypertension, heart failure, sleep apnea, and excess alcohol intake. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations'.) Maintenance antiarrhythmic drug therapy is not recommended after cardioversion in a patient with a transient or reversible cause (such as cardiac surgery, pericarditis, or pulmonary embolism). An option in such patients is beta blocker therapy after restoration of sinus rhythm, which may provide modest protection against recurrent AF [6]. However, short-term antiarrhythmic therapy can be considered in this situation as the underlying cause is treated in patients who are highly symptomatic. Anticoagulation: The proper use of anticoagulation in the period surrounding conversion to sinus rhythm is discussed separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Rate control: An atrioventricular (AV) nodal blocker, such as a beta blocker or a rate- slowing calcium channel blocker, is usually started before, or simultaneously with, antiarrhythmic drug therapy in patients who have demonstrated a moderate to rapid ventricular rate ( 110 beats per minute) during AF. Slowing of the rate generally improves symptoms prior to the restoration of sinus rhythm. This therapy is continued while the patient is in sinus rhythm to protect against a rapid ventricular rate should AF recur. This issue is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) Restoration of sinus rhythm: Many patients with AF in whom a rhythm control strategy is chosen will need sinus rhythm restored prior to the initiation of long-term antiarrhythmic drug therapy. The restoration of sinus rhythm is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion".) Some patients with relatively infrequent episodes of paroxysmal atrial fibrillation can be managed with antiarrhythmic therapy given only at the time of the episode. This form of outpatient "pill-in-the-pocket" therapy for recurrent AF is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Pharmacologic cardioversion'.) SELECTING AN ANTIARRHYTHMIC DRUG https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 3/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Once the issues discussed above have been addressed, an antiarrhythmic agent can be chosen. The choice of drug is significantly influenced both by drug and patient characteristics. As with all therapeutic interventions, the choice of agent should take into account the benefit to risk ratio of the therapy chosen. (See 'Proarrhythmia' below.) Amiodarone, dofetilide, flecainide, propafenone, sotalol, and less commonly dronedarone are the drugs we recommend to maintain sinus rhythm. (See 'Concerns about dronedarone' below.) For additional information regarding the therapeutic use of these drugs, including information regarding dosing and side effects, the reader is referred to individual UpToDate topics on these drugs or to the individual drug monographs in our drug database. The following points regarding antiarrhythmic drugs should be kept in mind in choosing therapy: Compared to other agents, amiodarone is associated with the greatest likelihood of maintaining sinus rhythm, but also with the highest risk of long-term complications [7,8]. In addition, a 2014 report raises the possibility that amiodarone use in patients taking warfarin is associated with an increased risk of stroke compared to those not taking the drug [9]. In this study, there was a lower time in the therapeutic range (of the international normalized ratio) in patients receiving amiodarone. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Quinidine, procainamide, and disopyramide are no longer recommended for patients with AF, except perhaps in patients with vagally mediated atrial fibrillation (AF), as there are more effective drugs and due to extracardiac side effects as well as the concern about proarrhythmia [10]. (See 'Proarrhythmia' below.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia [6,11,12]. Of course beta blockers may have already been initiated to slow the ventricular rate in AF. (See 'Proarrhythmia' below and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Beta blockers'.) The following patient characteristics may influence decision making: The clinical features of the patient, such as presence or absence of clinical heart disease. We believe it is prudent to obtain a two-dimensional echocardiogram to screen for structural heart disease (eg, left ventricular systolic dysfunction, left ventricular https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 4/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate hypertrophy, or valvular heart disease). An exercise or nuclear stress imaging test may be used to screen for coronary heart disease and is typically done before starting a class IC agent. (See 'Atrial fibrillation without structural heart disease' below and 'Atrial fibrillation associated with structural heart disease' below.) The presence of paroxysmal compared to persistent AF [1,13]. As examples, our experts rarely use dofetilide for paroxysmal AF and infrequently choose dronedarone for persistent AF due to reduced efficacy compared with amiodarone. The presence of vagally-mediated AF [14,15]. The 2016 European Society of Cardiology AF guideline suggest that, because of its long-lasting anticholinergic activity, disopyramide may be considered in patients with vagally-induced AF (eg, occurring most often in athletic young men with slow heart rates during rest or sleep), as long as the patient does not have prostatism or glaucoma [13,16]. The combination of disopyramide and either a beta blocker or a calcium channel blocker must be used cautiously because of the additive negative inotropic effects. If disopyramide cannot be given or is not tolerated, flecainide and amiodarone represent the sequential alternatives. Our experts use disopyramide cautiously due to concern for proarrhythmia. For patients with adrenergically-mediated AF (eg, occurring during exercise or other activity), we suggest beta blockers as first-line therapy, followed by sotalol and amiodarone. Antiarrhythmic drugs are associated with a potential for serious adverse side effects, particularly the induction of proarrhythmia. Thus, they should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risk associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' below.) As the expectation of antiarrhythmic therapy is to reduce the frequency and duration of episodes, improve quality of life, and prevent hospitalization, a recurrence of AF does not necessarily denote a failure of the medication or mandate a change to a different antiarrhythmic drug. Atrial fibrillation without structural heart disease Patients without structural heart disease include those with hypertension who do not have left ventricular hypertrophy. The author and reviewers of this topic generally select flecainide or propafenone as the first antiarrhythmic drug for these patients due to its relatively good side effect profile, efficacy, and ease of use. The use of these drugs in patients >70 years of age should be considered more cautiously, given the higher likelihood of underlying coronary artery disease. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 5/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate In these patients, flecainide, propafenone, amiodarone, dronedarone, sotalol, and dofetilide are superior to placebo for maintaining sinus rhythm. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) For those patients in whom flecainide or propafenone will not be used as the preferred agent, the following points can influence the choice of antiarrhythmic drug in patients without structural heart disease: In the Canadian Trial of Atrial fibrillation, AFFIRM, and the SAFE-T randomized trials, amiodarone was more effective than flecainide, propafenone, or sotalol (which have nearly equivalent efficacy to each other), but has a significantly higher rate of adverse side effects. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Amiodarone'.) In a meta-analysis of trials where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, amiodarone was found to be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events [17]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Both amiodarone and dronedarone are associated with significant side effects. We suggest carefully discussing these with the patient prior to initiating therapy. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of dronedarone".)In the EMERALD trial, Dofetilide had a somewhat better efficacy than sotalol. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dofetilide'.) Some cardiologists prefer to use low-dose amiodarone (100 to 200 mg per day), particularly in older patients, in preference to flecainide, sotalol, or dronedarone for two principal reasons: greater efficacy than sotalol and dronedarone ( figure 3) [18-20], and a very low incidence of torsades de pointes [21,22]. In addition, since amiodarone has beta blocking and calcium channel blocking activity, the ventricular rate is usually slower and better tolerated if AF does recur. If amiodarone is used for rhythm control, the need for additional medications to control rate (eg, beta blockers or calcium channel blockers) may be decreased. Despite these advantages, low-dose amiodarone still has appreciable toxicity, including thyroid disease, hepatic dysfunction, lung disease, neurologic abnormalities, and bradycardia [21,22]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 6/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Atrial fibrillation associated with structural heart disease Amiodarone, sotalol, and dofetilide are the most commonly recommended first-line drugs in patients with structural heart disease ( algorithm 1) [13]. Our authors and reviewers prefer either dronedarone or sotalol to amiodarone and dofetilide. Dronedarone is easier to use than sotalol (continuous monitoring of initiation required), but is less efficacious. (See "Clinical uses of sotalol".) These drugs (with the exception of dronedarone) were used for initial therapy in almost 70 percent of patients in AFFIRM, 88 percent of whom had organic heart disease and/or hypertension [4]. Amiodarone was significantly more effective than sotalol in the CTAF, AFFIRM, and SAFE-T trials [18-20]. However, in SAFE-T, sotalol was as effective as amiodarone in the subgroup of patients with coronary heart disease [19]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Coronary heart disease In patients with coronary heart disease who do not have heart failure, sotalol, dronedarone, dofetilide, and amiodarone are acceptable choices ( table 1 and algorithm 1) [13,23,24]. We prefer sotalol due to its better extracardiac side effect profiles. Flecainide and propafenone are contraindicated in this population. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Major side effects of class I antiarrhythmic drugs".) In the Cardiac Arrhythmia Suppression Trial (CAST) of patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction, flecainide increased mortality compared to placebo ( figure 4) [25]. Although propafenone was not used in CAST and may not have the same potential for proarrhythmia as flecainide and encainide [26], it cannot be recommended in patients with underlying heart disease [27]. The extension of this concern to structural heart disease other than coronary artery disease stems in part from the flecainide clinical and safety database, which was used in a retrospective study demonstrating that the presence of structural heart disease including valvular heart disease, congenital heart disease, and cardiomyopathies lead to an alarming increase in proarrhythmia and death [28]. Heart failure Amiodarone and dofetilide, are used in patients with AF and heart failure (HF) or those with a left ventricular ejection fraction less than 35 percent. Our authors and reviewers are more comfortable using dofetilide in this setting with an implantable defibrillator in place or in younger patients with less severe impairment of left ventricular systolic function. This issue is discussed in detail elsewhere. (See "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 7/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Sotalol, propafenone, dronedarone, and flecainide should not be used in patients with heart failure, due to studies showing an increase in mortality with these agents. (See "Clinical uses of sotalol" and "Amiodarone: Clinical uses" and "Major side effects of class I antiarrhythmic drugs".) Left ventricular hypertrophy Patients with significant left ventricular hypertrophy (defined as left ventricular wall thickness greater 1.4 cm for the purposes of this discussion) due to hypertension, hypertrophic cardiomyopathy, or aortic stenosis have underlying subendocardial ischemia and electrophysiologic abnormalities. These increase the risk for proarrhythmia with antiarrhythmic agents. (See "Left ventricular hypertrophy and arrhythmia" and 'Proarrhythmia' below and "Left ventricular hypertrophy: Clinical findings and ECG diagnosis".) Sotalol, flecainide and propafenone are thought to have a significant arrhythmic risk in patients with left ventricular hypertrophy (LVH). Dronedarone has been evaluated in patients with LVH and is thought to be relatively safe [24], although our experts rarely use it. Amiodarone is another therapeutic option. (See "Clinical uses of dronedarone".) Drug-resistant atrial fibrillation Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. Although some have suggested that combination antiarrhythmic drug therapy (eg, a class IC agent with sotalol or amiodarone, often in lower doses, or the combination of dronedarone plus ranolazine) may be an alternative, there are limited data to support such an approach and the patient may be exposed to a greater risk of proarrhythmia and other side effects [29]. As a result, combination antiarrhythmic drug therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy to prevent recurrent AF including surgery (such as the maze operation) or catheter ablation (such as pulmonary vein isolation). (See "Atrial fibrillation: Catheter ablation" and "The role of pacemakers in the prevention of atrial fibrillation" and "Atrial fibrillation: Surgical ablation".) INPATIENT VERSUS OUTPATIENT INITIATION Many patients begun on antiarrhythmic drug therapy should be hospitalized for continuous electrocardiographic monitoring due to a 10 to 15 percent incidence of adverse cardiac events during the initiation of therapy [30]. (See 'Proarrhythmia' below and "Arrhythmia management for the primary care clinician", section on 'Antiarrhythmic drugs'.) The two complications of greatest concern are bradycardia and proarrhythmia. Other adverse cardiac events can include significant QT prolongation, heart failure, rapid ventricular rate, https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 8/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate conduction abnormalities, hypotension, and stroke. The risk is greatest in the first 24 hours and in patients with a prior myocardial infarction. Outpatient initiation of antiarrhythmic drug therapy with the following agents may be considered: Flecainide or propafenone in patients in sinus rhythm who have no underlying structural heart disease, normal baseline QT intervals, and no profound bradycardia or suspected sinus or atrioventricular (AV) node dysfunction [13]. Amiodarone or dronedarone in selected patients who have no other risk factors for torsades de pointes (eg, hypokalemia, hypomagnesemia) or sinus node dysfunction or AV conduction disease. Dronedarone and amiodarone are the only two drugs that can be initiated in outpatients while in atrial fibrillation. Patients with an implantable cardioverter-defibrillator (ICD) represent another group in which outpatient initiation of therapy can be tried, since the ICD provides protection against the risks associated with bradyarrhythmias and tachyarrhythmias. However, one should be cognizant of the potential effects of antiarrhythmic drugs on ventricular defibrillation threshold and ventricular tachycardia cycle length, which could influence the efficacy of ICD therapy. The initiation of antiarrhythmic drugs in patients with paroxysmal AF while they are in sinus rhythm is also associated with some risk. In a review of 409 outpatient initiation trials for a history of recurrent AF or atrial flutter, adverse cardiac events occurred in 17 (4.5 percent); these included three deaths, three permanent pacemakers for bradycardia, and 11 dose reductions for bradycardia [31]. Inpatient initiation with continuous telemetry of higher-risk drugs such as dofetilide and sotalol is typically done over a course of three days, which encompasses five half-lives allowing for achievement of steady-state plasma concentrations. In highly selected patients (eg, normal renal function, no bradycardia, and normal QT interval), sotalol can be loaded as outpatient with event monitor and closely following electrocardiogram for QT interval while in sinus rhythm. LONG-TERM ISSUES AF recurrence Recurrent atrial fibrillation (AF) should not necessarily be labeled as treatment failure. Some patients will elect to continue drug therapy (and, in some cases, occasional cardioversion) because the arrhythmia burden has been substantially reduced as evidenced by episodes that are less frequent, shorter, or associated with milder symptoms. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 9/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nonpharmacologic therapies are another option in such patients. (See "Atrial fibrillation: Atrioventricular node ablation" and "Atrial fibrillation: Catheter ablation".) If a patient has unacceptable recurrent AF on one antiarrhythmic drug, the drug is discontinued and another (and on rare occasion a third) agent is tried. Dosing The starting and maintenance doses for amiodarone, dronedarone, propafenone, flecainide, sotalol, disopyramide, and dofetilide are found in respective LexiComp drug monographs available in UpToDate. Many factors including age, sex, weight, renal or hepatic function, and characteristics on the electrocardiogram influence the starting dose for many of these. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Drug-related arrhythmias and mortality The use of antiarrhythmic drugs is associated with possible life-threatening side effects. The greatest concerns with these agents are proarrhythmia (and consequent tachyarrhythmia) and bradycardia. Patients should be instructed to report symptoms suggestive of the development of drug related arrhythmias, such as syncope, lightheadedness or dizzy spells, or worsening exercise intolerance. (See "Arrhythmia management for the primary care clinician", section on 'Antiarrhythmic drugs' and "Arrhythmia management for the primary care clinician", section on 'Symptoms'.) A 2012 meta-analysis of 56 studies (20,771 patients) compared one or more antiarrhythmic drugs to control or to each other [32]. Compared to controls, the use of the class IA antiarrhythmics quinidine and disopyramide (odds ratio 2.39, 95% CI 1.03-5.59) or sotalol (2.47, 95% CI 1.2-5.05) was associated with increased all-cause mortality, whereas the use of amiodarone, dronedarone, and dofetilide was not (odds ratios were not calculated for flecainide or propafenone). All antiarrhythmics studied showed increased pro-arrhythmic effects (counting both bradyarrhythmias and tachyarrhythmias attributable to treatment), with the exceptions of amiodarone, dronedarone, and propafenone. Proarrhythmia All of the antiarrhythmic drugs used to maintain sinus rhythm have the potential to increase ectopy or induce or aggravate monomorphic ventricular tachycardia (VT), torsades de pointes, or ventricular fibrillation (VF); this is referred to as proarrhythmia ( table 1). In addition to its baseline potential to predispose the patient to proarrhythmia, a drug that is initially safe may become proarrhythmic when the patient develops coronary heart disease or heart failure or is treated with other medications that in combination may be arrhythmogenic. Thus, the patient should be alerted to the potential significance of symptoms such as syncope https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 10/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate and dyspnea and warned about the use of noncardiac drugs that can prolong the QT interval ( table 2). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) We agree with the following recommendations made according to drug class in the American College of Cardiology/American Heart Association/European Society of Cardiology guideline [13]: With type IC drugs, QRS widening should not be permitted to exceed 150 percent of the baseline QRS duration. Exercise testing may detect QRS widening that occurs only at rapid heart rates (use-dependent conduction slowing). Exercise testing is also a useful way to screen for exercise-induced proarrhythmia and is typically performed one to two weeks after drug initiation. For type IA or type III drugs ( table 3), with the possible exception of amiodarone, the corrected QT interval in sinus rhythm should remain below 520 milliseconds. More specific and conservative recommendations are available for dofetilide in the package insert. During follow-up, serum creatinine, potassium, and magnesium concentrations should be monitored periodically because proarrhythmia is increased by renal insufficiency, which can lead to drug accumulation, hyperkalemia, and hypermagnesemia. The presence of renal insufficiency warrants dose reduction or cessation of sotalol and dofetilide. In comparison, amiodarone is metabolized in the liver and dose adjustment is probably necessary in patients with hepatic dysfunction. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring", section on 'Adverse hepatic effects'.) Bradyarrhythmia Amiodarone and dronedarone can cause both sinus bradycardia and AV nodal block, with an overall incidence of bradycardic events of about 5 percent. Sotalol, like other beta blockers, can also cause bradycardia. In some cases, permanent pacemaker placement is necessary to permit continued use of these agents. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol".) Ambulatory monitoring Our authors and reviewers have differing thresholds for the use of ambulatory monitoring to screen for proarrhythmia and bradycardia, ranging from screening in the highest risk cases only to screening in everyone. Some experts suggest screening all patients with an ambulatory event monitor for at least two weeks after initiation of therapy, looking for QT interval prolongation or bradyarrhythmias. The basis for this recommendation is that many events occur after three days [31]. For those experts who are more selective based on patient risk, high-risk is defined as baseline bradycardia or borderline QT prolongation, heart failure, or systolic left ventricular dysfunction. Others perform routine monitoring when sotalol, flecainide, or propafenone are chosen. Dofetilide must be initiated in a setting with continuous monitoring. (See "Clinical use of dofetilide".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 11/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate For those patients who are not referred for ambulatory monitoring, we suggest that a 12-lead electrocardiogram be obtained after the initiation of antiarrhythmic drug therapy. Short- versus long-term therapy Based on concerns about drug related arrhythmias and the observation that the atrial action potential normalizes after two to four weeks of sinus rhythm (after AF), the concept that short-term therapy might be as effective and safer than long-term therapy has been proposed. This concept was tested in the Flec-SL non-inferiority trial, which randomly assigned 554 patients with persistent AF and who were intended to undergo cardioversion to either four weeks or six months of flecainide (200 to 300 mg per day) [33]. All patients had successful restoration of sinus rhythm and were then followed with daily telemetric electrocardiography (and Holter monitoring whenever AF was noted on two ECGs) for six months. The primary outcome of time to persistent AF or death occurred in 46 and 39 percent of patients, respectively, which did not meet the criteria of non-inferiority. In addition, a post-hoc analysis of patients who had not reached the primary endpoint in the first month found long- term therapy to be superior (Kaplan-Meier estimate of difference 14.3 percent; hazard ratio 0.3; p = 0.0001). We do not consider short-term therapy appropriate for most patients with persistent AF. Concerns about dronedarone Patients with severe heart failure (HF) (generally those with NYHA class III or IV HF, or those who have been hospitalized with HF in the past four weeks) or those with an ejection fraction of <35 percent should not receive dronedarone. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) The Permanent Atrial fibriLLAtion outcome Study (PALLAS) was designed to test the hypothesis that dronedarone would improve major outcomes in 10,000 patients with permanent AF, over 70 percent of whom had New York Heart Association heart failure class I to III or left ventricular systolic dysfunction at baseline. The rationale was that patients with permanent AF, which affects up to 50 percent of patients with AF, have an increased risk of adverse cardiovascular outcomes including death and myocardial infarction as well as systemic embolization. The ATHENA trial showed a significant reduction in cardiovascular events with dronedarone in patients with paroxysmal or persistent AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled), after a significantly increased risk (Hazard Ratio 2.29, 95% CI 1.34-3.94) of cardiovascular events https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 12/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [34]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. (See 'Summary and recommendations' below.) The European Medicines Agency and the United States Food and Drug Agency (USFDA) have advised against the use of dronedarone in patients with permanent AF [35,36]. In addition, the USFDA now recommends that people taking the drug should have an electrocardiogram every three months to make sure that AF has not become permanent. For patients taking dronedarone, routine monitoring of lung and liver function is not mandated by the USFDA; however, periodic monitoring may be reasonable [37]. (See "Clinical uses of dronedarone", section on 'Maintenance of sinus rhythm'.) Follow-up We consider the following approach to follow-up reasonable: We perform an ECG one week after initiation of any antiarrhythmic drug. We typically see patients within three months of initiating a new antiarrhythmic drug to assess efficacy and side effects. This is in addition to commonly performing ambulatory monitoring after drug initiation. Patients are typically seen every 6 to 12 months unless there are particular concerns regarding QT interval prolongation, bradycardia, or other issues identified on the ECG. Specific follow-up recommendations for individual drugs are presented separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol", section on 'Major side effects' and "Clinical use of dofetilide", section on 'Safety' and "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide' and "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) RECOMMENDATIONS OF OTHERS Our recommendations for the use of antiarrhythmic drugs to maintain sinus rhythm in patients with AF are generally in agreement with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society (2014) and its 2019 focused update, as well as the European Society of Cardiology (2016) [15,38-40]. (See 'Summary and recommendations' below.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 13/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS For those patients with atrial fibrillation (AF) in whom a rhythm-control strategy is chosen, the principal goal is to reduce symptoms by decreasing the frequency and duration of episodes [1,2]. (See 'Initial management decisions' above.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia. (See 'Selecting an antiarrhythmic drug' above.) Compared to placebo, amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective for the maintenance of sinus rhythm, but maintenance rates at one year are significantly less than 75 percent. Amiodarone is consistently more effective than the other antiarrhythmic drugs. (See 'Selecting an antiarrhythmic drug' above.)
electrocardiogram be obtained after the initiation of antiarrhythmic drug therapy. Short- versus long-term therapy Based on concerns about drug related arrhythmias and the observation that the atrial action potential normalizes after two to four weeks of sinus rhythm (after AF), the concept that short-term therapy might be as effective and safer than long-term therapy has been proposed. This concept was tested in the Flec-SL non-inferiority trial, which randomly assigned 554 patients with persistent AF and who were intended to undergo cardioversion to either four weeks or six months of flecainide (200 to 300 mg per day) [33]. All patients had successful restoration of sinus rhythm and were then followed with daily telemetric electrocardiography (and Holter monitoring whenever AF was noted on two ECGs) for six months. The primary outcome of time to persistent AF or death occurred in 46 and 39 percent of patients, respectively, which did not meet the criteria of non-inferiority. In addition, a post-hoc analysis of patients who had not reached the primary endpoint in the first month found long- term therapy to be superior (Kaplan-Meier estimate of difference 14.3 percent; hazard ratio 0.3; p = 0.0001). We do not consider short-term therapy appropriate for most patients with persistent AF. Concerns about dronedarone Patients with severe heart failure (HF) (generally those with NYHA class III or IV HF, or those who have been hospitalized with HF in the past four weeks) or those with an ejection fraction of <35 percent should not receive dronedarone. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) The Permanent Atrial fibriLLAtion outcome Study (PALLAS) was designed to test the hypothesis that dronedarone would improve major outcomes in 10,000 patients with permanent AF, over 70 percent of whom had New York Heart Association heart failure class I to III or left ventricular systolic dysfunction at baseline. The rationale was that patients with permanent AF, which affects up to 50 percent of patients with AF, have an increased risk of adverse cardiovascular outcomes including death and myocardial infarction as well as systemic embolization. The ATHENA trial showed a significant reduction in cardiovascular events with dronedarone in patients with paroxysmal or persistent AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled), after a significantly increased risk (Hazard Ratio 2.29, 95% CI 1.34-3.94) of cardiovascular events https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 12/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [34]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. (See 'Summary and recommendations' below.) The European Medicines Agency and the United States Food and Drug Agency (USFDA) have advised against the use of dronedarone in patients with permanent AF [35,36]. In addition, the USFDA now recommends that people taking the drug should have an electrocardiogram every three months to make sure that AF has not become permanent. For patients taking dronedarone, routine monitoring of lung and liver function is not mandated by the USFDA; however, periodic monitoring may be reasonable [37]. (See "Clinical uses of dronedarone", section on 'Maintenance of sinus rhythm'.) Follow-up We consider the following approach to follow-up reasonable: We perform an ECG one week after initiation of any antiarrhythmic drug. We typically see patients within three months of initiating a new antiarrhythmic drug to assess efficacy and side effects. This is in addition to commonly performing ambulatory monitoring after drug initiation. Patients are typically seen every 6 to 12 months unless there are particular concerns regarding QT interval prolongation, bradycardia, or other issues identified on the ECG. Specific follow-up recommendations for individual drugs are presented separately. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Clinical uses of sotalol", section on 'Major side effects' and "Clinical use of dofetilide", section on 'Safety' and "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide' and "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) RECOMMENDATIONS OF OTHERS Our recommendations for the use of antiarrhythmic drugs to maintain sinus rhythm in patients with AF are generally in agreement with recommendations from the American Heart Association/American College of Cardiology/Heart Rhythm Society (2014) and its 2019 focused update, as well as the European Society of Cardiology (2016) [15,38-40]. (See 'Summary and recommendations' below.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 13/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") SUMMARY AND RECOMMENDATIONS For those patients with atrial fibrillation (AF) in whom a rhythm-control strategy is chosen, the principal goal is to reduce symptoms by decreasing the frequency and duration of episodes [1,2]. (See 'Initial management decisions' above.) Beta blockers are modestly effective in maintaining sinus rhythm and can be tried first in selected patients, such as those without structural heart disease who are concerned about proarrhythmia. (See 'Selecting an antiarrhythmic drug' above.) Compared to placebo, amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective for the maintenance of sinus rhythm, but maintenance rates at one year are significantly less than 75 percent. Amiodarone is consistently more effective than the other antiarrhythmic drugs. (See 'Selecting an antiarrhythmic drug' above.) In addition to less-than-optimal efficacy, serious drug-related adverse side effects limit the use of these drugs. Antiarrhythmic drug therapy should be prescribed only by practitioners familiar with their use. Patients should be fully informed of both the benefits and risks https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 14/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate associated with the use of these drugs. (See 'Drug-related arrhythmias and mortality' above.) Based upon the potential for drug toxicity in the form of induced bradycardia or tachycardia, many patients will need to be hospitalized for continuous electrocardiographic monitoring. Dofetilide must be initiated in a setting with continuous monitoring. (See 'Inpatient versus outpatient initiation' above.) For patients with no structural heart disease and no apparent risk for drug-induced bradycardia or tachycardia, we suggest flecainide or propafenone as the preferred antiarrhythmic drug (Grade 2B). Amiodarone, dofetilide, dronedarone, or sotalol may be used, with sotalol chosen more often by our authors and reviewers. Practitioners should choose only those agents with which they have significant familiarity. (See 'Atrial fibrillation without structural heart disease' above.) For patients with coronary artery disease who do not have advanced heart failure, we suggest dronedarone or sotalol in preference to amiodarone (Grade 2B). Amiodarone is a reasonable choice in patients who prefer its greater efficacy despite its worse extracardiac side-effect profile. (See 'Coronary heart disease' above.) For patients with heart failure, we suggest amiodarone in preference to dofetilide (Grade 2B). Flecainide, propafenone, dronedarone, and sotalol are contraindicated in these patients. (See 'Heart failure' above.) For patients with left ventricular hypertrophy, either amiodarone or dronedarone is generally preferred to other antiarrhythmic agents. Our authors and reviewers have differing approaches, with some choosing amiodarone more often and others choosing dronedarone more often. (See 'Left ventricular hypertrophy' above.) After the initiation of antiarrhythmic drug therapy, screening for drug-associated arrhythmia with ambulatory monitoring should be considered, particularly for patients at high risk of drug-induced arrhythmia. This includes those with baseline bradycardia or borderline QT prolongation, heart failure, or systolic left ventricular dysfunction. (See 'Ambulatory monitoring' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 15/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 2. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. Am Heart J 2000; 139:752. 3. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003; 139:1009. 4. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 5. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 6. K hlkamp V, Schirdewan A, Stangl K, et al. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2000; 36:139. 7. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 8. Lafuente-Lafuente C, Mouly S, Long s-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006; 166:719. 9. Flaker G, Lopes RD, Hylek E, et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol 2014; 64:1541. 10. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials. Circulation 1990; 82:1106. 11. Steeds RP, Birchall AS, Smith M, Channer KS. An open label, randomised, crossover study comparing sotalol and atenolol in the treatment of symptomatic paroxysmal atrial fibrillation. Heart 1999; 82:170. 12. Plewan A, Lehmann G, Ndrepepa G, et al. Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol. Eur Heart J 2001; 22:1504. 13. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 57:223. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 16/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 14. Herweg B, Dalal P, Nagy B, Schweitzer P. Power spectral analysis of heart period variability of preceding sinus rhythm before initiation of paroxysmal atrial fibrillation. Am J Cardiol 1998; 82:869. 15. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 16. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12:1360. 17. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol 2009; 54:1089. 18. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. 19. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005; 352:1861. 20. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003; 42:20. 21. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology. Arch Intern Med 2000; 160:1741. 22. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997; 30:791. 23. Zimetbaum P, Josephson ME. Is there a role for maintaining sinus rhythm in patients with atrial fibrillation? Ann Intern Med 2004; 141:720. 24. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 17/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate 25. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781. 26. Podrid PJ, Anderson JL. Safety and tolerability of long-term propafenone therapy for supraventricular tachyarrhythmias. The Propafenone Multicenter Study Group. Am J Cardiol 1996; 78:430. 27. Podrid PJ, Lampert S, Graboys TB, et al. Aggravation of arrhythmia by antiarrhythmic drugs incidence and predictors. Am J Cardiol 1987; 59:38E. 28. Morganroth J, Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol 1986; 8:607. 29. Reiffel JA, Camm AJ, Belardinelli L, et al. The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism. Circ Arrhythm Electrophysiol 2015; 8:1048. 30. Maisel WH, Kuntz KM, Reimold SC, et al. Risk of initiating antiarrhythmic drug therapy for atrial fibrillation in patients admitted to a university hospital. Ann Intern Med 1997; 127:281. 31. Hauser TH, Pinto DS, Josephson ME, Zimetbaum P. Safety and feasibility of a clinical pathway for the outpatient initiation of antiarrhythmic medications in patients with atrial fibrillation or atrial flutter. Am J Cardiol 2003; 91:1437. 32. Lafuente-Lafuente C, Longas-Tejero MA, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev 2012; :CD005049. 33. Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open- label, blinded endpoint assessment trial. Lancet 2012; 380:238. 34. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 35. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/09/new s_detail_001344.jsp&murl=menus/news_and_events/news_and_events.jsp&mid=WC0b01ac0 58004d5c1. 36. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalPro ducts/ucm264204.htm. 37. http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm. 38. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 18/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 39. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 40. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1035 Version 60.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 19/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate GRAPHICS Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 20/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 21/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 22/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 23/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Types of proarrhythmia during treatment with antiarrhythmic drugs (AADs) for atrial fibrillation or atrial flutter according to the Vaughan Williams Classification Ventricular proarrhythmia Torsade de pointes (Vaughan Williams class IA and type III drugs) Sustained monomorphic ventricular tachycardia (usually class IC drugs) Sustained polymorphic ventricular tachycardia/ventricular fibrillation without long QT interval (class IA, IC, and III drugs) Atrial proarrhythmia Provocation of recurrence (probably class IA, IC, and III drugs) Conversion of atrial fibrillation (AF) to atrial flutter (usually class IC drugs) with 1:1 conduction Increase of defibrillation threshold (a potential problem with class IC drugs) Abnormalities of conduction or impulse formation Accelerate ventricular rate during AF (class IA and type IC drugs) Accelerate conduction over accessory pathway (digoxin, type IV drugs) Sinus node dysfunction, atrioventricular block (almost all drugs) Vaughan Williams classification of AADs used for the treatment of atrial fibrillation or flutter Class IA - Disopyramide, procainamide, quinidine Class IC - Flecainide, propafenone Class III - Amiodarone, dofetilide, ibutilide, sotalol Class IV - Nondihydropyridine calcium channel blockers (diltiazem and verapamil) Data from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial brillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to revise the 2001 guidelines for the management of patients with atrial brillation). J Am Coll Cardiol 2006; 48:e149. Graphic 66133 Version 4.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 24/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Encainide and flecainide increase cardiac mortality Results of the Cardiac Arrhythmia Suppression Trial (CAST) in patients with ventricular premature beats after myocardial infarction. Patients receiving encainide or flecainide had, when compared with those receiving placebo, a significantly lower rate of avoiding a cardiac event (death or resuscitated cardiac arrest) (left panel, p = 0.001) and a lower overall survival (right panel, p = 0.0006). The cause of death was arrhythmia or cardiac arrest. Data from Echt DS, Liebson PR, Mitchell B, et al. N Engl J Med 1991; 324:781. Graphic 59975 Version 5.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 25/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Some reported causes and potentiators of the long QT syndrome Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Other factors Androgen deprivation therapy Hypokalemia Myocardial ischemia or GnRH agonist/antagonist therapy Hypomagnesemia Bilateral surgical orchiectomy infarction, especially with Hypocalcemia Diuretic therapy via electrolyte disorders Starvation particularly hypokalemia and hypomagnesemia prominent T-wave Anorexia nervosa Herbs inversions Liquid protein diets Cinchona (contains quinine), iboga Intracranial Hypothyroidism (ibogaine), licorice extract in overuse via electrolyte disturbances disease Bradyarrhythmias HIV infection Sinus node dysfunction Hypothermia Toxic exposure: Organophosphate AV block: Second or third degree insecticides Medications* High risk Adagrasib Cisaparide Lenvatinib Selpercatinib (restricted availability) Ajmaline Levoketoconazole Sertindole Amiodarone Methadone Sotalol Delamanid Arsenic trioxide Mobocertinib Terfenadine Disopyramide Astemizole Papavirine (intracoronary) Vandetanib Dofetilide Bedaquline Vernakalant Dronedarone Procainamide Bepridil Ziprasidone Haloperidol (IV) Quinidine Chlorpromazine Ibutilide Quinine Ivosidenib Moderate risk Amisulpride (oral) Droperidol Inotuzumab Propafenone ozogamacin Azithromycin Encorafenib Propofol Isoflurane Capecitabine Entrectinib Quetiapine Carbetocin Erythromycin Ribociclib https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 26/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Certinib Escitalopram Levofloxacin Risperidone (systemic) Chloroquine Etelcalcetide Saquinavir Lofexidine Citalopram Fexinidazole Sevoflurane Meglumine antimoniate Clarithromycin Flecainide Sparfloxacin Clofazimine Floxuridine Sunitinib Midostaurin Clomipramine Fluconazole Tegafur Moxifloxacin Clozapine Fluorouracil (systemic) Terbutaline Nilotinib Crizotinib Thioridazine Olanzapine Flupentixol Dabrafenib Toremifene Ondansetrol (IV > Gabobenate Dasatinib Vemurafenib oral) dimeglumine Deslurane Voriconazole Osimertinib Gemifloxacin Domperidone Oxytocin Gilteritinib Doxepin Pazopanib Halofantrine Doxifluridine Pentamidine Haloperidol (oral) Pilsicainide Imipramine Pimozide Piperaquine Probucol Low risk Albuterol Fingolimod Mequitazine Ranolazine (due to bradycardia) Alfuzosin Fluoxetine Methotrimeprazine Relugolix Amisulpride (IV) Fluphenazine Metoclopramide (rare reports) Rilpivirine Amitriptyline Formoterol Metronidazole Romidepsin Anagrelide Foscarnet (systemic) Roxithromycin Apomorphine Fostemsavir Mifepristone Salmeterol Arformoterol Gadofosveset Mirtazapine Sertraline Artemether- Glasdegib Mizolastine lumefantrine Siponimod Goserelin Nelfinavir Asenapine Solifenacin Granisetron Norfloxacin Atomoxetine Sorafenib Hydroxychloroquine Nortriptyline Benperidol (rare reports) Sulpiride Ofloxacin (systemic) Bilastine Hydroxyzine Tacrolimus Olodaterol (systemic) Bosutinib Iloperidone Osilodrostat Tamoxifen Bromperidol Indacaterol Oxaliplatin Telavancin Buprenorphine Itraconazole Ozanimod Telithromycin Buserelin Ketoconazole (systemic) Pacritinib Teneligliptin Ciprofloxacin (Systemic) Lacidipine Paliperidone Tetrabenazine Cocaine (Topical) Lapatinib Panobinostat Trazodone Degarelix Lefamulin Pasireotide Triclabendazole https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 27/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Desipramine Leuprolide Pefloxacin Triptorelin Deutetrabenazine Leuprolide- norethindrone Periciazine Tropisetron Dexmedetomidine** Pimavanserin Vardenafil Levalbuterol Dolasetron Pipamperone Vilanterol Levomethadone Donepezil Pitolisant Vinflunine Lithium Efavirenz Ponesimod Voclosporin Loperamide in Eliglustat Primaquine Vorinostat overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 28/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 29/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 30/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 31/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
overdose Eribulin Promazine Zuclopenthixol Lopinavir Ezogabine Radotinib Macimorelin Mefloquine This is not a complete list of all corrected QT interval (QTc)-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous; QTc: rate-corrected QT interval on the electrocardiogram. Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM [1,2] 073161.pdf with additional data from CredibleMeds QT drugs list criteria may lead to some agents being classified differently by other sources. . The use of other classification Not available in the United States. In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. Withdrawn from market in most countries due to adverse cardiovascular effects. IV amisulpride antiemetic use is associated with less QTc prolongation than the higher doses administered orally as an antipsychotic. Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. The "low risk" category includes drugs with limited evidence of clinically significant QTc prolongation or TdP risk; many of these drugs have label warnings regarding possible QTc effects or recommendations to avoid use or increase ECG monitoring when combined with other QTc prolonging drugs. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 28/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. * The United States FDA labeling for the sublingual preparation of dexmedetomidine warns against use in patients at elevated risk for QTc prolongation. Both intravenous (ie, sedative) and sublingual formulations of dexmedetomidine have a low risk of QTc prolongation and have not been implicated in TdP. Over-the-counter; available without a prescription. Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. Data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at http://crediblemeds.org/. Graphic 57431 Version 142.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 29/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 30/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 31/32 7/5/23, 9:03 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations/print 32/32
7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation and flutter after cardiac surgery : Richard Lee, MD, MBA : Gabriel S Aldea, MD, Bradley P Knight, MD, FACC, John Pepper, MA, MChir, FRCS, FESC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 28, 2022. INTRODUCTION Atrial fibrillation (AF) and atrial flutter occur frequently after cardiac surgery. The development of these atrial arrhythmias prolongs hospital stay and is associated with worse long-term prognosis. Other supraventricular arrhythmias, including atrial arrhythmias such as atrioventricular nodal re-entrant tachycardia, are not common in this setting. (See "Atrioventricular nodal reentrant tachycardia".) This topic will review the pathogenesis, predictors, clinical course, prevention, and management of AF and atrial flutter occurring after cardiac surgery. Most of the observations on atrial arrhythmias come from patients who developed atrial fibrillation. Our approach to patients with atrial flutter is similar, unless otherwise specified. Ventricular tachyarrhythmias after cardiac surgery and arrhythmias after cardiac transplantation are discussed separately. (See "Early cardiac complications of coronary artery bypass graft surgery", section on 'Ventricular tachyarrhythmias' and "Heart transplantation in adults: Arrhythmias".) PATHOGENESIS Atrial fibrillation (AF) and atrial flutter can occur early in the postoperative period or as a late complication of cardiac surgery. A discussion of the mechanisms of AF in the general population is found elsewhere. (See "Mechanisms of atrial fibrillation".) https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 1/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Postoperative AF is likely related to a combination of perioperative factors. These include pre- existing degenerative changes in the atrial myocardium and perioperative conditions that result in abnormalities of several electrophysiologic parameters that promote the development of AF, such as dispersion of atrial refractoriness, increase in phase 3 depolarization, enhanced automaticity, increased interatrial conduction time, and decreased conduction velocity, atrial transmembrane potentials, and fluid and electrolyte shifts [1-5]. (See "The electrocardiogram in atrial fibrillation".) RISK FACTORS Although some patients develop atrial fibrillation (AF) after cardiac surgery without any apparent predisposing factors, most patients have at least one clinical predictor. Preoperative risk factors include [2,6-17]: Increasing age [6-12]. Previous history of AF. Mitral valvular disease, particularly mitral stenosis. Increased left atrial size or cardiomegaly. Previous cardiac surgery. Chronic obstructive pulmonary disease (COPD). Elevated preoperative hemoglobin A1c [18]. Low-intensity physical activity in the year prior to surgery [19]. Being a White person [20]. Obesity [17,21]. Absence of beta blocker or angiotensin converting enzyme inhibitor (ACE inhibitor) treatment or withdrawal of previous treatment. (See 'Prevention of atrial fibrillation and complications' below.) Preoperative digoxin use in some [7,13] but not all studies [14]. Higher preoperative plasma concentration of brain natriuretic peptide (BNP) [15]. (See "Natriuretic peptide measurement in heart failure".) https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 2/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Low-dose dopamine [22]. Severe right coronary artery stenosis [12]. Preoperative increase in P wave duration on surface (>116 msec) [16] or on signal averaged (>140 msec) ECG ( figure 1) [9,23]. (See "Signal-averaged electrocardiogram: Overview of technical aspects and clinical applications".) Hypokalemia and hypomagnesemia. (See 'Pathogenesis' above.) Alcohol use disorder. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Alcohol'.) PERIOPERATIVE RISK FACTORS Perioperative factors that have been implicated in the creation of atrial susceptibility to atrial fibrillation (AF) or atrial flutter include: Atrial injury from surgical handling, or cannulation, atrial suture lines. Acute atrial enlargement from pressure or volume overload. Inadequate myocardial protection during cardiopulmonary bypass. Atrial ischemia. Long bypass and aortic cross-clamp times. Hyperadrenergic state (eg, use of postoperative inotropic medications). Pulmonary complications, hypoxemia. Inflammation [24,25]. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'.) Hypokalemia and hypomagnesemia [26-29]. Pericardial effusion and pericarditis. Oxidative stress [30]. While mechanisms specific to late AF have not been identified, atrial flutter in these patients is re-entrant and may involve atypical isthmuses between natural barriers, atrial incisions, and scar https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 3/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate as well as the cavotricuspid isthmus [31-33]. Two potential negative risk factors are off-pump coronary artery bypass graft surgery (CABG) and preservation of the anterior fat pad: Off-pump CABG off-pump CABG is associated with a lower rate of postoperative AF than conventional CABG in some [34-36], but not all [37], studies. (See "Off-pump and minimally invasive direct coronary artery bypass graft surgery: Clinical use".) Preservation of the anterior fat pad Some [38], but not all [39], studies have found lower rate of postoperative AF with preservation of the anterior fat pad. However, none of these risk factors has adequate predictive accuracy to identify the individual patient at risk for postoperative atrial arrhythmia. As a result, risk models that use several factors have been created [6,40]. In one study, a multivariable risk model was derived in a cohort of 3093 patients, and then tested in a validation cohort of 1564 patients [6]. Predictors were identified for any postoperative AF as well as for recurrent AF. The risk score for any postoperative AF successfully stratified patients into groups at low risk (AF incidence <17 percent), medium risk (AF incidence 17 to 52 percent), and high risk (AF incidence >52 percent) ( table 1). While we do not routinely use any of these risk models, they highlight the individual risks. INCIDENCE AND TIME COURSE Atrial fibrillation (AF) occurs in 15 to 40 percent of patients in the early postoperative period following coronary artery bypass graft surgery (CABG) [1,6,41,42]. In a 2018 post-hoc analysis of 1812 patients without prior AF in the EXCEL trial, which compared CABG with percutaneous coronary intervention (PCI) for left main coronary artery disease, perioperative AF developed in 18.0 percent of those undergoing CABG (and 0.1 percent of those who received PCI). The incidence increases with increasing age [6-12,43]. (See "Left main coronary artery disease", section on 'Randomized trials' and 'Adverse outcomes following atrial fibrillation' below.) AF occurs in 37 to 50 percent after valve surgery [1,7,8], and in as many as 60 percent undergoing valve replacement plus CABG [1,7]. Atrial arrhythmias occur most often within the first few days after surgery [1,6,9,11]. In a prospective, multicenter study of 4657 patients undergoing surgery, the majority of first episodes of AF occurred by day two, while the majority of recurrent episodes occurred by day three. Forty-three percent of patients with AF had more than one episode [6]. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 4/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Among patients with postoperative AF who have no prior history of atrial arrhythmias, the AF is usually self-limited, as 15 to 30 percent convert within two hours and up to 80 percent in 24 hours [1,44,45]. The mean duration of AF in one report was 11 to 12 hours [45] and more than 90 percent are in sinus rhythm six to eight weeks following surgery [1,45-47]. In one report, for example, only 3 of 116 patients who developed AF after CABG were still in AF at six weeks [46]. AF may also occur late after cardiac surgery and the incidence is likely higher than appreciated because many patients may have continued asymptomatic episodes of AF. In a study of over 2000 patients enrolled in cardiac rehabilitation programs after cardiac surgery, 11 percent of patients developed AF (4.4 percent new-onset AF) [48]. Late postoperative AF was associated with adverse outcomes, including heart failure and rehospitalization. Atrial flutter is relatively uncommon compared to atrial fibrillation. CLINICAL MANIFESTATIONS AND DIAGNOSIS The development of atrial fibrillation or flutter after cardiac surgery may or may not lead to symptoms, such as palpitations, or to a change in the hemodynamic status of the patient. In some individuals with rapid ventricular rates, the blood pressure may fall and potentially be associated with a decline in the urine output. We are not aware of any studies that have systematically characterized the clinical manifestations of postoperative atrial fibrillation (AF) in coronary artery bypass graft surgery patients. In our experience, about 90 percent of these individuals are symptomatic and about 15 percent are hemodynamically unstable. The diagnosis of AF in the hospital is usually not difficult as most patients are on continuous monitoring. All patients should have documentation of the rhythm with a 12-lead electrocardiogram. (See "The electrocardiogram in atrial fibrillation".) Longer-term continuous AF screening may detect more episodes in postoperative cardiac surgery patients who are discharged from the hospital, but more studies are needed before we can recommend this as routine practice (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Screening'). In a randomized trial of 336 cardiac surgical patients with risk factors for stroke, use of continuous cardiac rhythm monitoring with wearable sensors increased the rate of AF detection within 30 days of discharge. In the intent-to-treat analysis, the primary end point of AF for at least six minutes occurred in 32 patients in the intervention group versus 3 patients in the usual care group (absolute difference, 17.9 percent 95% CI 11.5-24.3 percent) [49]. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 5/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate ADVERSE OUTCOMES FOLLOWING ATRIAL FIBRILLATION Potential adverse outcomes after the development of postoperative atrial fibrillation (AF) include stroke, death, and prolongation of hospital stay: Postoperative AF has been associated with an increased risk of in-hospital stroke in some [7,41,50-55] but not all series [56,57]. In some of these studies, it is possible that underlying comorbidities, such as older age, cerebrovascular or peripheral artery disease, and cardiopulmonary bypass time, are related to in-hospital stroke rather than the arrhythmia itself [43,52,56-59]. At least three studies with differing designs have evaluated the long-term thromboembolic risk of patients with new onset AF after coronary artery bypass graft surgery (CABG) and reached somewhat different conclusions: In the EXCEL trial of patients with left main coronary artery disease, new onset AF was an independent predictor of stroke at three years with a rate of 6.6 percent compared with 2.4 percent in patients without AF [43]. (See 'Incidence and time course' above.) In a cohort study of 2108 patients who developed postoperative AF and 8432 patients with nonvalvular AF, the risk of thromboembolism was lower in the former group (18.3 versus 29.7 events per 1000 person-years; adjusted hazard ratio 0.67, 95% CI 0.55-0.81) [60]. In addition, the risk was similar between the groups of patients with and without postoperative AF. In a post-hoc analysis of the ART randomized trial (see "Coronary artery bypass graft surgery: Graft choices", section on 'Two arterial grafts') comparing bilateral with single internal thoracic artery grafts, the cumulative incidence of cerebrovascular accident was higher in those with postoperative AF relative to those without (6.3 versus 3.7 percent; hazard ratio 1.53, 95% CI 1.06-2.23) [61]. Postoperative AF may identify a subset of patients with increased in-hospital and long-term mortality [6,25,41,42,62,63]. This was suggested by a retrospective study of 6475 patients undergoing CABG at a single institution, 994 (15 percent) of whom developed AF [41]. Patients with AF had significantly greater mortality in-hospital (7.4 versus 3.4 percent) and at four years (26 versus 13 percent). In a case-matched subset of 390 patients, the mortality at five years was significantly higher in those with AF (20 versus 7 percent). On multivariate analysis, postoperative AF was a predictor of long-term mortality in both the retrospective cohort (adjusted odds ratio 1.5) and the case-matched population (odds ratio 3.4). https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 6/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate In the EXCEL trial of patients with left main coronary artery disease, new onset AF was an independent predictor of all-cause death at three years with a rate of 11.4 percent compared with 4.3 percent in patients without AF [43]. (See 'Incidence and time course' above.) In another study of 1832 patients who underwent CABG, patients with postoperative AF had a higher long-term mortality (2.99 versus 1.34 per 100 person-years; adjusted hazard ratio 2.13, 95% CI 1.45-3.15) during a median follow-up of 51 months [42]. Patients with AF were at higher risk of dying from systemic embolism (adjusted hazard ratio 4.33, 95% CI 1.78-10.52), but not from other causes. Postoperative AF is associated with prolongation of the duration of hospitalization, with an increased length of stay between one and six days [7,11,43,50,51,64,65]. New onset AF added approximately six days to the hospital duration in the EXCEL trial of patients with left main coronary artery disease [43]. (See 'Incidence and time course' above.) PREVENTION OF ATRIAL FIBRILLATION AND COMPLICATIONS We recommend therapies to prevent the development of postoperative atrial fibrillation (AF) in patients undergoing cardiac surgery in an attempt to decrease the duration of hospitalization, to possibly decrease the risk of in-hospital stroke and death, and to decrease the need for anticoagulation in some patients. Prevention of atrial fibrillation The use of beta blockers, sotalol, amiodarone, atrial pacing, or antioxidant vitamins lowers the risk of postoperative AF [66]. Beta blockers are the best studied of these therapies and we prefer beta blockers to sotalol or amiodarone based on their ease of use and better safety profile. We do not recommend atrial pacing in most cases. There have been no studies comparing the relative efficacy and safety of the traditional antiarrhythmic drugs to antioxidant vitamins. Beta blockers Beta blocker administration is the most widely used prophylactic strategy based on numerous studies showing benefit, ease of use, and cost considerations [1,6,10,14,64,67-70]. Meta-analyses of randomized trials from 2002 and 2004 found that they reduced the risk of AF compared to placebo or no therapy (odds ratios of 0.35, 95% CI 0.26-0.49 and 0.39, 95% CI 0.28-0.52) [64,71]. However, a larger 2006 meta-analysis of 31 trials including 4452 patients performed separate analyses based on whether non-study beta blocker was allowed to be continued or not [72]. When trials confounded by postoperative non-study beta blocker withdrawal were excluded, the effect of beta blockers, although still significant, was less (OR 0.69, 95% CI 0.54-0.87). In addition, other between-trial differences (heterogeneity), such as https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 7/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate control group event rates which ranged between 5 and 54 percent, lead us to be unsure of the true magnitude of the benefit from beta blockers in patients who have not previously received them. The issue of whether some beta blockers lower the risk of postoperative AF more successfully than others has not been well studied. In a meta-analysis of randomized trials with 601 patients that compared carvedilol to metoprolol (succinate and tartrate), carvedilol reduced the incidence of AF (odds ratio 0.50, 95% CI 0.32-0.80) [73]. The benefit is seen when beta blockers are begun prior to or immediately after surgery. We feel the evidence is not strong enough for us to recommend one beta blocker over another. When possible, we start beta blockers at least 48 hours before surgery, due to concerns about the induction of excessive bradycardia. In addition, some experts are concerned about the increased risk of stroke seen in patients undergoing noncardiac surgery who receive beta blockers soon before surgery. (See "Management of cardiac risk for noncardiac surgery", section on 'Patients who may require preoperative initiation of therapy'.) If a patient is a candidate for initiation of a beta blocker but presents within the 48-hour window, our reviewers have differing approaches. Some will start low dose beta blocker at any time before surgery, while others will wait until after the patient has returned to the intensive care unit and is deemed "stable." The optimal duration of therapy for prevention of postoperative atrial arrhythmias is uncertain, but we often continue the beta blocker until the first postoperative visit. However, many patients who undergo CABG have a clear indication for the long-term use of beta blocker therapy (eg, previous myocardial infarction, left ventricular systolic dysfunction with heart failure, or hypertension). Sotalol Sotalol is a class III antiarrhythmic agent that has beta blocking activity. A 2011 meta-analysis of 15 randomized studies of patients undergoing cardiac surgery found that sotalol lowered the risk of AF compared to placebo (relative risk [RR] 0.55, 95% CI 0.45-0.66) [74]. Compared to beta blocker, sotalol was more effective (14 versus 23 percent; RR=0.64 [CI, 0.50- 0.84]). There was no significant difference in the rates between sotalol and amiodarone. Risks of sotalol include torsade de pointes and bradycardia. (See "Clinical uses of sotalol".) Sotalol is effective when begun 24 to 48 hours before surgery or four hours after surgery [75,76]. Amiodarone Most of our contributors prefer beta blockers to amiodarone for the preoperative prevention of AF. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 8/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Amiodarone lowers the incidence of postoperative AF by about 40 to 50 percent [64,71,77-82]. A 2006 meta-analysis of 18 trials that included nearly 3000 patients found that amiodarone lowered the risk of AF or atrial flutter compared to placebo (odds ratio [OR] 0.48, 95% CI 0.40- 0.57) [72]. However, amiodarone is associated with more adverse cardiac events compared to placebo, including bradycardia requiring temporary pacing (5.7 versus 2 percent), and QT prolongation (1.3 versus 0 percent) [82]. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Metoprolol was directly compared to amiodarone in an equivalence trial of 316 hemodynamically stable patients who underwent CABG or valve surgery [83]. The rates of the development of AF were similar (23.9 and 24.8 percent, respectively). A number of different preoperative regimens of amiodarone have been evaluated. It has been given orally one to seven days before surgery [78,79], intravenously immediately after surgery [80], or intravenously for 24 hours followed by oral therapy for four days [81]. The efficacy of these different regimens is illustrated by the following observations: One study randomly assigned 124 patients to oral amiodarone or placebo for a minimum of seven days prior to elective cardiac surgery, continuing the drug until discharge [78]. The mean total dose of amiodarone administered was 4.8 grams over 13 days (600 mg/day for seven days followed by 200 mg/day until discharge). The amiodarone group had a significant reduction in the incidence of postoperative atrial fibrillation (25 versus 53 percent) without any increase in fatal or nonfatal postoperative complications. Other oral regimens that have been effective include those that begin five days before surgery or one day before surgery [79]. The efficacy of postoperative intravenous therapy was documented in the ARCH trial in which 300 patients were randomly assigned to 1 gram of intravenous amiodarone per day for two days or placebo; therapy was begun immediately after CABG [80]. Amiodarone significantly reduced the incidence of atrial fibrillation (35 versus 47 percent for placebo), but did not lower the length of hospitalization (7.6 versus 8.2 days). In another report, intravenous amiodarone begun on call to the operating room and continued for 48 hours, followed by oral amiodarone for three days, also significantly reduced postoperative atrial fibrillation (6 versus 26 percent) [84]. Although some have suggested that amiodarone might be more effective than a beta blocker for the prevention of atrial fibrillation after cardiac surgery [85], this was not confirmed in two https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 9/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate meta-analyses [64,71]. Antioxidant vitamins Oxidative stress plays a role in ischemia-reperfusion injury, which occurs in open heart surgery. It is also involved in the pathogenesis of AF. Based on limited supportive evidence, as well as the absence of side effects in the short term or significant cost, we believe it is reasonable to give antioxidant vitamins to lower the rate of postoperative AF. (See "Reperfusion injury of the heart", section on 'Arrhythmias' and "Reperfusion injury of the heart", section on 'Antioxidant therapy' and 'Pathogenesis' above.) A 2011 meta-analysis evaluating five randomized trials comprising 567 patients found that the prophylactic use of the antioxidant vitamins C and E lowered the rate of postoperative AF (odds ratio 0.43, 95% CI 0.21-0.89) [86]. The conclusion of the meta-analysis is limited by the inclusion of small, low-quality studies. Subsequent to the meta-analysis, a small trial randomly assigned 203 patients scheduled to undergo on-pump cardiac surgery to supplementation with n-3 PUFA (1 gram twice daily), vitamin C (1 g/day), and vitamin E (400 international units/day) or placebo [87]. n-3 PUFA was started approximately seven days and the vitamins two days before surgery; treatment was continued until hospital discharge. The primary outcome of the occurrence of electrocardiographically confirmed postoperative AF occurred significantly less often in the antioxidant therapy group (9.7 versus 32 percent; relative risk 0.28, 95% CI 0.14-0.56). Due to the small number of events (postoperative AF), as well as the unusually low relative risk found, we believe this trial provides weak evidence in favor of antioxidant vitamins. In addition, we do not believe that the trial, which combined n-3 PUFA with vitamins, changes our view that n-3 PUFA are of no benefit in this setting. If antioxidant vitamins are given to prevent postoperative AF, we suggest using them with the timing and dosing used in the above trial and adding them to another preventative therapy. Atrial pacing Atrial pacing to prevent postoperative AF has been examined in a number of studies. Most [88-92], but not all [81,93,94], showed benefit. In a 2006 meta-analysis, pacing was associated with a significant reduction in AF (OR 0.60, 95% CI 0.47-0.77) [72]. With regard to the optimal pacing strategy (eg, left compared to right atrium or pacing from one or both atria), studies are not definitive [89-94]. Atrial pacing is not considered an invasive procedure in these patients because placement of temporary pacing wires is routinely done at the time of surgery. Reducing risk of pericardial effusion There are several methods to reduce the incidence of pericarditis and residual pericardial effusion. One approach we use is placement of a large drain (eg, Blake drain), left in postoperatively until they no longer drain. Colchicine can be added in this setting to prevent pericarditis when a drain is in place. However, outside of this particular https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 10/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate setting, the evidence supporting colchicine's efficacy in reducing postoperative AF is mixed. (See 'Ineffective or possibly effective therapies' below.) Posterior left pericardiotomy can reduce the incidence of pericardial effusions, which are common triggers for postoperative AF. In patients without a known diagnosis of AF, posterior left pericardiotomy was shown to reduce the incidence of postoperative AF after surgery on the coronary arteries, aortic valve, and/or ascending aorta, without additional risk of postoperative complications [95]. Patients undergoing mitral or tricuspid valve surgeries were not studied. In an adaptive randomized trial of 420 patients, patients assigned posterior left pericardiotomy had a lower incidence of postoperative AF compared with controls (17 versus 32 percent). Patients assigned posterior left pericardiotomy also had a lower incidence of pericardial effusion (12 versus 21 percent). Postoperative major events were similar in the intervention and control groups (3 versus 2 percent), and no pericardiotomy-related complications occurred. Factors that limited generalizability of this study were that it was done in a single center, and there were relatively high rates of postoperative AF, even in a study population at lower risk for AF. We await further studies before recommending this approach for all patients undergoing cardiac surgery. Ineffective or possibly effective therapies We do not recommend any of the following preventative strategies to prevent the development of atrial arrhythmias: Digoxin Digoxin, given preoperatively or postoperatively, does not appear to prevent AF [14,68,69,96]. Antiarrhythmic drugs Data about the prophylactic use of class I antiarrhythmic drugs to prevent postoperative AF are limited. Procainamide appears to reduce the number of episodes and duration of AF compared to placebo, but not the incidence of AF [97,98]. Calcium channel blockers Calcium channel blockers have uncertain utility in preventing AF after cardiac surgery [68,99-102]. Intravenous magnesium Based on the fact that hypomagnesia is a risk factor for AF (see 'Risk factors' above), magnesium supplementation has been evaluated as a possible therapy to reduce postoperative atrial arrhythmias [103-108]. In a 2006 meta-analysis of 22 trials including 2896 patients, supraventricular arrhythmias occurred significantly less often in patients treated with magnesium compared to controls (odds ratio 0.57, 95% CI 0.42-0.77) [72]. However, there was no effect on hospital stay, perioperative myocardial infarction, or mortality. There was also significant heterogeneity in the size of the effect among trials, and the possibility of publication bias was suggested. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 11/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate In a 2012 meta-analysis of seven randomized trials (n = 1028), which were felt to have no 2 heterogeneity (I = 0), intravenous magnesium reduced the incidence of postoperative AF (relative risk 0.64, 95% CI 0.50-0.83) [109]. Angiotensin inhibition Although angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have not previously been considered a specific therapy in patients with AF, a number of observations suggest benefit in nonsurgical settings. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".) A significant reduction in the incidence of postoperative AF (20 versus 34 percent) with ACE inhibitors was seen in an observational study of 4657 patients undergoing CABG [6]. However, in a study of 445 patients randomly assigned to placebo, ramipril, or spironolactone one week to four days prior to cardiac surgery, there was no significant difference in the rate of AF after surgery [110]. In a prospective study of 4657 patients undergoing CABG, postoperative AF occurred significantly less often in patients who were treated preoperatively and postoperatively with ACE inhibitors compared to those who were not (20 versus 34 percent, odds ratio 0.62) [6]. In addition, patients who had previously been taking ACE inhibitors and were withdrawn from therapy had a significant increase in risk (46 percent, odds ratio 1.69). The utility of these agents in preventing AF after cardiac surgery remains controversial, however, as other studies have not found a significant benefit [111-113]. A retrospective analysis of 8889 patients undergoing CABG described an increase in major adverse events, including postoperative renal dysfunction as well as AF, in patients receiving preoperative ACE inhibitors [114]. Given the inconsistency in the results among these studies, we do not recommend preoperative ACE inhibitors specifically for prevention of AF in patients undergoing CABG. Statins Some, but not all, studies have shown that statins lower the rate of postoperative AF [115,116]. A 2015 meta-analysis of 17 randomized trials that compared statin therapy with either placebo or no therapy prior to cardiac surgery (predominantly coronary artery bypass graft surgery) found that such treatment reduced the incidence of postoperative AF (odds ratio 0.54, 95% CI 0.43-0.67), but failed to influence short-term mortality or postoperative stroke [117,118]. However, the meta-analysis pointed out significant limitations of the evidence. The largest randomized trial of preoperative statin therapy was published after the meta- analysis. In the STICS trial, 1922 patients in sinus rhythm scheduled for elective cardiac surgery (87 percent CABG) were randomly assigned to receive perioperative rosuvastatin https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 12/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate (20 mg daily) or placebo up to eight days before surgery [116]. Any previously prescribed statin was stopped. The rate of the primary outcome of postoperative AF within five days of surgery was similar in both groups (21.1 and 20.5 percent, respectively; odds ratio 1.04, 95% CI 0.84-1.30). Of note, there was no difference in the rate of myocardial injury within 120 hours after surgery. In addition, rosuvastatin was associated with a significant absolute excess in the rate of postoperative acute kidney injury (24.7 versus 19.3 percent; p = 0.005). Based upon established benefits of statin therapy in patients with coronary heart disease, all patients should be on long-term statin. However, for patients who have not started statin therapy prior to CABG, we suggest waiting until after surgery, as there is no clear evidence of benefit from preoperative initiation and possible harm. (See "Coronary artery bypass surgery: Perioperative medical management", section on 'Statins'.) N-acetylcysteine N-acetylcysteine (NAC) has the potential to protect against the development of perioperative AF due to its antioxidant and anti-inflammatory properties. (See 'Pathogenesis' above.) This hypothesis was tested in a trial of 115 patients undergoing either CABG or valve surgery who were randomly assigned to either NAC or placebo given one hour before and continued for 48 hours after surgery [119]. The primary end point of an AF episode lasting longer than five minutes during hospitalization was seen in 15 patients and was significantly less common in those who received NAC (5.2 versus 21.2 percent). In a small study designed to evaluate the potential benefit of anti-inflammatory therapy (with NAC or carvedilol), 311 patients undergoing cardiac surgery who had no history of AF were randomly assigned to metoprolol, carvedilol, or carvedilol plus NAC [120]. The incidence of postoperative AF was significantly lower in the carvedilol plus NAC group compared to either of the other two interventions (35.9, 24.0, and 8.7 percent, respectively). Colchicine Colchicine reduces the incidence of the postpericardiotomy syndrome. (See "Post-cardiac injury syndromes", section on 'Prevention'.) The issue of whether colchicine can reduce the incidence of postoperative AF was addressed in a post hoc substudy. In COPPS, 360 patients undergoing cardiac surgery were randomly assigned to either colchicine 1.0 mg given twice daily on day one followed by 0.5 mg twice daily for one month (the dose was halved in patients <70 kg) or placebo [121]. The first dose was given on postoperative day three. The COPPS Prevention of Atrial Fibrillation (POAF) substudy evaluated outcomes in the 336 patients in sinus rhythm on day three. Colchicine significantly reduced the incidence of postoperative AF (12 versus 22 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 13/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate percent; relative risk reduction 45.5 percent, 95% CI 34.0-94.0 percent) at 30 days. In addition, patients taking colchicine had a significantly shorter in-hospital stay (9.4 versus 10.3 days). There was a trend toward a higher rate of side effects (9.5 versus 4.8 percent) and drug withdrawal (11.8 versus 6.6 percent) with colchicine, but no severe side effects were recorded. In the COPPS-2 trial, 360 patients scheduled for cardiac surgery were randomly assigned to oral colchicine or placebo before surgery [122]. The drug was continued for one month after surgery. At three months, there was no significant difference between the two groups in the secondary end point of postoperative AF (34 versus 41 percent, respectively). (See "Post-cardiac injury syndromes", section on 'Prevention'.) We believe there is insufficient evidence to recommend the routine use of colchicine, in part out of a concern that it may negatively impact wound healing and that it leads to gastrointestinal side effects. The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline states that colchicine may be considered [123,124]. This was not changed in the 2019 focused update [125]. Naproxen The potential benefit from naproxen was evaluated in the NAFARM trial, which randomly assigned 161 patients to either naproxen or placebo [126]. There was no significant difference in the rate of postoperative AF (7 versus 15 percent, respectively). The study was stopped early because of an increase in renal failure in the naproxen group. Glucocorticoid Based upon the hypothesis that perioperative inflammation may contribute to the development of AF, glucocorticoids have been suggested as prophylactic therapy. (See "Glucocorticoid effects on the immune system".) Two meta-analyses of small trials in which glucocorticoid treatment was compared to placebo or no treatment in adult cardiac surgery found 26 and 40 percent reductions in the incidence of AF, irrespective of the dose given [127,128]. However, the large, randomized SIRS trial, published after the meta-analyses, found no difference in the rate of new AF [129]. Due to their potential adverse effects on glucose metabolism, wound healing, infection, and the absence of a lowering of the risk of death, we do not recommend the routine use of glucocorticoid therapy to prevent AF. The potential role for glucocorticoid therapy for other outcomes is discussed separately. (See "Coronary artery bypass surgery: Perioperative medical management", section on 'Glucocorticoid therapy'.) https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 14/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Prevention of complications of atrial fibrillation While beta blockers, sotalol, amiodarone, and pacing decrease the risk of postoperative AF, the evidence is less robust that the risk of complications such as stroke, death, or length of stay can be prevented. It may be difficult to demonstrate a lowering of the risk of in-hospital stroke with these therapies, as AF is only one risk factor for stroke and as the incidence of stroke is low. (See 'Adverse outcomes following atrial fibrillation' above.) The best available evidence of the impact of these interventions on the complications of AF comes from a 2006 meta-analysis of heterogenous trials, which noted the following [72]: In 29 trials that evaluated length of stay, only amiodarone and pacing shortened the average length of stay (-0.60 days, 95% CI -0.92 to -0.29 and -1.3 days 95% CI -2.55 to -0.08, respectively). In 25 trials that reported on the incidence of postoperative stroke, the risk of stroke was decreased from 1.9 to 1.1 percent with treatment (odds ratio 0.63, 95% CI 0.41-0.98). Amiodarone was the only single intervention that significantly lowered the risk of stroke compared to placebo. Our approach to prevention We recommend preventative therapy to reduce the incidence of postoperative AF, especially in patients at high risk of its development. While the evidence is not robust, prevention of AF may lead to a lowering of the risk of in-hospital stroke and a shortened length of stay. In addition, successful prevention of AF will prevent the need for anticoagulation in some patients. Beta blockers, sotalol, amiodarone, and atrial pacing are significantly more effective than placebo in lowering the rate of postoperative AF [64,71,72]. There is some evidence to support the use of antioxidant vitamins for this purpose. We prefer beta blockers to amiodarone or sotalol due to lower cost and lower risk of potential side effects and to pacing because of its relative complexity and cost. Amiodarone or sotalol is a reasonable alternative in patients who cannot tolerate beta blockade. If possible, we prefer to start beta blockers prior to CABG. We suggest metoprolol 25 mg twice daily; the dose can be
statin was stopped. The rate of the primary outcome of postoperative AF within five days of surgery was similar in both groups (21.1 and 20.5 percent, respectively; odds ratio 1.04, 95% CI 0.84-1.30). Of note, there was no difference in the rate of myocardial injury within 120 hours after surgery. In addition, rosuvastatin was associated with a significant absolute excess in the rate of postoperative acute kidney injury (24.7 versus 19.3 percent; p = 0.005). Based upon established benefits of statin therapy in patients with coronary heart disease, all patients should be on long-term statin. However, for patients who have not started statin therapy prior to CABG, we suggest waiting until after surgery, as there is no clear evidence of benefit from preoperative initiation and possible harm. (See "Coronary artery bypass surgery: Perioperative medical management", section on 'Statins'.) N-acetylcysteine N-acetylcysteine (NAC) has the potential to protect against the development of perioperative AF due to its antioxidant and anti-inflammatory properties. (See 'Pathogenesis' above.) This hypothesis was tested in a trial of 115 patients undergoing either CABG or valve surgery who were randomly assigned to either NAC or placebo given one hour before and continued for 48 hours after surgery [119]. The primary end point of an AF episode lasting longer than five minutes during hospitalization was seen in 15 patients and was significantly less common in those who received NAC (5.2 versus 21.2 percent). In a small study designed to evaluate the potential benefit of anti-inflammatory therapy (with NAC or carvedilol), 311 patients undergoing cardiac surgery who had no history of AF were randomly assigned to metoprolol, carvedilol, or carvedilol plus NAC [120]. The incidence of postoperative AF was significantly lower in the carvedilol plus NAC group compared to either of the other two interventions (35.9, 24.0, and 8.7 percent, respectively). Colchicine Colchicine reduces the incidence of the postpericardiotomy syndrome. (See "Post-cardiac injury syndromes", section on 'Prevention'.) The issue of whether colchicine can reduce the incidence of postoperative AF was addressed in a post hoc substudy. In COPPS, 360 patients undergoing cardiac surgery were randomly assigned to either colchicine 1.0 mg given twice daily on day one followed by 0.5 mg twice daily for one month (the dose was halved in patients <70 kg) or placebo [121]. The first dose was given on postoperative day three. The COPPS Prevention of Atrial Fibrillation (POAF) substudy evaluated outcomes in the 336 patients in sinus rhythm on day three. Colchicine significantly reduced the incidence of postoperative AF (12 versus 22 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 13/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate percent; relative risk reduction 45.5 percent, 95% CI 34.0-94.0 percent) at 30 days. In addition, patients taking colchicine had a significantly shorter in-hospital stay (9.4 versus 10.3 days). There was a trend toward a higher rate of side effects (9.5 versus 4.8 percent) and drug withdrawal (11.8 versus 6.6 percent) with colchicine, but no severe side effects were recorded. In the COPPS-2 trial, 360 patients scheduled for cardiac surgery were randomly assigned to oral colchicine or placebo before surgery [122]. The drug was continued for one month after surgery. At three months, there was no significant difference between the two groups in the secondary end point of postoperative AF (34 versus 41 percent, respectively). (See "Post-cardiac injury syndromes", section on 'Prevention'.) We believe there is insufficient evidence to recommend the routine use of colchicine, in part out of a concern that it may negatively impact wound healing and that it leads to gastrointestinal side effects. The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline states that colchicine may be considered [123,124]. This was not changed in the 2019 focused update [125]. Naproxen The potential benefit from naproxen was evaluated in the NAFARM trial, which randomly assigned 161 patients to either naproxen or placebo [126]. There was no significant difference in the rate of postoperative AF (7 versus 15 percent, respectively). The study was stopped early because of an increase in renal failure in the naproxen group. Glucocorticoid Based upon the hypothesis that perioperative inflammation may contribute to the development of AF, glucocorticoids have been suggested as prophylactic therapy. (See "Glucocorticoid effects on the immune system".) Two meta-analyses of small trials in which glucocorticoid treatment was compared to placebo or no treatment in adult cardiac surgery found 26 and 40 percent reductions in the incidence of AF, irrespective of the dose given [127,128]. However, the large, randomized SIRS trial, published after the meta-analyses, found no difference in the rate of new AF [129]. Due to their potential adverse effects on glucose metabolism, wound healing, infection, and the absence of a lowering of the risk of death, we do not recommend the routine use of glucocorticoid therapy to prevent AF. The potential role for glucocorticoid therapy for other outcomes is discussed separately. (See "Coronary artery bypass surgery: Perioperative medical management", section on 'Glucocorticoid therapy'.) https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 14/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Prevention of complications of atrial fibrillation While beta blockers, sotalol, amiodarone, and pacing decrease the risk of postoperative AF, the evidence is less robust that the risk of complications such as stroke, death, or length of stay can be prevented. It may be difficult to demonstrate a lowering of the risk of in-hospital stroke with these therapies, as AF is only one risk factor for stroke and as the incidence of stroke is low. (See 'Adverse outcomes following atrial fibrillation' above.) The best available evidence of the impact of these interventions on the complications of AF comes from a 2006 meta-analysis of heterogenous trials, which noted the following [72]: In 29 trials that evaluated length of stay, only amiodarone and pacing shortened the average length of stay (-0.60 days, 95% CI -0.92 to -0.29 and -1.3 days 95% CI -2.55 to -0.08, respectively). In 25 trials that reported on the incidence of postoperative stroke, the risk of stroke was decreased from 1.9 to 1.1 percent with treatment (odds ratio 0.63, 95% CI 0.41-0.98). Amiodarone was the only single intervention that significantly lowered the risk of stroke compared to placebo. Our approach to prevention We recommend preventative therapy to reduce the incidence of postoperative AF, especially in patients at high risk of its development. While the evidence is not robust, prevention of AF may lead to a lowering of the risk of in-hospital stroke and a shortened length of stay. In addition, successful prevention of AF will prevent the need for anticoagulation in some patients. Beta blockers, sotalol, amiodarone, and atrial pacing are significantly more effective than placebo in lowering the rate of postoperative AF [64,71,72]. There is some evidence to support the use of antioxidant vitamins for this purpose. We prefer beta blockers to amiodarone or sotalol due to lower cost and lower risk of potential side effects and to pacing because of its relative complexity and cost. Amiodarone or sotalol is a reasonable alternative in patients who cannot tolerate beta blockade. If possible, we prefer to start beta blockers prior to CABG. We suggest metoprolol 25 mg twice daily; the dose can be titrated postoperative based on the heart rate and blood pressure. We continue this therapy until the first postoperative visit, unless there is a contraindication. The evidence to support the use of antioxidant vitamins is less robust than that for traditional antiarrhythmic drugs. While awaiting larger randomized trials, we believe it is reasonable to use antioxidant therapy as given in the small randomized trial [87]. MANAGEMENT https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 15/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate While prevention with beta blockers, amiodarone, sotalol, or pacing lowers the risk of postoperative atrial fibrillation (AF), many patients still develop AF (see 'Prevention of atrial fibrillation' above). We are uncertain as to the optimal management of these patients, in part because it is not known whether postoperative AF represents the same arrhythmia as AF occurring without cardiac surgery or if it possesses a similar natural history in terms of portending adverse events. We think the initial management should include correction of predisposing factors such as hypoxemia, electrolyte abnormalities, and hemodynamic instability as well as pain management and withdrawal of stimulating factors such as inotropic agents. Subsequent management relates to the issues of rate control versus rhythm control cardioversion and anticoagulation [130]. Options for management of AF include rate or rhythm control strategies. For patients with atrial flutter, we cardiovert to sinus rhythm prior to discharge in most cases, as this rhythm is more difficult than AF to control medically. Rate control Given the transient nature of the arrhythmia (see 'Incidence and time course' above), initial control of the ventricular response rate is an effective and relatively safe strategy in many patients who develop postoperative AF [44,131]. Rate control is most commonly achieved with beta blockers. The benefit is partly due to blockade of the augmented postoperative sympathetic state and to prevention of beta blocker withdrawal in patients on beta blockers preoperatively. Intravenous esmolol, a beta blocker with a short half-life, can be given for acute rate control if there is a concern for bradyarrhythmias, hypotension, or bronchospasm. Slowing of the ventricular rate in many AF patients receiving inotropic agents postoperatively can be achieved by lowering the dose or discontinuation of these agents. The optimal rate goal for patients with AF after cardiac surgery has not been determined. As these patients vary widely in many clinical features (co-morbidities, need for rapid ventricular rate, etc), we suggest that the optimal ventricular rate be determined on a case by case basis. In many patients, a ventricular rate of less than 110 beats per minute will prevent symptoms such as palpitations and allow for optimal cardiac performance. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.). Calcium channel blockers and digoxin are other atrioventricular (AV) nodal blockers that can control the ventricular rate in AF, but they are not more effective than beta blockers. In patients in whom alternate agents have not been successful in controlling the rate in atrial fibrillation, intravenous amiodarone can be used to slow the ventricular response. (See "Control of https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 16/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Rhythm control Restoration of sinus rhythm from well-tolerated postoperative AF is usually not necessary but occasionally can be beneficial. (See 'Incidence and time course' above.) Restoration of sinus rhythm is indicated in symptomatic patients or in those when rate control is difficult to achieve. An attempt at the restoration of sinus rhythm can be beneficial in patients with a low ejection fraction. In addition, cardioversion in asymptomatic patients may be reasonable when well-tolerated AF occurs near the time of anticipated hospital discharge or when it does not spontaneously terminate within 24 hours, so that oral anticoagulation can be avoided; this is particularly true in patients at high risk of bleeding. We believe that an attempt at cardioversion with either electrical or pharmacologic therapy is reasonable. The choice between the two should be made on local practice and patient conditions. Electrical therapy of AF involves direct current external transthoracic cardioversion and it is effective in approximately 95 percent of cases [132] (see "Cardioversion for specific arrhythmias"). For patients who are refractory to transthoracic cardioversion or when reversion is desirable but the patient's respiratory status makes anesthesia for electrical conversion potentially difficult, pharmacologic therapy with intravenous sotalol or amiodarone is reasonable. (See 'Sotalol' above and 'Amiodarone' above.) Amiodarone dosing regimens are available in the relevant drug monograph. The efficacy of antiarrhythmic drugs for reversion of postoperative AF is similar to that in AF not related to surgery [133-141]. (See "Atrial fibrillation: Cardioversion".) Rate versus rhythm control For patients who do not spontaneously revert to sinus rhythm within a few hours, rate control and rhythm control (with or without electrical cardioversion) appear to be comparable strategies [45,46,142]. The choice between the two strategies should take into account patient and physician preferences. Advantages of a rate control strategy include the absence of side effects from drug therapy; disadvantages include a slower resolution of AF, thereby leading to a potentially greater need for anticoagulation at discharge. In many patients, we chose a rhythm control strategy. In a study of patients with no history of AF undergoing cardiac surgery, 523 individuals were randomly assigned to either rate or rhythm control [142]. In the rate control group, the heart rate goal was less than 100 beats per minute and in the rhythm control group, amiodarone was given with or without a rate slowing drug. If AF persisted for 24 to 48 hours, electrical cardioversion was recommended. The primary end point was the total number of days of https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 17/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate hospitalization within 60 days after randomization. There was no difference between the two groups in the primary outcome (median, 5.1 and 5 days, respectively; p = 0.76). This study had limitations, such as including heterogenous patients and lacking the power to assess effect on death or serious adverse events. Anticoagulation Patients on long-term anticoagulant For AF patients who are taking warfarin or direct oral anticoagulants, we suggest stopping this therapy at least three days before surgery. We restart oral anticoagulant therapy three to five days after surgery. The role of bridging heparin therapy for patients at high risk of an embolic complication while off oral anticoagulant, such as those with AF and a prior embolic event, is discussed elsewhere. (See "Perioperative management of patients receiving anticoagulants".) Patients not taking anticoagulant prior to cardiac surgery Patients with AF or atrial flutter, regardless of the setting, are at risk for thromboembolic events; the magnitude of that risk varies based upon a number of factors. Thromboembolic risk is primarily limited to AF or atrial flutter of more than 48 hours duration and is greater in patients with certain high risk features (eg, rheumatic mitral valve disease, previous thromboembolism, hypertension, or heart failure) ( table 2) [130]. The general recommendations for anticoagulation in patients with AF are discussed in detail elsewhere. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation" and "Embolic risk and the role of anticoagulation in atrial flutter".) Patients who develop AF after cardiac surgery are at risk of thromboembolic events, including in- hospital stroke. However, in the individual post-surgical patient with an embolic event, the cause may be unclear, as underlying comorbidities are often responsible for such strokes, rather than the arrhythmia itself [56,64,143]. (See 'Incidence and time course' above.) Based on evidence that oral anticoagulant therapy prevents episodes of systemic embolization in the broad population of patients with atrial fibrillation, we believe that such therapy will lead to fewer embolic events in patients with postoperative AF. However, a reduction of events with anticoagulant therapy in this population has never been well studied. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) As factors other than AF contribute to in-hospital stroke rates, it is not clear that aggressive early anticoagulation (eg, intravenous heparin as a bridge to warfarin) will reduce the incidence of stroke. In addition, the bleeding risk associated with anticoagulation in the immediate postoperative period (within the first 48 hours in most patients) makes the overall impact of this approach less certain. The potential complications associated with anticoagulation were https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 18/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate illustrated in several observational series of patients who were treated with intravenous heparin or oral anticoagulants for a variety of indications [144-146]. When closely monitored, complication rates appear to be low [144,145]. However, one report found a significant increase in large pericardial effusions and tamponade in patients treated with warfarin, particularly when the International normalized ratio (INR) was above the therapeutic target [146]. These large effusions all occurred one week or more after surgery. Thus, when anticoagulation is initiated, the patient must be monitored carefully. (See "Perioperative management of patients receiving anticoagulants".) Similarly, the optimal duration of anticoagulation after hospital discharge is unknown. Among patients with new-onset AF after cardiac surgery, many will revert to and maintain sinus rhythm [1,45-47]. Due to the inability to reverse their therapeutic effect, we do not start newer oral anticoagulants in the early postoperative period. There are limited data at present, but this is an evolving strategy that may gain support as our understanding evolves [147]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Left atrial appendage closure Evidence is emerging that the left atrial appendage may play a major role in the development of stroke, and surgical closure may reduce this risk. Patients who have AF who are undergoing cardiac surgery for other indications may benefit from closure. Specific recommendations are provided separately. (See "Atrial fibrillation: Left atrial appendage occlusion".) Our approach to postoperative anticoagulation Among patients who develop AF following cardiac surgery, we suggest the following approach to anticoagulation: For patients with multiple episodes of AF or one episode that lasts more than 24 to 48 hours, we recommend the initiation of oral anticoagulant therapy, but only if bleeding risks are considered acceptable. As the role of direct thrombin and factor Xa inhibitors has not been established for patients with postoperative AF, we suggest that warfarin be chosen for most patients (International normalized ratio 2 to 3). We suggest continuation of anticoagulation for at least four weeks after return to sinus rhythm, particularly if the patient has risk factors for thromboembolism. Longer duration of anticoagulation is recommended by some of our experts in patients with high CHA DS - 2 2 VASc scores ( table 3), at low risk for bleeding based on the HAS-BLED score ( table 4), or at high risk of AF recurrence. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 19/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Long-term anticoagulation should be considered for patients who remain in AF or who have paroxysmal AF at four weeks. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) We suggest maintaining oral anticoagulation in patients in which a concomitant Cox-Maze procedure has been performed for at least three months, regardless of no postoperative atrial arrhythmias. (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure'.) After three months with no AF recurrence, anticoagulation may be interrupted, considering the patient risk profile for stroke by the CHA DS -VASc score ( table 3) [148]. 2 2 In most cases, we do not use intravenous heparin as a bridge to full oral anticoagulation, as the risk of postoperative bleeding outweighs the small benefit from stroke prevention. For patients with prior systemic or pulmonary embolization or those with a mechanical valve, bridging anticoagulation with heparin may be reasonable. Both intravenous and oral anticoagulation should be monitored closely, as bleeding complications, including pericardial effusion and tamponade increase with excessive anticoagulation. RECOMMENDATIONS OF OTHERS Guidelines from the American College of Cardiology Foundation/American Heart Association and the European Society of Cardiology [130,148,149]. Our recommendations are generally consistent with recommendations from these groups. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Coronary artery bypass graft surgery".) SUMMARY AND RECOMMENDATIONS Presentation Atrial fibrillation (AF) and atrial flutter occur frequently after cardiac surgery. Most episodes occur by the third postoperative day. (See 'Incidence and time course' above.) https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 20/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Adverse outcomes Potential adverse outcomes of these atrial arrhythmias include a longer length of stay, stroke, or death. (See 'Adverse outcomes following atrial fibrillation' above.) Preventive strategies Beta blockers, sotalol, amiodarone, atrial pacing, reducing the risk of pericardial effusion, and antioxidant vitamins lower the risk of the development of AF and atrial flutter after cardiac surgery and may reduce the length of stay and lower the risk of in-hospital stroke. (See 'Prevention of atrial fibrillation and complications' above.) For patients undergoing cardiac surgery, we recommend treatment with beta blockers (Grade 1B). Beta blocker therapy should be started prior to surgery and continued at least until the first postoperative visit unless contraindicated. We prefer oral metoprolol 25 mg twice daily. For patients who cannot take beta blockers, either amiodarone or sotalol may be used, with the decision based on patient characteristics and physician familiarity. (See 'Our approach to prevention' above.) We suggest antioxidant therapy in addition to beta blocker therapy (Grade 2C). We start this therapy two days prior to surgery and continue until discharge. We prefer the regimen of vitamin C (1 gram) and vitamin E (400 international units), each given daily. (See 'Our approach to prevention' above.) Management of postoperative atrial fibrillation Ventricular rate control For hemodynamically stable patients who develop postoperative AF, the optimal ventricular rate range should be determined for each patient. In many patients, this rate will be less than 110 beats per minute. Cardioversion For patients who develop well-tolerated postoperative AF and whose rate is well controlled, we suggest not performing cardioversion within the first 24 hours of its development (Grade 2B). Cardioversion may be required within this time frame for those whose AF is poorly tolerated or whose rate is not well controlled. (See 'Rhythm control' above.) Cardioversion in asymptomatic patients may be reasonable when well-tolerated AF is present near the time of anticipated hospital discharge, or when it does not spontaneously terminate within 24 to 48 hours, so that oral anticoagulation can be avoided. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 21/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Anticoagulation For patients with multiple episodes of AF or one episode that lasts more than 24 to 48 hours, and if the perioperative bleeding risks are considered reasonable, we recommend oral anticoagulation (Grade 1B). (See 'Our approach to postoperative anticoagulation' above.) We suggest anticoagulation with warfarin (international normalized ratio 2 to 3) rather than either a direct thrombin or factor Xa inhibitor (Grade 2C). For patients in whom anticoagulation is started and irrespective of the rhythm status at the time of discharge from the hospital, we suggest continuation of anticoagulation for at least four weeks, rather than stopping at the time of discharge (Grade 2C). ACKNOWLEDGMENT The UpToDate editorial staff would like to thank Drs. John M. Stulak, Manuel Castell , and Arie P. Kappetein for their contributions to previous versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Maisel WH, Rawn JD, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001; 135:1061. 2. Cox JL. A perspective of postoperative atrial fibrillation in cardiac operations. Ann Thorac Surg 1993; 56:405. 3. Tsikouris JP, Kluger J, Song J, White CM. Changes in P-wave dispersion and P-wave duration after open heart surgery are associated with the peak incidence of atrial fibrillation. Heart Lung 2001; 30:466. 4. Dupont E, Ko Y, Rothery S, et al. 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Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005; 46:872. 35. Athanasiou T, Aziz O, Mangoush O, et al. Do off-pump techniques reduce the incidence of postoperative atrial fibrillation in elderly patients undergoing coronary artery bypass https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 24/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate grafting? Ann Thorac Surg 2004; 77:1567. 36. Angelini GD, Taylor FC, Reeves BC, Ascione R. Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomised controlled trials. Lancet 2002; 359:1194. 37. Almassi GH, Pecsi SA, Collins JF, et al. Predictors and impact of postoperative atrial fibrillation on patients' outcomes: a report from the Randomized On Versus Off Bypass trial. J Thorac Cardiovasc Surg 2012; 143:93. 38. Cummings JE, Gill I, Akhrass R, et al. Preservation of the anterior fat pad paradoxically decreases the incidence of postoperative atrial fibrillation in humans. J Am Coll Cardiol 2004; 43:994. 39. White CM, Sander S, Coleman CI, et al. Impact of epicardial anterior fat pad retention on postcardiothoracic surgery atrial fibrillation incidence: the AFIST-III Study. J Am Coll Cardiol 2007; 49:298. 40. Amar D, Shi W, Hogue CW Jr, et al. Clinical prediction rule for atrial fibrillation after coronary artery bypass grafting. J Am Coll Cardiol 2004; 44:1248. 41. Villareal RP, Hariharan R, Liu BC, et al. Postoperative atrial fibrillation and mortality after coronary artery bypass surgery. J Am Coll Cardiol 2004; 43:742. 42. Mariscalco G, Klersy C, Zanobini M, et al. 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30. Kim YM, Kattach H, Ratnatunga C, et al. Association of atrial nicotinamide adenine dinucleotide phosphate oxidase activity with the development of atrial fibrillation after cardiac surgery. J Am Coll Cardiol 2008; 51:68. 31. Verma A, Marrouche NF, Seshadri N, et al. Importance of ablating all potential right atrial flutter circuits in postcardiac surgery patients. J Am Coll Cardiol 2004; 44:409. 32. Akar JG, Kok LC, Haines DE, et al. Coexistence of type I atrial flutter and intra-atrial re- entrant tachycardia in patients with surgically corrected congenital heart disease. J Am Coll Cardiol 2001; 38:377. 33. Seiler J, Schmid DK, Irtel TA, et al. Dual-loop circuits in postoperative atrial macro re-entrant tachycardias. Heart 2007; 93:325. 34. Wijeysundera DN, Beattie WS, Djaiani G, et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005; 46:872. 35. Athanasiou T, Aziz O, Mangoush O, et al. Do off-pump techniques reduce the incidence of postoperative atrial fibrillation in elderly patients undergoing coronary artery bypass https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 24/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate grafting? Ann Thorac Surg 2004; 77:1567. 36. Angelini GD, Taylor FC, Reeves BC, Ascione R. Early and midterm outcome after off-pump and on-pump surgery in Beating Heart Against Cardioplegic Arrest Studies (BHACAS 1 and 2): a pooled analysis of two randomised controlled trials. Lancet 2002; 359:1194. 37. Almassi GH, Pecsi SA, Collins JF, et al. Predictors and impact of postoperative atrial fibrillation on patients' outcomes: a report from the Randomized On Versus Off Bypass trial. J Thorac Cardiovasc Surg 2012; 143:93. 38. Cummings JE, Gill I, Akhrass R, et al. Preservation of the anterior fat pad paradoxically decreases the incidence of postoperative atrial fibrillation in humans. J Am Coll Cardiol 2004; 43:994. 39. White CM, Sander S, Coleman CI, et al. Impact of epicardial anterior fat pad retention on postcardiothoracic surgery atrial fibrillation incidence: the AFIST-III Study. J Am Coll Cardiol 2007; 49:298. 40. Amar D, Shi W, Hogue CW Jr, et al. Clinical prediction rule for atrial fibrillation after coronary artery bypass grafting. J Am Coll Cardiol 2004; 44:1248. 41. Villareal RP, Hariharan R, Liu BC, et al. Postoperative atrial fibrillation and mortality after coronary artery bypass surgery. J Am Coll Cardiol 2004; 43:742. 42. Mariscalco G, Klersy C, Zanobini M, et al. Atrial fibrillation after isolated coronary surgery affects late survival. Circulation 2008; 118:1612. 43. Kosmidou I, Chen S, Kappetein AP, et al. New-Onset Atrial Fibrillation After PCI or CABG for Left Main Disease: The EXCEL Trial. 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Prophylactic procainamide for prevention of atrial fibrillation after coronary artery bypass grafting: a prospective, double-blind, randomized, placebo-controlled pilot study. Crit Care Med 1993; 21:1474. 99. Davison R, Hartz R, Kaplan K, et al. Prophylaxis of supraventricular tachyarrhythmia after coronary bypass surgery with oral verapamil: a randomized, double-blind trial. Ann Thorac https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 29/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Surg 1985; 39:336. 100. Smith EE, Shore DF, Monro JL, Ross JK. Oral verapamil fails to prevent supraventricular tachycardia following coronary artery surgery. Int J Cardiol 1985; 9:37. 101. Malhotra R, Mishra M, Kler TS, et al. Cardioprotective effects of diltiazem infusion in the perioperative period. Eur J Cardiothorac Surg 1997; 12:420. 102. Seitelberger R, Hannes W, Gleichauf M, et al. 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The efficacy of supplemental magnesium in reducing atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2004; 77:824. 108. Cook RC, Humphries KH, Gin K, et al. Prophylactic intravenous magnesium sulphate in addition to oral {beta}-blockade does not prevent atrial arrhythmias after coronary artery or valvular heart surgery: a randomized, controlled trial. Circulation 2009; 120:S163. 109. Gu WJ, Wu ZJ, Wang PF, et al. Intravenous magnesium prevents atrial fibrillation after coronary artery bypass grafting: a meta-analysis of 7 double-blind, placebo-controlled, randomized clinical trials. Trials 2012; 13:41. 110. Pretorius M, Murray KT, Yu C, et al. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. Crit Care Med 2012; 40:2805. 111. Shariff N, Zelenkofske S, Eid S, et al. Demographic determinants and effect of pre-operative angiotensin converting enzyme inhibitors and angiotensin receptor blockers on the occurrence of atrial fibrillation after CABG surgery. BMC Cardiovasc Disord 2010; 10:7. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 30/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate 112. Coleman CI, Makanji S, Kluger J, White CM. Effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on the frequency of post-cardiothoracic surgery atrial fibrillation. Ann Pharmacother 2007; 41:433. 113. White CM, Kluger J, Lertsburapa K, et al. Effect of preoperative angiotensin converting enzyme inhibitor or angiotensin receptor blocker use on the frequency of atrial fibrillation after cardiac surgery: a cohort study from the atrial fibrillation suppression trials II and III. Eur J Cardiothorac Surg 2007; 31:817. 114. Bandeali SJ, Kayani WT, Lee VV, et al. Outcomes of preoperative angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting. Am J Cardiol 2012; 110:919. 115. Patti G, Chello M, Candura D, et al. Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study. Circulation 2006; 114:1455. 116. Zheng Z, Jayaram R, Jiang L, et al. Perioperative Rosuvastatin in Cardiac Surgery. N Engl J Med 2016; 374:1744. 117. Liakopoulos OJ, Kuhn EW, Slottosch I, et al. Preoperative statin therapy for patients undergoing cardiac surgery. Cochrane Database Syst Rev 2012; :CD008493. 118. Kuhn EW, Slottosch I, Wahlers T, Liakopoulos OJ. Preoperative statin therapy for patients undergoing cardiac surgery. Cochrane Database Syst Rev 2015; :CD008493. 119. Ozaydin M, Peker O, Erdogan D, et al. N-acetylcysteine for the prevention of postoperative atrial fibrillation: a prospective, randomized, placebo-controlled pilot study. Eur Heart J 2008; 29:625. 120. Ozaydin M, Icli A, Yucel H, et al. Metoprolol vs. carvedilol or carvedilol plus N-acetyl cysteine on post-operative atrial fibrillation: a randomized, double-blind, placebo-controlled study. Eur Heart J 2013; 34:597. 121. Imazio M, Brucato A, Ferrazzi P, et al. Colchicine reduces postoperative atrial fibrillation: results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) atrial fibrillation substudy. Circulation 2011; 124:2290. 122. Imazio M, Brucato A, Ferrazzi P, et al. Colchicine for prevention of postpericardiotomy syndrome and postoperative atrial fibrillation: the COPPS-2 randomized clinical trial. JAMA 2014; 312:1016. 123. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 31/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 124. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 125. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 126. Horbach SJ, Lopes RD, da C Guaragna JC, et al. Naproxen as prophylaxis against atrial fibrillation after cardiac surgery: the NAFARM randomized trial. Am J Med 2011; 124:1036. 127. Ho KM, Tan JA. Benefits and risks of corticosteroid prophylaxis in adult cardiac surgery: a dose-response meta-analysis. Circulation 2009; 119:1853. 128. Dieleman JM, van Paassen J, van Dijk D, et al. Prophylactic corticosteroids for cardiopulmonary bypass in adults. Cochrane Database Syst Rev 2011; :CD005566. 129. Whitlock RP, Devereaux PJ, Teoh KH, et al. Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 386:1243. 130. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006; 48:e149. 131. Solomon AJ, Kouretas PC, Hopkins RA, et al. Early discharge of patients with new-onset atrial fibrillation after cardiovascular surgery. Am Heart J 1998; 135:557. 132. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 133. Geelen P, O'Hara GE, Roy N, et al. Comparison of propafenone versus procainamide for the acute treatment of atrial fibrillation after cardiac surgery. Am J Cardiol 1999; 84:345. 134. McAlister HF, Luke RA, Whitlock RM, Smith WM. Intravenous amiodarone bolus versus oral quinidine for atrial flutter and fibrillation after cardiac operations. J Thorac Cardiovasc Surg https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 32/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate 1990; 99:911. 135. Gavaghan TP, Koegh AM, Kelly RP, et al. Flecainide compared with a combination of digoxin and disopyramide for acute atrial arrhythmias after cardiopulmonary bypass. Br Heart J 1988; 60:497. 136. Di Biasi P, Scrofani R, Paje A, et al. Intravenous amiodarone vs propafenone for atrial fibrillation and flutter after cardiac operation. Eur J Cardiothorac Surg 1995; 9:587. 137. Campbell TJ, Gavaghan TP, Morgan JJ. Intravenous sotalol for the treatment of atrial fibrillation and flutter after cardiopulmonary bypass. Comparison with disopyramide and digoxin in a randomised trial. Br Heart J 1985; 54:86. 138. VanderLugt JT, Mattioni T, Denker S, et al. Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery. Circulation 1999; 100:369. 139. Yilmaz AT, Dem rkili U, Arslan M, et al. Long-term prevention of atrial fibrillation after coronary artery bypass surgery: comparison of quinidine, verapamil, and amiodarone in maintaining sinus rhythm. J Card Surg 1996; 11:61. 140. Connolly SJ, Mulji AS, Hoffert DL, et al. Randomized placebo-controlled trial of propafenone for treatment of atrial tachyarrhythmias after cardiac surgery. J Am Coll Cardiol 1987; 10:1145. 141. Hjelms E. Procainamide conversion of acute atrial fibrillation after open-heart surgery compared with digoxin treatment. Scand J Thorac Cardiovasc Surg 1992; 26:193. 142. Gillinov AM, Bagiella E, Moskowitz AJ, et al. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. N Engl J Med 2016; 374:1911. 143. Kollar A, Lick SD, Vasquez KN, Conti VR. Relationship of atrial fibrillation and stroke after coronary artery bypass graft surgery: when is anticoagulation indicated? Ann Thorac Surg 2006; 82:515. 144. Gohlke H, Gohlke-B rwolf C, St rzenhofecker P, et al. Improved graft patency with anticoagulant therapy after aortocoronary bypass surgery: a prospective, randomized study. Circulation 1981; 64:II22. 145. Weber MA, Hasford J, Taillens C, et al. Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion. Am J Cardiol 1990; 66:1464. 146. Malouf JF, Alam S, Gharzeddine W, Stefadouros MA. The role of anticoagulation in the development of pericardial effusion and late tamponade after cardiac surgery. Eur Heart J 1993; 14:1451. 147. Anderson E, Johnke K, Leedahl D, et al. Novel oral anticoagulants vs warfarin for the management of postoperative atrial fibrillation: clinical outcomes and cost analysis. Am J https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 33/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Surg 2015; 210:1095. 148. Dunning J, Nagendran M, Alfieri OR, et al. Guideline for the surgical treatment of atrial fibrillation. Eur J Cardiothorac Surg 2013; 44:777. 149. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011; 58:e123. Topic 1011 Version 56.0 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 34/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate GRAPHICS Signal averaged electrocardiogram predicts atrial fibrillation after coronary artery bypass graft (CABG) surgery The incidence of atrial fibrillation (AF) after coronary artery bypass graft surgery is directly related to the duration of the P wave on a signal averaged ECG. Data from Zaman AG, Archbold RA, Helft G, et al. Circulation 2000; 101:1403. Graphic 60431 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 35/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Multivariable risk index for postoperative atrial fibrillation Predictor Risk points* Age <30 6 30-39 12 40-49 18 50-59 24 60-69 30 70-79 36 80 42 Medical history AF 7 COPD 4 Concurrent valve surgery 6 Withdrawal of treatment Beta blockers 6 ACE inhibitors 5 Preoperative and postoperative treatment Beta blockers 7 ACE inhibitors 5 Postoperative beta blocker treatment 11 Other treatment Potassium supplementation 5 NSAIDs 7 Sum of risk points Risk rank Postoperative AF risk <14 Low < 17 percent 14-31 Medium 17 to 52 percent >31 High > 52 percent AF: atrial fibrillation; COPD: chronic obstructive pulmonary disease; ACE inhibitors: angiotensin converting enzyme inhibitors; NSAIDs: nonsteroidal antiinflammatory drugs. https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 36/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate To calculate the estimated risk of postoperative atrial fibrillation, the sum of the risk points is determined. Scores are stratified into low risk (<14 points; AF incidence <17 percent), medium risk (14 to 31 points; AF incidence 17 to 52 percent) and high risk (>31 points; AF incidence >52 percent). Data from: Mathew JP, et al. JAMA 2004; 291:1720. Graphic 53732 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 37/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate CHADS score, thromboembolic risk, and effect of warfarin anticoagulation 2 Clinical parameter Points Congestive heart failure (any history) 1 Hypertension (prior history) 1 Age 75 years 1 Diabetes mellitus 1 Secondary prevention in patients with a prior ischemic stroke or a transient 2 ischemic attack; most experts also include patients with a systemic embolic event Events per 100 person-years* CHADS score 2 NNT Warfarin No warfarin 0 0.25 0.49 417 1 0.72 1.52 125 2 1.27 2.50 81 3 2.20 5.27 33 4 2.35 6.02 27 5 or 6 4.60 6.88 44 NNT: number needed to treat to prevent 1 stroke per year with warfarin. The CHADS score estimates the risk of stroke, which is defined as focal neurologic signs or symptoms that persist for more than 24 hours and that cannot be explained by hemorrhage, trauma, 2 or other factors, or peripheral embolization, which is much less common. Transient ischemic attacks are not included. All differences between warfarin and no warfarin groups are statistically significant, except for a trend with a CHADS score of 0. Patients are considered to be at low risk with a score of 0, at intermediate risk with a score of 1 or 2, and at high risk with a score 3. One exception is that most experts would consider patients with a prior ischemic stroke, transient ischemic attack, or 2 systemic embolic event to be at high risk, even if they had no other risk factors and, therefore, a score of 2. However, the great majority of these patients have some other risk factor and a score of at least 3. Data from: Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial brillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685; and CHADS2 score from Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. Graphic 61615 Version 8.0 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 38/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and CHA DS -VASc Stroke risk stratification with the CHADS and CHA DS -VASc scores 2 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 39/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 40/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use 1 or 2 (1 point each) Maximum 9 points HAS-BLED score Bleeds per 100 patient-years (total points) 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 41/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 42/43 7/5/23, 9:03 AM Atrial fibrillation and flutter after cardiac surgery - UpToDate Contributor Disclosures Richard Lee, MD, MBA No relevant financial relationship(s) with ineligible companies to disclose. Gabriel S Aldea, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. John Pepper, MA, MChir, FRCS, FESC No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-and-flutter-after-cardiac-surgery/print 43/43
7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Atrioventricular node ablation : Bradley P Knight, MD, FACC : N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 09, 2023. INTRODUCTION In patients with atrial fibrillation (AF), the ventricular rate is determined in large part by the conduction properties of the atrioventricular (AV) node. In the typical patient with untreated AF, the ventricular rate can reach 150 beats per minute or higher. There are three important reasons to prevent a rapid ventricular response in patients with AF: Avoidance of hemodynamic instability. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Avoidance of bothersome symptoms. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'History and physical examination'.) Avoidance of a tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) A rapid ventricular response can be prevented either by restoring sinus rhythm (ie, rhythm control) or by using therapies that reduce the ventricular response (ie, rate control) to AF. When rate control is chosen, it can usually be accomplished with pharmacologic therapy. However, some AF patients will respond poorly to or be intolerant of rate control medications. Options for such patients include reconsideration of a rhythm control strategy or nonpharmacologic methods to control the ventricular rate. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation" and "Management of atrial fibrillation: Rhythm control versus rate control".) https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 1/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate The use of AV node ablation to achieve rate control in AF will be reviewed here. Pharmacologic therapies for rate control in AF are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) GENERAL PRINCIPLES Choosing the appropriate rate control therapy for a patient with AF is guided by an understanding of the determinants of the ventricular rate and an assessment of the adequacy of rate control. The discussions of rate control and the determinants of ventricular rate in patients with AF are found elsewhere. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) There are several strategies for assessing the adequacy of rate control efforts. With any strategy, rate control should be assessed both at rest and with exertion. Rate control goals are discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) INDICATIONS AV node ablation is an option for rate control in AF patients who have failed medical therapy for rhythm control, have failed or are not candidates for catheter ablation for rhythm control, and have failed aggressive attempts at pharmacological rate control. Many of these patients are labeled as having permanent AF, which is the term used to identify individuals with persistent AF where a joint decision by the patient and clinician has been made to no longer pursue a rhythm control strategy. Patients who are candidates for AV node ablation should be highly symptomatic, hemodynamically intolerant of AF, or have cardiomyopathy that is thought to be at least some part tachycardia induced. In general, the procedure is most commonly performed in elderly patients, many of whom have a preexisting pacemaker or implantable cardioverter-defibrillator (ICD) ( table 1). Other patients include those who are not candidates for rhythm control with catheter ablation or drug therapy, those with refractory AF with tachycardia-induced cardiomyopathy, or those with a preexisting pacemaker. Careful thought needs to be given to other treatment options, including curative attempts with catheter ablation before proceeding to AV node ablation in patients in whom medical therapy has failed to control the ventricular rate. The specific clinical scenario will dictate the appropriateness of AV node ablation vis-a-vis other treatment options. In younger patients, all https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 2/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate treatment options should be considered/exhausted before proceeding to AV node ablation. AV node ablation may be more appropriate in older patients, particularly those with preexisting pacing devices, and in those in whom curative attempts at AF ablation are unlikely to be successful (eg, very longstanding/permanent AF, marked left atrial dilatation, etc). Prior to performing AV node ablation, the patient needs to be informed about the invasive nature of the procedure, the requirement for lifelong permanent pacemaker therapy, and the long-term risk of a pacing-induced cardiomyopathy when RV apical pacing is used. PROCEDURE AV node ablation usually produces complete AV block and often leaves the patient with a slow junctional or idioventricular escape rhythm. Consequently, patients require implantation of a permanent pacing device to adequately control the ventricular rate ( waveform 1A-B). If a preexisting pacemaker or ICD is not already in place, a permanent pacemaker or ICD is implanted prior to AV node ablation. This is usually carried out immediately prior to the AV node ablation, but in some cases the device may be implanted in advance of the ablation procedure. Traditional leaded devices are implanted in the subclavicular region; a leadless pacemaker may be implanted directly in the right ventricle. (See 'Device selection' below and "Permanent cardiac pacing: Overview of devices and indications", section on 'General considerations'.) If a functional pacemaker or ICD is in place and no system revision is planned, the femoral vein is generally used for access for ablation of the AV node. An ablation catheter is advanced to the AV junction where a bundle of His potential can be recorded. Radiofrequency ablation of the AV node/bundle of His is performed. Ablation lesions should be delivered at a site proximal in the AV conduction system where a large atrial electrogram is also recorded to increase the likelihood of a junctional escape rhythm after creation of AV bock to avoid pacemaker dependency. With a successful lesion, there is usually an accelerated junctional rhythm and then heart block. If initial ablation is ineffective, or if conduction recurs, a larger lesion can be created with either a larger tip or saline-irrigated catheter.(See "Overview of catheter ablation of cardiac arrhythmias".) On rare occasions, AV node ablation cannot be accomplished via the right heart. In these cases, establishing femoral arterial access allows passage of an ablation catheter retrograde across the AV node. A bundle of His potential can be recorded just below the aortic valve, in the septal aspect of the left ventricular (LV) outflow tract. Alternatively, ablation by way of the left heart can be accomplished using a patent foramen ovale or transseptal puncture. If left heart access is necessary, systemic anticoagulation with intravenous heparin is generally administered while the left heart is instrumented. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 3/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate If a leadless pacemaker is placed, the same femoral venous sheath can then be used to advance the ablation catheter (see "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'). Care must be taken to make sure that newly placed leads or a leadless pacemaker are not dislodged by the ablation catheter. In rare cases, when right heart ablation of the AV node is ineffective and a new leaded pacing system has just been placed, it may be reasonable to defer the left heart AV node ablation for days/weeks to obviate the need for intravenous heparin with the attendant risks of bleeding. Device selection Following AV node ablation (see 'Procedure' above), most patients are pacemaker dependent. Therefore a device with pacemaker capability must be in place prior to the ablation procedure. The choice of which type of pacing device is implanted depends on the patient's clinical profile. Single-chamber ventricular pacemaker In patients with persistent AF, a single-chamber (right) ventricular pacemaker is often adequate. After AV node ablation, the patient's ventricular rate will not naturally respond to increased demand; therefore, a device with rate-adaptive capabilities is used (ie, VVIR pacing). All contemporary pacemakers have rate-adaptive capabilities. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Rate responsiveness'.) Leadless RV pacing (see "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems') has also been used in association with AV node ablation [1]. Dual-chamber pacemaker In patients with paroxysmal AF, dual-chamber pacemakers are preferred to single-chamber devices because they maintain AV synchrony during periods of sinus rhythm (eg, DDDR pacing). (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Physiologic pacing'.) In order to prevent rapid ventricular pacing during episodes of AF, patients with dual-chamber pacemakers following AV node ablation should have devices with automatic mode-switching capabilities. All contemporary pacemakers have this ability. (See "Modes of cardiac pacing: Nomenclature and selection", section on 'Mode switching'.) In patients with paroxysmal AF, two randomized trials demonstrated that dual-chamber pacemakers with mode-switching capabilities improve symptoms and quality of life compared with single- or dual-chamber pacemakers without mode-switching capabilities [2,3]. Many patients who undergo AV node ablation with pacemaker implantation for paroxysmal AF eventually progress to persistent AF [4]. Although dual-chamber pacing has not been shown to prevent this progression [5], we favor dual-chamber pacing in patients with paroxysmal AF https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 4/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate because of the clinical benefits of physiologic pacing. (See "The role of pacemakers in the prevention of atrial fibrillation".) A leadless RV pacemaker capable of sensing atrial mechanical systole and providing AV synchrony has been approved by the U S Food and Drug administration. At this point, leadless RV pacing is not able to pace the atrium, so it would not be an optimal choice in a patient with sinus node dysfunction and paroxysmal AF who is to undergo AV node ablation. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Leadless systems'.) Cardiac resynchronization therapy The majority of well-selected patients improve hemodynamically following AV junction ablation and standard right ventricle (RV) pacing. However, RV pacing causes the RV to contract before the LV (interventricular dyssynchrony), which may impair LV systolic function, reduce functional status, and increase mortality. In patients with significant dyssynchrony due to intrinsic conduction disease or pacing, cardiac resynchronization therapy (CRT) can improve ventricular synchrony. Use of CRT in patients with AF with or without AV node ablation is presented separately. (See "Cardiac resynchronization therapy in atrial fibrillation", section on 'Atrioventricular node ablation'.) There is a trend toward using CRT in many patients who undergo AV node ablation. If the implant and ablation are to be done concurrently, we use CRT with an atrial lead if the AF is paroxysmal and no atrial lead if persistent/permanent. In addition to providing CRT, two ventricular leads mitigate the unlikely but potentially disastrous effects of RV lead dislodgment and loss of RV capture. If transient pacing inhibition due to RV lead malfunction is noted, the sensing vector can sometimes be reprogrammed to an LV vector, which may mitigate the need for urgent lead revision. If, however, in the unlikely event that RV lead dislodgement or fracture results in continuous oversensing and inhibition of pacing, the additional LV pacing lead will not prevent asystole. If the patient has a preexisting non-CRT device and is undergoing AV node ablation, we will usually see how the patient responds to unopposed RV pacing, particularly if LV function is preserved. If LV function is significantly depressed and/or systolic heart failure has already been an issue, we may upgrade the patient to a CRT pacing or defibrillator system (as appropriate) at the time of AV node ablation. The main "downsides" to concurrent device upgrade are the associated procedural risks, most notably the risk of infection in a patient who will be pacemaker dependent. Adding a device upgrade procedure to an AV ablation increases procedure time considerably, so in patients who are very tenuous hemodynamically due to rapid ventricular rates and/or rate controlling, it may be reasonable to initially perform AV node ablation alone, and then upgrade the device if the patient does not improve. The relative efficacy of CRT with AV node ablation for rate control and pulmonary vein isolation for rhythm control in patients with HF is discussed separately. (See "The management of atrial https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 5/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate fibrillation in patients with heart failure", section on 'Atrioventricular node ablation with pacing' and "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.) Implantable cardioverter-defibrillators All of the aforementioned pacing modalities (eg, single chamber, dual chamber, and CRT) and functions (eg, rate adaptive pacing and mode switching) are available on contemporary ICDs. Thus, patients with an ICD who require an AV node ablation procedure can sometimes be managed without changing the device. As most of these patients have significant LV dysfunction and systolic heart failure (given the indications for prophylactic ICD implantation), consideration should be given to upgrading to a CRT-D system with an atrial lead, if appropriate, at the time of AV node ablation. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".) Physiological pacing CRT (or biventricular pacing) is a strategy to avoid the dyssynchrony associated with standard RV apical pacing in patients who become pacemaker dependent after AV node ablation (see 'Cardiac resynchronization therapy' above). A potential alternative to CRT is the positioning of a pacing lead near the His bundle ( image 1) or deep in the ventricular septum near the area of the left bundle branch. A pacing lead near the His bundle will activate the native conduction system, resulting in less dyssynchrony and a more normal QRS complex. It is technically difficult to place a conventional pacing lead in a position that results in capture of the His bundle at a reasonable pacing output because the His bundle is insulated from the endocardium. Newer, small caliber, screw-in pacing leads that are delivered using a guiding sheath rather than a stylet may improve the ability to accomplish permanent His bundle capture [6]. The value of this approach was evaluated in a prospective single-center trial of 52 patients with heart failure and refractory AF who underwent attempted AV node ablation and permanent His bundle pacing; backup RV or LV leads were placed as well [7]. During His bundle pacing, the average QRS duration was 105 msec, compared with 107 msec at baseline. The mean New York Heart Association functional class improved from baseline 2.9 in patients with heart failure with reduced ejection fraction to 1.4 with His bundle pacing, and from baseline 2.7 in patients with heart failure with preserved ejection fraction to 1.4. LV end-diastolic dimension, LV ejection fraction (LVEF), and mitral regurgitation all improved with His bundle pacing compared with baseline. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 6/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Successful His bundle pacing is technically difficult to accomplish. In addition, lead dislodgement may be more likely compared with conventional pacing sites. Pacing thresholds may also be higher with His bundle pacing, leading to shorter generator longevity. Lead dislodgement would have serious complications in this setting due to complete heart block after ablation of the AV node. Another alternative to CRT is left bundle branch area pacing. Pacing the left bundle branch has been shown to avoid some of the limitations of His-bundle pacing such as high pacing thresholds and atrial oversensing, and has been used in patients undergoing AV node ablation. This is accomplished by placing an active fixation, sheath-delivered, pacing lead deep into the RV septum to capture the left bundle branch, giving rise to a relatively narrow QRS complex to minimize pacing-induced ventricular dyssynchrony. An image shows the position of the tip of a left bundle branch pacing lead in the RV septum during administration of contrast through the delivery sheath at the time of implant. (See "Permanent cardiac pacing: Overview of devices and indications".) Further studies in larger populations are necessary to clarify both the clinical benefits and safety of these physiological pacing approaches in patients undergoing AV node ablation. In addition, given the risks of lead dislodgement, the safety and efficacy of His bundle pacing should be compared against biventricular pacing. At this point, a backup RV lead is generally placed when His bundle pacing is employed, particularly in pacemaker-dependent patients. Ventricular rate regularization Ventricular rate regularization (or ventricular rate stabilization) is a pacemaker mode that can attenuate the rate and irregularity of the ventricular response during AF [8]. The ventricle is paced at a variable rate at or near the mean native rate. This causes concealed retrograde conduction into the AV node, which makes it refractory to subsequent anterograde impulses from the atria. This tends to reduce the number of short RR intervals, which may improve symptoms by making the ventricular rate more regular during AF and sometimes slower. A potential advantage of this approach is that no catheter ablation of the AV junction is performed. However, this technique may be less effective at controlling AF during physical activity than at rest. EFFICACY AV node ablation is highly effective, as demonstrated by the following reports: AV node ablation was acutely successful in 97.4 percent of 646 patients, although 3.5 percent had recurrence of AV conduction during follow-up [9]. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 7/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate In a report from the prospective Ablate and Pace trial, the procedure was successful in all but 1 of 156 patients who underwent radiofrequency ablation of the AV node [10]. Persistent complete heart block was present in 96 percent; 33 percent of patients had no escape rhythm, while 35 percent had an escape rhythm with an escape rate <40 beats per minute. OUTCOMES Symptoms and quality of life are significantly improved in patients with poorly controlled AF who undergo AV node ablation and permanent pacemaker implantation [11-15]. In a series of 107 such patients, ablative treatment was associated with significant reductions in [11]: Physician visits (5 versus 10 prior to ablation) Hospital admissions (0.17 versus 2.8 prior to ablation) Episodes of heart failure (8 versus 18 prior to ablation) Antiarrhythmic drug trials Further support for the benefits of this approach come from a meta-analysis of 21 studies, involving 1181 patients [12]. This report noted significant improvement in all 19 outcome measures evaluated, including quality of life, ventricular function, exercise duration, and health care use [12]. While such benefits are often due to improved LV systolic function, improvement in some patients occurs independent of changes in LVEF and probably results from the slower and more regular heart rate [13,14]. To date, there is no convincing evidence of a mortality benefit with AV node ablation [12,15,16]: AV node ablation has also been compared with other nonpharmacologic therapies. In the 2008 PABA-CHF study, in which 81 patients were randomly assigned to AV node ablation with cardiac resynchronization therapy pacing or pulmonary vein isolation, the composite primary endpoint (Minnesota Living with Heart Failure score, 6MW distance, EF) favored the pulmonary vein isolation group [17]. COMPLICATIONS AV node ablation incurs risks similar to other catheter ablation procedures that require right heart access, though typically only a single venous sheath is required. If a pacemaker or ICD is implanted immediately prior to AV node ablation, the risks of device implantation are also https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 8/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate incurred. If simple RV pacing is used, there will be a risk of developing LV dysfunction and/or heart failure. (See "Cardiac implantable electronic devices: Periprocedural complications".) Specific to patients who undergo AV node ablation and pacing is a very rare but catastrophic risk of ventricular fibrillation (VF) and sudden cardiac death (SCD). In a review of 334 patients who underwent AV node ablation, nine (2.7 percent) experienced SCD [18]. Four events occurred within four days of the procedure, an additional three events occurred within three months, and two occurred late and were thought to be unrelated to the procedure. Possible causes of post-ablation VF include [18-20]: Underlying heart disease Activation of the sympathetic nervous system Prolongation in action potential duration Repolarization abnormalities induced by bradycardia Increased dispersion of ventricular refractoriness The potential for reducing the frequency of early VF with post-ablation pacing at a higher rate was evaluated in a report of 235 patients [21]. The incidence of VF was 6 percent in the first 100 patients in whom the post-ablation chronic pacing rate was 70 beats per minute. In the next 135 patients, however, a pacing rate of 90 beats per minute was used for the first three months after the ablation, and there were no episodes of VF. Pacing at a rate of 90 beats per minute decreases sympathetic activity, which may contribute to the reduction in VF or SCD [19]. Other procedural risks are those related to catheter ablation and pacemaker/ICD implant/upgrade procedures. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) NEED FOR ANTICOAGULATION While AV node ablation results in adequate heart rate control, it does not stop the atria from fibrillating. Thus, the risk of thromboembolic events is not affected [22]. As a result, there is a need for long-term anticoagulation similar to that in patients with chronic AF whose heart rate control is achieved pharmacologically. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) RECOMMENDATIONS OF OTHERS https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 9/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Our recommendations for patients with AF in whom a rate control strategy has been chosen are in general agreement with those made in major societal guidelines [23-25]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Background Atrioventricular (AV) node ablation is an option for rate control in atrial fibrillation (AF) patients who have failed medical therapy for rhythm control, have failed or are not candidates for catheter ablation for rhythm control, and have failed aggressive attempts at pharmacological rate control. Indications For AF patients with a rapid ventricular response who do not respond to or are intolerant of aggressive attempts at pharmacologic therapy to slow the ventricular rate, and in whom nonpharmacologic approaches, including curative attempts at AF ablation, are not successful or appropriate, we recommend AV node ablation in association with implantation of a permanent pacing device to improve symptoms and quality of life (Grade 1B). (See 'Indications' above.) Pacing procedure For AF patients who undergo AV node ablation, a pacing device is needed to prevent symptomatic bradycardia. A single-chamber ventricular pacemaker with rate-adaptive capability may be appropriate for patients with persistent AF, and a dual- chamber pacemaker with both mode switching and rate-adaptive capabilities may be appropriate for patients with paroxysmal AF. The roles of cardiac resynchronization therapy, physiological pacing, and implantable cardioverter-defibrillator depend on left ventricular function, heart failure symptoms, and history. (See 'Device selection' above.) No need for anticoagulation AV node ablation has no impact on thromboembolic risk and most individuals require long-term oral anticoagulation. (See 'Need for anticoagulation' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 10/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Yarlagadda B, Turagam MK, Dar T, et al. Safety and feasibility of leadless pacemaker in patients undergoing atrioventricular node ablation for atrial fibrillation. Heart Rhythm 2018; 15:994. 2. Marshall HJ, Harris ZI, Griffith MJ, et al. Prospective randomized study of ablation and pacing versus medical therapy for paroxysmal atrial fibrillation: effects of pacing mode and mode- switch algorithm. Circulation 1999; 99:1587. 3. Kamalvand K, Tan K, Kotsakis A, et al. Is mode switching beneficial? A randomized study in patients with paroxysmal atrial tachyarrhythmias. J Am Coll Cardiol 1997; 30:496. 4. Gribbin GM, Bourke JP, McComb JM. Predictors of atrial rhythm after atrioventricular node ablation for the treatment of paroxysmal atrial arrhythmias. Heart 1998; 79:548. 5. Gillis AM, Connolly SJ, Lacombe P, et al. Randomized crossover comparison of DDDR versus VDD pacing after atrioventricular junction ablation for prevention of atrial fibrillation. The atrial pacing peri-ablation for paroxysmal atrial fibrillation (PA (3)) study investigators. Circulation 2000; 102:736. 6. Dandamudi G, Vijayaraman P. How to perform permanent His bundle pacing in routine clinical practice. Heart Rhythm 2016; 13:1362. 7. Huang W, Su L, Wu S, et al. Benefits of Permanent His Bundle Pacing Combined With Atrioventricular Node Ablation in Atrial Fibrillation Patients With Heart Failure With Both Preserved and Reduced Left Ventricular Ejection Fraction. J Am Heart Assoc 2017; 6. 8. Wood MA. Trials of pacing to control ventricular rate during atrial fibrillation. J Interv Card Electrophysiol 2004; 10 Suppl 1:63. 9. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020. 10. Curtis AB, Kutalek SP, Prior M, Newhouse TT. Prevalence and characteristics of escape rhythms after radiofrequency ablation of the atrioventricular junction: results from the registry for AV junction ablation and pacing in atrial fibrillation. Ablate and Pace Trial Investigators. Am Heart J 2000; 139:122. https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 11/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate 11. Fitzpatrick AP, Kourouyan HD, Siu A, et al. Quality of life and outcomes after radiofrequency His-bundle catheter ablation and permanent pacemaker implantation: impact of treatment in paroxysmal and established atrial fibrillation. Am Heart J 1996; 131:499. 12. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical outcomes after ablation and pacing therapy for atrial fibrillation : a meta-analysis. Circulation 2000; 101:1138. 13. Brown CS, Mills RM Jr, Conti JB, Curtis AB. Clinical improvement after atrioventricular nodal ablation for atrial fibrillation does not correlate with improved ejection fraction. Am J Cardiol 1997; 80:1090. 14. Weerasooriya R, Davis M, Powell A, et al. The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT). J Am Coll Cardiol 2003; 41:1697. 15. Ozcan C, Jahangir A, Friedman PA, et al. Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation. N Engl J Med 2001; 344:1043. 16. Garcia B, Clementy N, Benhenda N, et al. Mortality After Atrioventricular Nodal Radiofrequency Catheter Ablation With Permanent Ventricular Pacing in Atrial Fibrillation: Outcomes From a Controlled Nonrandomized Study. Circ Arrhythm Electrophysiol 2016; 9. 17. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 18. Ozcan C, Jahangir A, Friedman PA, et al. Sudden death after radiofrequency ablation of the atrioventricular node in patients with atrial fibrillation. J Am Coll Cardiol 2002; 40:105. 19. Hamdan MH, Page RL, Sheehan CJ, et al. Increased sympathetic activity after atrioventricular junction ablation in patients with chronic atrial fibrillation. J Am Coll Cardiol 2000; 36:151. 20. Evans GT Jr, Scheinman MM, Bardy G, et al. Predictors of in-hospital mortality after DC catheter ablation of atrioventricular junction. Results of a prospective, international, multicenter study. Circulation 1991; 84:1924. 21. Geelen P, Brugada J, Andries E, Brugada P. Ventricular fibrillation and sudden death after radiofrequency catheter ablation of the atrioventricular junction. Pacing Clin Electrophysiol 1997; 20:343. 22. Gasparini M, Mantica M, Brignole M, et al. Thromboembolism after atrioventricular node ablation and pacing: long term follow up. Heart 1999; 82:494. 23. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 12/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 24. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 25. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1012 Version 28.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 13/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate GRAPHICS Clinical factors favoring atrioventricular node ablation in patients with refractory atrial fibrillation Favors atrial fibrillation ablation Favors atrioventricular node ablation/pacing Clinical characteristics Age Younger Older, particularly very elderly Atrial fibrillation pattern Paroxysmal Persistent, particularly very longstanding ("permanent") Left atrial size Normal/near normal Markedly dilated Comorbidities Minimal Extensive Overall health Robust Frail Miscellaneous High infection risk Previous failed atrial fibrillation ablation Courtesy of Leonard Ganz, MD. Graphic 129004 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 14/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study in a person with atrial fibrillation Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the atrioventricular unction region (HBE1-2, HBE3-4), and the right ventricular apex (RVA3-4) in a patient with atrial fibrillation. The patient has extremely symptomatic, medically refractory atrial fibrillation with rapid ventricular rates and recurrent heart failure. The mapping catheter (HBE) has been maneuvered from the area of maximal His bundle activity to a more proximal position, where a larger atrial (A) and smaller His electrogram (H) are recorded. ECG: electrocardiograph; V: ventricular electrogram. Graphic 74286 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 15/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Intracardiac and surface ECG recordings during electrophysiologic study and radiofrequency catheter ablation of the AV junction in atrial fibrillation Three surface ECG leads (I, aVF, V1) and intracardiac recordings from the region of the atrioventricular junction (HBE1-2, HBE3-4), and the right ventricular apex (RVA3- 4) in a patient with atrial fibrillation. Application of radiofrequency (RF) energy from the tip of the mapping catheter (HBE1-2) causes complete AV nodal block; pacing (P) is initiated from the right ventricular apex. A permanent VVIR pacemaker was implanted, and the patient has noted a marked improvement in symptoms. ECG: electrocardiograph; AV: atrioventricular. Graphic 67363 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 16/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Para Hisian pacing lead Patient #6. Right anterior oblique (RAO) and left anterior oblique (LAO) fluoroscopic projections showing leads position during the "ablate and pace" procedure and Hisian pacing; 1 = quadripolar Hisian mapping catheter; 2 = screw-in bipolar lead positioned in close proximity to the His-bundle; 3 = bipolar passive fixation positioned in right ventricular apex. Reproduced with permission from: Occhetta E, Bortnik M, Magnani A, et al. Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation in chronic atrial brillation: a crossover, blinded, randomized study versus apical right ventricular pacing. J Am Coll Cardiol 2006; 47:1938. Copyright 2006 American College of Cardiology Foundation. Graphic 56944 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 17/18 7/5/23, 9:04 AM Atrial fibrillation: Atrioventricular node ablation - UpToDate Contributor Disclosures Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-atrioventricular-node-ablation/print 18/18
7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Cardioversion : Gerald V Naccarelli, MD, Warren J Manning, MD : Bradley P Knight, MD, FACC, Brian Olshansky, MD, James Hoekstra, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 26, 2022. INTRODUCTION The restoration (cardioversion) to sinus rhythm (SR) from atrial fibrillation (AF) is performed primarily to improve symptoms, but it may also prevent tachycardia-induced cardiomyopathy, facilitate management of congestive heart failure, and reduce the risk of inappropriate shocks in those with implanted defibrillators. This topic will focus on our approach to cardioversion and the efficacy and safety of the two most widely used approaches: electrical (direct current) and pharmacologic cardioversion. Other related topics include: (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Restoration of sinus rhythm in atrial flutter".) INDICATIONS In this topic, we are generally referring to cardioversion in stable patients with recently diagnosed symptomatic AF that does not terminate spontaneously. Cardioversion is indicated to improve symptoms, hemodynamic status from AF and in some cases, need for chronic anticoagulation. Among patients with early AF and who are at high risk https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 1/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate for cardiovascular complications, cardioversion with accompanying rhythm control strategy of AF management can reduce cardiovascular death or stroke. Patients who may benefit from rhythm versus rate control are discussed separately. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Indications for initial rhythm control'.) Cardioversion is most commonly performed in patients who are expected to have long-term maintenance of sinus rhythm, who are expected to convert to normal sinus rhythm, and are at low risk for cardioversion. These may be patients with persistent AF (ie, lasting >7 days) or even paroxysmal AF, if AF is highly symptomatic and cannot be otherwise controlled. It is also preferred in other patient groups. Long-term rhythm control Patients who will be placed on long-term antiarrhythmic drugs or who will undergo catheter ablation will have SR restored as the initial part of that process. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrial fibrillation: Catheter ablation".) Long-standing persistent AF It may be reasonable to attempt to restore SR in patients with long-standing, persistent AF who are symptomatic (or occasionally in patients with presumed permanent AF). An example of the latter is a patient with long-duration AF who now has developed increasing heart failure or worsening cardiomyopathy felt to be related to poorly controlled ventricular rate. However, maintenance of sinus rhythm even for a short time period is not assured. (See "Arrhythmia-induced cardiomyopathy" and "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control' and "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Frequently, the only way to determine if subtle, nonspecific symptoms are attributable to AF is to restore SR to observe for symptom improvement. Symptom improvement may be delayed for several weeks due to markedly delayed recovery of atrial mechanical function. Cardioversion may be used in patients who have very infrequent, persistent episodes who do not respond to a pill-in-the-pocket approach. These individuals may cardioverted as needed from time to time. (See 'Pill-in-the-pocket' below.) Unstable patients In some hemodynamically unstable patients who manifest with signs or symptoms such as hypotension, altered mental status, or heart failure, if there is time to attempt ventricular rate slowing or to wait for possible spontaneous reversion to SR, https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 2/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate cardioversion may be deferred. Emergency cardioversion should be performed if the patient is hemodynamically compromised due to an uncontrolled rapid ventricular rate or the lack of atrial contraction is thought to impair their cardiac output. If angina is felt to be related to the hemodynamic compromise or lack of atrial contraction with AF, we perform emergency cardioversion; however, the risk for a thromboembolic event needs to be considered. This includes patients with severe acute heart failure, ongoing myocardial ischemia, or hypotension. However, if hypotension occurs with a slow or moderate ventricular response (<110 beats/min), other causes of hypotension should be sought, such as myocardial infarction, pulmonary embolism, sepsis, pericardial effusion/tamponade, or hypovolemia. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF'.) REASONS NOT TO PERFORM CARDIOVERSION Patients in whom it is reasonable to avoid early cardioversion include: Those who are asymptomatic or minimally symptomatic, particularly those with multiple comorbidities, advanced age, or poor overall prognosis, where the risks of undergoing cardioversion and/or pharmacologic rhythm control may outweigh the benefits of restoring SR. Not performing cardioversion may also be appropriate in those with a low likelihood of long-term maintenance of SR, such as those with marked left atrial enlargement/dilatation, significant mitral regurgitation, or those with florid hyperthyroidism. Those who cannot receive anticoagulation, if indicated, are generally not candidates for cardioversion unless the duration of AF is less than 48 hours. (See 'Anticoagulation' below and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration uncertain or 48 or more hours'.) Those with left atrial thrombus identified during a transesophageal echocardiogram or who have presented with a thrombotic event (eg, stroke or transient ischemia). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Transesophageal echocardiography-based approach'.) Some experts would not pursue cardioversion in a person who has previously failed the procedure (ie, had only a brief period of sustained sinus rhythm following a prior cardioversion). Other reasons to consider not cardioverting include: https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 3/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Those where AF has been continuously present for more than one year [1-6]. Those with a left atrium that is markedly enlarged (atrial dimension >6.0 cm, 2 transthoracic echocardiographic biplane atrial volume index >48 mL/m ) [6-11]. Those with AF recurrence while taking adequate doses of appropriate antiarrhythmic drug therapy and who have recently undergone cardioversion. Drug refractory patients may have successful conversion to SR but are less likely to maintain SR long term. Cather ablation for AF may be a solution to maintaining SR for some patients in this situation. Those who do not or no longer respond to more than one antiarrhythmic drug are less likely to maintain SR with other drugs. Those for whom cardioversion with long-term maintenance of SR is likely to be unsuccessful if the underlying precipitant (eg, thyrotoxicosis, pericarditis, pneumonia, or mitral valve disease) has not been corrected prior to cardioversion. PRECARDIOVERSION ISSUES Prior to cardioversion with either electrical energy or antiarrhythmic drug therapy in stable patients, decisions regarding rate control, timing, and anticoagulation need to be made. Ventricular rate control Patients with a rapid ventricular response (>100 beats per minute) usually need control of their ventricular rate to improve symptoms. This can be achieved by oral (and occasionally intravenous) administration of short-acting beta blockers or nondihydropyridine calcium channel antagonists, such as diltiazem or verapamil [1]. In the acute setting, the target resting ventricular rate should usually be 80 to 100 beats per minute. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Anticoagulation Most patients who will undergo cardioversion should be anticoagulated as soon as the decision is made to cardiovert or after assessment of their clinical thromboembolic risk based on their CHA DS -VASc score. Issues related to anticoagulation around the time of 2 2 cardioversion are discussed in detail separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours'.) Timing Occasionally, hemodynamically unstable patients may need to be cardioverted urgently, without time to institute optimal oral anticoagulation (see 'Anticoagulation' above). For https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 4/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate these patients who are not chronically anticoagulated but are candidates, intravenous heparin or low molecular weight heparin should be started as soon as possible, possibly with a loading dose of heparin prior to cardioversion due to further transient impairment of atrial appendage mechanical function after cardioversion. For stable patients, the timing of elective cardioversion is determined in large part by the anticoagulant strategy chosen. If possible, patients with valvular and nonvalvular AF duration longer than 48 hours or of unknown duration should be therapeutically anticoagulated for at least four weeks or receive short-term anticoagulation followed by screening transesophageal echocardiography to exclude an atrial thrombus prior to cardioversion [12]. Some of our authors use this approach if the duration is longer than 24 hours. Patients with a history of neurologic event, diabetes, and heart failure also appear to be at high risk for thromboembolism post- cardioversion, and four weeks of anticoagulation or short-term anticoagulation with transesophageal echocardiography should be considered [13]. Evaluation for underlying cause It is useful to consider the potential for an underlying or precipitating cause, such as hyperthyroidism, but also acute pulmonary embolism, myopericarditis, pneumonia, pericarditis, or sepsis, though atrial fibrillation is rarely the sole manifestation of any of these other than hyperthyroidism. (See 'Reasons not to perform cardioversion' above and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Triggers'.) ELECTRICAL VERSUS PHARMACOLOGIC CARDIOVERSION This section compares an electrical with a pharmacologic approach for cardioversion. However, patients who fail pharmacologic cardioversion are generally referred for electrical cardioversion. Thus, the comparison is really an electrical compared with a pharmacologic/electrical approach. For a first episode, electrical cardioversion is preferred in most cases. This is particularly true for younger patients (<65 years of age) even if they have no symptoms. For other patients (not the first episode) who need to be cardioverted from AF to SR, either electrical or pharmacologic cardioversion (potentially followed by electrical cardioversion) is a reasonable approach. The choice between the two should take into account the strengths and weaknesses of each approach as well as patient preference. For most patients, we proceed directly to electrical cardioversion to avoid the potential of drug side effect and prolonged monitoring. Reasons to prefer electrical rather than pharmacologic cardioversion include: https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 5/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Avoiding drug side effects, including but not limited to transient hypotension or prolongation of the QTc interval. Avoiding need for prolonged telemetric monitoring to screen for a proarrhythmic response. This can result in longer observation periods in the emergency department or procedural area. Some antiarrhythmic agents have the potential to convert AF to atrial flutter. Superior efficacy as compared with pharmacologic cardioversion. In contrast, potential benefits from a pharmacologic (rather than an electrical) approach include: Avoiding the risk(s) of sedation (required at the time of electrical cardioversion) (see "Cardioversion for specific arrhythmias", section on 'Preparation and personnel') Testing for drug tolerance, in the occasional patient (eg, someone with long-standing AF) in whom it has been decided to continue oral antiarrhythmic drug therapy (see 'Preprocedural antiarrhythmic drugs' below) Studies comparing the two approaches are somewhat limited. Mortality outcomes following electrical and pharmacologic cardioversion were similar in an observational cohort of 7175 patients from a large anticoagulation registry [14]. There were 2427 (34 percent) patients who received pharmacological cardioversion and 4748 (66 percent) who received electrical cardioversion. During one-year follow-up, event rates (per 100 patient years) for mortality in patients who received electrical and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively. In the RAFF2 trial, 396 patients with acute AF were randomly assigned to pharmacologic cardioversion with intravenous procainamide or placebo followed by electrical cardioversion, if necessary [15]. The primary outcome of conversion to normal SR for at least 30 minutes at any time after randomization and up to a point immediately after three shocks occurred with equal frequency in the two groups (96 versus 92 percent, respectively; p = 0.07). After procainamide infusion, 52 percent of patients converted (median time of 23 minutes), therefore not requiring subsequent electrical cardioversion. RAFF2 demonstrates that it is feasible for patients to be rapidly cardioverted with medical therapy in the emergency department, resolving their acute symptoms and enabling discharge home. However, we do not anticipate adoption of intravenous procainamide in this setting due to the additional time required for chemical cardioversion compared with electrical cardioversion and https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 6/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate the general lack of familiarity and experience with procainamide and its potential side effects by emergency department clinicians and general cardiologists. Further, the drug has a substantial half-life, making the risk of torsades de pointes due to early discharge problematic. Ibutilide is an antiarrhythmic drug that is more familiar to most clinicians caring for these patients and more likely to be chosen in this setting if an initial pharmacologic approach is attempted. (See 'Specific antiarrhythmic drugs' below.) ELECTRICAL CARDIOVERSION Electrical cardioversion of AF is a commonly performed medical procedure with a high success rate and a low complication rate when performed in the setting of anticoagulation. (See 'Arrhythmic complications' below and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Rationale for anticoagulation'.) The overall immediate success rate of electrical cardioversion is greater than 90 percent [4,5,7- 10,16,17]. However, the overall success rate falls as the AF duration increases and early recurrences are possible. Preprocedural antiarrhythmic drugs Many patients who undergo direct current cardioversion do not receive pretreatment with antiarrhythmic drugs. This is particularly true for unstable and other patients who need immediate restoration of SR. Pretreatment with antiarrhythmic drugs may also be omitted in patients for whom long-term therapy is not anticipated, such as those with new onset AF or those in whom the potential for drug-induced arrhythmias are a concern. The following are reasons to consider initiation of antiarrhythmic drug therapy prior to electrical cardioversion: To increase the likelihood of successful cardioversion [1]. Sotalol, ibutilide, and dofetilide seem to decrease the cardioversion energy requirement and may be helpful in refractory patients. (See 'Electrical versus pharmacologic cardioversion' above.) To prevent recurrent episodes of AF soon after cardioversion. Ibutilide or verapamil may be useful in preventing early recurrences of AF after cardioversion, particularly if it is of recent onset [18,19]. To allow for an evaluation of tolerability of one or more drugs. For those patients in whom a decision has been made to attempt the long-term maintenance of SR with antiarrhythmic drug therapy, we believe it is reasonable to preferentially select an agent for cardioversion https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 7/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate that can also be used for long-term maintenance of SR (such as amiodarone, flecainide, or propafenone). To potentially avoid the need for intravenous sedation and subsequent electrical cardioversion. Procedure A detailed discussion of electrical cardioversion is found elsewhere. (See "Cardioversion for specific arrhythmias" and "Basic principles and technique of external electrical cardioversion and defibrillation".) The following are a few important points: If possible, the patient should be fasting for at least six hours. Oxygen saturation and electrolytes (particularly serum potassium) should be close to normal and anticoagulation status should be reviewed (anticoagulation status is crucial to prevent thromboembolism in the week after conversion; the need for and the type of anticoagulation depends on the patient s clinical presentation as discussed elsewhere), and drug levels, when measured, should be within the therapeutic range. Digoxin need not be withheld unless digitalis toxicity is suspected [20]. (See "Digitalis (cardiac glycoside) poisoning".) Electrical cardioversion, synchronized to the QRS complex, should be performed while the patient is under the influence of procedural sedation and is having blood pressure, heart rate, oxygen saturation, and carbon dioxide capnography monitored. Generally, cardioversion should be done in a situation where airway equipment and airway expertise are present. (See "Procedural sedation in adults: General considerations, preparation, monitoring, and mitigating complications".) Electrical cardioversion is very rarely associated with complications such as thromboembolism, respiratory distress due to acute heart failure, myocardial necrosis, skin burns, transient ventricular dysfunction, and transient arrhythmias including bradycardia. These are discussed in detail separately. (See "Cardioversion for specific arrhythmias", section on 'Complications'.) Postprocedural considerations Most cardioversions take place without any significant adverse events. However, the following should be kept in mind. Hemodynamic changes after reversion Left ventricular systolic function often improves and may normalize after achievement of SR, although it may take months for this to happen. In one study, left ventricular function improved soon after the restoration of SR, a change that was attributed to the reduction in heart rate and return of atrial mechanical contraction [21]. Atrial contractility improves more slowly (atrial "stunning ) when the duration of AF prior to https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 8/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate cardioversion is prolonged [22]. In uncommon instances, there can be ventricular "stunning." In these rare cases, there can be acute pulmonary edema after cardioversion. (See "Mechanisms of thrombogenesis in atrial fibrillation", section on 'Atrial stunning after cardioversion'.) Recurrence of AF after cardioversion The recurrence rate of AF after electrical cardioversion can be high, especially in patients with prior recurrences, a large left atrium, underlying structural disease, and a history of heart failure. There are times when it is appropriate to start an antiarrhythmic drug before cardioversion to lower the risk of recurrence soon after cardioversion. For the first attempt, however, especially if the heart is normal and there is no heart failure, a cardioversion without an antiarrhythmic is reasonable, particularly without maintenance antiarrhythmic therapy [23]. The timing of AF recurrence was evaluated in a review of 61 patients who had daily electrocardiographic recordings using transtelephonic monitoring: 57 percent had recurrent AF during the first month after cardioversion, with a peak incidence during the first five days [24]. This is one of the reasons that post-cardioversion anticoagulation should be used independently of CHADS or CHA DS -VASc score, as this may obviate the need for a transesophageal 2 2 2 echocardiogram or an additional month of anticoagulation prior to another cardioversion. Electrical cardioversion may be repeated if AF recurs acutely in patients who have not been pretreated with antiarrhythmic therapy. In such patients or those in whom cardioversion fails, the combination of an atrioventricular (AV) nodal blocker plus intravenous loading with amiodarone, ibutilide, or procainamide, or oral dosing with flecainide, sotalol, or propafenone may restore SR pharmacologically. If the AF persists, electrical cardioversion may be performed and if successful, the patient may be placed on long-term antiarrhythmic therapy. (See 'Pharmacologic cardioversion' below.) A separate issue is whether to perform repeat cardioversion for later recurrence. One study has shown that two repeat cardioversions increase the likelihood of maintaining SR long-term [25]. However, an important consideration is the time interval between AF episodes. In both of the above reports, a third cardioversion for recurrent AF was performed within seven days of the second cardioversion. Repeated cardioversion may be a reasonable approach for patients with AF that recurs after a longer duration of SR (eg, years). It is most likely to be successful in younger patients with fair exercise tolerance and AF duration of less than three years [26]. Repeat cardioversion or nonpharmacologic therapy (catheter ablation of AF or AV nodal ablation) may be necessary in patients who remain symptomatic when in recurrent AF. Arrhythmic complications Bradyarrhythmias are occasionally seen after electrical cardioversion, especially when patients are being treated with drugs to control the rate in AF, in https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 9/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate older patients with tachycardia-bradycardia syndrome, and those with known preexisting bradycardia; ventricular tachyarrhythmias are rare but torsades de pointes can occur in patients treated with class III antiarrhythmics, especially in the first 24 hours after cardioversion and especially if there is bradycardia after cardioversion. In a retrospective study of 6906 cardioversions of acute AF in 2868 patients, 63 patients had bradyarrhythmias (51 episodes of asystole >5 seconds and 12 episodes of bradycardia with heart rate <40 bpm) [27]. No episodes of ventricular arrhythmia requiring intervention were reported. Patients with sinus or AV node dysfunction, as in the tachycardia-bradycardia syndrome, are at higher risk for prolonged sinus pauses and bradycardia if AF is converted without a backup pacemaker. Nevertheless, the hemodynamic benefit from cardioversion may be sufficient to warrant restoration of SR with control of the atrial rate and/or AV conduction with a pacemaker. Physiologic pacing in patients with sinus node dysfunction and SR appears to decrease the likelihood of recurrent AF, especially if the initiation of AF episodes is bradycardia dependent [28]. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history" and "Sinus node dysfunction: Treatment".) PHARMACOLOGIC CARDIOVERSION As discussed above, we generally prefer electrical cardioversion to pharmacologic cardioversion in most patients.(See 'Electrical versus pharmacologic cardioversion' above.) Flecainide, propafenone, ibutilide, dofetilide, procainamide, and, to a lesser degree, amiodarone have efficacy for pharmacologic conversion of AF. Of these, we prefer flecainide or propafenone unless there is evidence for coronary artery disease, left ventricular systolic dysfunction, or the duration of AF is greater than seven days, in which case dofetilide, or to a lesser degree, amiodarone or ibutilide have some role for medical conversion. None of these drugs is as efficacious as electrical cardioversion. In order to avoid side effects and proarrhythmia, we do not use two or more antiarrhythmic drugs at the same time. Structural heart disease is a contraindication to the use of some of the antiarrhythmic drugs. For the purpose of this topic, we define it as any condition in which there is a deviation in the size, shape, function, or structure of the atria or ventricles (such as left ventricular hypertrophy or dilated cardiomyopathy). This also includes coronary artery disease. The definition does not include processes that alter the electrical properties of the heart, such as electrical activation, conduction, automaticity, or refractoriness. Specific antiarrhythmic drugs The following antiarrhythmic drugs have been used to cardiovert patients in AF: https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 10/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Flecainide is a very effective antiarrhythmic drug for the pharmacologic conversion of a patient with AF of short (<24 hours) duration. Flecainide should not be used in patients with structural heart disease, particularly those with left ventricular systolic dysfunction or with coronary artery disease. (See "Major side effects of class I antiarrhythmic drugs".) Intravenous flecainide (2 mg/kg over 10 minutes) acutely reverts recent onset AF in 67 to 92 percent of patients within six hours and is more effective than procainamide, sotalol, propafenone, and amiodarone. The intravenous preparation is not available in the United States. An oral dose of 200 to 300 mg has also been used. A single, large oral dose of flecainide (100 to 400 mg) is effective for AF reversion [29,30]. One study randomly assigned 79 patients to intravenous or large oral dose of flecainide. The rate of reversion to SR was similar at two hours (64 versus 68 percent for oral drug) and eight hours after treatment (72 versus 75 percent); however, the mean time to reversion was shorter with intravenous flecainide (52 versus 110 minutes) [31]. Propafenone is significantly more effective in paroxysmal as opposed to persistent AF, with rates likely approaching those seen with flecainide. As with flecainide, we do not recommend propafenone in patients with structural heart disease, particularly those with left ventricular systolic dysfunction or coronary artery disease. (See "Major side effects of class I antiarrhythmic drugs".) Intravenous propafenone (2 mg/kg over 10 to 20 minutes) is used in Europe for the acute termination of AF. Conversion rates of 23 to 54 percent in patients with AF of variable duration have been reported [32,33]. Oral propafenone can be given as a large dose of 450 to 600 mg. A single oral loading dose reverted AF in 56 to 83 percent of patients, depending upon the duration of AF, in one study [34,35]. The administration of propafenone prior to electrical cardioversion does not alter the energy requirements for, or the success rate of, cardioversion [36]. Dofetilide has primarily been studied for the medical conversion of persistent AF. Dofetilide has not been directly compared with amiodarone or vernakalant. Its principal use is to help maintain SR, rather than to be used for cardioversion. It has been used successfully in patients with structural heart disease. As an oral agent, it is rarely used solely for the purpose of cardioversion. It can be started prior to anticipated electrical cardioversion to help maintain SR shortly after either electrical or spontaneous cardioversion, or in those patients in whom it is chosen for the long-term maintenance of sinus rhythm. (See "Clinical use of dofetilide".) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 11/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Dofetilide is more effective than placebo for the conversion of persistent AF to SR, particularly at a dose of 500 mcg twice daily [37-39]. As an example, the SAFIRE-D study randomized 325 patients (including 60 percent with structural heart disease) with AF (n = 277) or atrial flutter (n = 48) to oral therapy with 125, 250, and 500 mcg twice daily [37]. Overall conversion rates were 6, 9.8, and 30 percent, respectively. Among patients who convert with dofetilide, successful conversion occurred in 70 percent within 24 hours, while 91 percent converted within 36 hours. Postmarket uncontrolled trials have suggested that oral dofetilide is useful in the medical conversion of persistent AF in up to 60 percent of patients [39]. Dofetilide also appears safe and efficacious in the setting of heart failure (including patients with AF); this is discussed separately. (See "Clinical use of dofetilide", section on 'Heart failure'.) Dofetilide has the disadvantage of requiring the patient to be hospitalized, as it can cause nonsustained ventricular tachycardia (VT), torsades de pointes, or sudden death [40,41]. In the SAFIRE-D trial, the incidence of torsades de pointes was 1.2 percent [37]. This risk is minimized by dosing based on the creatinine clearance and avoidance of other drugs that may cause torsades de pointes. Initiation of dofetilide is required to be in-hospital, under telemetry conditions by a doctor certified in its use, with a total of at least six dosages given before discharge. (See "Clinical use of dofetilide", section on 'Protocol for administration'.) Amiodarone (either oral or intravenous) is not particularly effective for cardioversion. If reversion to SR occurs it does so several hours later than with flecainide, propafenone, ibutilide, and vernakalant [42-52]. Intravenous amiodarone may be more effective in converting AF after it has been given for hours and days. Oral amiodarone requires long- term loading and is effective in converting about 25 percent of patients with persistent AF to SR after six weeks of loading. Thus, we do not recommend it solely for the purpose of cardioversion. It is not approved by the US Food and Drug Administration for the treatment of AF. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) However, amiodarone may occasionally have value before cardioversion in patients who will receive the drug long term for maintenance and may be considered as adjunctive therapy to increase the likelihood of successful cardioversion in patients who are known to be refractory to electrical cardioversion or in those in whom there is a concern about early relapse. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 12/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Intravenous amiodarone is given at a dose of 150 mg over 10 minutes, with a subsequent infusion of 1 mg/minute for six hours, then 0.5 mg/minute for 18 hours or change to oral maintenance dosing (eg, 100 to 200 mg once daily) [53]. It should be kept in mind that the drug will likely have a significant rate-slowing effect, which may be beneficial in some patients [54]. A table on monitoring for adverse effects is available ( table 1). Vernakalant is available in Europe and Canada in intravenous forms for the rapid conversion (50 percent conversion within 10 minutes) of recent onset AF (less than eight days duration for patients not undergoing surgery, and less than four days duration for post-cardiac surgery patients) to SR. This drug is not available in the United States. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Vernakalant'.) In a 2019 systematic review and meta-analysis of nine trials (n = 1358) comparing vernakalant with placebo, amiodarone, or ibutilide [55], significant methodological bias was found in four trials. The following was also found: Vernakalant was superior to placebo for conversion within 90 minutes (50 percent conversion; risk ratio 5.15, 95% CI 2.24-11.84). No significant difference in the rate of conversion was found comparing vernakalant with active drug (56 versus 24 percent; risk ratio 2.40, 95% CI 0.76-7.58). Ibutilide, due to its propensity to prolong repolarization and the QT interval, has the potential to provoke torsades de pointes. Ibutilide is available only as an intravenous preparation (1 mg over 10 minutes and potentially repeated once after 20 minutes) and is useful for the acute reversion of AF [56-58]. It has been used in patients with structural heart disease (but without heart failure). We use ibutilide very rarely in this setting. (See "Therapeutic use of ibutilide".) In trials, the acute AF conversion rate is 28 to 51 percent. Ibutilide is more effective at converting atrial flutter to SR, with conversion rates of 50 to 75 percent. Ibutilide can work in acute situations of persistent AF and can be used (with caution) in patients with structural heart disease. However, while these rates seem low compared with flecainide or propafenone, ibutilide has never been directly compared with these other drugs. In addition, the average conversion times with ibutilide seem shorter than with flecainide and propafenone. Arrhythmia conversion occurred within a mean of 27 to 33 minutes after the start of the infusion [57,58]. In comparative studies, ibutilide has been more effective for AF reversion https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 13/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate than procainamide (51 versus 21 percent and 32 versus 5 percent) [59,60] or intravenous sotalol (44 versus 11 percent) [61]. In four large series, the rate of torsades de pointes with ibutilide ranged between 3.6 and 8.3 percent [56-58,60]. Sustained episodes of torsades de pointes, requiring cardioversion, were seen in 1.7 to 2.4 percent. In addition to polymorphic VT, nonsustained monomorphic VT occurred in an additional 3.2 to 3.6 percent of patients [57,58]. Because of the risk of ventricular proarrhythmia, patients treated with ibutilide should be observed with continuous rhythm monitoring for at least four hours after the infusion or until the QTc interval has returned to baseline. Pretreatment with intravenous magnesium appears to minimize the risk of ibutilide-induced torsades de pointes without affecting the efficacy of conversion [62]. Risk factors for the development of torsades de pointes with ibutilide are heart failure, baseline increase in QTc interval, and low potassium or magnesium. Electrolytes should be checked and normalized before cardioversion with ibutilide. We occasionally use ibutilide in patients resistant to electrical cardioversion and in patients for whom anesthesia, in conjunction with direct current cardioversion, is not readily available. The recommended dose varies with patient size. For patients weighing less than 60 kg, the recommended dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) can be given. For patients weighing more than 60 kg, the recommended starting intravenous dose is 1 mg over 10 minutes. If AF does not terminate 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes can be given. Most patients studied have had arrhythmia for less than 90 days. Efficacy has not been proven with an AF duration exceeding 90 days. We do not use ibutilide in combination with other antiarrhythmic medications. Less effective or ineffective drugs Several medications such as quinidine and procainamide are no longer used for cardioversion as most of the agents presented above have greater efficacy or fewer side effects or both. The following antiarrhythmic drugs are not particularly effective for the restoration of SR: Sotalol Oral sotalol is less effective than quinidine [63] and equally effective to amiodarone for chemical cardioversion of AF (27 percent at 28 days) [64]. Intravenous sotalol is less effective than intravenous flecainide or ibutilide for reversion of AF [61,65]. Thus, we do not recommend either form for chemical cardioversion of AF. (See "Clinical uses of sotalol".) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 14/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Dronedarone We do not recommend dronedarone for the restoration of SR in patients with AF since conversion rates are very low [66]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Rate-control drugs such as digoxin, nondihydropyridine calcium channel blockers (eg, diltiazem or verapamil), and beta blockers have not been effective in restoring SR in placebo-controlled studies. Many clinicians overestimate the effectiveness (for cardioversion) of these agents [1,67-72]. Pill-in-the-pocket A "pill-in-the-pocket" approach with either flecainide (<70 kg: 200 mg; may not repeat in 24 hours; 70 kg: 300 mg; may not repeat in 24 hours) or propafenone can be used to terminate out-of-hospital paroxysmal AF of short duration after these drugs have been shown to be efficacious and safe in a monitored setting. In this approach, we have the patient take a diltiazem or a beta blocker 30 minutes or more (if they are not on chronic AV nodal
ibutilide, and vernakalant [42-52]. Intravenous amiodarone may be more effective in converting AF after it has been given for hours and days. Oral amiodarone requires long- term loading and is effective in converting about 25 percent of patients with persistent AF to SR after six weeks of loading. Thus, we do not recommend it solely for the purpose of cardioversion. It is not approved by the US Food and Drug Administration for the treatment of AF. (See "Amiodarone: Clinical uses" and "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) However, amiodarone may occasionally have value before cardioversion in patients who will receive the drug long term for maintenance and may be considered as adjunctive therapy to increase the likelihood of successful cardioversion in patients who are known to be refractory to electrical cardioversion or in those in whom there is a concern about early relapse. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 12/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Intravenous amiodarone is given at a dose of 150 mg over 10 minutes, with a subsequent infusion of 1 mg/minute for six hours, then 0.5 mg/minute for 18 hours or change to oral maintenance dosing (eg, 100 to 200 mg once daily) [53]. It should be kept in mind that the drug will likely have a significant rate-slowing effect, which may be beneficial in some patients [54]. A table on monitoring for adverse effects is available ( table 1). Vernakalant is available in Europe and Canada in intravenous forms for the rapid conversion (50 percent conversion within 10 minutes) of recent onset AF (less than eight days duration for patients not undergoing surgery, and less than four days duration for post-cardiac surgery patients) to SR. This drug is not available in the United States. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Vernakalant'.) In a 2019 systematic review and meta-analysis of nine trials (n = 1358) comparing vernakalant with placebo, amiodarone, or ibutilide [55], significant methodological bias was found in four trials. The following was also found: Vernakalant was superior to placebo for conversion within 90 minutes (50 percent conversion; risk ratio 5.15, 95% CI 2.24-11.84). No significant difference in the rate of conversion was found comparing vernakalant with active drug (56 versus 24 percent; risk ratio 2.40, 95% CI 0.76-7.58). Ibutilide, due to its propensity to prolong repolarization and the QT interval, has the potential to provoke torsades de pointes. Ibutilide is available only as an intravenous preparation (1 mg over 10 minutes and potentially repeated once after 20 minutes) and is useful for the acute reversion of AF [56-58]. It has been used in patients with structural heart disease (but without heart failure). We use ibutilide very rarely in this setting. (See "Therapeutic use of ibutilide".) In trials, the acute AF conversion rate is 28 to 51 percent. Ibutilide is more effective at converting atrial flutter to SR, with conversion rates of 50 to 75 percent. Ibutilide can work in acute situations of persistent AF and can be used (with caution) in patients with structural heart disease. However, while these rates seem low compared with flecainide or propafenone, ibutilide has never been directly compared with these other drugs. In addition, the average conversion times with ibutilide seem shorter than with flecainide and propafenone. Arrhythmia conversion occurred within a mean of 27 to 33 minutes after the start of the infusion [57,58]. In comparative studies, ibutilide has been more effective for AF reversion https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 13/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate than procainamide (51 versus 21 percent and 32 versus 5 percent) [59,60] or intravenous sotalol (44 versus 11 percent) [61]. In four large series, the rate of torsades de pointes with ibutilide ranged between 3.6 and 8.3 percent [56-58,60]. Sustained episodes of torsades de pointes, requiring cardioversion, were seen in 1.7 to 2.4 percent. In addition to polymorphic VT, nonsustained monomorphic VT occurred in an additional 3.2 to 3.6 percent of patients [57,58]. Because of the risk of ventricular proarrhythmia, patients treated with ibutilide should be observed with continuous rhythm monitoring for at least four hours after the infusion or until the QTc interval has returned to baseline. Pretreatment with intravenous magnesium appears to minimize the risk of ibutilide-induced torsades de pointes without affecting the efficacy of conversion [62]. Risk factors for the development of torsades de pointes with ibutilide are heart failure, baseline increase in QTc interval, and low potassium or magnesium. Electrolytes should be checked and normalized before cardioversion with ibutilide. We occasionally use ibutilide in patients resistant to electrical cardioversion and in patients for whom anesthesia, in conjunction with direct current cardioversion, is not readily available. The recommended dose varies with patient size. For patients weighing less than 60 kg, the recommended dose is 0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) can be given. For patients weighing more than 60 kg, the recommended starting intravenous dose is 1 mg over 10 minutes. If AF does not terminate 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes can be given. Most patients studied have had arrhythmia for less than 90 days. Efficacy has not been proven with an AF duration exceeding 90 days. We do not use ibutilide in combination with other antiarrhythmic medications. Less effective or ineffective drugs Several medications such as quinidine and procainamide are no longer used for cardioversion as most of the agents presented above have greater efficacy or fewer side effects or both. The following antiarrhythmic drugs are not particularly effective for the restoration of SR: Sotalol Oral sotalol is less effective than quinidine [63] and equally effective to amiodarone for chemical cardioversion of AF (27 percent at 28 days) [64]. Intravenous sotalol is less effective than intravenous flecainide or ibutilide for reversion of AF [61,65]. Thus, we do not recommend either form for chemical cardioversion of AF. (See "Clinical uses of sotalol".) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 14/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Dronedarone We do not recommend dronedarone for the restoration of SR in patients with AF since conversion rates are very low [66]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Rate-control drugs such as digoxin, nondihydropyridine calcium channel blockers (eg, diltiazem or verapamil), and beta blockers have not been effective in restoring SR in placebo-controlled studies. Many clinicians overestimate the effectiveness (for cardioversion) of these agents [1,67-72]. Pill-in-the-pocket A "pill-in-the-pocket" approach with either flecainide (<70 kg: 200 mg; may not repeat in 24 hours; 70 kg: 300 mg; may not repeat in 24 hours) or propafenone can be used to terminate out-of-hospital paroxysmal AF of short duration after these drugs have been shown to be efficacious and safe in a monitored setting. In this approach, we have the patient take a diltiazem or a beta blocker 30 minutes or more (if they are not on chronic AV nodal blocker) before the oral antiarrhythmic drug to prevent a rapid ventricular rate should conversion to atrial flutter occur. Some of our contributors prefer the patient to be observed in the emergency department (or potentially during inpatient hospitalization) the first time the "pill-in-the-pocket" approach is taken so that monitoring of safety and efficacy occurs. Some authors also instruct their patients to begin a direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) at the time of the beta blocker/diltiazem so as to decrease the risk of thrombus formation should the patient not convert to SR in the subsequent 48 hours and to prophylaxis for thrombus formation during the transient periconversion period of atrial appendage mechanical dysfunction. MAINTENANCE ANTIARRHYTHMIC DRUG THERAPY After successful electrical cardioversion, antiarrhythmic drugs increase the likelihood of long- term maintenance of SR [1]. The use of antiarrhythmic drugs to maintain SR is discussed elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) We do not generally recommend maintenance antiarrhythmic drugs after electrical cardioversion in patients with their first episode of non-valvular AF, particularly those at low risk for recurrence (eg, short-duration AF, normal or only mildly increased left atrial size, normal left ventricular systolic function, absence of valvular dysfunction) or those with a transient cause (eg, pericarditis, pulmonary embolism, and corrected or treated hyperthyroidism) [73]. (See 'Recurrence of AF after cardioversion' above.) https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 15/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate RECOMMENDATIONS OF OTHERS Societal guidelines are available [53,74-76]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Unstable patients For the uncommon patient who is hemodynamically unstable or has angina due to AF and is at low risk for thromboembolism, we recommend urgent electrical cardioversion rather than no cardioversion (Grade 1C). (See 'Indications' above.) Stable patients Most patients with AF do not need emergency or even urgent cardioversion, as rate slowing will often improve symptoms. We also attempt to defer cardioversion to allow for initiation of heparin anticoagulation. For select, stable patients with nonvalvular AF, the restoration of sinus rhythm (SR) with either electrical or pharmacologic cardioversion is necessary or reasonable (see 'Ventricular rate control' above and 'Indications' above): Symptomatic, first episode of AF For most symptomatic patients with new onset/first episode of AF, we suggest an attempt at cardioversion, as opposed to no attempt (Grade 2C). In patients who do have factors that predict a high likelihood of success of electrical cardioversion, and in whom long-term maintenance antiarrhythmic drug therapy is not planned, we suggest electrical instead of pharmacologic cardioversion (Grade 2B). (See 'Reasons not to perform cardioversion' above and 'Electrical versus pharmacologic cardioversion' above.) In such patients who are older or have multiple medical comorbidities, it is reasonable to avoid cardioversion if the symptoms can be minimized and pharmacologic ventricular rate control is achieved; the approach needs to be individualized. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 16/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Patients who fail long-term rate control For patients in whom a long-term rate control strategy has failed due to persistent symptoms, a rhythm control strategy involving cardioversion is reasonable. Infrequent episodes of AF Periodic electrical cardioversion is an option for patients with infrequent episodes of AF that do not spontaneously convert, including those being managed with a rhythm control strategy. Roles of rate control and anticoagulation Most patients in whom cardioversion is chosen will need the ventricular rate controlled and the need for anticoagulation assessed prior to cardioversion. (See 'Ventricular rate control' above and 'Anticoagulation' above.) Antiarrhythmic drugs These may be initiated prior to electrical cardioversion to increase the likelihood of a successful electrical cardioversion, to increase the likelihood of maintaining SR in the hours after cardioversion, or as the first step in a plan for long-term antiarrhythmic therapy. (See 'Preprocedural antiarrhythmic drugs' above.) For patients with AF and no structural heart disease (including no evidence of coronary artery disease) for whom pharmacologic cardioversion is chosen, we suggest either flecainide or propafenone rather than other antiarrhythmic drugs (Grade 2B). The choice between these two drugs should be influenced by the practitioner s experience and the clinical situation. (See 'Pharmacologic cardioversion' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. 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Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 1025 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 23/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate GRAPHICS Amiodarone baseline testing and monitoring for side effects Monitoring Area of interest for monitoring Possible adverse effect Baseline testing Follow-up testing Cardiac ECG (at baseline and Yearly QT prolongation; during loading dose) torsades de pointes After adding medications that interact with Symptomatic sinoatrial or conduction system amiodarone or prolong impairment the QT interval Implantable cardioverter- Defibrillation threshold testing (if clinically As needed for signs/symptoms Increased defibrillation threshold defibrillators indicated) Dermatologic Physical examination As needed for Photosensitivity to UV signs/symptoms light Blue-gray skin discoloration Endocrine TSH (with reflex testing 3 to 4 months after Hyperthyroidism, if abnormal) starting drug, then yearly hypothyroidism As needed for signs/symptoms Hepatic AST and ALT 6 months after starting drug, then yearly AST or ALT elevation 2 upper limit of reference range Ophthalmologic Eye examination Yearly Corneal microdeposits Optic neuropathy Pulmonary Chest radiograph, PFTs* Yearly for surveillance Pulmonary toxicity (cough, fever, dyspnea) Along with PFTs (including DLCO) and chest computed tomography for signs/symptoms Refer to UpToDate topics on pulmonary toxicity, thyroid toxicity, and clinical uses of amiodarone for additional information. https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 24/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate ECG: electrocardiogram; UV: ultraviolet; TSH: thyroid-stimulating hormone; AST: aspartate aminotransferase; ALT: alanine transaminase; PFTs: pulmonary function tests; DLCO: diffusing capacity of the lungs for carbon monoxide. There are differing opinions, and no concensus, of obtaining formal PFTs with assessment of diffusion capacity (ie, DLCO) as baseline testing in all patients. Some experts obtain baseline PFTs with DLCO prior to starting amiodarone, particularly among patients with underlying lung disease, while other experts rarely or never obtain baseline PFTs. Graphic 126072 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 25/26 7/5/23, 9:05 AM Atrial fibrillation: Cardioversion - UpToDate Contributor Disclosures Gerald V Naccarelli, MD Consultant/Advisory Boards: Acesion [Antiarrhythmic drug development]; InCarda Therapeutics [Antiarrhythmic drug development]; Milestone [Antiarrhythmic drug development]; Sanofi [Antiarrhythmic agent]. All of the relevant financial relationships listed have been mitigated. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. James Hoekstra, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-cardioversion/print 26/26
7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Catheter ablation : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 27, 2022. INTRODUCTION The three principal goals of therapy in patients with atrial fibrillation (AF) are the alleviation of symptoms, the prevention of tachycardia-mediated cardiomyopathy, and the reduction in the risk of stroke. The first two goals can be achieved with either a rate or rhythm control strategy (see "Management of atrial fibrillation: Rhythm control versus rate control"). For patients in whom a rhythm control strategy is chosen, catheter ablation (CA) and antiarrhythmic drug therapy are the two principle therapeutic strategies to reduce the frequency or eliminate episodes of AF. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) This topic will discuss the use of CA in patients with AF and provide the clinician with much of the information needed to discuss the procedure with the patient. The discussion of surgery to prevent recurrent AF is found elsewhere. (See "Atrial fibrillation: Surgical ablation".) Stroke prevention is usually achieved with anticoagulation. This topic is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) WHAT TO TELL YOUR PATIENT When discussing CA to reduce symptoms in an AF patient, the following information should be provided: https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 1/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate CA is a reasonable treatment option for AF patients when medications are unable to adequately control symptoms or are not tolerated. All patients who undergo CA must take oral anticoagulation for at least two to three months after the procedure. Anticoagulation should be continued long term in many patients with risk factors for stroke even if AF is not present after the ablation. This is because patients may continue to have some AF episodes that may be asymptomatic; in addition, the reduction in AF burden seen post-ablation has not yet been shown to reduce stroke risk. It is a common misconception that patients who undergo successful ablation can stop oral anticoagulation. About 70 to 75 percent of patients are symptom free at one year [1]. A lower percentage is likely for persistent AF (about 60 percent). About 50 percent of patients have detectable AF at one year (this includes symptomatic and asymptomatic patients) [2,3]. The success rate for ablation in patients with long-standing persistent AF (over one year) is poor. The risk of a major complication is about 4 percent, with vascular access complications being the most common. Other important, less common complications include stroke, cardiac perforation, or damage that includes injury to the pulmonary veins, esophagus, or phrenic nerve. The risk of dying within 30 days after an AF ablation procedure is about 1 in 1000 patients. The risk of a major complication is significantly higher at low-volume ablation centers. [4]. TECHNICAL CONSIDERATIONS Technical considerations for CA are presented separately. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) COMPARISON WITH ANTIARRHYTHMIC THERAPY For patients with symptomatic paroxysmal AF in a rhythm- rather than a rate-control strategy, either a trial of an antiarrhythmic drug or CA is a reasonable approach. We are more inclined to https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 2/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate perform CA in patients for whom the odds of success are high and if they prefer to avoid the use of long-term antiarrhythmic drug therapy. Studies comparing these strategies are discussed separately. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients without prior antiarrhythmic drug treatment'.) EFFICACY CA leads to significant symptom improvement in most patients. Over 70 to 75 percent are symptom free at one year. Some symptoms may be due to atrial or ventricular premature complexes rather than AF. The absence of symptomatic AF recurrence is the primary efficacy outcome in most studies. However, with continuous invasive monitoring, approximately 50 percent of patients have had one or more documented episodes lasting 30 seconds or longer at one year. This becomes part of the rationale to continue long-term oral anticoagulation in many patients. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Our approach to anticoagulation'.) How is recurrence defined and measured? Recurrence of AF after CA is categorized as early or late. Each have distinct mechanisms and management implications [5]. From a clinical perspective, recurrences after the initial two-to-three-month post-ablation healing phase are more clinically relevant. Early recurrences of AF are defined as those that occur within the first two to three months after CA. This period is often referred to as the "blanking period," and recurrences during this time are not included in studies examining the long-term success of AF ablation. Early recurrences occur as often as 40 percent of the time with radiofrequency ablation (RFA) [6] and about 17 percent of the time for those treated with second-generation cryoballoon [7]. It is postulated to be related to several potential mechanisms including sterile pericarditis, recovered pulmonary vein (PV) conduction, or proarrhythmic effects of the ablation procedure [8]. Some studies suggest that early recurrence appears to be a predictor of late recurrence, especially when the episodes occur late in the blanking period. However, most clinicians will treat early recurrences with antiarrhythmic drug therapy before consideration of repeat ablation in these patients. Episodes of AF occurring after three months are considered to be recurrent AF and are referred to as "late recurrent AF." The possible mechanisms for late recurrent AF following CA are discussed separately. (See "Mechanisms of atrial fibrillation", section on 'Specific clinical situations'.) https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 3/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate The frequency of late recurrent AF varies significantly across studies in part due to factors such as the method and intensity of surveillance, whether other atrial arrhythmias such as atrial flutter are counted, whether patients remained on antiarrhythmic drug therapy, and patient characteristics (eg, paroxysmal or persistent AF). In some studies, success has been defined as the absence of recurrent AF or other atrial arrhythmias with or without antiarrhythmic drug therapy; a more rigorous definition requires the absence of AF >30 seconds in patients not taking antiarrhythmic drugs. The following studies illustrate the rates of late recurrence [9]: The DISCERN AF study evaluated episodes of symptomatic and asymptomatic AF (as well as atrial flutter and atrial tachycardia) before and after the procedure in 50 patients (80 percent with paroxysmal AF), using an implantable cardiac monitor capable of recording all AF episodes [10]. The total atrial arrhythmia burden was significantly reduced by 86 percent from a mean of two hours per day per patient before to 0.3 hours per day after. The ratio of asymptomatic to symptomatic episodes increased significantly after ablation from 1.1 to 3.7. After 18 months and a mean of 1.4 ablations, 58 percent of patients were symptom free. A 2013 meta-analysis of 19 observational studies (n = 6167) with outcomes at 3 years found that freedom from atrial arrhythmia at long-term follow-up (mean 24 months) after a single procedure was about 53 percent [11]. With multiple procedures, the long-term success rate was nearly 80 percent. However, there are several limitations of this analysis, including significant heterogeneity among the studies, disparities in post-ablation AF surveillance, and the inclusion of patients ablated with early-generation technologies no longer in current use. In the MANTRA and RAAFT-2 randomized trials, which allowed for antiarrhythmic drug use after CA, freedom from AF at two years was 85 and 72 percent, respectively [12,13]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients without prior antiarrhythmic drug treatment'.) In a meta-analysis of seven studies of first-generation cryoballoon ablation, one-year freedom from AF was 73 percent, but the analysis evaluated studies that allowed inclusion of patients taking antiarrhythmic drug therapy in the CA group [14]. Two real-world population studies found significantly lower rates of freedom from AF when only patients not taking antiarrhythmic drug therapy were counted (40 and 41 percent at one year) [3,15]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 4/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate The 2019 CIRCA-DOSE study randomly assigned 346 patients with drug-refractory, paroxysmal AF to contact-force-guided RFA or two differing duration protocols for cryoballoon ablation [1] (see 'Technical considerations' above). All patients received an implantable loop recorder, and they also received noninvasive surveillance. Follow-up was for 12 months. The primary endpoint of one-year freedom from atrial tachyarrhythmia (symptomatic or asymptomatic) as detected by continuous rhythm monitoring was about 53 percent in the three groups. One-year freedom from symptomatic atrial tachyarrhythmia, defined by continuous monitoring, ranged between 73 and 79 percent (p = 0.87). AF burden was reduced by about 99 percent in the three groups (p = 0.36). Predictors of recurrence Recurrence is more likely in patients with underlying cardiovascular disease such as hypertension, complicated heart disease (including valvular heart disease), older age, persistent as opposed to paroxysmal AF, procedure performed at a low-volume center, untreated obstructive sleep apnea, obesity, increasing plasma B-type natriuretic peptide level, or left atrial (LA) dilation [8,16-22]. LA dilation We rarely perform CA in patients with long-standing persistent AF and severe LA dilation (>5.5 cm). LA dilation should be assessed by volume determination rather than linear measurements if possible [23]. One study has shown that an LA volume 130 cc, assessed by computed tomography, predicts a recurrence rate of >90 percent at one year [24]. Other LA remodeling parameters Greater atrial wall thickness, lipid composition, and epicardial fat volume on cardiac computed tomography also predict AF recurrence in observational studies, but low measurement reproducibility may limit their clinical use [25]. Among 732 patients undergoing CA, 270 had AF recurrence after seven months. Patients with AF recurrence had higher LA wall thickness (anterior wall 1.9 versus 1.7 mm), 3 epicardial adipose volume (145 versus 129 mm ) and lower LA wall attenuation reflective of higher lipid composition (-69.1 versus -67.5 Hounsfield Units). Comparison of radiofrequency and cryothermal ablation The commonly used approved energy sources for CA are RF and cryothermal ablation. The efficacy and safety associated with these two energy sources have been found to be similar in multiple studies [1,14,26-30]. The three major randomized trials comparing the two energy sources are as follows: In the FIRE AND ICE trial, 762 patients with symptomatic, drug-refractory, paroxysmal AF were randomly assigned to cryoballoon ablation or RFA [31]. The primary efficacy endpoint https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 5/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate was the first documented clinical failure (eg, recurrence of AF, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) following a 90-day blanking period after the index ablation. Arrhythmia surveillance was noninvasive. The mean duration of follow-up was 1.5 years. The primary efficacy endpoint was similar in both groups (34.6 versus 35.9 percent, respectively; hazard ratio 0.96, 95% CI 0.76-1.22). In the FreezeAF trial, 315 patients with paroxysmal AF were randomly assigned to RFA or cryoballoon ablation [26]. The primary endpoint of freedom from atrial arrhythmia with absence of persistent complications was similar in the two groups at 12 months (70.7 versus 73.6 percent). Arrhythmia surveillance was noninvasive. In the 2019 CIRCA-DOSE study, which is discussed above, the two energy sources led to similar efficacy outcomes. (See 'How is recurrence defined and measured?' above.) Complications of cryoballoon ablation may differ somewhat from standard RFA. Pericardial effusions, tamponade, and atrioesophageal fistula have been reported less frequently in cryoballoon ablation. Non-AF atrial tachyarrhythmias have also been less frequently reported in long-term follow-up of cryoballoon ablation. However, phrenic nerve paralysis has been reported in up to 6.3 percent of 1349 procedures, significantly higher than seen with standard RFA. Resolution occurs acutely in most patients and in >90 percent within one year [14]. The use of larger balloons that prevent distal ablation and the assessment of diaphragmatic compound motor action potentials have lowered the rate of this complication. Recordings of diaphragmatic electromyograms during cryoballoon ablation for AF accurately predict phrenic nerve injury [32]. Patients with persistent atrial fibrillation The majority of patients in the studies of CA presented above had paroxysmal AF. The efficacy of CA in patients with persistent AF is lower than in patients with paroxysmal AF [33]. Our threshold for recommending CA is higher for patients with persistent AF given the lower success rates. Also, we avoid the use of CA as first- line therapy in patients with persistent AF. We believe CA is a reasonable choice for individuals with symptomatic persistent AF who either fail or cannot tolerate antiarrhythmic drug therapy or, in certain circumstances (ie, tachycardia- mediated cardiomyopathy), where there may be a benefit to maintaining sinus rhythm even in the absence of symptoms. To improve outcomes, standard pulmonary vein isolation (PVI) with or without additional ablative lesions can be performed. However, the utility of these additional lesion sets has not been consistently demonstrated, and we recommend standard PVI without the creation of additional lesions for the first ablation attempt in the majority of patients. We consider https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 6/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate additional lesions in patients with long-standing persistent AF or a markedly enlarged LA (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'). In patients with persistent AF, one small randomized trial (VENUS) found that the addition of vein-of-Marshall ethanol (see "Mechanisms of atrial fibrillation", section on 'Role of premature atrial complex and other arrhythmia triggers') infusion to catheter ablation, compared with catheter ablation alone, increased the likelihood of remaining free of AF at 6 and 12 months [34]. Further study of this procedure is needed. A 2014 systematic review and meta-analysis identified 46 randomized trials and observational studies of 3819 patients who underwent CA for persistent AF [35]. Compared with medical therapy, CA reduced the risk of recurrent AF (odds ratio 0.32, 95% CI 0.20-0.53). Various ablation strategies were employed in the studies, and the most efficacious combined isolation of the PVs with limited linear ablation (eg, roof ablation, mitral isthmus ablation) within the LA. The success rate after two procedures was about 60 percent in all groups. (See 'Comparison with antiarrhythmic therapy' above.) The STAR AF II trial was published subsequently to the meta-analysis [2]. In this trial, 589 patients with persistent AF were randomly assigned in a 1:4:4 ratio to ablation with PVI alone, PVI plus ablation of electrograms showing complex fractionated activity, or PVI plus additional linear ablation across the LA roof and mitral valve isthmus. There was no significant difference in the rates of the primary endpoint of freedom from any documented recurrence of AF lasting longer than 30 seconds after a single ablation procedure at 18 months (59 versus 49 versus 46 percent, respectively). Although serious adverse events appeared to be lower in the PVI-alone group, there were too few events for this endpoint to achieve statistical significance. Patients with concomitant atrial flutter Atrial fibrillation and flutter often coexist in part due to their common risk factors. In many atrial flutter patients, AF is thought to be the inciting arrhythmia, and as much as 55 percent of patients who undergo ablation for typical atrial flutter are also found to have AF on long-term follow-up [36]. Some studies have shown that PV triggers play an important role in the development of flutter [37]. While ablation of the tricuspid annulus-inferior vena cava (TA-IVC) isthmus is a highly successful treatment option for atrial flutter, the ablation approach to the patient with concomitant AF and atrial flutter requires a more extensive approach and has been evaluated: In a study of 108 patients with both AF and typical atrial flutter, patients were randomly assigned to either a dual-ablative procedure (PVI and TA-IVC isthmus ablation, 49 patients) or PVI alone (59 patients) [38]. After ablation, the following observations were made: https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 7/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate During the first eight weeks post-procedure, none of the dual-procedure patients and 32 patients treated with PVI alone developed atrial flutter and required cardioversion and/or antiarrhythmic drugs. After eight weeks, all antiarrhythmic drugs were discontinued. Only three patients treated with PVI alone had further recurrences of atrial flutter, which was successfully treated with TA-IVC ablation. Seven of the dual-procedure patients and six of those treated with PVI alone developed recurrent AF. Of these 13 patients (12 percent of the total group), 10 underwent successful repeat PVI, and three remained in sinus rhythm on antiarrhythmic drugs. These findings suggest that AF initiated by PV triggers may be the precursor rather than the consequence of atrial flutter. This conclusion is consistent with the observation that atrial flutter often starts after a transitional rhythm of variable duration, usually AF [39,40]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Attempts to control all atrial arrhythmias in patients with atrial flutter by performing PVI alone or at the time of an atrial flutter ablation have been studied: In the Triple A trial, 60 patients with atrial flutter but no documented AF were randomized to receive antiarrhythmic drugs alone, ablation of the cavotricuspid isthmus (CTI), or PVI. The primary endpoint, defined as any recurrent atrial tachyarrhythmia, occurred in 82.4 percent of the drug-treated group, 60.9 percent in the CTI group, and 10 percent in the PVI group during a mean follow-up time of 1.42 years [37]. In the PReVENT AF study [41], 50 patients with atrial flutter and no documented AF were randomized to CTI ablation alone or with concomitant PVI. More patients in the isthmus- ablation-only group experienced new-onset AF during follow-up (52 versus 12 percent), and the one-year burden also favored the combined ablation group compared with the isthmus-ablation-only group (8.3 versus 4 percent). These findings suggest that PVI either alone or in conjunction with atrial flutter ablation may have a beneficial effect on long-term suppression of all atrial arrhythmias. However, we do not recommend performing this procedure in lieu of or at the time of TA-IVC ablation in patients whose only documented arrhythmia is atrial flutter given the potential risks associated with additional ablation. (See "Atrial flutter: Maintenance of sinus rhythm".) Patients with structural heart disease The presence of structural heart disease may influence both the safety and efficacy of ablation procedures. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 8/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Heart failure CA appears to be safe and effective for the prevention of AF recurrence in patients with heart failure or impaired left ventricular function. The experience with ablation in this setting is discussed elsewhere. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Cardiac resynchronization therapy CA as an alternative to cardiac resynchronization therapy with atrioventricular node ablation in patients with heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Preference for rhythm over rate control'.) Mitral valve prosthesis A potential concern with CA in patients with a mitral valve prosthesis is injury to the valve. Furthermore, entrapment of the ablation catheter in a mechanical mitral valve, necessitating open-heart surgery, has been reported in patients undergoing left-sided ablation procedures. This issue was addressed in a report of 26 patients with mitral valve prostheses who were compared with a matched group of 52 patients without a mitral valve prosthesis [42]. The rate of maintenance of sinus rhythm was the same in the two groups, but the patients with a mitral valve prosthesis had longer fluoroscopy times with greater radiation exposure and a higher rate of post-ablation atrial tachycardia (23 versus 2 percent). Rheumatic heart disease The role of CA for chronic AF in patients with rheumatic heart disease is not well defined. One study performed electrophysiologic mapping in 17 patients with mitral stenosis who had chronic AF and were converted to sinus rhythm after balloon valvulotomy [43]. An organized atrial arrhythmia, which degenerated into AF, was induced in all patients; the focus was most often near the coronary sinus ostium. RFA was successful in 13 patients and, after a mean follow-up of 32 weeks, 10 were still in sinus rhythm. Cardiac surgery Either the Maze procedure or off-pump CA using an epicardial approach should be considered in patients with AF and an indication for open-heart surgery. These approaches are not generally recommended for patients without an indication for cardiac surgery, except in special circumstances, because of the mortality and morbidity associated with surgery. (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure'.) Patients with hypertension Renal sympathetic nerve denervation has been proposed as an adjunctive treatment to CA in hypertensive AF patients. We do not feel the available evidence supports its use in this setting. The rationale for the adding renal nerve denervation to CA is that hypertension is a major risk factor for the development of AF and that many hypertensive AF patients have increased https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 9/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate sympathetic tone. Renal nerve denervation has been evaluated as a treatment for hypertension, but its efficacy has not yet been established. (See "Treatment of resistant hypertension".) The issue of whether renal nerve denervation, when added to CA, can further lower the rate of AF recurrence was evaluated in the ERADICATE-AF trial [44]. In this study, 302 hypertensive (paroxysmal) AF patients were randomly assigned to CA or CA plus renal nerve denervation. The primary endpoint of freedom from AF, atrial flutter, or tachycardia at 12 months occurred in 56.5 and 72.1 percent of the two groups, respectively (hazard ratio 0.57, 95% CI 0.38-0.85). There was no significant difference in the rate of procedural complications between the two groups. Although the use of renal denervation as adjunctive therapy to CA improved the primary outcome, the lack of a sham-control group, that is CA plus sham renal denervation, is a major limitation of this study. COMPLICATIONS The types and rates of complications that occur in patients undergoing CA vary from series to series ( table 1 and table 2). The overall rate of major complications is about 4 percent, with vascular access complications being the most frequent [45]. There may be an increased rate of adverse effects with more extensive circumferential ablation [46-50]. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) Two large studies published in 2013 came to somewhat differing conclusions as to whether the complication rate was falling with time: An analysis of 93,801 CA procedures performed in community hospitals in the United States between 2000 and 2010 did not identify a trend toward lower mortality [51]. The majority (81 percent) of procedures were performed in low-volume hospitals by low-volume operators. The overall frequency of complications was 6.29 percent, and there was a small but nonsignificant rise with time. In a meta-analysis of 192 published studies, including 83,236 patients, there was a significant decrease in the acute complication rate from 2007 to 2012 compared with 2000 to 2006 (2.6 versus 4 percent; p = 0.003) [52]. In these studies, cardiac complications accounted for at least 50 percent of all complications. Most [51,53], but not all [54], studies have suggested that advanced age and female sex are risk factors for complications. In addition, annual operator (<25 procedures) and hospital volume (<50 procedures) have been associated with adverse outcomes [51]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 10/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Complications reported in series of patients undergoing CA to prevent recurrent AF will be reviewed here. Other complications that might occur with any electrophysiology study, such as radiation exposure and valve, vascular, or myocardial injury, are discussed separately. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Complications'.) Mortality Early case series found a death rate of about 1 to 1.5 in every 1000 patients [55,56]. More recent studies suggest a mortality closer to 5 per 1000. In the two large series (2000 to 2010 and 2007 to 2012) discussed directly above, the in-hospital mortality rates varied between 4.6 and 0.6 per 1000 patients [51,52]. The leading causes of death were cardiac tamponade (n = 8, 25 percent), stroke (n = 5, 16 percent), and atrioesophageal fistula (n = 5, 16 percent). Other causes included pneumonia, pulmonary vein (PV) perforation, and sepsis [55]. Cardiac tamponade Cardiac tamponade resulting from perforation is the most frequent serious complication of CA for AF, occurring in slightly more than 1 percent of procedures using radiofrequency (RF) [53,55,57], and it is the leading cause of death [55]. Tamponade results from either catheter perforation of an atrial or ventricular free wall, especially with overheating during energy delivery, or less frequently with transseptal puncture. Some cases of tamponade may be delayed in onset. In one study of delayed tamponade, the median duration was 10 days, with a range of several hours up to 30 days [55]. Pericardial effusion associated with PV isolation (PVI) was significantly less common in patients who underwent cryoballoon ablation (0.8 versus 2.1 percent) in one meta-analysis [30]. The treatment of tamponade caused by CA is similar to that in other settings. (See "Cardiac tamponade", section on 'Treatment'.) Catheter entrapment Entrapment of the circular mapping (LASSO) catheter in the mitral valve apparatus is a rare complication that can require cardiac surgery to resolve. The estimated incidence of this complication ranges between 0.01 and 0.9 percent, and specific sites of transeptal puncture or catheter manipulation may predispose to this adverse event [58-60]. Pulmonary vein stenosis PV stenosis is a potential complication of ablation near or within the PVs. The lesion is characterized by fibrosis and scarring of the PV; specific pathologic changes include intimal thickening, thrombus formation, endocardial contraction, and proliferation of elastic laminae [61]. The diagnosis may be delayed or missed entirely, as symptomatic patients may come to attention months after their initial ablation. In one series, symptoms developed 4 3 months after the most recent ablation, and the average delay between the onset of symptoms and diagnosis was 4.4 5.4 months. Symptoms of PV stenosis include dyspnea with exertion (or less often at rest), cough, chest pain, hemoptysis, and recurrent lung infections [62,63]. The mean onset of symptoms is two to five months after the https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 11/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate procedure [62-64]. The intensity of symptoms may be directly related to the degree of obstruction and inversely related to the duration of time to develop the stenosis [65]. Incorrect diagnoses including pneumonia, bronchitis, or suspected malignancy are often considered and result in unnecessary testing, treatment, and delayed intervention. Delays in diagnosis and treatment may allow for progression of stenosis and irreversible intraparenchymal lung damage. The reported rate of PV stenosis depends not only on the factors described above, but also on the definition of stenosis severity and the intensity of screening. Early reports cited rates as high as 38 percent, but more studies cite rates for severe stenosis as low as 1 to 3 percent [53,58,63,66]. A minority of diagnosed patients appear to develop symptoms [67,68]. The incidence of severe PV stenosis is between 0.32 and 3.4 percent, but the risk may be lower with cryoballoon compared with radiofrequency energy [69]. The rate of PV stenosis requiring intervention may be as low as 0.1 to 0.3 percent [57]. Diagnostic evaluation for PV stenosis should be performed in patients who develop respiratory symptoms after RF ablation (RFA). The joint Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement of catheter and surgical ablation of AF suggests computed tomography or magnetic resonance imaging (MRI) as the preferred tests in suspected cases [65]. A ventilation/perfusion lung scan can also be used to diagnose PV stenosis. Stent placement is a more effective therapy for PV stenosis compared with balloon angioplasty [69]. It is associated with a significant and almost immediate improvement in symptoms and pulmonary blood flow [62-64]. In series of patients who underwent balloon angioplasty with or without stenting, in-segment or in-stent stenosis requiring repeat intervention developed in approximately 50 percent of patients [63,64]. The roles of either elective stenting or surgery are not well defined [65]. However, the incidence of PV stenosis has significantly decreased due to improvement in ablative techniques, especially with moving the ablation lesions toward the atrial side of the PV-atrial junction. Periprocedural embolic events Patients undergoing CA to prevent recurrent AF are at risk for embolic events before, during, and after the procedure. The incidence of clinical stroke or transient ischemic attack is between 0 and 2 percent [9]. The role of anticoagulant therapy in this setting is discussed in detail separately. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) MRI-detected brain lesions and cognitive impairment Stroke and transient ischemic attack are not the only neurologic sequelae of CA. Multiple MRI studies performed within 24 hours https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 12/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate after RFA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [70-72]. However, in a study of 60 AF patients at relatively low risk for stroke who underwent CA, only one patient developed new asymptomatic lesions on MRI soon after the procedure [73]. These lesions were presumed secondary to microemboli [74]. Studies of the impact of these lesions on neurocognitive function have come to differing conclusions as to the significance of these lesions, as illustrated by the following studies: The prevalence of cognitive impairment after RFA was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal AF, 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [75]. All RFA patients received periprocedural enoxaparin, and most patients with AF had a CHADS 2 score of 0 or 1 ( table 3). All patients underwent eight neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively. In a study of 37 patients with paroxysmal AF who underwent 41 ablation procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [72]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing. Vascular complications Vascular complications are among the most common adverse events related to AF ablation, likely due to the number and size of intravascular sheaths and the need for anticoagulation both during and immediately following the procedure. These complications include hematoma at the sites of catheter insertion, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Pseudoaneurysm and arteriovenous fistulae rates of 0.53 and 0.43 percent, respectively, have been reported [57,58]. This risk can be significantly reduced by the use of vascular ultrasound, which was demonstrated, in one study of 689 patients, to reduce the risk of vascular access complications from 5.3 to 1.1 percent [76]. Conservative management alone is usually sufficient for large hematomas and retroperitoneal bleeding, though anticoagulation may need to be held, and transfusion may be necessary in those patients where the risks of such interventions are warranted. Echo-guided manual compression and percutaneous intervention are usually effective treatments of femoral pseudoaneurysms or arteriovenous fistula, but direct surgical intervention is sometimes required [77]. Atrial esophageal fistula This is a potentially life-threatening medical emergency for which the exact mechanism is unknown. The overall incidence is 0.3 to 0.54 percent, and mortality is between 50 and 83 percent [78]. Early recognition can be missed due to the low awareness of https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 13/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate this rare complication. It is important for patients to be educated as to warning signs and to contact their AF ablation center should any suggestive symptoms develop. Clinical manifestations usually present one to four weeks post-ablation (range of 2 to 60 days), and the most common symptoms are fever, chest pain, and recurrent neurologic events from septic emboli. Chest computed tomography is the preferred diagnostic modality. Endoscopy with air insufflation should not be performed. Arrhythmic complications New reentrant circuits created by the ablation lesions can lead to atypical left atrial (LA) flutter. These circuits tend to develop around regions of LA scar and often involve the perimitral region. Due to anatomic variability and technical challenges, successful ablation is more difficult than that for typical right atrial flutter involving the isthmus of the inferior vena cava and tricuspid annulus. A significant percentage of LA flutter following PVI may also involve the musculature of the coronary sinus or the roof of the left atrium [79]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Typical atrial flutter may also occur after LA ablation due to alterations in activation patterns of the LA and may have an unusual electrocardiographic morphology. LA flutter appears to be more common following circumferential (as opposed to segmental) PVI [49,79-82]. In a randomized comparison of circumferential and segmental PVI, LA flutter developed in 9 of the 50 patients undergoing circumferential PVI, and in 1 of the 50 patients in the segmental PVI group [49]. In addition, many of the recurrent LA arrhythmias following segmental PVI are focal atrial tachycardias, as opposed to macroreentrant flutter circuits, and are often successfully treated with repeat isolation of the PVs. Other Other complications with their respective incidences are summarized: Phrenic nerve injury (<1 percent) [57,58] in patients receiving RFA (and up to 6.3 percent in those receiving cryoablation). (See 'Comparison of radiofrequency and cryothermal ablation' above.) Periesophageal vagal injury (gastric hypomotility) [48,83]. Acute coronary artery occlusion/injury (<1 percent) [65,84]. Iatrogenic atrial septal defect after cryoballoon ablation without clinical consequence (20 percent) [85]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 14/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate PREVENTION OF RECURRENCE The following therapies have been evaluated for their ability to prevent late recurrent AF; only treatment of obstructive sleep apnea (OSA) seems to be beneficial: Glucocorticoid therapy We do not believe there is sufficient evidence to recommend the use of prophylactic glucocorticoid therapy. Two observations raise the possibility that corticosteroid therapy might be useful for the prevention of early recurrence. Firstly, inflammation is associated with the development of AF, and systemic and local inflammatory responses may result from radiofrequency ablation (RFA) [86] (see "Epidemiology, risk factors, and prevention of atrial fibrillation",
the preferred tests in suspected cases [65]. A ventilation/perfusion lung scan can also be used to diagnose PV stenosis. Stent placement is a more effective therapy for PV stenosis compared with balloon angioplasty [69]. It is associated with a significant and almost immediate improvement in symptoms and pulmonary blood flow [62-64]. In series of patients who underwent balloon angioplasty with or without stenting, in-segment or in-stent stenosis requiring repeat intervention developed in approximately 50 percent of patients [63,64]. The roles of either elective stenting or surgery are not well defined [65]. However, the incidence of PV stenosis has significantly decreased due to improvement in ablative techniques, especially with moving the ablation lesions toward the atrial side of the PV-atrial junction. Periprocedural embolic events Patients undergoing CA to prevent recurrent AF are at risk for embolic events before, during, and after the procedure. The incidence of clinical stroke or transient ischemic attack is between 0 and 2 percent [9]. The role of anticoagulant therapy in this setting is discussed in detail separately. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) MRI-detected brain lesions and cognitive impairment Stroke and transient ischemic attack are not the only neurologic sequelae of CA. Multiple MRI studies performed within 24 hours https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 12/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate after RFA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [70-72]. However, in a study of 60 AF patients at relatively low risk for stroke who underwent CA, only one patient developed new asymptomatic lesions on MRI soon after the procedure [73]. These lesions were presumed secondary to microemboli [74]. Studies of the impact of these lesions on neurocognitive function have come to differing conclusions as to the significance of these lesions, as illustrated by the following studies: The prevalence of cognitive impairment after RFA was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal AF, 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [75]. All RFA patients received periprocedural enoxaparin, and most patients with AF had a CHADS 2 score of 0 or 1 ( table 3). All patients underwent eight neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively. In a study of 37 patients with paroxysmal AF who underwent 41 ablation procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [72]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing. Vascular complications Vascular complications are among the most common adverse events related to AF ablation, likely due to the number and size of intravascular sheaths and the need for anticoagulation both during and immediately following the procedure. These complications include hematoma at the sites of catheter insertion, pseudoaneurysm, arteriovenous fistula, or retroperitoneal bleeding. Pseudoaneurysm and arteriovenous fistulae rates of 0.53 and 0.43 percent, respectively, have been reported [57,58]. This risk can be significantly reduced by the use of vascular ultrasound, which was demonstrated, in one study of 689 patients, to reduce the risk of vascular access complications from 5.3 to 1.1 percent [76]. Conservative management alone is usually sufficient for large hematomas and retroperitoneal bleeding, though anticoagulation may need to be held, and transfusion may be necessary in those patients where the risks of such interventions are warranted. Echo-guided manual compression and percutaneous intervention are usually effective treatments of femoral pseudoaneurysms or arteriovenous fistula, but direct surgical intervention is sometimes required [77]. Atrial esophageal fistula This is a potentially life-threatening medical emergency for which the exact mechanism is unknown. The overall incidence is 0.3 to 0.54 percent, and mortality is between 50 and 83 percent [78]. Early recognition can be missed due to the low awareness of https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 13/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate this rare complication. It is important for patients to be educated as to warning signs and to contact their AF ablation center should any suggestive symptoms develop. Clinical manifestations usually present one to four weeks post-ablation (range of 2 to 60 days), and the most common symptoms are fever, chest pain, and recurrent neurologic events from septic emboli. Chest computed tomography is the preferred diagnostic modality. Endoscopy with air insufflation should not be performed. Arrhythmic complications New reentrant circuits created by the ablation lesions can lead to atypical left atrial (LA) flutter. These circuits tend to develop around regions of LA scar and often involve the perimitral region. Due to anatomic variability and technical challenges, successful ablation is more difficult than that for typical right atrial flutter involving the isthmus of the inferior vena cava and tricuspid annulus. A significant percentage of LA flutter following PVI may also involve the musculature of the coronary sinus or the roof of the left atrium [79]. (See "Electrocardiographic and electrophysiologic features of atrial flutter".) Typical atrial flutter may also occur after LA ablation due to alterations in activation patterns of the LA and may have an unusual electrocardiographic morphology. LA flutter appears to be more common following circumferential (as opposed to segmental) PVI [49,79-82]. In a randomized comparison of circumferential and segmental PVI, LA flutter developed in 9 of the 50 patients undergoing circumferential PVI, and in 1 of the 50 patients in the segmental PVI group [49]. In addition, many of the recurrent LA arrhythmias following segmental PVI are focal atrial tachycardias, as opposed to macroreentrant flutter circuits, and are often successfully treated with repeat isolation of the PVs. Other Other complications with their respective incidences are summarized: Phrenic nerve injury (<1 percent) [57,58] in patients receiving RFA (and up to 6.3 percent in those receiving cryoablation). (See 'Comparison of radiofrequency and cryothermal ablation' above.) Periesophageal vagal injury (gastric hypomotility) [48,83]. Acute coronary artery occlusion/injury (<1 percent) [65,84]. Iatrogenic atrial septal defect after cryoballoon ablation without clinical consequence (20 percent) [85]. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 14/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate PREVENTION OF RECURRENCE The following therapies have been evaluated for their ability to prevent late recurrent AF; only treatment of obstructive sleep apnea (OSA) seems to be beneficial: Glucocorticoid therapy We do not believe there is sufficient evidence to recommend the use of prophylactic glucocorticoid therapy. Two observations raise the possibility that corticosteroid therapy might be useful for the prevention of early recurrence. Firstly, inflammation is associated with the development of AF, and systemic and local inflammatory responses may result from radiofrequency ablation (RFA) [86] (see "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'). Secondly, glucocorticoid prophylaxis reduces the risk of the development of perioperative AF in patients undergoing coronary artery bypass graft surgery. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The possible benefit from prophylactic glucocorticoid therapy was evaluated in a study of 125 patients with paroxysmal AF who were randomly assigned to either three days of glucocorticoid therapy or placebo starting immediately after the procedure [87]. The rate of AF recurrence (primary endpoint) was significantly lower in the glucocorticoid group at one month (27 versus 49 percent), with most of the benefit occurring during the first three days (7 versus 31 percent). Treatment of OSA OSA is a predictor of recurrent AF after RFA. Patients with OSA who undergo CA should be encouraged to be evaluated for treatment with continuous positive airway pressure [88,89]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".) Colchicine Colchicine, another drug with antiinflammatory properties, has been shown to decrease the risk of postoperative AF after cardiac surgery, particularly in patients with post-pericardiotomy syndrome. However, pending additional studies showing benefit, we do not use prophylactic colchicine. (See "Post-cardiac injury syndromes", section on 'Prevention'.) The potential ability of colchicine to reduce the incidence of early recurrent AF after pulmonary vein isolation was evaluated in a study of 206 individuals with paroxysmal AF who were randomly assigned to colchicine 0.5 mg twice daily or placebo beginning on the day of CA and continuing for three months [90]. After follow-up of about 15 months, there https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 15/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate was a lower recurrence rate of AF in patients taking colchicine (31.1 versus 49.5 percent; odds ratio [OR] 0.46, 95% CI 0.26-0.81). Angiotensin inhibition The data are mixed as to whether angiotensin converting enzyme inhibitors/angiotensin II receptor blockers reduce AF after CA procedures. This issue is discussed elsewhere. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation", section on 'Catheter ablation of atrial fibrillation'.) Periprocedural weight reduction Some studies suggest that periprocedural weight reduction may be a helpful adjunct to CA. Pre-procedure weight reduction In a retrospective study of 600 patients, weight reduction before CA was associated with reduced AF occurrence [91]. Freedom from AF was observed in 420 patients (70 percent) at 15 months. Percent weight loss during the year before CA independently predicted freedom from AF through the next 15 months (OR 1.17, 95% CI 1.11-1.23). Post-procedure weight reduction The SORT-AF Study compared one-year AF burden in patients with obesity participating in a weight loss program versus usual care after CA [92]. The intervention group had a small reduction in weight loss (5 versus 1 kg in controls). AF burden (measured with implantable loop recorder) after ablation did not differ between the two groups (OR 1.14, 95% CI 0.37-3.6). However, a reduction in body mass index was associated with a decrease in AF recurrence in persistent compared with paroxysmal AF patients. FOLLOW-UP Surveillance for recurrence of atrial arrhythmias is important in patients who have undergone CA. We agree with the joint Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society expert consensus statement of catheter and surgical ablation of AF [65], which recommends the following: First visit with electrophysiologist at a minimum of three months, and then every six months for at least two years. Electrocardiograms (ECGs) at all visits; symptomatic (eg, palpitations) patients should be evaluated with some form of event monitoring. The optimal method for screening for episodes of AF after ablation is not known. In the above studies, late recurrent AF was detected by patient symptoms, serial ECGs, 24- to 48-hour Holter https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 16/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate monitoring, and implantable cardiac monitor [10,16,93,94]. Rhythm transmitters were also used in the first few months [94]. With the exceptions of implantable cardiac monitor, preexisting dual-chamber pacemaker, or implantable cardioverter-defibrillator with AF detection capabilities, these methods may underestimate the incidence of recurrence due to sampling error [95]. In addition, as has been well demonstrated, patients with AF have a high rate of asymptomatic episodes. (See "Paroxysmal atrial fibrillation", section on 'Natural history' and 'Efficacy' above.) MANAGEMENT OF RECURRENCE Some patients with symptomatic AF after CA are candidates for a repeat procedure. The decision to do so is usually based on a patient's assessment of the potential benefit and risks. Other patients may choose a trial of antiarrhythmic drug therapy to reduce symptoms. The most common reason for recurrence of paroxysmal AF is reconnection of previously ablated electrically active tissue. Based upon the recurrence rates of AF after ablation, many patients are candidates for repeat ablation. We tell our patients that the success rate is in the range of 50 to 85 percent for a single procedure based primarily on AF type and anatomy, and that about 20 percent of patients have at least a second procedure. Success rates after a second procedure can be as high as 90 percent. Some experts and patients have agreed to repeat the procedure a third time. Patients with a history of persistent AF have a lower success rate and are less often felt to be good candidates for repeat procedures. The issue of whether patients with AF recurrence should undergo a repeat procedure or be placed on antiarrhythmic drug therapy was addressed in a study that randomly assigned 154 patients with symptomatic, paroxysmal AF recurrence to either repeat ablation or antiarrhythmic drugs [96]. During three-year follow-up, fewer patients in the repeat ablation group demonstrated AF progression, defined as an increase in AF burden >30 percent relative to baseline based on insertable cardiac monitor (also sometimes referred to as implantable cardiac monitor or implantable loop recorder) data or development of persistent AF (25 versus 79 percent; p<0.01). Despite limitations of this study, it supports our approach of offering a second ablation procedure to most patients. CONTRAINDICATIONS While there are few absolute contraindications, the risks and benefits of AF ablation should be carefully considered in each patient. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 17/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Contraindications to AF ablation include preexisting left atrial or left atrial appendage thrombus, inability to safely administer anticoagulation during or after the procedure, inability to tolerate sedation, patients with atrial septal defect closure devices in whom transseptal access cannot be performed, and those with interruption of the inferior vena cava. While not contraindicated, ablations performed on those with very long-standing persistent AF (ie, >2 years), severe mitral stenosis or regurgitation, or large left atria are expected to have lower success rates. (See 'Predictors of recurrence' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of catheter ablation (CA) CA for atrial fibrillation (AF) leads to symptom improvement in many patients. However, it has not convincingly been shown to decrease the risks of embolization (eg, stroke) or death. (See 'Efficacy' above.) https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 18/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Efficacy Current techniques for CA should lead to one-year freedom from symptomatic AF while off antiarrhythmic drug therapy in about 75 to 90 percent of patients with drug- resistant paroxysmal AF and no significant structural heart disease. (See 'Efficacy' above.) Complications Important complications of CA include death, cardiac tamponade, stroke, vascular trauma, and phrenic nerve palsy ( table 1). Specific signs and symptoms can help identify complications ( table 2). (See 'Complications' above.) Recurrence For patients who have recurrent AF after a first ablation, there are two reasonable management strategies: a clinical trial of an antiarrhythmic agent or proceeding directly to a second ablation. Patients may have a preference for one or the other. (See 'Management of recurrence' above.) 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Schmidt M, Dorwarth U, Andresen D, et al. Cryoballoon versus RF ablation in paroxysmal atrial fibrillation: results from the German Ablation Registry. J Cardiovasc Electrophysiol 2014; 25:1. 28. Linhart M, Bellmann B, Mittmann-Braun E, et al. Comparison of cryoballoon and radiofrequency ablation of pulmonary veins in 40 patients with paroxysmal atrial fibrillation: a case-control study. J Cardiovasc Electrophysiol 2009; 20:1343. 29. Kojodjojo P, O'Neill MD, Lim PB, et al. Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium- term outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency ablation. Heart 2010; 96:1379. 30. Cardoso R, Mendirichaga R, Fernandes G, et al. Cryoballoon versus Radiofrequency Catheter Ablation in Atrial Fibrillation: A Meta-Analysis. J Cardiovasc Electrophysiol 2016; 27:1151. 31. Kuck KH, Brugada J, F rnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016; 374:2235. 32. Lakhani M, Saiful F, Parikh V, et al. Recordings of diaphragmatic electromyograms during cryoballoon ablation for atrial fibrillation accurately predict phrenic nerve injury. Heart Rhythm 2014; 11:369. 33. Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010; 7:835. 34. Valderr bano M, Peterson LE, Swarup V, et al. Effect of Catheter Ablation With Vein of Marshall Ethanol Infusion vs Catheter Ablation Alone on Persistent Atrial Fibrillation: The VENUS Randomized Clinical Trial. JAMA 2020; 324:1620. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 21/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate 35. Wynn GJ, Das M, Bonnett LJ, et al. Efficacy of catheter ablation for persistent atrial fibrillation: a systematic review and meta-analysis of evidence from randomized and nonrandomized controlled trials. Circ Arrhythm Electrophysiol 2014; 7:841. 36. Mittal S, Pokushalov E, Romanov A, et al. Long-term ECG monitoring using an implantable loop recorder for the detection of atrial fibrillation after cavotricuspid isthmus ablation in patients with atrial flutter. Heart Rhythm 2013; 10:1598. 37. Schneider R, Lauschke J, Tischer T, et al. Pulmonary vein triggers play an important role in the initiation of atrial flutter: Initial results from the prospective randomized Atrial Fibrillation Ablation in Atrial Flutter (Triple A) trial. Heart Rhythm 2015; 12:865. 38. Wazni O, Marrouche NF, Martin DO, et al. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Circulation 2003; 108:2479. 39. Waldo AL, Cooper TB. Spontaneous onset of type I atrial flutter in patients. J Am Coll Cardiol 1996; 28:707. 40. Waldo AL. Mechanisms of atrial flutter and atrial fibrillation: distinct entities or two sides of a coin? Cardiovasc Res 2002; 54:217. 41. Steinberg JS, Romanov A, Musat D, et al. Prophylactic pulmonary vein isolation during isthmus ablation for atrial flutter: the PReVENT AF Study I. Heart Rhythm 2014; 11:1567. 42. Lang CC, Santinelli V, Augello G, et al. Transcatheter radiofrequency ablation of atrial fibrillation in patients with mitral valve prostheses and enlarged atria: safety, feasibility, and efficacy. J Am Coll Cardiol 2005; 45:868. 43. Nair M, Shah P, Batra R, et al. Chronic atrial fibrillation in patients with rheumatic heart disease: mapping and radiofrequency ablation of flutter circuits seen at initiation after cardioversion. Circulation 2001; 104:802. 44. Steinberg JS, Shabanov V, Ponomarev D, et al. Effect of Renal Denervation and Catheter Ablation vs Catheter Ablation Alone on Atrial Fibrillation Recurrence Among Patients With Paroxysmal Atrial Fibrillation and Hypertension: The ERADICATE-AF Randomized Clinical Trial. JAMA 2020; 323:248. 45. Bertaglia E, Stabile G, Pappone A, et al. Updated national multicenter registry on procedural safety of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2013; 24:1069. 46. Pappone C, Oral H, Santinelli V, et al. Atrio-esophageal fistula as a complication of percutaneous transcatheter ablation of atrial fibrillation. Circulation 2004; 109:2724. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 22/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate 47. Scanavacca MI, D' vila A, Parga J, Sosa E. Left atrial-esophageal fistula following radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2004; 15:960. 48. Shah D, Dumonceau JM, Burri H, et al. Acute pyloric spasm and gastric hypomotility: an extracardiac adverse effect of percutaneous radiofrequency ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:327. 49. Karch MR, Zrenner B, Deisenhofer I, et al. Freedom from atrial tachyarrhythmias after catheter ablation of atrial fibrillation: a randomized comparison between 2 current ablation strategies. Circulation 2005; 111:2875. 50. Oral H, Scharf C, Chugh A, et al. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation. Circulation 2003; 108:2355. 51. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013; 128:2104. 52. Gupta A, Perera T, Ganesan A, et al. Complications of catheter ablation of atrial fibrillation: a systematic review. Circ Arrhythm Electrophysiol 2013; 6:1082. 53. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 54. Zado E, Callans DJ, Riley M, et al. Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in the elderly. J Cardiovasc Electrophysiol 2008; 19:621. 55. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 56. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:32. 57. Maan A, Shaikh AY, Mansour M, et al. Complications from catheter ablation of atrial fibrillation: a systematic review. Crit Pathw Cardiol 2011; 10:76. 58. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005; 111:1100. 59. Zeljko HM, Mont L, Sitges M, et al. Entrapment of the circular mapping catheter in the mitral valve in two patients undergoing atrial fibrillation ablation. Europace 2011; 13:132. 60. Kesek M, Englund A, Jensen SM, Jensen-Urstad M. Entrapment of circular mapping catheter in the mitral valve. Heart Rhythm 2007; 4:17. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 23/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate 61. Taylor GW, Kay GN, Zheng X, et al. Pathological effects of extensive radiofrequency energy applications in the pulmonary veins in dogs. Circulation 2000; 101:1736. 62. Saad EB, Marrouche NF, Saad CP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med 2003; 138:634. 63. Packer DL, Keelan P, Munger TM, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation 2005; 111:546. 64. Qureshi AM, Prieto LR, Latson LA, et al. Transcatheter angioplasty for acquired pulmonary vein stenosis after radiofrequency ablation. Circulation 2003; 108:1336. 65. European Heart Rhythm Association (EHRA), European Cardiac Arrhythmia Scoiety (ECAS), American College of Cardiology (ACC), et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4:816. 66. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003; 108:3102. 67. Arentz T, Weber R, Jander N, et al. Pulmonary haemodynamics at rest and during exercise in patients with significant pulmonary vein stenosis after radiofrequency catheter ablation for drug resistant atrial fibrillation. Eur Heart J 2005; 26:1410. 68. Di Biase L, Fahmy TS, Wazni OM, et al. Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up. J Am Coll Cardiol 2006; 48:2493. 69. Fender EA, Widmer RJ, Hodge DO, et al. Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation: Presentation, Management, and Clinical Outcomes. Circulation 2016; 134:1812. 70. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 71. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 72. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 24/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Circ Arrhythm Electrophysiol 2013; 6:843. 73. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 74. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 75. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 76. Sharma PS, Padala SK, Gunda S, et al. Vascular complications during catheter ablation of cardiac arrhythmias: A comparison between vascular ultrasound guided access and conventional vascular access. J Cardiovasc Electrophysiol 2016; 27:1160. 77. Waigand J, Uhlich F, Gross CM, et al. Percutaneous treatment of pseudoaneurysms and arteriovenous fistulas after invasive vascular procedures. Catheter Cardiovasc Interv 1999; 47:157. 78. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 79. Chugh A, Oral H, Good E, et al. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:83. 80. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001; 24:1774. 81. Cummings JE, Schweikert R, Saliba W, et al. Left atrial flutter following pulmonary vein antrum isolation with radiofrequency energy: linear lesions or repeat isolation. J Cardiovasc Electrophysiol 2005; 16:293. 82. Gerstenfeld EP, Callans DJ, Dixit S, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004; 110:1351. 83. Dumonceau JM, Giostra E, Bech C, et al. Acute delayed gastric emptying after ablation of atrial fibrillation: treatment with botulinum toxin injection. Endoscopy 2006; 38:543. 84. Roberts-Thomson KC, Steven D, Seiler J, et al. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation 2009; 120:1465. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 25/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate 85. Sieira J, Chierchia GB, Di Giovanni G, et al. One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014; 25:11. 86. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009; 103:1249. 87. Koyama T, Tada H, Sekiguchi Y, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56:1463. 88. Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62:300. 89. Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013; 10:331. 90. Deftereos S, Giannopoulos G, Efremidis M, et al. Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life. Heart Rhythm 2014; 11:620. 91. Peigh G, Wasserlauf J, Vogel K, et al. Impact of pre-ablation weight loss on the success of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2021; 32:2097. 92. Gessler N, Willems S, Steven D, et al. Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial. Europace 2021; 23:1548. 93. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 94. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 95. Senatore G, Stabile G, Bertaglia E, et al. Role of transtelephonic electrocardiographic monitoring in detecting short-term arrhythmia recurrences after radiofrequency ablation in patients with atrial fibrillation. J Am Coll Cardiol 2005; 45:873. 96. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013; 6:754. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 26/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Topic 949 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 27/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate GRAPHICS Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation
American College of Cardiology (ACC), et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007; 4:816. 66. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003; 108:3102. 67. Arentz T, Weber R, Jander N, et al. Pulmonary haemodynamics at rest and during exercise in patients with significant pulmonary vein stenosis after radiofrequency catheter ablation for drug resistant atrial fibrillation. Eur Heart J 2005; 26:1410. 68. Di Biase L, Fahmy TS, Wazni OM, et al. Pulmonary vein total occlusion following catheter ablation for atrial fibrillation: clinical implications after long-term follow-up. J Am Coll Cardiol 2006; 48:2493. 69. Fender EA, Widmer RJ, Hodge DO, et al. Severe Pulmonary Vein Stenosis Resulting From Ablation for Atrial Fibrillation: Presentation, Management, and Clinical Outcomes. Circulation 2016; 134:1812. 70. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 71. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 72. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 24/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Circ Arrhythm Electrophysiol 2013; 6:843. 73. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 74. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 75. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 76. Sharma PS, Padala SK, Gunda S, et al. Vascular complications during catheter ablation of cardiac arrhythmias: A comparison between vascular ultrasound guided access and conventional vascular access. J Cardiovasc Electrophysiol 2016; 27:1160. 77. Waigand J, Uhlich F, Gross CM, et al. Percutaneous treatment of pseudoaneurysms and arteriovenous fistulas after invasive vascular procedures. Catheter Cardiovasc Interv 1999; 47:157. 78. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 79. Chugh A, Oral H, Good E, et al. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. J Am Coll Cardiol 2005; 46:83. 80. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001; 24:1774. 81. Cummings JE, Schweikert R, Saliba W, et al. Left atrial flutter following pulmonary vein antrum isolation with radiofrequency energy: linear lesions or repeat isolation. J Cardiovasc Electrophysiol 2005; 16:293. 82. Gerstenfeld EP, Callans DJ, Dixit S, et al. Mechanisms of organized left atrial tachycardias occurring after pulmonary vein isolation. Circulation 2004; 110:1351. 83. Dumonceau JM, Giostra E, Bech C, et al. Acute delayed gastric emptying after ablation of atrial fibrillation: treatment with botulinum toxin injection. Endoscopy 2006; 38:543. 84. Roberts-Thomson KC, Steven D, Seiler J, et al. Coronary artery injury due to catheter ablation in adults: presentations and outcomes. Circulation 2009; 120:1465. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 25/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate 85. Sieira J, Chierchia GB, Di Giovanni G, et al. One year incidence of iatrogenic atrial septal defect after cryoballoon ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2014; 25:11. 86. Koyama T, Sekiguchi Y, Tada H, et al. Comparison of characteristics and significance of immediate versus early versus no recurrence of atrial fibrillation after catheter ablation. Am J Cardiol 2009; 103:1249. 87. Koyama T, Tada H, Sekiguchi Y, et al. Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial. J Am Coll Cardiol 2010; 56:1463. 88. Fein AS, Shvilkin A, Shah D, et al. Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation. J Am Coll Cardiol 2013; 62:300. 89. Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013; 10:331. 90. Deftereos S, Giannopoulos G, Efremidis M, et al. Colchicine for prevention of atrial fibrillation recurrence after pulmonary vein isolation: mid-term efficacy and effect on quality of life. Heart Rhythm 2014; 11:620. 91. Peigh G, Wasserlauf J, Vogel K, et al. Impact of pre-ablation weight loss on the success of catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol 2021; 32:2097. 92. Gessler N, Willems S, Steven D, et al. Supervised Obesity Reduction Trial for AF ablation patients: results from the SORT-AF trial. Europace 2021; 23:1548. 93. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 94. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 95. Senatore G, Stabile G, Bertaglia E, et al. Role of transtelephonic electrocardiographic monitoring in detecting short-term arrhythmia recurrences after radiofrequency ablation in patients with atrial fibrillation. J Am Coll Cardiol 2005; 45:873. 96. Pokushalov E, Romanov A, De Melis M, et al. Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. Circ Arrhythm Electrophysiol 2013; 6:754. https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 26/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Topic 949 Version 66.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 27/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate GRAPHICS Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation Back pain Musculoskeletal, retroperitoneal hematoma Physical exam, CT imaging Chest pain Pericarditis, pericardial effusion, Physical exam, chest coronary stenosis (ablation radiograph, ECG, related), pulmonary vein stenosis, musculoskeletal (after echocardiogram, stress test, cardiac catheterization, chest CT cardioversion), worsening reflux Cough Infectious process, bronchial irritation (mechanical, Physical exam, chest radiograph, chest CT cryoballoon), pulmonary vein stenosis Dysphagia Esophageal irritation (related to Physical exam, chest CT, MRI transesophageal echocardiography), atrioesophageal fistula Early satiety, nausea Gastric denervation Physical exam, gastric emptying study Fever Infectious process, pericarditis, atrioesophageal fistula Physical exam, chest radiograph, chest CT, urinalysis, laboratory blood work Fever, dysphagia, neurological symptoms Atrial esophageal fistula Physical exam, laboratory blood work, chest CT or MRI; avoid endoscopy with air insufflation Groin pain Pseudoaneurysm, AV fistula, hematoma Ultrasound of the groin, laboratory blood work; consider CT scan if ultrasound negative Hypotension Pericardial effusion/tamponade, bleeding, sepsis, persistent Echocardiography, laboratory blood work vagal reaction Hemoptysis Pulmonary vein stenosis or Chest radiograph, chest CT or occlusion, pneumonia MR scan, VQ scan Neurological symptoms Cerebral embolic event, atrial Physical exam, brain imaging, esophageal fistula chest CT or MRI https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 28/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Shortness of breath Volume overload, pneumonia, Physical exam, chest pulmonary vein stenosis, radiograph, chest CT, laboratory phrenic nerve injury blood work CT: computed tomography; ECG: electrocardiogram; MRI: magnetic resonance imaging; AV: atrioventricular. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127127 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 29/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Intraprocedural risks of ablation for atrial fibrillation Complication Incidence Diagnostic testing Air embolism <1% Nothing or cardiac catheterization Asymptomatic cerebral emboli 2 to 15% Brain MRI Cardiac tamponade 0.2 to 5% Echocardiography Coronary stenosis/occlusion <0.1% Cardiac catheterization Death <0.1 to 0.4% N/A Mitral valve entrapment <0.1% Echocardiography Permanent phrenic nerve paralysis 0 to 0.4% Chest radiograph, sniff test Radiation injury <0.1% None Stroke or TIA 0 to 2% Head CT/MRI, cerebral angiography Vascular complications 0.2 to 1.5% Vascular ultrasound, CT scan MRI: magnetic resonance imaging; TIA: transient ischemic attack; CT: computed tomography. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127125 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 30/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate CHADS score, thromboembolic risk, and effect of warfarin anticoagulation 2 Clinical parameter Points Congestive heart failure (any history) 1 Hypertension (prior history) 1 Age 75 years 1 Diabetes mellitus 1 Secondary prevention in patients with a prior ischemic stroke or a transient 2 ischemic attack; most experts also include patients with a systemic embolic event Events per 100 person-years* CHADS score 2 NNT Warfarin No warfarin 0 0.25 0.49 417 1 0.72 1.52 125 2 1.27 2.50 81 3 2.20 5.27 33 4 2.35 6.02 27 5 or 6 4.60 6.88 44 NNT: number needed to treat to prevent 1 stroke per year with warfarin. The CHADS score estimates the risk of stroke, which is defined as focal neurologic signs or symptoms that persist for more than 24 hours and that cannot be explained by hemorrhage, trauma, 2 or other factors, or peripheral embolization, which is much less common. Transient ischemic attacks are not included. All differences between warfarin and no warfarin groups are statistically significant, except for a trend with a CHADS score of 0. Patients are considered to be at low risk with a score of 0, at intermediate risk with a score of 1 or 2, and at high risk with a score 3. One exception is that most experts would consider patients with a prior ischemic stroke, transient ischemic attack, or 2 systemic embolic event to be at high risk, even if they had no other risk factors and, therefore, a score of 2. However, the great majority of these patients have some other risk factor and a score of at least 3. Data from: Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial brillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685; and CHADS2 score from Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. Graphic 61615 Version 8.0 https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 31/32 7/5/23, 9:05 AM Atrial fibrillation: Catheter ablation - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-catheter-ablation/print 32/32
7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Selection of candidates for anticoagulation : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 23, 2022. INTRODUCTION Atrial fibrillation (AF) is a major cause of morbidity and mortality in adults. While ischemic stroke due to embolization of left atrial thrombi is the most frequent clinical manifestation of embolization, embolization to other locations in the systemic circulation (and in the pulmonary circulation from right atrial thrombi) also occurs, but is less commonly recognized. Stroke associated with AF tends to be more extensive/larger than stroke related to carotid artery disease. Chronic oral anticoagulation (OAC) is recommended to reduce the risk of thromboembolism for most patients with AF. However, such therapy is associated with an increased risk of bleeding, and recommendations for its use must take both benefit and risk into account through shared decision-making with the patient. (See "Stroke in patients with atrial fibrillation".) This topic will focus on identifying which patients with AF require long-term/chronic OAC with either vitamin K antagonist (VKA; eg, warfarin) or direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]). The discussion here excludes patients with 2 rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ), a bioprosthetic valve (surgical or bioprosthetic) within the first three to six months after implantation, or a mechanical heart valve. Management for patients with these valve conditions is briefly discussed in a section below that provides links to related topics. (See 'Patients with valvular heart disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 1/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Other potentially relevant topics to the reader include: Choice of OAC for AF (see "Atrial fibrillation in adults: Use of oral anticoagulants") (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO DECIDING WHETHER TO ANTICOAGULATE Decision-making based upon risk assessment A first step in deciding which patients with AF should receive long-term oral anticoagulation (OAC) is to assess the individual patient s risks of thromboembolism and bleeding along with patient preferences. Long-term anticoagulation lowers the risk of clinical embolization in patients with AF, but its use is associated with an increased risk of bleeding. The benefits and risks of OAC with respect to reduction in risk of stroke and increment in risk of bleeding must be carefully considered and discussed with each patient. The greater the estimated reduction in absolute stroke risk compared with the increase in absolute risk of life- threatening or severely debilitating bleeding (such as intracranial hemorrhage), the more likely a patient is to benefit from long-term OAC. The benefit generally outweighs the risk for all but those with the lowest risk of thromboembolism. In cases of more balanced stroke reduction and bleeding risks, OAC is less likely to provide a net benefit. Risk scores are commonly used to assess thromboembolic and bleeding risks, although these tools are subject to a number of limitations. (See 'CHA2DS2-VASc score' below and 'Bleeding risk' below.) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Our approach to deciding whether to prescribe anticoagulant therapy for patients with AF (without severe or clinically significant rheumatic mitral stenosis [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) is as follows: For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC. For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1), the 2 2 specific nonsex risk factor present and the documented burden of AF influences decision making: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 2/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC. Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score point [1]. 2 2 For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. The frequency and duration of AF episodes vary widely over time and episodes are often asymptomatic. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1)( table 1), 2 2 we suggest against anticoagulant therapy. Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' below) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated, and to flag patients with high bleeding risk for early review and follow-up and to identify potential candidates for left atrial appendage occlusion [2-6]. (See 'Bleeding risk' below and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding'.) Effects of anticoagulation In identifying which patients with AF are likely to benefit from OAC, the relative risk reduction in thromboembolism with OAC identified in randomized trials (see 'General efficacy' below) is combined with estimates of baseline risk using the CHA DS - 2 2 VASc score to estimate the expected absolute risk reduction from OAC (see 'CHA2DS2-VASc score' below). The estimated absolute risk reduction for thromboembolic events is weighed against the estimated increase in absolute risk of intracranial hemorrhage (ICH) and other major bleeding complications. (See 'Bleeding risk' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 3/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate General efficacy For patients with AF, randomized trials have shown that therapeutic OAC (vitamin K antagonist [VKA] or DOAC) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo irrespective of baseline risk ( figure 1) [7-17]. A meta-analysis included six randomized trials comparing VKA (warfarin) with placebo or no treatment in a total of 2900 participants with AF (mean age at entry 69 years, 20 percent with prior stroke or transient ischemic attack) [14]. The overall rate of stroke was 2.2 percent/patient year in the warfarin group and 6.0 percent/patient year in the control group (relative risk reduction 0.64; 95% CI 0.49-0.74). The absolute risk reduction was 2.7 percent/year for primary prevention and 8.4 percent/year for secondary prevention. With warfarin therapy, all-cause mortality was reduced by 1.6 percent/year (relative risk reduction 0.26; 95% CI 0.03-0.43). While most of the evidence comparing OAC with placebo in patients involved treatment with VKA, a trial comparing edoxaban 15 mg daily with placebo in patients with AF 80 years old with low body weight found a similar relative reduction in risk of stroke or systemic embolism (2.3 versus 6.7 percent/year; hazard ratio 0.34, 95% CI 0.19-0.61) [18]. The possible implications of this study for edoxaban dose are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) CHA2DS2-VASc score Use We use the CHA DS -VASc score (calculator 1) to estimate thromboembolic risk in 2 2 patients with AF, while recognizing its limitations (see 'Potential alternatives' below and 'Limitations' below). This estimation of baseline thromboembolic risk is combined with the above information on relative risk reduction (see 'General efficacy' above) to estimate the expected absolute risk reduction. The annual risk of ischemic stroke in untreated patients is estimated to be 0.2, 0.6, and 2.2 percent for those with CHA DS -VASc scores of 0, 1, and 2 ( table 1) [19]. However, stroke 2 2 rates have varied substantially among studies, which may be due to differences in study populations and methodologies [2,20-24]. As an example, studies examining ischemic stroke rates in patients with a single risk factor have identified risks of <1 to 2.7 percent/year [25-27]. Among patients with AF, ischemic stroke is the dominant type of thromboembolic event. As an example, in a study including data on 39,973 participants in four randomized trials of anticoagulation, the incidence of nonstroke systemic embolic events (SEEs) was 0.23/100 person-years, and the incidence of cerebral embolism was 1.92/100 person-years [28]. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 4/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among those with SEEs, 58 percent occurred in the lower extremities, 31 percent in the visceral-mesenteric system, and 11 percent in the upper extremities. Among patients with AF treated with OAC, annual stroke risk is lowered by approximately two-thirds to <0.1, 0.2, and 0.6 percent, respectively. In addition to the lowering of stroke risk, there is evidence that warfarin, compared with no anticoagulant therapy, leads to less severe stroke episodes and lower 30-day stroke mortality [14,29]. The annual risk of intracranial bleeding with warfarin is 0.2, 0.3, and 0.5 percent, respectively. The risk of ICH with DOAC is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Among adults with AF, females have a modestly higher risk of thromboembolism than males, but female sex is associated with increased risk primarily in patients with at least two CHA DS - 2 2 VASc score non-sex risk score points [1,30]. Thus, we focus on non-sex risk factors when deciding whether OAC is indicated. For CHA DS -VASc score 2 in males or 3 in females (when the risk score points are 2 2 from two or more non-sex risk factors), the benefit from OAC generally exceeds the risks of severe bleeding [19,31-33]. For CHA DS -VASc score of 1 in males or 2 in females (one non-sex risk factor with a 2 2 value of 1), the risk of thromboembolism varies depending upon the non-sex risk factor [1]. Among the risk factors with a one-point value, age 65 to 74 years and the presence of heart failure have the greatest effect on thromboembolic risk [1], and OAC is recommended in patients with any of these risk factors. For CHA DS - VASc score of 0 in males or 1 in females (zero nonsex risk factors), the 2 2 thromboembolic risk is low [27], so no OAC is suggested. (See 'Approach to deciding whether to anticoagulate' above.) The warfarin versus placebo or aspirin trials were reported in the early 1990s, raising concerns that the findings may not be applicable to contemporary clinical practice [31,34,35]. Studies evaluating more contemporary data have found that the absolute risk of stroke in untreated patients has fallen from approximately 8 percent/year to 4 or 5 percent/year ( table 1), but the relative risk reduction attributable to anticoagulant therapy is in the same range as earlier studies [36,37]. A two-thirds risk reduction in thromboembolism using the more contemporary lower absolute risks is clinically important for patients with two or more nonsex risk factors and for selected patients with one nonsex risk factor. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 5/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Comparisons of the effects of VKA and DOAC are presented separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Potential alternatives A variety of risk scores, imaging methods, and biomarkers have been studied for their potential predictive value for thromboembolic risk in patients with AF [38]. The CHA DS -VASc score has been compared with potential alternatives including the CHADS 2 2 2 and ATRIA risk scores ( table 1 and table 5). The clinical utility of a risk score for individuals with AF hinges primarily on its accuracy in identifying those at lowest risk for thromboembolism, as anticoagulation is generally recommended for individuals with all but the lowest level of risk. Systematic reviews suggest that the CHA DS -VASc score generally performs better than the 2 2 CHADS and ATRIA scores in identifying low-risk patients, although there have been some 2 discrepant results for comparisons of CHA DS -VASc and ATRIA [38]. However, all these risk 2 2 scores are subject to the limitations discussed below. (See 'Limitations' below.) A potential alternative to the risk score approach is to calculate the risk for each patient based upon risk factors including age as a continuous variable using the Calculator of Absolute Stroke Risk (CARS) [1]. For patients with AF, there is no established role for routine cardiac imaging to assess thromboembolic risk. Transesophageal echocardiography (TEE) is used in patients with AF primarily to evaluate left and right atrial appendage anatomy/function to identify individuals who are free of atrial thrombi and are therefore candidates for early cardioversion (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation"). Thromboembolic risk is associated with cardiac imaging findings, including evidence of left atrial thrombus (generally assessed by TEE; less commonly assessed by cardiovascular magnetic resonance [CMR] or cardiac computed tomography [CCT]) and depressed left ventricular ejection fraction (which can be assessed by transthoracic echocardiography, TEE, CMR, CCT, or nuclear methods) [39]. However, imaging findings have not been shown to improve risk stratification in patients with AF [2]. Limitations Risk scores to estimate thromboembolic risk in patients with AF have limited predictive value when applied to individual patients. One limitation is that risk scores utilize point systems that do not reflect differences in risk among included risk factors. Risk factors assigned equal point values are associated with substantially different risks, as illustrated by the following examples for the CHA DS -VASc score 2 2 ( table 1) [1]: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 6/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Age 65 to 74 years is associated with substantially greater stroke risk than other risk factors assigned one point. A history of prior stroke, transient ischemic attack, or thromboembolic event is assigned two points, but the risk associated with this risk factor is more than five times the risk associated with risk factors assigned one point. The continuous risk of age is lumped into categories, so that ages 65 years and 74 years each confer one point, despite the much higher actual risk associated with the older age. Another limitation is that the event rates observed in populations used to generate risk score may differ from those occurring in different clinical settings (eg, community versus hospitalized) and patient populations with differing risk profiles. Also, some clinical features or conditions may impact the risk of thromboembolism but are not included in risk models; these include the duration or frequency of episodes of paroxysmal AF and the presence of conditions such as chronic kidney disease and elevated troponin level. Prediabetes has also been implicated as a possible risk factor for stroke in patients with AF [40]. The potential role of troponin measurement in the assessment of the risk of embolization in patients with AF is discussed separately. (See 'Chronic kidney disease' below and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Atrial fibrillation'.) Bleeding risk When OAC is considered, the major safety concern is the increased risk of bleeding, especially major bleeding, which includes events that require hospitalization, transfusion, or surgery, or that involve particularly sensitive anatomic locations. Thus, bleeding risk and related contraindications to OAC should be reviewed ( table 2). A systematic review comparing various bleeding risk scores in patients with AF found that the HAS-BLED risk score ( table 3) was the best predictor of bleeding risk [2], although all bleeding risk scores provide imprecise estimates for individual patients, do not provide estimates for specific types of major bleeds, and are based upon bleeding risk with warfarin. Two more recent studies confirmed the efficacy of the HAS-BLED score was comparable to or better than ORBIT score in patients treated with DOACs [41,42]. Among patients with AF, the three most important predictors of major bleeding (including ICH) are overanticoagulation with warfarin (defined as an international normalized ratio greater than 3.0), prior stroke, and older patient age [31,43-45]. (See "Risks and prevention of bleeding with oral anticoagulants".) The risk of bleeding was evaluated in a cohort of over 16,000 patients diagnosed with AF between 2005 and 2010 [37]. The incidence of major bleeding with current, recent, past, or no https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 7/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate VKA (warfarin) exposure was 3.8, 4.5, 2.7, and 2.9/100 patient-years, respectively. However, major bleeding includes ICH and extracranial bleeding, particularly gastrointestinal bleeding. ICH is the most serious bleeding complication, since the likelihood of mortality or subsequent major disability is substantially higher than with bleeding at other sites [46]. In this study and others, the annual risk of ICH in patients with AF who are not anticoagulated is estimated to be 0.2 percent/year; that risk approximately doubles with OAC with VKA [34,37]. Randomized trials have shown that the risk of ICH with DOAC (both direct thrombin and factor Xa inhibitors) is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Given differences in morbidity associated with different types of bleeding, we think most patients would weigh the reduction in risk of ischemic stroke primarily against the increase in risk of ICH, with less weight given to the risk of gastrointestinal bleed or other less serious bleeding. While the incremental absolute risk of ICH with VKA (approximately 0.2 percent/year) is not trivial, it is substantially less than the expected absolute reduction in risk of ischemic stroke from OAC for most patients with AF and two or more nonsex CHA DS -VASc risk factors. 2 2 One problem with the bleeding risk scores is that they were developed from studies that included bleeds of differing severity. While any bleed can lead to death or severe disability, most do not; the major exception is ICH. The morbidity associated with ICH is similar to that for ischemic stroke, while the morbidity associated with gastrointestinal bleeding is generally not as severe. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) For patients in the following clinical settings, the bleeding risk is significantly higher: Thrombocytopenia or known coagulation defect associated with bleeding Active bleeding or recent surgery with a concern for ongoing bleeding Prior severe bleeding (including ICH) while on an oral anticoagulant Aortic dissection Malignant hypertension Combined use of anticoagulant and antiplatelet (including regular use of nonsteroidal antiinflammatory) agents SPECIFIC PATIENT GROUPS Patients with valvular heart disease For patients with valvular heart disease (excluding those with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 8/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate implantation, or a mechanical heart valve), the above general approach to deciding on oral anticoagulation (OAC) applies, although the evidence in patients with severe native valve disease is more limited than for the general population of patients with AF [47]. (See 'Approach to deciding whether to anticoagulate' above.) Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with specific valve conditions are discussed separately: 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. (See "Antithrombotic therapy for mechanical heart valves".) Transcatheter bioprosthetic valve. (See "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach'.) AF type and management Paroxysmal AF Our approach to deciding whether to anticoagulate is generally similar for patients with paroxysmal AF (PAF; with or without symptoms) as for persistent, or permanent, AF, as described above (see 'Decision-making based upon risk assessment' above). However, the burden of AF (duration and frequency of episodes) is a factor for decision-making for selected patients in whom the balance of benefit versus risk of anticoagulation is uncertain, recognizing that it may not be possible to accurately estimate AF burden except in patients with cardiac implantable electronic devices that can measure AF burden. We consider the burden of AF in decision-making for patients aged <65 years and who have one nonsex CHA DS -VASc risk 2 2 factor. On the other hand, patients with AF with past history of embolic stroke are at high risk for a recurrent thromboembolic event, so the burden of AF would generally not impact the decision to anticoagulate. (See 'Decision-making based upon risk assessment' above.) As discussed separately, the risk of thromboembolism in patients with PAF appears to be lower than in patients with persistent AF, and thromboembolic risk is higher in those with greater AF burden (percentage of time in AF). (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) There are no definitive data to establish a threshold duration of AF episodes for the initiation of anticoagulant therapy. Some of our experts recommend a single threshold for duration of AF of https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 9/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 30 seconds, and others use a threshold as long as 24 hours [48]. Those experts who do not routinely anticoagulate patients with shorter-duration AF believe that the benefit is small and potentially outweighed by the bleeding risk. However, the AF burden is likely to vary over time, so a patient with 30 seconds of AF in one monitoring period may well have 30 hours of AF in the next monitoring period. While a large proportion of patients with short episodes of AF will go on to experience longer episodes, it is also true that the reverse occurs in a sizable percentage of patients experiencing long episodes of AF [49]. Also, the extent to which thromboembolic risk may continue during periods of sinus rhythm is uncertain. (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) Rhythm versus rate control For patients with AF, the process of deciding whether to anticoagulate is generally the same regardless of the choice between rhythm control or rate control strategies. As discussed separately, the risk of thromboembolism is not reduced by clinical maintenance of sinus rhythm. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Thromboembolic risk'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Older adults For older adults, we follow the general approach described above, including careful assessment the relative benefits and risks of OAC (see 'Decision-making based upon risk assessment' above). The approach to chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) In patients with documented frequent falls but without prior trauma (eg, fracture, subdural), we weight the risks and benefits of OAC versus left atrial appendage occlusion. In this clinical setting, we often recommend OAC and work to reduce the risk of falls. The risk of falls leading to subdural hematomas is increased in older adult patients taking oral anticoagulants independent of the agent chosen. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Age, race, and sex' and "Atrial fibrillation: Left atrial appendage occlusion".) A Taiwanese database study compared 15,756 older ( 90 years of age) adults with AF (11,064 receiving no antithrombotic therapy, 4075 receiving antiplatelet therapy, and 617 on warfarin) with 14,658 older adult patients without AF and without antithrombotic therapy [50]: Patients with AF had a greater risk of ischemic stroke (5.75 versus 3.00 percent/year; hazard ratio [HR] 1.93, 95% CI 1.74-2.14) and a similar risk of intracranial hemorrhage (ICH; 0.97 versus 0.54 percent/year; HR 0.85, 95% CI 0.66-1.09) compared with those without AF. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 10/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among patients with AF, warfarin use was associated with a lower stroke risk (3.83 versus 5.75 percent/year; HR 0.69, 95% CI 0.49-0.96) compared with no antithrombotic therapy. There was a nominal but nonsignificant increase in risk of ICH (HR 1.26, 95% CI 0.70-2.25). In a second, later cohort of patients 90 years of age with AF, 768 patients treated with warfarin were compared with 978 patients treated with a direct oral anticoagulant (DOAC) [50]. DOACs were associated with a lower risk of ICH compared with warfarin (0.42 versus 1.63 percent/year; HR 0.32, 95% CI 0.10-0.97) and similar rate of ischemic stroke (4.07 versus 4.59 percent/year; HR 1.16; 95% CI 0.61 2.22). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Older adults'.) Potential use of reduced-dose DOAC (edoxaban) in selected older adults with AF with low body weight is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) Chronic kidney disease For most patients with AF and chronic kidney disease (CKD), we follow the general approach to selection of candidates for OAC described above (see 'Approach to deciding whether to anticoagulate' above). However, some of our authors consider anticoagulation for the very uncommon CKD patient with a CHA DS -VASc score of 0 in males or 2 2 1 in females. For patients with CKD and AF, the following is our approach for deciding whether to anticoagulate ( figure 2): Stages 2, 3, and 4 and 5 (not on dialysis) For patients with estimated glomerular 2 filtration rate (eGFR) of 15 to 89 mL/min/1.73 m , our approach is similar to the general approach described above (see 'Decision-making based upon risk assessment' above), although there are very limited data for patients with end-stage kidney disease. Individualized risk assessment is performed to carefully weigh the benefits and risks of anticoagulation, with special attention to the bleeding risk associated with CKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Uremic bleeding'.) Stage 5 on dialysis Among patients with end-stage kidney disease on dialysis, we anticoagulate some higher-risk individuals (based on the CHA DS VASc score) after shared 2 2- decision-making and discussion of risks and benefits between the clinician and the patient. However, it is reasonable to not anticoagulate the following groups of individuals with AF and eGFR <30 mL/min (stages 4 and 5) given our uncertainty of the benefit-to-risk ratio for antithrombotic therapy in these patients: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 11/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to
11/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to OAC with a VKA (target INR 2.0 to 3.0) [79]. The trial was stopped at an interim analysis after a median follow-up of 1.3 years because VKA lowered the annual rate of the primary endpoint compared with combined antiplatelet therapy (3.9 versus 5.6 percent; relative risk [RR] 0.69, 95% CI 0.57-0.85). The ACTIVE A trial included 7554 patients with AF who were not candidates for warfarin OAC and were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to aspirin alone at the same dose [80]. After a median follow- up period of 3.6 years, patients treated with clopidogrel plus aspirin had a significantly lower annual rate of the primary combined endpoint (6.8 versus 7.8 percent; RR 0.89, 95% CI 0.81-0.98), which was primarily driven by a reduction in stroke (2.4 versus 3.3 percent; RR 0.72, 95% CI 0.62-0.83). On the other hand, dual antiplatelet therapy resulted in a higher rate of major bleeding (2.0 versus 1.3 percent/year; RR 1.57, 95% CI 1.29-1.92). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 14/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Aspirin monotherapy Aspirin (or other antiplatelet agent) is not an effective therapy for preventing thromboembolic events in patients with AF. In patients with AF, some but not all meta-analyses of clinical trials comparing aspirin with placebo have found that aspirin reduced the risk of stroke and systemic embolism ( table 6) [14,38,81]. In contrast, clinical trials have demonstrated that OAC (with VKA or DOAC) lowers the risk of thromboembolism compared with aspirin ( table 6) [9,14-17,82-84]. Aspirin plus low-dose warfarin In contrast to therapeutic adjusted-dose warfarin (target INR 2.0 to 3.0), low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with nonvalvular AF [17,85,86]. In the SPAF-III trial of 1044 patients with AF who were at high risk for embolism, low-dose warfarin plus aspirin had a much higher rate of ischemic stroke and systemic embolism than therapeutic adjusted-dose warfarin ( figure 4A-B) [85]. Aspirin plus full-dose warfarin Limited available data suggest that there is no benefit from adding aspirin to therapeutic OAC in patients with AF. In a post-hoc analysis of the SPORTIF trials in patients with AF, among patients taking aspirin plus warfarin (or aspirin plus the factor Xa inhibitor ximelagatran) experienced similar rates of stroke and systemic embolism as those taking warfarin alone (or ximelagatran alone) [87]. The risk of major bleeding was higher with aspirin plus warfarin compared with warfarin alone (3.9 versus 2.3 percent/year). The management of antithrombotic therapy for patients with AF treated with OAC who have a concurrent indication for antiplatelet therapy is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Concomitant antiplatelet therapy'.) RECOMMENDATIONS OF OTHERS Recommendations for choosing which patients with atrial fibrillation should be anticoagulated are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [38,88-90]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 15/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of oral anticoagulation (OAC) in atrial fibrillation (AF) In patients with AF, OAC reduces the risk of thromboembolism by approximately two-thirds across clinical risk factor profiles but also entails an increased risk of major bleeding. Deciding whether to anticoagulate For each patient, their estimated absolute risk reduction for thromboembolic events is weighed against their estimated increase in absolute risk of intracranial hemorrhage and other life-threatening or severely debilitating bleeding complications. (See 'Approach to deciding whether to anticoagulate' above.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 16/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate CHA DS -VASc risk score Our approach to deciding whether to prescribe anticoagulant 2 2 therapy for patients with AF (excluding those with rheumatic mitral stenosis that is severe 2 or clinically significant [mitral valve area 1.5 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after implantation, or a mechanical heart valve) is as follows (see 'Approach to deciding whether to anticoagulate' above): For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC (Grade 1A). For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1): 2 2 For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC (Grade 1A). Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score 2 2 point. For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1) ( table 1), 2 2 we suggest against OAC (Grade 2C). Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' above) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). Bleeding risk For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). (See 'Bleeding risk' above.) The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated to flag high-bleeding-risk patients for early https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 17/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate review and follow-up. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) Specific patient groups Our approach to OAC for patients with AF who are older, have chronic kidney disease, hyperthyroidism, and hypertrophic cardiomyopathy can sometimes differ for patients who are younger or do not have these conditions. (See 'Specific patient groups' above.) Contraindication to OAC For patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a surgical bioprosthetic valve within the first three to six months after implantation, or a mechanical valve) with an indication for OAC but who have a contraindication for long-term OAC, the primary alternative is left atrial appendage occlusion. For such patients, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic OAC. (See 'Alternatives to anticoagulation' above and "Atrial fibrillation: Left atrial appendage occlusion".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lee CJ, Toft-Petersen AP, Ozenne B, et al. Assessing absolute stroke risk in patients with atrial fibrillation using a risk factor-based approach. Eur Heart J Cardiovasc Pharmacother 2021; 7:f3. 2. Borre ED, Goode A, Raitz G, et al. Predicting Thromboembolic and Bleeding Event Risk in Patients with Non-Valvular Atrial Fibrillation: A Systematic Review. Thromb Haemost 2018; 118:2171. 3. Lip GY, Lane DA. Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost 2016; 14:1711. 4. Lip GY, Lane DA. Assessing bleeding risk in atrial fibrillation with the HAS-BLED and ORBIT scores: clinical application requires focus on the reversible bleeding risk factors. Eur Heart J 2015; 36:3265. 5. Guo Y, Lane DA, Chen Y, et al. Regular Bleeding Risk Assessment Associated with Reduction in Bleeding Outcomes: The mAFA-II Randomized Trial. Am J Med 2020; 133:1195. 6. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. 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Mixed comparison of stroke prevention treatments in individuals with nonrheumatic atrial fibrillation. Arch Intern Med 2006; 166:1269. 17. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 18. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735. 19. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012; 125:2298. 20. Nielsen PB, Chao TF. The risks of risk scores for stroke risk assessment in atrial fibrillation. Thromb Haemost 2015; 113:1170. 21. Nielsen PB, Larsen TB, Skj th F, et al. 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Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA2DS2-VASc score of 1. J Am Coll Cardiol 2015; 65:225. 26. Chao TF, Liu CJ, Wang KL, et al. Using the CHA2DS2-VASc score for refining stroke risk stratification in 'low-risk' Asian patients with atrial fibrillation. J Am Coll Cardiol 2014; 64:1658. 27. Lip GY, Skj th F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol 2015; 65:1385. 28. Bekwelem W, Connolly SJ, Halperin JL, et al. Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation: Incidence, Risk Factors, and Outcomes. Circulation 2015; 132:796. 29. Johnsen SP, Svendsen ML, Hansen ML, et al. Preadmission oral anticoagulant treatment and clinical outcome among patients hospitalized with acute stroke and atrial fibrillation: a nationwide study. Stroke 2014; 45:168. 30. Nielsen PB, Skj th F, Overvad TF, et al. Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA2DS2-VA Score Rather Than CHA2DS2-VASc? Circulation 2018; 137:832. 31. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009; 151:297. 32. Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a 'real world' nationwide cohort study. Thromb Haemost 2011; 106:739. 33. Banerjee A, Lane DA, Torp-Pedersen C, Lip GY. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb Haemost 2012; 107:584. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 20/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 34. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685. 35. Hart RG, Pearce LA. Current status of stroke risk stratification in patients with atrial fibrillation. Stroke 2009; 40:2607. 36. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012; 172:623. 37. Gallagher AM, van Staa TP, Murray-Thomas T, et al. Population-based cohort study of warfarin-treated patients with atrial fibrillation: incidence of cardiovascular and bleeding outcomes. BMJ Open 2014; 4:e003839. 38. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 39. Provid ncia R, Trigo J, Paiva L, Barra S. The role of echocardiography in thromboembolic risk assessment of patients with nonvalvular atrial fibrillation. J Am Soc Echocardiogr 2013; 26:801. 40. Kezerle L, Tsadok MA, Akriv A, et al. Pre-Diabetes Increases Stroke Risk in Patients With Nonvalvular Atrial Fibrillation. J Am Coll Cardiol 2021; 77:875. 41. Proietti M, Romiti GF, Vitolo M, et al. Comparison of HAS-BLED and ORBIT bleeding risk scores in atrial fibrillation patients treated with non-vitamin K antagonist oral anticoagulants: a report from the ESC-EHRA EORP-AF General Long-Term Registry. Eur Heart J Qual Care Clin Outcomes 2022; 8:778. 42. Wattanaruengchai P, Nathisuwan S, Karaketklang K, et al. Comparison of the HAS-BLED versus ORBIT scores in predicting major bleeding among Asians receiving direct-acting oral anticoagulants. Br J Clin Pharmacol 2022; 88:2203. 43. Poli D, Antonucci E, Grifoni E, et al. Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol 2009; 54:999. 44. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006; 48:e149. 45. Hughes M, Lip GY, Guideline Development Group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care. Risk factors for https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 21/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review. QJM 2007; 100:599. 46. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120:700. 47. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 48. Van Gelder IC, Healey JS, Crijns HJGM, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J 2017; 38:1339. 49. Diederichsen SZ, Haugan KJ, Brandes A, et al. Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders. J Am Coll Cardiol 2019; 74:2771. 50. Chao TF, Liu CJ, Lin YJ, et al. Oral Anticoagulation in Very Elderly Patients With Atrial Fibrillation: A Nationwide Cohort Study. Circulation 2018; 138:37. 51. V zquez E, S nchez-Perales C, Borrego F, et al. Influence of atrial fibrillation on the morbido- mortality of patients on hemodialysis. Am Heart J 2000; 140:886. 52. Genovesi S, Pogliani D, Faini A, et al. Prevalence of atrial fibrillation and associated factors in a population of long-term hemodialysis patients. Am J Kidney Dis 2005; 46:897. 53. Vazquez E, Sanchez-Perales C, Garcia-Garcia F, et al. Atrial fibrillation in incident dialysis patients. Kidney Int 2009; 76:324. 54. Wetmore JB, Mahnken JD, Rigler SK, et al. The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients. Kidney Int 2012; 81:469. 55. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. 56. Pokorney SD, Black-Maier E, Hellkamp AS, et al. Oral Anticoagulation and Cardiovascular Outcomes in Patients With Atrial Fibrillation and End-Stage Renal Disease. J Am Coll Cardiol 2020; 75:1299. 57. US Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, National Institutes of Health, National Institute of Diabetes, an d Digestive and Kidney Diseases, 2005. 58. Winkelmayer WC, Patrick AR, Liu J, et al. The increasing prevalence of atrial fibrillation among hemodialysis patients. J Am Soc Nephrol 2011; 22:349. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 22/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 59. Yang F, Chou D, Schweitzer P, Hanon S. Warfarin in haemodialysis patients with atrial fibrillation: what benefit? Europace 2010; 12:1666. 60. Marinigh R, Lane DA, Lip GY. Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol 2011; 57:1339. 61. Atar I, Kona D, A ikel S, et al. Frequency of atrial fibrillation and factors related to its development in dialysis patients. Int J Cardiol 2006; 106:47. 62. Abbott KC, Trespalacios FC, Taylor AJ, Agodoa LY. Atrial fibrillation in chronic dialysis patients in the United States: risk factors for hospitalization and mortality. BMC Nephrol 2003; 4:1. 63. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005; 45:S1. 64. Bozbas H, Atar I, Yildirir A, et al. Prevalence and predictors of arrhythmia in end stage renal disease patients on hemodialysis. Ren Fail 2007; 29:331. 65. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119:1363. 66. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367:625. 67. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912. 68. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population the Ohasama study. Nephrol Dial Transplant 2007; 22:1910. 69. Rold n V, Mar n F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013; 109:956. 70. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013; 6:868. 71. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 23/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 72. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2
63. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005; 45:S1. 64. Bozbas H, Atar I, Yildirir A, et al. Prevalence and predictors of arrhythmia in end stage renal disease patients on hemodialysis. Ren Fail 2007; 29:331. 65. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119:1363. 66. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367:625. 67. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912. 68. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population the Ohasama study. Nephrol Dial Transplant 2007; 22:1910. 69. Rold n V, Mar n F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013; 109:956. 70. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013; 6:868. 71. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 23/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 72. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 26/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 27/41 7/5/23, 9:03 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia (platelet count <50,000/microL) Absolute platelet count, platelet count trend, and platelet function (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or planned) Type of procedure and associated bleeding risk, interval between procedure and anticoagulation Previous intracranial hemorrhage Time interval since hemorrhage and underlying cause (eg, trauma or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled hypertension Absolute blood pressure and blood pressure trend This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 28/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 29/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 30/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Benefit of warfarin in chronic atrial fibrillation Efficacy of anticoagulation with warfarin to prevent ischemic stroke and other thromboemboli in 4 major studies. An intention to treat approach was used, and transient ischemic attack and hemorrhage were excluded. The numbers at the top represent the risk reduction with warfarin therapy, which ranged from 45 to 82%. SPAF: Stroke Prevention in Atrial Fibrillation; AFASAK: Copenhagen AFASAK Study; BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA: Canadian Atrial Fibrillation Anticoagulation Study. The data in the warfarin group in the SPAF assumes that half of the events were attributable to warfarin toxicity. Data from: Connolly SJ, Laupacis AN, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349. Graphic 79839 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 31/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 32/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 33/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 34/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ATRIA stroke risk model point scoring system Points without prior Risk factor Points with prior stroke stroke Age, y 85 6 9 75 to 84 5 7 65 to 74 3 7 <65 0 8 Female 1 1 Diabetes 1 1 CHF 1 1 Hypertension 1 1 Proteinuria 1 1 eGFR <45 or ESRD 1 1 Possible point scores range from 0 to 12 for those without a prior stroke and from 7 to 15 for those with a prior stroke. ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; CHF: congestive heart failure; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease. Reprinted with permission. J Am Heart Assoc 2013; 2:e000250. Copyright 2013 American Heart Association, Inc. Graphic 90032 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 35/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 36/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Prevalence of atrial fibrillation in chronic kidney disease patients The prevalence (percent) of atrial fibrillation in the general population and different cohorts of patients with CKD are shown: While patients with peritoneal dialysis appear to suffer less frequently from atrial fibrillation, in those on hemodialysis, the prevalence was observed to be 10- to 20-fold higher than in the general population. Age was in all groups a key factor. CKD: chronic kidney disease. Reproduced with permission from: Reinecke H, Brand E, Mesters R, et al. Dilemmas in the management of atrial brillation in chronic kidney disease. J Am Soc Nephrol 2009; 20:705. Copyright 2009 American Society of Nephrology. Graphic 55373 Version 6.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 37/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Meta-analysis of randomized controlled trials of warfarin and aspirin for primary prevention of stroke in atrial fibrillation Stroke Major bleeding Comparison Odds ratio, p Odds ratio, 95 p 95% CI value percent CI value Conventional dose warfarin versus placebo 0.31 (0.19 to 0.50) <0.001 1.88 (0.88 to 4.0) 0.10 Aspirin versus placebo 0.68 (0.46 to 0.06 0.82 (0.37 to 1.78) >0.2 1.02) Conventional dose warfarin versus aspirin 0.66 (0.45 to 0.04 1.61 (0.75 to 3.44) >0.2 0.99) Conventional dose warfarin versus low dose warfarin 0.52 (0.25 to 1.08) 0.08 2.21 (0.67 to 7.25) 0.19 Conventional dose warfarin versus low dose warfarin plus aspirin 0.44 (0.14 to 1.39) 0.16 1.14 (0.55 to 2.36) >0.2 Low dose warfarin versus aspirin 1.01 (0.49 to 2.06) >0.2 1.04 (0.43 to 2.48) >0.2 NOTE: The data in this table cannot be directly applied to clinical practice (an individual patient) since the decision to use warfarin or aspirin is importantly related to a patient's estimated risk of embolic events. Adapted from McNamara RL, Tamariz LJ, Segal JB, Bass EB. Ann Intern Med 2004; 139:1018. Graphic 66736 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 38/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Low-dose warfarin plus aspirin is not optimal in high-risk AF Cumulative event rate of patients with AF at high risk for thromboembolism in the SPAF III trial. High risk was defined as the presence of at least 1 of the following: previous thromboembolism, female older than 75 years of age, heart failure or severe left ventricular systolic dysfunction, and systolic pressure >160 mmHg. There was a much lower incidence of events with standard adjusted- dose warfarin therapy (INR 2 to 3) compared with treatment with aspirin and low-dose warfarin (INR 1.2 to 1.5; p<0.0001). AF: atrial fibrillation; INR: international normalized ratio. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 72790 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 39/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Increased stroke risk with low-dose warfarin plus aspirin in AF Results from the SPAF III trial of high-risk patients showing significantly higher event rates for intracranial hemorrhage and ischemic stroke in patients treated with fixed low-dose warfarin plus aspirin compared with standard adjusted-dose warfarin. The risk was greater in those with a previous thromboembolic event. AF: atrial fibrillation. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 62833 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 40/41 7/5/23, 9:04 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 41/41
7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Use of oral anticoagulants : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION Most patients with atrial fibrillation (AF) should receive long-term oral anticoagulation to decrease the risk of ischemic stroke and other embolic events. For most patients, the benefit from anticoagulation outweighs the associated increase in the risk of bleeding. The use of anticoagulant therapy for patients with AF who are not pregnant (excluding those 2 with rheumatic mitral stenosis that is moderate or severe [mitral valve area 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve) will be reviewed here. Management for patients with valve disease is briefly discussed in a section below that provides links to related topics on these specific valve conditions. (See 'Patients with valvular heart disease' below.) Related topics include: (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation for atrial fibrillation during pregnancy. (See "Supraventricular arrhythmias during pregnancy", section on 'Atrial fibrillation and flutter' and "Use of anticoagulants during pregnancy and postpartum".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 1/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO ANTICOAGULATION Choice of anticoagulant For patients with AF, we suggest the following sequential steps (related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation): Determine if anticoagulation is indicated. The identification of patients who should receive long-term oral anticoagulation is discussed separately. Prior to initiation of anticoagulant therapy, possible contraindications should be weighed ( table 1). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Select an anticoagulant. The following discussion applies to patients who are not pregnant. Selection of anticoagulant for use during pregnancy is discussed separately. (See "Supraventricular arrhythmias during pregnancy", section on 'Anticoagulation' and "Use of anticoagulants during pregnancy and postpartum".) For most patients with AF with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than vitamin K antagonist (VKA; eg, warfarin). For most patients with AF who have been treated with warfarin with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to a DOAC. However, it is reasonable to continue VKA in these patients for financial or other preferences. Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include: Clinical settings in which VKA (eg, warfarin; target international normalized ratio [INR] 2.0 to 3.0; TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' below): Patients with a mechanical heart valve of any type and location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 2/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump [P-gp] inducers, which can decrease the anticoagulant effect of DOACs and chronic antiviral agents, which may increase the anticoagulant effect of DOACs) ( table 2A-C) [1]. (See 'Drug interactions' below and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose creatinine clearance (CrCl by Cockcroft-Gault equation) is less than 25 to 30 mL/min. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting, as described below. (See 'Chronic kidney disease' below.) Evidence supporting this approach comes from randomized trials in patients with nonvalvular AF in which DOAC use resulted in similar or lower rates of both ischemic stroke and major bleeding compared with treatment with adjusted-dose warfarin (INR of 2.0 to 3.0) ( table 3) [2-8]. Important additional advantages of the DOAC agents include a high relative but small absolute reduction in the risk of intracranial hemorrhage (ICH), convenience (no requirement for routine testing of the INR), lack of susceptibility to dietary interactions, and markedly reduced susceptibility to drug interactions [3-6]. Disadvantages of DOAC include lack of efficacy and safety data in patients with severe chronic kidney disease, lack of easily available monitoring of blood levels and compliance, and higher patient cost in some health care settings. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) A meta-analysis including the RE-LY (dabigatran) [3,9], ARISTOTLE (apixaban) [5], ROCKET AF (rivaroxaban) [4], and ENGAGE AF-TIMI 48 (edoxaban) [10] trials supports the broad conclusion that DOAC agents are preferable to adjusted-dose VKA for most patients [2]. Compared with VKA (warfarin), DOAC reduced rates of mortality, stroke or systemic embolic event, and hemorrhagic stroke ( table 3). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 3/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Regarding the relative efficacy and safety of the DOAC agents, no randomized controlled trials (RCTs) directly comparing the DOACs have been published. Published observational studies have many limitations and are no substitute for head to head RCTs [11-16]. Initiation DOAC For patients with AF starting DOAC, effective anticoagulation is achieved within a few hours. We do not use heparin to bridge patients starting DOAC. For patients prescribed one of the DOACs, we suggest that clinicians review dosing recommendations from regulatory agencies and available in drug information compendia such as Lexicomp. (See 'Dosing' below.) Vitamin K antagonist Protocols for initiating VKA (eg, warfarin) are discussed separately. All patients should have an INR measured before starting therapy. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and 'Dosing' below.) For patients with AF starting VKA (eg, warfarin): With no intracardiac thrombus or prior history of thromboembolism, the risk of a thromboembolic event during the several days typically required to achieve therapeutic anticoagulation with warfarin is generally very low. Thus, it is reasonable for outpatients to initiate warfarin without low molecular weight heparin bridging. (See "Warfarin and other VKAs: Dosing and adverse effects".) With high risk of thromboembolism (eg, prior cerebrovascular event/transient ischemic attack or current intracardiac thrombus) and low risk of ICH, initiation of warfarin with a heparin bridging regimen may be reasonable in some clinical settings (eg, patient who is hospitalized for another condition such as heart failure and has no acute stroke) although there is no high quality evidence to support this approach. Management for patients with acute stroke is discussed below. (See 'Acute stroke' below.) Dosing DOACs Dosing recommendations for DOACs are largely derived from the doses tested in the randomized clinical trials ( table 3) [3-5,10,17,18]. Given differences in the characteristics and availability of DOACs, it is important for practitioners to develop familiarity with the clinical use of multiple DOAC agents. DOACs are generally administered at fixed doses without laboratory monitoring. Use in patients with chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 4/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Use of these agents including drug interactions ( table 2A-C) and dosing in patients with chronic renal insufficiency is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.): Apixaban The dose of apixaban is 5 mg twice daily (approximately 12 hours apart) unless the patient has two or more of the following: age 80 years, body weight 60 kg, or serum creatinine level 1.5 mg/dL [133 micromol/L]). Then the dose of apixaban is 2.5 mg twice daily. This dose adjustment is for moderate renal impairment. Data are lacking to inform use in patients with CrCL <15 mL/min or on dialysis. (See 'Chronic kidney disease' below.) Dabigatran For patients with CrCl >30 mL/min, the dose is 150 mg twice daily (approximately 12 hours apart). For most patients prescribed dabigatran, we suggest the 150 mg twice daily dose, as opposed to the 110 mg dose, based upon the results of the RE-LY trial. Where available, the 110 mg twice daily dose may be preferred in patients assessed to be at increased risk of bleeding or who are particularly concerned about the risk of bleeding. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) For patients with CrCL 15 to 30 mL/min, the dose is 75 mg orally, twice daily. Concomitant use of a P-gp inhibitor or antiviral should be avoided. We generally avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) For patients with CrCl <15 mL/min or on dialysis, no dosing recommendations are available. We avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) Edoxaban dosing varies according to the estimated glomerular filtration rate: For patients with a Cockcroft-Gault equation CrCl >95 mL/min, edoxaban should not be used due to lesser efficacy compared with warfarin in preventing stroke in this group due to high renal clearance. For such patients, another DOAC is an alternative. For patients with a CrCl of >50 to 95 mL/min, an edoxaban dose of 60 mg once daily is used. For patients with a CrCl of 15 to 50 mL/min, the dose is 30 mg once daily. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 5/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For patients with a CrCl of <15 mL/min, there are limited data, so edoxaban is avoided in these patients. For patients 65 years of age and with at least one of the following characteristics, the dose is 30 mg once daily: weight 60 kg or concomitant use of potent P-glycoprotein inhibitors (eg, verapamil, quinidine). For patients with advanced age ( 80 years) and low body weight (ie, 45 kg or 60 kg plus an additional risk factor), a lower dose of edoxaban (15 mg once daily) may be safe and effective. This approach is supported by the results of the ELDERCARE-AF trial in which 984 Japanese patients age 80 years or older were randomly assigned to receive edoxaban 15 mg or placebo daily [19]. The mean body weight of participants was low (50.6 11 kg). All patients were considered inappropriate candidates for standard oral anticoagulant regimens due to one or more of the following concerns: a low CrCL ( 15 and <30 mL/min), a history of bleeding, low body weight ( 45 kg), or use of a nonsteroidal antiinflammatory drug or an antiplatelet drug. The annualized rate of stroke or systemic embolism was 2.3 and 6.7 percent in the two groups, respectively (hazard ratio [HR] 0.34, 95% CI 0.19-0.61), and the rate of major bleeding was 3.3 and 1.8 percent, respectively (HR 1.87, 95% CI 0.90-3.89). ICH was rare in both groups (0.3 and 0.6 percent). In a prespecified subanalysis of this trial, findings were largely similar across different categories of renal dysfunction (ie, mild, moderate, and severe) [20]. (See 'Older adults' below.) Rivaroxaban If the CrCl is >50 mL/min, the rivaroxaban dose is 20 mg once daily with the largest meal of the day (>500 calories), usually the evening meal. If the CrCl is 15 to 50 mL/min, the rivaroxaban dose is 15 mg once daily with the largest meal of the day (>500 calories). If the CrCl <15 mL/min, avoid use of rivaroxaban. (See 'Chronic kidney disease' below.) Vitamin K antagonist For patients with AF treated with VKA (eg, warfarin), an INR between 2.0 and 3.0 is recommended with an average annual TTR >70 percent [21,22]. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1) [23-27]. Dosing of warfarin is discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 6/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Advanced age (over 74 years) is an independent risk factor for bleeding during anticoagulation as well as a risk factor for stroke. However, we recommend an INR between 2.0 and 3.0 for these patients as well [27]. Temporary interruption of anticoagulation Temporary interruption of oral anticoagulation for reasons of bleeding or urgent/elective surgery/invasive procedure results in an increased risk of thromboembolism after the period of effective anticoagulation has ended [28]. The optimal approach to such patients is unclear and likely depends on issues such as baseline thromboembolic risk, duration of anticoagulant interruption, and bleeding risk. These issues are discussed in detail separately. (See "Perioperative management of patients receiving anticoagulants" and "Management of anticoagulants in patients undergoing endoscopic procedures" and "Use of anticoagulants during pregnancy and postpartum" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure'.) The discussion of the management of anticoagulant therapy in the patient undergoing percutaneous coronary intervention is found separately [29,30]. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The reversal of the anticoagulant effect of warfarin and DOAC agents is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) Anticoagulant failure Thromboembolic events occur despite adequate anticoagulation in patients with AF. Predictors of these events include (see "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'): Transesophageal echocardiographic (TEE) evidence of dense spontaneous echo contrast and low left atrial appendage ejection velocity [31]. TEE evidence of complex aortic plaque [31]. TEE-detected thrombi can be related to clinical risk factors [32]. (See "Pathophysiology of ischemic stroke", section on 'Stroke subtypes'.) Subtherapeutic INR on VKA [33] or noncompliance in patients taking DOAC agents. Elevated D-dimer levels. In a single-center, prospective, observational study of 269 patients, D-dimer levels were elevated (at least 0.5 mcg/mL) in 23 percent, and elevated levels were significantly associated with a higher rate of thromboembolism (HR 15.8, 95% CI 3.33-75.5) [34]. Similarly, in a study of 829 patients with AF, elevated von Willebrand factor levels were associated with risk of thrombotic events [35]. However, we do not recommend routine https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 7/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate testing of D-dimer or von Willebrand factor in patients with AF, as incorporating such testing in anticoagulation decision-making has not been shown to alter outcomes in this setting. There are no studies of the optimal anticoagulation strategy for those experiencing a thromboembolic event. For those patients with a subtherapeutic INR with warfarin at the time of the event, an attempt should be made to identify the cause (compliance, drug/food interaction) and to consider switching to a DOAC if the annual TTR has been less than 70 percent [36]. For those on a twice-a-day DOAC, consideration of a once-a-day DOAC should be made if noncompliance is an issue. For those on a once-a-day DOAC, a different once-daily agent may be considered (eg, another once-daily DOAC or possibly warfarin because the INR can be followed). Though reasonable, none of these approaches is of proven benefit. Ischemic strokes with nonembolic causes occur in patients with AF as in patients without AF. These are not the target of anticoagulants. Occurrence of such a stroke is not a "failure" of anticoagulation. Other reasons for switching agents Some patients with AF may need to be switched from DOAC agent to VKA, from VKA to DOAC, or between DOAC agents for reasons other than anticoagulant failure (which is discussed above). (See 'Anticoagulant failure' above.) Reasons for switching from VKA to DOAC: As discussed above, most patients with AF treated with VKA should be switched to DOAC. (See 'Choice of anticoagulant' above.) Need for repeated invasive procedures, annual TTR <70 percent, convenience. Possible reasons for switching from DOAC to VKA: Out-of-pocket cost Development of severe kidney disease (see 'Chronic kidney disease' below) Development of a contraindication to DOAC use, as discussed above (see 'Choice of anticoagulant' above) Information on switching oral agents is provided separately ( table 4). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.) Recommendations for transitioning between DOACs and parenteral anticoagulants, including unfractionated heparin and low molecular weight heparin, are available in the individual drug https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 8/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate monographs for each DOAC. Drug interactions The individual DOACs are in varying degrees eliminated by CYP3A4 metabolism or are substrates of P-glycoprotein (P-gp) efflux pump and subject to pharmacokinetic drug interactions, although fewer in number than warfarin interactions. Drugs that inhibit CYP3A4 metabolism or P-gp efflux can increase DOAC levels (ie, greater anticoagulant effect and bleeding), whereas drugs that are inducers can decrease DOAC effect, which can lead to therapeutic failure. A detailed review of the different drug interactions can be found in tables ( table 2A-C) and the Lexicomp drug interaction program within UpToDate. Additional related content is discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) SPECIFIC PATIENT GROUPS Patients with valvular heart disease The above general considerations regarding choice of anticoagulant (DOAC versus VKA) apply to patients with valvular heart disease (excluding patients with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 2 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve in any location), although the evidence in patients with severe native valve disease is more limited than for the general population of AF patients [37]. (See 'Choice of anticoagulant' above.) Some patients with valvular lesions (without heart failure), such as mitral valve prolapse, nonrheumatic moderate or severe mitral regurgitation, mitral valve repair (except for the first three to six months postoperatively), or moderate or less aortic valvular conditions, have been enrolled in clinical trials of the DOACs. These trials also included a few patients (with or without heart failure) with severe native valvular conditions who were not scheduled to undergo valve replacement. As an example, in the ARISTOTLE trial, which compared apixaban with warfarin ( table 3), approximately 26 percent of the patients had a history of moderate or severe valvular heart disease or previous valve surgery (not including placement of a mechanical heart valve) [38]. While these patients had higher rates of stroke and systemic embolism than those without, the benefits of a lower rate of stroke/systemic embolism and major bleeding with apixaban (compared with warfarin) were similar to those without valvular heart disease. Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with the following specific valve conditions are discussed separately: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 9/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Antithrombotic therapy for mechanical heart valves" and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve in any location. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. The choice of anticoagulant after surgical valve procedures is discussed separately. (See "Antithrombotic therapy for mechanical heart valves" and 'Choice of anticoagulant' above.) Transcatheter bioprosthetic valve. The choice of anticoagulant after transcatheter valve procedures is discussed separately. (See 'Choice of anticoagulant' above and "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach' and "Transcatheter mitral valve repair", section on 'Antithrombotic therapy'.) Older adults For most older patients, including those over the age of 75 years, we prefer DOACs (also referred to as non-vitamin K oral anticoagulants [NOACs]) to warfarin because of the reduced risk of intracranial hemorrhage versus warfarin. Since there are no head to head randomized trials comparing DOACs in this patient group, we do not have a preference for a specific DOAC. Dose adjustment should be made if the patient meets relevant criteria such as renal function for the DOAC. The results of the ELDERCARE-AF trial are discussed separately. (See 'Dosing' above and 'Chronic kidney disease' below.) Chronic kidney disease Who to anticoagulate Our approach to deciding which AF patients with chronic kidney disease (CKD) to anticoagulate is presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) Choice of anticoagulant For patients with AF and CKD stage G2 or G3 ( figure 2) treated with oral anticoagulation, most of our contributors choose a DOAC rather than VKA. However, the evidence to support this choice in patients with CKD is limited [39-43]. One contributor prefers VKA in this setting given wider clinical experience. For patients with AF and severe kidney disease (stage G4 or G5; estimated glomerular filtration 2 rate <30 mL/min/1.73 m ), on dialysis, or with acute renal injury, DOAC is generally avoided and VKA is generally the preferred long-term anticoagulant. Patients with stage 4 and 5 CKD are at higher risk of having unpredictable sudden deterioration in renal function than patients with https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 10/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate normal renal function, and such deterioration could cause an abrupt reduction in clearance of a DOAC that depends on renal metabolism. In such a setting, use of an agent such as warfarin that allows for therapeutic drug monitoring may be preferred. An annual time in the therapeutic range of >70 percent is desirable. (See "Direct oral anticoagulants (DOACs) and parenteral direct- acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) If a DOAC is chosen for a patient with stage 4 or 5 CKD or on dialysis, our contributors prefer apixaban, in part because apixaban is less dependent on kidney function for clearance than other DOACs available in the US ( table 2A). The support for use of apixaban in these patients is largely based upon our clinical experience and observational studies [40,41]. In a subgroup analysis of the ARISTOTLE trial in patients with creatinine clearance (CrCl) 25 to 30 mL/min, the risk of major bleeding was significantly less with apixaban compared with warfarin (hazard ratio [HR] 0.34, 95% CI 0.14-0.80) [41]. We avoid dabigatran in patients with stage 4 or 5 CKD because a high percentage of the drug is renally cleared. These issues are discussed further separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.) Based upon pharmacokinetic modeling, the US Food and Drug Administration approved DOAC dosing for use in selected patients with CKD based upon Cockcroft-Gault CrCl as described above (see 'Dosing' above). Patients at risk for gastrointestinal bleeding Risk factors for gastrointestinal bleeding in patients on oral anticoagulants have been identified. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastrointestinal'.) Choosing apixaban or dabigatran over rivaroxaban or warfarin may be prudent to prevent major bleeding outcomes in AF patients at high risk of gastrointestinal bleeding. In a subgroup analysis of the ARISTOPHANES observational study, 381,054 individuals anticoagulated for nonvalvular AF and who were at high risk of gastrointestinal bleeding were followed for major bleeding outcomes [44]. Compared with warfarin, apixaban and dabigatran were associated with a lower risk of major bleeding (apixaban: HR 0.59, 95% CI 0.56-0.63; dabigatran: HR 0.78, 95% CI 0.70-0.86), whereas rivaroxaban was associated with a higher gastrointestinal bleeding risk (HR 1.11, 95% CI 1.05-1.16). Acute stroke Recommendations for the management (including the role of antithrombotic therapy) of patients with AF with an acute stroke are presented separately. Patients with AF for whom anticoagulant therapy is being considered and who have had an ischemic stroke within 30 days should be referred to a neurologist or other clinician who is experienced in managing https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 11/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate antithrombotic care in such patients. Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke is generally avoided as studies have shown that such treatment causes more harm than good (See "Stroke in patients with atrial fibrillation" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Concomitant antiplatelet therapy For patients with indications for both anticoagulant for AF and for antiplatelet therapy (for a concurrent condition), any potential benefit must take into account an increased risk of bleeding with concomitant antiplatelet and anticoagulant therapy. The combination of antiplatelet and anticoagulant increases the risk of bleeding compared with either alone [45]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) The potential use of both anticoagulant and antiplatelet therapies in patients with AF is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Efficacy and safety' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients" and "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The issue of whether aspirin is necessary for secondary prevention of cardiovascular disease in patients treated with anticoagulant for AF is discussed in detail separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The impact of antiplatelet therapy on bleeding (and efficacy) outcomes in patients taking either warfarin or dabigatran was evaluated in a post-hoc subgroup analysis of the RE-LY trial (see 'Choice of anticoagulant' above) in which approximately 40 percent of patients were taking concomitant aspirin or clopidogrel at some point during the study [46]. Very few patients were taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct
taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct factor Xa inhibitors (eg, apixaban, edoxaban, and rivaroxaban). DOACs are generally https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 15/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate administered at fixed doses without laboratory monitoring. Given differences in the characteristics and availability of DOACs, it is important for clinicians to be familiar with the clinical use of multiple DOAC agents ( table 2A and table 3). (See 'DOACs' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Clinician familiarity with dosing'.) Target INR For patients with AF treated with VKA (eg, warfarin), the target INR is between 2.0 and 3.0 with an average annual TTR 70 percent. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1). (See 'Vitamin K antagonist' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bellesini M, Bianchin M, Corradi C, et al. Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review. Clin Drug Investig 2020; 40:1001. 2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139. 4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883. 5. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981. 6. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013; 70:1486. 7. Salazar CA, del Aguila D, Cordova EG. Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation. Cochrane Database Syst Rev 2014; :CD009893. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 16/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 8. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2018; 3:CD008980. 9. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022512Orig1s025ltr.pdf (Ac cessed on December 05, 2018). 10. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369:2093. 11. Schneeweiss S, Gagne JJ, Patrick AR, et al. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012; 5:480. 12. Lip GYH, Keshishian A, Li X, et al. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. Stroke 2018; 49:2933. 13. Graham DJ, Baro E, Zhang R, et al. Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. Am J Med 2019; 132:596. 14. Andersson NW, Svanstr m H, Lund M, et al. Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation. Int J Cardiol 2018; 268:113. 15. Fralick M. Effectiveness and safety of apixaban. Ann Intern Med 2020; :463. 16. Ray WA, Chung CP, Stein CM, et al. Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation. JAMA 2021; 326:2395. 17. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 18. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013; 128:237. 19. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735. 20. Yoshida T, Nakamura A, Funada J, et al. Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial. Circulation 2022; 145:718. 21. Fuster V, Ryd n LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 17/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 2001; 104:2118. 22. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S. 23. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:546S. 24. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335:540. 25. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 26. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 27. Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. 28. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 129:1850. 29. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost 2011; 106:572. 30. Huber K, Airaksinen KJ, Cuisset T, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: similarities and dissimilarities between North America and Europe. Thromb Haemost 2011; 106:569. 31. Bernhardt P, Schmidt H, Hammerstingl C, et al. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol 2005; 45:1807. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 18/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 32. Tang RB, Dong JZ, Liu XP, et al. Is CHA2DS2-VASc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? Thromb Haemost 2011; 105:1107. 33. Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004; 126:1938. 34. Sadanaga T, Sadanaga M, Ogawa S. Evidence that D-dimer levels predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. J Am Coll Cardiol 2010; 55:2225. 35. Rold n V, Mar n F, Mui a B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57:2496. 36. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 37. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 38. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015; 132:624. 39. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. 40. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation 2018; 138:1519. 41. Stanifer JW, Pokorney SD, Chertow GM, et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation 2020; 141:1384. 42. Weir MR, Ashton V, Moore KT, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020; 223:3. 43. Su X, Yan B, Wang L, et al. Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis. Am J Kidney Dis 2021; 78:678. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 19/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 44. Lip GYH, Keshishian AV, Zhang Y, et al. Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding. JAMA Netw Open 2021; 4:e2120064. 45. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126:1185. 46. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 48. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. 49. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 50. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1031 Version 139.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 20/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate GRAPHICS Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia Absolute platelet count, platelet count trend, and platelet function (platelet count <50,000/microL) (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or Type of procedure and associated bleeding risk, interval between procedure and anticoagulation planned) Previous intracranial Time interval since hemorrhage and underlying cause (eg, trauma hemorrhage or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled Absolute blood pressure and blood pressure trend hypertension This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 21/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic Anticoagulant Bioavailability and Half-life drug clearance* interactions* Dabigatran 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase (Pradaxa) kidney dabigatran effect Unaffected by Prolonged food P-gp with kidney P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact and requires adults effect gastric acidity for absorption Avoidance of some combinations or dose adjustment may be needed Apixaban (Eliquis) 50% bioavailable 27% cleared by the kidney 12 hours Strong dual CYP3A4 and P-gp inhibitors can increase apixaban effect Prolonged in older adults Unaffected by food Metabolized, primarily by CYP3A4 Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase (Savaysa, Lixiana) edoxaban effect Unaffected by Reduced Prolonged in food efficacy in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 22/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate and CrCl >95 dose adjustment mL/minute may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% bioavailable Prolonged to 11 to 13 inhibitors can increase Metabolized, primarily by CYP3A4 hours in older adults Unaffected rivaroxaban effect by food P-gp substrate* 20 mg dose: Strong CYP3A4 66% inducers and/or P-gp inducers can decrease rivaroxaban bioavailable if taken when fasting; increased if taken with food effect Avoidance of some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 23/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The mechanism of this interaction is unknown. [1] Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 24/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate Strong inducers Moderate inducers inhibitors Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone therapy pack Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone* Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- Netupitant Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 25/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]).
Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 30/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 31/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 32/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 33/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Switching between oral anticoagulants Switching from a DOAC to warfarin Dabigatran Overlap warfarin with dabigatran for 3 days (normal renal function); 2 days (CrCl 30 to 50 mL/min); or 1 day (CrCl 15 to 30 mL/min); note that dabigatran can contribute to INR elevation. or- Overlap warfarin with dabigatran until the INR is therapeutic on warfarin (ASH).* Apixaban If continuous anticoagulation is needed, discontinue apixaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that apixaban can contribute to INR elevation. or- Overlap warfarin with apixaban until the INR is therapeutic on warfarin, testing right before the next apixaban dose to minimize the effect of apixaban on INR elevation (ASH).* Edoxaban Reduce dose by half (eg, from 60 to 30 mg daily or from 30 to 15 mg daily) and begin warfarin concurrently (PI). Discontinue edoxaban when the INR is 2; note that edoxaban can contribute to INR elevation. or- Discontinue edoxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). or- Overlap warfarin with edoxaban until the INR is therapeutic on warfarin, testing right before the next edoxaban dose to minimize the effect of edoxaban on INR elevation (ASH).* Rivaroxaban Discontinue rivaroxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that rivaroxaban can contribute to INR elevation. or- Overlap warfarin with rivaroxaban until the INR is therapeutic on warfarin, testing right before the next rivaroxaban dose to minimize the effect of rivaroxaban on INR elevation (ASH).* Switching from warfarin to a DOAC Dabigatran Stop warfarin, monitor the PT/INR, and start dabigatran when the INR https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 34/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate is <2 (PI). Apixaban Stop warfarin, monitor the PT/INR, and start apixaban when the INR is <2 (PI). Edoxaban Stop warfarin, monitor the PT/INR, and start edoxaban when the INR is 2.5 (PI). Rivaroxaban Stop warfarin, monitor the PT/INR, and start rivaroxaban when the INR is <3 (PI). Switching from one DOAC to a different DOAC Any DOAC Start the second DOAC when the next dose of the first DOAC would have been due; do not overlap. This table presents a reasonable approach to switching between oral anticoagulants. It does not substitute for clinical judgment regarding individual patient risks of thrombosis and bleeding. Individuals switching from a DOAC to warfarin are more likely to require continuous anticoagulation if they have had a recent thromboembolic event or if they are at especially high risk of thromboembolism. Refer to UpToDate topics on specific indications, perioperative management, and the use of DOACs and warfarin for further details. DOAC: direct oral anticoagulant; CrCl: creatinine clearance; INR: international normalized ratio; ASH: American Society of Hematology clinical practice guideline; PI: package insert; PT: prothrombin time. Two to three days of overlap after the INR becomes therapeutic may be needed in individuals with higher thrombosis risk, because the PT/INR will enter the therapeutic range before full anticoagulation occurs. In individuals overlapping warfarin and a DOAC, the DOAC may contribute to INR elevation. Prepared with information from: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. PRADAXA (dabigatran etexilate mesylate) capsules. US FDA approval 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022512s035lbl.pdf (Accessed on April 25, 2019). 3. ELIQUIS (apixaban) tablets. US FDA approval 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s020lbl.pdf (Accessed on April 25, 2019). 4. SAVAYSA (edoxaban) tablets. US FDA approval 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/206316s012lbl.pdf (Accessed on April 25, 2019). 5. XARELTO (rivaroxaban) tablets. US FDA approval 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022406s030s032lbledt.pdf (Accessed on April 25, 2019). Graphic 120639 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 35/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 36/37 7/5/23, 9:04 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 37/37
7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in patients undergoing noncardiac surgery : David Spragg, MD, FHRS, Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC, Jonathan B Mark, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 29, 2022. INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. Given the frequency of AF in the general population, many patients undergoing noncardiac surgery will have AF before, during, or after surgery. In some, the diagnosis is established, while in others it is new. Patients with AF are at increased risk for death, heart failure, and thromboembolic events. This risk likely increases around the time of noncardiac surgery due to perioperative stresses. This topic will focus on management issues specific to these patients. Other relevant topics include: (See "Atrial fibrillation and flutter after cardiac surgery".) (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) (See "Arrhythmias during anesthesia".) EPIDEMIOLOGY The prevalence of AF the United States is approximately 3 million [1], and it is increasing with time [2-4]. Projections of AF prevalence in the United States by the year 2050 range from 5.6 to https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 1/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate 16 million [1,4]. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) Thus, AF is common in patients who need to undergo noncardiac surgery. In a study of 38,047 patients undergoing noncardiac surgery over seven years, 4312 patients (11 percent) had a prior history of AF [5]. In the same study, a history of AF was associated with a 30-day postoperative mortality rate of 6.4 percent, compared with a rate of 2.9 percent in patients with coronary artery disease. This underscores the fact that perioperative mortality is twofold higher in patients with AF compared with those with coronary artery disease [5]. PATIENTS WITH KNOWN ATRIAL FIBRILLATION In patients with known AF, elective noncardiac surgery should be deferred until rate and rhythm are felt to be optimal for surgery and a decision has been made as to how to manage anticoagulant therapy. (See 'Emergency surgery' below.) Major cardiac events (eg, death, heart failure, or stroke) due to AF have two primary etiologies: AF with rapid ventricular response (leading to severe palpitations, cardiac ischemia, or global hemodynamic compromise) and systemic thromboembolism. The principal goals of the preoperative evaluation and management of patients with known AF are to ensure hemodynamic stability and optimal anticoagulation status in the perioperative period. Management of rhythm or rate Patients with known AF are typically managed long term with either a rhythm- or a rate-control strategy [6,7] (see "Management of atrial fibrillation: Rhythm control versus rate control"). A preoperative physical examination and electrocardiogram will clarify whether the patient is at their rate or rhythm control goal. Rhythm control Paroxysmal AF patients may present for noncardiac surgery in sinus rhythm or in AF (see "Paroxysmal atrial fibrillation", section on 'Management'). This is true for patients with or without ongoing drug therapy or prior catheter ablation. Asymptomatic recurrences of AF are common in patients who are on antiarrhythmic drug therapy or who have had prior ablation. In the absence of symptoms or rapid rates, there is generally no need to restore sinus rhythm or delay surgery. Rhythm-controlling drugs should be continued throughout the perioperative period. For patients who are expected to be in sinus rhythm due to the infrequent nature of their AF paroxysms or due to successful rhythm control strategies such as the use of antiarrhythmic drug therapy or prior catheter ablation, the presence of AF may be unexpected. The failure of the rhythm control strategy should be https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 2/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate investigated, unless surgery is urgent. A decision to proceed with surgery prior to addressing the failure of the rhythm control strategy will need to take into account the urgency of the surgery. In some patients, it may be prudent to proceed with surgery, as restoration of sinus rhythm with manipulation of antiarrhythmic drug therapy or another ablation procedure may delay surgery for weeks to months. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Atrial fibrillation: Cardioversion" and "Atrial fibrillation: Catheter ablation".) Rate control Patients presenting in AF should have the rate adequately controlled to avoid rapid ventricular rates and the possibility of ensuing cardiac ischemia. We do not suggest cardioversion in the preoperative period because this would mandate uninterrupted systemic anticoagulation for a minimum of four weeks after restoration of sinus rhythm, which may increase the risk of bleeding during the surgical procedure or be contraindicated. Major adverse cardiac events in AF patients undergoing noncardiac surgery may be due to inadequate rate control and attendant cardiac ischemia during the perioperative period. Rate control is most often achieved pharmacologically, with beta blockers, non-dihydropyridine calcium channel blockers, or (less frequently) digoxin. Prior to surgery, heart rates between 50 and 100 beats per minute (bpm) are reasonable as long as the patient is asymptomatic [8]. Postoperatively, in our experience, heart rates as high as 120 bpm are reasonable given the stressors of pain or hypovolemia, as long as these increased heart rates do not cause hemodynamic instability or myocardial ischemia. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Management of anticoagulation Many AF patients receive long-term oral anticoagulation to reduce the risk of embolic events (see "Atrial fibrillation in adults: Use of oral anticoagulants"). While some surgical procedures can be performed safely on patients who are systemically anticoagulated [9,10], interruption of anticoagulation during the perioperative period is required in others where the perioperative bleeding risk is high. This issue is discussed in detail elsewhere. (See "Perioperative management of patients receiving anticoagulants".) Certain surgical procedures (eg, cardiac device implantation) carry low bleeding risk, and may be performed safely without interruption of systemic anticoagulation [9]. In patients with high risk of periprocedural bleeding, however, interruption of anticoagulation may be necessary. Risk factors for periprocedural hemorrhage include recent major bleeding, thrombocytopenia, dual antiplatelet therapy, supratherapeutic anticoagulation (as indicated by international normalized ratio), or a history of perioperative bleeding in the past. https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 3/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate For those patients who will have their anticoagulation interrupted, thromboembolic risk and estimation of bleeding risk should be weighed to determine duration of anticoagulation cessation. Longer interruption will increase risk of systemic thromboembolism. Decisions about the timing and duration of anticoagulation interruption require communication between the surgical and anesthesia teams and the physicians managing the patient's anticoagulation. Suggestions for the discontinuation of non-vitamin K oral anticoagulants in the perioperative time period are made in a table ( table 1). This will facilitate an accurate assessment of bleeding and stroke risks, and establish a plan for the conduct of anesthesia. For instance, neuraxial procedures are typically contraindicated if there has been anticoagulation with dabigatran within the prior four to five days or factor Xa inhibitors within the prior three to five days, and anticoagulation should not be restarted until 24 hours after catheter removal [11,12]. In addition, it is critical that the patient is involved in the risk conversation. Some patients may opt to defer elective surgery, knowing that there is always some risk of stroke associated with interruption of oral anticoagulation. Determining when anticoagulation should be interrupted is critical, as premature interruption may unnecessarily increase stroke risk, and delayed interruption may increase surgical bleeding risk (see "Perioperative management of patients receiving anticoagulants", section on 'Timing of anticoagulant interruption'). In general, we suggest cessation of vitamin K antagonists roughly three to five days prior to anticipated surgery, and cessation of direct oral anticoagulants three days prior to surgery. Bridging therapy in patients at high risk for thromboembolism and taking warfarin may be performed with low molecular weight heparin, with the last injection typically delivered no less than 12 hours prior to surgery. Direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) should be discontinued for one to three days prior to surgery, depending on the risk of surgery, renal function, and the specific DOAC [13-15]. Manufacturer guidelines can be useful for guidance. The following are suggestions regarding anticoagulation cessation: Patients at highest risk of left atrial thrombus formation or embolization should undergo the shortest duration of anticoagulation cessation possible. Bridging therapy with low molecular weight heparin may be indicated if they are taking warfarin. Examples of such patients include those with CHA DS -VASc Score of 7, recent thromboembolic stroke or 2 2 systemic embolism, recent cardioversion, or echocardiogram showing left atrial thrombus. If there has been an intracranial hemorrhage or major bleed in the prior three months, however, bridging may have more risk than benefit. In those with a moderate risk of thromboembolism (CHA DS -VASc Score of 5 to 6 or prior 2 2 thromboembolism >3 months prior), the bleeding risks of bridging will need to be https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 4/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate balanced with risk of thromboembolism. Careful clinical decision making and discussion with the patient are encouraged. In general, if there is a high bleeding risk, bridging therapy should not be initiated. If the patient's bleeding risk is low and the patient has a history of a prior thromboembolic event, then bridging is encouraged. If there is a low bleeding risk and no prior thromboembolism, then bridging is not indicated. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.) Patients at low risk of thromboembolic events (CHA DS -VASc Score of 4) may safely 2 2 interrupt anticoagulation for longer periods than those at high thromboembolic risk. PATIENTS WITH NEWLY DISCOVERED ATRIAL FIBRILLATION A new diagnosis of AF may be made at the time of preoperative evaluation. A few other patients will develop AF intraoperatively or in the first day or two after surgery (see 'Postoperative atrial fibrillation' below). Our approach to these patients is generally similar to that in patients with new onset AF not related to noncardiac surgery. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) Preoperative atrial fibrillation AF diagnosed preoperatively may arise in the setting of a risk factor such as hypertension or from an underlying systemic disorder such as severe hyperthyroidism. Both the AF and the underlying disorder may be a source of perioperative risk unless recognized and managed. For these reasons, we suggest that newly discovered AF be treated as a potentially unstable condition that should preclude elective noncardiac surgery. Diagnosis and management of newly discovered AF are discussed elsewhere. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) However, for these patients presenting for minor surgical procedures, typically of limited duration and complexity (eg, monitored anesthesia care using local anesthetics with minimal anticipated blood loss), it may be reasonable to safely proceed despite new onset AF, as long as the patient is asymptomatic and hemodynamically stable. These patients should subsequently be referred for early evaluation and management of AF. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) Data on rates of incident AF discovered immediately prior to noncardiac surgery are largely lacking. Given the prevalence of AF in the general United States population of roughly 5 million, and the observation that prevalence of both AF and indications for noncardiac surgery both increase with age and systemic illnesses including hypertension and diabetes mellitus, it is https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 5/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate anticipated that health care providers will be confronted with newly discovered AF in the preoperative setting. (See 'Epidemiology' above.) Intraoperative atrial fibrillation For patients who develop intraoperative AF, the immediate concern is hemodynamic stability. Anticoagulation is not urgently required and can be considered after surgery. (See 'Anticoagulation after surgery' below.) If there is hemodynamic instability such as hypotension, evidence of pulmonary congestion, or electrocardiographic evidence of myocardial ischemia, cardioversion should be performed intraoperatively, as soon as this can be attempted without compromising the surgical procedure. Since intraoperative cardioversion requires placement of external defibrillation pads, deep sedation or general anesthesia, and possible patient repositioning to a supine position, the decision to perform this procedure requires thoughtful discussion between the anesthesiologist and surgeon. If the patient is hemodynamically stable, it is reasonable to perform a cardioversion at the end of the surgery while the patient is already under anesthesia. However, the physiological stress that may have triggered AF may still be present and the patient may develop recurrent AF after cardioversion. For those in whom cardioversion will not take place, rate control needs to be considered. Beta blockers or non-dihydropyridine calcium channel blockers are given to slow the heart rate intraoperatively in patients who develop AF. For most patients in the operating room, the heart rate goal is <100 to 110 beats per minute. The rate should also be guided by restoration of acceptable blood pressure and resolution of new electrocardiographic ST or T wave abnormalities. Intravenous esmolol 10 to 50 mg repeated as necessary or intravenous metoprolol 5 mg every five minutes for three doses is commonly used. Beta blockers should be used with caution in patients with known heart failure or volume overload. Another option is diltiazem 0.15 to 0.25 mg/kg given over two minutes as an intravenous bolus followed by infusion, which can then be titrated for effect. Diltiazem may be used in patients with heart failure if dosing is titrated cautiously [16]. These patients should subsequently be referred for early evaluation and management of AF. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) It is reasonable to continue the beta blocker or calcium channel blocker for four to six weeks after surgery [17]. Postoperative atrial fibrillation New onset AF is common after noncardiac surgery, with reported incidence rates between 0.4 and 3 percent [18-21]. Thoracic, pulmonary, vascular, and https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 6/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate abdominal surgeries are associated with the highest risk of postoperative AF [21]. The underlying cause or trigger for AF may be systemic inflammation, increased adrenergic tone, electrolyte abnormalities, anemia, hypothermia, hypoxia, or hypervolemia [22-24]. Postoperative AF is associated with increased mortality, length of stay, and cost. Patients are frequently not on telemetry when AF is first suspected, so it is not always clear when an episode began [22]. Predictors of AF include [18,20,23-26]: Male sex Prior history of AF Increased preoperative B-type natriuretic peptide Elevated heart rate Increased age Chronic kidney disease Hypertension Sepsis Heart failure Valvular heart disease An electrocardiogram should be obtained to confirm the diagnosis, and electrolytes should be evaluated. Unless there is a clinical suspicion for an acute coronary syndrome or electrocardiographic evidence of cardiac ischemia or injury, cardiac biomarkers including troponin are usually not needed. However, if there is uncertainty about the presence of ischemia or if the patient cannot provide an adequate history postoperatively, it is not unreasonable to test biomarkers. Reversible factors should be identified and addressed: Electrolyte abnormalities Hypoxia Acidosis Infection Pain Volume overload Management of the AF is then dependent on symptoms, duration of AF, and need for rate or rhythm control. If a home medication such as a beta blocker has been stopped, it should be reinitiated if possible [27]. https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 7/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate For those in whom sinus rhythm is desired, a rhythm control strategy should be pursued. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) This approach is recommended for those with symptomatic AF despite good rate control or in those where rate control is difficult to achieve. Rhythm control may also be preferred in patients who are felt to be unlikely to have a recurrence of AF, such as those who are younger, with fewer comorbidities, and with a small left atrium. It can be considered also for those who have not spontaneously converted within 24 hours where the desire is to avoid anticoagulation if possible, especially in those with a high bleeding risk. However, >50 percent of patients with new onset postoperative AF will convert back to normal sinus rhythm within 24 hours on their own [18,22]. Either electrical or pharmacologic cardioversion can be attempted, with the choice based on the patient's status and the local practice pattern. Direct current transthoracic cardioversion is effective about 95 percent of the time in converting to normal sinus rhythm. As a starting point, 120 to 200 joules for biphasic defibrillators and 200 joules for monophasic defibrillators may be used [28]. If AF has been present for greater than 48 hours, transesophageal echocardiography to ensure absence of left atrial appendage thrombus is advisable. Anticoagulation strategy is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion".) For those who have contraindications to anesthesia or in whom external electrical cardioversion has failed, intravenous amiodarone or ibutilide may be considered. In one nonrandomized observational study, amiodarone and diltiazem were equivalent for thoracic surgery patients in terms of conversion to normal sinus rhythm [29]. Another study of critically ill patients in a cardiology intensive care unit showed that diltiazem provided better rate control than amiodarone with equivalent rate of conversion to normal sinus rhythm, but that diltiazem treatment had to be discontinued more frequently, owing to hypotension [30]. The dose of diltiazem used, however, was not titrated and was fixed at a high dose of 20 mg/hour. Anticoagulation after surgery In patients with AF who have undergone noncardiac surgery, we recommend an anticoagulation approach similar to that used after cardiac surgery (see "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation'): If the patient is chronically on anticoagulation, it should be restarted when safe from a surgical bleeding perspective. For a single episode of AF lasting <48 hours, we do not recommend anticoagulation, unless there are very high-risk features (for thromboembolism) such as mitral stenosis. https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 8/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate For those with multiple episodes of AF or a single episode lasting >48 hours, we recommend using the CHA DS -VASc Score to determine stroke risk ( table 2), even 2 2 though it has not been validated in the postoperative population. In those with scores 2, we recommend anticoagulation for four weeks, assuming the perioperative bleeding risks are considered acceptable. As there are no comparative data regarding the use of warfarin, direct thrombin inhibitors, and anti-factor Xa inhibitors in the postoperative population, the decision of which agent to be used should be based on bleeding risk, cost, and patient preference. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) Owing to concerns of perioperative bleeding, we typically do not use bridging with intravenous heparin if a rate control strategy is used, unless there is a mechanical valve, CHA DS -VASc Score of 7, or systemic thromboembolic event within the prior three 2 2 months. Reassessment after four weeks is then made based on thromboembolic risk, bleeding risk, including the HAS-BLED score ( table 3), and patient preference. For those who are felt to be high risk for stroke, even if recurrent AF has not been documented, it may be preferable to continue anticoagulation indefinitely. Ambulatory monitoring can also be used to guide decision making. For those who have documented recurrences of AF after four weeks, long-term anticoagulation should be continued based on the CHA DS -VASc Score. (See "Atrial 2 2 fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) The risk of thromboembolism associated with new onset AF following noncardiac surgery has been evaluated in a few observational studies [21,31,32]. While the evidence is not strong, we interpret these studies as showing an increased risk of thromboembolism that is reduced with anticoagulation. The best available evidence comes from a 2018 registry study of over 1.5 million patients who underwent noncardiac surgery from 1996 to 2015, of whom 6048 were identified with postoperative AF. From these, 3830 patients were matched with 15,320 patients with nonvalvular AF. The long-term risk of thromboembolism was similar in the two groups (31.7 versus 29.9 events per 1000 person years; hazard ratio 0.95, 95% CI 0.85-1.07) during a mean follow-up of 3.2 years [21]. In addition, the risk of thromboembolism was comparably reduced (about 50 percent) with anticoagulation therapy in both groups. EMERGENCY SURGERY https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 9/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate If a patient presents for emergent or urgent surgery and is found to have a new diagnosis of AF prior to surgery, the following questions need to be asked and answered: Does the patient need to have restoration of sinus rhythm prior to surgery? In most cases, we do not attempt restoration of sinus rhythm, with either electrical or chemical cardioversion, prior to emergency surgery. The most common indication for doing so would be hemodynamic instability. Does the rate need to be slowed prior to surgery? We believe that most patients will benefit from a ventricular rate in AF that is less than 140 beats per minute (bpm). In many patients, we attempt to slow the rate to 100 to 110 bpm unless this leads to hypotension. Rate control can typically be achieved effectively and rapidly with an intravenous infusion of negative chronotropic drugs including esmolol, metoprolol, or diltiazem. These agents may significantly reduce blood pressure, which in some emergent situations may be detrimental and require vasoactive agents to provide systemic circulatory support. Does anticoagulant therapy need to be started prior to surgery? In most cases, the initiation of anticoagulation can be deferred until after surgery. We do not recommend urgent transesophageal echocardiography prior to surgery to screen for left atrial appendage thrombus. Rather, decisions to proceed to surgery should be made on the basis of clinical risk assessment. PATIENTS WITH ATRIAL FLUTTER We manage pre-, intra-, and postoperative atrial flutter in the same manner as AF, as there is little published evidence regarding perioperative atrial flutter. Decisions regarding anticoagulation, rate control, and rhythm can be approached similarly. Direct current cardioversion of atrial flutter typically requires lower energy, and in most patients it can be accomplished with 50 to 100 joules for biphasic devices and 100 joules for monophasic devices. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults".) https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 10/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate SUMMARY AND RECOMMENDATIONS Atrial fibrillation (AF) is highly prevalent in the population, and many individuals undergoing noncardiac surgery will carry the diagnosis or develop it in the perioperative period. (See 'Epidemiology' above.) The principal goals of the preoperative management of patients with known or newly discovered AF are to ensure hemodynamic stability and optimal anticoagulant status in the perioperative period. For patients with known AF: Prior to surgery, heart rates in AF between 50 and 100 beats per minute (bpm) are reasonable as long as the patient is asymptomatic. (See 'Management of rhythm or rate' above.) While some surgical procedures can be performed safely on patients who are systemically anticoagulated, interruption of anticoagulation during the perioperative period is required in others such as those in whom the perioperative bleeding risk is high. The decision to interrupt anticoagulation should be made on a case-by-case basis. (See 'Management of anticoagulation' above.) For patients with newly discovered AF: For individuals presenting for minor surgical procedures, typically of limited duration and complexity (eg, monitored anesthesia care using local anesthetics with minimal anticipated blood loss), it may be reasonable to proceed, as long as the patient is hemodynamically stable. (See 'Preoperative atrial fibrillation' above.) For patients who develop intraoperative AF, the immediate concern is hemodynamic stability. Anticoagulation is not urgently required and can be considered after surgery. For most patients in the operating room, the heart rate goal is <100 to 110 bpm. (See 'Intraoperative atrial fibrillation' above.) For those patients who develop postoperative AF (see 'Postoperative atrial fibrillation' above) and in whom sinus rhythm is desired, a rhythm control strategy should be pursued. This approach is recommended for those with symptomatic AF despite good rate control or in those where rate control is difficult to achieve. Rhythm control may also be preferred in patients who are felt to be unlikely to have a recurrence of AF, such as those who are younger, with fewer comorbidities, and with small left atrium. https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 11/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate For many patients with a single episode of AF lasting <48 hours, we do not recommend anticoagulation, unless there are very high-risk features for thromboembolism, such as mitral stenosis. (See 'Anticoagulation after surgery' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. 2. Krahn AD, Manfreda J, Tate RB, et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995; 98:476. 3. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004; 110:1042. 4. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114:119. 5. van Diepen S, Bakal JA, McAlister FA, Ezekowitz JA. Mortality and readmission of patients with heart failure, atrial fibrillation, or coronary artery disease undergoing noncardiac surgery: an analysis of 38 047 patients. Circulation 2011; 124:289. 6. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 7. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 8. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363. 9. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013; 368:2084. 10. Essebag V, Verma A, Healey JS, et al. Clinically Significant Pocket Hematoma Increases Long- Term Risk of Device Infection: BRUISE CONTROL INFECTION Study. J Am Coll Cardiol 2016; 67:1300. 11. Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 12/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017; 69:871. 12. Narouze S, Benzon HT, Provenzano DA, et al. Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg Anesth Pain Med 2015; 40:182. 13. Chan KE, Giugliano RP, Patel MR, et al. Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF. J Am Coll Cardiol 2016; 67:2888. 14. Lau YC, Proietti M, Guiducci E, et al. Atrial Fibrillation and Thromboembolism in Patients With Chronic Kidney Disease. J Am Coll Cardiol 2016; 68:1452. 15. Yao X, Shah ND, Sangaralingham LR, et al. Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction. J Am Coll Cardiol 2017; 69:2779. 16. Goldenberg IF, Lewis WR, Dias VC, et al. Intravenous diltiazem for the treatment of patients with atrial fibrillation or flutter and moderate to severe congestive heart failure. Am J Cardiol 1994; 74:884. 17. Frendl G, Sodickson AC, Chung MK, et al. 2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures. J Thorac Cardiovasc Surg 2014; 148:e153. 18. Bhave PD, Goldman LE, Vittinghoff E, et al. Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery. Am Heart J 2012; 164:918. 19. Blanco BA, Kothari AN, Halandras PM, et al. Transient atrial fibrillation after open abdominal aortic revascularization surgery is associated with increased length of stay, mortality, and readmission rates. J Vasc Surg 2017; 66:413. 20. Polanczyk CA, Goldman L, Marcantonio ER, et al. Supraventricular arrhythmia in patients having noncardiac surgery: clinical correlates and effect on length of stay. Ann Intern Med 1998; 129:279. 21. Butt JH, Olesen JB, Havers-Borgersen E, et al. Risk of Thromboembolism Associated With Atrial Fibrillation Following Noncardiac Surgery. J Am Coll Cardiol 2018; 72:2027. 22. Danelich IM, Lose JM, Wright SS, et al. Practical management of postoperative atrial fibrillation after noncardiac surgery. J Am Coll Surg 2014; 219:831. https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 13/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate 23. Passman RS, Gingold DS, Amar D, et al. Prediction rule for atrial fibrillation after major noncardiac thoracic surgery. Ann Thorac Surg 2005; 79:1698. 24. Simmers D, Potgieter D, Ryan L, et al. The use of preoperative B-type natriuretic peptide as a predictor of atrial fibrillation after thoracic surgery: systematic review and meta-analysis. J Cardiothorac Vasc Anesth 2015; 29:389. 25. La Manna G, Boriani G, Capelli I, et al. Incidence and predictors of postoperative atrial fibrillation in kidney transplant recipients. Transplantation 2013; 96:981. 26. Walsh SR, Oates JE, Anderson JA, et al. Postoperative arrhythmias in colorectal surgical patients: incidence and clinical correlates. Colorectal Dis 2006; 8:212. 27. Khanna AK, Naylor DF Jr, Naylor AJ, et al. Early Resumption of Blockers Is Associated with Decreased Atrial Fibrillation after Noncardiothoracic and Nonvascular Surgery: A Cohort Analysis. Anesthesiology 2018; 129:1101. 28. Link MS, Atkins DL, Passman RS, et al. Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S706. 29. Bobbio A, Caporale D, Internullo E, et al. Postoperative outcome of patients undergoing lung resection presenting with new-onset atrial fibrillation managed by amiodarone or diltiazem. Eur J Cardiothorac Surg 2007; 31:70. 30. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med 2001; 29:1149. 31. Gialdini G, Nearing K, Bhave PD, et al. Perioperative atrial fibrillation and the long-term risk of ischemic stroke. JAMA 2014; 312:616. 32. Makhija Z, Allen MS, Wigle DA, et al. Routine anticoagulation is not indicated for postoperative general thoracic surgical patients with new-onset atrial fibrillation. Ann Thorac Surg 2011; 92:421. Topic 113847 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 14/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate GRAPHICS Recommendations for discontinuation of direct oral anticoagulants in the perioperative time period Low risk for bleeding High risk for bleeding DTI Factor Xa inhibitor DTI Factor Xa inhibitor CrCl Discontinue CrCl Discontinue CrCl Discontinue CrCl Discontinue <15 No data, 96 hours <15 No data, 48 hours <15 No data <30 No data, 72 hours 15 to 29 72 hours 15 to 29 36 hours 15 to 29 120 hours 30 48 hours 30 to 49 48 hours 30 24 hours 30 to 49 96 hours 50 to 79 36 hours 50 to 79 72 hours 80 24 hours 80 48 hours DTI: direct thrombin inhibitor; CrCl: creatinine clearance. Adapted from: Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial brillation: A report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017; 69:871. Graphic 120231 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 15/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or aortic plaque) 1 5 7.2 Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 16/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate [3]
12/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017; 69:871. 12. Narouze S, Benzon HT, Provenzano DA, et al. Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of Pain Medicine, the International Neuromodulation Society, the North American Neuromodulation Society, and the World Institute of Pain. Reg Anesth Pain Med 2015; 40:182. 13. Chan KE, Giugliano RP, Patel MR, et al. Nonvitamin K Anticoagulant Agents in Patients With Advanced Chronic Kidney Disease or on Dialysis With AF. J Am Coll Cardiol 2016; 67:2888. 14. Lau YC, Proietti M, Guiducci E, et al. Atrial Fibrillation and Thromboembolism in Patients With Chronic Kidney Disease. J Am Coll Cardiol 2016; 68:1452. 15. Yao X, Shah ND, Sangaralingham LR, et al. Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction. J Am Coll Cardiol 2017; 69:2779. 16. Goldenberg IF, Lewis WR, Dias VC, et al. Intravenous diltiazem for the treatment of patients with atrial fibrillation or flutter and moderate to severe congestive heart failure. Am J Cardiol 1994; 74:884. 17. Frendl G, Sodickson AC, Chung MK, et al. 2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures. J Thorac Cardiovasc Surg 2014; 148:e153. 18. Bhave PD, Goldman LE, Vittinghoff E, et al. Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery. Am Heart J 2012; 164:918. 19. Blanco BA, Kothari AN, Halandras PM, et al. Transient atrial fibrillation after open abdominal aortic revascularization surgery is associated with increased length of stay, mortality, and readmission rates. J Vasc Surg 2017; 66:413. 20. Polanczyk CA, Goldman L, Marcantonio ER, et al. Supraventricular arrhythmia in patients having noncardiac surgery: clinical correlates and effect on length of stay. Ann Intern Med 1998; 129:279. 21. Butt JH, Olesen JB, Havers-Borgersen E, et al. Risk of Thromboembolism Associated With Atrial Fibrillation Following Noncardiac Surgery. J Am Coll Cardiol 2018; 72:2027. 22. Danelich IM, Lose JM, Wright SS, et al. Practical management of postoperative atrial fibrillation after noncardiac surgery. J Am Coll Surg 2014; 219:831. https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 13/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate 23. Passman RS, Gingold DS, Amar D, et al. Prediction rule for atrial fibrillation after major noncardiac thoracic surgery. Ann Thorac Surg 2005; 79:1698. 24. Simmers D, Potgieter D, Ryan L, et al. The use of preoperative B-type natriuretic peptide as a predictor of atrial fibrillation after thoracic surgery: systematic review and meta-analysis. J Cardiothorac Vasc Anesth 2015; 29:389. 25. La Manna G, Boriani G, Capelli I, et al. Incidence and predictors of postoperative atrial fibrillation in kidney transplant recipients. Transplantation 2013; 96:981. 26. Walsh SR, Oates JE, Anderson JA, et al. Postoperative arrhythmias in colorectal surgical patients: incidence and clinical correlates. Colorectal Dis 2006; 8:212. 27. Khanna AK, Naylor DF Jr, Naylor AJ, et al. Early Resumption of Blockers Is Associated with Decreased Atrial Fibrillation after Noncardiothoracic and Nonvascular Surgery: A Cohort Analysis. Anesthesiology 2018; 129:1101. 28. Link MS, Atkins DL, Passman RS, et al. Part 6: electrical therapies: automated external defibrillators, defibrillation, cardioversion, and pacing: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122:S706. 29. Bobbio A, Caporale D, Internullo E, et al. Postoperative outcome of patients undergoing lung resection presenting with new-onset atrial fibrillation managed by amiodarone or diltiazem. Eur J Cardiothorac Surg 2007; 31:70. 30. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med 2001; 29:1149. 31. Gialdini G, Nearing K, Bhave PD, et al. Perioperative atrial fibrillation and the long-term risk of ischemic stroke. JAMA 2014; 312:616. 32. Makhija Z, Allen MS, Wigle DA, et al. Routine anticoagulation is not indicated for postoperative general thoracic surgical patients with new-onset atrial fibrillation. Ann Thorac Surg 2011; 92:421. Topic 113847 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 14/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate GRAPHICS Recommendations for discontinuation of direct oral anticoagulants in the perioperative time period Low risk for bleeding High risk for bleeding DTI Factor Xa inhibitor DTI Factor Xa inhibitor CrCl Discontinue CrCl Discontinue CrCl Discontinue CrCl Discontinue <15 No data, 96 hours <15 No data, 48 hours <15 No data <30 No data, 72 hours 15 to 29 72 hours 15 to 29 36 hours 15 to 29 120 hours 30 48 hours 30 to 49 48 hours 30 24 hours 30 to 49 96 hours 50 to 79 36 hours 50 to 79 72 hours 80 24 hours 80 48 hours DTI: direct thrombin inhibitor; CrCl: creatinine clearance. Adapted from: Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial brillation: A report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017; 69:871. Graphic 120231 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 15/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted [1] CHADS acronym Score CHADS acronym ischemic stroke rate (% per year) 2 2 Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc acronym 2 2 [2] CHA DS -VASc acronym Score 2 2 (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or aortic plaque) 1 5 7.2 Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 16/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 Actual rates of stroke in contemporary cohorts might vary from these estimates. . References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 17/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED Bleeds per 100 patient-years score (total points) 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 18/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 19/20 7/5/23, 9:04 AM Atrial fibrillation in patients undergoing noncardiac surgery - UpToDate Contributor Disclosures David Spragg, MD, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Jonathan B Mark, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-patients-undergoing-noncardiac-surgery/print 20/20
7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Left atrial appendage occlusion : Ziyad M Hijazi, MD, MPH, FAAP, FACC, MSCAI, FAHA, FPICS, Jacqueline Saw, MD, FRCPC, FACC : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 24, 2023. INTRODUCTION The roles of percutaneous and surgical left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) are discussed here. AF is a common cause of embolic stroke and other thromboembolic complications. The LAA is a primary source for thromboembolism in AF. Whereas anticoagulation is recommended for most patients with AF, some patients have contraindications to long-term anticoagulation. Anticoagulation in patients with AF is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) RATIONALE AND LIMITATIONS Among patients with AF, thrombus in the LAA is the primary source for thromboemboli. A review of studies examining the site of left atrial thrombus (by transesophageal echocardiography [TEE], cardiac surgery, or autopsy) found that in patients with AF without rheumatic heart disease, 90 percent of left atrial thrombi were located in the LAA [1]. The importance of the LAA as a source for thromboemboli among patients with AF provides the rationale for ligation, amputation, or occlusion of the LAA, particularly for patients who have an indication for anticoagulation but cannot take long-term oral anticoagulation. However, the following caveats should be kept in mind: https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 1/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Ten percent of left atrial thrombi are not located in the LAA [1], so occluding the LAA may not completely eliminate the risk of embolism from the LA. Thrombogenesis in patients with AF may not be limited to the LA. The pathophysiology of thrombogenesis in AF, including left atrial structural and functional abnormalities and hypercoagulable state, is discussed further separately. (See "Mechanisms of thrombogenesis in atrial fibrillation" and "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) If the LAAO has an incomplete closure, this can result in a residual communication between the LAA and LA, also referred to as a residual jet. An incomplete jet is one that is >5 mm; these are believed to predispose to thrombus formation. The importance of smaller jets (ie, 5 mm) is uncertain, but one study suggested a low risk of thromboembolic events [2]. In this retrospective review of 6- and 12-month follow-up echocardiograms in over 400 patients who received the WATCHMAN device, there was no significant increase in the rate of thromboembolism in the 32 percent of patients with LAA residual jet width >5 mm compared with those with no residual jet or jet width 5 mm. It is likely that most residual holes are small and not associated with embolization of large clots. INDICATIONS The indications for surgical and nonsurgical closure are similar. Patients not undergoing cardiac surgery The following approaches apply to patients with AF with an indication for anticoagulation (based upon their estimated risk of stroke and other systemic thromboembolism ( table 1)) who have a contraindication to long-term anticoagulation. These approaches do not apply to patients with AF who have other indications for anticoagulation (eg, an implanted mechanical valve). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Patients with one or more of the following conditions may have a contraindication to long-term anticoagulation and may therefore have an indication for LAA occlusion: Thrombocytopenia or known coagulation defect associated with bleeding. Recurrent bleeding, including gastrointestinal, genitourinary, or respiratory sites. Prior severe bleeding, including intracranial hemorrhage. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 2/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate High risk of the patient falling (which may be evidenced by history of prior falls resulting in injury) despite safety measures. Strong indication for combined use of dual antiplatelet and anticoagulant therapy. Poor compliance with or intolerance of anticoagulant therapy. For patients not undergoing cardiac surgery who have AF with an indication for anticoagulation (based upon risk of stroke and other systemic thromboembolism ( table 1)) but cannot be on long-term oral anticoagulation, we suggest placement of a percutaneous LAAO device. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Approach to deciding whether to anticoagulate'.) However, it should be noted that short-term antithrombotic therapy (anticoagulant or dual antiplatelet therapy) is generally recommended after placement of the device as discussed below. (See 'After percutaneous closure' below.) Therefore, patients who cannot have even short-term blood-thinning medicines (anticoagulation therapy, P2Y12 inhibitors, and aspirin) are generally not candidates for LAAO. Most patients can tolerate at least one antiplatelet agent for a short duration. The efficacy and safety of percutaneous LAAO as an adjunct to long-term oral anticoagulation in patients with AF has not been established. A rationale for this approach would be to attempt to reduce the risk of stroke and other systemic embolic events beyond the risk reduction provided by anticoagulation, but this approach would entail procedural risks that might offset potential benefits. Both efficacy and safety of LAAO devices compared with long-term anticoagulation were demonstrated in a meta-analysis that included three randomized, open-label, controlled trials (PROTECT AF, PREVAIL, and PRAGUE-17) [3]. A total of 933 patients were randomly assigned to percutaneous LAA closure, and 583 were randomly assigned to oral anticoagulation (65 percent were on warfarin, and 35 percent on a direct oral anticoagulant [DOAC]) and followed for an average of 39 months. The mean age was 73.3 years, and the mean CHA DS -VASc score was 2 2 4.1. The study made the following observations. The implanted device was WATCHMAN, Amulet, and WATCHMAN FLX in 86, 13.5, and 0.5 percent, respectively. The mean age was 73.3 years, and the mean CHA DS -VASc score was 4.1. 2 2 Successful implantation occurred in 93.3 percent of patients https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 3/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate There was no significant difference in the all-stroke or systemic embolism rate between the groups (6.1 versus 5.8 percent; risk ratio [RR] 0.98, 95% CI 0.65-1.48). LAA closure was associated with a lower risk of hemorrhagic stroke (0.5 versus 2.4 percent; RR 0.22, 95% CI 0.08-0.58), cardiovascular death (5.4 versus 8.2 percent; RR 0.65, 95% CI 0.44-0.95), and all-cause death (14.3 versus 17.8 percent; RR 0.78, 95% CI 0.62-0.99). Major bleeding was similar in the two groups (RR 0.89, 95% CI 0.66-1.20), but non- procedure-related major bleeding was lower with LAA closure (RR 0.53, 95% CI 0.38-0.74). Procedure-related complications occurred in 6.8 percent. The efficacy of specific percutaneous LAA occlusion devices is described below. (See 'Percutaneous devices' below.) Patients undergoing surgery Surgical ligation or amputation of the LAA can be performed without significant morbidity or mortality in patients with AF who are undergoing cardiac surgery for other indications. Surgical ligation or amputation of the LAA can be performed without significant morbidity or mortality in patients with AF who are undergoing cardiac surgery for other indications. Surgical LAAO is most commonly performed in patients undergoing mitral valve or Maze surgery. (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure' and 'Surgical LAA closure' below.) For patients with AF who are undergoing surgery for another indication and who also have a CHA DS -VASc score of at least 2 ( table 1), we consider LAAO. 2 2 Patients with no contraindication to anticoagulation In such patients, we recommend concomitant surgical LAAO as an adjunct to oral anticoagulation, as LAAO may help further reduce future risk of thromboembolic events. A randomized trial and observational studies support the efficacy of LAAO for selected patients with AF undergoing cardiac surgery: Randomized trial The role of surgical LAAO as an adjunct to anticoagulation is supported by the results of the LAAOS III trial in individuals with AF (mean age 71) undergoing cardiac surgery for another indication with a CHA DS -VASc score of at least 2 2 2 (mean score of 4.2) [4]. In this multicenter trial, 2379 participants were randomly assigned to the occlusion group, and 2391 to the no-occlusion group, with a mean of 3.8 years of follow-up. A total of 92.1 percent of the participants received the assigned procedure. The majority of participants continued oral anticoagulation after the procedure (76.8 percent at three years). Stroke or systemic embolism occurred in 114 participants (4.8 percent) in the occlusion group and in 168 (7.0 percent) in the no- https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 4/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate occlusion group (hazard ratio [HR] 0.67, 95% CI 0.53-0.85). Incidence rates of perioperative major bleeding, hospitalization for heart failure, and death were similar in the two groups. Surgical LAAO is performed using a variety of techniques. In the LAAOS III trial, LAAO was performed by amputation and closure, stapler closure, double-layer linear closure from within the atrium (in patients undergoing minithoracotomy; this approach required transesophageal confirmation of occlusion), or closure with an approved surgical occlusion device [4]. Intraoperative TEE confirmation of LAA closure is recommended. Observational studies Two large retrospective cohort studies suggested a benefit from surgical LAAO in patients with AF undergoing cardiac surgery [5,6], whereas one smaller study did not [7]: In a study of 75,782 patients undergoing cardiac surgery, 8590 propensity-matched pairs (with and without surgical LAAO) were identified and studied; 74.9 percent had a history of AF, and 30.5 percent were taking an oral anticoagulant at baseline [6]. During follow-up (mean 2.1 years), LAAO was associated with a reduced risk of ischemic stroke or systemic embolism (1.14 versus 1.59 events per 100 patient-years; HR 0.73, 95% CI 0.56-0.96) and mortality (3.01 versus 4.30 events per 100 patient-years; HR 0.71, 95% CI 0.60-0.84). Most of the benefit was seen in patients with prior AF. LAAO was also associated with modestly higher rates of AF-related outpatient visits (11.96 versus 10.26 events per patient-year; rate ratio 1.17, 95% CI 1.10-1.24) and hospitalizations (0.36 versus 0.32 events per patient-year; rate ratio 1.13, 95% CI 1.05-1.21). In contrast, a smaller study (with 461 propensity-matched pairs) found similar risks of stroke and mortality in patients with and without surgical LAAO [7]. Patients with a contraindication to long-term anticoagulation In such patients, we suggest concomitant surgical LAAO, as the procedure is generally safe and may provide some protection against future stroke. However, there are limited data to support surgical LAAO without long-term anticoagulation. Long-term anticoagulation is usually used after surgical LAAO. Patients with an absolute contraindication to anticoagulation must be able to take dual antiplatelet therapy for up to six weeks postoperatively. (See 'After surgical occlusion' below.) In a retrospective cohort study of 10,524 Medicare recipients with AF undergoing cardiac surgery, surgical LAAO (n = 3892) compared with no occlusion (n = 6632) was significantly associated with lower risk of readmission for thromboembolism at three years (4.2 versus https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 5/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate 6.2 percent; HR 0.67; 95% CI 0.56-0.81) [5]. Among patients discharged without anticoagulation, LAAO was associated with a lower risk of thromboembolism (4.2 versus 6.0 percent; HR 0.26; 95% CI 0.17-0.40), but not among patients discharged with anticoagulation (4.1 versus 6.3 percent; HR 0.88; 95% CI 0.56-1.39). In the cohort of patients discharged with oral anticoagulation, surgical LAAO was not associated with thromboembolism but was associated with a lower risk for hemorrhagic stroke, presumably related to eventual discontinuation of oral anticoagulation among the LAAO patients. In patients without AF, there is no established role for LAAO. PREPROCEDURE PLANNING Among persons with AF, the anatomy of the LAA is heterogenous including varied shapes, neck and long axis diameters, and number of lobes [8]. Specific LAA measurements (eg, LAA depth and mouth diameter) can be useful for LAA closure planning; these can be obtained by transesophageal echocardiogram (TEE), coronary computed tomography angiography, or cardiac magnetic resonance imaging. No specific LAA preprocedural imaging is required for surgical LAAO. If upon cardiac imaging an LA/LAA thrombus is seen, the LAAO procedure is contraindicated. If an LAA thrombus is visualized, the we initiate or intensify anticoagulation (as appropriate) and continue it for six to eight weeks. At that time, we repeat LAA imaging to reassess the thrombus and if resolved, we perform LAAO. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Patients should be asked about sensitivity to Nitinol (an alloy made of nickel and titanium) or any other material that is part of the specific LAAO device; in the case of an allergy, the device would be contraindicated. For instance, both the Watchman and Amplatzer devices contain Nitinol. Nickel allergy is very common. (See "Nickel hypersensitivity and coronary artery stents".) Ideally, patients receiving a percutaneous device are able to tolerate oral anticoagulation (vitamin K antagonist or direct oral anticoagulant [DOAC]) or dual antiplatelet therapy for at least six weeks after the device is implanted and cannot have LAA clot present at the time of implantation. Some experts would perform LAAO in patients who cannot tolerate anticoagulants or antiplatelets, whereas others require at least two to four weeks of aspirin postprocedure. LAAO device implantation can be performed with transesophageal echocardiography (TEE) guidance under general anesthesia or intracardiac echocardiographic guidance under local anesthesia, but the practice varies [9,10]. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 6/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate PROCEDURE In most centers, the procedure is performed using transesophageal echocardiographic (TEE) guidance under deep sedation or general endotracheal anesthesia. Some centers perform the procedure under sedation and only fluoroscopic guidance. After vascular access is obtained in the femoral vein, a comprehensive TEE is performed (if it was not performed previously) to assess the LAA anatomy and specifically to rule out presence of any clot/thrombus, as this is a contraindication to proceed. After this, a transseptal puncture is performed. Obtaining the correct location of the puncture in the intraatrial septum is important and is guided by TEE. Once the septum is punctured, we administer heparin with a goal activated clotting time >250 seconds; this is done to avoid thrombosis of the percutaneous catheters and occlusion device. Angiography is performed in two orthogonal views for sizing. Device sizing and selection are based on the anatomy. Once the device is deployed, stability is assessed and then the device is released. Patients usually spend one night in the hospital and are discharged the following day on antiplatelets therapy. PERCUTANEOUS DEVICES Among the available percutaneous LAA closure devices, the WATCHMAN is the only device for which randomized trials have shown comparable efficacy and safety with long-term warfarin for the prevention of stroke and systemic embolization. The Amulet device was shown to be noninferior to the WATCHMAN device in the Amulet IDE study. Selection between the WATCHMAN FLX and AMULET device is largely based on anatomy and operator comfort/experience. The WATCHMAN (largely replaced by the second-generation WATCHMAN FLX), the Amplatzer Cardiac Plug, and the Amplatzer Amulet are the leading implanted LAA endovascular devices worldwide and have CE (The European Union device approval). The WATCHMAN, WATCHMAN FLX, and Amulet devices are approved by the United States Food and Drug Administration (FDA) ( table 2). Endovascular devices Percutaneous devices require a transseptal puncture from a femoral venous access to enable device implantation into the LAA from a purely endovascular approach ( figure 1). These procedures are done under transesophageal echocardiography (TEE) or intracardiac echocardiography guidance. Efficacy and some device-specific safety outcomes are discussed here. Procedural complications are discussed in greater detail below. (See 'Device safety and complications' below.) https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 7/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate WATCHMAN device The WATCHMAN device is the most commonly implanted percutaneous LAAO device and has the most robust data to support its use. It is a self-expandable cage deployed in the LAA, using a transseptal approach ( figure 1). The device is covered by a layer of permeable polyethylene terephthalate (PTFE) membrane, which endothelializes within 45 days in dog models. The WATCHMAN device comes in five sizes ( table 3) and has 10 fixation anchors to aid device stability. The second-generation WATCHMAN FLX device also comes in five sizes ( table 3), with a slightly broader range of dimensions, and has 12 fixation anchors. Efficacy randomized trials Newer-generation WATCHMAN devices were shown to be both efficacious and safe in a nonrandomized study of 400 patients (PINNACLE FLX study) [11]. The first-generation WATCHMAN device was comprehensively evaluated in two randomized trials (PROTECT AF and PREVAIL) in patients with nonvalvular AF eligible for oral anticoagulation [12,13]. The five-year outcomes of the PREVAIL trial, combined with the five-year outcomes of the PROTECT AF trial, were reported in 2017 [14]. The results demonstrated that LAA closure with WATCHMAN device provided stroke prevention in nonvalvular AF that was comparable to warfarin, with additional reductions in major bleeding, particularly hemorrhagic stroke, and mortality. In the PROTECT AF noninferiority trial, 707 patients with AF and a CHADS score 1 were 2 randomly assigned in a 2:1 ratio to either the device or long-term warfarin (international normalized ratio 2 to 3) and followed for 18 months ( table 4) [15]. Device implantation was successful in 91 percent of patients in whom it was attempted. Postimplantation, patients were continued on warfarin for 45 days, followed by switching warfarin to clopidogrel plus aspirin to six months, followed by aspirin alone indefinitely. The risk of composite outcome (stroke, systemic embolism, or cardiovascular death) was similar in the intervention and control groups (3 versus 4.9 events per 100 patient- years, respectively; rate ratio 0.62; 95% Bayesian credible interval 0.35-1.25). The primary safety endpoint (major bleeding, pericardial effusion, procedure-related stroke, or device embolization) occurred more often in the device group (7.4 versus 4.4 events per 100 patient-years, respectively; rate ratio 1.69; 95% Bayesian credible interval 1.01-3.19). Most of the events in the device group occurred early. Of these, approximately 50 percent were pericardial effusions requiring drainage. The device embolization rate was 0.6 percent. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 8/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate In a subsequent study from PROTECT AF, at 12 months, patients treated with the closure device had improvement in health-related quality-of-life measures, while these measures declined among patients treated with warfarin [12,13]. The PREVAIL study was mandated by the FDA to further evaluate the safety profile and confirm the efficacy of WATCHMAN for regulatory approval. This study randomly assigned 407 patients to WATCHMAN or warfarin. Participants had CHADS score 2, or 2 1, if 1 of the following was present: female 75 years old, left ventricular ejection fraction 30 to 34.9 percent, age 65 to 74 with diabetes or coronary artery disease, or age 65 with documented congestive heart failure [13]. At 18-month follow-up, the first coprimary efficacy endpoint (composite of stroke, systemic embolism, and cardiovascular/unexplained death) with WATCHMAN versus warfarin did not achieve noninferiority criteria (0.64 versus 0.063; rate ratio 1.07; 95% CI 0.57-1.89). However, the second coprimary efficacy endpoint (stroke or systemic embolism >7 days postrandomization) did achieve noninferiority (0.025 versus 0.020; risk difference 0.0053; 95% CI -0.0190 to 0.0273). Early safety events occurred in 2.2 percent of the WATCHMAN arm, which was significantly lower than in PROTECT AF, satisfying the prespecified safety performance goal. Evidence in patients with absolute contraindications to oral anticoagulation LAA closure with WATCHMAN has been evaluated in 150 patients with absolute contraindications to oral anticoagulation in nonrandomized studies. In the prospective multicenter, nonrandomized ASAP study, patients with a CHADS score 1 were treated 2 with WATCHMAN and six months of a thienopyridine (clopidogrel or ticlopidine), as well as life-long aspirin [16]. During a mean follow-up of 14.4 months, stroke or systemic embolism occurred at a rate of 2.3 percent per year. This rate was lower than predicted rates for CHADS -matched cohorts of individuals taking either aspirin (7.3 percent) or clopidogrel (5 2 percent). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Use'.) Real-world observational studies In the EWOLUTION study of real-world experience with WATCHMAN, procedural success was achieved in 98.5 percent, and serious procedural complications within seven days occurred in only 2.8 percent [17,18]. At one-year follow-up, the ischemic stroke rate was 1.1 percent, which represented 84 percent reduction compared with the historical estimate based upon CHA DS -VASc score [18]. 2 2 Amplatzer devices Globally, the Amplatzer devices (Cardiac Plug and Amulet) are the second most commonly implanted endovascular LAA closure devices after WATCHMAN. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 9/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Description and procedural success rates The Amplatzer Cardiac Plug ( figure 2) [19] device is constructed of Nitinol mesh, consisting of a proximal LA disk and a distal LAA lobe connected by a short waist. The lobe contains six pairs of stabilizing wires designed to increase stability within the appendage. The second-generation Amplatzer Cardiac Plug device (Amulet) received European device approval in 2013 and FDA approval in 2021, and incorporates significant advances, including wider lobe and more stabilizing wires (up to 10 pairs) for improved device stability, and larger lobe size to occlude larger appendages. A multicenter Amulet postmarketing registry report, including 1088 patients [20], showed procedural success was 99 percent. Procedural and in-hospital major adverse events occurred in 3.2 percent of patients. Amplatzer versus WATCHMAN The Amplatzer device is shorter than the WATCHMAN device and may be more advantageous in individuals with short appendages. In a randomized trial comparing the two devices, the Amulet device was noninferior to the WATCHMAN in terms of primary safety and efficacy endpoints, but was associated with more procedure-related complications. The Amulet IDE trial randomly assigned 1878 patients with AF (mean CHA DS -VASc score of 4.6) to receive either the Amulet or 2 2 WATCHMAN percutaneous LAAO device [21]. The rate of ischemic stroke or systemic embolism at 18 months was similar with the Amulet and WATCHMAN devices (2.8 percent for both). Major bleeding and all-cause death were similar in the two groups (10.6 versus 10 percent and 3.9 versus 5.1 percent, respectively). LAAO with residual jet 5 mm (ie, adequate LAA exclusion) was more frequent with the Amulet occluder than the WATCHMAN device (98.9 versus 96.8 percent, ie, Amulet was superior to WATCHMAN in reducing peridevice leak). However, the following rates of procedure-related complications were higher for Amulet versus WATCHMAN: Early pericardial effusion/tamponade (<2 days postprocedure; 1.3 versus 1.1 percent) Late pericardial effusion/tamponade (>2 days postprocedure; 1.1 versus 0.1 percent) Device embolization (0.7 versus 0.2 percent) WaveCrest device The WaveCrest is another endovascular device designed specifically for closure of the LAA. It is currently used in the European Union but is not approved for use in the United States. This device consists of a single lobe that occludes the LAA ( figure 3). Unlike WATCHMAN, the WaveCrest is covered by a foam layer on the LAA side and PTFE on the side facing the LA. It has several anchors along the LAA side. This device is meant to be deployed quite proximally in the LAA, rather than deep within the structure. Thus, this device is another alternative to the WATCHMAN device if the LAA is too small to accommodate deeper devices. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 10/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate LARIAT system The LARIAT system is a nonsurgical (percutaneous) device ( picture 1) approved by the FDA for soft tissue closure ("approximation") only [22-26], but not specifically for prevention of thromboembolism with LAAO. Its use for LAA closure is "off-label" in the United States, and it is rarely used. Unlike the endovascular devices, the LARIAT system requires access to both the endocardial and the epicardial space (the latter via a subxiphoid percutaneous approach). A magnetic guide is placed within the LAA to allow the epicardially placed lasso to tie off the LAA. Patients who have had prior cardiac surgery or unusual LAA anatomy are not candidates for this procedure ( table 2). The aMAZE trial randomly assigned 610 patients with persistent AF to LAA ligation with LARIAT plus pulmonary vein antral isolation (a type of catheter ablation of AF) versus pulmonary vein antral isolation alone and followed patients for efficacy at rhythm control (ie, freedom from antiarrhythmic medications) and safety [27]. The primary effectiveness endpoint (freedom from antiarrhythmic drug therapy at 12 months) was 64.3 percent in the LAA ligation/pulmonary vein antral isolation group versus 59.9 percent in the pulmonary vein antral isolation alone group (criterion for superiority not met). The primary safety endpoint occurred in 3.4 percent of the LAA ligation/pulmonary vein antral isolation group. Residual communication between the LA and LAA 1 mm at 12 months postprocedure occurred in the majority of patients in the LARIAT plus catheter ablation group (85 percent). SURGICAL LAA CLOSURE Types of surgical closure include stapler occlusion, amputation and suture, and epicardial device closure ( table 2). These are usually done in patients who are undergoing cardiac surgery for another indication such as coronary artery bypass grafting or cardiac valve replacement surgery. A detailed discussion of the risks and benefits of various types of surgical closure is beyond the scope of this topic. LAAO or excision may be incomplete, as has been detected by transesophageal echocardiography (TEE) studies. Patients with incomplete LAAO continue to be at risk for LAA thrombus and thromboembolic events. In three separate cases series, incomplete surgical LAA ligation was reported in 10 to 40 percent of patients undergoing the procedure [28-30]. Among 50 patients undergoing mitral valve surgery and LAAO, incomplete appendage closure occurred in 36 percent of patients, and stroke occurred in 22 percent of patients with incomplete appendage ligations [29]. A minimally invasive thoracotomy (versus median sternotomy) is a less invasive approach that provides transpericardial (epicardial) access for LAA closure with an endovascular device; https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 11/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate examples of devices used with this approach are listed in a table ( table 5) [31] The efficacy and safety of stand-alone thoracoscopic LAA appendectomy have not been established, and it is infrequently performed, given the widespread availability of percutaneous LAAO. The feasibility of stand-alone thoracoscopic LAA appendectomy was addressed in a study of 30 patients with AF and prior thromboembolism who had contraindications to oral anticoagulation [32]. Thoracoscopic LA appendectomy was not associated with increased mortality or major complications. At a mean follow-up of 16 months, no patients had experienced a recurrence of thromboembolism. POSTPROCEDURE MANAGEMENT Endocarditis prophylaxis We generally recommend bacterial endocarditis prophylaxis for up to six months after device placement. Antimicrobial regimens for prophylaxis and relevant procedures are discussed separately. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".) After percutaneous closure We prescribe short-term anticoagulation and obtain follow-up transesophageal echocardiograms (TEEs) in patients who have had percutaneous LAAO. Primary anticoagulation strategies For most patients, we prescribe an oral anticoagulant (warfarin with target international normalized ratio 2 to 3 or direct oral anticoagulant [DOAC]) plus aspirin (81 to 325 mg daily) for 45 days, followed by once-daily clopidogrel (75 mg) plus aspirin (81 to 325 mg) for six months; thereafter, we continue once-daily aspirin (81 to 325 mg) alone indefinitely. This protocol is based on that used in the PROTECT AF trial [12]. However, in patients with absolute contraindications to oral anticoagulation, dual antiplatelet therapy (aspirin plus clopidogrel) is used for six months postprocedure, as in the ASAP study, or for one to three months for patients at high risk of bleeding. As of September 2022, FDA labeling for patients with nonvalvular AF who undergo WATCHMAN FLX LAAO placement was expanded to include 45 days of oral anticoagulant therapy plus dual antiplatelet therapy. Data supportive of this approach were from an analysis of more than 17,000 patients from the NCDR-LAAO Registry, which demonstrated no significant difference in rates of major adverse events at 45 days postimplantation, whether patients were discharged from the hospital on dual antiplatelet therapy, a DOAC and aspirin, or warfarin and aspirin. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 12/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Alternative anticoagulation strategies Alternative imaging-based strategy An alternative strategy was used in the nonrandomized, newer-generation WATCHMAN study (PINNACLE FLX), which confirmed device safety and efficacy [11]. This strategy included treatment with a DOAC through at least a 45-day follow-up, with apixaban or rivaroxaban strongly recommended. Patients were also prescribed concomitant low-dose (81 to 100 mg) aspirin. On evidence of adequate LAA seal (leak 5 mm) at the 45-day TEE evaluation, patients were directed to discontinue DOAC therapy and begin a dual antiplatelet therapy regimen of clopidogrel (75 mg) plus low-dose aspirin until six months postimplantation, followed by low-dose aspirin indefinitely. If a leak >5 mm was measured at the 45-day follow-up, patients continued DOAC plus aspirin and were reevaluated at six months postimplant. If there were no leaks >5 mm at the subsequent follow-up visit, patients could forego dual antiplatelet therapy and proceed straight to life-long low-dose aspirin. Postimplantation follow-up visits were required at 45 days and 6, 12, 18, and 24 months. Long-term, half-dose DOAC This regimen versus standard anticoagulation treatment was tested in a nonrandomized study of 555 patients post-WATCHMAN device implantation [33]. The primary endpoint was a composite of device-related thrombosis, thromboembolic events, and bleeding. After 13 months, device-related thrombosis occurred in 12 patients, all in the full-dose DOAC group (3 versus 0 percent). The risk of nonprocedural major bleeding was more favorable in the half-dose DOAC group (0.5 percent versus 4 percent). The rate of the primary composite endpoint was higher in the standard treatment group (10 versus 1 percent). Further randomized studies are needed before we can make recommendations about the long-term, half-DOAC anticoagulation strategy. Postprocedural imaging We obtain a transthoracic echocardiogram one day postprocedure to ensure there is no pericardial effusion. We also obtain a TEE between one and six months postprocedure to screen for or device-related thrombus (DRT), pericardial effusion, or a peridevice leak. DRT is present in approximately 2 to 5 percent of patients, depending on time of screening and device type, and is associated with risk of stroke or transient ischemic attack [16,20,34-36]. For patients with documented DRT, the optimal antithrombotic regimen is not known. Options for treatment of DRT include one of the following anticoagulants that may be combined with aspirin: DOAC (such as apixaban or rivaroxaban; avoid dabigatran) for 8 to 12 weeks, warfarin (target international https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 13/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate normalized ratio 2 to 3) for 8 to 12 weeks, or low molecular weight heparin for two to four weeks [36]. It is important to check for any residual communication between the LA and LAA after device closure. In some cases, the presence of a leak will prompt shared decision- making discussions with patients regarding continued oral anticoagulation or closure of the leak with other devices such as a coil. It is uncertain if the size of the peridevice leak should guide further management, and prior data are mixed [37]. Previously, a peridevice leak of <5 mm was thought to be of little clinical significance (this amount of leak was arbitrarily used to define successful occlusion in device trials), whereas a leak 5 mm was an indication for continuing oral anticoagulation and/or additional endovascular procedure to close the residual leak (eg, with another percutaneous closure device or coils). Recent real-world, registry-based data suggest that small leaks may be associated with higher bleeding and thromboembolic risk [38]. (See 'Rationale and limitations' above.) A study of over 51,000 people in the National Cardiovascular Data LAAO Registry showed that small (>0 to 5 mm) leaks after LAAO were associated with a modestly higher incidence of thromboembolic and bleeding events, and large leaks (>5 mm) were not associated with adverse events, although higher proportions of these patients were maintained on anticoagulation. In this study, small leaks were common; 25.8 percent had small leaks and 0.7 percent had large leaks. A higher proportion of patients with large leaks were on warfarin at 45 days versus small or no leak (44.9 versus 34.4 and 32.4 percent, respectively). At 6 and 12 months, anticoagulant use decreased but remained more frequent in patients with large leaks. Thromboembolic and bleeding events were uncommon in all groups. However, compared with patients with no leak, those with small leaks had slightly higher odds of stroke/transient ischemic attack/systemic embolization (hazard ratio [HR] 1.15; 95% CI 1.03-1.29), major bleeding (HR 1.11; 95% CI, 1.03-1.12), and any major adverse events (HR 1.12; 95% CI 1.05-1.16). There were no significant differences in adverse events between patients with large leaks and patients with small or no leaks. After surgical occlusion Patients with no contraindication to anticoagulation These patients are treated with anticoagulation indefinitely. Long-term anticoagulation in patients with AF is discussed separately. (See 'Patients undergoing surgery' above and "Atrial fibrillation in adults: Use of oral anticoagulants".) https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 14/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Patients with a contraindication to long-term anticoagulation These patients are treated with anticoagulation (typically a DOAC) plus aspirin (81 to 325 mg daily) for six weeks to three months after the procedure, followed by TEE assessment of the completeness of occlusion. Patients with an absolute contraindication to oral anticoagulants instead receive dual antiplatelet therapy (once-daily aspirin 81 to 325 mg plus clopidogrel 75 mg) during the pre-TEE period of six weeks to three months. If the TEE demonstrates that the LAA is completely occluded and long-term anticoagulation is contraindicated, anticoagulation is discontinued, and aspirin is continued indefinitely. If any leak is present after surgical LAAO, oral anticoagulation should optimally be continued. This approach is supported by the results of an observational study of 72 patients undergoing surgical LAAO [39]. The study found that the risk of stroke or systolic embolism was higher in patients with incomplete LAA closure compared with those with complete closure (24 versus 2 percent during 44-month mean follow-up), despite similar rates of anticoagulation and recurrent AF. Among patients with incomplete closure, those with stroke or systemic embolism had smaller LAA neck diameters (2.8 versus 7.1 mm) than those without these adverse outcomes. DEVICE SAFETY AND COMPLICATIONS
clopidogrel) is used for six months postprocedure, as in the ASAP study, or for one to three months for patients at high risk of bleeding. As of September 2022, FDA labeling for patients with nonvalvular AF who undergo WATCHMAN FLX LAAO placement was expanded to include 45 days of oral anticoagulant therapy plus dual antiplatelet therapy. Data supportive of this approach were from an analysis of more than 17,000 patients from the NCDR-LAAO Registry, which demonstrated no significant difference in rates of major adverse events at 45 days postimplantation, whether patients were discharged from the hospital on dual antiplatelet therapy, a DOAC and aspirin, or warfarin and aspirin. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 12/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Alternative anticoagulation strategies Alternative imaging-based strategy An alternative strategy was used in the nonrandomized, newer-generation WATCHMAN study (PINNACLE FLX), which confirmed device safety and efficacy [11]. This strategy included treatment with a DOAC through at least a 45-day follow-up, with apixaban or rivaroxaban strongly recommended. Patients were also prescribed concomitant low-dose (81 to 100 mg) aspirin. On evidence of adequate LAA seal (leak 5 mm) at the 45-day TEE evaluation, patients were directed to discontinue DOAC therapy and begin a dual antiplatelet therapy regimen of clopidogrel (75 mg) plus low-dose aspirin until six months postimplantation, followed by low-dose aspirin indefinitely. If a leak >5 mm was measured at the 45-day follow-up, patients continued DOAC plus aspirin and were reevaluated at six months postimplant. If there were no leaks >5 mm at the subsequent follow-up visit, patients could forego dual antiplatelet therapy and proceed straight to life-long low-dose aspirin. Postimplantation follow-up visits were required at 45 days and 6, 12, 18, and 24 months. Long-term, half-dose DOAC This regimen versus standard anticoagulation treatment was tested in a nonrandomized study of 555 patients post-WATCHMAN device implantation [33]. The primary endpoint was a composite of device-related thrombosis, thromboembolic events, and bleeding. After 13 months, device-related thrombosis occurred in 12 patients, all in the full-dose DOAC group (3 versus 0 percent). The risk of nonprocedural major bleeding was more favorable in the half-dose DOAC group (0.5 percent versus 4 percent). The rate of the primary composite endpoint was higher in the standard treatment group (10 versus 1 percent). Further randomized studies are needed before we can make recommendations about the long-term, half-DOAC anticoagulation strategy. Postprocedural imaging We obtain a transthoracic echocardiogram one day postprocedure to ensure there is no pericardial effusion. We also obtain a TEE between one and six months postprocedure to screen for or device-related thrombus (DRT), pericardial effusion, or a peridevice leak. DRT is present in approximately 2 to 5 percent of patients, depending on time of screening and device type, and is associated with risk of stroke or transient ischemic attack [16,20,34-36]. For patients with documented DRT, the optimal antithrombotic regimen is not known. Options for treatment of DRT include one of the following anticoagulants that may be combined with aspirin: DOAC (such as apixaban or rivaroxaban; avoid dabigatran) for 8 to 12 weeks, warfarin (target international https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 13/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate normalized ratio 2 to 3) for 8 to 12 weeks, or low molecular weight heparin for two to four weeks [36]. It is important to check for any residual communication between the LA and LAA after device closure. In some cases, the presence of a leak will prompt shared decision- making discussions with patients regarding continued oral anticoagulation or closure of the leak with other devices such as a coil. It is uncertain if the size of the peridevice leak should guide further management, and prior data are mixed [37]. Previously, a peridevice leak of <5 mm was thought to be of little clinical significance (this amount of leak was arbitrarily used to define successful occlusion in device trials), whereas a leak 5 mm was an indication for continuing oral anticoagulation and/or additional endovascular procedure to close the residual leak (eg, with another percutaneous closure device or coils). Recent real-world, registry-based data suggest that small leaks may be associated with higher bleeding and thromboembolic risk [38]. (See 'Rationale and limitations' above.) A study of over 51,000 people in the National Cardiovascular Data LAAO Registry showed that small (>0 to 5 mm) leaks after LAAO were associated with a modestly higher incidence of thromboembolic and bleeding events, and large leaks (>5 mm) were not associated with adverse events, although higher proportions of these patients were maintained on anticoagulation. In this study, small leaks were common; 25.8 percent had small leaks and 0.7 percent had large leaks. A higher proportion of patients with large leaks were on warfarin at 45 days versus small or no leak (44.9 versus 34.4 and 32.4 percent, respectively). At 6 and 12 months, anticoagulant use decreased but remained more frequent in patients with large leaks. Thromboembolic and bleeding events were uncommon in all groups. However, compared with patients with no leak, those with small leaks had slightly higher odds of stroke/transient ischemic attack/systemic embolization (hazard ratio [HR] 1.15; 95% CI 1.03-1.29), major bleeding (HR 1.11; 95% CI, 1.03-1.12), and any major adverse events (HR 1.12; 95% CI 1.05-1.16). There were no significant differences in adverse events between patients with large leaks and patients with small or no leaks. After surgical occlusion Patients with no contraindication to anticoagulation These patients are treated with anticoagulation indefinitely. Long-term anticoagulation in patients with AF is discussed separately. (See 'Patients undergoing surgery' above and "Atrial fibrillation in adults: Use of oral anticoagulants".) https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 14/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Patients with a contraindication to long-term anticoagulation These patients are treated with anticoagulation (typically a DOAC) plus aspirin (81 to 325 mg daily) for six weeks to three months after the procedure, followed by TEE assessment of the completeness of occlusion. Patients with an absolute contraindication to oral anticoagulants instead receive dual antiplatelet therapy (once-daily aspirin 81 to 325 mg plus clopidogrel 75 mg) during the pre-TEE period of six weeks to three months. If the TEE demonstrates that the LAA is completely occluded and long-term anticoagulation is contraindicated, anticoagulation is discontinued, and aspirin is continued indefinitely. If any leak is present after surgical LAAO, oral anticoagulation should optimally be continued. This approach is supported by the results of an observational study of 72 patients undergoing surgical LAAO [39]. The study found that the risk of stroke or systolic embolism was higher in patients with incomplete LAA closure compared with those with complete closure (24 versus 2 percent during 44-month mean follow-up), despite similar rates of anticoagulation and recurrent AF. Among patients with incomplete closure, those with stroke or systemic embolism had smaller LAA neck diameters (2.8 versus 7.1 mm) than those without these adverse outcomes. DEVICE SAFETY AND COMPLICATIONS Percutaneous LAAO has become safer over time, possibly due to increased operator experience with the procedure and improvements in device iterations. Outcomes were compared between the 542 patients in the randomized study and 460 patients in the nonrandomized Continued Access Protocol registry who underwent WATCHMAN implantation after the randomized trial was completed [34]. A study done 10 years later showed a significant decline in the rate of procedure- or device-related safety events within seven days compared with those in the earlier randomized trial (3.7 versus 7.7 percent, respectively). In a large registry of over 38,000 WATCHMAN implantations, the procedural success rate was very high at 98.3 percent, which was even higher than reported in pivotal clinical trials such as PROTECT AF [40]. The complications of the LARIAT are described above. (See 'LARIAT system' above.) There are several potential complications that can arise from the procedure itself or that are due to the presence of the device in the LAA. Some of these complications can occur in the acute periprocedural period, whereas others occur over a longer time frame. Management of these complications is crucial and underscores the importance of aggressive patient follow-up using appropriate imaging to look for such complications. Furthermore, understanding factors that https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 15/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate lead to increased risk of complications is also important in terms of patient counseling and shared decision-making. Complications of cardiac surgery are described in detail separately. (See "Postoperative complications among patients undergoing cardiac surgery".) In patients undergoing percutaneous LAAO, these complications have been described: Death and cardiac arrest Death and cardiac arrest are infrequent complications of WATCHMAN procedures. Among 38,158 patients who underwent LAAO in the National Cardiovascular Data LAAO Registry, in-hospital, procedural-related death occurred in 0.19 percent and cardiac arrest in 0.24 percent of patients [40]. Vascular The majority of periprocedural complications are vascular (ie, resulting femoral vein puncture). The incidence of such complications is infrequent with adoption of newer techniques to access the femoral vein and to stop bleeding after the procedure. Complications that may arise due to the transseptal puncture itself can also be minimized with ultrasound-guided puncture. Among 38,158 people who underwent LAAO in the National Cardiovascular Data LAAO Registry, the prevalence of a major vascular complication was 0.15 percent [40]. Pericardial effusion The LA and LAA are thin walled; thus, manipulation of transseptal equipment, large-bore sheaths, and devices can traumatize the wall, resulting in pericardial effusion. The incidence of pericardial effusion has declined over time, with improved operator skills; in the earlier PROTECT-AF study of WATCHMAN devices, the incidence of pericardial effusion requiring intervention was 4.3 percent [34], whereas in the more recent WATCHMAN clinical trials and registries, the pooled incidence of cardiac tamponade was about 1.3 percent [41,42]. In a report from the National Cardiovascular Data LAAO Registry, among 65,355 patients, 881 (1.3 percent) developed procedural pericardial effusions, percutaneous drainage was performed in 1.18 percent, and cardiac surgery was performed in 0.27 percent of the study population [42]. Pericardial effusion not requiring intervention was reported in 669 patients (1.02 percent). Signs and symptoms of a pericardial effusion and tamponade are discussed separately. (See "Diagnosis and treatment of pericardial effusion", section on 'Clinical presentation'.) Periprocedure stroke Peridevice leaks (also called device-related leaks), air embolism, and device-related thrombus can lead to near-term stroke. Anticoagulation and antiplatelet therapy after the procedure are discussed above. (See 'Postprocedure management' above.) https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 16/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate In the National Cardiovascular Data LAAO registry, in-hospital ischemic stroke was documented in 0.12 and hemorrhagic stroke in 0.01 percent of patients, respectively [40]. Most events were related to air embolism from inadequate device prepping. Fewer complications are due to thromboembolism from preexisting or de-novo equipment- related LAA thrombus. Air embolism cerebral circulation can cause a transient ischemic attack or stroke. Once a thrombus is detected, additional heparin should be administered, and thrombus aspiration via a large sheath may be attempted. The procedure should be completed expeditiously with either deployment of the device or removal of the sheath/device from the LA. Full neurological assessment should be performed when the patient awakes from general anesthesia, and emergent stroke team consultation is required if the patient has neurological deficits. Device embolization Device embolization is a rare but serious complication of LAAO. With the legacy WATCHMAN device, the reported incidence was 0.24 percent in clinical trials [41], with an even lower incidence reported in the real-world National Cardiovascular Data LAAO registry at 0.07 percent [40]. Most embolizations do not cause symptoms; however, palpitations, heart failure, hypotension, and cardiac arrest had been reported. The first-line strategy for management is percutaneous retrieval of the embolized device. Device erosion This complication is very rare (occurring in <1 percent or patients) but can be devastating. Long-term follow-up with appropriate imaging (ie, a transesophageal echocardiogram [TEE] between one and six months postprocedure) to look for new pericardial effusion is important to screen for this complication [43]. The following issues regarding LAAO adverse events and hospital readmission are also important to recognize: Greater adverse events in females Females have a higher risk of in-hospital adverse events after LAAO [44]. In the National Cardiovascular Data Registry, 49,000 patients (41 percent female) underwent LAAO between 2016 and 2017. Females were more likely than males to experience any adverse event (6 versus 4 percent), including a pericardial effusion requiring drainage (1.2 versus 0.5 percent) or major bleeding (1.7 versus 0.8 percent). Also, female patients were more likely to have a hospital stay >1 day (16 versus 12 percent) or experience death (adjusted odds ratio 2.01; 95% CI 1.31-3.09), although death was rare and absolute differences minimal (0.3 versus 0.1 percent). Female patients in this study were older than male patients but less likely to have diabetes and heart failure. High readmission Among 14,000 patients with LAAO in the Nationwide Inpatient Sample between 2016 and 2017, the 30-day readmission rate was 9.4 percent [45]. Of these, 12 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 17/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate percent of readmissions were attributable to gastrointestinal bleeding. Risk factors for readmission included drug abuse ( odds ratio 4.1; 95% CI 1.34-12.54) and anemia (OR 1.88; 95% CI 1.12-3.18). RECOMMENDATIONS OF OTHER GROUPS The LAAOS III trial on surgical LAAO was completed after major society guidelines were published, so this evidence was not incorporated in those guidelines. (See 'Patients undergoing surgery' above.) A consensus statement from the European Heart Rhythm Association and the European Association of Percutaneous Cardiovascular Interventions published in 2020 states that LAAO is acceptable in patients with a contraindication to oral anticoagulation or those who are unwilling or unable to take oral anticoagulation [46]. The United States Food and Drug Administration (FDA) approval is somewhat more liberal than the European Society of Cardiology guideline for patients eligible for oral anticoagulation and has other indications for nonpharmacologic therapy (eg, lifestyle indications, labile international normalized ratio). The 2019 focused update of the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guideline for the management of patients with AF makes a weak recommendation for surgical excision of LAA at the time of cardiac surgery [47,48]. In addition, it states that percutaneous LAAO may be considered in patients with AF at increased risk of stroke who have contraindications to long-term anticoagulation. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS Rationale and limitations Among patients with atrial fibrillation (AF), thrombus in the left atrial appendage (LAA) is the primary source for thromboemboli. This is the rationale for excluding the appendage in selected patients. (See 'Rationale and limitations' above.) https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 18/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate However, thrombogenesis in patients with AF may not be limited to the LA, and the procedure does not always result in complete occlusion of the LAA. Indications Patients not undergoing cardiac surgery For patients with AF with an indication for anticoagulation (based upon risk of stroke and other systemic thromboembolism ( table 1)) but who have a contraindication to long-term anticoagulation, we suggest a percutaneous LAA occlusion (LAAO) procedure (Grade 2B). Among these devices, we prefer the WATCHMAN. (See 'Patients not undergoing cardiac surgery' above and 'WATCHMAN device' above.) This approach does not apply to patients with an indication for anticoagulation other than AF (eg, an implanted mechanical valve). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Patients with AF and a CHA DS -VASc score of at least 2 ( 2 table 1) who are 2 undergoing cardiac surgery for another indication For such patients, if there is no contraindication to long-term anticoagulation, we recommend concomitant surgical LAAO. (Grade 1B) (See 'Patients undergoing surgery' above.) For such patients, if there is a contraindication to long-term anticoagulation, we suggest concomitant surgical LAAO (Grade 2C). (See 'Patients undergoing surgery' above.) Preprocedure planning Specific LAA measurements can be useful for LAA closure planning; these can be obtained by transesophageal echocardiogram (TEE), cardiac computed tomography angiography, or cardiac magnetic resonance imaging. If cardiac imaging shows an LA/LAA thrombus, the LAAO procedure is contraindicated. (See 'Preprocedure planning' above.) Percutaneous devices The WATCHMAN device is the most commonly implanted percutaneous LAAO device and has the most robust data to support its use ( table 3). (See 'Percutaneous devices' above.) Surgical devices Types of surgical closure include stapler occlusion, amputation and suture, and epicardial device closure ( table 2). (See 'Surgical LAA closure' above.) Postprocedure management After percutaneous closure https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 19/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate We treat with short-term antithrombotic therapy (anticoagulant and antiplatelet therapy) after placement of the device. Patients with an absolute contraindication to oral anticoagulants instead receive dual antiplatelet therapy postprocedure. We obtain a TEE between one and six months postprocedure. Device-related thrombus and/or peridevice leak 5 mm may be indications for continued anticoagulation. (See 'After percutaneous closure' above.) After surgical occlusion Patients with a contraindication to long-term anticoagulation These patients are treated with short-term anticoagulation (typically a DOAC) plus aspirin for six weeks to three months after the surgery, followed by TEE assessment of the completeness of occlusion. Patients with an absolute contraindication to oral anticoagulants instead receive dual antiplatelet therapy during the pre-TEE period of six weeks to three months. If the TEE demonstrates that the LAA is completely occluded and long-term anticoagulation is contraindicated, only aspirin is continued indefinitely. If any leak is present postsurgical LAAO, oral anticoagulation should be continued. (See 'After surgical occlusion' above.) Patients with no contraindication to anticoagulation These patients are treated with anticoagulation indefinitely regardless of whether a rhythm control intervention is performed. (See 'Patients undergoing surgery' above.) Complications These are rare but include pericardial effusion/tamponade, vascular injury, device erosion or embolization, stroke, death, and cardiac arrest. (See 'Device safety and complications' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 20/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate 1. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardiac surgical patients with atrial fibrillation. Ann Thorac Surg 1996; 61:755. 2. Viles-Gonzalez JF, Kar S, Douglas P, et al. 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Surgical left atrial appendage ligation is frequently incomplete: a transesophageal echocardiograhic study. J Am Coll Cardiol 2000; 36:468. 30. Kanderian AS, Gillinov AM, Pettersson GB, et al. Success of surgical left atrial appendage closure: assessment by transesophageal echocardiography. J Am Coll Cardiol 2008; 52:924. 31. Ostermayer SH, Reisman M, Kramer PH, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO system) to prevent stroke in high-risk patients with non- rheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol 2005; 46:9. 32. Ohtsuka T, Ninomiya M, Nonaka T, et al. Thoracoscopic stand-alone left atrial appendectomy for thromboembolism prevention in nonvalvular atrial fibrillation. J Am Coll Cardiol 2013; 62:103. 33. Della Rocca DG, Magnocavallo M, Di Biase L, et al. Half-Dose Direct Oral Anticoagulation Versus Standard Antithrombotic Therapy After Left Atrial Appendage Occlusion. JACC Cardiovasc Interv 2021; 14:2353. 34. Reddy VY, Holmes D, Doshi SK, et al. Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. Circulation 2011; 123:417. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 23/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate 35. Bergmann MW, Ince H, Kische S, et al. Real-world safety and efficacy of WATCHMAN LAA closure at one year in patients on dual antiplatelet therapy: results of the DAPT subgroup from the EWOLUTION all-comers study. EuroIntervention 2018; 13:2003. 36. Saw J, Nielsen-Kudsk JE, Bergmann M, et al. Antithrombotic Therapy and Device-Related Thrombosis Following Endovascular Left Atrial Appendage Closure. JACC Cardiovasc Interv 2019; 12:1067. 37. Gabriels JK, Liu CF. Peri-Device Leak After Left Atrial Appendage Occlusion: Minding the Gap. JACC Clin Electrophysiol 2022; 8:779. 38. Alkhouli M, Du C, Killu A, et al. Clinical Impact of Residual Leaks Following Left Atrial Appendage Occlusion: Insights From the NCDR LAAO Registry. JACC Clin Electrophysiol 2022; 8:766. 39. Aryana A, Singh SK, Singh SM, et al. Association between incomplete surgical ligation of left atrial appendage and stroke and systemic embolization. Heart Rhythm 2015; 12:1431. 40. Freeman JV, Varosy P, Price MJ, et al. The NCDR Left Atrial Appendage Occlusion Registry. J Am Coll Cardiol 2020; 75:1503. 41. Reddy VY, Gibson DN, Kar S, et al. Post-Approval U.S. Experience With Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation. J Am Coll Cardiol 2017; 69:253. 42. Price MJ, Valderr bano M, Zimmerman S, et al. Periprocedural Pericardial Effusion Complicating Transcatheter Left Atrial Appendage Occlusion: A Report From the NCDR LAAO Registry. Circ Cardiovasc Interv 2022; 15:e011718. 43. Wilkins B, Fukutomi M, De Backer O, S ndergaard L. Left Atrial Appendage Closure: Prevention and Management of Periprocedural and Postprocedural Complications. Card Electrophysiol Clin 2020; 12:67. 44. Darden D, Duong T, Du C, et al. Sex Differences in Procedural Outcomes Among Patients Undergoing Left Atrial Appendage Occlusion: Insights From the NCDR LAAO Registry. JAMA Cardiol 2021; 6:1275. 45. Pasupula DK, Munir MB, Bhat AG, et al. Outcomes and predictors of readmission after implantation of a percutaneous left atrial appendage occlusion device in the United States: A propensity score-matched analysis from The National Readmission Database. J Cardiovasc Electrophysiol 2021; 32:2961. 46. Glikson M, Wolff R, Hindricks G, et al. EHRA/EAPCI expert consensus statement on catheter- based left atrial appendage occlusion - an update. EuroIntervention 2020; 15:1133. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 24/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 48. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 928 Version 61.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 25/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 26/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 27/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Endovascular left atrial appendage closure devices Device name Company Design Device sizes (mm) WATCHMAN* Boston Scientific Single-lobe occluder 21, 24, 27, 30, 33 with nitinol frame, PET membrane, 10 fixation anchors. WATCHMAN FLX* Boston Scientific Single-lobe occluder with nitinol frame, PET 20, 24, 27, 31, 35 membrane, 12 fixation anchors. Amplatzer Cardiac Plug (ACP) Abbott Lobe and disc (polyester mesh in 16, 18, 20, 22, 24, 26, 28, 30 both) nitinol mesh construct. Stabilizing wires. Amulet* Abbott Similar design as Amplatzer Cardiac Plug, but wider lobe and disc and more stabilizing wires. 16, 18, 20, 22, 25, 28, 31, 34 WaveCrest Coherex Medical Single-lobe occluder. 22, 27, 32 Nitinol frame, polyurethane foam, ePTFE membrane, retractable anchors. Occlutech LAA Occluder Occlutech Single-lobe occluder. Nitinol wire mesh, 15, 18, 21, 24, 27, 30, 33, 36, 39 stabilizing loops, nanomaterial covering. Lambre Lifetech Lobe and disc nitinol 16 to 36 frame. PET membrane. Distal barbs anchors. PET: polyethylene terephthalate; ePTFE: polytetrafluoroethylene; LAA: left atrial appendage; FDA: United States Food and Drug Administration; CE: conformit Europ enne (French for "European conformity"). FDA approved. CE mark refers to any product that may be freely traded in any part of Europe (ie, European Union) economic area. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 28/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Graphic 140267 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 29/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate WATCHMAN implant (A) Watchman left atrial appendage (LAA) closure technology. (B) Watchman LAA closure technology in anatomical position. Reproduced from: Jain AK, Gallagher S. Technology and guidelines Percutaneous occlusion of the left atrial appendage in non-valvular atrial brillation for the prevention of thromboembolism: NICE guidance. Heart 2011; 97:762, with permission from BMJ Publishing Group Ltd. Graphic 61636 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 30/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Epicardial percutaneous or surgical left atrial appendage closure devices Device name Company Design Device sizes (mm) LARIAT* SentreHeart Endocardial and LAA sizes up to 40 epicardial percutaneous access width, 20 height, 70 length required. Magnetically assisted snaring of LAA. AtriClip* AtriCure Surgical/thoracotomy approach. Parallel clip 35, 40, 45, 50 with polyester mesh. TigerPaw II* Marquet Surgical approach. Compliant soft silicone fastener. LAA: left atrial appendage; CE: conformit Europ enne (French for "European conformity").
Electrophysiol Clin 2020; 12:67. 44. Darden D, Duong T, Du C, et al. Sex Differences in Procedural Outcomes Among Patients Undergoing Left Atrial Appendage Occlusion: Insights From the NCDR LAAO Registry. JAMA Cardiol 2021; 6:1275. 45. Pasupula DK, Munir MB, Bhat AG, et al. Outcomes and predictors of readmission after implantation of a percutaneous left atrial appendage occlusion device in the United States: A propensity score-matched analysis from The National Readmission Database. J Cardiovasc Electrophysiol 2021; 32:2961. 46. Glikson M, Wolff R, Hindricks G, et al. EHRA/EAPCI expert consensus statement on catheter- based left atrial appendage occlusion - an update. EuroIntervention 2020; 15:1133. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 24/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 48. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 928 Version 61.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 25/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 26/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 27/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Endovascular left atrial appendage closure devices Device name Company Design Device sizes (mm) WATCHMAN* Boston Scientific Single-lobe occluder 21, 24, 27, 30, 33 with nitinol frame, PET membrane, 10 fixation anchors. WATCHMAN FLX* Boston Scientific Single-lobe occluder with nitinol frame, PET 20, 24, 27, 31, 35 membrane, 12 fixation anchors. Amplatzer Cardiac Plug (ACP) Abbott Lobe and disc (polyester mesh in 16, 18, 20, 22, 24, 26, 28, 30 both) nitinol mesh construct. Stabilizing wires. Amulet* Abbott Similar design as Amplatzer Cardiac Plug, but wider lobe and disc and more stabilizing wires. 16, 18, 20, 22, 25, 28, 31, 34 WaveCrest Coherex Medical Single-lobe occluder. 22, 27, 32 Nitinol frame, polyurethane foam, ePTFE membrane, retractable anchors. Occlutech LAA Occluder Occlutech Single-lobe occluder. Nitinol wire mesh, 15, 18, 21, 24, 27, 30, 33, 36, 39 stabilizing loops, nanomaterial covering. Lambre Lifetech Lobe and disc nitinol 16 to 36 frame. PET membrane. Distal barbs anchors. PET: polyethylene terephthalate; ePTFE: polytetrafluoroethylene; LAA: left atrial appendage; FDA: United States Food and Drug Administration; CE: conformit Europ enne (French for "European conformity"). FDA approved. CE mark refers to any product that may be freely traded in any part of Europe (ie, European Union) economic area. https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 28/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Graphic 140267 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 29/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate WATCHMAN implant (A) Watchman left atrial appendage (LAA) closure technology. (B) Watchman LAA closure technology in anatomical position. Reproduced from: Jain AK, Gallagher S. Technology and guidelines Percutaneous occlusion of the left atrial appendage in non-valvular atrial brillation for the prevention of thromboembolism: NICE guidance. Heart 2011; 97:762, with permission from BMJ Publishing Group Ltd. Graphic 61636 Version 5.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 30/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Epicardial percutaneous or surgical left atrial appendage closure devices Device name Company Design Device sizes (mm) LARIAT* SentreHeart Endocardial and LAA sizes up to 40 epicardial percutaneous access width, 20 height, 70 length required. Magnetically assisted snaring of LAA. AtriClip* AtriCure Surgical/thoracotomy approach. Parallel clip 35, 40, 45, 50 with polyester mesh. TigerPaw II* Marquet Surgical approach. Compliant soft silicone fastener. LAA: left atrial appendage; CE: conformit Europ enne (French for "European conformity"). CE mark refers to any product that may be freely traded in any part of Europe (ie, European Union) economic area. Approved for tissue apposition, not specifically for LAA occlusion. United States Food and Drug Administration approved. Current class 1 recall, not commercially available. Graphic 140269 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 31/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate CHADS score, thromboembolic risk, and effect of warfarin anticoagulation 2 Clinical parameter Points Congestive heart failure (any history) 1 Hypertension (prior history) 1 Age 75 years 1 Diabetes mellitus 1 Secondary prevention in patients with a prior ischemic stroke or a transient 2 ischemic attack; most experts also include patients with a systemic embolic event Events per 100 person-years* CHADS score 2 NNT Warfarin No warfarin 0 0.25 0.49 417 1 0.72 1.52 125 2 1.27 2.50 81 3 2.20 5.27 33 4 2.35 6.02 27 5 or 6 4.60 6.88 44 NNT: number needed to treat to prevent 1 stroke per year with warfarin. The CHADS score estimates the risk of stroke, which is defined as focal neurologic signs or symptoms that persist for more than 24 hours and that cannot be explained by hemorrhage, trauma, or other factors, or peripheral embolization, which is much less common. Transient ischemic attacks are not included. All differences between warfarin and no warfarin groups are statistically significant, 2 except for a trend with a CHADS score of 0. Patients are considered to be at low risk with a score of 0, at intermediate risk with a score of 1 or 2, and at high risk with a score 3. One exception is that most experts would consider patients with a prior ischemic stroke, transient ischemic attack, or systemic embolic event to be at high risk, even if they had no other risk factors and, therefore, a 2 score of 2. However, the great majority of these patients have some other risk factor and a score of at least 3. Data from: Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial brillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685; and CHADS2 score from Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. Graphic 61615 Version 8.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 32/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Amplatzer plug (A) Amplatzer cardiac plug. (B) Amplatzer cardiac plug in anatomical position. Reproduced from: Jain AK, Gallagher S. Percutaneous occlusion of the left atrial appendage in non-valvular atrial brillation for the prevention of thromboembolism: NICE guidance. Heart 2011; 97:762, with permission from BMJ Publishing Group Ltd. Graphic 82936 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 33/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate WaveCrest system Reproduced with permission. Copyright 2015 Coherex Medical, Inc. All rights reserved. Graphic 98061 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 34/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Lariat device for tissue approximation Reproduced with permission. Copyright 2014 SentreHEART, Inc. All rights reserved. Graphic 87967 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 35/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Epicardial percutaneous or surgical left atrial appendage closure devices Device sizes Approval Device name Company Design (mm) status LARIAT SentreHeart Endocardial and LAA sizes up to FDA approval epicardial percutaneous access 40 width, 20 height, 70 length CE Mark (for tissue apposition) required. Magnetically-assisted snaring of LAA. AtriClip AtriCure Surgical/thoracotomy approach. Parallel 35, 40, 45, 50 FDA approval CE Mark clip with polyester mesh. TigerPaw II Marquet Surgical approach. Compliant soft silicone fastener. Current class 1 recall, not commercially available FDA approval CE Mark AEGIS AEGIS Medical Innovations Epicardial subxiphoid percutneous approach. Electrode- guided navigation for Not yet LAA tissue capture. Cardioblate Closure System Medtronic Epicardial approach. Silicone band covered by polyester fabric. Not yet LAA: left atrial appendage. Graphic 105505 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 36/37 7/5/23, 9:05 AM Atrial fibrillation: Left atrial appendage occlusion - UpToDate Contributor Disclosures Ziyad M Hijazi, MD, MPH, FAAP, FACC, MSCAI, FAHA, FPICS Consultant/Advisory Boards: NuMED Inc [Coarctation of the aorta]. All of the relevant financial relationships listed have been mitigated. Jacqueline Saw, MD, FRCPC, FACC Grant/Research/Clinical Trial Support: Abbott Vascular [SCAD-spontaneous coronary artery dissection]; AstraZeneca [SCAD-spontaneous coronary artery dissection]; Boston Scientific [SCAD-spontaneous coronary artery dissection]; CIHR, Foundation of Canada [SCAD-spontaneous coronary artery dissection]; Michael Smith Foundation [SCAD-spontaneous coronary artery dissection]; National Institutes of Health [SCAD-spontaneous coronary artery dissection]; Servier [SCAD-spontaneous coronary artery dissection]; St Jude Medical [SCAD-spontaneous coronary artery dissection]; UBC Division of Cardiology [SCAD-spontaneous coronary artery dissection]. Consultant/Advisory Boards: Abbott Vascular [LAA closure]; AstraZeneca [LAA closure]; Bayer [Antiplatelet Therapy, LAA Closure]; Boston Scientific [LAA closure]; FEops [LAA closure]; Gore [LAA closure]; St Jude Medical [LAA closure]. Speaker's Bureau: AstraZeneca [LAA closure]; Bayer [SCAD (Watchman, ACP)]; Boston Scientific [LAA closure]; St Jude Medical [LAA closure]; Sunovion [LAA Closure]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-left-atrial-appendage-occlusion/print 37/37
7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Overview and management of new- onset atrial fibrillation : Kapil Kumar, MD : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 22, 2023. INTRODUCTION Atrial fibrillation (AF) is the most commonly treated cardiac arrhythmia. AF is generally associated with an irregularly irregular ventricular rhythm and absence of distinct P waves. This topic will provide a broad overview of the classification, clinical presentation, diagnosis, management, and sequelae of AF, including new-onset AF. The initiation and maintenance of AF reflect electrophysiologic alterations in atrial myocardium. The pathophysiology of AF is discussed in detail elsewhere. (See "Mechanisms of atrial fibrillation".) The epidemiology of AF including prevalence, risk factors, and associated chronic conditions is discussed in detail separately. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) The following topics provide detail about specific types of AF and other management issues: (See "Atrial fibrillation in adults: Use of oral anticoagulants".) (See "Management of atrial fibrillation: Rhythm control versus rate control".) (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 1/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate CLASSIFICATION AND TERMINOLOGY AF can be classified according to its duration and length of episodes; these were described in the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines on AF management [1]. Paroxysmal (ie, self-terminating or intermittent) AF Paroxysmal AF is defined as AF that terminates spontaneously or with intervention within seven days of onset. Episodes may recur with variable frequency. (See "Paroxysmal atrial fibrillation".) Persistent AF Persistent AF is defined as AF that fails to self-terminate within seven days. Episodes often require pharmacologic or electrical cardioversion to restore sinus rhythm. While a patient who has had persistent AF can have later episodes of paroxysmal AF, AF is generally considered a progressive disease. Long-standing persistent AF Long-standing persistent AF refers to AF that has lasted for more than 12 months. Permanent AF Permanent AF is a term used to identify persistent AF for which a joint decision by the patient and clinician has been made to no longer pursue a rhythm control strategy. Acceptance of persistent AF may change as symptoms, therapeutic options, and patient and clinician preferences evolve [1]. While AF typically progresses from paroxysmal to persistent states, patients can present with both types throughout their lives. AF can also be classified based by the way it presents or whether specific valvular conditions are present: Subclinical or occult AF This refers to AF that is largely asymptomatic and only becomes apparent in the setting of a thromboembolic event, acute heart failure exacerbation, other medical illness, or upon routine electrocardiogram (ECG) done for other purposes. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult atrial fibrillation' and "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation' and 'Common scenarios' below.) Screening for AF is discussed separately. (See 'Screening' below.) Valvular AF This refers to patients with moderate to severe mitral stenosis; these patients have a higher risk of stroke than patients without this condition. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 2/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Lone AF The term "lone AF" is a historical term that is now disfavored, as it may be confusing and does not enhance patient care [1,2]. The term lone AF has been used to describe AF in younger patients (eg, 60 years) with paroxysmal, persistent, or permanent AF who have no structural heart disease or cardiovascular risk factors. These characteristics identify a group of individuals with a CHA DS -VASc score of "0" and who are at lowest risk 2 2 for thromboembolism from AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) SCREENING We do not currently screen asymptomatic patients for AF. In a general population and among persons >65 years of age, screening has not been shown to be better than usual care (eg, pulse palpation on physical examination) for AF detection. Furthermore, screening showed modest to no benefit on reducing cardiovascular outcomes and death in one of two randomized studies. Screening may lead to more anticoagulation, but this has not been shown to be associated with robust protection from stroke or thromboembolic events [3-5]. The United States Preventive Services Task Force (USPSTF) also does not recommend screening for AF. Effects on cardiovascular outcomes and death Two randomized studies of screening for AF (with either single-lead ECGs or implantable loop recorders) showed only a modest or no reduction in clinical events and are also limited in that they included a narrow patient population that may not be widely generalizable. A randomized, unmasked, parallel group study in Sweden (STROKESTOP) of 28,768 individuals aged 75 to 76 years compared outcomes (ie, a composite of ischemic or hemorrhagic stroke, systemic embolism, bleeding leading to hospitalization, and all-cause death) in patients who underwent two-week intermittent ECG screening with subsequent anticoagulation strategy versus those who received usual care [3]. After a median follow-up of 6.9 years, somewhat fewer outcomes occurred in the intervention group than in the control group (5.45 versus 5.68 events per 100 years; hazard ratio [HR] 0.96; 95% CI 0.92- 1.00), but the overall risks and absolute benefit are very low. However, despite this low absolute risk reduction, an analysis using a Markov model based on the STROKESTOP study suggested that screening for AF in this older adult population may still be cost effective and possibly even cost saving [6]. In the LOOP study, 6004 individuals with stroke risk factors were randomly assigned to either implantable loop recorder monitoring (also called implantable cardiac monitor) or usual care [4]. Those in the implantable loop recorder group had three times the rates of https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 3/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate AF detection and anticoagulation initiation but no change in rates of stroke or arterial embolization. AF detection Data are mixed as to whether screening for AF increases the number of new AF cases detected; however, the potential benefit appears to be small at best. The choice of test used to detect AF and population characteristics likely impacts these results. In the VITAL-AF trial, 16 primary clinics were randomly assigned either to AF screening using a handheld single-lead ECG (AliveCor KardiaMobile) during vital sign assessments or to usual care [7]. More than 30,000 patients 65 years of age were followed for one year for the development of new-onset AF. New AF diagnosis in the screening and control groups was similar (1.72 versus 1.59 percent). In a prespecified subgroup analysis of persons aged 85 years, new AF diagnoses were more frequent in the screening versus control group (5.56 versus 3.76 percent). In a meta-analysis of three cluster randomized studies (not including VITAL-AF), screening identified more cases of AF compared with no screening when using one-time approaches (pulse palpation, ECG, and/or Holter monitor [absolute risk difference range 0.06 to 0.60 percentage points; relative risk range 1.04 to 1.58]). However, this difference was small and statistically significant in only one of the studies in the meta-analysis [5]. The Apple Watch in combination with iPhone application was evaluated in over 400,000 individuals without a history of AF [8]. Irregular pulse notifications were sent to 2161 participants (0.52 percent). Of these, 450 participants were sent and returned an ECG patch and were not otherwise excluded per study protocol. AF was present in 34 percent of 450 patients. Among those who were notified of an irregular pulse on the watch while wearing the patch, 84 percent were concordant with AF. The Apple Watch study did not employ the gold standard reference of 12-lead ECG analyzed by two cardiologists, which limits interpretation of device accuracy for AF detection. Accuracy of detection method The accuracies of specific AF detection tests were reviewed by the USPSTF [5]. In most studies, test accuracy was measured against the reference of 12-lead ECG (interpreted by two cardiologists). Sensitivity and specificity were generally high for single-lead ECG and oscillometric blood pressure monitors. Implantable cardiac monitors are more sensitive than ECG and external monitoring [9]. ECGs do not appear more effective than pulse palpation at AF detection. A USPSTF review of randomized trials and observational studies (17 studies and 135,300 patients age 65 years and older) found that systematic screening with ECG identified more cases of AF than no screening (absolute increase from 0.6 to 2.8 percent over 12 months) [10]. However, https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 4/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate systematic screening with ECG did not detect more cases than a systematic approach using pulse palpation. Enrichment of population to be screened Although at this time there is no sufficient evidence to screen for AF in broad populations, focusing screening efforts on patients at significantly higher risk for development of AF may be more fruitful. Using the CHADS2- VASc score can be a starting point, but risk scores such as the CHARGE-AF score derived from clinical variables [11], or a polygenic risk score derived from genetic testing [12] may potentially be more effective. The role of evaluating patients with cryptogenic stroke for AF is discussed separately. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult atrial fibrillation'.) CLINICAL PRESENTATION Symptoms AF may or may not have associated symptoms, and the spectrum of symptoms is broad and nonspecific. Typical symptoms include the following: Palpitations Tachycardia Fatigue Weakness Dizziness Lightheadedness Reduced exercise capacity Increased urination Mild dyspnea. Some patients have more severe symptoms. These include the following: Dyspnea at rest Angina Presyncope or rarely syncope Symptoms of stroke or other systemic embolic event Symptoms of heart failure (eg, dyspnea on exertion, peripheral edema, weight gain, and abdominal swelling from ascites) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 5/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The severity and extent of symptoms are affected by the patient's underlying cardiac condition, age, presence of diabetes [13,14], and rapidity and regularity of the ventricular response. For example, one study of 2400 AF patients showed that the 420 patients with diabetes felt fewer AF- related symptoms (eg, palpitations, dizziness, exercise intolerance [odds ratio 0.74; 95% CI 0.59- 0.92]), but had a worse quality of life (beta = -4.54; 95% CI -6.40 to -2.68) than those without diabetes [13]. Quality of life was measured on the 100-point European Quality of Life-5 Dimensions Questionnaire (EQ-5D). The hemodynamic consequences of AF are discussed in detail separately. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Common scenarios A new diagnosis of AF may result from several clinical scenarios that are described below: At the time of a routine examination, during which the patient complains of symptoms possibly due to AF or is being evaluated for another reason and is found to have an irregularly irregular pulse. On an ECG obtained for other reasons such as a preoperative evaluation. (See "The electrocardiogram in atrial fibrillation".) A patient with a stroke or other arterial thromboembolism can be found to have AF that had not been previously diagnosed [15]. In some cases, AF is detected during extended monitoring in an attempt to diagnose the cause for the stroke. (See "Stroke in patients with atrial fibrillation" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult atrial fibrillation'.) Subclinical AF can be also detected by intracardiac, implantable, or wearable monitors [16]. Subclinical AF usually occurs in individuals without characteristic symptoms of AF and without a prior diagnosis. Most of these individuals will have paroxysmal AF. A scientific statement from the American Heart Association on subclinical and cardiac implantable electronic device-detected AF was published in 2019 [16]. (See "Ambulatory ECG monitoring" and "Paroxysmal atrial fibrillation", section on 'Evaluation' and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'ECG monitoring and storage'.) The ASSERT study of 2580 patients (65 years or older) with either a dual-chamber pacemaker or implantable cardioverter-defibrillator, hypertension, and no history of AF found that at three months, subclinical AF was detected in about 10 percent of patients [17]. Clinical AF developed in about 16 percent of patients with subclinical AF. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 6/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate In a study of 590 individuals with stroke risk factors but without AF who underwent screening with an implantable loop recorder for an average of 40 months, 35 percent of participants were found to have AF [9]. During ECG monitoring with a 24-hour ambulatory monitor obtained for some other reason or during interrogation of an implanted cardiac rhythm device. (See "Ambulatory ECG monitoring" and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'ECG monitoring and storage'.) During hospitalization for another reason such as infection, recent myocardial infarction, thyrotoxicosis, pulmonary embolism, chronic obstructive pulmonary disease, myocarditis, and pericarditis, among others [18-21]. (See "Arrhythmias in COPD" and "Cardiovascular effects of hyperthyroidism" and "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Cardiac events and other noninfectious complications'.) During or after cardiac or noncardiac surgery. (See "Atrial fibrillation in patients undergoing noncardiac surgery" and "Atrial fibrillation and flutter after cardiac surgery" and "Arrhythmias during anesthesia", section on 'Atrial fibrillation'.) During recording from a patient-acquired recording device (eg, Apple watch, AliveCor KardiaMobile, etc). (See "The electrocardiogram in atrial fibrillation", section on 'Wearable consumer devices' and 'Screening' above.) EVALUATION History and physical examination Descriptions of any associated symptoms should include: Onset or date of discovery Possible precipitating factors Frequency and duration Severity of episodes and symptoms Qualitative characteristics Previous medical records of any prior supraventricular arrhythmias A semi-quantitative method to classify symptoms has been developed, but the clinical utility of such a system has not been demonstrated [22]. Associated conditions The presence and status of associated conditions such as other cardiovascular disease, cerebrovascular disease, diabetes, hypertension, chronic obstructive pulmonary disease, obstructive sleep apnea should be ascertained. (See https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 7/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Arrhythmias in COPD", section on 'Atrial fibrillation' and "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Atrial fibrillation'.) The presence of potentially reversible causes should be assessed (eg, hyperthyroidism, unhealthy alcohol use). (See "Overview of the clinical manifestations of hyperthyroidism in adults" and "Diagnosis of hyperthyroidism" and "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".) Physical examination The physical examination should focus on the cardiovascular system and any associated conditions. Abnormal findings may inform healthcare providers about associated conditions that might be contributing to the onset of AF and/or impacting the severity. Examples include heart murmurs or arterial pulse abnormalities indicative of mitral or aortic stenosis or regurgitation, hypertrophic cardiomyopathy, and signs and symptoms of heart failure. (See "Examination of the precordial pulsation" and "Auscultation of cardiac murmurs in adults" and "Examination of the jugular venous pulse" and "Examination of the arterial pulse".) During AF with an irregularly irregular pulse, there is commonly a slight variation in the intensity of the first heart sound. S4 sounds are not heard, and jugular venous "a" waves are absent since atrial contraction is lost. (See "Auscultation of heart sounds", section on 'Clinical significance of S4'.) An apical-radial pulse deficit is commonly observed in patients in AF. When one assesses the rates of the left ventricular apex and the radial pulse simultaneously, the radial pulse rate may be less than the apical heart rate. Since the heart rate is irregular, some ventricular contractions will occur, preceded by shorter periods of diastole in which there is a reduction in left ventricular filling. This results in ventricular beats with insufficient stroke volume to transmit the pressure wave to the arm. Variation in cuff blood pressure readings is also common during AF due to changes in the beat-to-beat cadence and changes in left ventricular filling and stroke volume. It is often necessary to measure the blood pressure multiple times and average these values to obtain a more accurate blood pressure readings. In addition, automated blood pressure machines may have difficulty in accurately measuring blood pressure during AF, so a manual blood pressure check is recommended. Electrocardiogram For all patients with suspected new-onset AF, we obtain a 12-lead ECG. On an ECG with AF, there are no discrete P waves but rapid, low-amplitude, continuously varying fibrillatory (f) waves are seen. The ventricular rhythm is generally irregularly irregular (lacking a repetitive pattern), although AF is uncommonly associated with a regular ventricular rate. The https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 8/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ECG in patients with AF is described in detail separately ( waveform 1). (See "The electrocardiogram in atrial fibrillation".) There are a number of potential pitfalls in the ECG diagnosis of AF. Errors in the diagnosis of AF are especially common with computerized ECG interpretation and in patients who are continuously or intermittently paced. Hence, it is important that the automated ECG interpretation provided by the machine is confirmed by a skilled reader. A baseline ECG, preferably in sinus rhythm, should also be evaluated for the following information: Markers of nonelectrical cardiac disease, such as left ventricular hypertrophy (possible hypertension) or Q waves (possible coronary artery disease). Markers of electrical heart disease, including the presence of ventricular pre-excitation or infranodal conduction disease (bundle branch block). The QT interval (to identify the potential risk of antiarrhythmic therapy) Evidence of severe bradycardia or sinus node dysfunction Echocardiogram We obtain a transthoracic echocardiogram (TTE) even if the physical examination is otherwise normal. We obtain a TTE in order to evaluate the size of the right and left atria and the size and systolic function of the right and left ventricles; to detect possible valvular heart disease, left ventricular hypertrophy, diastolic dysfunction, and pericardial disease; and to assess peak right ventricular and right atrial pressures. The TTE may also identify left atrial thrombus, although the sensitivity is low. Transesophageal echocardiography is much more sensitive for identifying thrombi in the left atrium or left atrial appendage and can be used to determine the need for anticoagulation prior to any attempt at pharmacologic or electrical cardioversion. (See "Role of echocardiography in atrial fibrillation" and 'Anticoagulation' below.) Additional cardiac testing We refer patients with signs or symptoms of ischemic heart disease for exercise testing. (See "Exercise ECG testing: Performing the test and interpreting the ECG results" and "Stress testing for the diagnosis of obstructive coronary heart disease".) Exercise testing is useful to help guide pharmacotherapy for AF, as some antiarrhythmic medications are contraindicated in patients with coronary artery disease. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Selecting an antiarrhythmic drug'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 9/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Ambulatory cardiac monitoring with event recorders, adhesive extended time event monitors, or insertable cardiac monitors (also sometimes referred to as implantable cardiac monitors or implantable loop recorders) can be used to identify the arrhythmia if it is intermittent and not captured on routine ECG. Ambulatory ECG monitoring can also be utilized to correlate symptoms to the arrhythmia along with assessment of the AF burden. Twenty-four- to 48-hour Holter monitoring mainly aids in the evaluation of overall ventricular response rates in individuals where a rate control strategy has been chosen and there is concern for inadequate heart rate control or bradycardia. (See "Ambulatory ECG monitoring".) Laboratory testing We obtain a complete blood count, serum electrolytes, and assessment of renal function, particularly in patients for whom a nonvitamin oral anticoagulant might be started. We do not order troponin unless acute ischemia is suspected. Clinical or subclinical hyperthyroidism is present in less than 5 percent of patients with AF [23]. A thyroid-stimulating hormone and free T4 levels should be obtained in all patients with a first episode of AF, or in those who develop an increase in AF frequency. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Hyperthyroidism'.) Other important baseline tests include a complete blood count to assess for underlying anemia or sign of infection and evaluation for diabetes mellitus [24]. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".) Other tests A chest radiograph may be a useful diagnostic test in selected patients with evidence of dyspnea and potential heart failure or risk of pneumonia. (See "Heart failure: Clinical manifestations and diagnosis in adults", section on 'Chest radiograph'.) INITIAL MANAGEMENT A useful framework for the general care of AF patients (including those with new-onset as well as longstanding AF) is the ABC (Atrial Fibrillation Better Care) pathway [25,26]. "A" can be considered for anticoagulation "B" for better symptom management "C" for cardiovascular risk factor and comorbid disease assessment and management. Observational studies [27,28], a post-hoc analysis of the AFFIRM trial [29], and a prospective randomized trial using a mobile application [30] suggest that the implementation of such a framework of care for AF patients may have a salutary impact on adverse cardiovascular events and hospitalizations, while being cost saving for healthcare systems [31]. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 10/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Management setting Outpatient versus emergency department Whereas most patients with newly diagnosed AF can often be managed in an outpatient setting, some unstable patients require direct hospital admission or transfer to emergency department from an outpatient setting. Indications for transfer to a facility with emergency services include the following: Hemodynamic instability and/or shock (manifested as hypotension, confusion, acute kidney injury, etc). Suspected or confirmed myocardial ischemia/infarction. Suspected or confirmed heart failure. (See "The management of atrial fibrillation in patients with heart failure".) Evidence of pre-excitation (eg, Wolff-Parkinson-White syndrome) on the ECG. Extreme, uncontrolled tachycardia. Severe symptoms that may require more urgent rate or rhythm control. Hypotension for which AF is suspected to be causal or contributory and for which standard therapy to treat underlying causes and hypotension have failed. Care must be given to other potentially inciting factors such as sepsis, fluid depletion, or vasodilation. For patients whose AF is thought to be secondary to an initiating comorbidity such as pneumonia, treatment of the underlying cause of AF is important and may reduce the long- term risk of recurrent AF. Finally, for those patients who require urgent management, we generally obtain the same baseline diagnostic tests as in stable patients unless other clinical characteristics suggest otherwise. In this case, the diagnostic approach should also include work-up for the suspected underlying condition (eg, pneumonia, pulmonary embolus, etc). Indications for hospitalization Many patients with new-onset AF who are evaluated in an emergency room may not need to be hospitalized. However, indications for hospitalization in these patients include: Patients in whom ablation of an accessory pathway is being considered, particularly if the AF was highly symptomatic and associated with hemodynamic collapse and rapid ventricular response rate. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 11/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Severe bradycardia or prolonged pauses, including after cardioversion. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Treatment of an associated medical problem, which is often the reason for the arrhythmia (eg, hypertension, infection, exacerbation of chronic obstructive pulmonary disease, pulmonary embolism, pericarditis, persistent myocardial ischemia). It should be noted that AF alone is not an indication to rule out myocardial infarction. Further management of heart failure or hypotension after control of the rhythm or rate. Initiation of antiarrhythmic drug therapy (if patient and drug characteristics necessitate hospitalization). Difficult-to-control ventricular rates with evidence of ischemia, congestive heart failure symptoms or signs, and severe symptoms are indications for at least a 24-hour admission. Referral to cardiologist AF is a common medical problem and can often be managed by primary care physicians without need for consultation with a cardiologist. We suggest patient referral when the physician is not comfortable with decision-making or when catheter ablation of AF is under consideration. Also, when cardioversion or antiarrhythmic drugs are contemplated, cardiology consultation is advantageous. Anticoagulation Every patient with AF should be evaluated for the need for antithrombotic therapy to prevent systemic embolization even for the first AF episode. This is accomplished by use of a risk-scoring system for incident stroke called the CHA DS -VASc score ( table 1). Other 2 2 factors that may improve prediction of risk of stroke for an individual patient with burden of AF include left atrial size and function and certain biomarkers (ie, NT-proBNP and high-sensitivity troponin-T) [32]. Patients who require antithrombotic therapy include those in whom cardioversion (whether electrically or pharmacologically) to sinus rhythm is being considered (regardless of the CHA DS -VASc score or method of cardioversion [electrical or pharmacologic]) 2 2 and those who meet criteria for long-term anticoagulation. All patients whose risk of embolization exceeds the risk of bleeding are candidates for long-term antithrombotic therapy. These issues are discussed in detail elsewhere. (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Triggers In some cases, onset of AF is triggered by another acute medical diagnosis: hyperthyroidism, acute pulmonary embolism, myopericarditis, pneumonia, after cardiac surgery, and certain drugs or supplements. Treatment of specific triggers or elimination of inciting factors may lead to years or even a lifetime without further episodes of AF. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 12/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The treatment of a suspected precipitating cause may result in reversion to sinus rhythm. For patients with severe hyperthyroidism, the main goal of therapy initially is rate control, anticoagulation, treatment of hyperthyroidism, and restoration of sinus rhythm once they are euthyroid. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Therapeutic approach'.) Treatment of AF in patients with heart failure and/or chronic obstructive pulmonary disease should generally be undertaken simultaneously with treatment of their other condition. (See "The management of atrial fibrillation in patients with heart failure", section on 'Correction of reversible causes'.) Cardiovascular risk factors Identifying and treating risk factors and comorbidities may help with AF symptoms and burden. Common risk factors and comorbidities that can lead to the development of AF include advanced age, hypertension, diabetes, obstructive sleep apnea, heart failure, and obesity. For most identified risk factors, we believe that treating the risk factor may reduce but not eliminate the likelihood of subsequent episodes of AF. A comprehensive description of risk factors for AF is discussed separately. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations' and "Overview of established risk factors for cardiovascular disease".) Symptom and hemodynamic management Unstable patients In some hemodynamically unstable patients who manifest with signs or symptoms such as hypotension, altered mental status, or heart failure, we attempt ventricular rate control. Slowing of the ventricular rate will sometimes lead to spontaneous reversion to sinus rhythm. Rate control is usually performed with a beta blocker or calcium channel blocker (verapamil or diltiazem). This is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) For patients with AF and heart failure, ventricular rate control strategies are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction'.) If the patient remains hemodynamically unstable, emergency cardioversion should be performed, particularly if the hemodynamic compromise is due to an uncontrolled rapid ventricular rate and/or we believe that the lack of atrial contraction is impairing cardiac output. Emergent therapy with rate control and/or cardioversion for unstable patients is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Unstable patients' and "Control of https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 13/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Determining urgency'.) Unless AF reverts spontaneously, a decision is made whether, when, and how cardioversion will be performed. Management of thromboembolic risk is a key consideration when cardioversion is considered. (See "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If we decide to perform emergency cardioversion, the risk for a thromboembolic event needs to be considered. Most patients who will undergo cardioversion should be anticoagulated as soon as the decision is made to cardiovert or after assessment of their clinical thromboembolic risk based on their CHA DS -VASc score. Issues related to anticoagulation around the time of 2 2 cardioversion are discussed in detail separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours' and "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Once the patient becomes hemodynamically stable, the remainder of the acute and long-term management is similar to that of stable patients. Stable patients For stable patients with new-onset AF who do not meet the above criteria for emergency management and in whom we have performed an evaluation, we try to accomplish the following in the outpatient setting: Evaluate the need to slow the ventricular rate. Discuss the possible need for cardioversion with the patient. If the patient is highly symptomatic or if there is new-onset AF even in the absence of symptoms, we usually attempt cardioversion. Among patients with new-onset AF, even if cardioversion is contemplated, it usually does not need to be performed urgently; the majority of these patients will spontaneously convert to sinus rhythm within 48 to 72 hours [33]. Among 1822 patients admitted to the hospital because of AF, 356 had an arrhythmia duration less than 72 hours. Sixty-eight percent of the patients with this short AF duration spontaneously reverted to sinus rhythm [33]. Two-thirds of those with spontaneous reversion had AF duration of less than 24 hours; AF duration less than 24 hours was the only predictor of spontaneous reversion. A detailed discussion of cardioversion, including reasons to not cardiovert, is found elsewhere. (See "Atrial fibrillation: Cardioversion" and "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 14/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The choice of electrical or pharmacologic cardioversion requires consideration of the efficacy and safety of the approach, comorbidities, stability, preferences of the patient, and comfort of the clinician to use one or the other approach. This issue is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion", section on 'Electrical versus pharmacologic cardioversion'.) Determine the need for acute and long-term anticoagulant therapy. Discuss the cause (if known) and natural history of AF. (See 'Sequelae' below.) Consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Schedule follow-up. (See 'Long-term management' below.) LONG-TERM MANAGEMENT Early follow-up Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. For many patients, a one-week follow-up visit, or as soon as possible if one week is not realistic for a particular patient, is a reasonable strategy. This early return is particularly important for patients started on antiarrhythmic drug therapy to assess safety, efficacy, and side effects that can be specific to their therapy. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Prevention of thromboembolism Following initial pre- and postcardioversion anticoagulation, the decision to continue long-term anticoagulation following a single reversible incident is debatable, and the decision is highly individualized based on the presumed future risk of recurrent AF in that individual (vis a vis CHA DS -VASc score). It is also reasonable to take 2 2 an observational approach following a reversible cause of AF involving clinical follow-up of symptoms and ambulatory monitoring for surveillance for possible recurrence. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation shared-decision making The shared decision-making between patients and providers includes benefits versus risks of taking anticoagulation and tradeoffs between warfarin and DOAC; providers should also be prepared to address patients https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 15/35 7/5/23, 9:11 AM
reversible causes'.) Cardiovascular risk factors Identifying and treating risk factors and comorbidities may help with AF symptoms and burden. Common risk factors and comorbidities that can lead to the development of AF include advanced age, hypertension, diabetes, obstructive sleep apnea, heart failure, and obesity. For most identified risk factors, we believe that treating the risk factor may reduce but not eliminate the likelihood of subsequent episodes of AF. A comprehensive description of risk factors for AF is discussed separately. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations' and "Overview of established risk factors for cardiovascular disease".) Symptom and hemodynamic management Unstable patients In some hemodynamically unstable patients who manifest with signs or symptoms such as hypotension, altered mental status, or heart failure, we attempt ventricular rate control. Slowing of the ventricular rate will sometimes lead to spontaneous reversion to sinus rhythm. Rate control is usually performed with a beta blocker or calcium channel blocker (verapamil or diltiazem). This is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) For patients with AF and heart failure, ventricular rate control strategies are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction'.) If the patient remains hemodynamically unstable, emergency cardioversion should be performed, particularly if the hemodynamic compromise is due to an uncontrolled rapid ventricular rate and/or we believe that the lack of atrial contraction is impairing cardiac output. Emergent therapy with rate control and/or cardioversion for unstable patients is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Unstable patients' and "Control of https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 13/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Determining urgency'.) Unless AF reverts spontaneously, a decision is made whether, when, and how cardioversion will be performed. Management of thromboembolic risk is a key consideration when cardioversion is considered. (See "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If we decide to perform emergency cardioversion, the risk for a thromboembolic event needs to be considered. Most patients who will undergo cardioversion should be anticoagulated as soon as the decision is made to cardiovert or after assessment of their clinical thromboembolic risk based on their CHA DS -VASc score. Issues related to anticoagulation around the time of 2 2 cardioversion are discussed in detail separately. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours' and "Atrial fibrillation: Cardioversion" and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Once the patient becomes hemodynamically stable, the remainder of the acute and long-term management is similar to that of stable patients. Stable patients For stable patients with new-onset AF who do not meet the above criteria for emergency management and in whom we have performed an evaluation, we try to accomplish the following in the outpatient setting: Evaluate the need to slow the ventricular rate. Discuss the possible need for cardioversion with the patient. If the patient is highly symptomatic or if there is new-onset AF even in the absence of symptoms, we usually attempt cardioversion. Among patients with new-onset AF, even if cardioversion is contemplated, it usually does not need to be performed urgently; the majority of these patients will spontaneously convert to sinus rhythm within 48 to 72 hours [33]. Among 1822 patients admitted to the hospital because of AF, 356 had an arrhythmia duration less than 72 hours. Sixty-eight percent of the patients with this short AF duration spontaneously reverted to sinus rhythm [33]. Two-thirds of those with spontaneous reversion had AF duration of less than 24 hours; AF duration less than 24 hours was the only predictor of spontaneous reversion. A detailed discussion of cardioversion, including reasons to not cardiovert, is found elsewhere. (See "Atrial fibrillation: Cardioversion" and "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 14/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate The choice of electrical or pharmacologic cardioversion requires consideration of the efficacy and safety of the approach, comorbidities, stability, preferences of the patient, and comfort of the clinician to use one or the other approach. This issue is discussed in detail elsewhere. (See "Atrial fibrillation: Cardioversion", section on 'Electrical versus pharmacologic cardioversion'.) Determine the need for acute and long-term anticoagulant therapy. Discuss the cause (if known) and natural history of AF. (See 'Sequelae' below.) Consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Schedule follow-up. (See 'Long-term management' below.) LONG-TERM MANAGEMENT Early follow-up Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. For many patients, a one-week follow-up visit, or as soon as possible if one week is not realistic for a particular patient, is a reasonable strategy. This early return is particularly important for patients started on antiarrhythmic drug therapy to assess safety, efficacy, and side effects that can be specific to their therapy. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Prevention of thromboembolism Following initial pre- and postcardioversion anticoagulation, the decision to continue long-term anticoagulation following a single reversible incident is debatable, and the decision is highly individualized based on the presumed future risk of recurrent AF in that individual (vis a vis CHA DS -VASc score). It is also reasonable to take 2 2 an observational approach following a reversible cause of AF involving clinical follow-up of symptoms and ambulatory monitoring for surveillance for possible recurrence. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation shared-decision making The shared decision-making between patients and providers includes benefits versus risks of taking anticoagulation and tradeoffs between warfarin and DOAC; providers should also be prepared to address patients https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 15/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate questions about out-of-pocket costs, as failure to do so could lead to patient harm. A qualitative study of 37 recorded clinical encounters showed that providers rarely are prepared to adequately address patient questions related to medication cost [34]. Among patients with AF, thrombus in the left atrial appendage is the primary source for thromboemboli. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Atrial stunning'.) A subset of patients who require long-term anticoagulation may be unable to take it due to high bleeding risk or poor adherence. In such patients, occlusion of the left atrial appendage may be considered. After left atrial appendage occlusion, patients are required to be on short-term anticoagulation. Left atrial appendage occlusion is described in detail separately. (See "Atrial fibrillation: Left atrial appendage occlusion".) AF recurrence Continuous cardiac monitoring studies have shown that approximately 90 percent of patients with AF have recurrent episodes of AF [35]. However, up to 90 percent of episodes are not recognized by the patient [36], and asymptomatic episodes lasting more than 48 hours are not uncommon, occurring in 17 percent of patients in a study that used continuous ECG monitoring to detect AF [35]. The latter study also showed that 40 percent of patients had episodes of AF-like symptoms in the absence of AF. (See "Paroxysmal atrial fibrillation", section on 'Natural history'.) Some methods to reduce AF recurrence and/or burden including the following: Alcohol reduction Alcohol is a modifiable risk factor for AF, and among people who consume an excessive amount of alcohol, reduction and abstinence appear to decrease the risk of recurrent AF and time in AF. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Alcohol'.) In one study, 140 symptomatic patients with paroxysmal or persistent AF who were in sinus rhythm at baseline and who consumed 10 or more standard drinks per week (about 120 g of pure alcohol) were randomly assigned to alcohol abstention or usual alcohol consumption [37]. After six months, patients underwent comprehensive rhythm monitoring. Patients assigned to abstinence had: Greater reduction in their alcohol intake from 16.8 to 2.1 standard drinks per week, while those in the usual consumption group reduced their consumption from 16.4 to 13.2 per week. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 16/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Lower rates of recurrent AF (53 versus 73 percent of the two groups). Recurrence of AF was also delayed in the abstinence group, and the AF burden was significantly lower. Weight loss and physical activity Among patients with AF, both of these measures can lead to healthy cardiac remodeling [38] and reduce AF burden [38,39] and cardiovascular mortality [40,41]: In one study, 150 patients with symptomatic AF and a body mass index in the 2 overweight or greater range ( 25 kg/m ) were randomized to a weight management intervention or general lifestyle advice [38]. After 15 months, participants assigned the intervention showed a greater reduction in weight compared with the general lifestyle advice group (14.3 versus 3.6 kg). The intervention group also had a greater reduction in AF symptom burden (11.8 versus 2.6 points), symptom severity scores (8.4 versus 1.7 points), number of AF episodes (2.5 fewer versus no change), and cumulative AF duration (692-minute decline versus 419-minute increase). Echocardiographic cardiac remodeling parameters also improved in the intervention versus control group (ie, reduction in interventricular septal thickness [1.1 and 0.6 mm] and reduction in left 2 atrial area [3.5 and 1.9 cm ]). In a nonrandomized intervention study, 149 patients undergoing a catheter ablation for symptomatic AF were offered a three-month cardiovascular risk factor management 2 program [39]. Patients had a body mass index of 27 kg/m plus at least one additional cardiovascular risk factor. Sixty-one patients opted for the risk factor management intervention and 88 did not (the control group). On follow-up, patients who chose the intervention lost weight, whereas the control group gained weight (-13.2 versus +1.5 kg). The intervention group had a mean systolic blood pressure reduction, whereas the control group had a blood pressure increase (-34.1 versus 20.6). Control of dyslipidemia was higher in the intervention compared with control group (46 versus 17 percent). More patients in the control group experienced AF recurrence (32.9 versus 9.7 percent; hazard ratio [HR] 2.6; 95 %CI, 1.7-4.0) compared with the intervention group. Among patients with AF, physical activity may lower cardiovascular mortality [40,41]. (See 'Benefit of physical activity' below.) Rate or rhythm control Once ventricular rate control is achieved, a decision regarding the long-term management (rhythm versus rate control) of AF should be made; this decision depends on many factors. These are discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) The following points should be kept in mind irrespective of the strategy chosen: https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 17/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Both strategies can fail in the short and long term. Consequently, many patients need to be reconsidered for the alternate strategy as the natural history of their disease progresses. All patients with AF, irrespective of strategy chosen/rhythm, should have their thromboembolic risk assessed and be managed accordingly. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) For patients who are managed with a rhythm-control strategy, rate control is necessary due to the possibility of recurrence of AF. The advantages and disadvantages of rhythm and rate control, and subgroups of patients for whom one or the other is preferred, are discussed in greater detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) A rhythm-control strategy uses either antiarrhythmic drug therapy, percutaneous catheter ablation, and/or a surgical procedure. Electrical cardioversion may be necessary to restore sinus rhythm. Antiarrhythmic medications are generally started before cardioversion and continued to maintain sinus rhythm (in the event of AF recurrence). (See "Atrial fibrillation: Surgical ablation", section on 'Maze procedure' and "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) The decision regarding which of the above rhythm-control methods to pursue is discussed in detail separately. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) Among patients undergoing cardiac surgery for another reason (eg, mitral valve or coronary artery bypass surgery), surgical ablation to control refractory AF can be done during the same procedure. Several surgical techniques have been developed for the control of refractory AF and maintenance of sinus rhythm. These surgical procedures appear effective at eliminating or reducing the frequency of AF in a high percentage of patients. For patients who are at high risk for stroke, long-term anticoagulation is still continued. This is discussed in detail separately. (See "Atrial fibrillation: Surgical ablation".) A rate-control strategy generally uses drugs that slow conduction across the atrioventricular node such as beta blockers, nondihydropyridine calcium channel blockers, or digoxin. Atrioventricular junction ablation with pacemaker placement is used in patients with persistent tachycardia, hemodynamic instability, and poorly tolerated and/or highly symptomatic AF, in whom rate control has not been successful. These approaches to ventricular rate control in AF are discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy" and "Atrial fibrillation: Atrioventricular node ablation".) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 18/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Most patients who present with AF will require slowing of the ventricular rate to improve symptoms. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Long-term follow-up Patients with paroxysmal, persistent, longstanding persistent, or permanent AF will need periodic care and occasional urgent evaluation during the natural history of their disease. (See 'Classification and terminology' above.) We suggest routine follow-up every 12 months in stable patients and sooner if there are changes in symptoms. Patients on high-risk antiarrhythmic therapy, such as dofetilide or sotalol, are often seen every six months. These patients may need to be under the care of a cardiologist and/or electrophysiology specialist for management of antiarrhythmic medications. From time to time, patients should be monitored for the following: Efficacy and safety of antithrombotic therapy (international normalized ratio for patients on warfarin and creatinine clearance for patients on antiarrhythmic therapy and other newer anticoagulants). Functional status, including change in symptoms (history). Efficacy and safety of antiarrhythmic drug therapy (eg, ECG, assessment of renal and hepatic function). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) Efficacy of rate control (history, ECG, and extended Holter monitoring if variability in heart rate is suspected). (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) In active patients with AF, we use stress testing to gauge adequacy of heart rate control in AF during exercise. Insufficient heart rate control in AF is a major factor for exercise intolerance in AF. (See "Ambulatory ECG monitoring".) Laboratory testing We obtain a complete blood count, serum electrolytes, and assessment of renal function, particularly in patients for whom a nonvitamin oral anticoagulant might be started. We do not order troponin unless acute ischemia is suspected. Clinical or subclinical hyperthyroidism is present in less than 5 percent of patients with AF [23]. A thyroid-stimulating hormone and free T4 levels should be obtained in all patients with a first episode of AF, or in those who develop an increase in AF frequency. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Hyperthyroidism'.) https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 19/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate SEQUELAE Myocardial infarction Myocardial infarction has been shown to occur as a result of a coronary artery thromboembolism resulting from AF [42,43]. However, large studies of this sequelae of AF are lacking. Also, myocardial infarction from demand ischemia (also called type 2 myocardial infarction) can also result from AF, usually in the setting of a rapid ventricular rate. (See "Diagnosis of acute myocardial infarction", section on 'Comparing type 1 and 2 myocardial infarction'.) Whereas tachyarrhythmias have been shown to account for about 25 percent of type 2 myocardial infarction [44], studies specifically studying AF and type 2 myocardial infarction are lacking. In patients with a recent myocardial infarction, the subsequent development of AF increases mortality [45,46]. This effect is primarily due to associated risk factors such as heart failure and cardiogenic shock and not due to AF itself [46,47]. Mortality AF and mortality AF is an independent risk factor for mortality across a wide age range and in both males and females, but the evidence is insufficient to establish AF as a cause of excess mortality rather than just a marker of high risk [48]. Rhythm-control trials among patients with AF suggest that those in sinus rhythm had lower mortality compared with those in AF [49,50]. In a secondary analysis of the randomized controlled AFFIRM trial of rhythm versus rate control in AF, the presence of sinus rhythm was associated with a significant reduction in mortality (hazard ratio [HR] 0.54; 95% CI 0.42-0.70) [49]. A similar benefit from being in sinus rhythm (relative risk 0.44; 95% CI 0.4-0.64) was noted in a separate trial of dofetilide in patients with reduced left ventricular function [50]. Strength of association Observational cohort studies have also shown that AF is associated with increased mortality [51-54]. In a post-hoc analysis of the Women's Health Study of 34,772 women with a median age of 53 who were free of AF, 2.9 percent developed AF at a median follow-up of 15.4 years [51]. New-onset AF was associated with a significantly increased adjusted risk of all-cause, cardiovascular, and noncardiovascular mortality (HR 2.14, 95% CI 1.64-2.77; HR 4.18, 95% CI 2.69-6.51; and HR 1.66, 95% CI 1.19- 2.30, respectively). Adjustment for nonfatal cardiovascular events such as myocardial infarction, stroke, or heart failure lowered these risks, but incident AF remained https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 20/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate significantly associated with all types of mortality (HR 1.7, HR 2.57, HR and 1.42, respectively). Sex difference Several observational studies have suggested that the association between AF and death is greater in women with AF compared with men [52,53]. In a retrospective study of 272,186 patients with incidental AF at the time of hospitalization and 544,344 matched AF-free controls, the adjusted relative risk of death with AF was higher in females compared with males across all age categories (2.15 versus 1.76 for those <65 years, 1.72 versus 1.36 for those ages 65 to 74 years, and 1.44 versus 1.24 for those 75 to 85 years) [52]. In 621 participants in the Framingham Heart Study, having AF led to an almost doubling of the risk of death in both men and women (adjusted odds ratio 1.9 for women and 1.5 for men) ( figure 1) [53]. This sex difference in the association between AF and mortality was also shown in a separate study of 15,000 men and women [54]. Cause of excess mortality In participants with AF in the Framingham Heart Study, both heart failure and stroke contributed to the excess mortality [53]. In addition, in an observational study of over 20,000 individuals in two cohorts, incident AF was associated with an increased risk of sudden cardiac death (HR 2.47; 95% CI 1.95-3.13) as well as nonsudden cardiac death (HR 2.98; 95% CI 2.52-3.53) [55]. The specific causes of death, as well as their frequency and predictors, were evaluated using follow-up data from the RE-LY trial comparing dabigatran with warfarin [56]. Among 18,113 randomized patients with a median follow-up of two years, the annual mortality rate was 3.84 percent. Cardiac deaths (sudden cardiac death and progressive heart failure) accounted for 37.4 percent of these; stroke and hemorrhagic death accounted for 9.9 percent. Predictors of mortality in patients with AF In the RE-LY trial , the strongest independent clinical predictors of cardiac death were heart failure, intraventricular conduction delay on an ECG, and prior myocardial infarction [56]. In a post-hoc analysis of the RACE II trial, the risk of cardiovascular morbidity and mortality was highest in those with the greatest symptom burden as assessed with the Toronto AF Severity Scale [57]. This finding was driven by the increased rate of heart failure hospitalizations. Benefit of physical activity As in the general population, among patients with AF, physical activity can significantly reduce cardiovascular mortality [40,41]. (See "The benefits and risks of aerobic exercise", section on 'Mortality'.) In a prospective Danish study of over 1100 individuals with AF, metabolic equivalents were used to estimate cardiorespiratory fitness, and patients were followed for up to nine years for mortality outcomes. This study observed that each one-metabolic equivalent task higher was https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 21/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate associated with a lower risk of all-cause mortality (HR 0.88; 95% CI 0.81-0.95) and cardiovascular disease mortality (HR 0.85; 95% CI 0.76-0.95) [40]. Patients meeting European Society of Cardiology physical activity recommendations had a lower risk of cardiovascular mortality compared with inactive patients (HR 0.54; 95% CI 0.34-0.86) [41]. Stroke and silent cerebral ischemia Stroke Stroke is the most frequent major complication of AF; this topic is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Silent cerebral ischemia Silent cerebral ischemia occurs in a patient who has specific lesions on imaging studies in the absence of clinical complaints or findings. Among patients with AF, these lesions are relatively common; this is discussed in detail separately. (See "Stroke in patients with atrial fibrillation", section on 'Silent cerebral infarction'.) Cognitive impairment and dementia AF increases the risk of cognitive impairment, all- cause dementia, vascular dementia, and Alzheimer's disease [58,59]. It is uncertain whether anticoagulation protects against dementia [59,60]. This is discussed in detail separately. (See "Risk factors for cognitive decline and dementia", section on 'Atrial fibrillation'.) Heart failure AF is a risk factor for new-onset heart failure. This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Epidemiology'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 22/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: Heart failure and atrial fibrillation (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Background Atrial fibrillation (AF) is the most common cardiac arrhythmia that can have adverse consequences related to a reduction in cardiac output (symptoms) and atrial and atrial appendage thrombus formation (stroke and peripheral embolization) ( waveform 1). Classification Patients are classified as having paroxysmal, persistent, longstanding persistent, or permanent AR. Other classifications include subclinical or occult AF. (See 'Classification and terminology' above.) Screening We do not screen asymptomatic patients for AF. There is no sufficient evidence that screening for AF will substantially detect more AF or protect against cardiac events. Electrocardiograms (ECGs) do not appear more effective than pulse palpation at AF detection. (See 'Screening' above.) Presentation and Evaluation A new diagnosis of AF can present in a variety of ways; sometimes the patient has symptoms of AF and other times it is picked up incidentally. (See 'Common scenarios' above.) Essential information from the patient's symptoms and past medical history, physical examination, electrocardiogram (ECG), and a transthoracic echocardiogram (TTE) should be obtained at the time of diagnosis and periodically during the course of the disease. Additional laboratory testing, such as thyroid stimulating hormone assay, and ambulatory https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 23/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate ECG monitoring may be necessary. (See 'History and physical examination' above and 'Laboratory testing' above.) Initial steps in all patients It is important to decide whether the patient should be managed as an outpatient or in the emergency room or acute hospital setting. When deciding, we take the patient's presentation, symptom burden, and associated conditions into consideration. (See 'Management setting' above.) Other initial steps for all patients include consideration of antithrombotic therapy, treatment of potentially reversible triggers of AF, and cardiovascular risk factor management. (See 'Initial management' above.) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Acute symptom management Symptom management starts with rate control of acute AF episodes and early decision-making regarding the need for cardioversion. Unstable patients In some hemodynamically unstable patients, ventricular rate control can be attempted; slowing of the ventricular rate sometimes leads to spontaneous reversion to sinus rhythm. If rate control does not work and the patient remains hemodynamically unstable, we pursue cardioversion; if we decide to perform emergency cardioversion, the risk for a thromboembolic event needs to be considered. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'AF duration less than 48 hours'.) Stable patients For stable patients, usually in the nonacute care setting, we discuss the need for possible cardioversion, need for acute and long-term anticoagulant therapy, the cause (if known), and natural history of AF. (See 'Sequelae' above.) We consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Long-term management Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. Lifestyle modification with reducing alcohol consumption, weight reduction, and increasing physical https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 24/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate activity can reduce AF burden and decrease recurrence. (See 'Long-term management' above.) Sequelae In the absence of a reversible precipitant, AF is typically recurrent. AF is associated with increased risk of mortality, stroke, silent cerebral ischemia, cognitive impairment, dementia, and heart failure. Physical activity and higher cardiorespiratory fitness may protect against mortality in AF. (See 'Sequelae' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 2. Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrillation: does it exist? J Am Coll Cardiol 2014; 63:1715. 3. Svennberg E, Friberg L, Frykman V, et al. Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021; 398:1498. 4. Svendsen JH, Diederichsen SZ, H jberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet 2021; 398:1507. 5. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for Atrial Fibrillation: US Preventive Services Task Force Recommendation Statement. JAMA 2022; 327:360. 6. Lyth J, Svennberg E, Bernfort L, et al. Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study. Eur Heart J 2023; 44:196. 7. Lubitz SA, Atlas SJ, Ashburner JM, et al. Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial. Circulation 2022; 145:946. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 25/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 8. Perez MV, Mahaffey KW, Hedlin H, et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med 2019; 381:1909. 9. Diederichsen SZ, Haugan KJ, Kronborg C, et al. Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder. Circulation 2020; 141:1510. 10. Jonas DE, Kahwati LC, Yun JDY, et al. Screening for Atrial Fibrillation With Electrocardiography: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018; 320:485. 11. Christophersen IE, Yin X, Larson MG, et al. A comparison of the CHARGE-AF and the CHA2DS2-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study. Am Heart J 2016; 178:45. 12. Marston NA, Garfinkel AC, Kamanu FK, et al. A polygenic risk score predicts atrial fibrillation in cardiovascular disease. Eur Heart J 2023; 44:221. 13. Bano A, Rodondi N, Beer JH, et al. Association of Diabetes With Atrial Fibrillation Phenotype and Cardiac and Neurological Comorbidities: Insights From the Swiss-AF Study. J Am Heart Assoc 2021; 10:e021800. 14. Echouffo-Tcheugui JB, Shrader P, Thomas L, et al. Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes: ORBIT-AF Registry. J Am Coll Cardiol 2017; 70:1325. 15. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370:2478. 16. Noseworthy PA, Kaufman ES, Chen LY, et al. Subclinical and Device-Detected Atrial Fibrillation: Pondering the Knowledge Gap: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e944. 17. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 18. Walkey AJ, Benjamin EJ, Lubitz SA. New-onset atrial fibrillation during hospitalization. J Am Coll Cardiol 2014; 64:2432. 19. Tung P, Levitzky YS, Wang R, et al. Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women. J Am Heart Assoc 2017; 6. 20. Lavie CJ, Pandey A, Lau DH, et al. Obesity and Atrial Fibrillation Prevalence, Pathogenesis, and Prognosis: Effects of Weight Loss and Exercise. J Am Coll Cardiol 2017; 70:2022. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 26/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 21. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004; 292:2471. 22. Wynn GJ, Todd DM, Webber M, et al. The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification. Europace 2014; 16:965. 23. Krahn AD, Klein GJ, Kerr CR, et al. How useful is thyroid function testing in patients with recent-onset atrial fibrillation? The Canadian Registry of Atrial Fibrillation Investigators. Arch Intern Med 1996; 156:2221. 24. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 25. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat Rev Cardiol 2017; 14:627. 26. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 27. Yoon M, Yang PS, Jang E, et al. Improved Population-Based Clinical Outcomes of Patients with Atrial Fibrillation by Compliance with the Simple ABC (Atrial Fibrillation Better Care) Pathway for Integrated Care Management: A Nationwide Cohort Study. Thromb Haemost 2019; 119:1695. 28. Pastori D, Pignatelli P, Menichelli D, et al. Integrated Care Management of Patients With Atrial Fibrillation and Risk of Cardiovascular Events: The ABC (Atrial fibrillation Better Care)
fibrillation", section on 'AF duration less than 48 hours'.) Stable patients For stable patients, usually in the nonacute care setting, we discuss the need for possible cardioversion, need for acute and long-term anticoagulant therapy, the cause (if known), and natural history of AF. (See 'Sequelae' above.) We consider consultation with a cardiologist. Reasons to consult a cardiologist include the need for cardioversion or the need to treat with antiarrhythmic drugs or catheter ablation. (See 'Management setting' above.) Long-term management Follow-up after an episode of acute AF is necessary to evaluate the safety and efficacy of rate or rhythm control, patient adherence with anticoagulant and antiarrhythmic therapy, need for continued therapies for AF, to discuss any strategies to reduce AF recurrence, and to assess the functional status of the patient. Lifestyle modification with reducing alcohol consumption, weight reduction, and increasing physical https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 24/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate activity can reduce AF burden and decrease recurrence. (See 'Long-term management' above.) Sequelae In the absence of a reversible precipitant, AF is typically recurrent. AF is associated with increased risk of mortality, stroke, silent cerebral ischemia, cognitive impairment, dementia, and heart failure. Physical activity and higher cardiorespiratory fitness may protect against mortality in AF. (See 'Sequelae' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Alan Cheng, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 2. Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrillation: does it exist? J Am Coll Cardiol 2014; 63:1715. 3. Svennberg E, Friberg L, Frykman V, et al. Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021; 398:1498. 4. Svendsen JH, Diederichsen SZ, H jberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet 2021; 398:1507. 5. US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Screening for Atrial Fibrillation: US Preventive Services Task Force Recommendation Statement. JAMA 2022; 327:360. 6. Lyth J, Svennberg E, Bernfort L, et al. Cost-effectiveness of population screening for atrial fibrillation: the STROKESTOP study. Eur Heart J 2023; 44:196. 7. Lubitz SA, Atlas SJ, Ashburner JM, et al. Screening for Atrial Fibrillation in Older Adults at Primary Care Visits: VITAL-AF Randomized Controlled Trial. Circulation 2022; 145:946. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 25/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 8. Perez MV, Mahaffey KW, Hedlin H, et al. Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. N Engl J Med 2019; 381:1909. 9. Diederichsen SZ, Haugan KJ, Kronborg C, et al. Comprehensive Evaluation of Rhythm Monitoring Strategies in Screening for Atrial Fibrillation: Insights From Patients at Risk Monitored Long Term With an Implantable Loop Recorder. Circulation 2020; 141:1510. 10. Jonas DE, Kahwati LC, Yun JDY, et al. Screening for Atrial Fibrillation With Electrocardiography: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018; 320:485. 11. Christophersen IE, Yin X, Larson MG, et al. A comparison of the CHARGE-AF and the CHA2DS2-VASc risk scores for prediction of atrial fibrillation in the Framingham Heart Study. Am Heart J 2016; 178:45. 12. Marston NA, Garfinkel AC, Kamanu FK, et al. A polygenic risk score predicts atrial fibrillation in cardiovascular disease. Eur Heart J 2023; 44:221. 13. Bano A, Rodondi N, Beer JH, et al. Association of Diabetes With Atrial Fibrillation Phenotype and Cardiac and Neurological Comorbidities: Insights From the Swiss-AF Study. J Am Heart Assoc 2021; 10:e021800. 14. Echouffo-Tcheugui JB, Shrader P, Thomas L, et al. Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes: ORBIT-AF Registry. J Am Coll Cardiol 2017; 70:1325. 15. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med 2014; 370:2478. 16. Noseworthy PA, Kaufman ES, Chen LY, et al. Subclinical and Device-Detected Atrial Fibrillation: Pondering the Knowledge Gap: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e944. 17. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366:120. 18. Walkey AJ, Benjamin EJ, Lubitz SA. New-onset atrial fibrillation during hospitalization. J Am Coll Cardiol 2014; 64:2432. 19. Tung P, Levitzky YS, Wang R, et al. Obstructive and Central Sleep Apnea and the Risk of Incident Atrial Fibrillation in a Community Cohort of Men and Women. J Am Heart Assoc 2017; 6. 20. Lavie CJ, Pandey A, Lau DH, et al. Obesity and Atrial Fibrillation Prevalence, Pathogenesis, and Prognosis: Effects of Weight Loss and Exercise. J Am Coll Cardiol 2017; 70:2022. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 26/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 21. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004; 292:2471. 22. Wynn GJ, Todd DM, Webber M, et al. The European Heart Rhythm Association symptom classification for atrial fibrillation: validation and improvement through a simple modification. Europace 2014; 16:965. 23. Krahn AD, Klein GJ, Kerr CR, et al. How useful is thyroid function testing in patients with recent-onset atrial fibrillation? The Canadian Registry of Atrial Fibrillation Investigators. Arch Intern Med 1996; 156:2221. 24. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 25. Lip GYH. The ABC pathway: an integrated approach to improve AF management. Nat Rev Cardiol 2017; 14:627. 26. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 27. Yoon M, Yang PS, Jang E, et al. Improved Population-Based Clinical Outcomes of Patients with Atrial Fibrillation by Compliance with the Simple ABC (Atrial Fibrillation Better Care) Pathway for Integrated Care Management: A Nationwide Cohort Study. Thromb Haemost 2019; 119:1695. 28. Pastori D, Pignatelli P, Menichelli D, et al. Integrated Care Management of Patients With Atrial Fibrillation and Risk of Cardiovascular Events: The ABC (Atrial fibrillation Better Care) Pathway in the ATHERO-AF Study Cohort. Mayo Clin Proc 2019; 94:1261. 29. Proietti M, Romiti GF, Olshansky B, et al. Improved Outcomes by Integrated Care of Anticoagulated Patients with Atrial Fibrillation Using the Simple ABC (Atrial Fibrillation Better Care) Pathway. Am J Med 2018; 131:1359. 30. Guo Y, Lane DA, Wang L, et al. Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation. J Am Coll Cardiol 2020; 75:1523. 31. Pastori D, Farcomeni A, Pignatelli P, et al. ABC (Atrial fibrillation Better Care) Pathway and Healthcare Costs in Atrial Fibrillation: The ATHERO-AF Study. Am J Med 2019; 132:856. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 27/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 32. Alkhouli M, Friedman PA. Ischemic Stroke Risk in Patients With Nonvalvular Atrial Fibrillation: JACC Review Topic of the Week. J Am Coll Cardiol 2019; 74:3050. 33. Danias PG, Caulfield TA, Weigner MJ, et al. Likelihood of spontaneous conversion of atrial fibrillation to sinus rhythm. J Am Coll Cardiol 1998; 31:588. 34. Martinez KA, Hurwitz HM, Rothberg MB. Qualitative Analysis of Patient-Physician Discussions Regarding Anticoagulation for Atrial Fibrillation. JAMA Intern Med 2022; 182:1260. 35. Israel CW, Gr nefeld G, Ehrlich JR, et al. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol 2004; 43:47. 36. Page RL, Wilkinson WE, Clair WK, et al. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation 1994; 89:224. 37. Voskoboinik A, Kalman JM, De Silva A, et al. Alcohol Abstinence in Drinkers with Atrial Fibrillation. N Engl J Med 2020; 382:20. 38. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial. JAMA 2013; 310:2050. 39. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014; 64:2222. 40. Garnvik LE, Malmo V, Janszky I, et al. Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study. Eur Heart J 2020; 41:1467. 41. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37:2315. 42. Schmitt J, Duray G, Gersh BJ, Hohnloser SH. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J 2009; 30:1038. 43. Garg RK, Jolly N. Acute myocardial infarction secondary to thromboembolism in a patient with atrial fibrillation. Int J Cardiol 2007; 123:e18. https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 28/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 44. Belkouche A, Yao H, Putot A, et al. The Multifaceted Interplay between Atrial Fibrillation and Myocardial Infarction: A Review. J Clin Med 2021; 10. 45. Crenshaw BS, Ward SR, Granger CB, et al. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries. J Am Coll Cardiol 1997; 30:406. 46. Eldar M, Canetti M, Rotstein Z, et al. Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. SPRINT and Thrombolytic Survey Groups. Circulation 1998; 97:965. 47. Goldberg RJ, Seeley D, Becker RC, et al. Impact of atrial fibrillation on the in-hospital and long-term survival of patients with acute myocardial infarction: a community-wide perspective. Am Heart J 1990; 119:996. 48. Leong DP, Eikelboom JW, Healey JS, Connolly SJ. Atrial fibrillation is associated with increased mortality: causation or association? Eur Heart J 2013; 34:1027. 49. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004; 109:1509. 50. Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001; 104:292. 51. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation. JAMA 2011; 305:2080. 52. Andersson T, Magnuson A, Bryngelsson IL, et al. All-cause mortality in 272,186 patients hospitalized with incident atrial fibrillation 1995-2008: a Swedish nationwide long-term case-control study. Eur Heart J 2013; 34:1061. 53. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98:946. 54. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med 2002; 113:359. 55. Chen LY, Sotoodehnia N, B kov P, et al. Atrial fibrillation and the risk of sudden cardiac death: the atherosclerosis risk in communities study and cardiovascular health study. JAMA Intern Med 2013; 173:29. 56. Marijon E, Le Heuzey JY, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long- https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 29/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate term anticoagulant therapy study. Circulation 2013; 128:2192. 57. Vermond RA, Crijns HJ, Tijssen JG, et al. Symptom severity is associated with cardiovascular outcome in patients with permanent atrial fibrillation in the RACE II study. Europace 2014; 16:1417. 58. Papanastasiou CA, Theochari CA, Zareifopoulos N, et al. Atrial Fibrillation Is Associated with Cognitive Impairment, All-Cause Dementia, Vascular Dementia, and Alzheimer's Disease: a Systematic Review and Meta-Analysis. J Gen Intern Med 2021; 36:3122. 59. Kim D, Yang PS, Yu HT, et al. Risk of dementia in stroke-free patients diagnosed with atrial fibrillation: data from a population-based cohort. Eur Heart J 2019; 40:2313. 60. Moffitt P, Lane DA, Park H, et al. Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review. Age Ageing 2016; 45:767. Topic 1022 Version 82.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 30/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate GRAPHICS 12 lead ECG of atrial fibrillation The 12 lead ECG shows atrial fibrillation. The QRS complex is narrow, P waves are absent, and the baseline between successive QRS complexes shows irregular coarse "fibrillatory waves." The QRS complexes occur at irregularly irregular intervals. Reproduced with permission by Samuel Levy, MD. Graphic 64217 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 31/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) 2 2 CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients Stroke and 2 2 (n = 73,538) thromboembolism event rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 5 8942 15.26 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 32/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 33/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Atrial fibrillation increases mortality in men and women Among 5209 subjects in the Framingham Heart Study, the mortality after a 10-year follow-up was higher in both men and women, aged 55 to 74, who had atrial fibrillation (AF) compared to those without AF (p <0.001) A similar relationship was seen in subjects between the ages of 75 and 94 (not shown). Data from Benjamin EJ, Wolf PA, D'Agostino RB, et al. Circulation 1998; 98:946. Graphic 71640 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 34/35 7/5/23, 9:11 AM Atrial fibrillation: Overview and management of new-onset atrial fibrillation - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-overview-and-management-of-new-onset-atrial-fibrillation/print 35/35
7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation: Surgical ablation : Richard Lee, MD, MBA : Gabriel S Aldea, MD, Edward Verrier, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 11, 2023. INTRODUCTION Atrial fibrillation (AF) is associated with an increased risk for stroke, heart failure, and death. An attempt to maintain sinus rhythm is made in patients based on the presence or absence of symptoms and evidence that myocardial function is being compromised. This may involve pharmacologic and nonpharmacologic strategies. The most commonly performed invasive procedure used in an attempt to maintain sinus rhythm is catheter ablation performed by an electrophysiologist in a specially designed hospital procedure room. This technique is discussed in detail elsewhere. (See "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) This chapter focuses on surgical ablation for the prevention of recurrent atrial fibrillation. The role of nonpharmacologic strategies for rate control in AF or to minimize thrombotic risk by left atrial appendage ligation, and an overview of the management of patients with AF, are presented separately. (See "Atrial fibrillation: Atrioventricular node ablation" and "Atrial fibrillation: Left atrial appendage occlusion" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) RATIONALE Work on the arrhythmic mechanisms for atrial fibrillation (AF) has led to a greater appreciation for the underlying process by which premature atrial complex (PAC; also referred to a premature https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 1/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate atrial beat, premature supraventricular complex, or premature supraventricular beat) can promote areas of microreentry within the atrium that ultimately lead to AF. (See "Mechanisms of atrial fibrillation".) Several surgical techniques have been developed to maintain sinus rhythm. In most cases, these techniques are employed in patients who are undergoing other cardiac surgery for some other reason (valve repair or replacement, coronary bypass grafting, or corrective surgery for congenital heart disease). The three principal goals of surgical intervention include [1]: Creation of conduction block to disrupt all micro- and macroreentrant circuits. (See "Mechanisms of atrial fibrillation", section on 'Mechanisms of atrial fibrillation: triggers and substrates'.) Reestablishment or maintenance of electrical atrioventricular synchrony. Restoration of atrial mechanical function in order to improve diastolic filling. MAZE PROCEDURE Developed in the 1980s, the Maze procedure aims to create a "maze" of functional myocardium within the atrium that allows for propagation of atrial depolarization while reducing the likelihood that the wavefront would promote microreentry. (See "Mechanisms of atrial fibrillation".) The most commonly performed procedure is referred to as the Cox-Maze IV and it consists of a pattern of linear scars created by incision or ablative technology such as radiofrequency or cryothermal ablation [2]. Most commonly, the procedure is performed at the time of other cardiac surgery, such as mitral valve surgery or coronary artery bypass graft surgery; the patient is on cardiopulmonary bypass. (See 'Indications' below.) Traditional approach The Maze procedure has evolved over the last 20 years. It originally created lines of scar by making several small incisions (referred to as "cut and sew") around the sinoatrial node as well as one to the atrial-superior vena caval junction (Maze I) through the sinus tachycardia region of the sinoatrial node. This unintentionally resulted in chronotropic incompetence and resulted in the Maze II procedure that modified the location of the incision to prevent this. The technical challenges of the Maze II procedure (eg, approach to the left atrium) eventually resulted in Maze III, which reduced the frequency of chronotropic incompetence, improved atrial transport function, and shortened procedure times ( figure 1) [3-9]. Eventually, https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 2/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate with the introduction of new technologies that created scar without incisions, such as cryothermia and radiofrequency, procedures were simplified and shortened. The "cut and sew" techniques became less frequently utilized and are now rarely performed. Although they are more complex and slightly more time consuming, approaches that treat both atria appear to be more effective [10]. However, it is important to point out that long-term follow-up on the efficacy of these procedures is limited. The "gold standard" is considered to be the Cox-Maze IV procedure, in which lines of ablation are created using bipolar radiofrequency and/or cryothermal energy devices. Several lines of scar are created from the superior vena cava to the inferior vena cava on the right atrium, which is then connected to the tricuspid annulus. On the left, the posterior wall of the left atrium containing all four pulmonary veins is isolated as a box. The box is then connected to the mitral valve annulus. In addition, the left atrial appendage is removed. The Maze procedure meets the three criteria for an ideal treatment of atrial fibrillation (AF) outlined above (see 'Rationale' above). In a five-year experience of 75 patients in one center, the procedure cured AF, restored atrioventricular synchrony, and preserved atrial transport function in all but one patient; six patients (9 percent) required antiarrhythmic medications [6]. Postoperative atrial pacemakers were implanted in 40 percent, mostly for preoperative sinus node dysfunction but occasionally for iatrogenic sinus node injury. This is a higher percent than has been observed in most contemporary series (see 'Need for pacemaker' below). Patients note a significant improvement in health-related quality of life, especially when compared with other cardiac procedures [8,11]. The addition of a Maze procedure does not appear to adversely impact outcomes after cardiac surgery. In a propensity-matched comparison of 485 patients undergoing Maze procedure and aortic valve replacement or coronary artery bypass graft surgery, there was no difference in any major morbidity or mortality. However, patients were on cardiopulmonary bypass longer and had a higher need for pacemakers [12]. Similar findings after mitral valve surgery have been reported in randomized trials [13]. A few studies have suggested that correcting AF at the time of cardiac surgery improves survival. In one study of 744 propensity-matched patients undergoing AF surgery at the time of other cardiac surgeries, patients who were successfully treated and free from antiarrhythmic medications at one year appeared to have improved survival, similar to patients without a history of AF. Those that remained in AF had a survival that was worse [14]. In another propensity-matched series of similar size, Maze-treated patients had a 10-year survival of 63 percent as compared with a 55 percent 10-year survival in similar patients whose AF was untreated [15]. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 3/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Radial approach The radial approach was developed after the Maze procedure to provide a more physiologic atrial activation-contraction sequence, thereby reducing the degree of left atrial dysfunction and optimizing the atrial contribution to left ventricular filling [16]. In contrast to the Maze procedure, in which the incisions desynchronize the activation sequence and often cut across the atrial coronary arteries, the incisions produced by the radial approach radiate from the sinus node toward the atrioventricular annular margins, paralleling the activation sequence and the atrial coronary arteries ( figure 2A-B) [17]. Left versus biatrial lesion set Some controversy exists as to the most appropriate lesion set. If only the left atrium is open in the case of a mitral valve repair or replacement without a tricuspid intervention, some surgeons have advocated a left-atrial-only approach [18]. In a series of 305 patients, there was an equal efficacy of a left-only approach, but a higher pacemaker implantation in those who underwent a biatrial lesion set [18]. Both of these findings were confirmed on a meta-analysis of 2225 patients from 10 studies [19]. The equivalent sinus restoration is supported by a randomized subgroup analysis of mitral valve patients that compared patients undergoing biatrial Mazes with pulmonary vein isolation alone [13]. However, in a 2008 analysis of 1723 patients, absence of a biatrial lesion set was a predictor of failure at 48 months [20]. This finding was also supported by a 2006 meta-analysis of 5885 patients in 69 studies [10]. More investigation may lead to a better understanding of which patients benefit from the biatrial lesion set. One study compared the outcome of 23 patients who underwent a radial approach with 13 who had a traditional Maze procedure [21]. The radial approach was technically easier than the Maze, was equally likely to restore sinus rhythm (90 versus 92 percent for the Maze), and was associated with better left atrial transport function after surgery, as assessed with Doppler echocardiography. However, this approach has not yet been widely adopted by the majority of surgeons. Minimally invasive approach While the Maze procedure is usually performed at the time of cardiac surgery using a sternotomy, it has also been performed through a thoracotomy with a minimally invasive approach to mitral valves [22,23]. However, there are limited data available on the efficacy of using this approach. Limitations and complications Atrial transport function One potential limitation to the Maze procedure is extensive damage to the atrial myocardium with resultant atrial dysfunction that may limit the hemodynamic benefit. In one series of 21 patients, the technique was effective in restoring sinus rhythm in 17 (85 percent) but atrial contractility improved in only 12 (71 percent) [24]. In one https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 4/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate series of 150 patients who had successful return of electrical sinus, poor atrial contraction resulted in a significant rate of late stroke [25]. In a series of 31 patients, echocardiography demonstrated left atrial function in 71 percent and right atrial function in 81 percent; however, function was reduced compared with age-matched control subjects [26]. A successful Maze procedure may improve atrial transport, but the degree of improvement will likely be dependent on preoperative dysfunction. Need for pacemaker A common complication is the need for postoperative pacemaker, which usually occurs in approximately 10 percent of patients in most reports. As with simple electrical cardioversion, the mere restoration of sinus rhythm in patients with long-standing persistent AF can result in sinus node dysfunction unrelated to the surgery itself. Sinus node dysfunction may manifest as severe sinus bradycardia, sinus pauses or sinus arrest, sinoatrial exit block, atrial tachyarrhythmias, alternating periods of atrial bradyarrhythmias and tachyarrhythmias, and inappropriate heart rate responses during exercise or emotional stress. These arrhythmias probably result from partial denervation of the sympathetic and parasympathetic systems of the heart [27]. However, there may be some association with the extent of AF procedure performed. The published results are highly variable, with early studies reporting a postoperative need for pacemaker as high as 40 percent. Another study found pacemaker placement in 20 percent [6,13]. As surgeons learn to avoid the sinus node on the right side, the pacemaker rate may fall further. The manifestations of sinus node dysfunction after the modified Maze surgical technique are time dependent and, in one series, resolved within 12 months after surgery [28]; resolution correlated with functional reinnervation [27]. However, in another study, sick sinus syndrome developed in 7 of 87 patients (8.4 percent) and a pacemaker was required in 70 percent [29]. Pacemakers are rarely required after pulmonary vein isolation alone. In one series, there were more pacemakers required after biatrial lesion sets were employed, as compared with left atrial lesion sets alone [18]. This suggests that not all pacemakers are due to native sinus node dysfunction and that at least some are related to the creation of the right-sided lesions. There may be a balance between procedural efficacy and pacemaker requirement. METHODS Endocardial surgical ablation Endocardial ablation is most often performed in an electrophysiologic suite by electrophysiologists using a catheter-based approach. However, the endocardial ablation of atrial tissue can also be performed in the operating room as an adjunct to cardiac surgery for other reasons or as a stand-alone procedure using a minimally invasive approach. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 5/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate The efficacy of the left atrial approach was evaluated in a multicenter controlled trial in which 103 patients undergoing endocardial radiofrequency ablation during cardiac surgery for predominantly valvular heart disease were compared with 27 patients who refused radiofrequency ablation [30]. Linear ablation lesions were created around the right and left pulmonary vein ostia, with a lesion connecting the pulmonary vein lesions and another lesion connecting the left pulmonary veins to the mitral annulus. Patients treated with ablation were more likely to be in sinus rhythm at hospital discharge (63 versus 18 percent in the control group) and at one year (81 versus 11 percent). A second study of 70 patients with either chronic or paroxysmal atrial fibrillation (AF) used minimally invasive surgical techniques with linear radiofrequency ablation to create a series of linear ablations around the orifices of the pulmonary veins in the left atrium [31]. During this procedure, the left atrium was accessed through small incisions in the chest (minimally invasive) and the patient was on femoro-femoral cardiopulmonary bypass. The mean intraoperative time was two hours, much shorter than with either the Maze procedure or catheter-based ablation techniques described below. At a mean follow-up of 1.5 years, AF was eliminated in 90 percent of patients. Epicardial procedures A minimally invasive approach using thoracoscopic pulmonary vein (and ganglionated plexi) isolation and ablation has been used to treat patients who have failed or are not candidates for antiarrhythmic drug therapy or catheter-based pulmonary vein catheter ablation (CA) [32-34]. However, we do not use this approach as the first interventional strategy. As a stand-alone procedure, these approaches are limited to pulmonary vein isolation, either as a box or islands around each side. An endocardial approach is necessary to connect any lesion to either the mitral or tricuspid valves. (See "Atrial fibrillation: Catheter ablation".) This procedure is performed with video-assisted thorascopic access to the epicardial space through small, either right-sided or bilateral thoracic incisions and primarily focuses on pulmonary vein isolation. The pulmonary veins are electrically isolated with a bipolar radiofrequency ablation clamp or suction-assisted unidirectional device. Depending on the center, additional ablation of ganglia or the left atrium are also performed epicardially. Individuals are not placed on bypass and linear epicardial lesions are delivered to the pulmonary veins. This technique can be used in a stand-alone fashion or in conjunction with an endocardial approach (see 'Hybrid approach' below). Complications of the traditional endocardial approach to catheter ablation, such as damage to the phrenic nerve and the development of thromboembolism, occur but may be less frequent through an epicardial ablation. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 6/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate The 2020 CASA-AF trial randomly assigned 120 patients with long-standing persistent atrial fibrillation (AF) to thoracoscopic surgical or catheter ablation [35]. The primary outcome of single-procedure freedom from AF/atrial tachycardia 30 seconds without antiarrhythmic drugs at 12 months occurred at a similar rate in both groups (26 versus 28 percent, respectively; odds ratio 1.13, 95% CI 0.46-2.83). One death was reported in the surgical ablation group, and over 12 months it was more expensive and provided fewer quality-adjusted life-years compared with catheter ablation (0.78 versus 0.85; p = 0.02). The FAST trial randomly assigned 124 patients with antiarrhythmic drug-refractory AF with left atrial dilatation and hypertension (33 percent) or failed prior CA (67 percent) to either minimally invasive surgical ablation or CA [36]. At 12 months, the primary end point of freedom from left atrial arrhythmia of greater than 30 seconds without antiarrhythmic drugs was significantly higher in the surgical ablation group (65.6 versus 36.5 percent). However, there were significantly more periprocedural complications, such as pneumothorax, major bleeding, and the need for pacemaker, in the surgical ablation group (35.4 versus 15.9 percent). The need for pacemaker placement was 3 percent after surgery and 0 percent after catheter ablation. Hybrid approach Surgeons and cardiologists are now combining to perform some of the lesions surgically and some in the electrophysiology lab or operating room in a "hybrid" approach. There are three different types of approaches: right thoracotomy [37], subxyphoid [38], and bilateral thoracoscopic [39]. The convergent procedure is a subxyphoid approach that requires both surgery and catheter ablation in a single hospitalization to complete. Long-term follow-up is needed. Both the right and bilateral thoracoscopic approaches allow for a staged or concomitant approach. The right thoracotomy uses unipolar suction-assisted radiofrequency ablation. The bilateral uses bipolar radiofrequency ablation clamps and is the only approach that allows for treatment of the left atrial appendage. Although initially a simultaneous or single-stage approach predominated, there has been a trend toward a staged approach, performing the electrophysiology portion only in the patients that fail initial surgery. In a small single-center series, the staged, bilateral approach has been demonstrated to be as efficacious as a "cut-and-sew" open Maze, but none of the reports is large enough to make definitive recommendations for any of these procedures. However, they do offer the potential for improving the success of treatment in challenging patients without the full extent of surgery or its complications. They may be considered in medically refractory AF patients who are unlikely to be successfully treated with catheter ablation alone. Comparison of methods The relative efficacy and safety of the different procedures has not been well studied. There are no large randomized trials, and available observational data are https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 7/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate inconsistent, as illustrated by the following: In a review of 70 patients, 40 underwent radiofrequency (RF) ablation and 30 underwent the surgical Maze procedure [40]. Those undergoing RF ablation and those undergoing the surgical Maze had similar rates of sinus rhythm at discharge (85 versus 73 percent) and at one year (91 versus 96 percent). A series of 56 patients who underwent RF ablation during surgery were compared with 56 matched historical controls [41]. Patients treated with the conventional surgical Maze were more likely than those treated with RF to be in sinus rhythm at discharge (88 versus 63 percent) and at last follow-up (92 versus 62 percent). In a series of 377 patients from a single institution, 220 underwent a surgical Maze procedure, and the remaining 157 were treated with RF ablation during surgery [42]. Patients treated with the conventional surgical procedure were more likely than those treated with RF to be in sinus rhythm at three months (91 versus 62 percent) and at six months (90 versus 75 percent). However, these results should be interpreted with caution for the following reasons: Each cohort included a heterogeneous mix of patients undergoing different surgeries with a variety of underlying cardiac disease and comorbidities. The RF procedures were not standardized, and in most cases, documentation of effective RF lesions was not performed. In percutaneous ablation procedures, documentation that ablation produces conduction block is an important predictor of success. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) INDICATIONS We believe it is reasonable to attempt to surgically ablate atrial fibrillation (AF) in carefully selected patients with a high burden of AF. Most of these patients will have been referred for cardiac surgery for another reason, such as significant valvular or coronary heart disease. It is uncommon for patients without an indication for open heart surgery to be referred for a surgical ablative procedure. We believe it is reasonable to perform concurrent surgical ablation at the time of mitral valve surgery in patients with a high burden of AF, including those with paroxysmal or persistent AF [2]. In patients undergoing mitral valve surgery, most often for mitral regurgitation, 30 to 50 percent have AF [14,43]. Most studies of the surgical treatment of AF have enrolled patients https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 8/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate undergoing mitral valve surgery, with the PRAGUE-12 randomized study being one exception [44]. The procedure should be performed only when it does not add significant additional surgical risk. Patients with prior cardiac surgery or those who cannot tolerate single lung ventilation are less than ideal candidates. In patients who have failed or are intolerant to antiarrhythmic drug therapy, have failed catheter ablation in the electrophysiology laboratory, and in whom a minimally invasive approach is feasible, it is reasonable to attempt this procedure [45]. (See 'Minimally invasive approach' above.) EFFICACY In most published series that compared patients undergoing surgical treatment of atrial fibrillation (AF) with those not, the burden of AF was lower with surgical treatment. This generally leads to improved quality of life and a lower use of antiarrhythmic drug therapy. Similar to patients undergoing traditional catheter ablation, there is no evidence that survival is improved [13,44,46]. The best evidence of long-term outcomes comparing ablation with no ablation during mitral valve surgery comes from a study of 260 patients with persistent or long-standing persistent AF who were randomly assigned to either surgical ablation or no ablation during the surgery [13]. Patients who were assigned to ablation received either pulmonary vein isolation or a biatrial Maze procedure. All patients underwent closure of the left atrial appendage. The primary end point of freedom from AF at both 6 and 12 months, as assessed by three-day continuous monitoring, occurred more often with ablation (63.2 versus 29.4 percent; p<0.001). There was no significant difference between the two ablation procedures for this outcome. Mortality was 6.8 percent in the ablation group and 8.7 percent in the no ablation group (hazard ratio 0.76, 95% CI 0.32-1.84). There was no significant difference in the rate of a composite secondary outcome that included cardiac or cerebrovascular adverse events, nor were there differences in the end points of functional class, quality-of-life measures, and medication use. However, the rate of implantation of a permanent pacemaker was higher with ablation (21.5 versus 8.1 per 100 patient-years; p = 0.01). Individual patient factors, such as symptom status, should determine whether AF ablation is performed in this setting. It is possible that the restoration of sinus rhythm might lead to improved clinical outcomes with longer follow-up in this relatively small study. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) A number of observational studies have demonstrated that performing a combined procedure with either "cut and sew" Maze [47-52] or catheter ablation [20,30,53-56] leads to a 60 to 80 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 9/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate percent likelihood of freedom from AF at one year. In an observational study of 576 patients who underwent the Cox-Maze IV procedure, overall freedom from AF was 78 percent at five years and freedom from AF off antiarrhythmic drugs was 66 percent [2]. In this study, there was no difference between those with paroxysmal and those with persistent/longstanding AF. The freedom from AF after surgery in single-center series has been reported to be as high as 92, 84, and 77 percent at 1, 5, and 10 years, respectively [57]. TREATMENT FAILURES Surgical approaches to prevent atrial fibrillation (AF) have a high rate of success (see 'Maze procedure' above). However, some patients have recurrent atrial arrhythmias including AF, typical flutter, atypical atrial flutter (often due to reentrant circuits around the surgical scars), and focal atrial tachycardias [58]. Such patients may be candidates for electrophysiology study and catheter ablation. (See "Atrial fibrillation: Catheter ablation", section on 'Management of recurrence' and "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) ANTICOAGULATION First two to three months All patients are anticoagulated with a direct oral anticoagulant (DOAC) or vitamin K antagonist (VKA) for at least two months after surgical ablation, regardless of their CHA DS -VASc score or rhythm status. 2 2 Subsequent anticoagulation decisions In patients who are at risk for stroke, anticoagulation therapy should be continued indefinitely after surgical ablation procedure regardless of the rhythm outcome [59]. Since surgical ablation to prevent AF can restore sinus rhythm long term, some have suggested that it may also reduce stroke risk and therefore the need for long-term anticoagulation, but there is no convincing evidence to support this approach. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Identifying patients at risk for stroke Identifying which patients are at risk for stroke and require long-term anticoagulation is not different in patients who have undergone surgical ablation. This is discussed separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".). There is limited information regarding the validity of the CHADS2 stroke score in predicting stroke risk in surgical ablation patients. Observational studies suggest overall low stroke rates following surgical ablation [60-63]. In a Swedish cohort study, 526 patients had a Cox- maze III procedure, including left atrial appendage excision, and were followed for https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 10/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate development of stroke/transient ischemic attack (TIA) [63]. A total of 29 patients had any stroke or TIA. There were 6 intracerebral bleeds, 4 perioperative strokes, 13 ischemic strokes, and six TIAs. The mean onset of postoperative stroke/TIAs was at seven years (incidence of 0.36 percent, 19 events per 5231 patient-years). In all CHADS2 groups, observed ischemic stroke/TIA rates were lower than predicted. Importantly, CHADS2 scores of 2 or greater were associated with increased risk of developing stroke compared with patients with lower scores (hazard ratio [HR] 2.15, 95% CI 0.87-5.32). However, in a separate study of 691 patients who underwent a surgical ablation, CHADS2 did not predict stroke but was related to increased bleeding [64]. Anticoagulant administration As for other patients with AF, a DOAC is generally preferred. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.) Patients who are treated with VKA (eg, those with a mechanical valve) who have a subtherapeutic international normalized ratio after the procedure are treated with early bridging anticoagulation with heparin (intravenous unfractionated heparin or low molecular weight heparin). Outcomes with surgical left atrial appendage occlusion (with or without a Maze procedure) are discussed further separately. (See "Atrial fibrillation: Left atrial appendage occlusion".) RECOMMENDATIONS OF OTHERS The Society of Thoracic Surgeons 2017 clinical practice guideline for the surgical treatment of atrial fibrillation (AF) makes the following strong recommendations [65]: Surgical ablation for AF is recommended at the time of concomitant isolated aortic valve replacement, isolated coronary artery bypass graft surgery (CABG), and aortic valve replacement plus CABG to restore sinus rhythm. Surgical ablation for AF is recommended at the time of concomitant mitral operations to restore sinus rhythm. Stand-alone surgical ablation for symptomatic AF without structural heart disease is reasonable in patients who have failed a class I or III antiarrhythmic medication or catheter-based therapy. The following recommendations were made in the Heart Rhythm Society/European Heart Rhythm Association/European Cardiac Arrhythmia Society/Asia Pacific Heart Rhythm https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 11/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Society/Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulaci n Card aca y Electrofisiolog a) expert consensus statement on catheter and surgical ablation of atrial fibrillation [66]: Surgical ablation for AF is recommended at the time of concomitant isolated aortic valve replacement, isolated CABG, and aortic valve replacement plus CABG to restore sinus rhythm if the patient is symptomatic and refractory or intolerant to one class I or III antiarrhythmic medication. Surgical ablation for AF is recommended at the time of concomitant mitral operations to restore sinus rhythm for all symptomatic AF patients. Stand-alone surgical ablation is reasonable for persistent and long-standing patients who have failed one or more attempts at catheter ablation who prefer a surgical approach after review of safety and efficacy of options. For paroxysmal AF, it may also be considered after one or more catheter attempts. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 12/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate SUMMARY AND RECOMMENDATIONS Several surgical techniques have been developed for the control of refractory atrial fibrillation (AF) and maintenance of sinus rhythm. In most patients, these techniques are employed as adjunctive therapy in patients undergoing other cardiac surgery for some other reason, such as mitral valve or coronary artery bypass surgery. (See 'Indications' above.) These surgical procedures appear effective at eliminating or reducing the frequency of AF in a high percentage of patients. (See 'Maze procedure' above and 'Endocardial surgical ablation' above.) After surgical ablation, we continue anticoagulation in patients at high risk for stroke. For all others, we often discontinue anticoagulation two to three months after successful restoration of sinus rhythm and particularly in patients at high risk for bleeding. Patients in persistent AF should receive continued anticoagulation. This practice applies only to patients who have had the left atrial appendage removed or ligated. Patients with recurrent AF after one of these procedures may be candidates for electrophysiology study and catheter ablation. (See 'Treatment failures' above and "Atrial fibrillation: Catheter ablation".) ACKNOWLEDGMENT The UpToDate editorial staff thank Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ferguson TB Jr, Cox JL. Surgery for atrial fibrillation. In: Cardiac Electrophysiology: From Cell to Bedside, 2nd ed, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 1995. p.1567. 2. Henn MC, Lancaster TS, Miller JR, et al. Late outcomes after the Cox maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2015; 150:1168. 3. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 13/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991; 101:406. 4. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. J Thorac Cardiovasc Surg 1991; 101:584. 5. Cox JL, Boineau JP, Schuessler RB, et al. Electrophysiologic basis, surgical development, and clinical results of the maze procedure for atrial flutter and atrial fibrillation. Adv Card Surg 1995; 6:1. 6. Cox JL, Boineau JP, Schuessler RB, et al. Five-year experience with the maze procedure for atrial fibrillation. Ann Thorac Surg 1993; 56:814. 7. Kosakai Y, Kawaguchi AT, Isobe F, et al. Modified maze procedure for patients with atrial fibrillation undergoing simultaneous open heart surgery. Circulation 1995; 92:II359. 8. L nnerholm S, Blomstr m P, Nilsson L, et al. Effects of the maze operation on health-related quality of life in patients with atrial fibrillation. Circulation 2000; 101:2607. 9. Cox JL, Jaquiss RD, Schuessler RB, Boineau JP. Modification of the maze procedure for atrial flutter and atrial fibrillation. II. Surgical technique of the maze III procedure. J Thorac Cardiovasc Surg 1995; 110:485. 10. Barnett SD, Ad N. Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg 2006; 131:1029. 11. Grady KL, Lee R, Suba ius H, et al. Improvements in health-related quality of life before and after isolated cardiac operations. Ann Thorac Surg 2011; 91:777. 12. Ad N, Henry L, Hunt S, Holmes SD. Do we increase the operative risk by adding the Cox Maze III procedure to aortic valve replacement and coronary artery bypass surgery? J Thorac Cardiovasc Surg 2012; 143:936. 13. Gillinov AM, Gelijns AC, Parides MK, et al. Surgical ablation of atrial fibrillation during mitral- valve surgery. N Engl J Med 2015; 372:1399. 14. Lee R, McCarthy PM, Wang EC, et al. Midterm survival in patients treated for atrial fibrillation: a propensity-matched comparison to patients without a history of atrial fibrillation. J Thorac Cardiovasc Surg 2012; 143:1341. 15. Musharbash FN, Schill MR, Sinn LA, et al. Performance of the Cox-maze IV procedure is associated with improved long-term survival in patients with atrial fibrillation undergoing cardiac surgery. J Thorac Cardiovasc Surg 2018; 155:159. 16. Nitta T, Lee R, Watanabe H, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling. Ann Thorac Surg 1999; 67:36. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 14/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate 17. Nitta T, Lee R, Schuessler RB, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation I. Concept, anatomic and physiologic bases and development of a procedure. Ann Thorac Surg 1999; 67:27. 18. Soni LK, Cedola SR, Cogan J, et al. Right atrial lesions do not improve the efficacy of a complete left atrial lesion set in the surgical treatment of atrial fibrillation, but they do increase procedural morbidity. J Thorac Cardiovasc Surg 2013; 145:356. 19. Phan K, Xie A, Tsai YC, et al. Biatrial ablation vs. left atrial concomitant surgical ablation for treatment of atrial fibrillation: a meta-analysis. Europace 2015; 17:38. 20. Melo J, Santiago T, Aguiar C, et al. Surgery for atrial fibrillation in patients with mitral valve disease: results at five years from the International Registry of Atrial Fibrillation Surgery. J Thorac Cardiovasc Surg 2008; 135:863. 21. Nitta T, Ishii Y, Ogasawara H, et al. Initial experience with the radial incision approach for atrial fibrillation. Ann Thorac Surg 1999; 68:805. 22. Ad N, Henry L, Friehling T, et al. Minimally invasive stand-alone Cox-maze procedure for patients with nonparoxysmal atrial fibrillation. Ann Thorac Surg 2013; 96:792. 23. Moten SC, Rodriguez E, Cook RC, et al. New ablation techniques for atrial fibrillation and the minimally invasive cryo-maze procedure in patients with lone atrial fibrillation. Heart Lung Circ 2007; 16 Suppl 3:S88.
have failed one or more attempts at catheter ablation who prefer a surgical approach after review of safety and efficacy of options. For paroxysmal AF, it may also be considered after one or more catheter attempts. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 12/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate SUMMARY AND RECOMMENDATIONS Several surgical techniques have been developed for the control of refractory atrial fibrillation (AF) and maintenance of sinus rhythm. In most patients, these techniques are employed as adjunctive therapy in patients undergoing other cardiac surgery for some other reason, such as mitral valve or coronary artery bypass surgery. (See 'Indications' above.) These surgical procedures appear effective at eliminating or reducing the frequency of AF in a high percentage of patients. (See 'Maze procedure' above and 'Endocardial surgical ablation' above.) After surgical ablation, we continue anticoagulation in patients at high risk for stroke. For all others, we often discontinue anticoagulation two to three months after successful restoration of sinus rhythm and particularly in patients at high risk for bleeding. Patients in persistent AF should receive continued anticoagulation. This practice applies only to patients who have had the left atrial appendage removed or ligated. Patients with recurrent AF after one of these procedures may be candidates for electrophysiology study and catheter ablation. (See 'Treatment failures' above and "Atrial fibrillation: Catheter ablation".) ACKNOWLEDGMENT The UpToDate editorial staff thank Alan Cheng, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Ferguson TB Jr, Cox JL. Surgery for atrial fibrillation. In: Cardiac Electrophysiology: From Cell to Bedside, 2nd ed, Zipes DP, Jalife J (Eds), Saunders, Philadelphia 1995. p.1567. 2. Henn MC, Lancaster TS, Miller JR, et al. Late outcomes after the Cox maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2015; 150:1168. 3. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 13/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 1991; 101:406. 4. Cox JL. The surgical treatment of atrial fibrillation. IV. Surgical technique. J Thorac Cardiovasc Surg 1991; 101:584. 5. Cox JL, Boineau JP, Schuessler RB, et al. Electrophysiologic basis, surgical development, and clinical results of the maze procedure for atrial flutter and atrial fibrillation. Adv Card Surg 1995; 6:1. 6. Cox JL, Boineau JP, Schuessler RB, et al. Five-year experience with the maze procedure for atrial fibrillation. Ann Thorac Surg 1993; 56:814. 7. Kosakai Y, Kawaguchi AT, Isobe F, et al. Modified maze procedure for patients with atrial fibrillation undergoing simultaneous open heart surgery. Circulation 1995; 92:II359. 8. L nnerholm S, Blomstr m P, Nilsson L, et al. Effects of the maze operation on health-related quality of life in patients with atrial fibrillation. Circulation 2000; 101:2607. 9. Cox JL, Jaquiss RD, Schuessler RB, Boineau JP. Modification of the maze procedure for atrial flutter and atrial fibrillation. II. Surgical technique of the maze III procedure. J Thorac Cardiovasc Surg 1995; 110:485. 10. Barnett SD, Ad N. Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg 2006; 131:1029. 11. Grady KL, Lee R, Suba ius H, et al. Improvements in health-related quality of life before and after isolated cardiac operations. Ann Thorac Surg 2011; 91:777. 12. Ad N, Henry L, Hunt S, Holmes SD. Do we increase the operative risk by adding the Cox Maze III procedure to aortic valve replacement and coronary artery bypass surgery? J Thorac Cardiovasc Surg 2012; 143:936. 13. Gillinov AM, Gelijns AC, Parides MK, et al. Surgical ablation of atrial fibrillation during mitral- valve surgery. N Engl J Med 2015; 372:1399. 14. Lee R, McCarthy PM, Wang EC, et al. Midterm survival in patients treated for atrial fibrillation: a propensity-matched comparison to patients without a history of atrial fibrillation. J Thorac Cardiovasc Surg 2012; 143:1341. 15. Musharbash FN, Schill MR, Sinn LA, et al. Performance of the Cox-maze IV procedure is associated with improved long-term survival in patients with atrial fibrillation undergoing cardiac surgery. J Thorac Cardiovasc Surg 2018; 155:159. 16. Nitta T, Lee R, Watanabe H, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling. Ann Thorac Surg 1999; 67:36. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 14/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate 17. Nitta T, Lee R, Schuessler RB, et al. Radial approach: a new concept in surgical treatment for atrial fibrillation I. Concept, anatomic and physiologic bases and development of a procedure. Ann Thorac Surg 1999; 67:27. 18. Soni LK, Cedola SR, Cogan J, et al. Right atrial lesions do not improve the efficacy of a complete left atrial lesion set in the surgical treatment of atrial fibrillation, but they do increase procedural morbidity. J Thorac Cardiovasc Surg 2013; 145:356. 19. Phan K, Xie A, Tsai YC, et al. Biatrial ablation vs. left atrial concomitant surgical ablation for treatment of atrial fibrillation: a meta-analysis. Europace 2015; 17:38. 20. Melo J, Santiago T, Aguiar C, et al. Surgery for atrial fibrillation in patients with mitral valve disease: results at five years from the International Registry of Atrial Fibrillation Surgery. J Thorac Cardiovasc Surg 2008; 135:863. 21. Nitta T, Ishii Y, Ogasawara H, et al. Initial experience with the radial incision approach for atrial fibrillation. Ann Thorac Surg 1999; 68:805. 22. Ad N, Henry L, Friehling T, et al. Minimally invasive stand-alone Cox-maze procedure for patients with nonparoxysmal atrial fibrillation. Ann Thorac Surg 2013; 96:792. 23. Moten SC, Rodriguez E, Cook RC, et al. New ablation techniques for atrial fibrillation and the minimally invasive cryo-maze procedure in patients with lone atrial fibrillation. Heart Lung Circ 2007; 16 Suppl 3:S88. 24. Sandoval N, Velasco VM, Orjuela H, et al. Concomitant mitral valve or atrial septal defect surgery and the modified Cox-maze procedure. Am J Cardiol 1996; 77:591. 25. Buber J, Luria D, Sternik L, et al. Left atrial contractile function following a successful modified Maze procedure at surgery and the risk for subsequent thromboembolic stroke. J Am Coll Cardiol 2011; 58:1614. 26. Albirini A, Scalia GM, Murray RD, et al. Left and right atrial transport function after the Maze procedure for atrial fibrillation: an echocardiographic Doppler follow-up study. J Am Soc Echocardiogr 1997; 10:937. 27. Pasic M, Musci M, Siniawski H, et al. The Cox maze iii procedure: parallel normalization of sinus node dysfunction, improvement of atrial function, and recovery of the cardiac autonomic nervous system. J Thorac Cardiovasc Surg 1999; 118:287. 28. Pasic M, Musci M, Siniawski H, et al. Transient sinus node dysfunction after the Cox-maze III procedure in patients with organic heart disease and chronic fixed atrial fibrillation. J Am Coll Cardiol 1998; 32:1040. 29. Izumoto H, Kawazoe K, Kitahara H, Kamata J. Operative results after the Cox/maze procedure combined with a mitral valve operation. Ann Thorac Surg 1998; 66:800. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 15/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate 30. Mantovan R, Raviele A, Buja G, et al. Left atrial radiofrequency ablation during cardiac surgery in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2003; 14:1289. 31. Kottkamp H, Hindricks G, Autschbach R, et al. Specific linear left atrial lesions in atrial fibrillation: intraoperative radiofrequency ablation using minimally invasive surgical techniques. J Am Coll Cardiol 2002; 40:475. 32. Krul SP, Driessen AH, van Boven WJ, et al. Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgical-electrophysiological approach for atrial fibrillation. Circ Arrhythm Electrophysiol 2011; 4:262. 33. Edgerton JR, Brinkman WT, Weaver T, et al. Pulmonary vein isolation and autonomic denervation for the management of paroxysmal atrial fibrillation by a minimally invasive surgical approach. J Thorac Cardiovasc Surg 2010; 140:823. 34. Beyer E, Lee R, Lam BK. Point: Minimally invasive bipolar radiofrequency ablation of lone atrial fibrillation: early multicenter results. J Thorac Cardiovasc Surg 2009; 137:521. 35. Haldar S, Khan HR, Boyalla V, et al. Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial. Eur Heart J 2020; 41:4471. 36. Boersma LV, Castella M, van Boven W, et al. Atrial fibrillation catheter ablation versus surgical ablation treatment (FAST): a 2-center randomized clinical trial. Circulation 2012; 125:23. 37. Muneretto C, Bisleri G, Bontempi L, et al. Successful treatment of lone persistent atrial fibrillation by means of a hybrid thoracoscopic-transcatheter approach. Innovations (Phila) 2012; 7:254. 38. Kiser AC, Landers MD, Boyce K, et al. Simultaneous catheter and epicardial ablations enable a comprehensive atrial fibrillation procedure. Innovations (Phila) 2011; 6:243. 39. Lee R, McCarthy PM, Passman RS, et al. Surgical treatment for isolated atrial fibrillation: minimally invasive vs. classic cut and sew maze. Innovations (Phila) 2011; 6:373. 40. Chiappini B, Mart n-Su rez S, LoForte A, et al. Cox/Maze III operation versus radiofrequency ablation for the surgical treatment of atrial fibrillation: a comparative study. Ann Thorac Surg 2004; 77:87. 41. Stulak JM, Dearani JA, Sundt TM 3rd, et al. Superiority of cut-and-sew technique for the Cox maze procedure: comparison with radiofrequency ablation. J Thorac Cardiovasc Surg 2007; 133:1022. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 16/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate 42. Doty JR, Doty DB, Jones KW, et al. Comparison of standard Maze III and radiofrequency Maze operations for treatment of atrial fibrillation. J Thorac Cardiovasc Surg 2007; 133:1037. 43. Gillinov AM, Saltman AE. Ablation of atrial fibrillation with concomitant cardiac surgery. Semin Thorac Cardiovasc Surg 2007; 19:25. 44. Budera P, Straka Z, Osman k P, et al. Comparison of cardiac surgery with left atrial surgical ablation vs. cardiac surgery without atrial ablation in patients with coronary and/or valvular heart disease plus atrial fibrillation: final results of the PRAGUE-12 randomized multicentre study. Eur Heart J 2012; 33:2644. 45. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012; 14:528. 46. Abo-Salem E, Lockwood D, Boersma L, et al. Surgical Treatment of Atrial Fibrillation. J Cardiovasc Electrophysiol 2015; 26:1027. 47. Sueda T, Imai K, Ishii O, et al. Efficacy of pulmonary vein isolation for the elimination of chronic atrial fibrillation in cardiac valvular surgery. Ann Thorac Surg 2001; 71:1189. 48. de Lima GG, Kalil RA, Leiria TL, et al. Randomized study of surgery for patients with permanent atrial fibrillation as a result of mitral valve disease. Ann Thorac Surg 2004; 77:2089. 49. Yuda S, Nakatani S, Kosakai Y, et al. Long-term follow-up of atrial contraction after the maze procedure in patients with mitral valve disease. J Am Coll Cardiol 2001; 37:1622. 50. Kim KB, Cho KR, Sohn DW, et al. The Cox-Maze III procedure for atrial fibrillation associated with rheumatic mitral valve disease. Ann Thorac Surg 1999; 68:799. 51. Handa N, Schaff HV, Morris JJ, et al. Outcome of valve repair and the Cox maze procedure for mitral regurgitation and associated atrial fibrillation. J Thorac Cardiovasc Surg 1999; 118:628. 52. Fujita T, Kobayashi J, Toda K, et al. Long-term outcome of combined valve repair and maze procedure for nonrheumatic mitral regurgitation. J Thorac Cardiovasc Surg 2010; 140:1332. 53. Deneke T, Khargi K, Grewe PH, et al. Left atrial versus bi-atrial Maze operation using intraoperatively cooled-tip radiofrequency ablation in patients undergoing open-heart surgery: safety and efficacy. J Am Coll Cardiol 2002; 39:1644. 54. Sie HT, Beukema WP, Elvan A, Ramdat Misier AR. Long-term results of irrigated radiofrequency modified maze procedure in 200 patients with concomitant cardiac surgery: six years experience. Ann Thorac Surg 2004; 77:512. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 17/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate 55. Gaita F, Riccardi R, Caponi D, et al. Linear cryoablation of the left atrium versus pulmonary vein cryoisolation in patients with permanent atrial fibrillation and valvular heart disease: correlation of electroanatomic mapping and long-term clinical results. Circulation 2005; 111:136. 56. Deneke T, Khargi K, Grewe PH, et al. Efficacy of an additional MAZE procedure using cooled- tip radiofrequency ablation in patients with chronic atrial fibrillation and mitral valve disease. A randomized, prospective trial. Eur Heart J 2002; 23:558. 57. Khiabani AJ, MacGregor RM, Bakir NH, et al. The long-term outcomes and durability of the Cox-Maze IV procedure for atrial fibrillation. J Thorac Cardiovasc Surg 2022; 163:629. 58. McElderry HT, McGiffin DC, Plumb VJ, et al. Proarrhythmic aspects of atrial fibrillation surgery: mechanisms of postoperative macroreentrant tachycardias. Circulation 2008; 117:155. 59. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 60. McCarthy PM, Gillinov AM, Castle L, et al. The Cox-Maze procedure: the Cleveland Clinic experience. Semin Thorac Cardiovasc Surg 2000; 12:25. 61. Lapenna E, De Bonis M, Giambuzzi I, et al. Long-term Outcomes of Stand-Alone Maze IV for Persistent or Long-standing Persistent Atrial Fibrillation. Ann Thorac Surg 2020; 109:124. 62. Alb ge A, Jid us L, St hle E, et al. Early and long-term mortality in 536 patients after theCox- maze III procedure: a national registry-based study. Ann Thorac Surg 2013; 95:1626. 63. Alb ge A, Sartipy U, Kenneb ck G, et al. Long-Term Risk of Ischemic Stroke After the Cox- Maze III Procedure for Atrial Fibrillation. Ann Thorac Surg 2017; 104:523. 64. Ad N, Henry L, Shuman DJ, Holmes SD. A more specific anticoagulation regimen is required for patients after the cox-maze procedure. Ann Thorac Surg 2014; 98:1331. 65. Badhwar V, Rankin JS, Damiano RJ Jr, et al. The Society of Thoracic Surgeons 2017 Clinical Practice Guidelines for the Surgical Treatment of Atrial Fibrillation. Ann Thorac Surg 2017; 103:329. 66. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 18/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Topic 1046 Version 36.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 19/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate GRAPHICS MAZE III procedure Modification of the posterior incisions to the vena cava and placement of the septal incision posterior to the orifice of the superior vena cava (SVC) are noted. CS: coronary sinus; FO: foramen ovale; IVC: inferior vena cava; LAA: left atrial appendage; MV: mitral valve; RAA: right atrial appendage; SAN: sinoatrial node; TV: tricuspid valve. Reproduced from: Cheng A, Shah A, Hogue CW. Cardiac electrophysiology: Diagnosis and treatment. In: Kaplan's Cardiac Anesthesia, 6th ed, Kaplan JA, Reich DL, Lake CL, Konstadt SN (Eds), Saunders, Philadelphia 2011. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 58985 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 20/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Schema of the maze procedure and the radial approach for atrial fibrillation The large outer circle denotes the atria and its outer limit is bounded by the atrioventricular annular margins. The small circle indicates the sinoatrial node (SAN), the shaded area indicates the isolated portion of the atrium, and the atrial coronary arteries, arising at the atrioventricular groove, are also schematically drawn. Arrows indicate the activation wavefront from the sinoatrial node, radiating toward the annular margins. The radial approach (right panel) preserves a more physiologic activation sequence and the blood supply to most atrial segments, whereas the atrial incisions of the maze procedure (left panel) desynchronize the activation sequence, and some of the incisions cross the atrial coronary arteries. Reprinted with permission from the Society of Thoracic Surgeons. Netta T, Cox R, Schuessler RB, et al. Ann Thorac Surg 1999; 67:27. http://www.elsevier.com/locate/jacc http://www.sciencedirect.com Graphic 69962 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 21/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Schematic representation of atrial activation in sinus rhythm and after the maze procedure or the radial approach The normal activation sequence of the left atrium is maintained with the radial approach while it is altered with the Maze procedure. Thick lines represent the surgical incisions and the solid areas represent parts of the atria surgically isolated or excised; dashed lines represent normal conduction pathways between the atrial appendages, the interatrial septum, and the crista terminalis. Arrows indicate the activation sequence. AVN: atrioventricular node; SAN: sinoatrial node; RAA: right atrial appendage; LAA: left atrial appendage; SVC: superior vena cava; IVC: inferior vena cava; PVs: pulmonary veins. Reprinted with permission from the Society of Thoracic Surgeons. Netta T, Cox R, Schuessler RB, et al. Ann Thorac Surg 1999; 67:27. Graphic 50845 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 22/23 7/5/23, 9:12 AM Atrial fibrillation: Surgical ablation - UpToDate Contributor Disclosures Richard Lee, MD, MBA No relevant financial relationship(s) with ineligible companies to disclose. Gabriel S Aldea, MD No relevant financial relationship(s) with ineligible companies to disclose. Edward Verrier, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-surgical-ablation/print 23/23
7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cardiac resynchronization therapy in atrial fibrillation : E Kevin Heist, MD, PhD : Frederick Masoudi, MD, MSPH, FACC, FAHA, Bradley P Knight, MD, FACC : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 09, 2022. INTRODUCTION In patients with ventricular dyssynchrony due to intrinsic conduction disease or permanent right ventricular pacing, cardiac resynchronization therapy (CRT) with biventricular pacing can improve ventricular synchrony. This is accomplished with an additional pacemaker lead, typically implanted lateral to the left ventricle via a coronary vein. Among selected patients with heart failure (HF) who are in sinus rhythm, CRT improves cardiac performance, symptoms, and overall survival. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) In patients who are in sinus rhythm, the pacing mode during CRT is programmed to an atrial tracking mode such as DDD(R) or VDD(R) with an atrioventricular (AV) delay short enough to coordinate depolarization of the ventricles with pacing. However, in patients with atrial fibrillation (AF), atrial tracking is not possible, so other pacing modes are required. AF is common in patients with HF, with a prevalence ranging from 5 percent in patients with New York Heart Association (NYHA) functional class I HF to 40 percent in patients with NYHA class IV HF ( table 1) [1]. (See 'Practical considerations' below.) The use of CRT in patients with AF will be reviewed here. The general use of CRT in patients in sinus rhythm and the rationale for and mechanisms of benefit of CRT are discussed further separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT'.) https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 1/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate RATIONALE AND MECHANISM OF BENEFIT Hemodynamic benefit CRT is useful to restore intra- and interventricular synchrony when ventricular contraction is dyssynchronous due to intrinsic conduction disease (typically manifest as a broad QRS complex, often with left bundle branch block), or ventricular pacing. The rationale and theoretical mechanism of benefit of CRT in patients with AF is similar to that in patients with sinus or atrial-paced rhythm. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT' and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Mechanisms of benefit'.) There are sufficient data to evaluate the role of CRT in patients with AF, as discussed below, although most major clinical trials evaluating the benefit of CRT have been performed predominantly or exclusively in patients in sinus or atrial-paced rhythms. (See 'Cardiac resynchronization therapy outcomes in patients with atrial fibrillation' below.) Effect of cardiac resynchronization therapy on atrial fibrillation CRT is not indicated to reduce the burden of AF [2]. Although CRT has a favorable impact on potential risk factors for AF such as neurohormonal activation, left ventricular systolic dysfunction, atrial size, and degree of mitral regurgitation [3-6], CRT has not been shown to decrease the incidence of new or recurrent AF in clinical trials. Although AF was not a prespecified endpoint of the large randomized trials, CRT was not observed to decrease the incidence of AF [7,8]. However, some patients with AF that is considered "permanent" may convert to sinus rhythm after placement of CRT devices, with factors predictive of a higher conversion rate including smaller left ventricular diastolic dimension, narrower post-CRT QRS complex, smaller left atrial size, and AV nodal ablation [9]. Some observational studies suggested an association between CRT and reduced AF burden [10,11]. CLINICAL SETTINGS FOR USE Among patients with chronic AF, CRT may be considered in three overlapping clinical settings: AV block due to conduction system disease, following AV node ablation, and systolic HF with evidence of ventricular dyssynchrony (based on QRS width and morphology). Atrioventricular block Among patients requiring pacemaker therapy for AV block caused by conduction system disease, CRT may ameliorate the negative effects of dyssynchrony induced by right ventricular (RV) pacing alone. Evidence supporting this approach in patients with AF or sinus rhythm is discussed below. This clinical setting overlaps with the HF setting since the study https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 2/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate population included patients with AV block and concomitant HF with reduced systolic function. (See 'Patients requiring a pacemaker for atrioventricular block' below.) Atrioventricular node ablation Among patients with AF treated with AV node ablation to achieve definitive rate control, CRT may ameliorate the negative effects of dyssynchrony induced by RV pacing alone. This clinical setting overlaps with the HF setting since patients with HF and/or left ventricular (LV) systolic dysfunction may be most likely to benefit from CRT following AV node ablation. (See 'Following AV node ablation' below.) The most common nonpharmacologic approach to ventricular rate control in AF is catheter- based radiofrequency ablation of the AV node and/or the His bundle with subsequent electronic pacing. Because the procedure is invasive and results in pacemaker dependency, it is generally reserved for patients in whom pharmacologic rate control therapy is unsuccessful. The majority of well-selected patients for AV node ablation to address inadequate rate control in AF improve hemodynamically following AV node ablation and standard RV pacing. However, RV pacing causes the RV to contract before the LV (interventricular dyssynchrony) and causes the interventricular septum to contract before the lateral wall (intraventricular dyssynchrony). Thus, chronic ventricular pacing, by inducing ventricular dyssynchrony [12,13], may impair LV systolic function, reduce functional status, and increase mortality. Patients with moderate or severe mitral regurgitation and/or LV dysfunction appear to be at the highest risk of clinical deterioration with chronic RV pacing. CRT may ameliorate the negative effects of RV pacing. (See "Atrial fibrillation: Atrioventricular node ablation" and "Overview of pacemakers in heart failure".) Heart failure While patients with AF and concomitant HF may benefit from CRT, the evidence to support this therapy in patients with AF is not as strong as that for patients in sinus rhythm. This clinical setting overlaps with the AV block clinical scenario as well as the AV node ablation clinical scenario, since AV node ablation appears to promote the efficacy of CRT by eliminating native AV conduction, thereby ensuring almost 100 percent biventricular pacing. (See 'Patients with heart failure' below.) OUR APPROACH Indications for cardiac resynchronization therapy in patients with atrial fibrillation Our approach for this patient population is consistent with major society guideline recommendations [2]: For patients with AF undergoing AV node ablation or strict pharmacologic rate control. In patients with AF and an LV ejection fraction (LVEF) 35 percent who require ventricular https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 3/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate pacing or otherwise meet CRT criteria and in whom AV nodal ablation or pharmacologic rate control will allow near 100 percent ventricular pacing with CRT, we suggest CRT. "Otherwise meets CRT criteria" in this context means either the patient has left bundle branch block (LBBB), a QRS duration 120 ms, and NYHA functional class II, III; or ambulatory class IV HF symptoms on optimal recommended medical therapy or has a non- LBBB pattern with a QRS duration 150 and NYHA class III or ambulatory class IV HF symptoms. This recommendation is based upon data in patients with HF receiving CRT with or without prior AV node ablation. (See 'Following AV node ablation' below and 'Patients with heart failure' below.) A similar recommendation is included in major society guidelines [14-17]. For patients with AV block requiring pacemaker placement, we suggest CRT for patients with NYHA functional class I, II, or III HF who have LVEF 50 percent and AV block (with AF or sinus rhythm) who are expected to require a high percentage of ventricular pacing. Patients with AF treated with effective rhythm control (either with antiarrhythmic drugs or AF ablation resulting in successful maintenance of sinus rhythm) are generally treated the same as patients in sinus rhythm in regard to indications for CRT (see "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Rationale for CRT' and "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Mechanisms of benefit'). It is notable that studies of AF ablation have shown improvement in LVEF with maintenance of sinus rhythm [18,19]. Therefore, reassessment of LVEF several months after restoration of sinus rhythm is achieved is recommended before determining candidacy for CRT. Practical considerations In patients with AF with AV block or a slow ventricular response during AF, CRT can be achieved with a VVIR setting for those with chronic AF or DDDR setting with mode switching for those with paroxysmal AF. Procedural risks of CRT placement in AF patients are comparable to risks in patients with sinus rhythm, although an atrial lead (and its attendant risks) can be avoided in patients in permanent AF for whom there is no future plan to try to achieve sinus rhythm. A high rate of biventricular pacing is required to achieve maximum benefit from CRT, which may be difficult to achieve in patients with AF without AV block. The biventricular pacing rates reported by the CRT device may be misleading since these rates include fusion and pseudofusion (ventricular complexes representing a combination of paced and intrinsically https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 4/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate conducted beats) [20]. Ambulatory rhythm monitoring may be required to adequately assess the extent of biventricular pacing in patients with intact AV conduction. Many patients who have the above indications for CRT are also candidates for an implantable cardioverter-defibrillator and should receive CRT-D rather than CRT-P. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) CARDIAC RESYNCHRONIZATION THERAPY OUTCOMES IN PATIENTS WITH ATRIAL FIBRILLATION Patients requiring a pacemaker for atrioventricular block Evidence supporting the use of CRT in patients undergoing pacemaker placement for AV block comes from the BLOCK HF trial [21]. The trial randomly assigned 691 patients with indications for pacing for AV block and an LVEF 50 percent with NYHA class I, II, or III HF to standard RV or biventricular pacing following CRT device implantation. Of note, over 50 percent of trial subjects had AF at baseline. The following results were reported: Biventricular pacing reduced the composite outcome (mortality, urgent care visit for HF requiring intravenous therapy, or a 15 percent increase in LV end-systolic index) compared with RV pacing during average 37-month follow-up (45.8 versus 55.6 percent; hazard ratio 0.74; 95% credible interval 0.60 to 0.90). LV lead complications occurred in 6.4 percent of patients. Following AV node ablation A randomized trial found that CRT improves HF symptoms in selected patients with chronic AF who have undergone AV node ablation and have NYHA functional class II or III HF or LVEF 45 percent [22]. Observational studies and small randomized trials support the value of CRT in patients with AF who undergo AV node ablation, particularly for patients with reduced LV systolic function or HF [23-25]. In the randomized PAVE trial, 184 patients with chronic AF (83 percent with NYHA class II or III HF) underwent AV node ablation to treat medically refractory rapid ventricular rates and were randomly assigned to receive a standard RV pacing or CRT pacing system [25]. At six-month follow-up, the following results were noted: CRT resulted in significantly greater increases in six-minute walking distance, peak oxygen consumption with exercise, and exercise duration compared with standard RV pacing (31 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 5/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate versus 24 percent improvement, respectively). The improvement in six-minute walk distance with CRT was limited to patients with an LVEF 45 percent or NYHA class II or III HF. CRT resulted in more frequent preservation of the LVEF compared with RV pacing. Based upon these observations, society guidelines recommend CRT system placement in patients who have undergone AV node ablation for chronic AF and have NYHA class II or III HF. Patients with heart failure The limited data on CRT in patients with AF and HF suggest a benefit from CRT (particularly among patients with high rates of ventricular pacing), though the benefit of CRT may be less in patients with AF than that in patients in sinus rhythm. Patients with atrial arrhythmias were excluded from most of the major CRT trials, such as CARE- HF and COMPANION [26]. In the CARE-HF trial comparing CRT with pharmacologic therapy alone, although mortality was higher among patients who developed new AF during follow-up, this subgroup benefitted from CRT for all major study endpoints [7]. In the RAFT trial comparing implantable cardioverter-defibrillator (ICD) with CRT plus ICD (CRT-D), CRT-D provided no benefit compared with ICD alone in the subgroup of 229 patients with AF [27,28]. However, less than one-third of patients treated with CRT received 95 percent ventricular pacing during the first six months of follow-up. In comparison with other trials suggesting CRT benefit in patients with AF, this negative result in the RAFT study is generally interpreted to relate to the low percentage of biventricular pacing achieved in the study. Observational studies and small randomized trials suggest a benefit from CRT in individuals with AF [3,29-33]. A meta-analysis of observational data from five studies (four prospective cohort studies and the MUSTIC randomized trial [30]) compared responses to CRT in 797 patients in sinus rhythm and 367 patients with AF [29]. The overall use of AV node ablation in patients with AF was 56 percent. The NYHA functional class improved similarly in patients with sinus rhythm and those with AF, although relative improvements in the six-minute walk test and health status were greater in patients with sinus rhythm. A later meta-analysis of 23 observational studies included 7495 CRT recipients, 25.5 percent of whom had AF [34]. The meta-analysis compared outcomes in patients with AF to outcomes in patients in sinus rhythm but did not address the question of CRT efficacy in patients with AF. Patients with AF had higher rates of clinical non-response to CRT (34.5 versus 26.7 percent) and higher risks of death (10.8 versus 7.1 percent per year) than patients in sinus rhythm. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 6/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate AF was also associated with less improvement in quality of life, six-minute walk distance, and LV end-systolic volume, but not LVEF. Among patients with AF, those undergoing AV node ablation had a lower risk of clinical non-response and lower mortality rate than those who did not undergo AV node ablation. The MUSTIC-AF trial was not included in the larger meta-analysis since the trial did not include patients in sinus rhythm. This study included 59 patients with HF and chronic AF with a wide QRS complex requiring a permanent pacemaker because of a slow ventricular rate; the patients were randomly assigned to either single site RV pacing or biventricular pacing in a crossover design [3,30]. Sixty-three percent of patients had undergone AV node ablation. Only 39 patients completed the six-month crossover trial, which limits interpretation [3]. Using an intention-to- treat analysis, there were no significant differences in exercise tolerance or peak oxygen consumption. In contrast, among the 37 patients who received effective therapy (97 to 100 percent paced rhythm), biventricular pacing was associated with a significant increase in six- minute walk distance and peak oxygen consumption. A later observational registry study compared outcomes in patients with HF with QRS duration of 120 ms and LVEF of 35 percent receiving CRT (n = 4471) with patients with these characteristics receiving no device therapy (n = 4888) [33]. CRT-D use was associated with lower risks of mortality and hospital readmission in the study population, including the subgroup of 3357 patients with AF. Role of atrioventricular node ablation in patients with heart failure and atrial fibrillation For patients with LV dyssynchrony, benefit from CRT requires biventricular pacing to occur most of the time (ie, intrinsic dyssynchronous conduction should be rare). This can be difficult to accomplish in patients with AF if conduction through the AV node is rapid despite optimal medical therapy for rate control. However, AV node ablation eliminates intrinsic conduction, resulting in ventricular pacing 100 percent of the time. (See "The management of atrial fibrillation in patients with heart failure", section on 'Atrioventricular node ablation with pacing'.) The role of AV node ablation in combination with CRT was evaluated in an observational series of 673 patients receiving a CRT device for conventional indications (LVEF 35 percent, NYHA class II, and a QRS duration >120 msec) [35]. Among the 162 patients in the cohort with chronic AF, 48 received medical therapy for rate control and 114 underwent AV node ablation. In contrast to the above-described studies in which AV node ablation was necessary for rate control, AV node ablation in this study was performed to ensure frequent biventricular pacing (>85 percent of the time). https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 7/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate At four-year follow-up, the following findings were noted: Patients with AF and sinus rhythm had similar improvements in LVEF, reverse remodeling, and exercise tolerance. Among patients with AF, the improvements with CRT were observed only in those who had undergone AV node ablation. Despite biventricular pacing more than 85 percent of the time, patients with AF treated with medications for rate control experienced no improvement in LV function or functional capacity. Another observational study suggested that AV node ablation plus CRT may significantly improve survival compared with CRT alone [36]. Among 1285 patients treated with CRT, 243 were in AF. Rate control was achieved by AV node ablation in 188 and medical therapy in 55; all had at least 85 percent biventricular pacing. During 34-month median follow-up, mortality was significantly lower in patients treated with AV node ablation (4.3 versus 15.2 percent in patients treated with drugs for rate control, adjusted hazard ratio 0.26 for all-cause mortality and 0.15 for HF mortality). These results suggest that clinicians should target complete (100 percent) biventricular pacing in patients with AF for CRT to achieve maximum benefit. A study reporting on 36,935 patients whose CRT devices were followed in a remote monitoring network found that higher proportions of biventricular pacing were associated with a lower risk of death. The optimal cut- point was 98.4 percent, and patients with a biventricular pacing percentage above 99.6 percent experienced up to a 24 percent lower mortality risk compared with those with lesser percentages of CRT [37]. This observation has not been confirmed by randomized trials. Until such data are available, the indications for biventricular pacing in combination with AV node ablation are uncertain. This approach may be considered particularly in patients with significant LV dysfunction at baseline and those who deteriorate with RV pacing [23,38]. Patients with symptomatic atrial fibrillation or refractory heart failure The APAF trial found that CRT reduced HF-related morbidity in a mixed population of patients with AF. The trial enrolled patients with permanent AF with either symptomatic AF with poorly controlled ventricular rate or drug-refractory HF, LV systolic dysfunction, and wide QRS who underwent AV node ablation and placement of a biventricular pacemaker [39]. The 186 patients were randomly assigned to programming of either RV apical pacing or CRT with median 20-month follow-up. CRT reduced the composite primary endpoint of death from HF, hospitalization due to HF, or worsening HF (11 percent in the CRT group versus 26 percent in the RV group). https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 8/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate CRT reduced rates of HF hospitalization or clinically worsening HF. Total mortality was similar in the two groups. ROLE OF CONDUCTION SYSTEM PACING In patients with AF, it is unknown whether conduction system pacing (ie, achieving cardiac resynchronization by pacing the His bundle or the left bundle branch area) is superior to traditional CRT with an LV lead. Additional information on conduction system pacing can be found separately. (See "Overview of pacemakers in heart failure".) COMPARISON WITH PULMONARY VEIN ISOLATION The decision to use pulmonary vein isolation to reestablish normal sinus rhythm versus CRT with or without AV node ablation should be made on a case-by-case basis, depending on several factors, including the institutional success rates with catheter ablation and patient preference. Limited data are available comparing CRT with or without AV node ablation with other therapies for patients with AF and HF. Although a small randomized trial found that pulmonary vein isolation improved symptoms compared with CRT with AV node ablation at six-month follow-up, longer-term data are not available. (See "Atrial fibrillation: Catheter ablation" and "The management of atrial fibrillation in patients with heart failure".) The PABA-CHF trial of 81 patients with antiarrhythmic drug-resistant AF and NYHA class II or III HF and LVEF 40 percent compared pulmonary vein isolation with CRT with AV node ablation [18]. At six months, the pulmonary vein isolation group had significantly better Minnesota Living with Heart Failure questionnaire scores (60 versus 82), longer six-minute walk distance (340 versus 297 m), and higher LVEF (35 versus 28 percent). Later trials of AF ablation versus drug therapy in patients with HF demonstrated clinical benefits of ablation; in CASTLE-AF, the primary composite endpoint of death from any cause or hospitalization for HF occurred in fewer patients in the ablation group [19]. These studies are discussed in detail separately (see "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'). Although these studies did not compare AF ablation with CRT (with or without AV nodal ablation), the evidence of clinical benefit of AF ablation compared with drug therapy in HF patients supports AF ablation as an option for HF patients, which in some cases may obviate the need for CRT. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 9/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Cardiac resynchronization therapy (The Basics)") SUMMARY AND RECOMMENDATIONS Effect of cardiac resynchronization on atrial fibrillation Although cardiac resynchronization therapy (CRT) improves some potential risk factors for atrial fibrillation (AF), such as atrial size and left ventricular (LV) systolic function, CRT has not been shown to decrease the incidence of new or recurrent AF. (See 'Effect of cardiac resynchronization therapy on atrial fibrillation' above.) Indications for cardiac resynchronization therapy in patients with atrial fibrillation In patients with AF and an LV ejection fraction (LVEF) 35 percent who require ventricular pacing or otherwise meet CRT criteria and in whom atrioventricular (AV) nodal ablation or pharmacologic rate control will allow near 100 percent ventricular pacing with CRT, we suggest CRT (Grade 2B). (See 'Indications for cardiac resynchronization therapy in patients with atrial fibrillation' above.) "Otherwise meets CRT criteria" in this context means either left bundle branch block (LBBB) and a QRS duration 120 ms and New York Heart Association (NYHA) functional https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 10/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate class II, III, or ambulatory class IV heart failure (HF) symptoms on optimal recommended medical therapy; or a non-LBBB pattern with a QRS duration 150 and NYHA class III or ambulatory class IV HF symptoms. For patients with AV block requiring pacemaker placement, we suggest CRT for patients with NYHA functional class I, II, or III HF who have LVEF 50 percent and AV block (with AF or sinus rhythm) who are expected to require a high percentage of ventricular pacing (Grade 2B). (See 'Indications for cardiac resynchronization therapy in patients with atrial fibrillation' above.) Role of defibrillator placement Most patients who are candidates for CRT are also candidates for an implantable cardioverter-defibrillator and should receive a combined device. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".) Comparison of CRT and pulmonary vein isolation Pulmonary vein isolation is another potential treatment option in patients with AF and HF. The decision to use pulmonary vein isolation aimed at reestablishing normal sinus rhythm versus CRT with or without AV node ablation should be made on a case-by-case basis depending on several factors, including the likelihood of successful maintenance of sinus rhythm after AF ablation, the institutional success rates with catheter ablation, and patient preference. Pulmonary vein isolation may result in better symptom control compared with CRT plus AV node ablation at short-term follow-up, but comparative long-term effects are not known. (See 'Comparison with pulmonary vein isolation' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Leonard I Ganz, MD, FHRS, FACC, Michael Cao, MD, and Leslie A Saxon, MD, who contributed as authors to earlier versions of this topic review. The UpToDate editorial staff acknowledges Wilson Colucci, MD, who contributed as section editor to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol 2003; 91:2D. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 11/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 2. European Heart Rhythm Association, European Society of Cardiology, Heart Rhythm Society, et al. 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management. Heart Rhythm 2012; 9:1524. 3. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002; 23:1780. 4. Saxon LA, De Marco T, Schafer J, et al. Effects of long-term biventricular stimulation for resynchronization on echocardiographic measures of remodeling. Circulation 2002; 105:1304. 5. St John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003; 107:1985. 6. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol 2003; 42:1454. 7. Hoppe UC, Casares JM, Eiskjaer H, et al. Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure. Circulation 2006; 114:18. 8. Saxon LA. Does cardiac resynchronization therapy reduce the incidence of atrial fibrillation, and does atrial fibrillation compromise the cardiac resynchronization therapy effect? Heart Rhythm 2007; 4:S31. 9. Gasparini M, Steinberg JS, Arshad A, et al. Resumption of sinus rhythm in patients with heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study. Eur Heart J 2010; 31:976. 10. Fung JW, Yu CM, Chan JY, et al. Effects of cardiac resynchronization therapy on incidence of atrial fibrillation in patients with poor left ventricular systolic function. Am J Cardiol 2005; 96:728. 11. H gl B, Bruns HJ, Unterberg-Buchwald C, et al. Atrial fibrillation burden during the post- implant period after crt using device-based diagnostics. J Cardiovasc Electrophysiol 2006; 17:813. 12. Vernooy K, Dijkman B, Cheriex EC, et al. Ventricular remodeling during long-term right ventricular pacing following His bundle ablation. Am J Cardiol 2006; 97:1223. 13. Tops LF, Schalij MJ, Holman ER, et al. Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol 2006; 48:1642. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 12/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 14. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation 2012; 126:1784. 15. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147. 16. Dickstein K, Vardas PE, Auricchio A, et al. 2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur J Heart Fail 2010; 12:1143. 17. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787. 18. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 19. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 20. Kamath GS, Cotiga D, Koneru JN, et al. The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy. J Am Coll Cardiol 2009; 53:1050. 21. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368:1585. 22. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p030035 (A ccessed on September 19, 2014). 23. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol 2002; 39:1258. 24. Brignole M, Gammage M, Puggioni E, et al. Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation. Eur Heart J 2005; 26:712. 25. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005; 16:1160. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 13/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 26. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539. 27. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363:2385. 28. Healey JS, Hohnloser SH, Exner DV, et al. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2012; 5:566. 29. Upadhyay GA, Choudhry NK, Auricchio A, et al. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol 2008; 52:1239. 30. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002; 40:111. 31. Khadjooi K, Foley PW, Chalil S, et al. Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation. Heart 2008; 94:879. 32. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007; 99:1252. 33. Khazanie P, Hammill BG, Qualls LG, et al. Clinical effectiveness of cardiac resynchronization therapy versus medical therapy alone among patients with heart failure: analysis of the ICD Registry and ADHERE. Circ Heart Fail 2014; 7:926. 34. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 2011; 8:1088. 35. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006; 48:734. 36. Gasparini M, Auricchio A, Metra M, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008; 29:1644. 37. Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011; 8:1469. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 14/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 38. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002; 288:3115. 39. Brignole M, Botto G, Mont L, et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J 2011; 32:2420. Topic 3515 Version 19.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 15/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate GRAPHICS NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause
heart failure and permanent atrial fibrillation undergoing cardiac resynchronization therapy: a longitudinal observational study. Eur Heart J 2010; 31:976. 10. Fung JW, Yu CM, Chan JY, et al. Effects of cardiac resynchronization therapy on incidence of atrial fibrillation in patients with poor left ventricular systolic function. Am J Cardiol 2005; 96:728. 11. H gl B, Bruns HJ, Unterberg-Buchwald C, et al. Atrial fibrillation burden during the post- implant period after crt using device-based diagnostics. J Cardiovasc Electrophysiol 2006; 17:813. 12. Vernooy K, Dijkman B, Cheriex EC, et al. Ventricular remodeling during long-term right ventricular pacing following His bundle ablation. Am J Cardiol 2006; 97:1223. 13. Tops LF, Schalij MJ, Holman ER, et al. Right ventricular pacing can induce ventricular dyssynchrony in patients with atrial fibrillation after atrioventricular node ablation. J Am Coll Cardiol 2006; 48:1642. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 12/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 14. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation 2012; 126:1784. 15. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 62:e147. 16. Dickstein K, Vardas PE, Auricchio A, et al. 2010 focused update of ESC Guidelines on device therapy in heart failure: an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac and resynchronization therapy. Developed with the special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur J Heart Fail 2010; 12:1143. 17. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33:1787. 18. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 19. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 20. Kamath GS, Cotiga D, Koneru JN, et al. The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy. J Am Coll Cardiol 2009; 53:1050. 21. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368:1585. 22. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=p030035 (A ccessed on September 19, 2014). 23. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol 2002; 39:1258. 24. Brignole M, Gammage M, Puggioni E, et al. Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation. Eur Heart J 2005; 26:712. 25. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005; 16:1160. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 13/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 26. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539. 27. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363:2385. 28. Healey JS, Hohnloser SH, Exner DV, et al. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail 2012; 5:566. 29. Upadhyay GA, Choudhry NK, Auricchio A, et al. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol 2008; 52:1239. 30. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002; 40:111. 31. Khadjooi K, Foley PW, Chalil S, et al. Long-term effects of cardiac resynchronisation therapy in patients with atrial fibrillation. Heart 2008; 94:879. 32. Delnoy PP, Ottervanger JP, Luttikhuis HO, et al. Comparison of usefulness of cardiac resynchronization therapy in patients with atrial fibrillation and heart failure versus patients with sinus rhythm and heart failure. Am J Cardiol 2007; 99:1252. 33. Khazanie P, Hammill BG, Qualls LG, et al. Clinical effectiveness of cardiac resynchronization therapy versus medical therapy alone among patients with heart failure: analysis of the ICD Registry and ADHERE. Circ Heart Fail 2014; 7:926. 34. Wilton SB, Leung AA, Ghali WA, et al. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 2011; 8:1088. 35. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006; 48:734. 36. Gasparini M, Auricchio A, Metra M, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J 2008; 29:1644. 37. Hayes DL, Boehmer JP, Day JD, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm 2011; 8:1469. https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 14/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate 38. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002; 288:3115. 39. Brignole M, Botto G, Mont L, et al. Cardiac resynchronization therapy in patients undergoing atrioventricular junction ablation for permanent atrial fibrillation: a randomized trial. Eur Heart J 2011; 32:2420. Topic 3515 Version 19.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 15/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate GRAPHICS NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina with strenuous or rapid Patients can perform to completion any activity requiring 7 metabolic equivalents (ie, can carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or anginal pain. prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional dyspnea, or anginal pain. stress, or only during the few hours after awakening. Walking more than 2 blocks on the level and climbing more than 1 flight of foxtrot, walk at 4 mph on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Marked limitation of ordinary physical activity. Walking 1 to 2 blocks on the level and climbing 1 flight in Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip Less-than-ordinary normal conditions. and make bed, clean https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 16/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate physical activity causes fatigue, palpitation, dyspnea, or anginal pain. windows, walk 2.5 mph, bowl, play golf, dress without stopping) but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac disease resulting in inability to carry on any physical activity Inability to carry on any physical activity without discomfort. Anginal syndrome may Patients cannot or do not perform to completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity be present at rest. equivalents. Cannot carry out activities listed above (specific activity scale III). is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 17/18 7/5/23, 9:12 AM Cardiac resynchronization therapy in atrial fibrillation - UpToDate Contributor Disclosures E Kevin Heist, MD, PhD Equity Ownership/Stock Options: Oracle Health [Device diagnostics]. Consultant/Advisory Boards: Biotronik [Cardiac resynchronization therapy and atrial fibrillation]; Boston Scientific [Cardiac resynchronization therapy and atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Frederick Masoudi, MD, MSPH, FACC, FAHA Consultant/Advisory Boards: Bristol Meyers Squibb [Hypertrophic cardiomyopathy]; Colorado Prevention Center [Diabetes trial steering committee, study sponsor, Better Therapeutics]; TurningPoint [Utilization policy review]. Other Financial Interest: American College of Cardiology [Cardiovascular disease]; Massachusetts Medical Society [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cardiac-resynchronization-therapy-in-atrial-fibrillation/print 18/18
7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 13, 2022. INTRODUCTION The primary trigger for most episodes of atrial fibrillation (AF) is an electrical discharge(s) within one of the four pulmonary veins (see "Mechanisms of atrial fibrillation", section on 'Triggers of AF'). The cornerstone of any procedure aimed at reducing AF burden is the electrical isolation of the pulmonary veins so that these discharges do not trigger the initiation of AF. In those with persistent and longstanding persistent AF, and in some patients with paroxysmal AF, additional areas, often in one or both of the atria or surrounding structures, are targeted for ablation, as they may also serve as a source of AF triggers or maintenance. Catheter ablation (CA) is the procedure that is used to prevent the initiation of AF by electrically isolating these triggers from the rest of the atrial chamber tissue. This topic is intended to be viewed primarily by non-electrophysiologists. Electrophysiologists may be more interested in other topics: (See "Overview of catheter ablation of cardiac arrhythmias".) (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) (See "Atrial fibrillation: Catheter ablation".) (See "Invasive diagnostic cardiac electrophysiology studies".) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 1/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation".) PATIENT SELECTION A major clinical goal of CA is a reduction in AF-related symptoms. CA is superior to medical therapy at improving quality of life. Therefore, it is generally reserved for individuals with symptoms attributable to the arrhythmia, which most often include palpitations, shortness of breath, or generalized fatigue [1,2]. Even if they have no AF-related symptoms, older individuals with early AF (duration <1 year) and additional cardiovascular conditions also benefit from therapies aimed at maintaining sinus rhythm; these therapies include CA [3]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Recommendations of others'.) Patients should be considered for ablation for AF after the history and physical exam have been reviewed and there is documentation of symptomatic correlation with AF on electrocardiogram (ECG) or other forms of monitoring. Modifiable risk factors including obesity, excessive alcohol intake, and sleep apnea should be addressed, as they are important components of AF treatment and impact the success of any rhythm control intervention [4-8]. AF CA may be appropriate in the following groups: Patients with paroxysmal or persistent AF who have tried a class I or III antiarrhythmic drug ablation can be considered if such medications are either unsuccessful or are not tolerated. Some individuals may choose ablation as first-line therapy. For patients with long-standing persistent AF, a trial of one or more class I or III antiarrhythmic drugs is recommended. Ablation as first-line therapy can be considered in those with contraindications to drugs. Asymptomatic younger individuals and patients with heart failure due to reduced ejection fraction may also benefit from ablation [9,10]. We do not perform CA in: Individuals who are too frail to safely undergo the procedure. Patients with a left atrial appendage thrombus. Individuals with bleeding diathesis who cannot receive intra- and postprocedural anticoagulation. PREPROCEDURAL PREPARATION https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 2/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Once a patient has been selected for AF ablation, the clinician performing the procedure or their designee should obtain informed consent from the patient. This involves shared decision- making after discussing the indications, benefits, risks, and alternatives of the planned procedure. Sedation options include general anesthesia that requires an endotracheal tube or monitored anesthesia care with sedation but not requiring intubation. Most procedures are performed under general anesthesia. Medication management Most physicians performing ablation will discontinue antiarrhythmic drugs prior to the ablation with the rationale that it may help to identify the triggers of the AF at the time of the procedure. We acknowledge that many other electrophysiologists will continue them. There are no well-performed studies to guide practice. With regard to oral anticoagulation, randomized trials have demonstrated superior efficacy and safety of uninterrupted anticoagulation throughout the ablation procedure compared with temporary discontinuation of anticoagulation and bridging with low molecular weight heparin. Most operators, including the authors, perform the procedure on uninterrupted or minimally interrupted direct-acting oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) such as warfarin. A meta-analysis of 17,434 patients from 12 observational trials and one randomized trial compared uninterrupted warfarin with interrupted warfarin and heparin bridging at the time of AF ablation. Uninterrupted warfarin was associated with significant reductions in stroke and major and minor bleeding [11]. Studies have shown that patients on uninterrupted DOACs have either lower (dabigatran, edoxaban [12,13]) or similar (rivaroxaban, apixaban) [14,15] bleeding risks compared with those on uninterrupted VKA. Studies of DOACS with lower bleeding risks compared with VKA: The RE-CIRCUIT trial randomized 704 patients undergoing AF ablation to uninterrupted dabigatran or VKA. The incidence of major bleeding events during and up to eight weeks after ablation was lower with dabigatran than with warfarin (1.6 versus 6.9 percent) [12]. In a trial of 614 patients undergoing CA, participants were randomly assigned to uninterrupted edoxaban or VKA. Major bleeds were nonsignificantly lower in persons assigned to edoxaban compared with VKA (0.2 versus 2 percent; hazard ratio 0.16; 95% CI 0.02-1.73) [13]. Studies of DOACS with similar bleeding risks compared with VKA: https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 3/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate In a trial of rivaroxaban or VKA in people undergoing AF ablation, bleeding events were similar in the two study arms [14]. In a trial that compared uninterrupted apixaban with placebo, the rates of clinically significant and major bleeding were also similar for both groups (10.6 versus 9.8 percent) [15]. Imaging All patients with AF, not just those being considered for CA, should undergo transthoracic echocardiography (TTE) to evaluate for factors that may affect treatment including the presence and extent of valvular disease, chamber size, and ventricular function. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Echocardiogram'.) Transesophageal echocardiography (TEE), which is superior to TTE for finding atrial thrombus, is often performed within 24 hours prior to ablation since the presence of thrombus in the left atrium or left atrial appendage is a contraindication to AF ablation. Some operators may choose to forego TEE in patients with a low risk of stroke (ie, CHA DS -VASc 1) who are expected to be 2 2 in sinus rhythm at the time of the procedure and who have been and will be maintained on uninterrupted anticoagulation throughout the periprocedural timeframe. Some operators will individualize the need for preprocedure TEE and tend to only perform it in higher-risk patients. Risk factors for left atrial appendage thrombus prior to ablation include hypertrophic cardiomyopathy, ejection fraction <30 percent, persistent or longstanding persistent AF, and elevated CHA DS -VASc score [16]. In a study of 1058 preprocedure TEEs, the rate of detection of 2 2 left atrial thrombus or prethrombus was 1 percent in patients with paroxysmal AF in sinus rhythm and 2 percent for patients with paroxysmal AF who were in AF at the time of the procedure. The risk increased with increasing CHADS score [17]. 2 Computed tomography (CT) or cardiac magnetic resonance imaging (cMRI) may be performed preablation to define the left atrial anatomy, specifically the number, size, and location of the pulmonary veins ( figure 1). Data are emerging to suggest that these imaging techniques are also highly sensitive for left atrial thrombus, and many operators use CT or cMRI to evaluate for left atrial thrombus instead of TEE in low-risk individuals. A comparison of cMRI with TEE to evaluate preablation left atrial appendage thrombus demonstrated 100 percent sensitivity and 99.2 percent specificity for equilibrium phase delayed enhancement CMR with a long inversion time [18]. New high-dimensional mapping catheters used during the procedure can create high- definition structural geometry, and for many operators has obviated the need for preprocedure imaging. PROCEDURAL ISSUES https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 4/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Ablation for AF is among the most complicated procedures performed by electrophysiologists. The procedure should be performed in centers with experience with complex electrophysiologic procedures and capabilities in managing acute complications. Advancements in procedural technologies and techniques have significantly shortened the duration of ablation procedures for AF. Total procedure time typically ranges from 1.5 to 4 hours [19]. The ablation is performed using uni- or bilateral femoral venous access and transseptal puncture for accessing the left atrium. Anesthesia Ablation for AF is performed in the fasting state with general anesthesia or monitored anesthesia care (MAC) using sedation. In a retrospective cohort study of CA performed under either general anesthesia or conscious sedation, conscious sedation had shorter total procedure times and equivalent success rates compared with general anesthesia [20]. In a retrospective cohort study of CA performed under either general anesthesia or MAC, MAC had shorter total procedure times and equivalent success rates with general anesthesia [19]. Agents typically used for conscious sedation include short-acting benzodiazepines (eg, midazolam) and opioids (eg, fentanyl) in divided doses [21]. The type of anesthesia used for AF ablation procedures is dependent on several variables including the expected complexity and duration of the procedure, energy source being utilized, patient comorbidities, patient preference, and availability of anesthesia support. Patient immobility is important to optimize catheter contact and reduce movement error in the anatomic mapping systems. Paralytics should not be used when testing for phrenic nerve capture during ablation. High frequency ventilation, also called jet ventilation, which utilizes a respiratory rate greater than four times the normal value. (>150 [Vf] breaths per minute) and very small tidal volumes, is used in some centers to aid catheter stability and has been associated with improved outcomes [22]. Intraprocedural medications In addition to anesthetic agents, intravenous heparin is administered throughout the AF ablation procedure to reduce the risk of thrombus formation on the catheters, sheaths, left atrium and left atrial appendage, and at ablation sites. Heparin is administered prior to or immediately after transseptal access has been achieved with a targeted activated clotting time (ACT) of >300 seconds. Target ACT may be reached faster and with lower loading doses in patients undergoing ablation on uninterrupted vitamin K antagonists (VKA) compared with non-vitamin K antagonist oral anticoagulants (NOACs; also referred to as direct acting oral anticoagulants [DOAC]) [23]. Additionally, time to target ACT varies amongst the NOACs, with average time in minutes required to achieve a target ACT of >300 seconds https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 5/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate significantly longer in those receiving uninterrupted dabigatran or apixaban compared with those receiving rivaroxaban [24]. Protamine can be used to reverse anticoagulation at the time of sheath removal post-procedure. Esophageal imaging and temperature monitoring The proximity of the esophagus to the posterior left atrium makes it susceptible to thermal injury (see 'Complications' below). Atrioesophageal fistula, typically occurring one to four weeks post-ablation, is a potentially lethal consequence of AF ablation, with a reported incidence of 0.02 to 0.11 percent. To minimize risk, operators will limit energy delivery in the posterior wall in areas adjacent to the esophagus. As the esophagus can have a highly variable position that can vary throughout the procedure, visualization of the esophagus can be performed using electroanatomic mapping, intracardiac ultrasound (ICE), or barium paste. Many operators use an esophageal temperature probe to assess the effects of ablation on intraluminal temperature, though this practice has not yet been shown to reduce the risk of fistula formation given the low incidence of these events. Given the very low overall incidence of fistula, there have been no randomized data to demonstrate superiority of one esophageal monitoring strategy over another. Consequently, minimization of power delivery to the atrial tissue adjacent to the esophagus or minimization of temperature elevation remain surrogates for procedural safety Vascular ultrasound CA for AF requires multiple sheaths with large diameters in one or both femoral veins in patients receiving oral and intravenous anticoagulation. These issues make vascular complications the most common complications of AF ablation. Access can be obtained through the modified Seldinger approach. Vascular ultrasound has been used for venipuncture guidance and postprocedural evaluation. In a cohort study of 1435 patients undergoing cryoballoon ablation for AF, major clinical events occurred in 1.7 percent of those patients who had their procedure performed without ultrasound guidance versus 0 percent in those that did have ultrasound guidance [25]. In a multicenter, randomized trial, 320 patients were randomized to ultrasound guided versus conventional venipuncture. Major complications were low and not significantly different between groups. Puncture time, inadvertent arterial puncture, and need for extra puncture attempts were all significantly reduced in the ultrasound arm [26]. Intracardiac ultrasound Intracardiac ultrasound allows for real-time imaging of cardiac anatomy. The probe is placed in the right atrium via the inferior vena cava. Common uses of ICE include the identification of intra- and extracardiac anatomic structures such as the esophagus, facilitation of transseptal puncture, guidance of catheter placement, and recognition of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 6/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate complications including thrombus formation on sheaths and catheters and early recognition of pericardial effusion. Fluoroscopy Mapping and ablation of AF requires precise navigation of catheters within the left atrium and localization of intra- and extracardiac structures. Fluoroscopy is used to assess catheter placement, to visualize catheter movement, and to assess proximity to adjacent structures such as the esophagus when marked by an intraluminal catheter or barium paste. Patient and physician exposure to ionizing radiation during AF ablation are highly variable, and radiation injury to the patient is reported in <0.1 percent of cases. Efforts to reduce patient and physician exposure to ionizing radiation have successfully relied on alternative imaging modalities, including ICE and electroanatomic mapping. (See "Radiation-related risks of imaging".) Electroanatomic mapping Electroanatomic mapping systems combine real-time, detailed information of the anatomy and electrical properties of the cardiac structures under evaluation. These systems (Carto [Biosense Webster], NAVX [Abbott], and Rhythmia [Boston Scientific]) use diagnostic and ablation catheters and navigation patches on the patient's skin to create a three- dimensional anatomical map used to help localize critical sites for ablation. ABLATION TECHNIQUES AND TARGETS Energy sources There are three US Food and Drug Administration (FDA)-approved energy sources for AF ablation: radiofrequency energy, cryothermal energy in the form of cryoballoon, and laser balloon. This issue is discussed in detail elsewhere. (See "Overview of catheter ablation of cardiac arrhythmias", section on 'Energy sources used for ablation'.) The commonly used and approved energy sources for CA are radiofrequency and cryothermal. The efficacy and safety associated with these two energy sources have been found to be similar in multiple studies. This issue is discussed elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Comparison of radiofrequency and cryothermal ablation'.) Pulmonary vein isolation Complete electrical isolation of all PVs using circumferential, wide area pulmonary vein isolation (PVI) is the goal of most procedures. The following explains the rationale. The initiation of AF requires a trigger either within or near the atrium (eg, PVs, crista terminalis, superior vena cava), and substrate within the atrium to maintain AF [9] (see "Mechanisms of atrial fibrillation", section on 'Basic atrial electrophysiology'). The anatomic significance of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 7/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate triggers and substrate differs somewhat, depending upon whether the AF is paroxysmal, persistent, or permanent (see "Paroxysmal atrial fibrillation", section on 'Introduction'). In patients with paroxysmal AF, PV triggers are the primary stimulus in most cases. As AF becomes more persistent, non-PV sources become more important [27]. The following important observations regarding triggers came from early studies of patients with paroxysmal AF and have guided the development of successful ablation techniques for AF [28-30]. AF is commonly triggered by ectopic beats from muscle fibers (fascicles) extending from the left atrium into the PVs ( figure 1). Ectopic foci are localized to the PVs in approximately 90 percent of patients with predominantly structurally normal hearts [31]. Most patients have multiple foci that can act as triggers. Most (94 percent) of the foci are 2 to 4 cm inside the PVs, with the left superior vein being the most common site [28]. The remaining foci are usually in the right or left atrium. The superior vena cava is a much less common site of triggering ectopic beats [28]. Because of these observations, early attempts at ablation targeted these focal ectopic beats within the PV [28]. This approach was limited by: Inconsistent ability to identify the triggering beats during electrophysiology study. Difficulties with precise localization of appropriate ablation sites. The risk of PV stenosis, which can occur following ablation within the PVs. (See "Atrial fibrillation: Catheter ablation".) These limitations lead to the adoption of ablative techniques focused on the complete electrical isolation of all PVs using circumferential wide area PVI. The majority of ablations performed use radiofrequency energy or cryothermy (cryoballoon ablation). Infrared laser received FDA approval in 2018. Circumferential PVI involves the creation of confluent ablation lesions that encircle the ostia of all four PVs, usually in two pairs (ie, a left- and right-sided circles) [32-34]. The goal is to electrically isolate the PVs from the left atrium. For ablation using radiofrequency energy, power, duration, and the catheter contact force determine the size and the depth of the lesion created. It is generally felt that some lesions create edema but not scars, leading to temporary but not permanent ablation, and this ultimately leads to electrical reconnection of the left atrium to the https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 8/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate PVs. Greater power, longer duration, and greater contact force improve the efficacy of the procedure but lead to an increase in complications such as cardiac perforation [35,36]. The efficacy and safety of high-power, short-duration ablation, which creates larger, shallower, and more homogeneous lesions, is under evaluation [37]. Circumferential PVI results in extensive ablation across a wider area of the left atrium. Because of the more extensive ablation, this technique may provide additional methods for preventing AF, including autonomic denervation, elimination of triggering foci outside the PVs, and alteration of the left atrial substrate necessary for perpetuating AF. However, more extensive ablation, particularly in the posterior left atrium, may increase the rate of complications, including the development of left atrial tachycardias or flutters months or years after the ablation. The relative efficacy and safety of these methods are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) Use of a contact force-sensing catheter We use a contact force-sensing catheter in all patients with AF undergoing radiofrequency CA (RFA). The TOCCASTAR study found that patients who underwent CA with this catheter and who received a higher force ( 10 grams) had significantly lower rates of AF recurrence at one year. Use of adenosine-guided pulmonary vein isolation The administration of intravenous adenosine can be used to unmask dormant conduction at the time of CA. Reconnection rates are high in RFA, with three large studies finding rates of 21 (ADVICE), 27 (UNDER-ATP), and 34 percent [38-40]. The use of adenosine to guide additional CA has been shown to improve arrhythmia-free survival in some studies using RFA. Some technical aspects of the procedure are discussed separately. (See 'Ablation techniques and targets' above.) In the ADVICE study, 534 patients with paroxysmal AF who had failed drug therapy underwent a standard PV isolation procedure using radiofrequency energy [38]. Patients were observed for spontaneous recovery of conduction over 20 minutes to allow for reconnected PVs to be reisolated before adenosine administration. Intravenous adenosine was then given to all patients. The 284 patients in whom dormant conduction (evidence of persistent PV conduction) was unmasked by adenosine were randomly assigned to additional adenosine-guided ablation to abolish dormant conduction or to no additional ablation. Among the 250 patients without dormant conduction, 117 were enrolled in a registry. The primary endpoint of the time to first recurrence of symptomatic electrocardiographically documented atrial tachyarrhythmia was between 91 and 365 days. The following findings were noted: Dormant PV conduction was present in 284 (53 percent) of patients. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 9/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Freedom from symptomatic atrial tachycardia occurred more often with adenosine-guided further ablation (69.4 versus 42.3 percent; hazard ratio [HR] 0.44, 95% CI 0.31-0.64). Among patients in the registry, approximately 56 percent remained free from symptomatic atrial tachyarrhythmia. The rate of serious adverse events was similar in both groups. Limitations of this study include lack of generalizability (does not apply to patients undergoing cryoablation), lack of use of force-sensing catheters, which are used by many of our experts, and the use of "dormant connection" as an endpoint rather than AF recurrence. In the UNDER-ATP trial, 2113 patients with paroxysmal, persistent, or long-lasting AF were randomly assigned to either adenosine-guided PV isolation (1112 patients) or conventional PV isolation (1001 patients) [39]. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 seconds or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at one year with the blanking period of 90 days post-ablation. Among patients assigned to adenosine-guided PV isolation, adenosine provoked dormant PV conduction in 307 patients (27.6 percent). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4 percent). At one year, 68.7 percent of patients in the adenosine-guided PV isolation group and 67.1 percent of patients in the conventional PV isolation group were free from the primary endpoint, with no significant difference (adjusted HR 0.89; 95% CI 0.74-1.09; p = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the one-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; p = 0.16). Based on these studies, the use an adenosine in patients undergoing CA with radiofrequency energy is at the discretion of the operator. Confirmation of complete isolation Unlike many other cardiac ablation procedures, AF does not need to be present or induced at the time of the ablation procedure nor is termination of AF or inability to reinduce the arrhythmia a required endpoint of the procedure. For PVI, acute procedural success is defined as electrical isolation of all PVs [41]. This is defined by entry block or the inability to electrically capture PV myocardial tissue distal to the area of ablation when pacing is performed proximal to the ablation line. To do this, a circular catheter is positioned just distal to the PV ostium for the purpose of recording electrograms within the PVs. Confirmation is attempted after a 30-minute waiting period after isolation. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 10/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Some operators also test for exit block, defined by the inability to capture atrial myocardium when pacing is performed within the PV distal to the ablation line. There is a high correlation between AF recurrences and the demonstration of persistent or recurrent conduction between the PVs and left atrium (see "Atrial fibrillation: Catheter ablation", section on 'Efficacy'). Recurrent PV conduction explains most cases of recurrence; it is thought to be due to recovery of function of tissue that has been acutely injured (ie, edema and inflammation) but not permanently scarred. Administration of adenosine has been shown to identify PVs with dormant conduction by transiently restoring excitability and conduction across circumferential ablation lines at risk of reconnection [38]. However, improvements in ablation tools and techniques have significantly reduced the routine use of adenosine. It is used at the discretion of the operator. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) Ablation targets in persistent atrial fibrillation In contrast to patients with paroxysmal AF, patients with persistent AF (and in particular longstanding persistent AF) often have multiple triggers distributed throughout the atria in addition to triggers within the PV [42]. It is thought that mechanisms that maintain rather than trigger the arrhythmia are more important in these individuals. These observations may explain the reduced efficacy of CA procedures that are limited to PVI in patients with longstanding persistent AF seen in most studies. In these patients, additional lesions are often needed to prevent recurrence of AF. These lesions are often placed anatomically in the left atrial posterior wall and roof, in the left atrial appendage, coronary sinus, or in the right atrium. Additional targets include sites of complex fractionated electrograms and rotors [43,44] (see "Mechanisms of atrial fibrillation", section on 'Mechanisms of atrial fibrillation: triggers and substrates'). Though the goal of additional lesion sets are to modify the AF substrate, these approaches may also result in proarrhythmia through the creation of new reentrant circuits. Data supporting the benefits and optimal approach for the treatment of persistent AF are inconclusive and are often individualized by patient and operator. Additional ablation targets/techniques outside the PVs include: Non-PV triggers (eg, coronary sinus, posterior left atrium, crista terminalis) Complex fractionated electrograms (CFAEs) Linear ablation (LA roof, mitral isthmus) Other thoracic veins (superior vena cava, coronary sinus) Posterior wall isolation Left atrial appendage isolation Ablation of cardiac autonomic nerves (ganglionic plexi) Focal impulse and rotor modulation (FIRM) phase mapping-guided ablation Stepwise approach (PVI, CFAE, linear, coronary sinus) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 11/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate POSTPROCEDURAL ISSUES After the procedure, patients usually remain supine for a fixed period (usually two to four hours) following sheath removal to promote hemostasis at the venous puncture sites. Vascular closure devices allow for more rapid hemostasis and shorter time to ambulation. Most centers keep patients overnight following the procedure. Same-day discharge has become increasingly common given the shorter procedure times and use of venous closure techniques [45,46]. Post-discharge medications Oral anticoagulation is usually continued [47] for at least two months to ensure that the increased risk of embolization associated with the procedure has returned to a baseline risk, regardless of CHADS VA Sc score. This also allows for adequate time 2 2 to document an absence of recurrence of AF for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [48]. Importantly, there are no randomized data on the safety of discontinuing anticoagulation post-ablation for patients who have presumably maintained sinus rhythm. The risk of AF recurrence, the recognized proportional increase in the burden of asymptomatic AF, and the uncertainty surrounding the causal association between the arrhythmia itself and stroke all support the recommendation to risk stratify patients for oral anticoagulation use based on CHA DS -VASc no differently than if an 2 2 ablation had not been performed. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Postprocedural anticoagulation'.) Antiarrhythmic medications may or may not be continued after the procedure. Our preference is to stop them after the procedure. Patients in whom consideration should be given to continuing them include patients with long-standing persistent AF or patients with debilitating AF symptoms. Post-discharge follow-up At the time of discharge, patients are given instructions on activity and what potential complications to look for. They should refrain from heavy physical activity, including exercise and weight lifting, for the week post-procedure to allow for complete healing of the vascular access sites. Baths should also be avoided for one week to reduce infection risk. In patients without identified post-procedural complications such as vascular access site problems, we wait three months to reevaluate the patient [9] (see 'Complications' below). Patients with potential complications should be seen immediately. Patients who develop symptoms should contact either their primary care physician, general cardiologist, or electrophysiologist to discuss the need for early evaluation. Yearly follow-up with a physician thereafter is also recommended. These ongoing interactions with the medical profession allow the patient's clinical status to be evaluated, including an https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 12/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate assessment of the presence or absence of AF, as well as their stroke risk profile and anticoagulation needs. These interactions also provide an opportunity to focus on the treatment of associated diseases and lifestyle modifications [9]. Routine ECG should be performed at the time of follow-up visits, and more intense monitoring may be performed as dictated by patient symptoms and the clinical impact of AF detection [41]. Evaluation for recurrent atrial fibrillation The primary purpose of the first follow-up visit around the three-month mark is to determine the success of the procedure. Screening for post- procedure AF is discussed separately. (See "Atrial fibrillation: Catheter ablation", section on 'Follow-up'.) In general, we do not evaluate the patient for the presence of AF prior to three months, as early episodes do not necessarily predict the long-term success or failure of the procedure. They can often be managed with antiarrhythmic drugs or cardioversion. Repeat ablation during this time is rarely necessary. During this three-month healing phase, there is resolution of inflammation and consolidation of lesion formation. This time period is referred to in clinical research trials as the "post-procedure blanking period." Anticoagulants are continued throughout this period regardless of the patient's CHA DS -VASc score ( table 1). Antiarrhythmic drugs and/or electrical cardioversion 2 2 are used during this blanking period at the discretion of the treating physician and usually reserved for those with debilitating symptoms or recurrent persistent AF. Success rates The success rate of AF ablation is dependent on multiple factors including patient selection, technique, definition of success, and the intensity and duration of rhythm monitoring post-ablation. For research purposes, the primary endpoint of AF ablation trials is freedom from recurrent AF/ atrial tachycardia (AT) defined as the absence of any recurrent AF/AT >30 seconds without antiarrhythmic drugs. Using this strict definition, the one-year success rate for paroxysmal AF is approximately 70 to 80 percent and 60 to 70 percent for persistent AF at most experienced centers. However, a greater proportion of patients will derive an improvement in AF-related symptoms from ablation, and studies using implantable cardiac monitors or other devices that can record all episodes of AF have shown an AF burden reduction of over 98 percent [49]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients with prior antiarrhythmic drug treatment'.) Complications Complications are discussed in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 13/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pulmonary vein origin of atrial fibrillation (AF) The primary trigger for most episodes
11/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate POSTPROCEDURAL ISSUES After the procedure, patients usually remain supine for a fixed period (usually two to four hours) following sheath removal to promote hemostasis at the venous puncture sites. Vascular closure devices allow for more rapid hemostasis and shorter time to ambulation. Most centers keep patients overnight following the procedure. Same-day discharge has become increasingly common given the shorter procedure times and use of venous closure techniques [45,46]. Post-discharge medications Oral anticoagulation is usually continued [47] for at least two months to ensure that the increased risk of embolization associated with the procedure has returned to a baseline risk, regardless of CHADS VA Sc score. This also allows for adequate time 2 2 to document an absence of recurrence of AF for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [48]. Importantly, there are no randomized data on the safety of discontinuing anticoagulation post-ablation for patients who have presumably maintained sinus rhythm. The risk of AF recurrence, the recognized proportional increase in the burden of asymptomatic AF, and the uncertainty surrounding the causal association between the arrhythmia itself and stroke all support the recommendation to risk stratify patients for oral anticoagulation use based on CHA DS -VASc no differently than if an 2 2 ablation had not been performed. (See "Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation", section on 'Postprocedural anticoagulation'.) Antiarrhythmic medications may or may not be continued after the procedure. Our preference is to stop them after the procedure. Patients in whom consideration should be given to continuing them include patients with long-standing persistent AF or patients with debilitating AF symptoms. Post-discharge follow-up At the time of discharge, patients are given instructions on activity and what potential complications to look for. They should refrain from heavy physical activity, including exercise and weight lifting, for the week post-procedure to allow for complete healing of the vascular access sites. Baths should also be avoided for one week to reduce infection risk. In patients without identified post-procedural complications such as vascular access site problems, we wait three months to reevaluate the patient [9] (see 'Complications' below). Patients with potential complications should be seen immediately. Patients who develop symptoms should contact either their primary care physician, general cardiologist, or electrophysiologist to discuss the need for early evaluation. Yearly follow-up with a physician thereafter is also recommended. These ongoing interactions with the medical profession allow the patient's clinical status to be evaluated, including an https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 12/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate assessment of the presence or absence of AF, as well as their stroke risk profile and anticoagulation needs. These interactions also provide an opportunity to focus on the treatment of associated diseases and lifestyle modifications [9]. Routine ECG should be performed at the time of follow-up visits, and more intense monitoring may be performed as dictated by patient symptoms and the clinical impact of AF detection [41]. Evaluation for recurrent atrial fibrillation The primary purpose of the first follow-up visit around the three-month mark is to determine the success of the procedure. Screening for post- procedure AF is discussed separately. (See "Atrial fibrillation: Catheter ablation", section on 'Follow-up'.) In general, we do not evaluate the patient for the presence of AF prior to three months, as early episodes do not necessarily predict the long-term success or failure of the procedure. They can often be managed with antiarrhythmic drugs or cardioversion. Repeat ablation during this time is rarely necessary. During this three-month healing phase, there is resolution of inflammation and consolidation of lesion formation. This time period is referred to in clinical research trials as the "post-procedure blanking period." Anticoagulants are continued throughout this period regardless of the patient's CHA DS -VASc score ( table 1). Antiarrhythmic drugs and/or electrical cardioversion 2 2 are used during this blanking period at the discretion of the treating physician and usually reserved for those with debilitating symptoms or recurrent persistent AF. Success rates The success rate of AF ablation is dependent on multiple factors including patient selection, technique, definition of success, and the intensity and duration of rhythm monitoring post-ablation. For research purposes, the primary endpoint of AF ablation trials is freedom from recurrent AF/ atrial tachycardia (AT) defined as the absence of any recurrent AF/AT >30 seconds without antiarrhythmic drugs. Using this strict definition, the one-year success rate for paroxysmal AF is approximately 70 to 80 percent and 60 to 70 percent for persistent AF at most experienced centers. However, a greater proportion of patients will derive an improvement in AF-related symptoms from ablation, and studies using implantable cardiac monitors or other devices that can record all episodes of AF have shown an AF burden reduction of over 98 percent [49]. (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy", section on 'Patients with prior antiarrhythmic drug treatment'.) Complications Complications are discussed in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 13/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Pulmonary vein origin of atrial fibrillation (AF) The primary trigger for most episodes of AF involves electrical discharges within one or more pulmonary veins (PVs) ( figure 1). A principal goal of any procedure is to reduce the frequency of AF and electrically isolate the PVs so that these discharges do not activate atrial tissue. (See 'Introduction' above.) Clinical goal of catheter ablation (CA) The major clinical goal of CA is a reduction in AF- related symptoms. CA is superior to medical therapy at improving a patient's quality of life. Therefore, it is generally reserved for individuals with symptoms attributable to the arrhythmia, which most often include palpitations, shortness of breath, or generalized fatigue. Even if they have no AF-related symptoms, older individuals with early AF (duration <1 year) and additional cardiovascular conditions also benefit from therapies aimed at maintaining sinus rhythm; these therapies include CA. (See 'Patient selection' above.) https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 14/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Role of shared decision-making AF ablation is a complicated procedure with defined risks. Shared decision-making among the patient, primary care physician, general cardiologist, and electrophysiologist is essential. Ablation techniques Radiofrequency, cryothermal, and laser energy are the approved energy sources for CA of AF. (See 'Energy sources' above.) Various methods of CA have been used, and most focus on isolating the triggers in the PVs from the vulnerable substrate in the left atrium. The most common technique is circumferential PV isolation. (See 'Pulmonary vein isolation' above.) Complications Treating physicians should be aware of three serious complications that can occur postprocedurally: pericardial effusion causing cardiac tamponade, an atrial esophageal fistula, and PV stenosis ( table 2 and table 3). (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1275. 2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Heart Rhythm 2017; 14:e445. 3. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1305. 4. Larsson SC, Drca N, Wolk A. Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis. J Am Coll Cardiol 2014; 64:281. 5. Congrete S, Bintvihok M, Thongprayoon C, et al. Effect of obstructive sleep apnea and its treatment of atrial fibrillation recurrence after radiofrequency catheter ablation: A meta- analysis. J Evid Based Med 2018; 11:145. 6. Pathak RK, Middeldorp ME, Lau DH, et al. Aggressive risk factor reduction study for atrial fibrillation and implications for the outcome of ablation: the ARREST-AF cohort study. J Am Coll Cardiol 2014; 64:2222. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 15/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 7. 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Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm 2017; 33:369. 10. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med 2018; 378:417. 11. Nairooz R, Sardar P, Payne J, et al. Meta-analysis of major bleeding with uninterrupted warfarin compared to interrupted warfarin and heparin bridging in ablation of atrial fibrillation. Int J Cardiol 2015; 187:426. 12. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017; 376:1627. 13. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40:3013. 14. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805. 15. Reynolds MR, Allison JS, Natale A, et al. A Prospective Randomized Trial of Apixaban Dosing During Atrial Fibrillation Ablation: The AEIOU Trial. JACC Clin Electrophysiol 2018; 4:580. 16. Gunawardene MA, Dickow J, Schaeffer BN, et al. Risk stratification of patients with left atrial appendage thrombus prior to catheter ablation of atrial fibrillation: An approach towards an individualized use of transesophageal echocardiography. J Cardiovasc Electrophysiol 2017; 28:1127. 17. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 16/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 18. Kitkungvan D, Nabi F, Ghosn MG, et al. Detection of LA and LAA Thrombus by CMR in Patients Referred for Pulmonary Vein Isolation. JACC Cardiovasc Imaging 2016; 9:809. 19. Kuck KH, Brugada J, F rnkranz A, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med 2016; 374:2235. 20. Wasserlauf J, Knight BP, Li Z, et al. Moderate Sedation Reduces Lab Time Compared to General Anesthesia during Cryoballoon Ablation for AF Without Compromising Safety or Long-Term Efficacy. Pacing Clin Electrophysiol 2016; 39:1359. 21. Di Biase L, Conti S, Mohanty P, et al. General anesthesia reduces the prevalence of pulmonary vein reconnection during repeat ablation when compared with conscious sedation: results from a randomized study. Heart Rhythm 2011; 8:368. 22. Sivasambu B, Hakim JB, Barodka V, et al. Initiation of a High-Frequency Jet Ventilation Strategy for Catheter Ablation for Atrial Fibrillation: Safety and Outcomes Data. JACC Clin Electrophysiol 2018; 4:1519. 23. Briceno DF, Villablanca PA, Lupercio F, et al. Clinical Impact of Heparin Kinetics During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and Meta-Regression. J Cardiovasc Electrophysiol 2016; 27:683. 24. Nagao T, Inden Y, Yanagisawa S, et al. Differences in activated clotting time among uninterrupted anticoagulants during the periprocedural period of atrial fibrillation ablation. Heart Rhythm 2015; 12:1972. 25. Str ker E, de Asmundis C, Kupics K, et al. Value of ultrasound for access guidance and detection of subclinical vascular complications in the setting of atrial fibrillation cryoballoon ablation. Europace 2019; 21:434. 26. Yamagata K, Wichterle D, Roub cek T, et al. Ultrasound-guided versus conventional femoral venipuncture for catheter ablation of atrial fibrillation: a multicentre randomized efficacy and safety trial (ULTRA-FAST trial). Europace 2018; 20:1107. 27. Kurotobi T, Iwakura K, Inoue K, et al. Multiple arrhythmogenic foci associated with the development of perpetuation of atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:39. 28. Ha ssaguerre M, Ja s P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339:659. 29. Chen SA, Hsieh MH, Tai CT, et al. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation 1999; 100:1879. 30. Tsai CF, Tai CT, Hsieh MH, et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava: electrophysiological characteristics and results of https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 17/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate radiofrequency ablation. Circulation 2000; 102:67. 31. Lee G, Spence S, Teh A, et al. High-density epicardial mapping of the pulmonary vein-left atrial junction in humans: insights into mechanisms of pulmonary vein arrhythmogenesis. Heart Rhythm 2012; 9:258. 32. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation 2000; 102:2619. 33. Pappone C, Santinelli V. The who, what, why, and how-to guide for circumferential pulmonary vein ablation. J Cardiovasc Electrophysiol 2004; 15:1226. 34. Oral H, Knight BP, Tada H, et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002; 105:1077. 35. Reddy VY, Shah D, Kautzner J, et al. The relationship between contact force and clinical outcome during radiofrequency catheter ablation of atrial fibrillation in the TOCCATA study. Heart Rhythm 2012; 9:1789. 36. Neuzil P, Reddy VY, Kautzner J, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact force during initial treatment: results from the EFFICAS I study. Circ Arrhythm Electrophysiol 2013; 6:327. 37. Bourier F, Duchateau J, Vlachos K, et al. High-power short-duration versus standard radiofrequency ablation: Insights on lesion metrics. J Cardiovasc Electrophysiol 2018; 29:1570. 38. Macle L, Khairy P, Weerasooriya R, et al. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet 2015; 386:672. 39. Kobori A, Shizuta S, Inoue K, et al. Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial. Eur Heart J 2015; 36:3276. 40. Ghanbari H, Jani R, Hussain-Amin A, et al. Role of adenosine after antral pulmonary vein isolation of paroxysmal atrial fibrillation: A randomized controlled trial. Heart Rhythm 2016; 13:407. 41. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012; 14:528. 42. Lin JL, Lai LP, Tseng YZ, et al. Global distribution of atrial ectopic foci triggering recurrence of atrial tachyarrhythmia after electrical cardioversion of long-standing atrial fibrillation: a bi- https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 18/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate atrial basket mapping study. J Am Coll Cardiol 2001; 37:904. 43. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004; 43:2044. 44. Narayan SM, Patel J, Mulpuru S, Krummen DE. Focal impulse and rotor modulation ablation of sustaining rotors abruptly terminates persistent atrial fibrillation to sinus rhythm with elimination on follow-up: a video case study. Heart Rhythm 2012; 9:1436. 45. Bartoletti S, Mann M, Gupta A, et al. Same-day discharge in selected patients undergoing atrial fibrillation ablation. Pacing Clin Electrophysiol 2019; 42:1448. 46. Natale A, Mohanty S, Liu PY, et al. Venous Vascular Closure System Versus Manual Compression Following Multiple Access Electrophysiology Procedures: The AMBULATE Trial. JACC Clin Electrophysiol 2020; 6:111. 47. Eitel C, Koch J, Sommer P, et al. Novel oral anticoagulants in a real-world cohort of patients undergoing catheter ablation of atrial fibrillation. Europace 2013; 15:1587. 48. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long- term follow-up in nationwide cohort of Denmark. Eur Heart J 2015; 36:307. 49. Lohrmann G, Kaplan R, Ziegler PD, et al. Atrial fibrillation ablation success defined by duration of recurrence on cardiac implantable electronic devices. J Cardiovasc Electrophysiol 2020; 31:3124. Topic 95704 Version 21.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 19/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate GRAPHICS Junction of left atrium and pulmonary veins The common pattern of the superficial myocardial fibers of the left atrium (posterior aspect). A main circular fascicle (a, a', a", and a"') runs peripherally around the area of the openings of the pulmonary veins. An interatrial fascicle (b) runs between the right (RA) and the left (LA) atrium. Some fibers (c) descend from the left atrium into the left part (a') of the main circular fascicle. Circular fibers leaving the main fascicle turn around the openings of the pulmonary veins, forming sphincter-like structures; other fibers extend over the https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 20/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate veins as myocardial sleeves. Loops of fibers coming from the atrium are seen over the right superior pulmonary vein (RSPV) and returning to the atrium. Oblique, vertical (e), and transverse (f, f') fascicles of fibers are also seen on the posterior atrial surface. LA: left atrium; RA: right atrium; SVC: superior vena cava; IVC: inferior vena cava; RSPV: right superior pulmonary vein; LSPV: left superior pulmonary vein; RIPV: right inferior pulmonary vein; LIPV: left inferior pulmonary vein. From: Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. Circulation 1966; 34:412. DOI: 10.1161/01.cir.34.3.412. Copyright 1966. Adapted with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 127240 Version 3.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 21/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Clinical risk factors for stroke, transient ischemic attack, and systemic embolism in the CHA DS -VASc score 2 2 (A) The risk factor-based approach expressed as a point based scoring system, with the acronym CHA DS -VASc 2 2 (NOTE: maximum score is 9 since age may contribute 0, 1, or 2 points) CHA DS -VASc risk factor Points 2 2 Congestive heart failure +1 Signs/symptoms of heart failure or objective evidence of reduced left ventricular ejection fraction Hypertension +1 Resting blood pressure >140/90 mmHg on at least 2 occasions or current antihypertensive treatment Age 75 years or older +2 Diabetes mellitus +1 Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral hypoglycemic agent and/or insulin Previous stroke, transient ischemic attack, or thromboembolism +2 Vascular disease +1 Previous myocardial infarction, peripheral artery disease, or aortic plaque Age 65 to 74 years +1 Sex category (female) +1 (B) Adjusted stroke rate according to CHA DS -VASc score 2 2 CHA DS -VASc score Patients Stroke and 2 2 (n = 73,538) thromboembolism event rate at 1-year follow-up (%) 0 6369 0.78 1 8203 2.01 2 12,771 3.71 3 17,371 5.92 4 13,887 9.27 5 8942 15.26 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 22/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate 6 4244 19.74 7 1420 21.50 8 285 22.38 9 46 23.64 CHA DS -VASc: Congestive heart failure, Hypertension, Age ( 75; doubled), Diabetes, Stroke (doubled), Vascular disease, Age (65 to 74), Sex. 2 2 Part A from: Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial brillation developed in collaboration with EACTS. Europace 2016; 18(11):1609-1678. By permission of Oxford University Press on behalf of the European Society of Cardiology. Copyright 2016 Oxford University Press. Available at: www.escardio.org/. Graphic 83272 Version 29.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 23/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Intraprocedural risks of ablation for atrial fibrillation Complication Incidence Diagnostic testing Air embolism <1% Nothing or cardiac catheterization Asymptomatic cerebral emboli 2 to 15% Brain MRI Cardiac tamponade 0.2 to 5% Echocardiography Coronary stenosis/occlusion <0.1% Cardiac catheterization Death <0.1 to 0.4% N/A Mitral valve entrapment <0.1% Echocardiography Permanent phrenic nerve 0 to 0.4% Chest radiograph, sniff test paralysis Radiation injury <0.1% None Stroke or TIA 0 to 2% Head CT/MRI, cerebral angiography Vascular complications 0.2 to 1.5% Vascular ultrasound, CT scan MRI: magnetic resonance imaging; TIA: transient ischemic attack; CT: computed tomography. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127125 Version 1.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 24/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Signs and symptoms of complications of catheter ablation to prevent atrial fibrillation within a month post-ablation Sign/symptom Differential Suggested evaluation Back pain Musculoskeletal, retroperitoneal hematoma Physical exam, CT imaging Chest pain Pericarditis, pericardial effusion, coronary stenosis (ablation Physical exam, chest radiograph, ECG, related), pulmonary vein stenosis, musculoskeletal (after echocardiogram, stress test, cardiac catheterization, chest CT cardioversion), worsening reflux Cough Infectious process, bronchial Physical exam, chest irritation (mechanical, cryoballoon), pulmonary vein stenosis radiograph, chest CT Dysphagia Esophageal irritation (related to transesophageal Physical exam, chest CT, MRI echocardiography), atrioesophageal fistula Early satiety, nausea Gastric denervation Physical exam, gastric emptying study Fever Infectious process, pericarditis, atrioesophageal fistula Physical exam, chest radiograph, chest CT, urinalysis, laboratory blood work Fever, dysphagia, neurological Atrial esophageal fistula Physical exam, laboratory blood symptoms work, chest CT or MRI; avoid endoscopy with air insufflation Groin pain Pseudoaneurysm, AV fistula, Ultrasound of the groin, hematoma laboratory blood work; consider CT scan if ultrasound negative Hypotension Pericardial effusion/tamponade, bleeding, sepsis, persistent Echocardiography, laboratory blood work vagal reaction Hemoptysis Pulmonary vein stenosis or occlusion, pneumonia Chest radiograph, chest CT or MR scan, VQ scan Neurological symptoms Cerebral embolic event, atrial esophageal fistula Physical exam, brain imaging, chest CT or MRI Shortness of breath Volume overload, pneumonia, Physical exam, chest pulmonary vein stenosis, radiograph, chest CT, laboratory https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 25/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate phrenic nerve injury blood work CT: computed tomography; ECG: electrocardiogram; MRI: magnetic resonance imaging; AV: atrioventricular. Adapted from: Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial brillation: Executive summary. J Interv Card Electrophysiol 2017; 50:1. Available at: https://link.springer.com/article/10.1007%2Fs10840-017-0277-z. Copyright 2017 The Authors. Reproduced under the terms of the Creative Commons Attribution License 4.0. Graphic 127127 Version 1.0 https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 26/27 7/5/23, 9:12 AM Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/catheter-ablation-for-the-treatment-of-atrial-fibrillation-technical-considerations-for-non-electrophysiologists/print 27/27
7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 05, 2022. INTRODUCTION Ischemic stroke and systemic embolization are major causes of death and disability in patients with atrial fibrillation (AF). This topic will focus on the role of anticoagulant therapy to prevent embolization in patients scheduled to undergo catheter ablation (CA). The role of anticoagulant therapy in the broad population of patients with AF is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Other aspects of CA are discussed elsewhere. (See "Atrial fibrillation: Catheter ablation" and "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy" and "Overview of catheter ablation of cardiac arrhythmias" and "Patient education: Catheter ablation for the heart (The Basics)" and "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non-electrophysiologists".) OUR APPROACH TO ANTICOAGULATION There are three periods when a decision or decisions have to be made about anticoagulation in a patient scheduled for catheter ablation (CA). Preprocedural We effectively anticoagulate most patients, irrespective of CHA DS -VASC 2 2 score ( table 1) or presence or absence of sinus rhythm, with either a vitamin K antagonist (VKA) or a direct oral anticoagulant (DOAC; also referred to as non-vitamin K oral https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 1/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate anticoagulants [NOAC]) for at least three weeks prior to CA. It is reasonable to not use preprocedural anticoagulation in AF patients in sinus rhythm (and who are likely to remain in sinus rhythm for three weeks prior to the procedure) with a CHA DS -VASC score of 0. 2 2 (See 'Preprocedural issues' below.) Periprocedural We continue VKA in the periprocedural period. For most patients taking once-a-day DOACs, we hold the dose the day before and the morning of the procedure. For twice-a-day DOACs, some of our experts hold both doses the day before the procedure while others hold only the evening dose before the procedure; no drug is given the morning of the procedure. Uninterrupted DOAC may be reasonable for the uncommon patient who is at very high risk of a periprocedural stroke. Studies support the fact that uninterrupted DOACs may be superior to uninterrupted warfarin for patients who require continued anticoagulation due to high risk of thromboembolism. All patients receive a continuous infusion of unfractionated heparin (UFH); the activated clotting time is maintained at greater than 300 seconds during the procedure. (See 'Periprocedural issues' below.) Postprocedural UFH is stopped at the end of the procedure and the sheaths are pulled when the activated clotting time is <180 to 200 seconds. For patients previously taking a VKA, the next dose is given approximately 24 hours after the prior dose. For those patients in whom the international normalized ratio was <2.0 prior to the procedure, we restart UFH without a bolus six hours after sheath pull, increase the oral warfarin the night of the procedure, and we continue UFH until the INR is 2.0. Another reasonable approach is to stop UFH the morning after the procedure and start low molecular weight heparin, usually at half the normal dose (0.5 mg/kg twice daily) to avoid bleeding. (See 'Postprocedural anticoagulation' below.) For patients previously taking a DOAC, we suggest restarting it - six hours after sheath removal (and in the absence of any related bleeding). Some experts give intravenous heparin (no bolus; drip at 1000 to 1200 units per hour) or low molecular weight heparin (enoxaparin 0.5 mg/kg) starting six hours after sheath pull, that is uncomplicated by bleeding, and continue until the morning after the ablation. Other experts no longer give a heparin after sheath pull. Long-term We continue oral therapy with the previously prescribed oral anticoagulant for two to three months regardless of CHA DS -VASc score. After this period, the decision 2 2 to continue on long-term anticoagulation is based on the patients underlying stroke risk regardless of whether rhythm control has been achieved. For those patients whose risk for https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 2/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate embolization is very low, such as those with a CHA DS -VASc score of 0 ( table 1), we stop 2 2 anticoagulation at the two-to-three-month visit. INCIDENCE, TIMING, AND MECHANISM OF EMBOLISM The risk of stroke, transient ischemic attack, or other manifestation of embolization is increased at the time of catheter ablation (CA) and is in the range of 0.4 to 2.0 percent [1-3]. These rates come from studies of patients who are receiving anticoagulant therapy and would be higher off such treatment. Most strokes occur within 24 to 48 hours after the procedure [3]. However, embolic events thought attributable to the procedure have been reported to occur for up to one week [4]. The following are potential causes of periprocedural embolization: Withdrawal of anticoagulation before the procedure Catheter manipulation within the left atrium, which may dislodge preexisting thrombus Catheter trauma to the left atrial endothelium, which increases the risk of thrombus formation Thrombus formation on the ablation catheters or left atrial guide sheaths Conversion to sinus rhythm during the procedure in some patients (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation") Asymptomatic embolism Not all emboli to the brain are symptomatic. Multiple magnetic resonance imaging (MRI) studies performed within 24 hours after CA have demonstrated new cerebral lesions in 7 to 44 percent of asymptomatic patients [5-10]. These lesions are presumed secondary to microemboli [11]. Studies of the subsequent impact of these lesions on neurocognitive function have come to somewhat differing conclusions as to the significance of these lesions: The prevalence of cognitive impairment after radiofrequency CA (RFA) was evaluated in a study of 150 patients: 60 undergoing ablation for paroxysmal atrial fibrillation (AF), 30 for persistent AF, 30 for supraventricular tachycardia, and 30 matched AF patients awaiting RFA (the control group) [12]. All CA patients received periprocedural enoxaparin and most patients with AF had a CHADS score of 0 or 1 ( table 1). All patients underwent eight 2 neuropsychological tests at baseline and at 2 and 90 days after RFA. The prevalence of neurocognitive dysfunction at day 90 was 13, 20, 3, and 0 percent, respectively, in these four groups of patients. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 3/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate In a study of 37 patients with paroxysmal AF who underwent 41 CA procedures, MRI performed within 48 hours showed new brain lesions in 41 percent of patients and 44 percent of procedures [8]. Follow-up MRI at six months found glial scar in about 12 percent of those with lesions. However, there was no decline of neurocognitive function on testing performed after six months. PREPROCEDURAL ISSUES All patients not at low risk of stroke should be treated with long-term anticoagulant therapy using one of the novel oral anticoagulants or warfarin. Thus, many patients will be receiving anticoagulation when scheduled for catheter ablation (CA) and should continue their anticoagulant. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Summary and recommendations'.) For patients not taking long-term anticoagulant therapy due to a low risk of stroke, there are no studies that have compared differing anticoagulant strategies prior to CA; thus, the optimal preprocedural anticoagulation strategy is not known. For these patients, including those in sinus rhythm, most of our experts carry out a minimum of three weeks of effective oral anticoagulation prior to the procedure. The rationale for doing so is that many episodes of atrial fibrillation (AF) are asymptomatic and these episodes will have placed the patient at risk of embolization at the time of catheter manipulation. We also believe it is reasonable to not use preprocedural anticoagulation in AF patients in sinus rhythm (and who are likely to remain in sinus rhythm for three weeks prior to the procedure) with a CHA DS -VASc score of 0. 2 2 When three weeks of effective anticoagulant therapy has not been carried out, preprocedural transesophageal echocardiography (TEE) should be performed (see 'Role of transesophageal echocardiography' below); patients with evidence of left atrial thrombus are not candidates for CA unless it resolves with anticoagulation. Choice of anticoagulant For patients started on oral anticoagulant therapy prior to catheter ablation, we prefer one of the direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) group to warfarin. This preference is based on our preference for these agents in the general AF population. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Most but not all observational studies comparing one NOAC to warfarin have found similar efficacy [13] and safety [14-21]. At least three meta-analyses of observational studies comparing https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 4/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate warfarin to dabigatran have come to similar conclusions [22-24]. A 2016 meta-analysis of 25 studies (11,686 patients) comparing DOACs with uninterrupted VKAs found no significant difference in the rate of stroke or transient ischemic attacks (odds ratio 1.35, 95% CI 0.62-2.94) and major bleeding (odds ratio 0.80, 95% CI 0.65-1.00) [25]. Switching oral anticoagulant As stated directly above, we prefer one of the DOAC group to warfarin for patients undergoing catheter ablation. For patients receiving long-term warfarin therapy, there is no evidence that switching to DOAC prior to catheter ablation improves outcomes. Thus, we do not switch from warfarin to an DOAC. We do not have a preference for one DOAC over another and thus we do not switch DOAC. Based on the evidence presented above that suggests that uninterrupted dabigatran is superior to uninterrupted warfarin, we switch patients from warfarin to dabigatran. Role of transesophageal echocardiography Most patients, including those with effective preprocedural oral anticoagulation, should have a TEE performed prior to (generally the day before) CA. The presence of left atrial thrombus is a contraindication to the procedure [26,27]. Transthoracic echocardiography is not a replacement for TEE in this setting. Two reasons to perform TEE prior to (generally the day before) CA are that it adds significant length to the CA, and some complications of TEE, such as a retropharyngeal hematoma, can be aggravated by the unfractionated heparin used during the procedure. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'LA/LAA thrombi'.) We acknowledge that some experts will omit a TEE in the lowest-risk patients who have been taking effective anticoagulant therapy for at least three weeks, such as those in sinus rhythm who have no significant structural heart disease or those with a CHA DS -VASc score of 0 2 2 ( table 1) [27]. These experts often prefer that a pre-ablation magnetic resonance image confirms the absence of left atrial appendage thrombus in these patients who do not undergo preprocedural TEE. In a study of 97 patients undergoing pulmonary vein isolation, contrast- enhanced MRI demonstrated 100 percent concordance with TEE for the presence and absence of left atrial appendage thrombus [28,29]. An attempt to determine the need for preprocedural TEE in patients at low risk for embolization was made in an analysis of 1058 patients who had TEE performed within 24 hours of pulmonary vein isolation [30]. The frequency of left atrial thrombus or sludge was evaluated according to the CHADS score. (See "Echocardiography in detection of cardiac and aortic sources of systemic 2 embolism".) A CHADS score of 0 was present in 47 percent of patients. Left atrial or left atrial 2 appendage thrombus or sludge was found in 0.6 and 1.5 percent of all patients and the https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 5/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate frequency increased with ascending CHADS scores (percents in parentheses): 0 (0), 1 (2), 2 (5), 3 2 (9), 4 to 6 (11). We do not use intracardiac echocardiography or computed tomography as a substitute for TEE. Each of these has been shown to be inferior in this setting [31,32]. PERIPROCEDURAL ISSUES The two principal periprocedural anticoagulant issues are how to manage the oral anticoagulant and whether/how to use parenteral anticoagulant. Management of oral anticoagulants For patients taking long-term oral anticoagulant who present for catheter ablation, the approach depends on which anticoagulant the patient has been taking. Patients taking long-term vitamin K antagonist For patients taking a VKA prior to catheter ablation, we prefer the strategy of uninterrupted VKA to a strategy of a heparin bridge. We do not hold doses of VKA unless the international normalized ratio (INR) is >3.0. (See "Perioperative management of patients receiving anticoagulants", section on 'Bridging anticoagulation'.) One randomized trial [33] and most observational studies [3,34,35] have shown that continuous anticoagulation with warfarin, compared with warfarin discontinuation with a heparin bridge, is associated with a lower rate of embolization and an equivalent or lower bleeding rate [36]. In the COMPARE trial, 1584 patients with paroxysmal or persistent atrial fibrillation (AF) (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology') and CHADS score 1 were randomly assigned to warfarin discontinuation two 2 to three days before ablation and bridging with low molecular weight heparin (1 mg/kg enoxaparin twice daily until the evening before the procedure) or continuation of therapeutic warfarin (three to four weeks with an INR 2.0 to 3.0) [33]. The primary end point of the incidence of thromboembolic events (stroke, transient ischemic attack, or systemic thromboembolism) in the 48 hours after ablation occurred more frequently with warfarin discontinuation (4.9 versus 0.25 percent; odds ratio 13, 95% CI 3.1-55.6). The incidence of major bleeding complications was similar in the two groups (0.76 versus 0.38 percent, respectively). The majority of events occurred in patients with persistent AF. One limitation of the trial is that operators were not blinded to the anticoagulation strategy. For patients in whom a strategy of continuous anticoagulation with warfarin has been chosen, the optimal immediate-preprocedural range for the INR is not known. In a retrospective study of https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 6/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 1113 patients undergoing radiofrequency catheter ablation for AF, bleeding and vascular complications were less prevalent when the INR was 2.0 and 3.0 (5 percent), compared with 2.0 (10 percent) or 3.0 (12 percent) [37]. The optimal INR range was calculated to be 2.1 to 2.5. Patients taking DOACs In most studies that have evaluated periprocedural outcomes in patients taking direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]), the DOAC was held prior to the procedure. In one trial, 326 patients undergoing AF ablation were randomized to uninterrupted DOAC, procedure day single-dose skipped DOAC, or 24-hour skipped DOAC [38]. The intraprocedural heparin dose was higher in the 24-hour skipped group, but the incidence of major bleeding and postprocedural hemoglobin levels were not significantly different among the treatment groups and different DOACs. There were no fatal events or thromboembolic complications. For most patients taking once-a-day DOACs in the morning, we hold the dose the day before and also the day of the procedure. For those that take once-a-day DOACs with the evening meal or later, we hold only a single dose the day before the procedure. For twice-a-day DOACs, some of our experts hold both doses the day before the procedure while others hold only the evening dose before the procedure and the morning of the procedure. For a small minority of patients, such as those at particularly high risk of a periprocedural stroke, including those with a high CHA DS -VASc score in whom intraprocedural cardioversion is 2 2 planned, no interruption of (continuous) oral anticoagulation with a DOAC is a reasonable alternative to interruption. (See 'Choice of anticoagulant' above.) Small randomized trials of dabigatran, rivaroxaban, edoxaban, and apixaban suggest that outcomes with uninterrupted DOACs are similar to those with uninterrupted warfarin [39-42]. Use of intravenous heparin As catheter ablation (CA) is associated with an increase (from baseline) in the risk of a periprocedural thromboembolic event, we recommend that all patients receive intraprocedural heparin. (See 'Incidence, timing, and mechanism of embolism' above.) We start with a loading dose of 100 units/kg at the beginning of the procedure. Others start the loading dose before transeptal puncture, while others give half the dose before and half the dose after transeptal puncture [43]. A continuous infusion is used to maintain the activated clotting time greater than 300 seconds; the first activated clotting time is performed 10 to 15 minutes after the loading dose. Heparin is stopped at the end of the procedure and the sheaths are pulled when the activated clotting time is <180 to 200 seconds. Protamine can be given after the procedure before removing vascular sheaths. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 7/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Intracardiac echocardiography is done at the end of the CA procedure to ensure that there is no pericardial effusion. If a pericardial effusion is found we take the following approach: For small effusions, we observe and continue with the anticoagulation protocol. If moderate, we reverse anticoagulation and observe. If large, we reverse anticoagulation and perform pericardiocentesis. (See "Diagnosis and treatment of pericardial effusion", section on 'Treatment'.) For patients with hemodynamic compromise, regardless of the size of the effusion, we perform pericardiocentesis and reverse anticoagulation. POSTPROCEDURAL ANTICOAGULATION The approach to anticoagulation within the first 24 hours after a successful procedure is determined in large part by preprocedural anticoagulant approach (see 'Preprocedural issues' above). There have been no studies comparing one approach to another. In the absence of any related bleeding, we suggest the following approach: For those previously taking warfarin, and for whom the management of the international normalized ratio was not problematic, we suggest continuing warfarin. The first postprocedural dose should be the day after the procedure, assuming a dose was given the morning of the procedure. (See 'Patients taking long-term vitamin K antagonist' above.) For patients taking warfarin whose procedure was done with a subtherapeutic international normalized ratio, we restart intravenous heparin without a bolus six hours after sheath pull and start low molecular weight heparin the morning after the procedure. Low molecular weight heparin is continued until the international normalized ratio is therapeutic. When low molecular weight heparin is used, some of our experts give the first dose at 50 percent. For patients previously taking a direct oral anticoagulant (DOAC; also referred to as non- vitamin K oral anticoagulants [NOAC]), DOAC may be restarted four to six hours after sheath pull. Alternatively, some experts delay restarting these newer agents until the morning after the procedure. If the DOAC is restarted the morning after the procedure, we give either intravenous unfractionated heparin (no bolus; drip at 1000 to 1200 units per hour starting six hours after sheath pull and continued until the morning after the procedure) or low https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 8/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate molecular weight heparin (enoxaparin 0.5 mg/kg; typically a single dose administered six hours after sheath pull). For patients previously not taking any oral agent, we suggest starting either a DOAC or warfarin. A first dose of either agent can be given six hours after an uncomplicated procedure. Patients started on warfarin will need to receive bridging treatment for a few days with low molecular weight heparin, as described directly above. LONG-TERM ANTICOAGULATION We continue oral therapy with the previously prescribed oral anticoagulant [44] for at least two months to ensure that the increased risk of embolization associated with the procedure, which lasts for about four weeks, has returned to a baseline risk and that there has been adequate time to document an absence of recurrence of atrial fibrillation (AF) for those patients in whom practitioners and patients are contemplating discontinuing anticoagulation [45]. (See 'Incidence, timing, and mechanism of embolism' above.) After this two-month period of mandatory oral anticoagulation, we generally restore the anticoagulant regimen in place prior to the procedure. For those patients without evidence of recurrent AF and whose risk for embolization is very low, such as those with a CHA DS -VASc 2 2 score of 0 ( table 1), we stop anticoagulation. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'CHA2DS2-VASc score'.) Some experts are comfortable stopping anticoagulation in patients with a CHA DS -VASc score 2 2 of 1 ( table 1) after sufficient documentation of the absence of recurrent episodes of AF. We believe this approach has not been adequately tested. Therefore, we tell patients and referring physicians that the desire to stop long-term anticoagulation is not an indication for catheter ablation (CA) by itself. For all patients with a CHA DS -VASc score of >1 ( table 1) after CA, irrespective of whether or 2 2 not recurrence has been documented, we maintain the patient on long-term oral anticoagulation [46,47]. The optimal approach to chronic anticoagulation after successful CA, defined as no evidence of recurrence, is uncertain [48]. It is known that late recurrent AF occurs in 20 to 30 percent of patients, but the methods used in some studies likely underestimate the incidence [49-52]. (See "Atrial fibrillation: Catheter ablation", section on 'Efficacy'.) https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 9/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate In a 2019 meta-analysis of five studies with nearly 4000 patients that evaluated safety and efficacy of long-term oral anticoagulation (OAC) compared with no OAC, the following was found during a mean follow-up of nearly 40 months [53]: In patients with a CHA DS -VASc score 2, OAC continuation was associated with a 2 2 decrease in the risk of thromboembolic events (risk ratio [RR] 0.41, 95% CI 0.21-0.82) but an increased risk of intracranial hemorrhage (ICH; RR 5.78, 95% CI 1.33-25.08). The absolute risk decrease in thromboembolic risk was 1.14 percent, while the increase in ICH was 0.7 percent. In patients with a CHA DS -VASc score of 0 or 1, the risk of ICH from OAC exceeded any 2 2 potential decrease in thromboembolic risk. The issue of the role of long-term anticoagulation was indirectly addressed by at least three studies that found a lower incidence of stroke comparing successful CA to antiarrhythmic drug therapy [54-56]. In a retrospective study of 174 matched pairs of AF individuals with a CHA2DS2- VASc score 1 who were treated with either antiarrhythmic drug therapy or CA and treated for at least three months with warfarin, the rate of stroke/transient ischemic attack was lower with the CA group (0.59 versus 2.21 percent per year) [54]. In those individuals treated with CA and in whom there was no AF recurrence, the stroke rate was very low compared to those with recurrence (0.8 versus 5.4 percent) after a mean follow-up period of 47 months. In addition, it is not known if asymptomatic recurrences result in a persistent thromboembolic risk in patients who have undergone CA. A low risk of stroke was reported in a series of 755 patients with longstanding persistent AF who underwent CA or a tailored approach [57]. In this cohort, anticoagulation was discontinued three months after the procedure in the majority of the 522 patients who did not have evidence of recurrent AF. During a median follow-up of 25 months, none of the patients who stopped anticoagulation had a stroke. Although these results are encouraging, the study cohort had a low baseline thromboembolic risk, with most having a CHADS2-VASc score of 0 to 2 ( table 1). Some of these patients, such as those with lone AF, would not require chronic oral anticoagulation whether or not they had a successful CA procedure. The following recommendations were made in the 2019 update of the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline [58,59]: Systemic anticoagulation was recommended for at least two months in all patients following CA. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 10/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate After two months, the decision to continue anticoagulation should be based on the patient s risk factors for stroke and risk of bleeding, and not on the type of AF. The guideline acknowledges that recurrent episodes of AF, which may be asymptomatic, occur. The 2012 focused update of the European Society of Cardiology AF guideline recommends long- term oral anticoagulation CHA DS -VASc score of 2 [60]. The 2015 position document on 2 2 antithrombotic management in patients undergoing electrophysiological procedures states " the decision for oral anticoagulation depends on the patient s stroke risk profile and not the perceived success or failure of ablation " [43]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Catheter ablation of atrial fibrillation".) SUMMARY AND RECOMMENDATIONS The risk of stroke, transient ischemic attack, or other significant manifestation of embolization is increased, compared to baseline risk, at the time of catheter ablation (CA) for atrial fibrillation. (See 'Incidence, timing, and mechanism of embolism' above.) We perform a preprocedural transesophageal echocardiogram in most patients undergoing CA. The finding of intracardiac thrombus is a contraindication to the procedure. (See 'Role of transesophageal echocardiography' above.) Most patients scheduled to undergo CA who have been receiving long-term oral anticoagulation should continue to do so until the procedure. For those low-risk patients who have not been receiving long-term anticoagulation, including those in sinus rhythm at the time of the procedure, we suggest at least three weeks of effective anticoagulation prior to CA rather than no preprocedural anticoagulation (Grade 2C). An alternate approach is presented above. (See 'Preprocedural issues' above.) All patients should receive intraprocedural anticoagulation with intravenous heparin, irrespective of the patient s baseline thromboembolic risk and whether or not the procedure is performed on uninterrupted warfarin. (See 'Periprocedural issues' above.) https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 11/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate For patients taking long-term oral anticoagulant with warfarin who present for CA, we recommend continuing such therapy rather than stopping and using a heparin bridge (Grade 1A). For patients taking long-term oral anticoagulant with a newer oral anticoagulant who present for CA, we suggest discontinuing such therapy before the procedure rather than continuing it (Grade 2B). (See 'Periprocedural issues' above.) For the uncommon patient who is at very high risk of a periprocedural stroke, it is reasonable to not discontinue direct oral anticoagulants (DOAC; also referred to as non- vitamin K oral anticoagulants [NOAC]). (See 'Patients taking DOACs' above.) DOAC may be restarted four to six hours after sheath pull. Alternatively, DOAC may be restarted the morning after the procedure in patients who are treated overnight with either intravenous unfractionated heparin (no bolus; drip at 1000 to 1200 units per hour starting six hours after sheath pull and continued until the morning after the procedure) or low molecular weight heparin (enoxaparin 0.5 mg/kg; typically a single dose at six hours after sheath pull). (See 'Patients taking DOACs' above.) Oral anticoagulation is continued for at least two months after the procedure in all patients. After two months, the decision to continue anticoagulation should be based on the patient s risk factors for stroke and risk of bleeding and not on the type of AF or outcome of the procedure. (See 'Long-term anticoagulation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 2. 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A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol 2013; 36:172. 16. Winkle RA, Mead RH, Engel G, et al. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2012; 23:264. 17. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 13/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 2013; 6:460. 18. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:861. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014; 63:982. 20. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhythm Electrophysiol 2014; 7:576. 21. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59:1168. 22. Provid ncia R, Albenque JP, Combes S, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart 2014; 100:324. 23. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013; 15:1412. 24. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013; 15:1407. 25. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016; 117:926. 26. Knight BP. Transesophageal echocardiography before atrial fibrillation ablation: looking before cooking. J Am Coll Cardiol 2009; 54:2040. 27. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 14/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thor 28. Rathi VK, Reddy ST, Anreddy S, et al. Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. Heart Rhythm 2013; 10:1021. 29. Chen J, Zhang H, Zhu D, et al. Cardiac MRI for detecting left atrial/left atrial appendage thrombus in patients with atrial fibrillation : Meta-analysis and systematic review. Herz 2019; 44:390. 30. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 31. Saksena S, Sra J, Jordaens L, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with
1. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: incidence and predictors. J Cardiovasc Electrophysiol 2008; 19:627. 2. Cappato R, Calkins H, Chen SA, et al. Prevalence and causes of fatal outcome in catheter ablation of atrial fibrillation. J Am Coll Cardiol 2009; 53:1798. 3. Page SP, Herring N, Hunter RJ, et al. Periprocedural stroke risk in patients undergoing catheter ablation for atrial fibrillation on uninterrupted warfarin. J Cardiovasc Electrophysiol 2014; 25:585. 4. Kosiuk J, Kornej J, Bollmann A, et al. Early cerebral thromboembolic complications after radiofrequency catheter ablation of atrial fibrillation: incidence, characteristics, and risk factors. Heart Rhythm 2014; 11:1934. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 12/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 5. Michaud GF. Silent cerebral embolism during catheter ablation of atrial fibrillation: how concerned should we be? Circulation 2010; 122:1662. 6. Gaita F, Caponi D, Pianelli M, et al. Radiofrequency catheter ablation of atrial fibrillation: a cause of silent thromboembolism? Magnetic resonance imaging assessment of cerebral thromboembolism in patients undergoing ablation of atrial fibrillation. Circulation 2010; 122:1667. 7. Schrickel JW, Lickfett L, Lewalter T, et al. Incidence and predictors of silent cerebral embolism during pulmonary vein catheter ablation for atrial fibrillation. Europace 2010; 12:52. 8. Herm J, Fiebach JB, Koch L, et al. Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. Circ Arrhythm Electrophysiol 2013; 6:843. 9. Verma A, Debruyne P, Nardi S, et al. Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. Circ Arrhythm Electrophysiol 2013; 6:835. 10. Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. Pacing Clin Electrophysiol 2013; 36:1328. 11. Haines DE. ERACEing the risk of cerebral embolism from atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2013; 6:827. 12. Medi C, Evered L, Silbert B, et al. Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. J Am Coll Cardiol 2013; 62:531. 13. Shah RR, Pillai A, Schafer P, et al. Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. Am J Cardiol 2017; 120:404. 14. Kim JS, She F, Jongnarangsin K, et al. Dabigatran vs warfarin for radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm 2013; 10:483. 15. Nin T, Sairaku A, Yoshida Y, et al. A randomized controlled trial of dabigatran versus warfarin for periablation anticoagulation in patients undergoing ablation of atrial fibrillation. Pacing Clin Electrophysiol 2013; 36:172. 16. Winkle RA, Mead RH, Engel G, et al. The use of dabigatran immediately after atrial fibrillation ablation. J Cardiovasc Electrophysiol 2012; 23:264. 17. Bassiouny M, Saliba W, Rickard J, et al. Use of dabigatran for periprocedural anticoagulation in patients undergoing catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 13/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 2013; 6:460. 18. Maddox W, Kay GN, Yamada T, et al. Dabigatran versus warfarin therapy for uninterrupted oral anticoagulation during atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:861. 19. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of uninterrupted rivaroxaban for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2014; 63:982. 20. Dillier R, Ammar S, Hessling G, et al. Safety of continuous periprocedural rivaroxaban for patients undergoing left atrial catheter ablation procedures. Circ Arrhythm Electrophysiol 2014; 7:576. 21. Lakkireddy D, Reddy YM, Di Biase L, et al. Feasibility and safety of dabigatran versus warfarin for periprocedural anticoagulation in patients undergoing radiofrequency ablation for atrial fibrillation: results from a multicenter prospective registry. J Am Coll Cardiol 2012; 59:1168. 22. Provid ncia R, Albenque JP, Combes S, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart 2014; 100:324. 23. Bin Abdulhak AA, Khan AR, Tleyjeh IM, et al. Safety and efficacy of interrupted dabigatran for peri-procedural anticoagulation in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace 2013; 15:1412. 24. Hohnloser SH, Camm AJ. Safety and efficacy of dabigatran etexilate during catheter ablation of atrial fibrillation: a meta-analysis of the literature. Europace 2013; 15:1407. 25. Wu S, Yang YM, Zhu J, et al. Meta-Analysis of Efficacy and Safety of New Oral Anticoagulants Compared With Uninterrupted Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation. Am J Cardiol 2016; 117:926. 26. Knight BP. Transesophageal echocardiography before atrial fibrillation ablation: looking before cooking. J Am Coll Cardiol 2009; 54:2040. 27. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 14/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thor 28. Rathi VK, Reddy ST, Anreddy S, et al. Contrast-enhanced CMR is equally effective as TEE in the evaluation of left atrial appendage thrombus in patients with atrial fibrillation undergoing pulmonary vein isolation procedure. Heart Rhythm 2013; 10:1021. 29. Chen J, Zhang H, Zhu D, et al. Cardiac MRI for detecting left atrial/left atrial appendage thrombus in patients with atrial fibrillation : Meta-analysis and systematic review. Herz 2019; 44:390. 30. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol 2009; 54:2032. 31. Saksena S, Sra J, Jordaens L, et al. A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with atrial fibrillation: the intracardiac echocardiography guided cardioversion helps interventional procedures study. Circ Arrhythm Electrophysiol 2010; 3:571. 32. Martinez MW, Kirsch J, Williamson EE, et al. Utility of nongated multidetector computed tomography for detection of left atrial thrombus in patients undergoing catheter ablation of atrial fibrillation. JACC Cardiovasc Imaging 2009; 2:69. 33. Di Biase L, Burkhardt JD, Santangeli P, et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129:2638. 34. Santangeli P, Di Biase L, Horton R, et al. Ablation of atrial fibrillation under therapeutic warfarin reduces periprocedural complications: evidence from a meta-analysis. Circ Arrhythm Electrophysiol 2012; 5:302. 35. Kuwahara T, Takahashi A, Takahashi Y, et al. Prevention of periprocedural ischemic stroke and management of hemorrhagic complications in atrial fibrillation ablation under continuous warfarin administration. J Cardiovasc Electrophysiol 2013; 24:510. 36. Di Biase L, Gaita F, Toso E, et al. Does periprocedural anticoagulation management of atrial fibrillation affect the prevalence of silent thromboembolic lesion detected by diffusion cerebral magnetic resonance imaging in patients undergoing radiofrequency atrial https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 15/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate fibrillation ablation with open irrigated catheters? Results from a prospective multicenter study. Heart Rhythm 2014; 11:791. 37. Kim JS, Jongnarangsin K, Latchamsetty R, et al. The optimal range of international normalized ratio for radiofrequency catheter ablation of atrial fibrillation during therapeutic anticoagulation with warfarin. Circ Arrhythm Electrophysiol 2013; 6:302. 38. Yu HT, Shim J, Park J, et al. When is it appropriate to stop non-vitamin K antagonist oral anticoagulants before catheter ablation of atrial fibrillation? A multicentre prospective randomized study. Eur Heart J 2019; 40:1531. 39. Calkins H, Willems S, Gerstenfeld EP, et al. Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation. N Engl J Med 2017; 376:1627. 40. Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36:1805. 41. Hohnloser SH, Camm J, Cappato R, et al. Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial. Eur Heart J 2019; 40:3013. 42. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J 2018; 39:2942. 43. Sticherling C, Marin F, Birnie D, et al. Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC Working Group Thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS). Europace 2015; 17:1197. 44. Eitel C, Koch J, Sommer P, et al. Novel oral anticoagulants in a real-world cohort of patients undergoing catheter ablation of atrial fibrillation. Europace 2013; 15:1587. 45. Karasoy D, Gislason GH, Hansen J, et al. Oral anticoagulation therapy after radiofrequency ablation of atrial fibrillation and the risk of thromboembolism and serious bleeding: long- term follow-up in nationwide cohort of Denmark. Eur Heart J 2015; 36:307. 46. Schreiber D, Rostock T, Fr hlich M, et al. Five-year follow-up after catheter ablation of persistent atrial fibrillation using the stepwise approach and prognostic factors for success. Circ Arrhythm Electrophysiol 2015; 8:308. 47. Jacobs V, May HT, Bair TL, et al. The impact of risk score (CHADS2 versus CHA2DS2-VASc) on long-term outcomes after atrial fibrillation ablation. Heart Rhythm 2015; 12:681. 48. Kaufman ES, Waldo AL. The impact of asymptomatic atrial fibrillation. J Am Coll Cardiol 2004; 43:53. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 16/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 49. Saad EB, Marrouche NF, Saad CP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: emergence of a new clinical syndrome. Ann Intern Med 2003; 138:634. 50. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001; 104:2539. 51. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003; 42:185. 52. Verma A, Wazni OM, Marrouche NF, et al. Pre-existent left atrial scarring in patients undergoing pulmonary vein antrum isolation: an independent predictor of procedural failure. J Am Coll Cardiol 2005; 45:285. 53. Romero J, Cerrud-Rodriguez RC, Diaz JC, et al. Oral anticoagulation after catheter ablation of atrial fibrillation and the associated risk of thromboembolic events and intracranial hemorrhage: A systematic review and meta-analysis. J Cardiovasc Electrophysiol 2019; 30:1250. 54. Lin YJ, Chao TF, Tsao HM, et al. Successful catheter ablation reduces the risk of cardiovascular events in atrial fibrillation patients with CHA2DS2-VASc risk score of 1 and higher. Europace 2013; 15:676. 55. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol 2011; 22:839. 56. Hunter RJ, McCready J, Diab I, et al. Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death. Heart 2012; 98:48. 57. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006; 114:759. 58. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 59. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74:104. https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 17/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate 60. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14:1385. Topic 94502 Version 27.0 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 18/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or aortic plaque) 1 5 7.2 Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 19/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 Actual rates of stroke in contemporary cohorts might vary from these estimates. . References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 20/21 7/5/23, 9:13 AM Catheter ablation to prevent recurrent atrial fibrillation: Anticoagulation - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/catheter-ablation-to-prevent-recurrent-atrial-fibrillation-anticoagulation/print 21/21
7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical uses of dronedarone : Rod Passman, MD, MSCE, Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA : Mark S Link, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2023. INTRODUCTION Dronedarone, a noniodinated congener of amiodarone, was developed as an antiarrhythmic agent for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Because of the molecular and structural differences between dronedarone and amiodarone, in particular the deletion of the iodine molecules which are present in amiodarone, researchers have hypothesized that dronedarone will have fewer thyroid and pulmonary effects than amiodarone. Clinical trials have shown the clinical use and short-term safety (up to 21 months) of dronedarone for the maintenance of sinus rhythm following cardioversion in patients with AF [1]. The efficacy and tolerability of dronedarone in children and adolescents aged <18 years have not been established. A review of the pharmacology of dronedarone, its clinical uses, adverse effects, and drug interactions will be presented here. The clinical uses and toxicities of amiodarone and the choice of antiarrhythmic agents in the management of AF are discussed separately. (See "Amiodarone: Clinical uses".) (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 1/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate ELECTROPHYSIOLOGY AND MECHANISMS OF ACTION Dronedarone is a class III antiarrhythmic agent ( table 1) and a potent blocker of multiple intracardiac ion channels with many electrophysiological properties in common with amiodarone [2]. Like amiodarone, dronedarone has antiadrenergic (ie, beta blocking) properties and inhibits multiple transmembrane potassium currents, including the delayed rectifier current, the ultra-rapid delayed rectifier current, the inward rectifier current, and the transient outward current. In addition, dronedarone blocks inward depolarizing sodium and L-type calcium currents. PHARMACOLOGIC DATA/PHARMACOKINETICS Limited pharmacokinetic data are available for dronedarone and are derived primarily from data in the US Food and Drug Administration (FDA) prescribing information and from data in the FDA briefing document [3]. Dronedarone is approximately 70 to 94 percent absorbed after oral administration, but its absolute bioavailability is only approximately 15 percent due to significant first pass metabolism. Peak plasma concentrations are achieved within three to six hours. However, there is a significant food effect which increases plasma dronedarone concentrations between two- and threefold when the drug is taken with food [3]. Following the initiation of dronedarone 400 mg twice daily, steady-state plasma concentrations are reached within four to eight days [4]. The clearance of dronedarone is principally nonrenal, with a terminal half-life of approximately 24 hours [3]. This is markedly shorter than the half-life of amiodarone, which has an effective half-life of up to 50 days. Dronedarone is highly bound to plasma proteins and is not associated with significant tissue accumulation. Therefore, it has been postulated that systemic side effects secondary to long-term usage of the drug, such as liver toxicity, pulmonary fibrosis, or thyroid dysfunction will be minimized in comparison to amiodarone. However, long-term toxicity data are not yet available. Dronedarone has been shown to increase serum creatinine by 10 to 15 percent, a change which appears to resolve once the drug is discontinued [5]. A phase I trial of dronedarone (400 mg twice daily for seven days) in 12 healthy males reported a decrease in creatinine clearance of 18 percent (compared with placebo) without adverse effects on glomerular filtration rate or renal plasma flow [5]. Partial inhibition of tubular organic cation transporters has been suggested as a mechanism to explain the decrease in creatinine clearance. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 2/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial, with some suggestion that this cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms [6]. In a report of patient samples from the ATHENA trial, dronedarone exerted direct inhibitory effects on parameters of hemostasis and platelet reactivity at plasma concentrations typically achieved after routine clinical dosing [7]. These actions appear to be independent of the drug's antiarrhythmic properties and suggest a previously unknown pleiotropic effect. The active metabolite of dronedarone, SR35021A, demonstrates direct anticoagulant and antiplatelet effects in vitro at plasma concentrations typically achieved during conventional therapeutic dosing. These antithrombotic effects are likely to have contributed to the reported beneficial effects of dronedarone on ischemic events in patients with paroxysmal AF [6]. Further studies are needed to better understand the mechanisms involved and to gauge the magnitude of these pleiotropic effects of dronedarone in patients. METABOLISM AND DRUG INTERACTIONS Oral dronedarone 400 mg twice daily (taken with morning and evening meals) is approved for the maintenance of normal sinus rhythm in patients with a history of atrial fibrillation or atrial flutter. Dronedarone is metabolized by the CYP3A4 system in the liver and has many potential drug interactions Additional information can also be found using the Lexicomp drug interactions tool. As dronedarone primarily undergoes hepatic metabolism, its clearance may also be altered in patients with hepatic impairment. No dose adjustment is required in patients with renal insufficiency. The pharmacokinetics of dronedarone in patients with severe hepatic impairment have not been assessed; however, administration of dronedarone to patients with severe hepatic impairment is contraindicated [3]. Currently, there are no dose adjustment recommendations for patients with moderate hepatic impairment; however, data provided from the manufacturer indicate that patients with moderate hepatic impairment achieve higher dronedarone values with the potential to rise to supra-therapeutic concentrations [3]. (See "Drugs and the liver: Metabolism and mechanisms of injury".) Several drugs or classes of medications deserve special mention, as the risks associated with concomitant administration of dronedarone are potentially significant [3]: Ketoconazole and other potent CYP3A inhibitors Repeated doses of ketoconazole, a strong CYP3A4 inhibitor, result in a 17-fold increase in dronedarone exposure and a ninefold increase in the peak concentration (C ). Concomitant use of ketoconazole as max https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 3/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate well as other potent CYP3A inhibitors ( table 2) such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated. Dronedarone is also a CYP2D6 inhibitor and causes a modest increase in bioavailability of metoprolol in CYP2D6 extensive metabolizers [8]. (See "Drugs and the liver: Metabolism and mechanisms of injury".) QT prolonging medications Coadministration of drugs with the potential to prolong the QT interval (such as some phenothiazines, tricyclic antidepressants, some macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated due to the risk of inducing torsade de pointes-type ventricular tachycardia. (See "Overview of the acute management of tachyarrhythmias", section on 'Polymorphic ventricular tachycardia'.) Digoxin Concomitant administration of dronedarone and digoxin results in higher serum digoxin levels, likely due to a P-glycoprotein-mediated interaction in the kidney, and may be associated with a greater risk of death [4,9]. Studies have shown that when compared with placebo, concurrent digoxin and dronedarone administration was associated with an approximately 40 percent increase in digoxin levels [9,10]. Additionally, among 1070 patients from the PALLAS trial who were taking digoxin and randomized to dronedarone (544 patients) or placebo (526 patients), there were 15 cardiovascular deaths in patients receiving dronedarone (compared with two deaths in patients receiving placebo; adjusted hazard ratio [HR] 7.3, 95% CI 1.7-32.2) [9]. (See "Digitalis (cardiac glycoside) poisoning".) When dronedarone and digoxin are co-administered, a 50 percent digoxin dose reduction is recommended because of increased digoxin exposure [11-13]. Digoxin levels should be monitored closely to maintain serum concentrations of 0.5 to 0.8 ng/mL, with additional digoxin dose reductions as needed. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".) Oral anticoagulants Dronedarone increases serum warfarin exposure by 1.2-fold and does not cause clinically significant prolongation of INR values. Clinical trials have not identified a clinically significant interaction between dronedarone and warfarin [14,15]. A small, single-center crossover trial evaluating the competitive thrombin inhibitor dabigatran in 16 healthy volunteers demonstrated that dabigatran levels were increased when it was administered with dronedarone (1.7- to 2.0-fold greater than dabigatran alone) [16]. The increase was within the range seen with other dabigatran-drug combinations, and no dose adjustment has been recommended. Rivaroxaban levels can also increase when given concurrently with dronedarone, particularly in patients with decreased renal function [3]. The same is true for apixaban, and while no specific dose adjustments are required, patients should be routinely evaluated for signs and symptoms of blood loss. A study from a United States Claims Database showed a modest increased risk of gastrointestinal https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 4/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate bleeding when dronedarone was used with dabigatran (HR 1.40; 95% CI 1.01-1.93) or rivaroxaban (HR 1.31; 95% CI 1.01-1.69) [17]. There was no increased risk of intracranial hemorrhage associated with combined use of dronedarone and any nonvitamin K oral anticoagulant. Metoprolol Dronedarone increases the bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect [8]. These effects are modest when taking dronedarone 400 mg twice daily, and no dose adjustment is necessary. Neither higher doses of dronedarone nor metoprolol combinations have been evaluated; however, the potential for more marked effects on left ventricular function could be expected with higher doses [8]. In addition, while other beta blockers have not been reported, it is likely that a similar negative inotropic effect could result. Statins Dronedarone increases simvastatin, rosuvastatin, and atorvastatin exposure by 1.4- to 4-fold, which increases the potential for statin-induced myopathy [3]. (See "Statin muscle-related adverse events".) Grapefruit juice Grapefruit juice is a moderate inhibitor of CYP3A and results in a threefold increase in dronedarone exposure and a 2.5 increase in C . Therefore, patients max should avoid beverages containing grapefruit juice when using dronedarone [3]. Calcium channel blockers Verapamil, diltiazem, and nifedipine are moderate CYP3A inhibitors and increase dronedarone exposure by approximately 1.4 to 1.7-fold [3]. DRUG APPROVAL AND RESTRICTIONS Dronedarone is approved for maintenance of sinus rhythm in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation. Dronedarone is contraindicated in patients with permanent atrial fibrillation who will not or cannot be cardioverted to normal sinus rhythm. The use of dronedarone in these patients has resulted in increases in death, stroke, and heart failure hospitalizations when compared with placebo [18]. Other contraindications to dronedarone include: Concomitant use of strong CYP3A inhibitors. NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization. Severe hepatic disease. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 5/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate History of amiodarone-induced lung toxicity. Bradycardia <50 beats per minute, advanced AV block (second or third degree), or sick sinus syndrome, except when used in conjunction with a pacemaker. Use caution when administering dronedarone to Asian patients. Pharmacokinetic studies show Asian males (Japanese) have an approximate twofold higher dronedarone exposure than White males. DOSING AND MONITORING The adult and geriatric dose of dronedarone is 400 mg PO twice daily. Safety and efficacy in adolescents, children, and infants have not been established. Dose adjustments are not needed in mild to moderate liver impairment. Dronedarone use is contraindicated in severe liver impairment. Discontinue Class I or III antiarrhythmics (eg, amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong CYP3A4 inhibitors (eg, ketoconazole) prior to initiating dronedarone therapy. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' below.) INDICATIONS/CLINICAL USES Overview Dronedarone is primarily used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter ( algorithm 1) and no evidence of moderate to severe heart failure due to left ventricular systolic function [19]. Although spontaneous cardioversion occasionally occurs following the initiation of dronedarone, its efficacy is low for chemical cardioversion, and other drugs should be used. Dronedarone should not be used exclusively as a rate control medication given the greater likelihood of adverse cardiovascular events (based on the PALLAS trial preliminary results) and the availability of other agents for this purpose [19]. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 6/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Dronedarone has been reported to significantly increase mortality in patients with recently decompensated NYHA class III and IV heart failure and, as such, is contraindicated in this population. Little evidence has been published indicating that dronedarone has any efficacy in the treatment of ventricular arrhythmias. Because of this, there is no role for dronedarone in the treatment of ventricular tachyarrhythmias. Maintenance of sinus rhythm For the maintenance of sinus rhythm in patients with AF, dronedarone has been consistently shown to be more effective than placebo. In the ADONIS, EURIDIS, and DAFNE trials, patients treated with dronedarone compared with placebo had significantly longer times to first recurrence of AF and significantly greater chances of remaining in sinus rhythm at 6 and 12 months [1,20]. As an example, the following significant benefits from dronedarone therapy were noted in the ADONIS and EURIDIS trials [1,21]: A longer time to first recurrence of AF compared with placebo (96 versus 41 days in EURIDIS, 158 versus 59 days in ADONIS, and 116 versus 53 days on pooled analysis). A significantly higher percentage of patients remaining in sinus rhythm at 12 months (36 versus 25 percent receiving placebo). A significantly reduced risk of recurrent AF in patients who had previously failed another antiarrhythmic drug, with the greatest reduction among patients who failed therapy with a class Ic agent ( table 1) [21]. Compared with placebo, post-ablation patients treated with dronedarone in the ATHENA study had a reduced risk of recurrent AF (57 versus 71 percent) and a prolonged median time to first AF/AFL recurrence (561 days versus 180 days). There was no difference in the risk of first CV hospitalization/all-cause mortality [22]. At 12 months post-ablation, patients treated with dronedarone compared with sotalol had lower risks of hospitalization (HR 0.70; 95% CI 0.66-0.93) and proarrhythmia (HR 0.83; 95% CI 0.73-0.94) [23]. These findings were predominantly attributable to lower rates of atrial- tachyarrhythmia-related hospitalizations and lower rates of bradycardic proarrhythmia and need for pacemaker implantation. One trial directly compared dronedarone with amiodarone, which has long been considered to be the most effective antiarrhythmic drug for the maintenance of sinus rhythm following cardioversion for AF or atrial flutter. The DIONYSOS trial was a double-blind trial of 504 patients with AF that randomly assigned patients to dronedarone or amiodarone [24]. Patients were followed for at least six months, with a primary composite endpoint of recurrence of AF https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 7/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate (including unsuccessful electrical cardioversion, no spontaneous conversion, and no electrical cardioversion) or premature study drug discontinuation for intolerance or lack of efficacy. After 12 months of treatment, the primary composite endpoint was significantly more likely to have occurred in patients receiving dronedarone (75 versus and 59 percent in the amiodarone group, respectively; hazard ratio [HR] 1.59; 95% CI 1.28-1.98). This result was mainly driven by a more frequent recurrence of AF in the dronedarone group (64 versus 42 percent with amiodarone). However, there was a trend toward less frequent study drug discontinuation for intolerance in the dronedarone group (10 versus 12 percent in the amiodarone group). (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials", section on 'Dronedarone'.) Based upon the DIONYSOS study, dronedarone is less effective than amiodarone for the maintenance of sinus rhythm in patients with AF. While short-term toxicities appear to be less common among patients taking dronedarone, there are limited data regarding long-term toxicities. Our recommendations regarding the role of dronedarone in the maintenance of sinus rhythm are presented separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) Chemical cardioversion of AF Dronedarone is only rarely effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients) [20]. As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Ventricular rate control in AF Dronedarone slows the resting ventricular heart rate by approximately 10 to 15 beats per minute in patients who develop recurrent AF and has been shown to reduce the maximum heart rate with exercise by up to 25 beats per minute [1,10,25]. However, dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. (See 'Effect on cardiovascular mortality' below and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) Changing to another antiarrhythmic drug In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 8/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, clinical trial data describe three approaches: In the ADONIS and EURIDIS trials, dronedarone was initiated immediately upon discontinuation of amiodarone [1]. In the ERATO trial, patients underwent a two-month washout from amiodarone prior to initiation of dronedarone [10]. In the ATHENA trial, patients discontinued amiodarone one month prior to initiating dronedarone [6]. In general, dronedarone can be started promptly after amiodarone discontinuation, except in cases of clinically significant bradycardia or QT prolongation. SAFETY CONCERNS Effect on cardiovascular mortality There has never been any clear evidence of an overall mortality benefit with class I or class III antiarrhythmic medications ( table 1), including dronedarone, when used for the maintenance of sinus rhythm. Early post-hoc analyses of dronedarone trials suggested that patients receiving dronedarone may have reduced cardiovascular mortality and stroke risk. However, a preliminary analysis of the PALLAS trial showed increased mortality when dronedarone was used solely as a rate controlling agent in patients with chronic AF. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) A post-hoc analysis of the EURIDIS and ADONIS trials described above reported reduced rates of hospitalization or death in patients taking dronedarone [1]. In the ATHENA trial, the largest trial of dronedarone to evaluate cardiovascular hospitalization and mortality, 4628 patients with AF who were thought to be at high risk of cardiovascular events were randomly assigned to receive dronedarone or placebo; patients with NYHA class IV heart failure were excluded [6]. When compared with placebo, dronedarone was associated with a significant reduction in cardiovascular mortality (2.7 versus 3.9 percent, HR 0.71, 95% CI 0.51-0.98) that was mostly due to a reduction in arrhythmic mortality. Additionally, a post-hoc analysis of 1405 patients (followed for 2.5 years) from the ATHENA trial with paroxysmal or persistent AF and established coronary heart disease (CHD) demonstrated significantly lower rates of death or cardiovascular https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 9/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate hospitalization in those taking dronedarone (38 percent versus 47 percent with placebo; HR 0.73; 95% CI 0.62-0.86) [26]. Based upon the results of the ATHENA trial, the PALLAS trial was designed to test the hypothesis that dronedarone would improve major cardiovascular outcomes in patients with permanent rather than paroxysmal AF. Patients in PALLAS were treated with standard therapies for AF and then randomly assigned to dronedarone or placebo. The study was stopped early (3236 patients enrolled) after a significantly increased risk (HR 2.29, 95% CI 1.34-3.94) of cardiovascular events (cardiovascular death, myocardial infarction, stroke and systemic embolism) was observed in the dronedarone arm [27]. The individual secondary end points of stroke, death from cardiovascular causes, and hospitalization for heart failure were also significantly increased in the dronedarone group. While patients enrolled in the PALLAS trial were older, had a higher prevalence of baseline comorbidities including heart failure compared with those enrolled in ATHENA, and were in chronic AF with no plans for rhythm control, we are concerned about these findings which further underscore the potential toxicities of AADs. When used in routine clinical practice according to the appropriate guidelines and restrictions, dronedarone appears to be as safe as, or safer than, other antiarrhythmic drugs. In an analysis of nearly 175,000 Swedish patients with a diagnosis of AF between 2010 and 2012 (4856 received dronedarone, while 170,139 who did not served as the control population, mean follow-up 1.6 years) that used multivariable adjustment and propensity score matching to address baseline differences in the populations, patients who received dronedarone had significantly lower mortality compared with controls who did not receive dronedarone (1.31 versus 2.73 percent following adjustment and propensity score matching; HR 0.41; 95% CI 0.33-0.51) [28]. Patients receiving dronedarone also had lower mortality when compared with the general population. Our recommendations regarding the use of dronedarone for the maintenance of the sinus rhythm are discussed in detail separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone' and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Long-term follow-up'.) Patients with moderate to severe heart failure Because of the increase in mortality in patients with moderate to severe heart failure, dronedarone should NOT be used for the treatment of AF in such patients. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Summary and recommendations'.) https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 10/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate The ANDROMEDA trial was a randomized, double-blind trial comparing dronedarone with placebo in 627 patients with a history of AF or atrial flutter hospitalized with symptomatic heart failure (NYHA III and IV) and a left ventricular ejection fraction 35 percent [29]. The primary endpoint was death from any cause or hospitalization for worsening heart failure. The trial was stopped prematurely because of significantly increased mortality in the dronedarone arm (8 versus 4 percent in the placebo arm, HR 2.13, 95% CI 1.07-4.25). The excess mortality in the dronedarone arm was primarily due to heart failure, with the risk being highest in those with the most severely reduced left ventricular systolic function. There were no significant differences with respect to arrhythmic or sudden death and other nonfatal adverse events (except for higher serum creatinine levels in the dronedarone arm). In a 2012 meta-analysis of seven randomized controlled trials (10,676 patients) involving dronedarone (six trials used placebo, and one trial used amiodarone as the comparator), dronedarone use was associated with a non-significant trend toward higher cardiovascular and 2 all-cause mortality but with significant heterogeneity in the outcomes (I of 75 and 53 percent respectively), with ATHENA identified as the source of the heterogeneity [30]. When the data 2 were reanalyzed following exclusion of the ATHENA data, the outcomes were homogeneous (I of 0), with the risk of both cardiovascular (relative risk [RR] 2.33, 95% CI 1.49-3.64) and all-cause (RR 1.75, 95% CI 1.15-2.66) mortality significantly increased in users of dronedarone. In the above-mentioned analysis of nearly 175,000 Swedish patients, dronedarone patients with a diagnosis of heart failure were reported to have lower mortality compared with other heart failure patients (HR 0.40; 95% CI 0.30-0.53) and compared with the general population [28]. While these data do not supplant the results of the prior randomized trials and meta-analysis, they are reassuring that dronedarone, when used according to prescribing guidelines and restrictions, appears to be as safe as, or safer than, other antiarrhythmic drugs. In contrast to those with moderate to severe congestive heart failure due to left ventricular dysfunction, a post-hoc analysis of 221 patients in the ATHENA trial found that dronedarone was associated with a reduction in the risk of death or cardiovascular hospitalization (HR 0.76; 95% CI, 0.69-0.84); results were similar in subgroups of patients with persistent atrial fibrillation or atrial flutter, heart failure with preserved ejection fraction, and heart failure with mildly reduced ejection fraction [31]. Ventricular arrhythmia/ICDs Other than a case report describing complete suppression of ventricular tachycardia that was resistant to multiple antiarrhythmic drugs and endocardial ablation, there are no clinical data evaluating the use of dronedarone for the treatment of ventricular tachyarrhythmias or for the prevention of appropriate ICD shocks for ventricular tachycardia or ventricular fibrillation [32]. Pending further evidence of benefit, dronedarone https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 11/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate should not be prescribed for the treatment of ventricular arrhythmias. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Antiarrhythmic drugs'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Supraventricular arrhythmias".) SUMMARY AND RECOMMENDATIONS Background Dronedarone is a class III antiarrhythmic agent that may be considered for the maintenance of sinus rhythm in patients with atrial fibrillation (AF). Dronedarone has many electrophysiological properties in common with amiodarone, including its antiadrenergic (ie, beta blocking) properties and the ability to inhibit multiple transmembrane potassium, sodium, and calcium currents. (See 'Electrophysiology and mechanisms of action' above and "Amiodarone: Clinical uses".) Metabolism and drug interactions Because of its hepatic metabolism, there are numerous potential drug interactions with dronedarone. Concomitant use of dronedarone with some medications (eg, ketoconazole, class I antiarrhythmic drugs) is contraindicated, while its use with other medications (eg, digoxin, warfarin, statins) may require dose adjustment. (See 'Metabolism and drug interactions' above.) Maintenance of sinus rhythm Dronedarone (400 mg twice daily) is used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter and no evidence of heart failure or left ventricular systolic dysfunction who have spontaneously reverted to sinus rhythm or in whom cardioversion is planned. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' above.) Not as a rate control medication Dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. Dronedarone is only rarely https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 12/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients). As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See 'Ventricular rate control in AF' above and 'Effect on cardiovascular mortality' above and 'Chemical cardioversion of AF' above.) Changing to another medication In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, dronedarone can usually be started immediately after amiodarone discontinuation unless there is clinically significant bradycardia or QT prolongation. (See 'Changing to another antiarrhythmic drug' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 2. Varr A, Tak cs J, N meth M, et al. Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol 2001; 133:625. 3. MULTAQ Dronedarone tablets prescribing information products.sanofi.us/Multaq/Multaq.p df (Accessed on June 16, 2011). 4. Hoy SM, Keam SJ. Dronedarone. Drugs 2009; 69:1647. 5. Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol 2007; 64:785. 6. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 7. Zafar MU, Santos-Gallego CG, Smith DA, et al. Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions. Atherosclerosis 2017; https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 13/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate 266:81. 8. Damy T, Pousset F, Caplain H, et al. Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin Pharmacol 2004; 18:113. 9. Hohnloser SH, Halperin JL, Camm AJ, et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol 2014; 7:1019. 10. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J 2008; 156:527.e1. 11. Vallakati A, Chandra PA, Pednekar M, et al. Dronedarone-induced digoxin toxicity: new drug, new interactions. Am J Ther 2013; 20:e717. 12. Dorian P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 2010; 15:15S. 13. Dronedarone tablets. European Medicines Agency (EMA) Summary of product characteristic s. Last updated October 29, 2014. European Medicines Agency. www.ema.europa.eu/ema/in dex.jsp. 14. Shirolkar SC, Fiuzat M, Becker RC. Dronedarone and vitamin K antagonists: a review of drug- drug interactions. Am Heart J 2010; 160:577. 15. Patel C, Yan GX, Kowey PR. Dronedarone. Circulation 2009; 120:636. 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 17. Gandhi SK, Reiffel JA, Boiron R, Wieloch M. Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database). Am J Cardiol 2021; 159:79. 18. Multaq [package insert]. Bridgewater, NJ: Sanofi-aventis; 2014. 19. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 20. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 21. Guerra F, Hohnloser SH, Kowey PR, et al. Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents. Clin Cardiol 2014; 37:717. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 14/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate 22. Vamos M, Calkins H, Kowey PR, et al. Efficacy and safety of dronedarone in patients with a prior ablation for atrial fibrillation/flutter: Insights from the ATHENA study. Clin Cardiol 2020; 43:291. 23. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 24. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 25. Page RL, Connolly SJ, Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol 2011; 107:1019. 26. Pisters R, Hohnloser SH, Connolly SJ, et al. Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial. Europace 2014; 16:174. 27. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 28. Friberg L. Safety of dronedarone in routine clinical care. J Am Coll Cardiol 2014; 63:2376. 29. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 30. Chatterjee S, Ghosh J, Lichstein E, et al. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. Am J Cardiol 2012; 110:607.
Maintenance of sinus rhythm Dronedarone (400 mg twice daily) is used for the maintenance of sinus rhythm in patients with paroxysmal or persistent AF or atrial flutter and no evidence of heart failure or left ventricular systolic dysfunction who have spontaneously reverted to sinus rhythm or in whom cardioversion is planned. Hepatic function testing should be performed at the time of dronedarone initiation and repeated once or twice within the first six months and yearly thereafter. An electrocardiogram should be performed annually and at the time of any clinical change (ie, recurrent arrhythmia). (See 'Maintenance of sinus rhythm' above.) Not as a rate control medication Dronedarone should NOT be prescribed exclusively as a rate control medication given the availability of other agents for this purpose and the results of the PALLAS trial, which demonstrated an increase in cardiovascular mortality when dronedarone was used solely as a rate controlling agent. Dronedarone is only rarely https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 12/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate effective for the chemical cardioversion of AF or atrial flutter to sinus rhythm (less than 10 percent of patients). As such, dronedarone should NOT be used for this purpose. However, as there is a potential for cardioversion during drug initiation, standard precautions should be taken to minimize the risk of thromboembolic events (ie, therapeutic anticoagulation for at least three weeks or a transesophageal echocardiogram for assessment of left atrial thrombus). (See 'Ventricular rate control in AF' above and 'Effect on cardiovascular mortality' above and 'Chemical cardioversion of AF' above.) Changing to another medication In patients who have developed recurrent AF despite antiarrhythmic therapy, it may be necessary to switch antiarrhythmic drugs. Because of the potential for QT prolongation and torsades de pointes, concomitant use of dronedarone and class I or III antiarrhythmic drugs ( table 1) that prolong the QT interval is contraindicated, and at least five half-lives should be allowed between changes in antiarrhythmic agents with the exception of amiodarone. While there are no specific recommendations concerning the transition from amiodarone to dronedarone, dronedarone can usually be started immediately after amiodarone discontinuation unless there is clinically significant bradycardia or QT prolongation. (See 'Changing to another antiarrhythmic drug' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987. 2. Varr A, Tak cs J, N meth M, et al. Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol 2001; 133:625. 3. MULTAQ Dronedarone tablets prescribing information products.sanofi.us/Multaq/Multaq.p df (Accessed on June 16, 2011). 4. Hoy SM, Keam SJ. Dronedarone. Drugs 2009; 69:1647. 5. Tschuppert Y, Buclin T, Rothuizen LE, et al. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol 2007; 64:785. 6. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668. 7. Zafar MU, Santos-Gallego CG, Smith DA, et al. Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions. Atherosclerosis 2017; https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 13/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate 266:81. 8. Damy T, Pousset F, Caplain H, et al. Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects. Fundam Clin Pharmacol 2004; 18:113. 9. Hohnloser SH, Halperin JL, Camm AJ, et al. Interaction between digoxin and dronedarone in the PALLAS trial. Circ Arrhythm Electrophysiol 2014; 7:1019. 10. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the Efficacy and safety of dRonedArone for the cOntrol of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J 2008; 156:527.e1. 11. Vallakati A, Chandra PA, Pednekar M, et al. Dronedarone-induced digoxin toxicity: new drug, new interactions. Am J Ther 2013; 20:e717. 12. Dorian P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 2010; 15:15S. 13. Dronedarone tablets. European Medicines Agency (EMA) Summary of product characteristic s. Last updated October 29, 2014. European Medicines Agency. www.ema.europa.eu/ema/in dex.jsp. 14. Shirolkar SC, Fiuzat M, Becker RC. Dronedarone and vitamin K antagonists: a review of drug- drug interactions. Am Heart J 2010; 160:577. 15. Patel C, Yan GX, Kowey PR. Dronedarone. Circulation 2009; 120:636. 16. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 17. Gandhi SK, Reiffel JA, Boiron R, Wieloch M. Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database). Am J Cardiol 2021; 159:79. 18. Multaq [package insert]. Bridgewater, NJ: Sanofi-aventis; 2014. 19. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. 20. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 2003; 24:1481. 21. Guerra F, Hohnloser SH, Kowey PR, et al. Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents. Clin Cardiol 2014; 37:717. https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 14/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate 22. Vamos M, Calkins H, Kowey PR, et al. Efficacy and safety of dronedarone in patients with a prior ablation for atrial fibrillation/flutter: Insights from the ATHENA study. Clin Cardiol 2020; 43:291. 23. Wharton JM, Piccini JP, Koren A, et al. Comparative Safety and Effectiveness of Sotalol Versus Dronedarone After Catheter Ablation for Atrial Fibrillation. J Am Heart Assoc 2022; 11:e020506. 24. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol 2010; 21:597. 25. Page RL, Connolly SJ, Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol 2011; 107:1019. 26. Pisters R, Hohnloser SH, Connolly SJ, et al. Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial. Europace 2014; 16:174. 27. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011; 365:2268. 28. Friberg L. Safety of dronedarone in routine clinical care. J Am Coll Cardiol 2014; 63:2376. 29. K ber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008; 358:2678. 30. Chatterjee S, Ghosh J, Lichstein E, et al. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. Am J Cardiol 2012; 110:607. 31. Vaduganathan M, Piccini JP, Camm AJ, et al. Dronedarone for the treatment of atrial fibrillation with concomitant heart failure with preserved and mildly reduced ejection fraction: a post-hoc analysis of the ATHENA trial. Eur J Heart Fail 2022; 24:1094. 32. Shaaraoui M, Freudenberger R, Levin V, Marchlinski FE. Suppression of ventricular tachycardia with dronedarone: a case report. J Cardiovasc Electrophysiol 2011; 22:201. Topic 16216 Version 31.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 15/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate GRAPHICS Revised (2018) Vaughan Williams classification of antiarrhythmic drugs abridged table Class 0 (HCN channel blockers) Ivabradine Class I (voltage-gated Na+ channel blockers) Class Ia (intermediate dissociation): Quinidine, ajmaline, disopyramide, procainamide Class Ib (rapid dissociation): Lidocaine, mexilitine Class Ic (slow dissociation): Propafenone, flecainide Class Id (late current): Ranolazine Class II (autonomic inhibitors and activators) Class IIa (beta blockers): Nonselective: carvedilol, propranolol, nadolol Selective: atenolol, bisoprolol, betaxolol, celiprolol, esmolol, metoprolol Class IIb (nonselective beta agonists): Isoproterenol Class IIc (muscarinic M2 receptor inhibitors): Atropine, anisodamine, hyoscine, scopolamine Class IId (muscarinic M2 receptor activators): Carbachol, pilocarpine, methacholine, digoxin Class IIe (adenosine A1 receptor activators): Adenosine Class III (K+ channel blockers and openers) Class IIIa (voltage dependent K+ channel blockers): https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 16/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, vernakalant Class IIIb (metabolically dependent K+ channel openers): Nicorandil, pinacidil Class IV (Ca++ handling modulators) Class IVa (surface membrane Ca++ channel blockers): Bepridil, diltiazem, verapamil Class IVb (intracellular Ca++ channel blockers): Flecainide, propafenone Class V (mechanosensitive channel blockers): No approved medications Class VI (gap junction channel blockers) No approved medications Class VII (upstream target modulators) Angiotensin converting enzyme inhibitors Angiotensin receptor blockers Omega-3 fatty acids Statins HCN: hyperpolarization-activated cyclic nucleotide-gated; Na: sodium; K: potassium; Ca: calcium. Graphic 120433 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 17/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- containing coformulations Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, and norethindrone therapy pack Darunavir Phenobarbital Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- Mifepristone* Pexidartinib palonosetron Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- ritonavir plus dasabuvir Netupitant Nilotinib Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 18/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified [1,2] Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 19/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Strategies for rhythm control in patients with paroxysmal* and persistent AF AF: atrial fibrillation; CAD: coronary artery disease; HF: heart failure; LVH: left ventricular hypertrophy; AV: atrioventricular. Catheter ablation is only recommended as first-line therapy for patients with paroxysmal AF (Class IIa recommendation). Drugs are listed alphabetically. Depending on patient preference when performed in experienced centers. Not recommended with severe LVH (wall thickness >1.5 cm). Should be used with caution in patients at risk for torsades de pointes ventricular tachycardia. Should be combined with AV nodal blocking agents. Reproduced from: January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014. DOI: 10.1016/j.jacc.2014.03.021. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 95079 Version 3.0 https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 20/21 7/5/23, 9:13 AM Clinical uses of dronedarone - UpToDate Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Mark S Link, MD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-uses-of-dronedarone/print 21/21
7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clopidogrel resistance and clopidogrel treatment failure : Udaya S Tantry, PhD, Charles H Hennekens, MD, DrPH, James L Zehnder, MD, Paul A Gurbel, MD : Lawrence LK Leung, MD, Donald Cutlip, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 09, 2021. INTRODUCTION Clopidogrel, an oral platelet P2Y receptor blocker, is used with aspirin in patients who undergo 12 coronary artery stenting or who have an acute coronary syndrome (ACS) to reduce the risk of subsequent cardiovascular events such as stent thrombosis or recurrent ACS. Nonetheless, adverse cardiovascular events occur despite the use of dual antiplatelet therapy and are partly attributable to the variable pharmacodynamics of aspirin and P2Y receptor blockers. 12 This topic will address whether there is a clinical role for screening patients for P2Y drug 12 resistance and the management of patients who have clinical events despite clopidogrel therapy. The issues concerning aspirin nonresponse and resistance are presented separately. (See "Nonresponse and resistance to aspirin".) The indications for P2Y inhibitor use for the treatment of coronary artery disease are discussed 12 elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving primary PCI' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Information for patients'.) The indications for P2Y inhibitor use in stroke are discussed separately. (See "Long-term 12 antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Clopidogrel'.) https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 1/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate DEFINITIONS "Nonresponsiveness" to an antiplatelet drug is a pharmacodynamic phenomenon where there is no clinically meaningful change in platelet function after treatment. In studies employing light transmittance aggregometry, a change in maximal aggregation 10 percent from baseline, using adenosine diphosphate (ADP) as the agonist, is defined as "resistance." The percent change between pretreatment and on-treatment platelet function (ie, "responsiveness") can be categorized as "nonresponsive" ( 10 percent), "hypo-responsive" (10 to 20 percent), or "responsive" (>20 percent). Heightened platelet reactivity (HPR), also called high on-treatment platelet reactivity, to ADP during clopidogrel therapy indicates persistent suboptimal response of the P2Y receptor 12 (clopidogrel target). It is based on one measurement of on-treatment platelet reactivity. Usually, the cut points of HPR have been linked to clinical risk of thrombosis based on nonrandomized comparisons of stented patients. The evidence to support these cut points is described elsewhere. (See 'HPR and thrombotic events' below.) Clopidogrel treatment failure is best defined as the occurrence of a thrombotic event/ischemic event during clopidogrel therapy in patients with HPR. Treatment failure may result from patient noncompliance and/or inadequate antiplatelet response to clopidogrel. As multiple signaling pathways mediate platelet activation and the occurrence of thrombotic events, a treatment strategy directed against a single pathway, cannot be expected to prevent the occurrence of all events. In this context, not all ischemic events in patients taking clopidogrel may be due to lack of clopidogrel pharmacodynamic effect. There are multiple mechanisms involved in the genesis of a thrombotic event that may overcome the pharmacodynamic effects of clopidogrel. Therefore, a patient taking clopidogrel after stenting may have a new ischemic event in the presence of potent response to clopidogrel as measured by a platelet function assay. PREVALENCE It has been estimated that between 16 and 50 percent of patients treated with clopidogrel have high on-treatment platelet reactivity (HPR) [1]. HPR is dependent on the cut-off value used for each assay: the higher the cut-off, the lower the percent of patients with HPR. In addition, poor biologic response is determined by factors other than HPR. (See 'Potential explanations' below.) https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 2/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Clopidogrel response variability was initially demonstrated by measuring adenosine diphosphate-induced (ADP) platelet aggregation, as well as p-selectin and activated GP IIb/IIIa expression, at baseline and serially for 30 days after stenting in patients treated with a 300 mg clopidogrel load followed by 75 mg daily therapy. Some patients had no demonstrable antiplatelet effect; when the absolute difference between pre- and post-treatment platelet aggregation was 10 percent, patients were labelled regarded as "resistant" [2]. The prevalence of resistant patients was 31 percent at day five post-stenting, and it fell to 15 percent at day 30. ( figure 1). In addition, the level of platelet reactivity early after a standard clopidogrel regimen for coronary stenting was directly related to the pre-treatment reactivity. It has been reported that patients treated with clopidogrel (or prasugrel) who were hyper-responsive to ADP before treatment were likely to be hyper-responsive to ADP during platelet P2Y receptor blocker treatment [3,4]. 12 A reduction in platelet reactivity over time (after initiation of therapy) has been observed in some [5-8], but not all [9], studies. For example, two studies have shown a decrease in the prevalence of high on-treatment platelet reactivity of up to 50 percent at day 30 compared to day one post- stenting [2,6,7]. The reason for this time-dependent decrease is not clear. POTENTIAL EXPLANATIONS Clopidogrel response variability has been attributed to variability in active metabolite generation that is caused by: variable absorption, which is influenced by an ABCB1 gene polymorphism [1,10]; functional variability in CYP isoenzyme activity, which is influenced by single nucleotide polymorphisms (SNPs); and drug-drug interactions. The latter two are discussed below. Variation in clopidogrel metabolism Clopidogrel is a pro-drug that requires conversion into an active metabolite for biologic activity after oral administration. Approximately 85 percent of absorbed clopidogrel is hydrolyzed by human carboxylesterase-1 into an inactive carboxylic acid metabolite, and 15 percent is metabolized into an active metabolite by hepatic cytochrome P450 (CYP). Hepatic biotransformation involves a two-step oxidative process. In the first step, the thiophene ring of clopidogrel is oxidized to form 2-oxo-clopidogrel by CYP2C19, CYP1A2, and CYP2B6. In the second step, CYP3A4, CYP2B6, CYP2C19, and CYP2C9 catalyze the formation of the active metabolite (R-130964). It has been proposed that CYP2C19 is the major enzyme involved in the generation of clopidogrel active metabolite [11]. Among several polymorphisms of CYP2C19, the two most frequent variants associated with loss- of-function (LoF SNPs) are CYP2C192, a G681A mutation in exon 5 resulting in an aberrant splice site leading to the production of a truncated, nonfunctioning protein and CYP2C193, a https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 3/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate G636A mutation in exon 4 resulting in a premature stop codon [12-15]. The 17 variant is associated with increased gene transcription and increased enzyme function. The prevalence of LoF SNPs varies with race; the prevalence in Eastern Asian populations is up to 65 percent, whereas it is approximately 30 percent in White populations [16]. Interaction with other drugs Clopidogrel metabolism is potentially influenced by concomitantly administered agents, such as proton pump inhibitors (PPIs), calcium channel blockers (CCBs), or warfarin, which inhibit or enhance CYP activity or compete with clopidogrel during hepatic cytochrome P450-mediated metabolism [1]. Although the influence of these interactions on clopidogrel pharmacokinetics and pharmacodynamics has been reported, no prospective study has conclusively demonstrated a clinically important effect of these drugs in patients treated with clopidogrel. In addition, demographic variables such as age, renal failure, diabetes, and body mass index also influence the platelet response to adenosine diphosphate (ADP) by either directly affecting platelet function or by affecting clopidogrel metabolism. The final platelet reactivity phenotype and clinical outcomes of patients treated with clopidogrel is the result of all of these influences [1]. Drugs without clinically meaningful interaction Some drugs could cause an interaction with clopidogrel, but trials or studies do not support a clinically important interaction. These drugs include: Statins Although some studies have suggested a possible association between lipid soluble statin administration and pharmacodynamic effects of clopidogrel, the clinical relevance of these pharmacodynamics findings has not been demonstrated. Although such a relationship may be explained by the fact that some statins are metabolized by some of the same pathways as clopidogrel, the totality of evidence suggests that clinicians need not preferentially prescribe any particular statin with coadministration of clopidogrel [17-19]. (See "Statins: Actions, side effects, and administration", section on 'Drug interactions'.) Proton pump inhibitors In most patients, we believe that PPIs and clopidogrel can be used together. We agree with the 2009 US Food and Drug Administration notice that suggests that patients who take clopidogrel should consult with their clinician if they are taking a PPI or considering PPI use [20,21]. Despite the known pharmacodynamic interaction between PPIs and clopidogrel, which decreases the antiplatelet effect of clopidogrel, the available evidence suggests that PPIs do not decrease the clinical efficacy of clopidogrel [22-26]. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 4/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Examples of studies supporting this approach include the following: In a systematic review of published data, simultaneous use of a P2Y inhibitor and 12 a PPI did not significantly increase the risk of major adverse cardiovascular events (4.5 versus 4.7 percent in the PPI group; relative risk [RR] 0.99, 95% CI 0.76-1.28) [26]. In one of the largest trials in the meta-analysis, 3761 patients treated with clopidogrel were randomly assigned to either omeprazole or placebo [24]. There was no significant difference in cardiovascular events (4.9 versus 5.7 percent with placebo; hazard ratio [HR] 0.99, 95% CI 0.68-1.44) and a lower rate of gastrointestinal bleeding in patients assigned to omeprazole (1.1 versus 2.9 percent with placebo; HR 0.34, 95% CI 0.18-0.63). Calcium channel blockers CCBs inhibit CYP3A4, and there has been a concern that they may decrease the efficacy of clopidogrel. Some [27,28], but not all [29-31], studies have suggested a possible deleterious impact of CCB on clopidogrel efficacy. Based on the current totality of evidence, we do not recommend the restriction of CCB use in patients who are prescribed clopidogrel. Drugs with uncertain clinical interaction Examples of drugs that can alter the metabolism of clopidogrel but whose clinical interaction is not well-established include: Drugs that may increase the activity of clopidogrel by inducing CYP P450 enzymes: Rifampin [32,33] St. John s wort [34] Drugs that may decrease the activity of clopidogrel by inhibiting CYP P450 enzymes: Polyunsaturated omega-3 fatty acids [35] Erythromycin, troleandomycin Ketoconazole Diabetes mellitus Patients with diabetes mellitus have increased platelet activation [5,36-38] and a higher percent of circulating immature platelets [39]. These characteristics could, in theory, counteract the inhibitory effect of clopidogrel (or aspirin) on platelets [37,40-43]. The totality of available evidence is incomplete and inconsistent [44-48]. It has been postulated that patients with diabetes mellitus may require increased doses of one or both of these agents in order to show an optimal therapeutic effect [49], or may be https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 5/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate candidates for a more potent platelet inhibitor (eg, prasugrel [50,51], ticagrelor [52-55]). (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus", section on 'Platelet activation' and "Platelet biology", section on 'Prasugrel' and "Platelet biology", section on 'Platelet agonists and their receptors'.) Renal insufficiency There is no convincing evidence chronic kidney disease (CKD) significantly influences platelet response to clopidogrel [56,57]. Noncompliance Noncompliance with clopidogrel therapy is common and offers a plausible explanation for the lack of clinical benefit [15,58,59]. Smoking In subgroup analyses of randomized trials of clopidogrel therapy, nonsmokers taking clopidogrel had less clinical benefit than did smokers taking clopidogrel. This effect is referred to as a "smoker's paradox" [60-63]. The stimulation of CYP1A2 associated with smoking enhances platelet inhibition by clopidogrel; smoking cessation reverses this effect [28,29,42,60- 62,64-67]. Although this subgroup finding may be due to chance, lower clopidogrel active metabolite exposure and pharmacodynamic effects of clopidogrel in nonsmokers relative to smokers is a plausible alternative explanation for the smokers paradox [68]. The magnitude of the effect of smoking on the efficacy of clopidogrel was evaluated in a 2013 systematic review, meta-analysis, and indirect comparison of randomized trials that included nearly 75,000 patients (29 percent smokers) in which clopidogrel was compared to placebo, aspirin, or another platelet P2Y receptor blocker [63]. Among the subgroup of smokers, 12 patients taking clopidogrel had a 25 percent reduction in the primary composite outcome of cardiovascular death, myocardial infarction (MI), and stroke compared to the control therapy (RR 0.75, 95% CI 0.67-0.83). In the subgroup of nonsmokers, patients taking clopidogrel had a smaller 8 percent reduction (0.92, 95% CI 0.87-0.98). Finally, it has been hypothesized, that the underlying pathobiology of thrombosis may differ between smokers and nonsmokers [69]. HPR AND THROMBOTIC EVENTS Most, but not all, descriptive and observational analytic studies contribute to the formulation of the hypothesis of an association between "resistance" to clopidogrel or high on-treatment platelet reactivity (HPR) and subsequent cardiovascular events after percutaneous coronary intervention (PCI) or peripheral artery intervention: Platelet function and outcomes https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 6/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate In a case series of aggregometry, 60 patients undergoing primary PCI for ST-elevation MI (STEMI) who were in the lowest quartile of clopidogrel responsiveness at day six (compared to baseline levels) had the highest rates of ischemic events during follow-up [70]. In the PREPARE POST-STENTING study, a threshold of approximately 50 percent maximal periprocedural aggregation (with 20 micromol adenosine diphosphate [ADP]) was associated with six-month ischemic event occurrence [71]. In subsequent studies, approximately 40 percent aggregation (with 20 micromol ADP) was associated with the onset of risk for stent thrombosis occurrence and approximately 40 percent platelet aggregation (5 micromol ADP) among patients receiving long-term clopidogrel and aspirin therapy before stenting was associated with 12-month ischemic event occurrence [72,73]. In a case series of 340 patients undergoing PCI, those with high posttreatment reactivity measured by VerifyNow (>235 P2Y reaction units [PRU]) had higher rates of 12 cardiovascular death (2.8 versus 0 percent, p = 0.04) and stent thrombosis (4.6 versus 0 percent, p = 0.004) [74]. In a case series of 1608 patients undergoing elective PCI using the Multiplate analyzer, low responders as indicated by upper quintile platelet reactivity (approximately 482 aggregation units (AU)min) had a significantly higher risk of definite stent thrombosis and a higher mortality rate within 30 days compared with patients less than 482 AU*min [75]. In a case series of 802 consecutive patients undergoing elective PCI receiving a loading dose of 600 mg clopidogrel followed by 75 mg daily [76], platelet aggregation was assessed immediately before PCI by optical aggregometry following 5 micromol ADP. Multivariate analysis confirmed platelet aggregation above the median level as a significant independent predictor of the 30-day composite of death, MI, and target lesion revascularization (relative risk [RR] 6.7, 95% CI 1.5-29). On-treatment platelet reactivity utilizing the VerifyNow P2Y point-of-care assay was 12 evaluated in a study of 683 patients with acute coronary syndromes (ACS) who were treated with aspirin and clopidogrel and were scheduled to undergo PCI [77]. In a multivariate model, a residual platelet reactivity (RPR) 240 PRU was a significant and independent predictor of cardiovascular death and nonfatal MI at 12 months (hazard ratio [HR] 2.5, 95% CI 1.3-5.1). No significant association was found between a high RPR and target vessel revascularization. A subsequent meta-analysis, which included this study, concluded that an RPR 230 PRU was associated with a significantly higher rate of the composite end point of death, MI, and stent thrombosis (HR 2.10, 95% CI 1.62-2.73), as well as a significantly higher rate for each of the individual end points of death, MI, and stent thrombosis [78]. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 7/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate The prospective registry, ADAPT-DES, is the largest case series of platelet function study conducted, which was in patients treated with stenting. Platelet reactivity was assessed using VerifyNow point-of-care assays in 8582 patients (52 percent ACS patients) after successful PCI. HPR (>208 PRU) was independently associated with 30-day definite/probable stent thrombosis (HR 3.0, p = 0.005), one-year definite/probable stent thrombosis (HR 2.49, p = 0.001), and MI (HR 1.42, p = 0.01); and two-year definite/probable stent thrombosis (adjusted HR 1.84, p = 0.009) and MI (HR 1.33, p = 0.01). In addition, >208 PRU was independently associated with a lower incidence of bleeding at one year (HR 0.73, p = 0.002) and at two years (HR 0.82, p = 0.02) [79,80]. A monotonic association between successively higher PRU quintiles and two-year stent thrombosis was observed, whereas the greatest risk of clinically relevant bleeding occurred in the lowest PRU quintile, with similar risks across the four higher quintiles. These relationships remained significant in fully adjusted multivariable analyses (adjusted HR for stent thrombosis in Q5 versus Q1: 2.32, 95% CI 1.17-4.59; p = 0.02; adjusted HR for clinically relevant bleeding in Q5 versus Q1: 0.61, 95% CI 0.47-0.77; p<0.001). ADAPT-DES provides important and relevant information to the formulation of hypotheses about patients with HPR and culprit-lesion morphology, as well as adverse plaque morphology. Specifically, three-vessel coronary artery disease, incidence of fibroatheroma, elevated percentage of plaque burden, and longer culprit lesion attenuated plaque length [81]. Those prescribed a PPI had higher HPR (odds ratio 1.38, 95% CI 1.25-1.52; p = 0.0001) and also a greater rate of postdischarge adverse outcomes (HR 1.21, 95% CI 1.04-1.42; p = 0.02) [82]. After further analysis of patients who were treated with DAPT at two years in the ADAPT DES study (comprising 46 percent of patients), those with HPR prescribed clopidogrel had higher rates of definite or probable stent thrombosis (adjusted HR 2.16, p = 0.003), MI (adjusted HR 1.35, p = 0.02), freedom from clinically relevant bleeding (adjusted HR 0.74, p = 0.002), and all-cause mortality (adjusted HR 1.36, p = 0.04) [83]. These results are useful to formulate but not test hypotheses and may be due, all or in part, to confounding by indication. In addition, however, they are compatible with the "therapeutic window of P2Y inhibition" at moderately inhibited PRU to avoid the risk of ischemic event 12 occurrences and bleeding and contribute to the formulation of the platelet hypothesis for which personalized antiplatelet therapy is being prescribed [84]. Systemic review and meta-analysis of individual patient data on MACE outcomes using 13 prospective observational studies with 6478 clopidogrel-treated patients revealed that the strength of the association between MACE risk and platelet reactivity as measured by ADP- induced aggregation by conventional aggregometry was increased significantly (p = 0.04) https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 8/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate with the number of risk factors present (age >75 years, ACS at inclusion, diabetes, and hypertension). Platelet reactivity allowed the reclassification of 44 percent of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high-risk patients [85]. In this regard, it should be noted that meta-analyses of observational studies will surely reduce the role of chance but also introduce bias and confounding as the individual studies are not randomized [86,87]. In the PRECLOP's case series of 100 patients undergoing infrainguinal angioplasty or stenting and taking clopidogrel 75 mg daily were assessed with VerifyNow prior to the procedure [88]. At one year, the primary composite end point (death, major stroke, major amputation, target vessel revascularization, and bypass) increased with increasing quartile of PRU (4, 12, 52, and 84 percent, respectively; all p<0.05 except for the first versus second quartile). Since case series are descriptive and are hypothesis formulating but not testing, some medically managed patients do not support this hypothesis: In the TRILOGY randomized trial, 9326 patients with medically managed unstable angina or non-ST elevation MI were randomly assigned to treatment with either clopidogrel or prasugrel and 27.5 percent of these patients were included in the platelet function substudy [89]. Platelet function was measured serially up to 30 months after randomization by the VerifyNow assay. There was only a modest, unadjusted association between on- treatment PRU values and HPR status with ischemic event occurrence that did not persist after multivariable adjustment. In the ADIRE case series of 771 stable cardiovascular outpatients, platelet reactivity to ADP was not associated with three-year major cardiovascular adverse events [90]. Loss of function gene carriers and outcomes Evidence from prospective studies of P2Y 12 therapy suggest higher rates of cardiovascular events in patients with loss of function CYP2C19 gene variants who are taking clopidogrel [91-95]. As examples: In an NIH Implementing Genomics In Practice (IGNITE) study, patients with a LoF gene variant treated with clopidogrel had higher rates MACE after PCI. After 1 year of observation, CYP2C19 LOF allele carriers who received clopidogrel were more likely to experience a MACE than those allele carriers who received alternative therapy (adjusted HR 2.21, p = 0.021). In patients who received either prasugrel or ticagrelor, patients with a CYP2C19 LOF allele had a similar risk of MACE when compared to patients without a LOF allele (adjusted HR 0.81, 95% CI 0.48-1.35; p = 0.41) [91]. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 9/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate In a meta-analysis of randomized trials designed to compare the efficacy of clopidogrel to either prasugrel or ticagrelor in CYP219 LOF gene carriers, patients with a CYP219 LOF gene variant had a higher risk of cardiovascular events with clopidogrel than with other P2Y inhibitors (RR 1.42, 95% CI 1.2-1.7) [92]. Patients without a LoF gene variant had a 12 similar risk of cardiovascular events with clopidogrel or alternative P2Y therapy (RR 1.0, 12 95% CI 0.8-1.25). Patients with PCI comprised 77 percent of the sample. CLINICAL MANIFESTATIONS AND DIAGNOSIS As mentioned above, clopidogrel treatment failure is the occurrence of a thrombotic event/ischemic event during clopidogrel therapy in patients with heightened platelet reactivity (HPR). These events are usually stent thrombosis or recurrent acute coronary syndrome (ACS). The clinical presentations of these events are discussed separately. (See "Coronary artery stent thrombosis: Clinical presentation and management", section on 'Clinical presentation' and "Diagnosis of acute myocardial infarction".) A definitive diagnosis of clopidogrel treatment failure requires the finding of HPR on laboratory testing in a patient with either stent thrombosis or recurrent ACS. In most patients, we do not believe testing for clopidogrel hyporesponsiveness is necessary. If the patient appears to have been taking clopidogrel as prescribed, switching to a more potent antiplatelet is reasonable. (See 'Management of possible clopidogrel failure' below.) If a decision is made to use one of the following tests to assess the degree of platelet P2Y 12 receptor inhibition (responsiveness to antiplatelet therapy), we are most comfortable with the VerifyNow P2Y assay, as the largest body of data correlating platelet reactivity to clinical 12 outcomes has been obtained with it. The following laboratory methods are used to assess the degree of platelet P2Y receptor 12 inhibition (responsiveness to antiplatelet therapy): Point-of-care and near point-of-care assays: VerifyNow P2Y assay, Multiplate Analyzer, 12 thrombelastography with Platelet Mapping Assay, and platelet function assay-100 with collagen-adenosine diphosphate (ADP) cartridge. VerifyNow and Multiplate assays have been widely used to demonstrate the relation of HPR to clinical outcomes in observational studies. VerifyNow has been used in the main prospective clinical trials of personalized antiplatelet therapy [96]. With the VerifyNow P2Y assay, values >208 PRU are required for 12 the finding of HPR. With Multiplate, values >47 AU are required for HPR. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 10/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate ADP-induced aggregation measured by light transmittance aggregometry using platelet rich plasma. Values >46 percent with 5 micromol ADP or >59 percent with 20 micromol ADP are required for the finding of HPR. P2Y receptor reactivity determined by the degree of reduction in the maximal levels of 12 vasodilator stimulated phosphoprotein (VASP) phosphorylation (P) stimulated by P after GE1 the addition of ADP. VASP-P is measured by flow cytometry and is specific in determining P2Y receptor activity. With VASP, values >50 percent PRI are required for the finding of 12 HPR. The cut-off values presented above are derived from studies that have used receiver operating characteristic (ROC) curve analysis used to define a threshold or cut-point of on-treatment platelet reactivity associated with the optimal combination of sensitivity and specificity to identify thrombotic/ischemic risk. It should be noted that such cut-points may depend on the subset of patients studied. In fact, cut-off values have been mainly investigated in patients undergoing percutaneous coronary intervention (PCI) and different targets may be obtained in other settings depending on patient management or baseline risk profile. The consistent findings across multiple investigations support the important role of HPR in the etiology of ischemic events after PCI, including stent thrombosis, and suggest the existence of a threshold level of platelet reactivity below which ischemic events may be prevented. The observed cut-off values for platelet reactivity noted above had a very high negative predictive value for thrombotic/ischemic event occurrence. However, the positive predictive value is low for all assays. This is consistent with the fact that although a major determinant of thrombotic events, HPR is not the sole factor responsible for these events [1]. A 2010 consensus statement proposed cut-off values based on receiver operating characteristic curve analysis for different platelet function assays to be used in future studies of personalized antiplatelet therapy [1]. A meta-analysis of studies employing the VerifyNow point-of-care assay lends further support for the potential role of monitoring of P2Y receptor inhibitor therapy as 12 a diagnostic marker [78]. Taken together, these data are compatible with the hypothesis that adequate protection against ischemic events with clopidogrel therapy might be achieved by overall low to moderate levels of post-treatment platelet reactivity. Some studies suggested that the prognostic value of HPR can be improved by the addition of classical clinical and procedural risk factors and suggested that a comprehensive algorithm including clinical as well as laboratory findings (platelet reactivity and genotype) should be considered in future personalized antiplatelet therapy investigations to optimize outcomes [97,98]. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 11/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate SCREENING The utility of routine screening for clopidogrel hyporesponsiveness or nonresponsiveness is controversial [99]. In the absence of a well-established benefit of genotype-guided therapy, we do not routinely test patients for clopidogrel resistance with genetic testing to detect loss of function gene carriers (eg, CYP2C19 allele testing) or with platelet function testing to detect P2Y resistance [100,101]. 12 Some experts recommend routine testing based on biological plausibility and observational studies that suggest an association between genotype or platelet function and stent thrombosis. In contrast, most randomized trials do not show a benefit of genotype-guided [102-104] or platelet reactivity-guided [105-108] antiplatelet therapy. As examples: The TAILOR-PCI was a large trial of gene-guided antiplatelet therapy in the drug-eluting stent era [102]. In this trial, 5302 patients undergoing percutaneous coronary intervention (PCI; 84 percent for acute coronary syndrome [ACS]) and who were to receive 12 months of DAPT were randomly assigned to clopidogrel therapy or genotype-guided therapy. In the genotype-guided arm, CYP2C19 LoF allele carriers were given ticagrelor and wild-type allele carriers received clopidogrel; all patients in the standard-therapy arm received clopidogrel. The primary analysis only included patients with LoF alleles, which included 903 patients in the genotype-guided group and 946 patients in the standard therapy group. Genotype- guided therapy was associated with a nonsignificant 34 percent reduction in the primary endpoint of cardiovascular death, myocardial infarction (MI), stroke, stent thrombosis, or severe recurrent ischemia at 12 months (4.0 versus 5.9 percent; hazard ratio [HR] 0.66, 95% CI 0.43-1.02). The reduction in the endpoint was primarily driven by a reduction in severe recurrent ischemia (ie, ECG changes leading to urgent revascularization without a diagnosis of MI, cardiac angina). The risk of major or minor bleeding was similar in both groups. In a prespecified sensitivity analysis that assessed repeated events, genotype-guided therapy was associated with a significant 40 percent reduction in the primary endpoint compared with standard therapy (HR 0.60, 95% CI 0.41-0.89). The POPULAR GENETICS trial found that genotype-guided therapy in patients with STEMI was associated with similar rates of MACE [103]. In this trial, 1242 patients were randomly assigned to gene-guided therapy and 1246 were assigned to standard care. In the gene- guided group, LoF carriers received prasugrel or ticagrelor, while all patients in the standard therapy group received either prasugrel or ticagrelor. The rate of all-cause death, myocardial infarction, definite stent thrombosis, stroke, and bleeding were similar between https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 12/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate groups (5.1 versus 5.9 percent in the standard therapy group; absolute rate difference 0.7 percent; 95% CI 2.0 to -0.7). In the ANTARCTIC randomized trial, 877 ACS patients aged 75 years or older who underwent coronary stenting and were treated with prasugrel 5 mg were randomly assigned to platelet monitoring or no monitoring groups [107]. There was no difference between the two strategies in the primary composite end point of cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and bleeding complications at 12 months (28 percent in both groups) or the single end point of bleeding events. The chief strength of ANTARCTIC is the randomized design, but limitations include the fact that, with low-dose prasugrel, the need to intensify therapy for high platelet reactivity was uncommon in the monitoring group (approximately 4 percent). In addition, almost all of the P2Y dose adjustments in ANTARCTIC were de-intensification from prasugrel to 12 clopidogrel in an attempt to reduce bleeding. The ARCTIC trial and subsequent ARCTIC-Monitoring study did not demonstrate a clear benefit of platelet function-guided antiplatelet therapy prior to PCI or during one year of follow-up and noted high variability in agreement between platelet function assays [105,106]. MANAGEMENT OF POSSIBLE CLOPIDOGREL FAILURE Patients who have stent thrombosis or an acute coronary syndrome (ACS) while taking clopidogrel may have clopidogrel resistance or hypo-/nonresponsiveness. As no adequately powered study has clearly demonstrated that testing for clopidogrel hyporesponsiveness improves clinically important outcomes, most of our authors and reviewers do not perform these tests. For these patients, based on studies that have shown that more potent platelet P2Y receptor 12 blockers (such as ticagrelor or prasugrel) lower on-treatment platelet reactivity, most of our experts switch to one of these drugs. However, two of our authors perform platelet function testing and point-of-care genetic testing to assess for clopidogrel hyporesponsiveness in these cases and manage the patient accordingly: the finding of platelet resistance leads to a recommendation for ticagrelor or prasugrel; the finding of adequate clopidogrel effect leads to continuation of clopidogrel therapy. None of the interventions discussed below, including the use of a more potent agent, has been shown to improve long-term clinical outcomes. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 13/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Acute coronary syndrome Adjusting the loading dose Achieving a platelet reactivity level below high on-treatment platelet reactivity (HPR) by selectively increasing the clopidogrel loading dose based upon laboratory evidence for clopidogrel resistance has been shown to benefit short-term outcome [109-116]. The clinical benefit of increasing the clopidogrel loading dose on reducing the incidence of subsequent adverse cardiac events was shown in a prospective randomized trial of 162 patients scheduled to undergo percutaneous coronary intervention (PCI). Clopidogrel hypo- nonresponsiveness was defined as an in vitro vasodilator-stimulated phosphoprotein phosphorylation analysis (VASP index) >50 percent after a 600 mg loading dose of clopidogrel [111]. All patients with a VASP index >50 percent were randomly assigned to a control group or VASP-guided group. In the comparison group, PCI was carried out without an additional bolus of clopidogrel, whereas in the VASP-guided group, up to three additional boluses of 600 mg of clopidogrel were given in 24-hour increments. The VASP index was then assessed 12 hours after administration until an index <50 percent was achieved, following which PCI was performed. The following findings were noted: In the VASP-guided group, 38 patients required two doses of clopidogrel to achieve a VASP index <50 percent, 14 required three doses, and 15 required four doses. Despite a total clopidogrel dose of 2400 mg, 11 patients (14 percent) remained "resistant" and received PCI. There were no major adverse cardiac events in this subgroup. The number of serious adverse cardiac events (two cardiovascular deaths, four acute or subacute stent thromboses, two recurrent ACS) during the one-month follow-up was significantly less in the VASP-guided group (0 versus 8 events). Adjusting the maintenance dose The following studies in which the maintenance dose was adjusted did not show improvement in long-term clinical outcome: In the GRAVITAS trial, 2214 subjects with high platelet reactivity on clopidogrel (as measured by the VerifyNow P2Y test) following PCI with a drug-eluting stent, were 12 assigned at random to treatment with either standard dose (no loading dose, 75 mg/day) or high dose (600 mg loading dose, 150 mg/day thereafter) clopidogrel for 60 days [6]. The primary study end point (six-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis) was virtually identical in those receiving either standard or high dose clopidogrel (2.3 percent in each group; hazard ratio 1.01; 95% CI 0.58-1.76). In addition to being underpowered, there are other potential https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 14/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate
In contrast, most randomized trials do not show a benefit of genotype-guided [102-104] or platelet reactivity-guided [105-108] antiplatelet therapy. As examples: The TAILOR-PCI was a large trial of gene-guided antiplatelet therapy in the drug-eluting stent era [102]. In this trial, 5302 patients undergoing percutaneous coronary intervention (PCI; 84 percent for acute coronary syndrome [ACS]) and who were to receive 12 months of DAPT were randomly assigned to clopidogrel therapy or genotype-guided therapy. In the genotype-guided arm, CYP2C19 LoF allele carriers were given ticagrelor and wild-type allele carriers received clopidogrel; all patients in the standard-therapy arm received clopidogrel. The primary analysis only included patients with LoF alleles, which included 903 patients in the genotype-guided group and 946 patients in the standard therapy group. Genotype- guided therapy was associated with a nonsignificant 34 percent reduction in the primary endpoint of cardiovascular death, myocardial infarction (MI), stroke, stent thrombosis, or severe recurrent ischemia at 12 months (4.0 versus 5.9 percent; hazard ratio [HR] 0.66, 95% CI 0.43-1.02). The reduction in the endpoint was primarily driven by a reduction in severe recurrent ischemia (ie, ECG changes leading to urgent revascularization without a diagnosis of MI, cardiac angina). The risk of major or minor bleeding was similar in both groups. In a prespecified sensitivity analysis that assessed repeated events, genotype-guided therapy was associated with a significant 40 percent reduction in the primary endpoint compared with standard therapy (HR 0.60, 95% CI 0.41-0.89). The POPULAR GENETICS trial found that genotype-guided therapy in patients with STEMI was associated with similar rates of MACE [103]. In this trial, 1242 patients were randomly assigned to gene-guided therapy and 1246 were assigned to standard care. In the gene- guided group, LoF carriers received prasugrel or ticagrelor, while all patients in the standard therapy group received either prasugrel or ticagrelor. The rate of all-cause death, myocardial infarction, definite stent thrombosis, stroke, and bleeding were similar between https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 12/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate groups (5.1 versus 5.9 percent in the standard therapy group; absolute rate difference 0.7 percent; 95% CI 2.0 to -0.7). In the ANTARCTIC randomized trial, 877 ACS patients aged 75 years or older who underwent coronary stenting and were treated with prasugrel 5 mg were randomly assigned to platelet monitoring or no monitoring groups [107]. There was no difference between the two strategies in the primary composite end point of cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and bleeding complications at 12 months (28 percent in both groups) or the single end point of bleeding events. The chief strength of ANTARCTIC is the randomized design, but limitations include the fact that, with low-dose prasugrel, the need to intensify therapy for high platelet reactivity was uncommon in the monitoring group (approximately 4 percent). In addition, almost all of the P2Y dose adjustments in ANTARCTIC were de-intensification from prasugrel to 12 clopidogrel in an attempt to reduce bleeding. The ARCTIC trial and subsequent ARCTIC-Monitoring study did not demonstrate a clear benefit of platelet function-guided antiplatelet therapy prior to PCI or during one year of follow-up and noted high variability in agreement between platelet function assays [105,106]. MANAGEMENT OF POSSIBLE CLOPIDOGREL FAILURE Patients who have stent thrombosis or an acute coronary syndrome (ACS) while taking clopidogrel may have clopidogrel resistance or hypo-/nonresponsiveness. As no adequately powered study has clearly demonstrated that testing for clopidogrel hyporesponsiveness improves clinically important outcomes, most of our authors and reviewers do not perform these tests. For these patients, based on studies that have shown that more potent platelet P2Y receptor 12 blockers (such as ticagrelor or prasugrel) lower on-treatment platelet reactivity, most of our experts switch to one of these drugs. However, two of our authors perform platelet function testing and point-of-care genetic testing to assess for clopidogrel hyporesponsiveness in these cases and manage the patient accordingly: the finding of platelet resistance leads to a recommendation for ticagrelor or prasugrel; the finding of adequate clopidogrel effect leads to continuation of clopidogrel therapy. None of the interventions discussed below, including the use of a more potent agent, has been shown to improve long-term clinical outcomes. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 13/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Acute coronary syndrome Adjusting the loading dose Achieving a platelet reactivity level below high on-treatment platelet reactivity (HPR) by selectively increasing the clopidogrel loading dose based upon laboratory evidence for clopidogrel resistance has been shown to benefit short-term outcome [109-116]. The clinical benefit of increasing the clopidogrel loading dose on reducing the incidence of subsequent adverse cardiac events was shown in a prospective randomized trial of 162 patients scheduled to undergo percutaneous coronary intervention (PCI). Clopidogrel hypo- nonresponsiveness was defined as an in vitro vasodilator-stimulated phosphoprotein phosphorylation analysis (VASP index) >50 percent after a 600 mg loading dose of clopidogrel [111]. All patients with a VASP index >50 percent were randomly assigned to a control group or VASP-guided group. In the comparison group, PCI was carried out without an additional bolus of clopidogrel, whereas in the VASP-guided group, up to three additional boluses of 600 mg of clopidogrel were given in 24-hour increments. The VASP index was then assessed 12 hours after administration until an index <50 percent was achieved, following which PCI was performed. The following findings were noted: In the VASP-guided group, 38 patients required two doses of clopidogrel to achieve a VASP index <50 percent, 14 required three doses, and 15 required four doses. Despite a total clopidogrel dose of 2400 mg, 11 patients (14 percent) remained "resistant" and received PCI. There were no major adverse cardiac events in this subgroup. The number of serious adverse cardiac events (two cardiovascular deaths, four acute or subacute stent thromboses, two recurrent ACS) during the one-month follow-up was significantly less in the VASP-guided group (0 versus 8 events). Adjusting the maintenance dose The following studies in which the maintenance dose was adjusted did not show improvement in long-term clinical outcome: In the GRAVITAS trial, 2214 subjects with high platelet reactivity on clopidogrel (as measured by the VerifyNow P2Y test) following PCI with a drug-eluting stent, were 12 assigned at random to treatment with either standard dose (no loading dose, 75 mg/day) or high dose (600 mg loading dose, 150 mg/day thereafter) clopidogrel for 60 days [6]. The primary study end point (six-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis) was virtually identical in those receiving either standard or high dose clopidogrel (2.3 percent in each group; hazard ratio 1.01; 95% CI 0.58-1.76). In addition to being underpowered, there are other potential https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 14/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate explanations for the neutral results of GRAVITAS trial [117]. In a time-dependent analysis of GRAVITAS, <208 PRU was independently associated with the 60 days primary end point (hazard ratio [HR] 0.23, 95% CI 0.05-0.98) and tended to be an independent predictor at six months (HR 0.54, 95% CI 0.28-1.04) [118]. Only a minority of patients receiving high-dose clopidogrel achieved <208, indicating that high-dose clopidogrel regimen may have been sub-optimal and a more potent intervention that reduces HPR to a greater extent would have had greater potential to improve clinical outcomes given the very low event rate. In support of this hypothesis, the ELEVATE-TIMI (Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction) 56 trial showed that up to 225 mg of clopidogrel might be necessary to overcome HPR in patients carrying one loss-of-function cytochrome 2C19 gene (see below). GRAVITAS enrolled a population at low absolute risk for ischemic events despite displaying HPR. The majority of patients had stable angina, were successfully treated with PCI, and periprocedural events were not included in the primary end point. The tested pharmacologic intervention was administered more than 12 hours after PCI and the associated acute vessel injury/stent deployment, which may have been too late to blunt a platelet-related incipient lesion. Finally, it is possible that a single platelet function test may not reliably reflect the effect of clopidogrel on adenosine diphosphate- induced platelet reactivity in all patients [117]. In the CREATIVE trial, 1078 patients undergoing PCI who had low responsiveness to clopidogrel, as assessed by thromboelastography, were randomly assigned to standard antiplatelet therapy (clopidogrel 75 mg daily plus aspirin 100 mg daily), double-dose clopidogrel (clopidogrel 150 mg daily plus aspirin 100 mg daily), or adjunctive use of cilostazol (cilostazol 100 mg twice daily plus aspirin 100 mg daily plus clopidogrel 75 mg daily) [119]. The primary end point of the incidence of major adverse cardiac and cerebrovascular events at 18 months occurred in 14.4, 10.6, and 8.5 percent of the three groups, respectively (HR 0.72, 96% CI 0.47-1.09 and 0.55, 95% CI 0.35-0.87, comparing double-dose clopidogrel or adjunctive cilostazol, respectively). There were no significant differences in the rates of major bleeding. The ELEVATE study of PCI demonstrated that 225 mg daily clopidogrel is required to reduce platelet reactivity (<50 platelet reactivity index as measured by VASP phosphorylation assay) in CYP2C192 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers [120]. Clinical outcomes were not assessed. Use of alternative antiplatelet agents There are no randomized trials that have tested whether the substitution (for clopidogrel) of more potent platelet P2Y receptor blockers 12 (ticagrelor and prasugrel) in patients with HPR lowers the risk of subsequent adverse cardiovascular outcomes. Since the use of these two drugs has been shown to lower on- https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 15/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate treatment platelet reactivity, it may be prudent to adopt this strategy [54,121,122] and we believe this is a reasonable approach. Practitioners and patients should be aware of the higher risk of bleeding with these agents. Further support for this approach derives from data summarized below: In a randomized, single-blind, cross-over study, prasugrel was more efficient in reducing platelet function compared to clopidogrel as measured by VerifyNow P2Y assay. The 12 prevalence of HPR was significantly lower in all patients (7.5 versus 35.8 percent), in CYP2C192 carriers (5.3 versus 47.4 percent), and in noncarriers (8.8 versus 29.4 percent). In another randomized, crossover study, the same authors demonstrated that 10 mg prasugrel therapy was very effective in overcoming HPR rate compared to 150 mg clopidogrel therapy in CYP2C192 carriers (0 versus 100 percent) [123]. In the RAPID GENE study, 200 patients undergoing PCI were randomly assigned to either rapid point-of-care genotyping for the CYP2C192 allele or standard treatment. Carriers were given 10 mg prasugrel daily, while noncarriers and those in the standard treatment group were given 75 mg of clopidogrel daily [122]. The primary end point was high on- treatment platelet reactivity after one week of antiplatelet therapy, which occurred in none of the 23 carriers in the genotyping group treated with prasugrel compared with 7 of the 23 carriers (30 percent) in the standard treatment group who were treated with clopidogrel. In a post-hoc subgroup analysis of data from the ONSET/OFFSET and RESPOND studies, the prevalence of high on-treatment platelet reactivity, using a number of different laboratory assays, was significantly lower for those treated with ticagrelor (0 to 8 percent) than for those treated with clopidogrel (21 to 81 percent) [121]. (See "Platelet biology", section on 'Prasugrel' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".) In the TRIGER-PCI randomized trial of 212 patients with stable coronary artery disease and high on-treatment platelet reactivity undergoing PCI, a 10 mg daily dose of prasugrel was effective in reducing on-treatment platelet reactivity compared to 75 mg daily dose clopidogrel [108]. However, the study was terminated early for futility because of extremely low event rates. In a randomized trial of STEMI patients undergoing PCI, two-hour post-dose, HPR (>208 PRU) prevalence was 46.2 and 34.6 percent in patients treated with ticagrelor and prasugrel, respectively. Efficacy, defined as reducing platelet reactivity during the first 24 hours of STEMI was similar in the two groups [124]. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 16/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate In two studies, aspirin and clopidogrel response was evaluated by VerifyNow assay in patients undergoing elective PCI. Poor responders to aspirin or clopidogrel were treated with a glycoprotein (GP) IIb/IIIa receptor inhibitor which decreased 30-day as well as one- year post-PCI ischemic events without increased bleeding rates [125,126]. Previous large scale studies of personalized antiplatelet therapy that used the VerifyNow P2Y assay mainly recruited low-risk patients undergoing PCI and mostly used the 12 suboptimal therapy of 150 mg daily clopidogrel to overcome HPR [6,106,108]. The latter studies failed to demonstrate the utility of personalization of antiplatelet therapy. In a study of 714 patients with ACS undergoing PCI, platelet function was measured by Multiplate analyzer, and patients with HPR on standard clopidogrel therapy were treated with high-dose clopidogrel or prasugrel at the discretion of the treating physician. In this study, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at one year was higher in the high-dose clopidogrel group compared to patients without HPR (HR 2.27, 95% CI 1.45-3.55), whereas outcomes were similar between the prasugrel treated group and patients without HPR (HR 0.90, 95% CI 0.44-1.81) [127]. The latter outcomes were associated with significantly lower platelet reactivity in the prasugrel treated group compared with the high-dose clopidogrel treated group (p<0.0001). The TROPICAL ACS trial, discussed elsewhere, provides some additional evidence for switching P2Y receptor blockers in patients with an ACS. (See "Acute non-ST-elevation 12 acute coronary syndromes: Early antiplatelet therapy", section on 'Switching from ticagrelor or prasugrel to clopidogrel'.) A randomized, pharmacodynamic trial of clopidogrel 300 mg daily, ticagrelor 90 mg twice daily, or ticagrelor 60 mg twice daily in 162 aspirin-treated stable patients who underwent PCI found the following [128]: Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel at one month. There was no impact of ticagrelor on in vitro adenosine uptake or adenosine plasma levels with either ticagrelor dose compared with clopidogrel. A genotyping substudy of TROPIC ACS revealed that CYP2C192 and CYP2C1917 carrier status in rapid metabolizers correlates with platelet reactivity in ACS patients on clopidogrel. Based on these results, the authors suggested that CYP2C19 genotyping can play a valuable role for preselecting patients who will and who may not be suitable for early guided deescalation of antiplatelet treatment. They also demonstrated that in https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 17/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate patients treated with platelet-function-guided deescalation strategy, genotyping may not provide added benefit in predicting ischemic or bleeding risk [129]. The CREATIVE trial presented above suggests that triple therapy with clopidogrel, aspirin, and cilostazol may be beneficial. (See 'Adjusting the maintenance dose' above.) In the HOST-REDUCE-POLYTECH-ACS trial, conducted in South Korea, 2338 ACS patients undergoing PCI were randomly assigned to the de-escalation strategy of 10 mg prasugrel for one month followed by 5 mg prasugrel versus conventional strategy of 10 mg prasugrel for one year in addition to 100 mg aspirin in both groups. The primary endpoint of net adverse clinical events (all-cause death, nonfatal MI, stent thrombosis, repeat revascularization, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium [BARC] criteria) was similar between groups (Kaplan-Meier estimate 7.2 percent in the de- escalation group and 10.1 percent in the conventional group, a statistically significant reduction [HR 0.70, 95% CI 0.52-0.92; p equivalence = 0.012]). Ischemic risk was similar between the groups (HR 0.76, 95% CI 0.40-1.45; p = 0.40) while bleeding risk was significantly decreased in the de- escalation group (HR 0.48, 95% CI 0.32-0.73; p = 0.0007). Stent thrombosis The approach to additional antiplatelet therapy in patients with stent thrombosis taking clopidogrel is presented separately. (See "Coronary artery stent thrombosis: Clinical presentation and management", section on 'Long-term antiplatelet therapy'.) LOW PLATELET REACTIVITY AND BLEEDING While dual antiplatelet therapy (DAT) lowers the risk of ischemic events in patients undergoing percutaneous coronary intervention, the risk of bleeding is increased, particularly when more potent P2Y receptor inhibitors are used. In this setting, low platelet reactivity (LPR) is 12 associated with an increased risk of bleeding. A consensus document highlighting the above observations with a therapeutic window concept and updated cutoffs for high on-treatment platelet reactivity and LPR for P2Y receptor inhibitor therapy has been published [130]. 12 However, we do not recommend screening for low platelet reactivity, as there are insufficient data to support its use. Platelet function testing offers the possibility of discerning the optimal drug choice and dosing strategy for an individual patient. The safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing was investigated in the open-label, assessor-blinded, TROPICAL-ACS trial, which is discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Switching from ticagrelor or prasugrel to clopidogrel'.) https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 18/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST- elevation myocardial infarction (STEMI)".) SUMMARY AND RECOMMENDATIONS "Resistance" or "nonresponsiveness/hyporesponsiveness" to an antiplatelet drug is a pharmacodynamic phenomenon in which there is no significant reduction in platelet function after treatment as compared to the baseline. High on-treatment platelet reactivity (HPR) is a similar concept and indicates persistent response of the P2Y receptor 12 (clopidogrel target) based on one measurement of on-treatment platelet reactivity. (See 'Definitions' above.) Most, but not all, studies have found a positive association between patients with hypo-/nonresponsiveness or HPR and subsequent thrombotic/ischemic events after percutaneous coronary intervention. (See 'HPR and thrombotic events' above.) Clopidogrel treatment failure is the occurrence of a thrombotic/ischemic event during clopidogrel therapy in patients with heightened platelet reactivity (HPR). These events are usually stent thrombosis or recurrent acute coronary syndrome (ACS). (See 'Clinical manifestations and diagnosis' above.) For patients who have been started on clopidogrel, we do not routinely test patients for clopidogrel resistance with genetic testing to detect loss of function gene carriers (eg, CYP2C19 allele testing) or with platelet function testing to detect P2Y resistance. (See 12 'Screening' above.) The optimal approach to patients taking clopidogrel for a prior ACS (without stenting) who develop a subsequent ACS is not known. For these patients, we suggest switching from clopidogrel to a more potent platelet P2Y receptor blocker rather than any other strategy 12 (Grade 2C). (See 'Management of possible clopidogrel failure' above.) 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42. Price MJ, Nayak KR, Barker CM, et al. Predictors of heightened platelet reactivity despite dual-antiplatelet therapy in patients undergoing percutaneous coronary intervention. Am J Cardiol 2009; 103:1339. 43. Labarthe B, Th roux P, Angio M, Ghitescu M. Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 2005; 46:638. 44. Erlinge D, Varenhorst C, Braun OO, et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 2008; 52:1968. 45. Gaborit B, Fr re C, Cuisset T, et al. Enhanced post-clopidogrel platelet reactivity in diabetic patients is independently related to plasma fibrinogen level but not to glycemic control. J Thromb Haemost 2009; 7:1939. 46. Morel O, El Ghannudi S, Hess S, et al. The extent of P2Y12 inhibition by clopidogrel in diabetes mellitus patients with acute coronary syndrome is not related to glycaemic control: roles of white blood cell count and body weight. Thromb Haemost 2012; 108:338. 47. Angiolillo DJ, Bernardo E, Capodanno D, et al. Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 23/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate antiplatelet therapy. J Am Coll Cardiol 2010; 55:1139. 48. Mangiacapra F, Patti G, Peace A, et al. Comparison of platelet reactivity and periprocedural outcomes in patients with versus without diabetes mellitus and treated with clopidogrel and percutaneous coronary intervention. Am J Cardiol 2010; 106:619. 49. Frelinger AL 3rd, Michelson AD. Clopidogrel linking evaluation of platelet response variability to mechanism of action. J Am Coll Cardiol 2005; 46:646. 50. Siller-Matula J, Schr r K, Wojta J, Huber K. Thienopyridines in cardiovascular disease: focus on clopidogrel resistance. Thromb Haemost 2007; 97:385. 51. Montalescot G, Sideris G, Cohen R, et al. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study. Thromb Haemost 2010; 103:213. 52. Storey RF, Husted S, Harrington RA, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50:1852. 53. James S, Akerblom A, Cannon CP, et al. 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Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post- stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46:1820. 72. Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 25/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate potential antiplatelet therapeutic target. Platelets 2008; 19:595. 73. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46:1827. 74. Price MJ, Endemann S, Gollapudi RR, et al. 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Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary Syndromes: The PHARMCLO Trial. J Am Coll Cardiol 2018; 71:1869. 105. Montalescot G, Rang G, Silvain J, et al. High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: A landmark analysis of the ARCTIC study. Circulation 2014; 129:2136. 106. Collet JP, Cuisset T, Rang G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012; 367:2100. 107. Cayla G, Cuisset T, Silvain J, et al. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388:2015. 108. Trenk D, Stone GW, Gawaz M, et al. 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Orme RC, Parker WAE, Thomas MR, et al. Study of Two Dose Regimens of Ticagrelor Compared with Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease (STEEL-PCI). Circulation 2018. 129. Gross L, Trenk D, Jacobshagen C, et al. Genotype-Phenotype Association and Impact on Outcomes following Guided De-Escalation of Anti-Platelet Treatment in Acute Coronary Syndrome Patients: The TROPICAL-ACS Genotyping Substudy. Thromb Haemost 2018; 118:1656. 130. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 30/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Coll Cardiol 2013; 62:2261. Topic 6684 Version 105.0 https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 31/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate GRAPHICS Clopidogrel nonresponsiveness varies according to duration of therapy Relationship between frequency of patients and absolute change in aggregation ( Aggregation [percent]) in response to 5 mol/L ADP at 2 hours, 24 hours, 5 days, and 30 days after stenting. Aggregation (percent) is defined as baseline aggregation (percent) minus post-treatment aggregation (percent). Resistance, as defined herein, is Aggregation (percent) 10 percent. Resistance is present in those patients subtended by double-headed arrow. Curves represent normal distribution of data and were created by Statistica software. Reproduced with permission from: Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the e ect of pretreatment platelet reactivity. Circulation 2003; 107:2908. Copyright 2003 Lippincott Williams & Wilkins. Graphic 87715 Version 5.0 https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 32/33 7/5/23, 9:13 AM Clopidogrel resistance and clopidogrel treatment failure - UpToDate Contributor Disclosures Udaya S Tantry, PhD No relevant financial relationship(s) with ineligible companies to disclose. Charles H Hennekens, MD, DrPH Patent Holder: Brigham and Women's Hospital [Co-inventor on patents concerning inflammatory markers and cardiovascular disease, C-reactive protein]. Consultant/Advisory Boards: Amgen [Migraine, cardiovascular disease]; UCB [Osteoporosis]. All of the relevant financial relationships listed have been mitigated. James L Zehnder, MD No relevant financial relationship(s) with ineligible companies to disclose. Paul A Gurbel, MD Equity Ownership/Stock Options: Merck [Cardiology]. Grant/Research/Clinical Trial Support: Amgen [Lipid-lowering therapy]; Bayer Healthcare [Antiplatelet therapy]; Haemonetics [Cardiology device]; Hikari Dx [Cardiology device]; Instrumentation Laboratory [Cardiology device]; Janssen [Antithrombotic therapy]; Nirmidas Biotech [COVID-19 biomarker]; Novartis [Lipid-lowering therapy]; Otitopic Inc [Antiplatelet therapy]; Precisio Biolog [COVID-19 biomarker]; R-Pharma International [Antithrombotic therapy]. Consultant/Advisory Boards: Adeno [Cardiology]; Bayer [Antiplatelet therapy]; Cleveland Clinic [Cardiology]; Innovative Sciences [Cardiology]; Janssen [Antiplatelet therapy]; Otitopic Inc [Antiplatelet therapy]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, MD No relevant financial relationship(s) with ineligible companies to disclose. Donald Cutlip, MD Consultant/Advisory Boards: MedAlliance [Drug-eluting balloon]. Other Financial Interest: Baim Institute for Clinical Research [Clinical research]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure/print 33/33
7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy : Rachel Kaplan, MD, MS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 27, 2023. INTRODUCTION In patients with atrial fibrillation (AF), the ventricular rate is modulated by the conduction properties of the atrioventricular (AV) node. In the typical patient with untreated AF, the ventricular rate can reach 150 beats/min or higher. The use of pharmacologic therapies to achieve rate control in AF will be reviewed here. Nonpharmacologic therapies for rate control in AF are discussed separately. (See "Atrial fibrillation: Atrioventricular node ablation".) Further information regarding the overall management of patients with AF, including anticoagulation and choice of rhythm versus rate control, is discussed separately: (See "Atrial fibrillation in adults: Use of oral anticoagulants".) (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) (See "Management of atrial fibrillation: Rhythm control versus rate control".) The control of ventricular rate of AF in patients with heart failure is discussed separately; thus, this topic focuses only on patients with AF who do not have heart failure. (See "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 1/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate PATHOPHYSIOLOGY Atrial fibrillation During AF, electrical activity in the atria can exceed 400 beats/min. The majority of these impulses do not conduct to the ventricles because of the electrophysiologic properties of the AV node. (See "Mechanisms of atrial fibrillation", section on 'Role of the atrioventricular node'.) AV nodal tissue consists of so-called "slow response" fibers, giving it decremental conduction properties. In most myocardial tissue, the initial depolarizing phase of the action potential (phase 0) is mediated by rapid sodium channels. In contrast, in the slow response fibers of the AV node, phase 0 is mediated by an inward calcium current, which uses a kinetically slow channel. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) The relatively slow kinetics of the inward calcium current limit conduction velocity through the AV node, and therefore the ventricular rate during AF. In addition to these intrinsic properties, the AV node is also richly supplied and affected by both components of the autonomic nervous system. AV conduction is enhanced by sympathetic fibers and slowed by parasympathetic fibers ( figure 1). In the typical patient with untreated AF, the ventricular rate during the day varies between 90 and 170 beats/min. The ventricular rate may be slower (eg, less than 60 beats/min) in the following settings: Increased vagal tone. Drugs that affect AV nodal conduction. AV nodal disease, which should be suspected if the ventricular rate is below 60 beats/min in the absence of a drug that slows AV conduction. A ventricular rate above 200 beats/min suggests one or more of the following: Catecholamine excess Enhanced AV nodal conduction Parasympathetic withdrawal Hyperthyroidism An accessory pathway as occurs in the preexcitation syndrome. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) Drug mechanisms of action The ventricular rate in AF is slowed using beta blockers or calcium channel blockers, and to a lesser extent digoxin or amiodarone. In general, calcium https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 2/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate channel blockers are effective at rest and during exercise, beta blockers are similarly effective at rest but more effective during exercise, and digoxin is reasonably effective at rest but less effective than the other drugs during exercise. Thus, it is particularly important to assess ventricular rate with exertion in patients treated with digoxin alone. These agents slow AV nodal conduction based upon the following physiologic mechanisms ( figure 2) [1,2]: Calcium channel blockade Blockade of the calcium channel with the nondihydropyridine calcium channel blockers verapamil and diltiazem. Beta blockade Decreased sympathetic tone and slowed AV nodal conduction with beta blockers. Enhancement of parasympathetic tone This is done with vagotonic drugs, the most important of which is digoxin. RATIONALE FOR RATE LOWERING Specific reasons for slowing the ventricular rate in patients with AF include the following: Hemodynamic instability This may be acute and may require urgent therapy. This is discussed in detail separately. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Symptoms Patients with AF may or may not have associated symptoms, and the spectrum of symptoms is broad. Typical symptoms include palpitations, tachycardia, fatigue, weakness, dizziness, lightheadedness, reduced exercise capacity, increased urination, or mild dyspnea. Symptoms of AF are discussed in detail separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Symptoms'.) Tachycardia-mediated cardiomyopathy Persistently increased ventricular rates in AF have been associated with left ventricular cardiomyopathy. While this issue has not been well studied, we believe that this phenomenon is unlikely to occur if the ventricular rate is kept below 110 beats/min, which is the recommended ventricular rate goal. This is discussed in detail separately. (See "Arrhythmia-induced cardiomyopathy".) Potential mortality benefit There is some evidence to suggest a mortality benefit from rate control. In a large, population-based cohort study in Taiwan, mortality in individuals receiving beta blockers (43,879), nondihydropyridine calcium channel blockers (18,466), and digoxin (38,898) was compared with mortality in individuals not taking a rate-control https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 3/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate drug. Patients were excluded if they were taking more than one rate-slowing drug. After adjustment for baseline differences, the risk of death was lower in patients receiving beta blockers (adjusted hazard ratio [HR] 0.76; 95% CI 0.74-0.78) and calcium channel blockers (adjusted HR 0.93; 95% CI 0.90-0.96). However, the risk of death was higher in the group receiving digoxin (adjusted HR 1.12; 95% CI 1.10-1.14). We recommend caution in applying to clinical practice the findings in this nonrandomized study. Spontaneous conversion to sinus rhythm Some patients whose rate has been slowed and who then tolerate AF may spontaneously convert to normal sinus rhythm without the need for electrical cardioversion. Spontaneous conversion is most likely to occur in patients with a duration of AF of less than 48 hours, or in patients with a history of short, self- limited episodes [3]. The rate of spontaneous conversion has been reported to be around 50 percent at 48 hours [3]. In a retrospective study of 438 patients with AF, if the AF onset was <48 hours, spontaneous conversion occurred in 77 percent compared with 36 percent in the group with first onset AF >48 hours [4]. In a separate study of 943 patients, spontaneous conversion was shown to occur most frequently in patients with first-onset AF <24 hours, a lower body mass index, and normal left atrial size [5]. EVALUATION AND GOAL VENTRICULAR RATE Evaluation and monitoring of ventricular rate In practice, the ventricular rate can be assessed by measurement of both the resting ventricular rate and use of one of the following to assess exercise: Six-minute walk test (at moderate exercise) ( table 1). Either submaximal or maximal exercise electrocardiogram (ECG) testing. (See "Exercise ECG testing: Performing the test and interpreting the ECG results".) A 24-hour ambulatory monitor can also be used to evaluate efficacy. (See "Ambulatory ECG monitoring".) For patients with an implantable pacemaker or defibrillator, device interrogation provides useful diagnostic data to assess rate control, including a ventricular rate histogram during episodes of AF. For young active patients, we recommend either an exercise ECG test or ambulatory monitoring during exercise. For older or sedentary patients, measuring ventricular rate after walking briskly around the office or upstairs may provide sufficient information. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 4/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Wearable devices, such as an electronic watch that connects with a smartphone application, also can provide ventricular rate data. Caution is advised with relying entirely on photoplethysmography, which may undersense individual beats in AF and report an inaccurately low heart rate [6]. Heart rate reports should be verified with ECG strips, which may also be obtainable from some wearable technologies. These methods of assessing ventricular rate can be used both at the start of therapy and for long-term follow-up. In the assessment of ventricular rate control, average ventricular rate is considered the most important parameter. Ventricular rates during peak exercise may also be valuable. Assessment of rate control can be confusing when using monitors that display continuous beat-to-beat ventricular rate rather than average ventricular rate. Goal ventricular rate The optimal long-term ventricular rate for patients in AF has not been firmly established [7]. For most symptomatic patients with AF, we suggest a ventricular rate goal of 85 beats/min. In general, the goal is to control the rate during activity to prevent or treat symptoms. If the ventricular rate during AF is faster than would be expected during sinus rhythm and occurs at a time that correlates with the patient's symptoms, then rate control medications are usually titrated upwards. In the subset of patients with AF who are asymptomatic and have permanent AF, a less strict rate control goal of <110 beats/min may be reasonable. These patients should be monitored for the development of tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) Alternative goal rates that are similar to those recommended for patients in sinus rhythm with heart disease can also be used: resting heart rate 80 beats/min and 110 beats/min during moderate exercise such as with the six-minute walk. Goals similar to these were used in many of the trials of rate versus rhythm control, such as AFFIRM [8]. The AFFIRM study is discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'High cardiovascular risk'.) The prevention of symptoms during normal activities or exercise is a primary goal of therapy. It is important to consider that symptoms may be due to either inadequate rate control or relative bradycardia (eg, in patients with tachycardia-bradycardia syndrome). (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Thus, for those patients in whom a lenient strategy is chosen but who remain symptomatic, an attempt should be made to decrease symptoms by setting a lower rate goal. A more https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 5/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate lenient rate-control strategy offers the advantages of less medication (fewer drug side effects, lower cost) and fewer outpatient visits to achieve ventricular rate control. The recommended goal rate is based on the observation that 85 beats/min was the mean achieved rate for patients assigned lenient rate control in the RACE study [9]. In this trial of patients with permanent AF, adhering to a strict rather than lenient rate-control strategy did not improve cardiovascular or safety outcomes. This study also supports our practice in which achieving strict rate control is not necessary in many physically active patients with AF who are minimally symptomatic. In the RACE study, 614 physically active patients with permanent AF were randomly assigned either lenient rate control (resting heart rate <110 beats/min) or a strict rate control (resting heart rate <80 beats/min and heart rate during moderate exercise <110 beats per minute). Patients were followed for the primary outcome of cardiovascular death, hospitalization for heart failure, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The following findings were noted: Similar efficacy of lenient and strict rate control After three years, the estimated cumulative incidence of the primary outcome was similar in both groups (12.9 versus 14.9 percent, respectively; hazard ratio [HR] 0.84; 90% CI 0.58-1.21). Fewer people in strict versus lenient group met heart rate target The percentage of patients was 98 and 75 percent, respectively [10]. More medical visits in strict rate-control group There were nearly nine times as many visits (684 versus 75) to achieve rate control target(s) in the strict control. Low resting heart rates were achieved in the lenient group too In patients assigned to lenient rate control, the mean resting rates at the end of follow-up was 85+14 beats/min compared with 76+14 beats/min in those assigned to strict control. The results of the RACE trial must be tempered given that the lenient-control group was in fact treated more aggressively than the protocol required. In addition, RACE included only patients with permanent AF, so the results are not generalizable to those with paroxysmal or persistent AF. INITIAL CONSIDERATIONS The initial management of patients with AF and a rapid ventricular response involves the following: Determining if urgent therapy is needed. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 6/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Choosing between a rate and rhythm control strategy. Determining if there is preexcitation. Determining urgency In a patient with new or recurrent AF with a rapid ventricular response, the immediate goals are to stabilize hemodynamics (if necessary) and to improve symptoms. Thus, the intensity of initial rate control therapy (eg, inpatient versus outpatient or oral versus intravenous therapy) depends upon the clinical scenario. Urgent therapy In patients who are clinically or hemodynamically unstable (eg, myocardial ischemia, pulmonary edema, hypotension) due to AF and a rapid ventricular response, treatment options include intravenous rate-control medications and/or immediate cardioversion. (See 'Urgent therapy' below.) Elective therapy Patients who have mild or no symptoms and whose ventricular rate is mildly to moderately elevated (eg, 120 beats/min) can be managed with the addition or increase of oral rate-control medications. (See 'Elective and long-term management' below.) Deciding on rate control The advantages and disadvantages of rhythm and rate control, as well as whether there are subgroups of patients for whom one or the other should be preferred, are discussed separately. (See "Management of atrial fibrillation: Rhythm control versus rate control".) Caution in preexcitation syndrome Among patients with AF and preexcitation, initial therapy is aimed at reversion to sinus rhythm. Usual treatments for rate control (ie, calcium channel blockers, beta blockers, digoxin, and amiodarone) should not be given because they may paradoxically increase the ventricular response in patients with AF. Intravenous procainamide or ibutilide should be given if hemodynamics are stable, and direct current cardioversion should be performed if the patient is unstable. This is discussed in detail separately. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.) The preferred long-term therapy of preexcited AF is ablation of the accessory pathway. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Catheter ablation'.) URGENT THERAPY https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 7/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate This section describes our approach to urgent ventricular rate control in patients with AF who do not have heart failure. Rate control of patients who have AF and heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Acute decompensation'.) Choice of initial urgent therapy Patients who require urgent therapy need to be in a monitored setting. In patients without symptomatic hypotension (eg, in those with ischemia without hypotension), we select diltiazem as the initial agent. Intravenous (IV) esmolol, verapamil, or other IV beta blockers such as metoprolol are reasonable alternatives to diltiazem. If it is uncertain whether the patient will become hypotensive with a beta blocker, we use esmolol since this medication has a very short half-life and can be immediately discontinued if needed. (See 'Hypotensive patient' below.) In the absence of larger randomized trials, much of the current management relies on clinical experience rather than evidence. Diltiazem may have a less pronounced negative inotropic effect than verapamil [11]. The IV preparation is convenient and effective for acute control of the ventricular rate in AF [12-14], while oral therapy is effective for chronic rate control [15,16]. In our experience, either a beta blocker or calcium channel blocker could result in hypotension, and therefore careful blood pressure monitoring is needed regardless of the choice of medication. Small, heterogenous studies of urgent control of ventricular rate in AF suggest higher efficacy for IV diltiazem versus IV beta blocker therapy: One meta-analysis of three studies including 160 patients and comparing effects of IV diltiazem versus IV metoprolol showed an average of 9 mm lower systolic blood pressure with diltiazem at 15 minutes following treatment but no differences at earlier or later timepoints (ie 5, 10, or 30 minutes) [17]. In a meta-analysis of 17 randomized and cohort studies (1214 patients), patients given IV diltiazem compared with IV metoprolol had higher efficacy of successful rate control (relative risk [RR] 1.11; 95% CI 1.06-1.16). Efficacy was defined differently in various studies (eg, achieving a heart rate <100 beats/min or lowering heart rate by at least 20 percent). Those treated with IV diltiazem also had shorter average onset time (RR per minute of onset -1.13; 95% CI -1.97 to -0.28) and lower ventricular rate (RR difference in beats/min -9.48; 95% CI -12.13 to -6.82) and less impact on (weighted mean difference 3.76 mmHg; 95% CI 0.20-7.33). There was no significant difference in adverse events between treatment regimens [17]. Normotensive patient In most normotensive patients with AF with a rapid ventricular rate, we first try IV diltiazem ( table 2). https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 8/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate The suggested regimen for IV diltiazem is derived from the Diltiazem Atrial Fibrillation/Atrial Flutter Study Group [12-14]. The efficacy of this regimen was evaluated in a report of 84 consecutive patients with AF, atrial flutter, or both [14]. The overall response rate was 94 percent. The continuous infusion maintained adequate rate control for 10 hours or longer in a dose- dependent fashion: 47 percent at 5 mg/hour; 68 percent after titration to 10 mg/hour; and 76 percent after titration to 15 mg/hour ( figure 3). Hypotension occurred in 13 percent and was symptomatic in almost 4 percent. All such patients responded to an infusion of normal saline. Weight-based dosing of IV diltiazem is further supported in a study of 252 patients who received IV diltiazem for acute rate control in the emergency department. Weight-based dosing (0.25 mg/kg) was associated with higher rates of rate control without increased adverse effects [18]. Hypotensive patient Asymptomatic and not on a vasopressor If the patient is mildly hypotensive but asymptomatic and does not require a vasopressor, we typically start metoprolol tartrate (short- acting) 25 mg by mouth every six hours and up-titrate as needed and as tolerated by 12.5 mg every six hours until the rate is controlled. Other IV beta blockers and calcium channel blockers may cause worsening hypotension. Patients with inadequate response Urgent combination therapy In patients who do not adequately respond to initial therapy with either an IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy ( table 2). Digoxin should not be used if preexcitation is present. Urgent alternative therapy In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone for acute control of the ventricular rate ( table 2). In such patients, the use of amiodarone for rate control is a short-term strategy (eg, hours to days). The drug should not be used if preexcitation is present. Careful attention to anticoagulation is also necessary because there is a small chance of cardioversion with amiodarone. If none of these therapies work, we typically opt for acute cardioversion rather than continued attempts at rate control (with evaluation of the left atrial appendage thrombus if warranted and clinically feasible and appropriate anticoagulation strategy). Symptomatic hypotension and/or on a vasopressor If the hypotension is symptomatic and requires a vasopressor, we typically opt for acute cardioversion rather than rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 9/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate anticoagulation strategy). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If the patient is on a vasopressor that can exacerbate tachycardia (eg, epinephrine or norepinephrine), we may elect to switch the vasopressor to a vasoconstrictor (eg, phenylephrine) if this is a reasonable alternative. (See "Use of vasopressors and inotropes".) Management of patients in whom cardioversion is unsuccessful is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) Alternative therapies we do not suggest We do not use IV magnesium for control of ventricular rate in AF despite a small body of supporting evidence because very few patients are refractory to other therapies and would require it. Magnesium does have physiologic properties suggesting that it might have efficacy for rate control in AF. Initial small studies provided the rationale for a clinical trial in which 199 patients presenting with rapid AF (mean baseline ventricular rate 142 beats/min) were treated with usual therapy for rate control (most often digoxin) and randomly assigned to IV magnesium sulfate (2.5 g over 20 minutes followed by 2.5 g over two hours) or placebo [19]. Magnesium therapy increased the likelihood of achieving a ventricular rate <100 beats/min (65 versus 34 percent with placebo) and conversion to sinus rhythm (27 versus 12 percent with placebo). However, the difference in mean ventricular rate never exceeded 12 beats/min. The benefit of magnesium was modest, preferred primary therapies (calcium channel blocker, beta blocker) were used in only 12 to 13 percent of the patients, and magnesium was associated with side effects such as flushing and hypotension. A separate meta-analysis of six trials and 745 patients showed similar results [20]. Ivabradine blocks the pacemaker current, which is primarily thought to affect the sinoatrial node; however, some studies have shown that this current is also expressed in the atrioventricular node. Accordingly, a few studies are investigating the use of ivabradine for ventricular rate control in AF. One retrospective study of 18 patients with permanent AF showed average reduction in ventricular rate from 104.6 to 89 [21]. A randomized trial has been proposed to study ivabradine in patients with permanent AF (BRAKE-AF trial). At the present time, there is insufficient evidence to recommend the routine use of ivabradine for ventricular rate control in AF [22]. Transition to oral medications When making a transition from IV to oral therapy, we first ensure that the patient has tolerated the IV medication well. For instance, beta blockers may have a variety of adverse effects that can be important in patients with AF. (see "Major side effects of beta blockers") https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 10/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate When transitioning from IV to oral medications, we generally convert the total daily dose of the IV medication to an equivalent divided or long-acting oral dose of a medication in the same class. We often use pharmacy or pharmacist-based reference for appropriate conversion dosages. For example, if a patient is placed on IV diltiazem, we will usually convert the patient to a short or long-acting oral formulation of diltiazem that gives an equivalent daily dose of the medication. A general formula for approximate conversion from IV diltiazem to the daily oral dose is [(infusion rate x3)+3]x10 [23]. Example conversions from IV to oral dosing for diltiazem and metoprolol are shown in a table ( table 2). Other nuances of long-term rate control medications are discussed separately. (See 'Elective and long-term management' below.) ELECTIVE AND LONG-TERM MANAGEMENT Choice of nonurgent therapy Although there are differences in the efficacy of the various drugs, it is likely that monitoring and adjustments to therapy are more important components of successful rate-control strategies than the initial drug selection. Studies of specific pharmacologic agents for management of AF are small and heterogeneous. A study of 25 clinical trials showed no difference in effectiveness for different diltiazem or verapamil formulations (eg, immediate release, sustained release, or controlled delivery). There was also no evidence of differences in effectiveness for extended-release diltiazem and verapamil [24]. Long-acting or sustained-release formulations are typically preferred for chronic management to facilitate medication compliance. One study reviewed 54 trials that evaluated 17 different agents used for rate control [25]. The studies were all relatively small (6 to 239 patients) and had relatively short follow-up periods of eight weeks or less. Most compared single agents with placebo. Due to extensive variability in methods and outcome assessments, a meta-analysis of the trials could not be performed. However, the following observations were noted: Both beta blockers and calcium channel blockers were effective Diltiazem, verapamil, and most beta blockers (atenolol, metoprolol, timolol, pindolol, and nadolol) were all effective in reducing the ventricular rate during rest and exercise. The beta blockers labetalol, xamoterol, and celiprolol were less effective at rest but did reduce ventricular rates during exercise. Mixed results for digoxin versus placebo Trials comparing digoxin with placebo reported inconsistent results, particularly when heart rate during exercise was assessed. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 11/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Digoxin was effective when added to beta blocker or calcium channel blocker The combination of digoxin with a beta blocker or calcium channel blocker reduced heart rate both at rest and with exertion. Thus, pharmacologic therapy can achieve adequate rate control in approximately 80 percent of patients. However, achieving this goal requires close monitoring, medication adjustments, and often combination therapy. Although there are differences in the efficacy of the various drugs, it is likely that monitoring and adjustments to therapy are more important components of successful rate-control strategies than the initial drug selection. AFFIRM trial Among evaluations of rate-control drugs, the study with the largest sample size and longest follow-up is a post-hoc analysis from the AFFIRM trial [26]. The original AFFIRM trial assigned patients with AF to either rate or rhythm control, and a post-hoc analysis compared the efficacy of various rate-control medications. In this post-hoc study, over 2000 patients assigned to rate control were given medications according to physician preference. Effectiveness of rate control was defined as a resting heart rate 80 beats/minute, exertional heart rate 110 beats/min during six-minute walk test or average heart rate during 24-hour ambulatory Holter monitoring ECG 100 beats/min (at least 18 hours of interpretable monitoring), and no heart rate >110 percent maximum predicted age-adjusted exercise heart rate. The overall effectiveness (meeting both rest and exertion heart rate goals) of initial monotherapy therapy was most effective for beta blockers (59 percent), followed by digoxin (58 percent), and then calcium channel blockers (38 percent). At five-year follow-up, adequate rate control increased from approximately 60 to 80 percent of patients. Only 58 percent of patients had adequate rate control with the first drug or combination used. Patients initially treated with a beta blocker were significantly less likely than those treated with calcium channel blockers or digoxin to have their drug regimen changed. Limitations of this study included nonrandom assignment of specific rate-control medication and an inadequate baseline assessment of heart rate. Initial therapy In patients who do require elective management or in those transitioning to long-term therapy, we usually suggest an oral beta blocker or nondihydropyridine calcium channel blocker. Reasons for these preferences are discussed below. Beta blockers We prefer beta blockers in the following groups of patients: Recent myocardial infarction. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 12/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Heart failure due to systolic dysfunction. Inappropriate increase in ventricular rate during exercise. Surges in sympathetic function that trigger AF. Beta blockers may be particularly useful in states of high adrenergic tone (eg, postoperative AF) [27,28]. In the first two settings, beta blockers improve patient survival. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting ventricular rate and blunt the ventricular rate response to exercise. Most beta blockers appear to have similar efficacy. For patients with heart failure with systolic dysfunction, the preferred agents for treatment are metoprolol succinate, carvedilol, carvedilol continuous release, and bisoprolol. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, beta-blocker therapy was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) There is the most supporting evidence for metoprolol, atenolol, and nadolol. Atenolol and nadolol have the advantages of a long half-life and are typically given once daily. Long- acting propranolol can be effective. Bisoprolol and carvedilol are also used ( table 2). It should be noted that beta blockers are contraindicated or relatively contraindicated in some patients, and others cannot tolerate the side effects. (See "Major side effects of beta blockers".) Beta blockers have additional properties that may make them preferred to other rate- control drugs in some AF patients: Patients with systolic dysfunction This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 13/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Patients with AF triggered by sympathetic dysfunction Beta blockers may reduce the incidence of AF recurrence in patients with episodes of AF that are triggered by surges in sympathetic activity [27,28]. Some patients with paroxysmal AF also have sinus node dysfunction, with tachycardia- bradycardia syndrome. In such patients, beta blockers with intrinsic sympathomimetic activity may be useful since they are less likely to worsen bradycardia than standard beta blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Calcium channel blocker A nondihydropyridine calcium channel blocker is preferred in patients with chronic lung disease and in patients who do not tolerate beta blockers. Among the calcium channel blockers, verapamil has a somewhat greater blocking effect on the AV node than diltiazem, and the choice between these drugs is often dictated by side effects ( table 2). In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, calcium channel blocker therapy was shown to be effective in achieving goal ventricular rate in 38 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) Calcium channel blockers have a number of characteristics that need to be considered when they are administered to patients with AF: Variable effect on sinoatrial (SA) nodal function Although both verapamil and diltiazem have an inhibitory effect on the sinus node, their vasodilator effects cause a reflex release of catecholamines that usually maintains or slightly accelerates the SA nodal rate. However, patients with the sinus node dysfunction may be particularly sensitive to the effects of calcium channel blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Negative ionotropic effects Both verapamil and diltiazem have negative inotropic effects, although this is less pronounced with diltiazem. As a result, these drugs should be used with caution in patients with heart failure and in patients taking other negative inotropes, such as beta blockers. They should not be given if the patient is hypotensive. Side effects in older patients With either verapamil or diltiazem, it should be remembered that older patients are more likely to develop side effects, especially those that are cardiac in nature. Although the same maximum doses may be tolerated, it is usually appropriate to titrate more slowly. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 14/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate In summary, diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Failure class III or IV), preexcitation syndrome, or significant hypotension. In addition, these drugs should be given with caution to patients with sinus node dysfunction, significant liver disease, mild hypotension, marked first-degree heart block, or the concurrent intake of other drugs that inhibit SA nodal function or slow AV nodal conduction. Considerations for patients with heart failure are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction' and "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with preserved ejection fraction'.) Combination therapy Combination therapy In patients initially tried on a beta blocker or calcium channel
heart rate during 24-hour ambulatory Holter monitoring ECG 100 beats/min (at least 18 hours of interpretable monitoring), and no heart rate >110 percent maximum predicted age-adjusted exercise heart rate. The overall effectiveness (meeting both rest and exertion heart rate goals) of initial monotherapy therapy was most effective for beta blockers (59 percent), followed by digoxin (58 percent), and then calcium channel blockers (38 percent). At five-year follow-up, adequate rate control increased from approximately 60 to 80 percent of patients. Only 58 percent of patients had adequate rate control with the first drug or combination used. Patients initially treated with a beta blocker were significantly less likely than those treated with calcium channel blockers or digoxin to have their drug regimen changed. Limitations of this study included nonrandom assignment of specific rate-control medication and an inadequate baseline assessment of heart rate. Initial therapy In patients who do require elective management or in those transitioning to long-term therapy, we usually suggest an oral beta blocker or nondihydropyridine calcium channel blocker. Reasons for these preferences are discussed below. Beta blockers We prefer beta blockers in the following groups of patients: Recent myocardial infarction. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 12/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Heart failure due to systolic dysfunction. Inappropriate increase in ventricular rate during exercise. Surges in sympathetic function that trigger AF. Beta blockers may be particularly useful in states of high adrenergic tone (eg, postoperative AF) [27,28]. In the first two settings, beta blockers improve patient survival. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting ventricular rate and blunt the ventricular rate response to exercise. Most beta blockers appear to have similar efficacy. For patients with heart failure with systolic dysfunction, the preferred agents for treatment are metoprolol succinate, carvedilol, carvedilol continuous release, and bisoprolol. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, beta-blocker therapy was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) There is the most supporting evidence for metoprolol, atenolol, and nadolol. Atenolol and nadolol have the advantages of a long half-life and are typically given once daily. Long- acting propranolol can be effective. Bisoprolol and carvedilol are also used ( table 2). It should be noted that beta blockers are contraindicated or relatively contraindicated in some patients, and others cannot tolerate the side effects. (See "Major side effects of beta blockers".) Beta blockers have additional properties that may make them preferred to other rate- control drugs in some AF patients: Patients with systolic dysfunction This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 13/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Patients with AF triggered by sympathetic dysfunction Beta blockers may reduce the incidence of AF recurrence in patients with episodes of AF that are triggered by surges in sympathetic activity [27,28]. Some patients with paroxysmal AF also have sinus node dysfunction, with tachycardia- bradycardia syndrome. In such patients, beta blockers with intrinsic sympathomimetic activity may be useful since they are less likely to worsen bradycardia than standard beta blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Calcium channel blocker A nondihydropyridine calcium channel blocker is preferred in patients with chronic lung disease and in patients who do not tolerate beta blockers. Among the calcium channel blockers, verapamil has a somewhat greater blocking effect on the AV node than diltiazem, and the choice between these drugs is often dictated by side effects ( table 2). In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, calcium channel blocker therapy was shown to be effective in achieving goal ventricular rate in 38 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) Calcium channel blockers have a number of characteristics that need to be considered when they are administered to patients with AF: Variable effect on sinoatrial (SA) nodal function Although both verapamil and diltiazem have an inhibitory effect on the sinus node, their vasodilator effects cause a reflex release of catecholamines that usually maintains or slightly accelerates the SA nodal rate. However, patients with the sinus node dysfunction may be particularly sensitive to the effects of calcium channel blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Negative ionotropic effects Both verapamil and diltiazem have negative inotropic effects, although this is less pronounced with diltiazem. As a result, these drugs should be used with caution in patients with heart failure and in patients taking other negative inotropes, such as beta blockers. They should not be given if the patient is hypotensive. Side effects in older patients With either verapamil or diltiazem, it should be remembered that older patients are more likely to develop side effects, especially those that are cardiac in nature. Although the same maximum doses may be tolerated, it is usually appropriate to titrate more slowly. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 14/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate In summary, diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Failure class III or IV), preexcitation syndrome, or significant hypotension. In addition, these drugs should be given with caution to patients with sinus node dysfunction, significant liver disease, mild hypotension, marked first-degree heart block, or the concurrent intake of other drugs that inhibit SA nodal function or slow AV nodal conduction. Considerations for patients with heart failure are discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction' and "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with preserved ejection fraction'.) Combination therapy Combination therapy In patients initially tried on a beta blocker or calcium channel blocker with persistently high ventricular rates, the combination of a beta blocker and a calcium channel blocker can be tried in most patients. In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, this combination was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) Adding digoxin In patients who do not achieve adequate rate control on maximum- tolerated doses of a beta blocker and nondihydropyridine calcium channel blocker together, we suggest adding digoxin if AV nodal ablation, pharmacologic rhythm control, or catheter ablation of AF are not being considered. (see "Atrial fibrillation: Atrioventricular node ablation", section on 'Indications'). When digoxin is added to either a beta blocker or calcium channel blocker or to both, patients should be carefully monitored for bradycardia and hypotension. Also, patients with significant left ventricular dysfunction may not tolerate triple therapy ( table 2). Digoxin levels should be obtained periodically for the purpose of detecting potentially high levels. We attempt to keep the level in the lower half of the normal range. Digoxin toxicity is discussed in detail separately. (See "Digitalis (cardiac glycoside) poisoning" and "Cardiac arrhythmias due to digoxin toxicity".) Combination therapy with digoxin was studied in a post-hoc analysis of the AFFIRM rate versus rhythm control trial. The overall effectiveness (meeting both rest and exertion ventricular rate goals) of combination therapy with digoxin was described as follows: Beta blocker plus digoxin 68 percent https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 15/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Calcium channel blocker plus digoxin 60 percent Beta blocker plus calcium channel blocker plus digoxin 76 percent The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) In patients with AF, the following summarizes evidence regarding the efficacy and safety of digoxin as a combination drug for rate control: Three large observational studies of digoxin use among patients with AF have yielded mixed results, with at least two finding an increase in all-cause mortality of about 20 percent [29,30] and one finding no increase [31]. The best available evidence regarding the relationship between digoxin use in AF patients (either alone or in combination with a beta blocker or calcium channel blocker) and mortality comes from a post-hoc subgroup analysis of the ARISTOTLE trial of anticoagulant therapy [32]. The following findings were reported: Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR] 1.09; 95% CI 0.96-1.23) Digoxin concentration 1.2 ng/mL was associated with an increased risk of death (adjusted HR 1.56; 95% CI 1.20-2.04) New digoxin use was associated with a higher risk of death (adjusted HR 1.78; 95% CI 1.37-2.31) Having heart failure versus not having heart failure did not change these effects. The use of digoxin in patients with AF and heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction'.) Alternative medications Amiodarone For patients with AF, there is a limited role for amiodarone as a long-term agent for rate control. Due to the increased risk of side effects, the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline states that amiodarone can be used as second-line therapy for chronic rate control only when other therapies are unsuccessful or contraindicated [33,34]. We agree with this guideline, and for patients treated with amiodarone for long-term rate control of AF, we require careful follow-up, including monitoring for known medication side effects. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 16/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Data supporting the use of amiodarone as a rate-control agent for AF are more limited compared with evidence supporting its use for pharmacologic rhythm control of AF. In one study, IV amiodarone (7 mg/kg), flecainide, or placebo were given to 98 patients with recent-onset AF (0.5 to 72 hours) [35]. Even when AF did not revert to sinus rhythm, amiodarone promptly slowed the ventricular rate during the eight-hour observation period ( figure 4). In addition, in critically ill patients, amiodarone may be less likely to cause systemic hypotension than IV diltiazem [36]. Digoxin monotherapy In patients without hypotension or severe heart failure, we do not generally use digoxin as a single agent for the following reasons [33,34]: Association with higher mortality in patients with high digoxin levels. It may not be appropriate for use in older patients. There are additional reasons that digoxin should not be used as an initial drug for rate control in most settings Generally less effective rate control compared with beta blockers or calcium channel blockers, particularly during exercise when vagal tone is low and sympathetic tone is high [37]. This is because the drug slows the ventricular rate during AF, primarily by vagotonic inhibition of AV nodal conduction. Digoxin is only rarely effective at terminating AF. One study suggests that digoxin may have a similar efficacy for rate control as bisoprolol [38]. However, the higher toxicity profile and risk of mortality prevent us from using it as monotherapy. Refractory to rate-control medications Some patients will not achieve adequate ventricular rate control with pharmacologic therapy due to poor response to or intolerance of initial, combination, and alternative medications. In such cases, the options are as follows: AV nodal ablation with permanent pacemaker placement If a patient has high refractory ventricular rates despite initial therapy, combination, and other pharmacotherapies, they may be referred for AV nodal ablation with pacemaker placement to achieve adequate rate control of their AF. This is discussed in detail separately. (See "Atrial fibrillation: Atrioventricular node ablation".) Switching to rhythm control In some patients, it is prudent to reconsider a rhythm- control strategy to control the ventricular rate. This is discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Atrioventricular node ablation".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 17/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Monitoring and adjustments These are more important components of successful rate- control strategies than initial drug selection. Once an effective rate control regimen has been developed, it is reasonable to periodically assess adequacy of rate control; monitoring for both bradycardia and tachycardia is important. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Additional cardiac testing' and 'Evaluation and goal ventricular rate' above.) It is also reasonable to monitor left ventricular function in patients treated with a pharmacologic rate-control strategy to make sure that a tachycardia-related cardiomyopathy has not developed. Some experts perform an echocardiogram every two to three years in asymptomatic patients with higher average ventricular rates while others do not. (See "Tests to evaluate left ventricular systolic function".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)") Beyond the Basics topic (See "Patient education: Atrial fibrillation (Beyond the Basics)".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 18/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate SUMMARY AND RECOMMENDATIONS Rationale and rate goal We slow the ventricular rate in patients with atrial fibrillation (AF) to treat symptoms, stabilize hemodynamics symptoms, and/or to avoid tachycardia- mediated cardiomyopathy. (See 'Rationale for rate lowering' above.) We target a mean rate-control goal of <85 beats/min for symptomatic patients with AF. For asymptomatic patients with permanent AF, a more lenient mean rate-control goal of <110 beats/min may be reasonable. (See 'Evaluation and goal ventricular rate' above.) Caution in preexcitation syndrome In these patients, initial therapy is aimed at reversion to sinus rhythm rather than rate control. Amiodarone, digoxin, verapamil, diltiazem, and adenosine are contraindicated with preexcited AF, and beta blockers also should not be used. (See "Treatment of arrhythmias associated with the Wolff-Parkinson- White syndrome", section on 'When to avoid AV nodal blockers'.) Urgent therapy Normotensive patients In these patients, we suggest intravenous nondihydropyridine calcium channel blockers such as diltiazem ( table 2) (Grade 2B). (See 'Urgent therapy' above and 'Normotensive patient' above.) In patients who do not adequately respond to initial therapy with either an IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy (Grade 2C). (See 'Combination therapy' above.) Asymptomatic hypotensive patients who do not require vasopressor We typically start oral metoprolol tartrate (short-acting) until the rate is controlled. In patients who do not adequately respond to initial therapy with either IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy ( table 2). (See 'Asymptomatic and not on a vasopressor' above.) In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone as a short-term rate- control strategy ( table 2). Careful attention to anticoagulation is also necessary because there is a small chance of cardioversion with amiodarone. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 19/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If none of these therapies work, we typically opt for acute cardioversion rather than continued attempts at rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate anticoagulation strategy). Symptomatic hypotensive patients and/or those requiring vasopressors If the hypotension is symptomatic and requires a vasopressor, we typically opt for acute cardioversion rather than rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate anticoagulation strategy). (See 'Symptomatic hypotension and/or on a vasopressor' above and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Elective and long-term management We start an oral beta blocker or nondihydropyridine calcium channel blocker. (See 'Choice of nonurgent therapy' above.) Combination therapy We try a combination of oral beta blocker and calcium channel blocker if monotherapy is not effective. (See 'Combination therapy' above.) Alternative short-term therapy In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone for acute control of the ventricular rate (Grade 2C). (See 'Alternative medications' above.) Refractory to rate control In patients who have a poor response or intolerance to pharmacologic therapy, options are: Atrioventricular (AV) nodal ablation with permanent pacemaker placement. (See "Atrial fibrillation: Atrioventricular node ablation".) Switching to rhythm control. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Atrioventricular node ablation".) Monitoring Careful follow-up for side effects such as bradycardia or persistent tachycardia is imperative. (See 'Monitoring and adjustments' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 20/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate REFERENCES 1. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 2. Atrial fibrillation: current understandings and research imperatives. The National Heart, Lung, and Blood Institute Working Group on Atrial Fibrillation. J Am Coll Cardiol 1993; 22:1830. 3. Mariani MV, Pierucci N, Piro A, et al. Incidence and Determinants of Spontaneous Cardioversion of Early Onset Symptomatic Atrial Fibrillation. Medicina (Kaunas) 2022; 58. 4. Lindberg S, Hansen S, Nielsen T. Spontaneous conversion of first onset atrial fibrillation. Intern Med J 2012; 42:1195. 5. Pluymaekers NAHA, Dudink EAMP, Weijs B, et al. Clinical determinants of early spontaneous conversion to sinus rhythm in patients with atrial fibrillation. Neth Heart J 2021; 29:255. 6. Knight S, Lipoth J, Namvari M, et al. The Accuracy of Wearable Photoplethysmography Sensors for Telehealth Monitoring: A Scoping Review. Telemed J E Health 2023; 29:813. 7. Dorian P. Rate control in atrial fibrillation. N Engl J Med 2010; 362:1439. 8. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 9. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363. 10. Groenveld HF, Tijssen JG, Crijns HJ, et al. Rate control efficacy in permanent atrial fibrillation: successful and failed strict rate control against a background of lenient rate control: data from RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation). J Am Coll Cardiol 2013; 61:741. 11. B hm M, Schwinger RH, Erdmann E. Different cardiodepressant potency of various calcium antagonists in human myocardium. Am J Cardiol 1990; 65:1039. 12. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1989; 63:1046. 13. Ellenbogen KA, Dias VC, Plumb VJ, et al. A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study. J Am Coll Cardiol 1991; 18:891. 14. Ellenbogen KA, Dias VC, Cardello FP, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter. Am J Cardiol 1995; 75:45. 15. Steinberg JS, Katz RJ, Bren GB, et al. Efficacy of oral diltiazem to control ventricular response in chronic atrial fibrillation at rest and during exercise. J Am Coll Cardiol 1987; 9:405. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 21/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 16. Roth A, Harrison E, Mitani G, et al. Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation. Circulation 1986; 73:316. 17. Lan Q, Wu F, Han B, et al. Intravenous diltiazem versus metoprolol for atrial fibrillation with rapid ventricular rate: A meta-analysis. Am J Emerg Med 2022; 51:248. 18. Posen A, Bursua A, Petzel R. DOsing Strategy Effectiveness of Diltiazem in Atrial Fibrillation With Rapid Ventricular Response. Ann Emerg Med 2023; 81:288. 19. Davey MJ, Teubner D. A randomized controlled trial of magnesium sulfate, in addition to usual care, for rate control in atrial fibrillation. Ann Emerg Med 2005; 45:347. 20. Ramesh T, Lee PYK, Mitta M, Allencherril J. Intravenous magnesium in the management of rapid atrial fibrillation: A systematic review and meta-analysis. J Cardiol 2021; 78:375. 21. Chan YH, Hai JJ, Wong CK, et al. Ventricular rate control with ivabradine in patients with permanent atrial fibrillation. J Interv Card Electrophysiol 2022; 65:597. 22. Fontenla A, L pez-Gil M, Tamargo-Men ndez J, et al. Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project. Rev Esp Cardiol (Engl Ed) 2020; 73:368. 23. Sorrentino MJ. Switching from drip to oral diltiazem therapy. Postgrad Med 1998; 104:37. 24. Drug Class Review: Calcium Channel Blockers: Final Report, Oregon Health & Science Univer sity. 25. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 26. Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004; 43:1201. 27. Park CS, Lee HY. Clinical utility of sympathetic blockade in cardiovascular disease management. Expert Rev Cardiovasc Ther 2017; 15:277. 28. Dobrev D, Aguilar M, Heijman J, et al. Postoperative atrial fibrillation: mechanisms, manifestations and management. Nat Rev Cardiol 2019; 16:417. 29. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64:660. 30. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 22/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet 2015; 385:2363. 31. Allen LA, Fonarow GC, Simon DN, et al. Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort. J Am Coll Cardiol 2015; 65:2691. 32. Lopes RD, Rordorf R, De Ferrari GM, et al. Digoxin and Mortality in Patients With Atrial Fibrillation. J Am Coll Cardiol 2018; 71:1063. 33. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 34. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 35. Donovan KD, Power BM, Hockings BE, et al. Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation. Am J Cardiol 1995; 75:693. 36. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med 2001; 29:1149. 37. Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B. Rate control in atrial fibrillation. Lancet 2016; 388:818. 38. Kotecha D, Bunting KV, Gill SK, et al. Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial. JAMA 2020; 324:2497. Topic 938 Version 69.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 23/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate GRAPHICS Physiology of the AV node in AF The atrioventricular (AV) node modulates the response between the atrium and the ventricle. In atrial fibrillation, the atrial rate is up to 600 beats per minute while the ventricular rate in response is 90 to 170 beats per minute; this difference in the rate results from several properties of the AV node that impede impulse conduction. The AV node generates a slow action potential (AP) that is mediated by calcium (Ca++) ion currents; the node is therefore slow response tissue. Parasympathetic innervation via the vagus nerve also slows conduction, while activation of the sympathetic nervous system speeds conduction. Graphic 75699 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 24/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Effect of drugs on AV function in AF Various drugs can slow conduction through the atrioventricular node in atrial fibrillation by altering its physiology. The calcium (Ca++) channel blockers, primarily diltiazem and verapamil, block the influx of calcium and therefore slow conduction by reducing the upstroke of the action potential; digoxin, carotid massage, Valsalva maneuver, and edrophonium are vagotonic and slow conduction by increasing parasympathetic effects on the node; beta blockers slow conduction by offsetting sympathetic inputs; and adenosine slows conduction only transiently by increasing potassium conduction and decreasing calcium influx. Graphic 51932 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 25/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate [2,3] Six-minute walk test technique Flat, straight corridor 30 m (100 feet) in length Turnaround points marked with a cone Patient should wear comfortable clothes and shoes Patient rests in chair for at least 10 minutes prior to test (ie, no warm-up period) Heart rate and pulse oxygen saturation (SpO ) should be monitored throughout the test 2 If the patient is using supplemental oxygen, record the flow rate and type of device [1] Have patient stand and rate baseline dyspnea and overall fatigue using Borg scale* Set lap counter to zero and timer to six minutes Instruct the patient: Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog. Pivot briskly around the cone. Standardized encouragement statements should be provided at one minute intervals, such as "You are doing well. You have _ minutes to go" and "Keep up the good work. You have _ minutes to go." At the end of the test, mark the spot where the patient stopped on the floor If using a pulse oximeter, measure the pulse rate and SpO and record 2 [1] After the test record the Borg* dyspnea and fatigue levels Ask, "What, if anything, kept you from walking farther?" Calculate the distance walked and record Refer to UpToDate table on the modified Borg Scale. Reference: 1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377. 2. American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166:111. 3. Holland AE, Spruit MA, Troosters T, et al. An o cial European Respiratory Society/American Thoracic Society technical standard: eld walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1428. Graphic 90285 Version 4.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 26/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Medications and doses for ventricular rate control in adult patients with atrial fibrillation Medication IV dosing Oral dosing* Notes Diltiazem Bolus dosing: IR: 30 mg 4 times daily; increase as needed to IV regimen usually controls the ventricular First bolus: 0.25 achieve ventricular rate control; usual dose: 120 mg/kg (average adult dose: 20 mg) rate within 4 to 5 minutes. to 480 mg/day in 3 or 4 administered over 2 Some experts use a lower bolus dose of 5 divided doses. minutes; if dose is tolerated but does to 15 mg if there is concern for ER: 120 mg once daily or in 2 divided doses not produce desired response (ie, 20% hypotension. depending on formulation ; increase as reduction in baseline heart rate or heart rate 100 beats/min) within 15 minutes, administer a second needed to achieve ventricular rate control; usual dose: 120 to 480 mg/day. bolus. Second bolus: 0.35 mg/kg (average adult dose: 25 mg) administered over 2 minutes. In those who respond to the first or second bolus, initiate a continuous infusion at 5 to 10 mg/hour. May increase in 5 mg/hour increments as needed to a maximum of 15 mg/hour. Esmolol Rapid titration with bolus Not available as oral Due to short half-life, doses: preparation. useful when uncertain if patient will become 500 mcg/kg loading dose administered over 1 minute, hypotensive with a beta blocker. followed by a continuous infusion of 50 mcg/kg/minute. Reassess after 4 minutes. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 27/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If response is inadequate, administer a second bolus of 500 mcg/kg and increase infusion to 100 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, administer a third and final bolus of 500 mcg/kg and increase infusion to 150 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, may increase infusion to a maximum of 200 mcg/kg/minute. OR Slow titration without bolus doses: Initiate continuous infusion at 50 mcg/kg/minute; if needed based on clinical response, may increase in 50 mcg/kg/minute increments at 30- minute intervals to a maximum of 200 mcg/kg/minute. Verapamil Bolus dosing: 5 to 10 mg administered over 2 to 3 IR: 40 mg 3 to 4 times daily; increase as needed Rate control is often achieved with 1 or 2 minutes; may repeat every 15 to 30 minutes as to achieve ventricular rate control; maximum dose: bolus doses. With IV administration, needed and tolerated. 480 mg/day in 3 to 4 divided doses. onset of effect on AV node is within 2 Once rate control is achieved with bolus doses, minutes and peak https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 28/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate initiate a continuous infusion at 5 mg/hour; ER : 120 or 180 mg once daily; increase as needed effect is in 10 to 15 minutes. titrate based on clinical to achieve ventricular rate Control of the ventricular response is response to a maximum of 20 mg/hour. control; maximum dose: 480 mg/day in 1 to 2 lost in approximately divided doses. 90 minutes if repeated boluses or a maintenance infusion are not given. Metoprolol Bolus dosing: 2.5 to 5 mg IR (metoprolol tartrate): administered over 2 minutes; may repeat at 5- 25 mg twice daily; increase dose gradually minute intervals up to a (eg, by 12.5 mg every 6 total dose of 15 mg. hours) as needed and tolerated to achieve While subsequent doses can be given intravenously, ventricular rate control; maximum dose: 100 mg the optimal regimen is not well defined, and oral twice daily. administration is ER (metoprolol succinate): preferable. 50 mg once daily; increase dose gradually as tolerated to achieve ventricular rate control; maximum dose: 400 mg once daily. Propranolol Bolus dosing: 1 mg IR: 10 mg 3 to 4 times administered over 1 minute; may repeat at 2- daily; increase dose gradually as tolerated to minute intervals for up to 3 achieve ventricular rate doses. control; maximum dose: 40 mg 3 to 4 times daily. ER: 60 mg once daily; increase as needed to achieve ventricular rate control up to 160 mg once daily. Digoxin TDD: 0.25 to 0.5 mg administered over several TDD: 0.5 mg once, followed by 0.25 mg every May use as add-on therapy in patients who minutes, followed by 0.25 mg every 6 hours for a 6 hours for a total loading dose of 0.75 to 1.5 mg.
Effect of drugs on AV function in AF Various drugs can slow conduction through the atrioventricular node in atrial fibrillation by altering its physiology. The calcium (Ca++) channel blockers, primarily diltiazem and verapamil, block the influx of calcium and therefore slow conduction by reducing the upstroke of the action potential; digoxin, carotid massage, Valsalva maneuver, and edrophonium are vagotonic and slow conduction by increasing parasympathetic effects on the node; beta blockers slow conduction by offsetting sympathetic inputs; and adenosine slows conduction only transiently by increasing potassium conduction and decreasing calcium influx. Graphic 51932 Version 1.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 25/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate [2,3] Six-minute walk test technique Flat, straight corridor 30 m (100 feet) in length Turnaround points marked with a cone Patient should wear comfortable clothes and shoes Patient rests in chair for at least 10 minutes prior to test (ie, no warm-up period) Heart rate and pulse oxygen saturation (SpO ) should be monitored throughout the test 2 If the patient is using supplemental oxygen, record the flow rate and type of device [1] Have patient stand and rate baseline dyspnea and overall fatigue using Borg scale* Set lap counter to zero and timer to six minutes Instruct the patient: Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog. Pivot briskly around the cone. Standardized encouragement statements should be provided at one minute intervals, such as "You are doing well. You have _ minutes to go" and "Keep up the good work. You have _ minutes to go." At the end of the test, mark the spot where the patient stopped on the floor If using a pulse oximeter, measure the pulse rate and SpO and record 2 [1] After the test record the Borg* dyspnea and fatigue levels Ask, "What, if anything, kept you from walking farther?" Calculate the distance walked and record Refer to UpToDate table on the modified Borg Scale. Reference: 1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377. 2. American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166:111. 3. Holland AE, Spruit MA, Troosters T, et al. An o cial European Respiratory Society/American Thoracic Society technical standard: eld walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1428. Graphic 90285 Version 4.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 26/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Medications and doses for ventricular rate control in adult patients with atrial fibrillation Medication IV dosing Oral dosing* Notes Diltiazem Bolus dosing: IR: 30 mg 4 times daily; increase as needed to IV regimen usually controls the ventricular First bolus: 0.25 achieve ventricular rate control; usual dose: 120 mg/kg (average adult dose: 20 mg) rate within 4 to 5 minutes. to 480 mg/day in 3 or 4 administered over 2 Some experts use a lower bolus dose of 5 divided doses. minutes; if dose is tolerated but does to 15 mg if there is concern for ER: 120 mg once daily or in 2 divided doses not produce desired response (ie, 20% hypotension. depending on formulation ; increase as reduction in baseline heart rate or heart rate 100 beats/min) within 15 minutes, administer a second needed to achieve ventricular rate control; usual dose: 120 to 480 mg/day. bolus. Second bolus: 0.35 mg/kg (average adult dose: 25 mg) administered over 2 minutes. In those who respond to the first or second bolus, initiate a continuous infusion at 5 to 10 mg/hour. May increase in 5 mg/hour increments as needed to a maximum of 15 mg/hour. Esmolol Rapid titration with bolus Not available as oral Due to short half-life, doses: preparation. useful when uncertain if patient will become 500 mcg/kg loading dose administered over 1 minute, hypotensive with a beta blocker. followed by a continuous infusion of 50 mcg/kg/minute. Reassess after 4 minutes. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 27/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If response is inadequate, administer a second bolus of 500 mcg/kg and increase infusion to 100 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, administer a third and final bolus of 500 mcg/kg and increase infusion to 150 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, may increase infusion to a maximum of 200 mcg/kg/minute. OR Slow titration without bolus doses: Initiate continuous infusion at 50 mcg/kg/minute; if needed based on clinical response, may increase in 50 mcg/kg/minute increments at 30- minute intervals to a maximum of 200 mcg/kg/minute. Verapamil Bolus dosing: 5 to 10 mg administered over 2 to 3 IR: 40 mg 3 to 4 times daily; increase as needed Rate control is often achieved with 1 or 2 minutes; may repeat every 15 to 30 minutes as to achieve ventricular rate control; maximum dose: bolus doses. With IV administration, needed and tolerated. 480 mg/day in 3 to 4 divided doses. onset of effect on AV node is within 2 Once rate control is achieved with bolus doses, minutes and peak https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 28/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate initiate a continuous infusion at 5 mg/hour; ER : 120 or 180 mg once daily; increase as needed effect is in 10 to 15 minutes. titrate based on clinical to achieve ventricular rate Control of the ventricular response is response to a maximum of 20 mg/hour. control; maximum dose: 480 mg/day in 1 to 2 lost in approximately divided doses. 90 minutes if repeated boluses or a maintenance infusion are not given. Metoprolol Bolus dosing: 2.5 to 5 mg IR (metoprolol tartrate): administered over 2 minutes; may repeat at 5- 25 mg twice daily; increase dose gradually minute intervals up to a (eg, by 12.5 mg every 6 total dose of 15 mg. hours) as needed and tolerated to achieve While subsequent doses can be given intravenously, ventricular rate control; maximum dose: 100 mg the optimal regimen is not well defined, and oral twice daily. administration is ER (metoprolol succinate): preferable. 50 mg once daily; increase dose gradually as tolerated to achieve ventricular rate control; maximum dose: 400 mg once daily. Propranolol Bolus dosing: 1 mg IR: 10 mg 3 to 4 times administered over 1 minute; may repeat at 2- daily; increase dose gradually as tolerated to minute intervals for up to 3 achieve ventricular rate doses. control; maximum dose: 40 mg 3 to 4 times daily. ER: 60 mg once daily; increase as needed to achieve ventricular rate control up to 160 mg once daily. Digoxin TDD: 0.25 to 0.5 mg administered over several TDD: 0.5 mg once, followed by 0.25 mg every May use as add-on therapy in patients who minutes, followed by 0.25 mg every 6 hours for a 6 hours for a total loading dose of 0.75 to 1.5 mg. do not adequately respond to a calcium total loading dose of 0.75 to 1.5 mg. channel blocker and/or beta blocker; not Maintenance dose (for use after administration of IV or oral TDD): 0.125 generally used as monotherapy. to 0.25 mg once daily. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 29/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Amiodarone Loading dose: 150 mg over 10 minutes followed by 1 mg/minute for 6 hours, Following IV infusion, administer 400 to 1200 May use in select patients requiring mg/day in divided doses urgent therapy who are intolerant of other then 0.5 mg/minute for 18 hours; may administer to complete a total (IV plus oral) loading dose of preferred agents (ie, repeat boluses of 150 mg over 10 minutes as needed, not to exceed 6 to 8 additional bolus doses approximately 10 grams. Consider overlapping IV calcium channel blockers, beta blockers, and oral therapy for 24 to 48 hours. digoxin). Due to small chance of per 24 hours. cardioversion, careful attention to Usual maintenance dose: 100 to 200 mg once daily. anticoagulation is necessary. This table shows doses of drugs that can be used for ventricular rate control in adult patients with atrial fibrillation who do not have heart failure. It should be used in conjunction with UpToDate content on control of ventricular rate in patients with atrial fibrillation. When initiating or altering therapy, use of a drug interactions database, such as Lexicomp drug interactions, is advised. IV: intravenous; IR: immediate-release; ER: extended-release; AV: atrioventricular; TDD: total digitalizing dose. Oral dosing in this table is initial dosing for patients requiring nonurgent therapy, unless otherwise noted. For patients transitioning from IV to oral therapy, UpToDate authors typically convert the total daily dose of the IV medication to an equivalent divided or long-acting oral dose of a medication in the same class. Refer to UpToDate topic on control of ventricular rate in patients with atrial fibrillation for discussion. Diltiazem extended-release is available in 12- and 24-hour formulations. Refer to a drug information reference, such as Lexicomp drug information included with UpToDate, or local product information for dosing details. Verapamil ER delayed-onset capsules (ie, Verelan PM and generics) are not interchangeable with other ER formulations and are intended for management of hypertension. Digoxin has a narrow therapeutic window and can cause significant toxicity. Individual patient characteristics (eg, kidney function, body habitus, concomitant medications) should be carefully considered when determining loading and maintenance dosing regimens. Dosing in this table does not account for dose adjustments. For discussion of dosing and monitoring, refer to UpToDate content on treatment with digoxin. Amiodarone use is associated with a relatively high incidence of adverse effects. Refer to related UpToDate content for discussion, including monitoring. Graphic 141646 Version 2.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 30/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Dose response to diltiazem for rate control in atrial fibrillation Kaplan-Meier analysis of the percentage of patients maintaining a therapeutic rate control response to each dose level of intravenous diltiazem infusion in patients who initially responded to bolus diltiazem. Maintenance of rate control was greater at doses of 10 to 15 mg/h. Data from Ellenbogen KA, Dias VC, Cardello FP, et al. Am J Cardiol 1995; 75:45. Graphic 80630 Version 3.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 31/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Efficacy of amiodarone in rate control for atrial fibrillation Effect of intravenous placebo, amiodarone, and flecainide on the ventricular response to atrial fibrillation in patients who failed to revert to sinus rhythm after the initiation of therapy. Amiodarone slowed the ventricular response, an effect that was not seen with flecainide or placebo. Although flecainide was less effective for rate control, it was associated with earlier reversion to sinus rhythm than amiodarone or placebo. Note that the time scale is nonlinear. Data from Donovan KD, Power BM, Hockings GE, et al. Am J Cardiol 1995; 75:693. Graphic 81119 Version 3.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 32/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Contributor Disclosures Rachel Kaplan, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 33/33
7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Epidemiology, risk factors, and prevention of atrial fibrillation : David Spragg, MD, FHRS : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 30, 2022. INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice. Patients are at increased risk for death, heart failure, hospitalization, and thromboembolic events [1-3]. The epidemiology of, disease associations with, and risk factors for AF will be reviewed here. An overview of the presentation and management of patients with AF is discussed elsewhere. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) EPIDEMIOLOGY Atrial fibrillation (AF) is a global health care problem with evidence suggesting an increasing prevalence and incidence worldwide [4-6]. A systematic review of worldwide population-based studies (n = 184) estimated that the number of individuals with AF in 2010 was 33.5 million. Most of the studies below have evaluated individuals living in North America or Europe, but other geographies will be specified. Prevalence The prevalence of AF depends upon population characteristics, with differences apparent due to age, sex, race, geography, and time period. The following data are primarily derived from studies in which an electrocardiogram was obtained during an office visit rather https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 1/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate than ambulatory monitoring. The prevalence of paroxysmal AF, which is more likely to be detected with ambulatory monitoring, is much higher. Age AF is uncommon in infants and children and when present, almost always occurs in association with structural heart disease. Healthy young adults are also at low risk [7]. The prevalence of AF increases with age ( figure 1) [2,8-11]. This relationship to age was demonstrated in the ATRIA study, a cross-sectional study of almost 1.9 million subjects in a health maintenance organization in the United States [11]. The overall prevalence of AF was 1 percent; 70 percent were at least 65 years old and 45 percent were 75 years old. The prevalence of AF ranged from 0.1 percent among adults less than 55 years of age to 9 percent in those 80 years of age ( figure 2). In the STROKESTOP study discussed below, the prevalence of AF in a 75- to 76-year-old population (2011) in Sweden was about 12 percent [12]. Similar patterns were reported in a European population-based prospective cohort study of 6808 subjects 55 years of age [10]. The prevalence of AF was 5.5 percent, ranging from 0.7 percent in those aged 55 to 59 years and 17.8 percent for those 85 years of age. Sex The prevalence was higher in men than women (1.1 versus 0.8 percent), a difference seen in every age group ( figure 2 and figure 1). In another study, the rates were 6 versus 5.1 percent, respectively [10]. Race/ethnicity In one study, AF was more frequent in Whites compared with Black Americans over the age of 50 years (2.2 versus 1.5 percent) [11]. It has not been determined whether those from a Black population are at lower risk or if those from a White population are at higher risk [13]. A study that included nearly 14,000,000 patients receiving hospital-based care in California (United States) between 2005 and 2009 evaluated the relationship between race and incident AF [14]. Adjustment was made for known AF risk factors and patient demographics. Compared with White Americans, Black (hazard ratio [HR] 0.84), Hispanic (HR 0.78), and Asian (HR 0.78) Americans each had a lower AF risk after adjustment. Geography In one study, the age-adjusted prevalence rate (per 100,000 population) was highest in North America (700 to 775) and lowest in Japan and South Korea (250 to 325) [6]. The rate in China was also relatively low (325 to 400). Time period The prevalence of AF in the population is increasing. In a community-based study of 1.4 million patients in England and Wales, the age-standardized prevalence of AF between 1994 and 1998 increased by 22 and 14 percent in men and women, respectively [8]. In the ATRIA study, it was estimated that 2.3 million adults in the United States had AF https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 2/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate in 1996 and 1997, and that this will increase to 5.6 million by the year 2050, with more than 50 percent being more than 80 years of age [11]. In a report from the United States, the prevalence of AF in 2005 was 3.03 million, and the projected prevalence for 2050 was 7.56 million [15]. In another study, the estimated age-adjusted prevalence rates (per 100,000 population) were 570 in men and 360 in women and 596 (men) and 373 (women) in 1990 and 2010, respectively [6]. Subclinical atrial fibrillation Subclinical AF refers to asymptomatic episodes in a patient without a prior history of AF, which are detected only by monitoring techniques. The prevalence of subclinical AF is presented separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Clinical presentation'.) Incidence The incidence of AF, similar to the prevalence, increases with advancing age [10,16- 18]. In a longitudinal study in which 3983 male Air Force recruits were followed for 44 years, 7.5 percent developed AF [18]. The risk increased with advancing age (from 0.5 per 1000 person- years before age 50 to 9.7 per 1000 person years after age 70). The lifetime risk for the development of AF was analyzed in a report from the Framingham Heart Study [19]. A total of 8725 patients were followed from 1968 to 1999 (176,166 person-years of follow-up); 936 developed AF. The risk of developing AF from age 40 to age 95 was 26 percent for men and 23 percent for women. Lifetime risk did not change substantially with increasing index age because AF incidence rose with age; the risk of developing AF from age 80 to age 95 was 23 percent for men and 22 percent for women. PATHOGENESIS Irrespective of the underlying risk factor(s), changes in the anatomy and electrophysiology of the atrial myocardium are likely important. Thus, atrial fibrillation (AF) is usually associated with some underlying heart disease. Atrial enlargement, an elevation in atrial pressure, or infiltration or inflammation of the atria are often seen. Premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) appears to be most important as a trigger in patients with paroxysmal AF who have normal or near-normal hearts. The relative importance of PAC or other triggers versus an abnormal substrate is much less clear in patients with significant structural heart disease. (See "The electrocardiogram in atrial fibrillation".) The mechanisms of AF are presented in detail separately. (See "Mechanisms of atrial fibrillation".) https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 3/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate CHRONIC DISEASE ASSOCIATIONS Hypertensive heart disease and coronary heart disease (CHD) are the most common underlying chronic disorders in patients with atrial fibrillation (AF) in developed countries. Rheumatic heart disease, although now uncommon in developed countries, is associated with a much higher incidence of AF. Paroxysmal AF (PAF) is associated with the same disorders as chronic (permanent) AF. (See "Paroxysmal atrial fibrillation".) Hypertensive heart disease In a longitudinal study of male air crew recruits, a history of hypertension increased the risk of developing AF 1.42-fold [18]. Although this is a relatively small increase in risk, the high frequency of hypertension in the general population results in hypertensive heart disease being the most common underlying disorder in patients with AF [16]. Coronary disease AF is not commonly associated with CHD unless it is complicated by acute myocardial infarction (MI) or heart failure (HF). AF occurs transiently in 6 to 10 percent of patients with an acute MI, presumably due to atrial ischemia or atrial stretching secondary to HF [20-23]. These patients have a worse prognosis that is mostly due to comorbidities such as older age and HF. (See "Supraventricular arrhythmias after myocardial infarction", section on 'Atrial fibrillation'.) The incidence of AF is much lower in patients with chronic stable CHD [24,25]. In the Coronary Artery Surgical Study (CASS), which included over 18,000 patients with angiographically documented coronary artery disease, AF was present in only 0.6 percent [24]. These patients probably had chronic AF; the prevalence of PAF may be higher. AF was associated with age greater than 60, male sex, mitral regurgitation (MR), and HF; there was no association between AF and the number of coronary arteries involved. Valvular heart disease Almost any valvular lesion that leads to significant stenosis or regurgitation is associated with the development of AF. The following are representative frequencies: In a review of 89 patients with mitral valve prolapse (and grade 3 or 4 MR) and 360 with flail leaflets, the rate of development of AF was about 5 percent per year with both types of lesions [26]. The major independent risk factors were age 65 years and baseline left atrial dimension 50 mm. Rheumatic heart disease is now uncommon in developed countries. It is, however, associated with a high prevalence of AF [27,28]. In a study of approximately 1100 patients with rheumatic heart disease, the prevalence varied with the type of valve disease [28]: https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 4/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Mitral stenosis (MS), MR, and tricuspid regurgitation 70 percent MS and MR 52 percent Isolated MS 29 percent Isolated MR 16 percent Heart failure AF and HF often occur together, and each may predispose to the other [29]. Among patients with HF, the prevalence of AF is variable, depending in part upon the severity of HF. Issues related to AF in patients with HF and cardiomyopathy are discussed in detail separately. (See "The management of atrial fibrillation in patients with heart failure".) Hypertrophic cardiomyopathy AF has been reported in 10 to 28 percent of patients with hypertrophic cardiomyopathy [30-32]. The prognostic importance of AF in these patients is unclear, with some reports showing a worse prognosis [32] and others no increase in mortality [31]. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation".) Congenital heart disease AF has been reported in approximately 20 percent of adults with an atrial septal defect [33]. However, the incidence of AF is related to age, ranging in one series from 15 percent for those aged 40 to 60, to 61 percent for those over the age of 60 [34]. AF and/or atrial flutter also occurs in other forms of congenital heart disease that affect the atria, including Ebstein anomaly and patent ductus arteriosus, and after surgical correction of some other abnormalities, including ventricular septal defect, tetralogy of Fallot, pulmonic stenosis, and transposition of the great vessels. Venous thromboembolic disease Venous thromboembolic disease, which includes deep vein thrombosis and pulmonary embolism, is associated with an increased risk of AF. The mechanism is not known but has been speculated to be related to the increase in pulmonary vascular resistance and cardiac afterload, which may lead to right atrial strain [35,36]. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Diagnostic evaluation'.) The incidence of AF in patients with acute or chronic venous thromboembolic disease has not been well studied. It has been reported to be in the 10 to 14 percent range in patients with documented pulmonary embolism [37,38]. The impact of incident venous thromboembolism (VTE) on the future risk of AF was evaluated in a prospective population-based study of nearly 30,000 individuals of whom 1.8 percent had an incident VTE event and 5.4 percent were diagnosed with AF during 16-year follow-up [36]. The risk of AF was higher in those with VTE than in those without after multivariable adjustment (hazard ratio 1.63, 95% CI 1.22-2.17). This risk was particularly high in the first six months after the VTE event. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 5/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Obstructive sleep apnea AF is associated with pulmonary disease and obstructive sleep apnea in particular [39-44]. In a 2020 study of 188 consecutive patients with AF and no prior diagnosis of sleep apnea who were scheduled to undergo AF ablation, home sleep apnea testing was positive in 155 (82.4 percent), and of these 82 percent had a predominant obstructive component [45]. Among the 155 patients, sleep apnea was considered severe in 23.2 percent, moderate in 32.9 percent, and mild in 43.8 percent. Continuous positive airway pressure therapy was prescribed in 85.9 percent of the patients with moderate or severe sleep apnea. There is a possible causal relationship between obstructive sleep apnea (OSA) and AF [46-49]. In a series of 39 patients diagnosed with both PAF and OSA, patients receiving treatment with continuous positive pressure ventilation had a lower incidence of AF recurrence at 12 months (42 versus 82 percent for patients who were not treated) [46]. In another observational study, the incidence of OSA was compared between 151 patients referred for cardioversion for AF and 312 controls without AF referred for general cardiology evaluation [47]. OSA was significantly more common in the patients with AF than in the control group (49 versus 32 percent). Finally, preoperative sleep studies were performed in a series of 121 patients referred for coronary artery bypass surgery [48]. Postoperative AF was significantly more common among the 49 patients with an abnormal sleep study (39 versus 18 percent in patients with normal sleep studies). (See "Obstructive sleep apnea and cardiovascular disease in adults", section on 'Atrial fibrillation'.) 2 Obesity Obese individuals (body mass index [BMI] >30 kg/m ) are significantly more likely to 2 develop AF than those with a normal BMI (<25 kg/m ) [50-52]. In the Framingham Heart Study, every unit increase in BMI was associated with an approximate 5 percent increase in risk [53]. (See "Overweight and obesity in adults: Health consequences".) A primary mechanism for the role of obesity may be an increase in the size of the left atrium. Increased left atrial pressure and volume, often associated with diastolic dysfunction, as well as a shortened effective refractory period in the left atrium and in the proximal and distal pulmonary veins have been identified as potential factors facilitating and perpetuating AF in obese patients [54]. Inflammation and pericardial fat may also play a role [50]. (See "Mechanisms of atrial fibrillation" and 'Other factors' below.) There is some evidence to suggest that long-term weight loss is associated with a reduction of AF burden [51,55]. Diabetes In a study of over 4700 individuals without valvular heart disease in the Framingham Heart Study, the presence of diabetes was associated with a significantly increased risk for the development of AF in multivariate analysis (odds ratio 1.1 for men and 1.5 for https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 6/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate women) [56]. Increased left ventricular mass and increased arterial stiffness have been put forth as possible mechanisms [57]. Metabolic syndrome As discussed above, the presence of hypertension, diabetes, or obesity is associated with an increased likelihood of the development of AF. The metabolic syndrome includes these three, as well as dyslipidemia. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Definition'.) The potential relationship between the metabolic syndrome and the development of AF was evaluated in a prospective, observational cohort study of 28,449 Japanese citizens [58]. Using the 2005 criteria for the metabolic syndrome approved by the American Heart Association and the National Heart, Lung, and Blood Institute, 4544 individuals met criteria for the metabolic syndrome at baseline [59]. During a mean follow-up for 4.5 years, AF developed in 265 patients. The risk of developing AF was significantly greater in those individuals with the metabolic syndrome (hazard ratio 1.61, 95% CI 1.21-2.15), as well as in those with individual components of hypertension, obesity, low high density lipoprotein cholesterol and impaired glucose tolerance, but not elevated triglycerides. Chronic kidney disease Chronic kidney disease (CKD) increases the risk of the development of AF. The following two prospective, cohort studies are representative: In a study of 235,818 individuals, the hazard ratio for the development of AF was 1.32 for 2 patients with estimated glomerular filtration rates (eGFRs) of 30 to 59 mL/min/1.73m compared with those with normal renal function [60]. The relationship between CKD and AF was evaluated in a report of 10,328 individuals free of AF participating in the Atherosclerosis Risk in Communities (ARIC) study who had a baseline cystatin C-based estimated glomerular filtration rate (eGFR ) [61]. Compared 2 cys with individuals with eGFR 90 mL/min/m , the multivariable hazard ratios for the cys development of AF were significantly increased at 1.3, 1.6, and 3.2 in those with eGFR 2 of cys 60 to 89, 30 to 59, and 15 to 29 mL/min/m , respectively, during a median follow-up of 10.1 years. In addition, macroalbuminuria and microalbuminuria were significantly associated with higher AF risk. The incidence and prevalence of AF in patients with CKD are presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) POTENTIALLY REVERSIBLE TRIGGERS https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 7/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate The medical conditions listed above, which are associated with an increased risk of the development of atrial fibrillation (AF), are chronic. Historically, it has been assumed that the risk of AF decreases after a non-chronic (secondary) condition has been corrected. However, there is some evidence to suggest that the risk remains. In the Framingham Heart Study, 1409 individuals with new onset AF were evaluated for their risk of subsequent occurrences based on whether they had a secondary precipitant or not [62]. A precipitant was found in 439 (31 percent) and included cardiothoracic surgery (30 percent), infection (23 percent), non-cardiothoracic surgery (20 percent), and acute myocardial infarction (18 percent). Other secondary precipitants included acute alcohol consumption, thyrotoxicosis, acute pericardial disease, acute pulmonary embolism, and other acute pulmonary pathology. While the 15-year cumulative incidence of recurrent AF was significantly lower among those with secondary causes (62 versus 71 percent), the finding that AF recurred in the majority with secondary causes was unexpected. Surgery AF occurs in relation to a variety of different types of surgery, with the incidence greatest in patients undergoing cardiac surgery: Cardiac surgery AF has been reported in up to 30 to 40 percent of patients in the early postoperative period following coronary artery bypass graft surgery (CABG) [63-66], in 37 to 50 percent after valve surgery [63,66,67], and in as many as 60 percent undergoing valve replacement plus CABG [63,66]. This topic is discussed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery".) Cardiac transplantation AF has been described in 10 to 24 percent of patients with a denervated transplanted heart, often in the absence of significant rejection [66,68]. Most episodes occur within the first two weeks, while AF developing after two weeks may be associated with an increased risk of subsequent death [68,69]. (See "Heart transplantation in adults: Arrhythmias", section on 'Supraventricular arrhythmias'.) Noncardiac surgery AF is less common after noncardiac compared with cardiac surgery. The reported incidence of new onset AF in patients undergoing noncardiac surgery ranges from 1 and 40 percent. This broad range is likely due to variability in patient and surgical characteristics [70,71]. The largest experience comes from a review of 4181 patients over the age of 50 who were in sinus rhythm prior to major noncardiac surgery [72]. The incidence of perioperative AF was 4.1 percent; most episodes occurred within the first three days after surgery. The risk was greatest with intrathoracic surgery (odds ratio 9.2). In another series of 2588 undergoing noncardiac thoracic surgery, the incidence of AF was 12.3 percent [73]. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 8/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Hyperthyroidism Patients with hyperthyroidism have an increased risk of developing AF [74]. In one population-based study of 40,628 patients with clinical hyperthyroidism, 8.3 percent had AF or atrial flutter [75]. AF occurred in 10 to 20 percent of patients over age 60 but in less than 1 percent of patients under age 40. Men were more likely to have AF than women (12.1 versus 7.6 percent). (See "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) Increased beta adrenergic tone may be in part responsible for the development of AF in hyperthyroidism and may also contribute to the rapid ventricular response in this setting. In addition, excess thyroid hormone increases the likelihood of AF in experimental animals, even in the presence of beta receptor and vagal blockade [76]; it is likely that this observation applies to humans. The mechanism is unknown, but may be related to an increased automaticity and enhanced triggered activity of pulmonary vein cardiomyocytes, which can be a source of ectopic beats that initiate AF [77]. The risk of AF is also increased in patients with subclinical hyperthyroidism (defined as a low serum thyroid stimulating hormone concentration and normal serum thyroid hormone concentrations) [78-80]. The increase in risk is illustrated by the following observations: In a prospective study, 2007 subjects 60 years of age who did not have AF were followed for 10 years [78]. The subsequent age-adjusted incidence of AF was significantly higher among those with a low serum thyroid stimulating hormone concentration compared with those with a normal value (28 versus 10 per 1000 person-years). In a review of 23,638 subjects, the prevalence of AF in those with clinical and subclinical hyperthyroidism was similar (14 and 13 percent, respectively) and higher than that in euthyroid subjects (2.3 percent) [79]. A possible relationship between AF and hypothyroidism has been suggested but not proven [81,82]. Since hypothyroidism is present in 5 to 10 percent of the general population, it is not surprising that some patients with AF have hypothyroidism (7.7 percent with subclinical disease in one report [80]) that may not be causally related. OTHER FACTORS A number of risk factors not discussed above are associated with an increased risk for the development of atrial fibrillation (AF). Family history The presence of AF in a first-degree relative, particularly a parent, has long been associated with an increase in risk, independent of standard risk factors such as age, sex, https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 9/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate hypertension, diabetes, or clinically overt heart disease [83]. (See 'Epidemiology' above and 'Chronic disease associations' above.) In an analysis of over 4400 individuals in the Framingham Heart Study, the occurrence of AF in a first degree relative was associated with a significantly increased risk of incident AF (multivariable-adjusted hazard ratio [HR] 1.40, 95% CI 1.13-1.74) [84]. The strength of this relationship was greater when only first-degree relatives with premature onset (age 65 years) were considered. Genetic factors For the vast majority of AF patients, we do not suggest genetic screening as it does not change clinical management. Exceptions are when there is concern for a rare disorder that has a high stroke risk irrespective of CHA DS -VASc score such as AF in Emery 2 2 Dreifuss muscular dystrophy or Lamin disorder. For most patients with AF, one or more of the nongenetic disease associations discussed above are present. However, evidence suggests that AF is heritable, and in younger patients, there may be increased genetic susceptibility of AF [85]. Among 1300 participants who underwent whole genome sequencing, disease-associated rare variants in cardiomyopathy and arrhythmia genes were identified in 10 percent of participants younger than 66 years and 17 percent of those younger than 30 years. Disease-associated rare variants were more prevalent in genes associated with inherited cardiomyopathy syndromes than inherited arrhythmia syndromes. The heritability of AF is complex. For the majority of patients, genetic susceptibility, if present, is probably a polygenic phenomenon, meaning that it is due to the combined effects of a number of genes. Polygenic inheritance can explain why some diseases cluster in families, but do not demonstrate the classic Mendelian inheritance patterns of monogenic disorders. However, a small number of families demonstrate monogenic inheritance characteristics. Polygenic inheritance Polygenic inheritance appears to be more common and could explain the modest elevation in the relative risk of AF in first- and second-degree relatives of affected individuals. Evidence supporting a heritable component to AF susceptibility includes: In a review of 914 patients with AF, 50 (5 percent) had a family history of AF (one to nine additional relatives affected) [86]. In an analysis of 2243 offspring in the Framingham Heart Study, those with parental AF had a significantly higher incidence of developing AF than those without parental AF (4.1 versus 2.7 percent, adjusted odds ratio 1.85) [83]. This effect was more pronounced when the https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 10/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate analysis was limited to patients with age of AF onset less than 75 years and to those without prior myocardial infarction, heart failure, or valve disease (odds ratio 3.17). A population study in Iceland evaluated the heritability of AF in a cohort of 5269 patients diagnosed over a 16-year period [87]. Among patients with AF, the degree of relatedness was significantly greater than among matched controls. In addition, the relative risk of developing AF was higher in the relatives of patients than those of controls. Monogenic inheritance Some families have been identified in which AF inheritance follows more typical Mendelian patterns, consistent with a single disease-causing gene. Both autosomal dominant and autosomal recessive forms have been identified. Genetic linkage analysis has identified loci at 10q22-q24, 11p15.5, 6q14-16, 3p22-p25, and 4q25 [88-92]. At the 4q25 locus, several single-nucleotide polymorphisms have been identified [93]. In these individuals, penetrance is variable and the polymorphisms can affect the clinical expression of familial AF [94]. An autosomal recessive pattern of AF inheritance was reported in a large family from Uruguay [95]. Clinical manifestations included AF during fetal life, neonatal sudden death, ventricular tachyarrhythmias, and waxing and waning cardiomyopathy. A genetic locus on chromosome 5p13 was linked to disease in this family. Chromosomal loci are large areas with multiple genes, and a specific genetic defect is not yet known for most loci. Examples of a monogenic cause of AF include: The 11p15.5 locus is associated with a gain-of-function mutation in the KVLQT1 (KCNQ1) gene, the protein product of which is the alpha-subunit of the slowly acting component of the outward-rectifying potassium current (IKs) [89]. This mutation is thought to initiate and maintain AF by reducing the action potential duration and effective refractory period in atrial myocytes. A different gain-of-function mutation in this gene has been associated with the congenital short QT syndrome, while loss-of-function mutations are associated with long QT syndrome, type 1. (See "Congenital long QT syndrome: Pathophysiology and genetics", section on 'Type 1 LQTS (LQT1)'.) An autosomal dominant form of AF, usually in association with a dilated cardiomyopathy, has been associated with mutations in SCN5A, the cardiac sodium channel gene. In a report of individuals with SCN5A mutations, 27 percent had early features of dilated cardiomyopathy (mean age at diagnosis 20 years), 43 percent had AF (mean age at https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 11/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate diagnosis 28 years), and 38 percent had dilated cardiomyopathy (mean age at diagnosis 48 years) [91]. (See "Genetics of dilated cardiomyopathy".) Mutations in SCN5A have also been identified in several other cardiac disorders, including the long QT syndrome, the Brugada syndrome, familial atrioventricular conduction block, and familial sinus node dysfunction. (See "Brugada syndrome: Epidemiology and pathogenesis" and "Congenital long QT syndrome: Pathophysiology and genetics" and "Etiology of atrioventricular block" and "Sinus node dysfunction: Epidemiology, etiology, and natural history".) Birth weight A possible relationship between birth weight and the development of AF was evaluated in a prospective study of nearly 28,000 women over the age of 45 years, who were free of AF at baseline [96]. The age-adjusted HRs (with <2.5 kg [5.5 pounds] being the referent group) for incident AF increased significantly (1, 1.3, 1.28, 1.7, and 1.71) from the lowest to the highest birth weight category (<2.5 [5.5], 2.5 [5.5] to 3.2 [7.1], 3.2 [7.1] to 3.9 [8.6], 3.9 [8.6] to 4.5, and >4.5 [9.9] kg [pounds]), during a median follow-up of 14.5 years. Inflammation and infection Inflammatory processes may play a role in the genesis of AF. Measurement of serum C-reactive protein (CRP), an acute phase reactant, has been used to assess the relationship between AF and inflammation. Observational studies have reported elevated serum levels of CRP in patient populations with any of the following characteristics: later (after known high CRP) development of AF [97], history of atrial arrhythmias [98], failed cardioversion [99], recurrence of AF after cardioversion [100], and development of AF after cardiac surgery. (See "Atrial fibrillation and flutter after cardiac surgery".) However, inflammation is more likely a marker for other conditions associated with AF, as opposed to being a direct cause or a perpetuating agent. The strongest evidence against a direct causal role for inflammation, as detected by an elevation in CRP, comes from a Mendelian randomization study that evaluated nearly 47,000 individuals in two cohorts from Copenhagen, Demark [101]. (See "Mendelian randomization".) The following observations were made: After multifactorial adjustment, a CRP level in the upper versus lower quintile was associated with a significantly increased risk of the development of AF (hazard ratio 1.77, 95% CI 1.22-2.55). Genotype combinations of four CRP polymorphisms were significantly associated with up to a 63 percent increase in plasma CRP levels, but not with an increased risk of the development of AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 12/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Thus, inflammation, as determined by CRP, is not likely to be causative of AF. In addition to inflammation as detected by serum CRP, new onset AF and other acute cardiac events have been associated with pneumococcal pneumonia [102]. (See "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Cardiac events and other noninfectious complications'.) The risk of AF increases after infection with the influenza virus [103]. Pericardial (epicardial) fat Pericardial fat, also referred to as epicardial fat, is the fat depot within the pericardial sac, which is in between the visceral and parietal pericardium. It has inflammatory properties: both obesity and inflammation are risk factors for AF [104,105]. In a study of 126 patients with AF and 76 controls, those with AF had a significantly higher pericardial fat volume (102 versus 76 ml) [104]. This was true for patients with either paroxysmal or persistent AF, and was independent of other traditional predictors of AF, including left atrial enlargement. Autonomic dysfunction The autonomic nervous system may be involved in the initiation and maintenance of AF. It may be particularly important in patients with paroxysmal AF, as both heightened vagal and sympathetic tone can promote AF. Vagal tone is predominant in normal hearts, which may explain why vagally-mediated AF is often seen in athletic young men without apparent heart disease who have slow heart rates during rest or sleep; such patients may also have an electrocardiogram (ECG) pattern of typical atrial flutter alternating with AF [106,107]. In comparison, AF induced by increased sympathetic tone may be observed in patients with underlying heart disease or during exercise or other activity [107]. (See "Paroxysmal atrial fibrillation", section on 'Pathogenesis'.) Findings on the electrocardiogram Abnormal QT or P-wave duration are associated with an increased risk of AF: Corrected QT interval Individuals with either congenital long QT syndrome or short QT syndrome have an increased risk of AF [108,109]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Short QT syndrome".) The issue of whether there is an association between the corrected QT interval (QTc) and the risk of AF in the general population was addressed in a study of 281,277 individuals without baseline AF in the greater Copenhagen region who were followed for a median st period of 5.7 years after a first ECG [110]. Individuals with a QTc <372 ms (1 percentile) or th 419 ms (60 percentile) had an increased risk (adjusted hazard ratios [HRs] 1.45 up to 1.44, respectively) compared with the reference group (411 to 419 ms). The risk increased in a dose-dependent manner above 419 ms and was strongest among individuals with lone AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 13/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate P-wave duration The relationship between P-wave duration and the risk of AF was evaluated in a study of nearly 285,933 individuals, of whom 9550 developed AF during a median follow-up period of 6.7 years [111]. Compared with the reference group (100 to 105 milliseconds [ms]), individuals with very short ( 89 ms; HR 1.6), intermediate (112 to 119 ms; HR 1.22), long (120 to 129; HR 1.5), and very long P wave duration ( 130 ms; HR 2.06) had an increased risk. Premature atrial complex PAC is important as a trigger of PAF (see 'Pathogenesis' above). The issue of whether they are predictor of incident AF was evaluated in a study of 1260 adults without prevalent AF who underwent 24-hour ambulatory ECG (Holter) monitoring at baseline [112]. During a median follow-up of 13.0 years, 27 percent developed incident AF. After adjusting for other known predictors of AF, PAC count (by quartile) was significantly associated with incident AF; the adjusted HRs comparing quartile 2, 3, and 4 with quartile 1 were 2.17, 2.79, and 4.92, respectively. Other supraventricular tachyarrhythmias Spontaneous transition between typical atrial flutter and AF has been observed, although little is known about the mechanism of this conversion [113,114]. In addition, AF is, in some patients, associated with paroxysmal supraventricular tachycardia (PSVT) [115-117]. The most common causes of PSVT are atrioventricular nodal re-entrant tachycardia and atrioventricular reentrant tachycardia, which occurs in patients with the Wolff-Parkinson-White syndrome or concealed accessory pathways. (See "Atrioventricular nodal reentrant tachycardia" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) The association between AF and PSVT was illustrated in a report that evaluated 169 patients who presented with PSVT and were followed by clinic visits and transtelephonic ECG monitoring during symptomatic episodes [115]. Nineteen percent had an episode of AF during a mean follow-up of 31 months. Neither the mechanism nor the rate of the PSVT was associated with the time to occurrence of AF. Enhanced vagal tone, as determined by baroreflex sensitivity, or an increase in dispersion of right atrial refractory periods may contribute to the development of AF associated with PSVT [118]. Alternatively, an atrial premature beat can cause stable PSVT to degenerate into AF. Among patients with Wolff-Parkinson-White syndrome, the mechanism of AF may be retrograde conduction via the accessory pathway of a premature beat, stimulating the atrial myocardium during its vulnerable period [119]. Ablation of the accessory pathway reduces the incidence of subsequent AF [119,120]. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 14/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Low serum magnesium In an observational study of over 3500 participants in the
highest birth weight category (<2.5 [5.5], 2.5 [5.5] to 3.2 [7.1], 3.2 [7.1] to 3.9 [8.6], 3.9 [8.6] to 4.5, and >4.5 [9.9] kg [pounds]), during a median follow-up of 14.5 years. Inflammation and infection Inflammatory processes may play a role in the genesis of AF. Measurement of serum C-reactive protein (CRP), an acute phase reactant, has been used to assess the relationship between AF and inflammation. Observational studies have reported elevated serum levels of CRP in patient populations with any of the following characteristics: later (after known high CRP) development of AF [97], history of atrial arrhythmias [98], failed cardioversion [99], recurrence of AF after cardioversion [100], and development of AF after cardiac surgery. (See "Atrial fibrillation and flutter after cardiac surgery".) However, inflammation is more likely a marker for other conditions associated with AF, as opposed to being a direct cause or a perpetuating agent. The strongest evidence against a direct causal role for inflammation, as detected by an elevation in CRP, comes from a Mendelian randomization study that evaluated nearly 47,000 individuals in two cohorts from Copenhagen, Demark [101]. (See "Mendelian randomization".) The following observations were made: After multifactorial adjustment, a CRP level in the upper versus lower quintile was associated with a significantly increased risk of the development of AF (hazard ratio 1.77, 95% CI 1.22-2.55). Genotype combinations of four CRP polymorphisms were significantly associated with up to a 63 percent increase in plasma CRP levels, but not with an increased risk of the development of AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 12/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Thus, inflammation, as determined by CRP, is not likely to be causative of AF. In addition to inflammation as detected by serum CRP, new onset AF and other acute cardiac events have been associated with pneumococcal pneumonia [102]. (See "Pneumococcal pneumonia in patients requiring hospitalization", section on 'Cardiac events and other noninfectious complications'.) The risk of AF increases after infection with the influenza virus [103]. Pericardial (epicardial) fat Pericardial fat, also referred to as epicardial fat, is the fat depot within the pericardial sac, which is in between the visceral and parietal pericardium. It has inflammatory properties: both obesity and inflammation are risk factors for AF [104,105]. In a study of 126 patients with AF and 76 controls, those with AF had a significantly higher pericardial fat volume (102 versus 76 ml) [104]. This was true for patients with either paroxysmal or persistent AF, and was independent of other traditional predictors of AF, including left atrial enlargement. Autonomic dysfunction The autonomic nervous system may be involved in the initiation and maintenance of AF. It may be particularly important in patients with paroxysmal AF, as both heightened vagal and sympathetic tone can promote AF. Vagal tone is predominant in normal hearts, which may explain why vagally-mediated AF is often seen in athletic young men without apparent heart disease who have slow heart rates during rest or sleep; such patients may also have an electrocardiogram (ECG) pattern of typical atrial flutter alternating with AF [106,107]. In comparison, AF induced by increased sympathetic tone may be observed in patients with underlying heart disease or during exercise or other activity [107]. (See "Paroxysmal atrial fibrillation", section on 'Pathogenesis'.) Findings on the electrocardiogram Abnormal QT or P-wave duration are associated with an increased risk of AF: Corrected QT interval Individuals with either congenital long QT syndrome or short QT syndrome have an increased risk of AF [108,109]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Short QT syndrome".) The issue of whether there is an association between the corrected QT interval (QTc) and the risk of AF in the general population was addressed in a study of 281,277 individuals without baseline AF in the greater Copenhagen region who were followed for a median st period of 5.7 years after a first ECG [110]. Individuals with a QTc <372 ms (1 percentile) or th 419 ms (60 percentile) had an increased risk (adjusted hazard ratios [HRs] 1.45 up to 1.44, respectively) compared with the reference group (411 to 419 ms). The risk increased in a dose-dependent manner above 419 ms and was strongest among individuals with lone AF. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 13/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate P-wave duration The relationship between P-wave duration and the risk of AF was evaluated in a study of nearly 285,933 individuals, of whom 9550 developed AF during a median follow-up period of 6.7 years [111]. Compared with the reference group (100 to 105 milliseconds [ms]), individuals with very short ( 89 ms; HR 1.6), intermediate (112 to 119 ms; HR 1.22), long (120 to 129; HR 1.5), and very long P wave duration ( 130 ms; HR 2.06) had an increased risk. Premature atrial complex PAC is important as a trigger of PAF (see 'Pathogenesis' above). The issue of whether they are predictor of incident AF was evaluated in a study of 1260 adults without prevalent AF who underwent 24-hour ambulatory ECG (Holter) monitoring at baseline [112]. During a median follow-up of 13.0 years, 27 percent developed incident AF. After adjusting for other known predictors of AF, PAC count (by quartile) was significantly associated with incident AF; the adjusted HRs comparing quartile 2, 3, and 4 with quartile 1 were 2.17, 2.79, and 4.92, respectively. Other supraventricular tachyarrhythmias Spontaneous transition between typical atrial flutter and AF has been observed, although little is known about the mechanism of this conversion [113,114]. In addition, AF is, in some patients, associated with paroxysmal supraventricular tachycardia (PSVT) [115-117]. The most common causes of PSVT are atrioventricular nodal re-entrant tachycardia and atrioventricular reentrant tachycardia, which occurs in patients with the Wolff-Parkinson-White syndrome or concealed accessory pathways. (See "Atrioventricular nodal reentrant tachycardia" and "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".) The association between AF and PSVT was illustrated in a report that evaluated 169 patients who presented with PSVT and were followed by clinic visits and transtelephonic ECG monitoring during symptomatic episodes [115]. Nineteen percent had an episode of AF during a mean follow-up of 31 months. Neither the mechanism nor the rate of the PSVT was associated with the time to occurrence of AF. Enhanced vagal tone, as determined by baroreflex sensitivity, or an increase in dispersion of right atrial refractory periods may contribute to the development of AF associated with PSVT [118]. Alternatively, an atrial premature beat can cause stable PSVT to degenerate into AF. Among patients with Wolff-Parkinson-White syndrome, the mechanism of AF may be retrograde conduction via the accessory pathway of a premature beat, stimulating the atrial myocardium during its vulnerable period [119]. Ablation of the accessory pathway reduces the incidence of subsequent AF [119,120]. https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 14/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Low serum magnesium In an observational study of over 3500 participants in the Framingham Offspring Study, individuals in the lower quartile of serum magnesium were approximately 50 percent more likely to develop AF compared with those in the upper quartiles after multivariable adjustment [121]. Alcohol Alcohol is both a chronic risk factor for the development of new AF and also an acute trigger for AF episodes. AF occurs in up to 60 percent of binge drinkers with or without an underlying alcoholic cardiomyopathy [122]. Most cases occur during and following weekends or holidays when alcohol intake is increased, a phenomenon that has been termed "the holiday heart syndrome." However, even modest amounts of alcohol (one to two drinks) can trigger AF in some patients [123]. In a case-crossover study, 100 individuals free of alcohol dependence and with AF wore transdermal ethanol sensors and continuous ECG monitors for four weeks. Among the 56 persons who had an AF episode during this time period, having had one alcoholic drink doubled the odds of having AF (odds ratio [OR] 2.02 [95% CI 1.38-3.17]) and having two or more alcohol drinks tripled the odds of having an AF episode (OR 3.58 [CI 1.63-7.89]) in the next four hours. This study demonstrated a probable dose-response relationship between the amount of alcohol consumed and the likelihood of triggering an AF episode. The evidence is mixed for long-term alcohol consumption being a risk factor for developing new AF. Moderate, long-term alcohol consumption was not shown to be a risk factor for AF in relatively small studies [56,124,125]. However, a positive association was found in a 2014 study of 79,019 men and women free from AF at baseline [126]. Compared with current drinkers of <1 drink per week, the multivariable risk ratios of AF were 1.01 (95% CI 0.94-1.09) for one to six drinks per week, 1.07 (95% CI 0.98-1.17) for 7 to 14 drinks per week, 1.14 (95% CI 1.01-1.28) for 15 to 21 drinks per week, and 1.39 (95% CI 1.22-1.58) for >21 drinks per week. Heavy alcohol consumption is associated with a greater increase in incidence of AF. Two large cohort studies found an increased incidence among men with heavy alcohol consumption (HR 1.45 in both) [127,128]. Neither study found a correlation between heavy alcohol use and AF in women, but the ability to detect such a correlation was limited by the small numbers of women with alcohol consumption in this range. Another study of 1055 cases of AF occurring during long-term follow-up found an increased risk (relative risk 1.34, 95% CI 1.01-1.78) with consumption of more than 36 grams per day (approximately >3 drinks/day) [125]. Caffeine There is a widespread belief that caffeine, particularly at high doses, is associated with palpitations and a number of arrhythmias, including AF and supraventricular and ventricular ectopy. However, despite the theoretical relationship between caffeine and arrhythmogenesis, there is no evidence in humans that ingestion of caffeine in doses typically https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 15/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate consumed can provoke AF or any other spontaneous arrhythmia [129]. (See "Cardiovascular effects of caffeine and caffeinated beverages", section on 'Arrhythmias'.) Fish and fish oil supplements Observational data has suggested that dietary fish intake or fish oil supplements, particularly those rich in long-chain n-3 fatty acids, may reduce the incidence of arrhythmias, although evidence is mixed with regard to both atrial and ventricular arrhythmias. (See "Overview of sudden cardiac arrest and sudden cardiac death", section on 'Fish intake and fish oil'.) With regard to dietary fish intake and incident AF, three cohort studies (approximately 45,000, 48,000, and 5000 individuals) found no relationship [130-132], while one (approximately 5000 individuals) suggested a reduction in AF burden [133]. Medications Certain medications can cause or contribute to the development of AF [134]. These include theophylline [135], adenosine [136], and, since increased vagal tone can induce AF [107], drugs that enhance vagal tone, such as digitalis. (See 'Autonomic dysfunction' above.) Bisphosphonates (eg, alendronate, risedronate, etidronate) are widely used in the treatment of osteoporosis, and concern has been raised that these drugs can cause AF. The weight of evidence suggests that the risk of AF from oral bisphosphonates is small, if it exists at all. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atrial fibrillation'.) Case-control studies have suggested a modest increased risk for the development of AF in patients taking nonsteroidal anti-inflammatory drugs [137-140]. However, the absence of an accepted biologic mechanism and the susceptibility of case-control studies to unmeasured confounders makes us cautious about the strength of this association [141]. Certain antiarrhythmic drugs may increase the risk of AF. A 2020 scientific statement from the American Heart Association details drugs associated with AF [142]. While exhaustive, this statement includes many medications for which the association with AF is likely relatively weak. Ivabradine, a selective blocker of the I channel that slows the sinus rate, has been associated f with a higher incidence of AF [143]. A meta-analysis of 11 studies suggests a 15 percent excess of AF in patients treated with ivabradine [144]. Regular physical activity The relationship between physical activity and the development of AF is uncertain. Some [145-147], but not all [148-150], studies have suggested that regular physical activity is associated with a risk of AF in the general population. In a 2013 meta-analysis of four prospective cohorts (n = 43,672), and after dividing subjects into four or five groups on the basis of cumulative physical activity per week, there was no difference in the risk of AF https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 16/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate comparing patients in the maximum and minimal groups (odds ratio 1.08, 95% CI 0.97-1.21) [151]. Air pollution Air pollution, and specifically fine particulate matter, is associated with increased cardiovascular disease mortality. (See "Overview of possible risk factors for cardiovascular disease", section on 'Air pollution'.) Whether air pollution is associated with episodes of AF was evaluated in a study of 176 patients with dual chamber implantable cardioverter-defibrillators that were capable of detecting episodes of AF. After follow-up of nearly two years, there were 328 episodes of AF lasting 30 seconds or more found in 49 patients [152]. The potential impact of multiple parameters of air pollution, (measured hourly) on the development of AF was examined. The odds of AF increased significantly as the concentration of particulate matter increased in the two hours prior to the event. Night shift work Data from The United Kingdom Biobank study showed that both current and lifetime night shift exposures were associated with increased AF risk, regardless of genetic AF risk [153]. This cohort had 283,657 participants with 5777 incident AF events over an approximately 10-year follow-up. Usual or permanent night shift workers (4 percent), compared with day workers (83 percent), had higher risks of AF (HR 1.16, 95% CI 1.02-1.32). Workers with a >10-year duration of night shifts (2.4 percent) had a higher AF risk compared with day workers (HR 1.18, 95% CI 0.99-1.40). Workers with three to eight night shifts per month but not <3 per month or >8 per month had an increased risk of developing AF (HR 1.22, 95% CI 1.02-1.45; HR 0.88, 95% CI 0.64 1.21; HR 1.05, 95% CI 0.86-12.8, respectively). A potential limitation of this study is the inability to fully account for underlying socioeconomic factors. A limitation of this sub-analysis was relatively low AF event rates in the group with <3 and >8 shifts per month. Whether decreasing or stopping shift work protects against later AF is uncertain. RISK PREDICTION MODELS Models that attempt to predict the risk of development of atrial fibrillation (AF) have been developed but are not widely employed. Using the Framingham Heart Study population, age, sex, systolic blood pressure, treatment for hypertension, PR interval, clinically significant cardiac murmur, body mass index, and heart failure were incorporated into a risk prediction model that predicts an individual's absolute risk over 10 years [154]. This model has been validated in two geographically and racially diverse cohorts in the age range of 45 to 95 years and predicted the five-year incidence of AF with https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 17/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate moderate accuracy (C statistic 0.66 to 0.68) [155]. Other models have been studied, including one in a racially diverse population [156]. However, the benefit of using risk prediction models in this setting has not been established. There are no studies linking this with improved outcomes. PREVENTION For many risk factors of AF, preventive strategies that significantly reduce risk of incident AF have not been identified. The following are possible preventive strategies: Healthy fats There is weak evidence that dietary modifications such as extra virgin olive oil or n-3 polyunsaturated fatty acids in fish oil lower the risk of the development of AF [157,158]. Mediterranean diet The PREDIMED primary prevention trial found that a Mediterranean diet enriched with either extra virgin olive oil or mixed nuts reduces the incidence of stroke, MI, and cardiovascular mortality [159] (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.) In a post-hoc analysis of PREDIMED, the group that received the Mediterranean diet supplemented with extra virgin olive oil had a lower risk of development of AF compared with the control group (hazard ratio [HR] 0.62; 95% CI 0.45-0.85) [160]. Blood pressure lowering Among patients with hypertension, a study suggests that lowering blood pressure reduced the risk of the development of AF. In the SPRINT trial, intensive compared with standard blood pressure lowering was associated with a lower risk of developing new AF (HR 0.74, 95% CI 0.56-0.98) [161]. (See "Goal blood pressure in adults with hypertension".) Cardiac pacing The role of pacing for the prevention of AF is discussed separately. (See "The role of pacemakers in the prevention of atrial fibrillation".) Although cardiac resynchronization therapy (CRT) improves some potential risk factors for AF. such as atrial size and left ventricular systolic function, CRT has not been shown to decrease the incidence of new or recurrent AF. This is discussed in detail separately. (See "Cardiac resynchronization therapy in atrial fibrillation".) https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 18/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate SUMMARY Epidemiology The incidence and prevalence of atrial fibrillation (AF) depends upon the population studied and the intensity of monitoring. Both increase significantly with increasing age. (See 'Epidemiology' above.) Chronic disease associations Hypertensive heart disease and coronary heart disease are the most common chronic disease associations in patients with AF in developed countries. Other frequent causes include alcohol excess, heart failure, valvular heart disease including both regurgitant and stenotic lesions, and hyperthyroidism. (See 'Chronic disease associations' above.) AF occurs in relation to a variety of different types of surgery; the incidence is greatest in patients undergoing coronary artery bypass graft or cardiac valve surgery. (See 'Chronic disease associations' above.) Chronic, heavy alcohol use does increase the risk of AF in men, while the impact of heavy alcohol use in women is less clear. Chronic moderate alcohol use does not appear to increase the incidence of AF in men or women. (See 'Chronic disease associations' above.) Genetic factors The heritability of AF is complex. For the majority of patients, genetic susceptibility, if present, is probably a polygenic phenomenon, meaning that it is due to the combined effects of a number of genes. (See 'Genetic factors' above.) Risk Prediction Models to predict the risk of subsequent AF have been developed. However, a benefit from using such models has not been established. (See 'Risk prediction models' above.) 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Effect of Intensive Blood Pressure Lowering on the Risk of Atrial Fibrillation. Hypertension 2020; 75:1491. Topic 1004 Version 58.0 https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 30/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate GRAPHICS Prevalence of atrial fibrillation by sex and age Lifetime risk for developing atrial fibrillation (AF) from the Framingham Heart Study. Men and women without AF at 40 years of age were determined to have a 26 and 23 percent likelihood of developing incident AF by 80 years of age. Reproduced with permission from: Magnani JW, Rienstra M, Lin H, et al. Atrial brillation: Current knowledge and future directions in epidemiology and genomics. Circulation 2011; 124:1982. Copyright Lippincott Williams & Wilkins. Graphic 82929 Version 4.0 https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 31/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Prevalence of atrial fibrillation with age In a cross-sectional study of almost 1.9 million men and women, the prevalence of atrial fibrillation increases with age, ranging from 0.1 for those <55 years of age to over 9 percent in those 85 years of age. At all ages, the prevalence is higher in men than women. Data from Go AS, Hylek EM, Phillips K, et al. Prevalence of diagnosed atrial brillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. Graphic 77268 Version 5.0 https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 32/33 7/5/23, 9:30 AM Epidemiology, risk factors, and prevention of atrial fibrillation - UpToDate Contributor Disclosures David Spragg, MD, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/epidemiology-risk-factors-and-prevention-of-atrial-fibrillation/print 33/33
7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm : Gregory YH Lip, MD, FRCPE, FESC, FACC, Jordan M Prutkin, MD, MHS, FHRS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 23, 2023. INTRODUCTION Atrial fibrillation (AF) can lead to a fall in cardiac output that is often clinically significant. Potential consequences include a fall in blood pressure, decreased exercise capacity, and pulmonary congestion, all of which are manifestations of heart failure (HF). In addition, AF and HF often occur together, and each may predispose to the other [1]. The hemodynamic effects of AF and of cardioversion will be reviewed here. The clinical aspects and treatment of AF in patients with HF and cardiomyopathy are discussed separately. (See "The management of atrial fibrillation in patients with heart failure".) ADVERSE HEMODYNAMICS IN AF Many patients with atrial fibrillation (AF) develop a modest decline in left ventricular performance that typically returns to the previous baseline following reversion to sinus rhythm [2-5]. The magnitude of this effect and its reversibility were illustrated in a report of 15 patients with AF who were successfully cardioverted and maintained sinus rhythm for one month; 11 of these patients maintained sinus rhythm for three months [4]. The mean duration of AF was three months (range 5 to 254 days). The following findings were noted after cardioversion: The mean left ventricular ejection fraction (LVEF) increased from 47 percent at baseline to 55 percent immediately after cardioversion to 61 percent at one month; there was no https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 1/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate further increase at three months. The improvement in LVEF occurred in all but one patient. The maximum improvement in LVEF by one month coincides with the time to full recovery of left atrial contractile function [6]. (See 'Atrial stunning' below.) The increase in LVEF was primarily due to enhanced diastolic filling resulting from two factors: (1) an increase in cycle length, which may involve both regularization of the heart rate and avoidance of short cycle lengths that impair ventricular contractility; and (2) the return of left atrial contractile function, as determined by peak A wave velocity, which increases the atrial contribution to ventricular filling [3,4]. The improvement in LVEF following reversion to sinus rhythm is associated with an increase in exercise capacity. (See 'Improved exercise capacity' below.) The deleterious hemodynamic effects of chronic uncontrolled AF are more pronounced in some patients who develop a reversible tachycardia-mediated cardiomyopathy. (See 'Tachycardia- mediated cardiomyopathy' below.) Hemodynamic deterioration also occurs in patients with underlying heart failure (HF). This issue was examined in a prospective observational study of 344 patients with HF who were initially in sinus rhythm; 28 developed AF over 19 months, 18 of whom developed chronic AF [7]. Chronic AF was associated with significant worsening of New York Heart Associated functional class (mean 2.4 to 2.9) ( table 1) and a significant reduction in cardiac index (mean 2.2 to 1.8). The relatively modest changes may have reflected excellent control of the ventricular rate (78 beats/min) at the time the measurements were made. Consistent with this hypothesis is the observation that the onset of AF in 8 of the 18 patients with chronic AF was associated with overt cardiac decompensation, which presumably led to therapy to control the ventricular rate. (See "The management of atrial fibrillation in patients with heart failure".) Contributing factors The following factors may contribute to the adverse hemodynamic changes in AF: A rapid or slow heart rate; if maintained, a chronic tachycardia can lead to a rate-related cardiomyopathy (atrial or ventricular). The irregular rhythm. Loss of atrial systole (also called the atrial "kick") required for optimal ventricular filling. Activation of neurohumoral vasoconstrictors such as angiotensin II and norepinephrine. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 2/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate Another problem demonstrated in animal models is that AF may beget AF by causing electrical remodeling of the atria, which promotes perpetuation of the arrhythmia [8,9]. This proarrhythmic process is reversible with the maintenance of sinus rhythm. The clinical relevance of this observation remains uncertain. (See "Mechanisms of atrial fibrillation", section on 'Maintenance of atrial fibrillation'.) Rapid ventricular response The dependence of cardiac output on heart rate is greatest in patients with left ventricular dysfunction, which is often associated with a relatively fixed stroke volume. As an example, the cardiac output is optimal over a narrow range of heart rates in patients with a myocardial infarction, falling significantly with slower or faster heart rates [10]. A rapid ventricular response is also particularly deleterious in patients with mitral stenosis in whom the reduction in the duration of diastole diminishes the time available for filling of the left ventricle across the stenotic valve [11]. The optimal heart rate for patients in permanent AF is discussed separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) Tachycardia-mediated cardiomyopathy Persistent, uncontrolled tachycardia can have a cardiomyopathic effect that impairs left ventricular function. This phenomenon is called a tachycardia-mediated cardiomyopathy and is reversible when the tachycardia is controlled. (See "Arrhythmia-induced cardiomyopathy".) AF occurs in 10 to 30 percent of patients with HF but can be even higher as heart failure worsens. In most of these patients, the underlying heart disease is thought to predispose to AF. (See "The management of atrial fibrillation in patients with heart failure".) However, in some patients, restoration of sinus rhythm or control of the rapid ventricular response markedly improves or even normalizes the LVEF, indicating that the left ventricular dysfunction was primarily due to the rapid AF rather than an underlying dilated cardiomyopathy [12-14]. The benefit may be more predictable with reversion to sinus rhythm [13,15]. The following observations illustrate the potential magnitude of this effect: In one report, the LVEF was measured before and at a mean of 4.7 months after cardioversion in 12 patients with chronic AF and presumed idiopathic dilated cardiomyopathy [13]. There was an improvement in mean LVEF from 32 percent at baseline to 53 percent at follow-up; the LVEF returned to normal in six of the patients. This improvement persisted at one year in the 10 patients who remained in sinus rhythm, while there was a marked deterioration in left ventricular function in the two patients with recurrent AF. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 3/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate Among patients treated with rate control, the largest reported experience comes from the multicenter Ablate and Pace Trial (APT), a prospective registry of patients undergoing atrioventricular (AV) nodal ablation and pacemaker implantation for refractory AF [14]. The registry included 63 patients with left ventricular dysfunction (LVEF 45 percent); after atrioventricular (AV) nodal ablation, 16 (25 percent) displayed a marked improvement in LVEF to over 45 percent. The mean increase in LVEF in these patients was 27 percentage points. Irregular heart rate The hypothesis that an irregular rhythm itself, independent of the ventricular rate and the restoration of atrial systole, can impair hemodynamics is based in part upon short-term observations that irregular ventricular pacing or induced AF results in a decrease in cardiac output, an elevation in central venous pressure, and an increase in sympathetic nerve activity compared to regular ventricular or atrial pacing at the same mean heart rate [16,17]. Further support for the adverse effect of an irregular heart rate comes from a study of 14 patients with chronic AF and a normal ventricular response in the absence of drugs that block AV nodal conduction [18]. AV nodal ablation and insertion of a ventricular pacemaker resulted in a regular rhythm, improvements in left ventricular function, functional capacity, and the sense of well-being [18]. The adverse hemodynamic effect of an irregular rhythm may be mediated by several factors: Beat-to-beat variations in atrial pressure (preload). The influence of preload on left ventricular ejection (Frank-Starling mechanism) is important in AF only when afterload is relatively low [19]. Beat-to-beat variations in myocardial contractility [20-22]. Among patients with AF, the preceding RR interval has a significant positive correlation with left ventricular ejection, as a shorter RR interval (more rapid ventricular response) reduces the LVEF [20]. This effect is independent of end-diastolic volume, indicating that it cannot be explained by the Frank- Starling mechanism. In addition, the "pre-preceding" RR interval has a negative correlation with left ventricular ejection, which has been ascribed to postextrasystolic potentiation [20,23]. Inefficient ventricular mechanics due to abrupt changes in cycle length [16]. Atrial systole Contraction of the left atrium injects a volume of blood under pressure into the left ventricle, leading to increments in ventricular diastolic volume, end-diastolic pressure, https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 4/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate and stroke volume [24,25]. Loss of atrial systole can therefore diminish the stroke volume. This may be particularly important when left ventricular compliance is reduced and in mitral stenosis. Left ventricular compliance is reduced in patients with diastolic dysfunction. In such patients, there is a relative shift of left ventricular filling to the later part of diastole with a greater dependence upon atrial contraction. Clinical examples in which AF can lead to hemodynamic deterioration in patients with diastolic dysfunction include advanced aortic stenosis, which often produces a hypertrophied, poorly compliant left ventricle, and hypertrophic cardiomyopathy. The importance of atrial systole has been demonstrated in patients with hypertrophic cardiomyopathy, which is typically associated with an increased atrial contribution to ventricular filling (31 versus 16 percent in controls in one report) [26]. In addition, loss of the atrial contraction-induced increase in left ventricular end-diastolic volume can increase the degree of outflow tract obstruction. The net effect is that the acute onset of AF leads to worsening symptoms in the great majority of patients with hypertrophic cardiomyopathy (41 of 46 in one study) [27]. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Pathophysiology of heart failure with preserved ejection fraction".) Among patients with mitral stenosis, the onset of AF can lead to hemodynamic deterioration. Two factors contribute to this adverse effect: the loss in atrial systole, which plays an important role in the generation of adequate left atrial pressure to maintain blood flow across the stenotic valve and may also reduce effective mitral valve area; and the rapid ventricular response which, due to the reduction in the duration of diastole, diminishes the time available for filling of the left ventricle [11]. The relevance of atrial systole, irregular rate, and ejection fraction was assessed in patients with systolic HF who underwent AF ablation versus AV node ablation with biventricular pacing [28]. In those who underwent AF ablation, there was a greater improvement in ejection fraction, six- minute walk test, and quality-of-life scores. It is not clear, however, whether it was due to the restoration of sinus rhythm in the AF group or presence of pacing, even though it was biventricular, in the AV node ablation group. Neurohumoral activation The fall in cardiac output in rapid AF may increase afterload by activating neurohumoral vasoconstrictors. In addition, AF may reversibly increase the secretion of atrial natriuretic peptide [29,30] which, via activation of other propeptides and neurohumoral mechanisms, could influence systemic hemodynamics. As an example, one study of 100 patients with and without AF found that patients with AF had higher levels of N-terminal atrial natriuretic peptide (ANP) (2.6 versus 1.7 ng/mL in those without AF); this association was independent of https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 5/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate left atrial volume and LVEF [31]. In patients with HF and AF, the association between AF and ANP interferes with the association between left ventricular dysfunction and ANP. While one study did not find a higher level of plasma B-type natriuretic peptide (BNP) in AF patients compared to those without [31], other studies have [32,33]. (See "Natriuretic peptide measurement in heart failure".) The relationship between baseline BNP and recurrence of AF after successful AF ablation is discussed elsewhere. Mitral regurgitation Preliminary data has suggested that, in a small number of patients, AF can lead to increased mitral annular dilatation and mitral regurgitation (MR). This was shown in a report of 12 patients (out of 18,695 open heart surgeries) who had AF and moderate or greater MR, with normal left ventricular size and function but symptoms of dyspnea [34]. They underwent mitral ring annuloplasty and surgical ablation, with an improvement in symptoms and MR. The presence of AF can create a cycle of worsening AF burden and increasing MR, which can be reversed with a persistent return to normal sinus rhythm [35]. Increased left atrial size in the presence of normal left ventricular function has been associated with increased mitral annular size and more severe MR in some studies [36], but not in all [37,38]. HEMODYNAMICS AFTER CONVERSION OF CHRONIC AF TO SINUS RHYTHM As noted above, the restoration of sinus rhythm produces a rapid increase in left ventricular ejection fraction (LVEF) in most patients with atrial fibrillation (AF) [2-4]. In one report, for example, the LVEF increased from 47 to 55 percent immediately after cardioversion and to 61 percent at one month [4]. The improvement in LVEF was primarily due to enhanced diastolic filling resulting from two factors: an increase in cycle length, which may involve both regularization of the heart rate and avoidance of short cycle lengths that impair ventricular contractility; and the return of left atrial contractile function. There appears to be no change in markers of intrinsic myocardial contractility. A similar improvement in LVEF has been demonstrated in patients treated with radiofrequency catheter ablation to maintain sinus rhythm. The magnitude of this effect was illustrated in a report of 58 patients with heart failure and AF in whom the mean LVEF improved from 35 to 56 percent and the mean New York Heart Association (NYHA) class fell from 2.3 to 1.4 ( table 1) after successful ablation [39]. The greatest improvement was seen within the first three months. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Atrial stunning Cardioversion of AF leads to an increased risk of thromboembolism, particularly if patients are not anticoagulated before, during, and after the procedure. Most https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 6/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate emboli occur within the first week after cardioversion. In addition to dislodgement of pre- existing thrombi, some patients develop de novo thrombi that are thought to be due at least in part to persistent depression of left atrial systolic function, which can last for several weeks after successful cardioversion [6]. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Rationale for anticoagulation'.) The transient atrial contractile dysfunction following cardioversion, also known as atrial "stunning," may result from a tachycardia-induced atrial cardiomyopathy, which is caused in part by impaired cellular handling of calcium [40-42]. An evaluation of stunning in a canine model revealed the following [43]: Stunning occurred with AF duration of only one hour. In this study and in reports of humans with AF and atrial flutter [42,44], the peak left atrial contractile velocities were lower after reversion to sinus rhythm than during the arrhythmia. Stunning was more profound and of longer duration in the left atrial appendage than the left atrium itself. Reduced left atrial appendage function occurs with all forms of reversion to sinus rhythm including spontaneous cardioversion [45], external or internal direct current (DC) (electric) cardioversion [6,44,46-49], and pharmacologic cardioversion [50]. The degree of stunning appears to be greater after electrical compared to spontaneous or pharmacologic cardioversion [45], but is not related to the total amount of energy used if electrical cardioversion is performed [46,47]. Estimates of the frequency of early atrial stunning (immediately to within three days post- cardioversion) range from 20 to 55 percent [44-46]. At one week, the rate is 10 to 25 percent [45,46]. The net effect of stunning is that left atrial contractility is reduced by up to 75 percent [41] and left appendage flow velocity falls after the restoration of sinus rhythm [42,44], which can lead to local stasis, as manifested by the onset of or an increase in spontaneous echo contrast [44,48,49], and the formation of new thrombi [48,51-53]. (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation", section on 'Rationale for anticoagulation'.) The duration of the left atrial dysfunction is related in part to the duration of AF [6,50]. In a review of 60 patients who underwent successful cardioversion, full recovery of atrial mechanical function was attained within 24 hours in patients with AF for 2 weeks, within one week in patients with AF for two to six weeks, and within one month with more prolonged AF [6]. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 7/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate Recovery of atrial function is typically demonstrated by return of peak A wave velocity on Doppler echocardiography [6,50]. The time course of recovery of left atrial function could explain why the great majority of embolic events in patients who remain in sinus rhythm occur within the first 10 days after cardioversion [54,55]. De novo thrombus formation can also result in part from activation of the coagulation system and a hypercoagulable state following cardioversion [56-58]. In one study, for example, an increase in plasma concentrations of the markers of thrombin generation and activity (thrombin- antithrombin complex and fibrinopeptide A) was found soon after pharmacologic cardioversion to sinus rhythm [56]. As with atrial function, hemostatic markers return to normal by two to four weeks after cardioversion [57,58]. Pulmonary edema An uncommon hemodynamic complication of DC cardioversion is pulmonary edema. In a review of the literature, pulmonary edema was reported in approximately 1.2 percent of cases, half of them within three hours but as late as four days after cardioversion [59]. A lower incidence of 0.4 percent was noted in a report of consecutive outpatient cardioversions at a single institution [60]. Pulmonary edema after cardioversion is more common in patients with left ventricular dysfunction or valvular heart disease [59]. Possible mechanisms for the development of pulmonary edema after cardioversion include acute left ventricular contractile dysfunction [61], which may be due in part to transient interruption of myocardial cellular respiration [62], acute left atrial dysfunction [46], and the return of right atrial before left atrial systolic function [63]. Improved exercise capacity As mentioned above, most patients in whom AF is reverted to sinus rhythm have a significant increase in LVEF [2-4]. One beneficial effect of the improvement in hemodynamics is enhanced exercise capacity [64-66]. The magnitude of this effect was illustrated in a study of 63 consecutive patients with chronic AF who were electrically cardioverted in whom peak oxygen consumption (peak VO2) was measured before and one month after cardioversion [65]. At one month, the mean peak VO2 in the 37 patients in sinus rhythm had significantly increased from 21.4 to 23.7 mL/min per kg, while those who had reverted to AF showed no change in oxygen consumption. The patients who remained in sinus rhythm also had a significant reduction in peak heart rate and an improvement in NYHA functional class. The benefits from restoration of sinus rhythm were seen in patients with and without underlying heart disease and showed some further improvement at two-year follow-up. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 8/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate Similar benefits were noted in the radiofrequency ablation study of 58 patients with heart failure (HF) cited above [39]. The mean NYHA class significantly improved from 2.3 to 1.4 after ablation in association with improvements in quality of life, exercise capacity, and exercise time. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rhythm control'.) Mitral regurgitation A study of 53 patients examined the effect of AF ablation in those with at least moderate mitral regurgitation (MR) and ejection fraction 50 percent compared to those with only mild or less MR [35]. At baseline, those with at least moderate MR were more likely to have persistent AF, older age, and larger mitral annular dimension. Of those who had a successful AF ablation with no recurrence during follow-up, 76 percent had a reduction in MR to mild or less, whereas only 18 percent in the group with an AF recurrence had an improvement in MR. In addition, those with an apparently successful ablation were found to have a decrease in left atrial volume, mitral annular dimension, and mitral annular jet area, with no change in ejection fraction or left ventricular end diastolic dimension, though there was a small decrease in left ventricular end systolic dimension. The authors use the term atrial functional mitral regurgitation to describe an enlarged left atrium leading to MR in the absence of pathology of the mitral valve, which can improve by AF ablation that decreases left atrial size. The exact relationship to symptoms or mortality associated with this is unknown at the current time. SUMMARY Many patients with atrial fibrillation (AF) develop a modest decline in left ventricular performance that typically returns to the previous baseline following reversion to sinus rhythm. The following factors may contribute to the adverse hemodynamic changes in AF: A rapid or slow heart rate; if maintained, a chronic tachycardia can lead to a rate-related cardiomyopathy (atrial or ventricular). The irregular rhythm. Loss of atrial systole required for optimal ventricular filling. Activation of neurohumoral vasoconstrictors. Increased mitral regurgitation. The restoration of sinus rhythm produces a rapid increase in left ventricular systolic performance in most patients with AF. This translates into an improvement in exercise https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 9/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate capacity. A transient atrial contractile dysfunction may follow cardioversion; it is also known as atrial "stunning. 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cardiomyopathy: a longitudinal study. J Am Coll Cardiol 1990; 15:1279. 28. Khan MN, Ja s P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359:1778. 29. Roy D, Paillard F, Cassidy D, et al. Atrial natriuretic factor during atrial fibrillation and supraventricular tachycardia. J Am Coll Cardiol 1987; 9:509. 30. Hornestam B, Hall C, Held P, et al. N-terminal proANF in acute atrial fibrillation: a biochemical marker of atrial pressures but not a predictor for conversion to sinus rhythm. Digitalis in Acute Atrial Fibrillation (DAAF) Trial group. Am Heart J 1998; 135:1040. 31. Rossi A, Enriquez-Sarano M, Burnett JC Jr, et al. Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and Doppler-echocardiographic study. J Am Coll Cardiol 2000; 35:1256. 32. Jourdain P, Bellorini M, Funck F, et al. Short-term effects of sinus rhythm restoration in patients with lone atrial fibrillation: a hormonal study. Eur J Heart Fail 2002; 4:263. 33. Silvet H, Young-Xu Y, Walleigh D, Ravid S. Brain natriuretic peptide is elevated in outpatients with atrial fibrillation. Am J Cardiol 2003; 92:1124. 34. Kihara T, Gillinov AM, Takasaki K, et al. Mitral regurgitation associated with mitral annular dilation in patients with lone atrial fibrillation: an echocardiographic study. Echocardiography 2009; 26:885. 35. Gertz ZM, Raina A, Saghy L, et al. Evidence of atrial functional mitral regurgitation due to atrial fibrillation: reversal with arrhythmia control. J Am Coll Cardiol 2011; 58:1474. 36. Tanimoto M, Pai RG. Effect of isolated left atrial enlargement on mitral annular size and valve competence. Am J Cardiol 1996; 77:769. 37. Otsuji Y, Kumanohoso T, Yoshifuku S, et al. Isolated annular dilation does not usually cause important functional mitral regurgitation: comparison between patients with lone atrial fibrillation and those with idiopathic or ischemic cardiomyopathy. J Am Coll Cardiol 2002; 39:1651. 38. Zhou X, Otsuji Y, Yoshifuku S, et al. Impact of atrial fibrillation on tricuspid and mitral annular dilatation and valvular regurgitation. Circ J 2002; 66:913. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 12/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate 39. Hsu LF, Ja s P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004; 351:2373. 40. Sun H, Gaspo R, Leblanc N, Nattel S. Cellular mechanisms of atrial contractile dysfunction caused by sustained atrial tachycardia. Circulation 1998; 98:719. 41. Schotten U, Ausma J, Stellbrink C, et al. Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. Circulation 2001; 103:691. 42. Sanders P, Morton JB, Morgan JG, et al. Reversal of atrial mechanical stunning after cardioversion of atrial arrhythmias: implications for the mechanisms of tachycardia- mediated atrial cardiomyopathy. Circulation 2002; 106:1806. 43. Louie EK, Liu D, Reynertson SI, et al. "Stunning" of the left atrium after spontaneous conversion of atrial fibrillation to sinus rhythm: demonstration by transesophageal Doppler techniques in a canine model. J Am Coll Cardiol 1998; 32:2081. 44. Grimm RA, Stewart WJ, Maloney JD, et al. Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: characterization by simultaneous transesophageal echocardiography. J Am Coll Cardiol 1993; 22:1359. 45. Mattioli AV, Castelli A, Andria A, Mattioli G. Clinical and echocardiographic features influencing recovery of atrial function after cardioversion of atrial fibrillation. Am J Cardiol 1998; 82:1368. 46. Harjai K, Mobarek S, Abi-Samra F, et al. Mechanical dysfunction of the left atrium and the left atrial appendage following cardioversion of atrial fibrillation and its relation to total electrical energy used for cardioversion. Am J Cardiol 1998; 81:1125. 47. Omran H, Jung W, Rabahieh R, et al. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997; 29:131. 48. Fatkin D, Kuchar DL, Thorburn CW, Feneley MP. Transesophageal echocardiography before and during direct current cardioversion of atrial fibrillation: evidence for "atrial stunning" as a mechanism of thromboembolic complications. J Am Coll Cardiol 1994; 23:307. 49. Falcone RA, Morady F, Armstrong WF. Transesophageal echocardiographic evaluation of left atrial appendage function and spontaneous contrast formation after chemical or electrical cardioversion of atrial fibrillation. Am J Cardiol 1996; 78:435. 50. Shapiro EP, Effron MB, Lima S, et al. Transient atrial dysfunction after conversion of chronic atrial fibrillation to sinus rhythm. Am J Cardiol 1988; 62:1202. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 13/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate 51. Stoddard MF, Dawkins PR, Prince CR, Longaker RA. Transesophageal echocardiographic guidance of cardioversion in patients with atrial fibrillation. Am Heart J 1995; 129:1204. 52. Black IW, Fatkin D, Sagar KB, et al. Exclusion of atrial thrombus by transesophageal echocardiography does not preclude embolism after cardioversion of atrial fibrillation. A multicenter study. Circulation 1994; 89:2509. 53. Moreyra E, Finkelhor RS, Cebul RD. Limitations of transesophageal echocardiography in the risk assessment of patients before nonanticoagulated cardioversion from atrial fibrillation and flutter: an analysis of pooled trials. Am Heart J 1995; 129:71. 54. Gentile F, Elhendy A, Khandheria BK, et al. Safety of electrical cardioversion in patients with atrial fibrillation. Mayo Clin Proc 2002; 77:897. 55. Berger M, Schweitzer P. Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 1998; 82:1545. 56. Oltrona L, Broccolino M, Merlini PA, et al. Activation of the hemostatic mechanism after pharmacological cardioversion of acute nonvalvular atrial fibrillation. Circulation 1997; 95:2003. 57. Lip GY, Rumley A, Dunn FG, Lowe GD. Plasma fibrinogen and fibrin D-dimer in patients with atrial fibrillation: effects of cardioversion to sinus rhythm. Int J Cardiol 1995; 51:245. 58. Abe, Y, Kim, et al. Evidence for the intravascular hyperclotting state induced by atrial fibrillation itself (abstract). J Am Coll Cardiol 1996; 27(Suppl A):35A. 59. Upshaw CB Jr. Hemodynamic changes after cardioversion of chronic atrial fibrillation. Arch Intern Med 1997; 157:1070. 60. Botkin SB, Dhanekula LS, Olshansky B. Outpatient cardioversion of atrial arrhythmias: efficacy, safety, and costs. Am Heart J 2003; 145:233. 61. Fung KC, Tan HC, Kritharides L. Acute reductions in ventricular myocardial tissue velocities after direct current cardioversion of atrial fibrillation. J Am Soc Echocardiogr 2003; 16:656. 62. Trouton TG, Allen JD, Young IS, et al. Altered cardiac oxygen extraction, lactate production and coronary blood flow after large dose transthoracic DC countershocks. Pacing Clin Electrophysiol 1993; 16:1304. 63. Mayosi BM, Commerford PJ. Pulmonary edema following electrical cardioversion of atrial fibrillation. Chest 1996; 109:278. 64. Atwood JE, Myers J, Sullivan M, et al. The effect of cardioversion on maximal exercise capacity in patients with chronic atrial fibrillation. Am Heart J 1989; 118:913. 65. Gosselink AT, Crijns HJ, van den Berg MP, et al. Functional capacity before and after cardioversion of atrial fibrillation: a controlled study. Br Heart J 1994; 72:161. https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 14/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate 66. Gosselink AT, Bijlsma EB, Landsman ML, et al. Long-term effect of cardioversion on peak oxygen consumption in chronic atrial fibrillation. A 2-year follow-up. Eur Heart J 1994; 15:1368. Topic 1041 Version 23.0 https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 15/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate GRAPHICS NYHA and other classifications of cardiovascular disability Canadian NYHA functional [1] Cardiovascular Specific activity Class [3] classification Society functional scale [2] classification I Patients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause Ordinary physical activity, such as walking and climbing stairs, does not cause angina. Angina with strenuous or rapid Patients can perform to completion any activity requiring 7 metabolic equivalents (ie, can carry 24 lb up 8 steps; do outdoor work undue fatigue, palpitation, dyspnea, or anginal pain. prolonged exertion at work or recreation. [shovel snow, spade soil]; do recreational activities [skiing, basketball, squash, handball, jog/walk 5 mph]). II Patients with cardiac disease resulting in Slight limitation of ordinary activity. Patients can perform to completion any activity requiring 5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, Walking or climbing stairs rapidly, walking uphill, walking or stair- climbing after meals, in cold, in wind, or when under emotional dyspnea, or anginal pain. stress, or only during the few hours after awakening. Walking more than 2 blocks on the level and climbing more than 1 flight of foxtrot, walk at 4 mph on level ground) but cannot and do not perform to completion activities requiring 7 metabolic equivalents. ordinary stairs at a normal pace and in normal conditions. III Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Marked limitation of ordinary physical activity. Walking 1 to 2 blocks on the level and climbing 1 flight in Patients can perform to completion any activity requiring 2 metabolic equivalents (eg, shower without stopping, strip Less-than-ordinary normal conditions. and make bed, clean https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 16/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate physical activity causes fatigue, palpitation, dyspnea, or anginal pain. windows, walk 2.5 mph, bowl, play golf, dress without stopping) but cannot and do not perform to completion any activities requiring >5 metabolic equivalents. IV Patients with cardiac disease resulting in inability to carry on any physical activity Inability to carry on any physical activity without discomfort. Anginal syndrome may Patients cannot or do not perform to completion activities requiring >2 metabolic without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity be present at rest. equivalents. Cannot carry out activities listed above (specific activity scale III). is undertaken, discomfort is increased. NYHA: New York Heart Association. References: 1. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the th Heart and Great Vessels, 9 ed, Little, Brown & Co, Boston 1994. p.253. 2. Campeau L. Grading of angina pectoris. Circulation 1976 54:522. 3. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: Advantages of a new speci c activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 17/18 7/5/23, 9:14 AM Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm - UpToDate Contributor Disclosures Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Jordan M Prutkin, MD, MHS, FHRS No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hemodynamic-consequences-of-atrial-fibrillation-and-cardioversion-to-sinus-rhythm/print 18/18
7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation : Martin S Maron, MD : Samuel L vy, MD, William J McKenna, MD : Todd F Dardas, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 03, 2023. INTRODUCTION Hypertrophic cardiomyopathy (HCM) is a genetically determined heart muscle disease caused by mutations in one of several sarcomere genes that encode components of the contractile apparatus. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) HCM is characterized by left ventricular hypertrophy (LVH) of various morphologies ( figure 1) and is commonly associated with atrial arrhythmias. The evaluation and management of supraventricular tachycardias, primarily atrial fibrillation (AF), in patients with HCM will be reviewed here. Other aspects of the clinical manifestations, diagnosis, and management of HCM in adults are discussed separately: (See "Hypertrophic cardiomyopathy: Natural history and prognosis".) (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".) (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".) (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction".) (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 1/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".) EPIDEMIOLOGY In patients with HCM, the prevalence of AF appears to be four- to sixfold higher than similarly aged patients in the general population, with an incidence in the range of 2 to 5 percent per year [1-3]. AF is rare in young patients with HCM who are less than 30 years of age. AF is paroxysmal in approximately two-thirds of patients and persistent or permanent in the remaining one-third: In a cohort of 4591 patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) who were followed for a mean of 5.4 years, 20 percent developed AF at some point (no data were presented to determine paroxysmal versus permanent AF or burden of AF) [4]. In a cohort of 1558 consecutive patients with HCM who were followed at a referral center for an average of 4.8 years, AF occurred in 304 patients (20 percent), with 74 percent being paroxysmal AF and 26 percent developing permanent AF [5]. In a case-control study of 104 patients with HCM (52 case patients with HCM and AF at some point during follow-up, 52 controls with HCM and normal sinus rhythm) diagnosed between 1960 and 1985, AF was present in approximately 5 percent of patients at the time of diagnosis of HCM and developed in an additional 10 percent during the five years following diagnosis [1]. In a retrospective study of 75 patients with HCM with a dual-chamber implantable cardioverter-defibrillator (ICD) but no known history of AF, 21 patients (28 percent) developed AF over an average follow-up of five years [3]. Eighteen of the 21 patients developed asymptomatic AF episodes (ie, clinically silent), most of which lasted less than one hour; however, 13 of the 18 patients with clinically silent AF had more than one episode, and 8 of the 18 ultimately developed symptoms attributed to AF. Nonfatal embolic stroke occurred in 1 patient associated with asymptomatic AF and without other risk factors. PATHOPHYSIOLOGY HCM is associated with a thick and noncompliant LV resulting in some degree of diastolic dysfunction in nearly all patients. Thus, patients with HCM are thought to be particularly https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 2/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate dependent on the contribution of atrial systole to provide optimal LV filling and cardiac output. Diastolic dysfunction significantly impacts affected patients tolerance of AF and other atrial tachyarrhythmias. AF, with loss of atrial kick and associated rapid ventricular rates results in reduced diastolic LV filling time and LV filling, which contributes to increased heart failure symptoms. (See "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis" and "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF'.) Thus, diastolic dysfunction has a significant impact on a patient's ability to tolerate AF and other atrial tachyarrhythmias. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) PREDISPOSING FACTORS Several factors appear to be associated with risk for development of AF in patients with HCM, including [2,6,7]: Increased left atrial diameter (eg, left atrial dimension >45 mm) and volume Increasing age Left atrial dysfunction Severe and diffuse hypertrophy LV ejection fraction (LVEF), particularly when LVEF <50 percent (end-stage HCM) In contrast to these risk factors, the presence or severity of an LV outflow tract gradient does not appear to be associated with an increased incidence of AF [8]. There are limited data on atrial pathology in HCM, but some studies have shown extensive atrial fibrosis similar to that seen in patients with long-standing HF [7]. Myocyte disarray, present in the ventricular myocardium, has not been reported in the atria, and the expression of sarcomeric protein mutations in atrial tissue has not been studied. CLINICAL MANIFESTATIONS While AF is often poorly tolerated in HCM and may be associated with significant symptoms and clinical deterioration, its impact of morbidity and mortality can be significantly mitigated with modern AF management [1,2,5,9]. While most patients with HCM who develop AF have prominent symptoms, not all patients are symptomatic. The clinical manifestations of AF in patients with HCM can be divided into acute symptoms and long-term consequences. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 3/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Acute presentation For many patients with HCM, acute symptoms associated with AF are similar to symptoms of AF in patients without HCM such as palpitations, dyspnea, and chest pain. However, some patients with HCM and AF, especially those with LV outflow tract (LVOT) obstruction or severe diastolic dysfunction, develop symptomatic hypotension with lightheadedness, presyncope, or syncope. These symptoms are caused by decreased LV diastolic filling time during the tachycardia, which may also provoke or worsen an LVOT gradient. As an example, in a series of 52 patients with HCM who developed AF, the acute onset of AF was associated with worsening of functional class in 89 percent of patients [1]. With reversion to sinus rhythm or, to a lesser extent, with control of the ventricular rate, nearly all patients returned to their baseline functional class. Long-term sequelae The long-term studies of patients with HCM of both paroxysmal and persistent/permanent AF have been most strongly linked to an increase in limiting symptoms and an increase in risk of thromboembolic stroke, with less evidence linking AF to increasing heart failure-related death [1,2,10,11]. Unlike ventricular arrhythmias, AF and other atrial tachyarrhythmias are generally not associated with an increased risk of sudden cardiac death, though there are case reports in which AF with a rapid ventricular response has degenerated into ventricular tachycardia and ventricular fibrillation [9,12,13]. (See 'Prognosis' below.) Conflicting data on the impact of AF on stroke and functional status in patients with HCM have been reported, which can be largely attributed to the application of contemporary therapies to treat AF, including advancement in catheter ablation techniques as well as surgical intervention with Cox-Maze and increasing recognition for low burden of AF to recommend anticoagulation for stroke prophylaxis: In a cohort of 480 patients, 22 percent of whom had paroxysmal or chronic AF, stroke risk was markedly increased in the patients with AF compared with those in sinus rhythm (21 percent for patients with AF versus 3 percent without AF; ) [2]. Additionally, the development of AF was associated with an increased risk of severe functional limitation (odds ratio 2.8 for developing NYHA class III/IV symptoms). The risk of stroke and deterioration of functional status was highest in patients with LVOT obstruction. In a cohort of 1558 patients, among whom 304 patients (20 percent) developed AF over a mean follow-up of 4.8 years, only 18 patients with AF (6 percent) experienced an embolic event, with only two deaths directly attributable to the embolic event (annual mortality of 0.1 percent due to thromboembolism) and no evidence to support the assertion that AF leads to long-term deterioration in functional status, including risk for progressive heart https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 4/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate failure [5]. The risk of stroke was significantly higher among patients with AF not on long- term antithrombotic therapy (14 versus 2 percent). DIAGNOSIS The diagnosis of AF is usually suspected in a patient with palpitations, dyspnea, or chest pain with an irregularly irregular pulse present on physical examination. However, not all patients with AF are symptomatic, but AF should be suspected in an asymptomatic patient with an irregularly irregular pulse on physical examination. In these situations, an electrocardiogram (ECG) should be promptly performed to verify the diagnosis. Since left atrial (LA) size is a strong independent predictor of future AF, European guidelines recommend that all patients with HCM and LA diameter 45 mm undergo 48-hour ECG monitoring every 6 to 12 months to detect episodes of "silent" AF [14]. This recommendation is based on expert opinion with no published data on the efficacy of screening for AF with ECG monitoring. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Electrocardiogram'.) Patients with intermittent symptoms suggestive of paroxysmal AF may not be in AF at the time of the examination and initial ECG. In such patients, ambulatory monitoring for up to four weeks can aid in making the diagnosis. (See "Atrial fibrillation: Overview and management of new- onset atrial fibrillation", section on 'Additional cardiac testing' and "Ambulatory ECG monitoring".) TREATMENT Atrial fibrillation In general, the therapeutic options for AF in patients with HCM are similar to those for patients without HCM ( algorithm 1), with some caveats [15,16]. Since patients with HCM are frequently less tolerant of AF than patients without HCM, we favor a more aggressive approach to the maintenance of sinus rhythm in patients with HCM than in other settings. In addition, patients with HCM and AF are at an increased risk of thromboembolic events, including stroke, and the threshold to introduce anticoagulation should generally be low [15,16]. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) Initial management The initial management of AF in patients with HCM is similar to that for any patient with AF [16-19]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 5/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate In patients who are asymptomatic or have only mild to moderate symptoms, initial therapy includes slowing the ventricular rate and concurrent initiation of anticoagulation therapy ( algorithm 1). Beta blockers and nondihydropyridine calcium channel blockers (ie, verapamil and diltiazem) are preferred as first-line agents in most patients, and intravenous preparations are preferred to oral preparations when rapid control of rate is necessary. Digoxin should be avoided as a rate control agent in patients with HCM. (See 'Rate control' below.) In patients with severe symptoms or who are hemodynamically unstable related to AF, urgent cardioversion should be performed. The management of new-onset AF is discussed separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) Long-term management Rhythm control In the majority of patients with HCM, AF is not well tolerated, often producing severe, limiting symptoms. A rate control strategy is a reasonable first option for all patients. However, given how symptomatic many patients with HCM are when they develop AF, and the low efficacy in controlling these symptoms with AV nodal blocking agents, greater weight should be given to pursuing an early rhythm control strategy. Notably, in patients with HCM who have asymptomatic paroxysmal or chronic AF, there are no clinical trials addressing the benefits of a rate versus rhythm control strategy. In this clinical scenario, expert opinion has generally supported rate control for AF in patients with HCM who are asymptomatic. (See 'Rate control' below.) Rhythm control in patients with HCM and AF can be accomplished with either chemical or electrical cardioversion to restore sinus rhythm and antiarrhythmic drugs to suppress recurrences of AF, with catheter or surgical ablation in special circumstances ( algorithm 1). The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) AF guidelines and the 2014 European Society of Cardiology (ESC) HCM guidelines, as well as the 2016 ESC AF guidelines and the 2020 AHA/ACC HCM guidelines, concluded that the weight of evidence or opinion was in favor of the usefulness of antiarrhythmic drugs to prevent recurrent AF, although there are no randomized controlled trials evaluating the efficacy of either antiarrhythmic drug therapy or catheter ablation for preventing long-term recurrence of AF in patients with HCM [17,19,20]. There are few data to support the selection of a particular antiarrhythmic agent for maintenance of sinus rhythm in patients with HCM [17,19]. While data are limited, for maintenance of sinus rhythm in most patients with HCM and AF, our experts generally use sotalol as first-line https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 6/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate antiarrhythmic therapy. Sotalol should be started on an inpatient basis, regardless of whether the patient has an ICD or not, monitoring over several doses for clinically significant prolongation of the QT interval or proarrhythmia. As an alternative initial therapeutic option, disopyramide may be used but is considered less effective in suppressing AF than sotalol, and due to the possibility that disopyramide may accelerate atrioventricular (AV) conduction, it must be given in combination with an AV nodal blocking agent, such as a beta blocker or a nondihydropyridine calcium channel blocker [17,21]. In addition, the use of disopyramide should be confined to patients with left ventricular outflow tract obstruction (where it has been demonstrated to be safe), as its use in nonobstructive patients can increase filling pressures and may cause heart failure symptoms. One exception to the use of sotalol (or disopyramide) in suppressing AF would be to consider amiodarone initially in those patients with HCM in whom long-term use of the drug is unlikely based on the patient's advanced age or if a short-term duration of antiarrhythmic therapy is planned. If sotalol is not efficacious or not well tolerated, dofetilide could be considered, but limited data exist on its safety in HCM [22], and therefore in most circumstances its use should be confined to those patients with ICDs. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) In selected cases, for patients with nonobstructive HCM who have recurrent AF resulting in worsening symptoms and functional status, catheter-based radiofrequency ablation may be most appropriate, while isolated maze could be considered as an alternative option. Catheter ablation of AF with a technique of pulmonary vein isolation appears to be safe and effective for patients with HCM, with outcomes that may be similar to patients with other forms of structural heart disease who have AF [23-30]. As examples: Among a single-center cohort of 79 patients with HCM and AF refractory to antiarrhythmic medications who underwent catheter ablation, 71 percent of patients had no documented recurrent AF over an average of 35 months following the ablation [26]. However, in a different cohort of 49 patients who underwent 72 catheter ablation procedures, freedom from AF at one-year post-ablation was only 44 percent, dropping to 32 percent at three- years post-ablation [5]. In a systematic review and meta-analysis that included 531 patients from 15 nonrandomized trials, with significant heterogeneity among the various patient cohorts, freedom from AF following a single procedure (at the latest available follow-up which ranged between 11 and 54 months) averaged 46 percent, which increased to 66 percent following repeat ablation procedures [28]. Similar results were reported in a separate systematic review and meta-analysis that included 139 patients from six studies, in which the freedom from AF was 39 percent after a single procedure [29]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 7/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Catheter ablation of AF is discussed in detail separately. (See "Atrial fibrillation: Catheter ablation".) Similarly, in patients with obstructive HCM who are undergoing surgical myectomy and who have symptomatic AF, an adjunctive surgical Cox-Maze procedure for AF ablation should be considered as a possible therapeutic option that has been shown to be safe and effective only in case reports and small series of patients [5,14,31-33]. Among a single-center cohort of 62 patients who underwent surgical Cox-Maze IV procedure at the time of septal myectomy between 2004 and 2015, freedom from AF at one-, three-, and five-year post-procedure was 85, 69, and 64 percent, respectively [33]. (See "Atrial fibrillation: Surgical ablation".) Rate control Because of the lack of controlled data demonstrating a benefit from maintaining sinus rhythm in patients with HCM and AF, and also because of the potential side effects associated with antiarrhythmic drugs, some patients and clinicians will select a rate control strategy, particularly in asymptomatic or minimally symptomatic patients ( algorithm 1). For patients in whom a rate control strategy is selected, we recommend the use of beta blockers, calcium channel blockers, or the two drugs in combination, rather than digoxin. For the majority of patients with HCM, onset of AF results in an acute development of limiting symptoms (or worsening of existing symptoms), which often substantially impacts the patient's quality of life. For this reason, the goal is often maintenance of sinus rhythm, as restoration of atrial contribution to stroke volume is so important. However, in the minority of patients with HCM and AF who are asymptomatic, a rate control strategy can be considered initially or in those patients who have failed efforts at rhythm control and who are not candidates for an ablation procedure. Ventricular rate control can be achieved with pharmacologic or nonpharmacologic means. Beta blockers, nondihydropyridine calcium channel blockers (ie, verapamil and diltiazem), or the two drugs in combination are usually adequate to control the ventricular rate [14,17,18,20]. Although there are no data on the use and safety of digoxin as a rate control agent in HCM, based on expert opinion and standard practice, digoxin should not be used in patients with AF and HCM, since it can increase inotropy, which could exacerbate heart failure symptoms in the majority of patients with HCM who have preserved systolic function. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) When the ventricular rate cannot be controlled with medications and the patient is not considered a candidate for catheter or surgical ablation of AF, AV nodal ablation with pacemaker implantation will provide definitive control of the ventricular rate [14]. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 8/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Anticoagulation Limited evidence is available to guide anticoagulant therapy in patients with HCM and AF. Patients with HCM and AF are at significant risk of thromboembolism, although risk factors for thromboembolism have not been well defined [2,14,17,20]. Since patients with HCM were not included in most clinical trials of thromboprophylaxis in AF, the CHA DS -VASc score cannot be applied to patients with this condition to determine the risk of 2 2 thromboembolism. For symptomatic AF For patients with HCM and symptomatic AF, we recommend chronic oral anticoagulation ( algorithm 1). This recommendation applies for symptomatic AF, regardless of the duration of episodes of AF. Either a direct oral anticoagulant (DOAC; eg, dabigatran, rivaroxaban, apixaban, edoxaban) or warfarin (with a target international normalized ratio [INR] of 2 to 3) can be chosen as the initial thrombotic regimen in patients with HCM and AF [15,19]. Support for this approach to comes from a study of 304 HCM patients with AF followed for a mean of 4.8 years [5]. Embolic events occurred in only 2 percent of patients taking anticoagulation therapy compared with 14 percent among HCM patients with AF not taking anticoagulation. Only two deaths were directly attributable to an embolic event (annual mortality of 0.1 percent due to thromboembolism). Whether a threshold amount of AF exists to recommend anticoagulation is uncertain, and, since patients with HCM are not included in most clinical trials of thromboprophylaxis in AF, the CHA DS -VASc score cannot be applied to patients with this disease to determine the benefit of 2 2 anticoagulation. Several studies have documented the increased risk of thromboembolic events in patients with HCM and AF [2,17,19,34,35]. In a series of 480 patients with HCM, of whom 22 percent had paroxysmal or chronic AF, stroke risk was markedly increased in the patients with AF compared with those in sinus rhythm (odds ratio 17.7) [2]. The elevated risk of thromboembolic events includes patients treated with rhythm control who appear to be in normal sinus rhythm, given the risk of recurrent AF with minimal or no symptoms. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Specific antithrombotic regimens in patients with HCM have not been studied in randomized trials. Both warfarin therapy (with a target INR of 2 to 3) and the DOACs (eg, dabigatran, rivaroxaban, apixaban, edoxaban) have been shown to be efficacious in other populations without HCM. Data from observational studies suggest that both warfarin and DOACs are safe and effective in reducing thromboembolic risk. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 9/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Among 2397 patients with HCM and AF treated with anticoagulation who were enrolled in a nationwide Korean database between 2013 and 2016 and followed for 1.6 years, rates of embolic ischemic stroke and bleeding complications were significantly lower among patients treated with a DOAC compared with warfarin [36]. Among 2198 patients with HCM and AF treated with anticoagulation who were identified from a United States commercial insurance database between 2010 and 2015, rates of embolic ischemic stroke and bleeding were similar between warfarin and DOACs over short-term follow-up [37]. Either approach can be considered as the initial antithrombotic regimen in patients with HCM and AF [14,17,20]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) For asymptomatic AF In patients with HCM, asymptomatic or subclinical AF can be detected by external monitoring or device downloads. There are limited data on the prevalence of subclinical AF in HCM. Among 30 patients with HCM, 14 were noted to have evidence of subclinical AF over a follow-up of 595 days [38]. Among 114 patients with HCM followed for 2.8 years, subclinical AF detected by device download occurred at a rate of 4 percent per year [39]. In a retrospective study of patients with HCM with a dual-chamber ICD but no known history of AF, patients developed asymptomatic AF episodes (ie, clinically silent), most of which lasted less than one hour; however, 13 of the 18 patients with clinically silent AF had more than one episode [3]. There is debate regarding the burden of subclinical AF necessary to recommend DOACs for stroke prophylaxis. Extrapolating from non-HCM studies, episodes of subclinical AF >24 hours were associated with increased stroke risk compared with shorter episodes [40]. For this reason, the 2020 AHA/ACC HCM guidelines recommend DOAC therapy for patients with HCM detected with subclinical AF >24 hours duration [19]. For shorter episodes of >5 minutes to 24 hours, it would also be reasonable to consider DOAC therapy while also taking into consideration important clinical variables, such as length and burden of AF episodes, and the strengths and limitations of long-term anticoagulation therapy, including bleeding risk, for an individual patient. Atrial flutter and other supraventricular tachycardias The approach to the management of atrial flutter in patients with HCM is similar to the approach in patients without HCM. Given https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 10/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate the high success rates for radiofrequency ablation in eliminating atrial flutter, this should be considered early in patients with HCM. (See "Atrial flutter: Maintenance of sinus rhythm", section on 'RF catheter ablation'.) Nonsustained supraventricular tachycardias (SVTs) are commonly found during ambulatory electrocardiographic monitoring in patients with HCM. The majority of these events are asymptomatic and self-limited. Up to 25 percent of patients with HCM will have such arrhythmias, but they rarely require therapy [41]. (See "Narrow QRS complex tachycardias: Clinical manifestations, diagnosis, and evaluation" and "Overview of the acute management of tachyarrhythmias".) PROGNOSIS In addition to the symptoms associated with AF and the risk of worsening heart failure and stroke, mortality is higher in adults with HCM who develop AF [2,42,43]. In a single-center cohort of 3673 patients with HCM evaluated between 1975 and 2012, 650 patients (18 percent) had AF; patients with AF were older and more often symptomatic, and AF was associated with increased total mortality (adjusted hazard ratio 1.5, 95% CI 1.3-1.7) [43]. In a cohort of 202 Italian adults with HCM who were followed for up to 30 years (mean 10 years), the 57 patients (28 percent) with AF had a significantly higher mortality at 15 years (24 versus 3 percent in patients with HCM and no AF) [42]. In a cohort of 480 adults with HCM from the United States and Italy who were followed for an average of 9.1 years, intermittent or permanent AF significantly increased the rate of HCM-related death, primarily due to heart failure deaths and not sudden cardiac death [2]. The risk of death was associated with the presence of left ventricular outflow tract obstruction and AF onset before age 50 years. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Cardiomyopathy".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 11/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)") Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Epidemiology In patients with hypertrophic cardiomyopathy (HCM), the prevalence of atrial fibrillation (AF) appears to be four- to sixfold higher than in similarly aged patients in the general population, with an incidence in the range of 2 percent per year. (See 'Epidemiology' above.) Risk factors Several factors predispose to the development of AF in patients with HCM, including increased left atrial diameter and volume, left atrial dysfunction, increasing age, and left ventricular ejection fraction (LVEF), particularly when LVEF <50 percent (end-stage HCM). In contrast to these risk factors, the presence or severity of an LV outflow tract (LVOT) gradient does not appear to be associated with an increased incidence of AF. (See 'Predisposing factors' above.) Clinical manifestations While most patients with HCM who develop AF have fairly prominent symptoms, not all patients will be symptomatic. The acute symptoms associated with AF in patients with HCM, which may include palpitations, dyspnea, and chest pain, are similar to the symptoms of AF in patients without HCM. However, patients with HCM, especially those with an LVOT gradient, are also at risk for hypotension, lightheadedness, presyncope, and syncope. (See 'Clinical manifestations' above.) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 12/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate The long-term consequences of both paroxysmal and persistent/permanent AF in patients with HCM include an increase in limiting symptoms and risk of thromboembolic stroke, as well as decreased overall functional status. Unlike ventricular arrhythmias, however, AF is not clearly associated with an increased risk of sudden cardiac death. (See 'Clinical manifestations' above.) Diagnosis The diagnosis of AF is usually suspected in a patient with palpitations, dyspnea, or chest pain with an irregularly irregular pulse present on physical examination and confirmed by obtaining an ECG. (See 'Diagnosis' above.) Initial management In patients who are asymptomatic or have only mild to moderate symptoms, the initial management of AF is similar to other patients with AF and includes slowing the ventricular rate and concurrent initiation of anticoagulation therapy ( algorithm 1). (See 'Initial management' above and "Atrial fibrillation: Cardioversion" and "Cardioversion for specific arrhythmias".) In patients with severe symptoms or who are hemodynamically unstable related to AF, urgent cardioversion should be performed. Long-term management Rhythm versus rate control In symptomatic patients with HCM and paroxysmal or persistent AF, we suggest a rhythm control strategy (Grade 2C). This can be accomplished with either chemical or electrical cardioversion to restore sinus rhythm and antiarrhythmic drugs to suppress recurrences of AF. Although various professional society guidelines have concluded that the available data were insufficient to recommend one antiarrhythmic drug over another, our experts generally use sotalol (rather than amiodarone or disopyramide). In selected cases, catheter-based radiofrequency ablation or a surgical maze procedure may be appropriate. (See 'Rhythm control' above.) A rate control strategy is also reasonable. For patients in whom a rate control strategy is selected, we recommend the use of beta blockers, calcium channel blockers, or the two drugs in combination, rather than digoxin (Grade 1B). (See 'Rate control' above.) If rate control is not achieved with medications and catheter or surgical ablation is not an option, patients may undergo atrioventricular (AV) nodal ablation with placement of a permanent pacemaker for definitive rate control. (See 'Rate control' above.) Anticoagulation The CHA DS -VASc score has not been studied in patients with HCM 2 2 and therefore cannot be applied to patients with AF and HCM to determine need for https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 13/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate anticoagulation. For patients with HCM and clinical AF and subclinical AF >24 hours duration, we recommend chronic oral anticoagulation (Grade 1A). Either warfarin (with a target international normalized ratio [INR] of 2 to 3) or one of the direct oral anticoagulants (DOACs; eg, dabigatran, rivaroxaban, apixaban) can be chosen as the initial thrombotic regimen in patients with HCM and AF. For patients with shorter episodes of subclinical AF, anticoagulation therapy may be reasonable. (See 'Treatment' above and "Atrial fibrillation in adults: Use of oral anticoagulants".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Robinson K, Frenneaux MP, Stockins B, et al. Atrial fibrillation in hypertrophic cardiomyopathy: a longitudinal study. J Am Coll Cardiol 1990; 15:1279. 2. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001; 104:2517. 3. Rowin EJ, Orfanos A, Estes NA, et al. Occurrence and Natural History of Clinically Silent Episodes of Atrial Fibrillation in Hypertrophic Cardiomyopathy. Am J Cardiol 2017. 4. Ho CY, Day SM, Ashley EA, et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 2018; 138:1387. 5. Rowin EJ, Hausvater A, Link MS, et al. Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy. Circulation 2017; 136:2420. 6. Tani T, Tanabe K, Ono M, et al. Left atrial volume and the risk of paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2004; 17:644. 7. Sivalokanathan S, Zghaib T, Greenland GV, et al. Hypertrophic Cardiomyopathy Patients With Paroxysmal Atrial Fibrillation Have a High Burden of Left Atrial Fibrosis by Cardiac Magnetic Resonance Imaging. JACC Clin Electrophysiol 2019; 5:364. 8. Savage DD, Seides SF, Maron BJ, et al. Prevalence of arrhythmias during 24-hour electrocardiographic monitoring and exercise testing in patients with obstructive and nonobstructive hypertrophic cardiomyopathy. Circulation 1979; 59:866. 9. Stafford WJ, Trohman RG, Bilsker M, et al. Cardiac arrest in an adolescent with atrial fibrillation and hypertrophic cardiomyopathy. J Am Coll Cardiol 1986; 7:701. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 14/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate 10. Spirito P, Chiarella F, Carratino L, et al. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989; 320:749. 11. Higashikawa M, Nakamura Y, Yoshida M, Kinoshita M. Incidence of ischemic strokes in hypertrophic cardiomyopathy is markedly increased if complicated by atrial fibrillation. Jpn Circ J 1997; 61:673. 12. Suzuki M, Hirayama T, Marumoto K, et al. Paroxysmal atrial fibrillation as a cause of potentially lethal ventricular arrhythmia with myocardial ischemia in hypertrophic cardiomyopathy a case report. Angiology 1998; 49:653. 13. Boriani G, Rapezzi C, Biffi M, et al. Atrial fibrillation precipitating sustained ventricular tachycardia in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2002; 13:954. 14. Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014; 35:2733. 15. MacIntyre C, Lakdawala NK. Management of Atrial Fibrillation in Hypertrophic Cardiomyopathy. Circulation 2016; 133:1901.
'Epidemiology' above.) Risk factors Several factors predispose to the development of AF in patients with HCM, including increased left atrial diameter and volume, left atrial dysfunction, increasing age, and left ventricular ejection fraction (LVEF), particularly when LVEF <50 percent (end-stage HCM). In contrast to these risk factors, the presence or severity of an LV outflow tract (LVOT) gradient does not appear to be associated with an increased incidence of AF. (See 'Predisposing factors' above.) Clinical manifestations While most patients with HCM who develop AF have fairly prominent symptoms, not all patients will be symptomatic. The acute symptoms associated with AF in patients with HCM, which may include palpitations, dyspnea, and chest pain, are similar to the symptoms of AF in patients without HCM. However, patients with HCM, especially those with an LVOT gradient, are also at risk for hypotension, lightheadedness, presyncope, and syncope. (See 'Clinical manifestations' above.) https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 12/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate The long-term consequences of both paroxysmal and persistent/permanent AF in patients with HCM include an increase in limiting symptoms and risk of thromboembolic stroke, as well as decreased overall functional status. Unlike ventricular arrhythmias, however, AF is not clearly associated with an increased risk of sudden cardiac death. (See 'Clinical manifestations' above.) Diagnosis The diagnosis of AF is usually suspected in a patient with palpitations, dyspnea, or chest pain with an irregularly irregular pulse present on physical examination and confirmed by obtaining an ECG. (See 'Diagnosis' above.) Initial management In patients who are asymptomatic or have only mild to moderate symptoms, the initial management of AF is similar to other patients with AF and includes slowing the ventricular rate and concurrent initiation of anticoagulation therapy ( algorithm 1). (See 'Initial management' above and "Atrial fibrillation: Cardioversion" and "Cardioversion for specific arrhythmias".) In patients with severe symptoms or who are hemodynamically unstable related to AF, urgent cardioversion should be performed. Long-term management Rhythm versus rate control In symptomatic patients with HCM and paroxysmal or persistent AF, we suggest a rhythm control strategy (Grade 2C). This can be accomplished with either chemical or electrical cardioversion to restore sinus rhythm and antiarrhythmic drugs to suppress recurrences of AF. Although various professional society guidelines have concluded that the available data were insufficient to recommend one antiarrhythmic drug over another, our experts generally use sotalol (rather than amiodarone or disopyramide). In selected cases, catheter-based radiofrequency ablation or a surgical maze procedure may be appropriate. (See 'Rhythm control' above.) A rate control strategy is also reasonable. For patients in whom a rate control strategy is selected, we recommend the use of beta blockers, calcium channel blockers, or the two drugs in combination, rather than digoxin (Grade 1B). (See 'Rate control' above.) If rate control is not achieved with medications and catheter or surgical ablation is not an option, patients may undergo atrioventricular (AV) nodal ablation with placement of a permanent pacemaker for definitive rate control. (See 'Rate control' above.) Anticoagulation The CHA DS -VASc score has not been studied in patients with HCM 2 2 and therefore cannot be applied to patients with AF and HCM to determine need for https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 13/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate anticoagulation. For patients with HCM and clinical AF and subclinical AF >24 hours duration, we recommend chronic oral anticoagulation (Grade 1A). Either warfarin (with a target international normalized ratio [INR] of 2 to 3) or one of the direct oral anticoagulants (DOACs; eg, dabigatran, rivaroxaban, apixaban) can be chosen as the initial thrombotic regimen in patients with HCM and AF. For patients with shorter episodes of subclinical AF, anticoagulation therapy may be reasonable. (See 'Treatment' above and "Atrial fibrillation in adults: Use of oral anticoagulants".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Robinson K, Frenneaux MP, Stockins B, et al. Atrial fibrillation in hypertrophic cardiomyopathy: a longitudinal study. J Am Coll Cardiol 1990; 15:1279. 2. Olivotto I, Cecchi F, Casey SA, et al. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001; 104:2517. 3. Rowin EJ, Orfanos A, Estes NA, et al. Occurrence and Natural History of Clinically Silent Episodes of Atrial Fibrillation in Hypertrophic Cardiomyopathy. Am J Cardiol 2017. 4. Ho CY, Day SM, Ashley EA, et al. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 2018; 138:1387. 5. Rowin EJ, Hausvater A, Link MS, et al. Clinical Profile and Consequences of Atrial Fibrillation in Hypertrophic Cardiomyopathy. Circulation 2017; 136:2420. 6. Tani T, Tanabe K, Ono M, et al. Left atrial volume and the risk of paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2004; 17:644. 7. Sivalokanathan S, Zghaib T, Greenland GV, et al. Hypertrophic Cardiomyopathy Patients With Paroxysmal Atrial Fibrillation Have a High Burden of Left Atrial Fibrosis by Cardiac Magnetic Resonance Imaging. JACC Clin Electrophysiol 2019; 5:364. 8. Savage DD, Seides SF, Maron BJ, et al. Prevalence of arrhythmias during 24-hour electrocardiographic monitoring and exercise testing in patients with obstructive and nonobstructive hypertrophic cardiomyopathy. Circulation 1979; 59:866. 9. Stafford WJ, Trohman RG, Bilsker M, et al. Cardiac arrest in an adolescent with atrial fibrillation and hypertrophic cardiomyopathy. J Am Coll Cardiol 1986; 7:701. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 14/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate 10. Spirito P, Chiarella F, Carratino L, et al. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989; 320:749. 11. Higashikawa M, Nakamura Y, Yoshida M, Kinoshita M. Incidence of ischemic strokes in hypertrophic cardiomyopathy is markedly increased if complicated by atrial fibrillation. Jpn Circ J 1997; 61:673. 12. Suzuki M, Hirayama T, Marumoto K, et al. Paroxysmal atrial fibrillation as a cause of potentially lethal ventricular arrhythmia with myocardial ischemia in hypertrophic cardiomyopathy a case report. Angiology 1998; 49:653. 13. Boriani G, Rapezzi C, Biffi M, et al. Atrial fibrillation precipitating sustained ventricular tachycardia in hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2002; 13:954. 14. Authors/Task Force members, Elliott PM, Anastasakis A, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014; 35:2733. 15. MacIntyre C, Lakdawala NK. Management of Atrial Fibrillation in Hypertrophic Cardiomyopathy. Circulation 2016; 133:1901. 16. Veselka J, Anavekar NS, Charron P. Hypertrophic obstructive cardiomyopathy. Lancet 2017; 389:1253. 17. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 18. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 124:e783. 19. Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2020; 142:e558. 20. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 15/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 21. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med 1997; 336:775. 22. Moore JC, Trager L, Anzia LE, et al. Dofetilide for suppression of atrial fibrillation in hypertrophic cardiomyopathy: A case series and literature review. Pacing Clin Electrophysiol 2018; 41:396. 23. Liu X, Ouyang F, Mavrakis H, et al. Complete pulmonary vein isolation guided by three- dimensional electroanatomical mapping for the treatment of paroxysmal atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy. Europace 2005; 7:421. 24. Kilicaslan F, Verma A, Saad E, et al. Efficacy of catheter ablation of atrial fibrillation in patients with hypertrophic obstructive cardiomyopathy. Heart Rhythm 2006; 3:275. 25. Gaita F, Di Donna P, Olivotto I, et al. Usefulness and safety of transcatheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy. Am J Cardiol 2007; 99:1575. 26. Bassiouny M, Lindsay BD, Lever H, et al. Outcomes of nonpharmacologic treatment of atrial fibrillation in patients with hypertrophic cardiomyopathy. Heart Rhythm 2015; 12:1438. 27. Santangeli P, Di Biase L, Themistoclakis S, et al. Catheter ablation of atrial fibrillation in hypertrophic cardiomyopathy: long-term outcomes and mechanisms of arrhythmia recurrence. Circ Arrhythm Electrophysiol 2013; 6:1089. 28. Zhao DS, Shen Y, Zhang Q, et al. Outcomes of catheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy: a systematic review and meta-analysis. Europace 2016; 18:508. 29. Providencia R, Elliott P, Patel K, et al. Catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: a systematic review and meta-analysis. Heart 2016; 102:1533. 30. Zheng S, Jiang W, Dai J, et al. Five-year outcomes after catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiovasc Electrophysiol 2020; 31:621. 31. Chen MS, McCarthy PM, Lever HM, et al. Effectiveness of atrial fibrillation surgery in patients with hypertrophic cardiomyopathy. Am J Cardiol 2004; 93:373. 32. Matsui Y, Fukada Y, Imai T, et al. Combined cox maze procedure, septal myectomy, and mitral valve replacement for severe hypertrophic obstructive cardiomyopathy complicated by chronic atrial fibrillation. Ann Thorac Cardiovasc Surg 2003; 9:323. 33. Boll G, Rowin EJ, Maron BJ, et al. Efficacy of Combined Cox-Maze IV and Ventricular Septal Myectomy for Treatment of Atrial Fibrillation in Patients With Obstructive Hypertrophic Cardiomyopathy. Am J Cardiol 2020; 125:120. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 16/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate 34. Darby AE, Dimarco JP. Management of atrial fibrillation in patients with structural heart disease. Circulation 2012; 125:945. 35. Tsuda T, Hayashi K, Fujino N, et al. Effect of hypertrophic cardiomyopathy on the prediction of thromboembolism in patients with nonvalvular atrial fibrillation. Heart Rhythm 2019; 16:829. 36. Lee HJ, Kim HK, Jung JH, et al. Novel Oral Anticoagulants for Primary Stroke Prevention in Hypertrophic Cardiomyopathy Patients With Atrial Fibrillation. Stroke 2019; 50:2582. 37. Noseworthy PA, Yao X, Shah ND, Gersh BJ. Stroke and Bleeding Risks in NOAC- and Warfarin- Treated Patients With Hypertrophic Cardiomyopathy and Atrial Fibrillation. J Am Coll Cardiol 2016; 67:3020. 38. Wilke I, Witzel K, M nch J, et al. High Incidence of De Novo and Subclinical Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy and Cardiac Rhythm Management Device. J Cardiovasc Electrophysiol 2016; 27:779. 39. van Velzen HG, Theuns DA, Yap SC, et al. Incidence of Device-Detected Atrial Fibrillation and Long-Term Outcomes in Patients With Hypertrophic Cardiomyopathy. Am J Cardiol 2017; 119:100. 40. Van Gelder IC, Healey JS, Crijns HJGM, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J 2017; 38:1339. 41. McKenna WJ, England D, Doi YL, et al. Arrhythmia in hypertrophic cardiomyopathy. I: Influence on prognosis. Br Heart J 1981; 46:168. 42. Cecchi F, Olivotto I, Montereggi A, et al. Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population. J Am Coll Cardiol 1995; 26:1529. 43. Siontis KC, Geske JB, Ong K, et al. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high-risk population. J Am Heart Assoc 2014; 3:e001002. Topic 4926 Version 38.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 17/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate GRAPHICS Morphologic variants of hypertrophic cardiomyopathy HCM typically presents with asymmetric or localized areas of LV hypertrophy, which are diagrammed in B to J. (A) Normal LV wall thickness. (B) ASH. (C) Sigmoid septum, which is more common in older adults. (D) Midcavity hypertrophy associated with midcavity obstruction. (E) Predominantly free wall hypertrophy, an unusual pattern in HCM. (F) LV wall thinning (associated with low LV ejection fraction) and biatrial enlargement. (G) Predominantly apical LV hypertrophy. (H) Severe concentric hypertrophy with cavity obliteration. (I) Biventricular hypertrophy. (J) Mild to moderate symmetric hypertrophy. https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 18/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate HCM: hypertrophic cardiomyopathy; LV: left ventricular; ASH: asymmetrical septal hypertrophy. Graphic 58156 Version 6.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 19/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Management of atrial fibrillation in patients with hypertrophic cardiomyopathy Algorithmic approach to the management of AF in patients with HCM. The approach in this population is sim AF management, with consideration of all three major management questions (anticoagulation, rate control, patient. AF: atrial fibrillation; HCM: hypertrophic cardiomyopathy; BB: beta blocker; CCB: calcium channel blocker; INR CV: cardioversion; RFA: radiofrequency ablation. Patients with AF and rapid HR who are unstable should undergo urgent electrical cardioversion. Graphic 119349 Version 1.0 https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 20/21 7/5/23, 9:14 AM Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation - UpToDate Contributor Disclosures Martin S Maron, MD Grant/Research/Clinical Trial Support: iRhythm [Hypertrophic cardiomyopathy]. Consultant/Advisory Boards: Cytokinetics [Steering committee, REDWOOD-HCM]; Edgewise Pharmaceuticals [Myosin inhibitor for treatment of symptomatic hypertrophic cardiomyopathy]; Imbria Pharmaceuticals [Hypertrophic cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Samuel L vy, MD No relevant financial relationship(s) with ineligible companies to disclose. William J McKenna, MD Consultant/Advisory Boards: Bristol Meyers Squibb [Novel pharmacological treatments for HCM]; Cytokinetics [Novel pharmacological treatments for HCM]; Health in Code [Genetic testing in inherited cardiac disease]; Tenaya Therapeutics [Gene therapy in cardiomyopathy]. All of the relevant financial relationships listed have been mitigated. Todd F Dardas, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hypertrophic-cardiomyopathy-in-adults-supraventricular-tachycardias-including-atrial-fibrillation/print 21/21
7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy : Rod Passman, MD, MSCE : Bradley P Knight, MD, FACC, N A Mark Estes, III, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 25, 2023. INTRODUCTION For patients with atrial fibrillation (AF), the two principal goals of long-term therapy are to improve quality of life (eg, symptom control) and to prevent associated morbidity and mortality (principally the prevention of thromboembolism). (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on 'Adverse hemodynamics in AF' and "Atrial fibrillation in adults: Use of oral anticoagulants".) In asymptomatic or minimally symptomatic patients with AF, there is often no need to pursue aggressive measures to maintain sinus rhythm. For those patients who might feel better in sinus rhythm, rate- and rhythm-control strategies improve symptoms, but neither has been conclusively shown to improve survival compared to the other. The factors determining the choice between these two strategies are discussed elsewhere. (See "Management of atrial fibrillation: Rhythm control versus rate control".) For those patients in whom a rhythm control strategy is chosen, catheter ablation or antiarrhythmic drugs are the two principle therapeutic options. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) This topic will compare the efficacy and safety of these two options for rhythm control and provide recommendations for choosing one or the other. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 1/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate CLASSIFICATION The following terms are used in the classification of patients with atrial fibrillation (AF). In the studies discussed in this topic, some, but not all, of these groups have been included (see "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'): Paroxysmal (ie, self-terminating or intermittent) AF Paroxysmal AF is defined as recurrent AF ( 2 episodes) that terminates spontaneously in seven days or less, usually less than 24 hours. (See "Paroxysmal atrial fibrillation".) Persistent AF Persistent AF is defined as AF that fails to self-terminate within seven days. Episodes often require pharmacologic or electrical cardioversion to restore sinus rhythm. While a patient who has had persistent AF can have later episodes of paroxysmal AF, AF is generally considered a progressive disease. In individuals with paroxysmal AF, progression to persistent and permanent AF occurs in >50 percent beyond 10 years despite antiarrhythmic therapy [1]. Long-standing persistent AF Long-standing persistent AF refers to persistent AF that has lasted for one year or more [2]. Permanent AF Permanent AF is a term used to identify individuals with persistent AF where a decision has been made to no longer pursue a rhythm control strategy. CATHETER ABLATION AND ANTIARRHYTHMIC DRUG THERAPY General considerations Catheter ablation uses either cryoablation (cryotherapy) or radiofrequency ablation (RFA). AF will recur in one year in approximately 20 to 40 percent of patients who have a catheter ablation, although overall AF burden is often markedly decreased [3]; a recurrence is defined as an AF episode >30 seconds in duration on routine monitoring. Important complications from catheter ablation include cardiac tamponade, pulmonary vein stenosis (<1 percent), phrenic nerve paralysis (about 3 percent with cryoballoon), and rare instances of stroke and atrioesophageal fistula [4,5]. These and other complications are described in detail separately. (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) A 2017 randomized comparison between cryoablation and RFA showed similar success rates, as did a meta-analysis of observational studies [6,7]. (See "Atrial fibrillation: Catheter ablation" and https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 2/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate "Catheter ablation for the treatment of atrial fibrillation: Technical considerations for non- electrophysiologists".) Commonly employed drugs to maintain sinus rhythm are amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone. Approximately 25 to 50 percent of people who receive antiarrhythmic medications will have recurrent AF within one year. Important side effects of antiarrhythmics include proarrhythmia, bradyarrhythmia, and organ toxicity in the case of amiodarone. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials".) Approach For patients with symptomatic paroxysmal AF, in whom rhythm rather than a rate control is pursued, we suggest catheter ablation as first-line therapy in some patients as an alternative to antiarrhythmic drugs (AADs); this is particularly true for younger patients or patients who are poor candidates for AAD therapy or are concerned about the potential complications of AADs. Other factors that may impact the safety and efficacy of catheter ablation also need to be considered when deciding between catheter ablation and AAD. For patients with symptomatic paroxysmal or persistent AF who have failed or become intolerant to one or more AADs, we recommend catheter ablation. For patients with symptomatic persistent or longstanding persistent AF who have failed or become intolerant of one or more AADs or who choose not to start antiarrhythmic therapy, we suggest catheter ablation. Initial treatment of paroxysmal AF with catheter cryoballoon ablation was associated with a lower incidence of persistent AF or recurrent atrial tachyarrhythmia over three years of follow-up than initial use of AADs. Three hundred and three patients were assigned to undergo initial rhythm-control therapy with catheter ablation or to receive antiarrhythmic therapy. Over 36 months of follow-up the following findings were noted: Patients assigned catheter ablation had less persistent AF compared with patients assigned to AADs (1.9 versus 7.4 percent; hazard ratio [HR] 0.25 95% CI 0.09-0.70). Patients assigned catheter ablation had less recurrent atrial tachyarrhythmia, which occurred in 87 patients in the ablation group (56.5 percent) and in 115 in the AAD group (77.2 percent; 56.5 versus 77.2 percent; HR 0.51 95% CI 0.38-0.67). Serious adverse events occurred in seven patients (4.5 percent) in the ablation group and in 15 (10.1 percent) in the AAD group. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 3/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate PATIENTS WITHOUT PRIOR ANTIARRHYTHMIC DRUG TREATMENT Some patients with paroxysmal or persistent atrial fibrillation (AF) (see 'Classification' above) prefer a rhythm as opposed to a rate control strategy in order to decrease symptoms (see "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Summary and recommendations'). For patients who have chosen rhythm control and who have not previously received antiarrhythmic drug (AAD) therapy, we usually start with AAD rather than CA. On occasion, initial treatment with CA may be appropriate. All patients need to be informed of the possibility of recurrence of symptoms and adverse events with both therapies. Recurrence rates and side effects are discussed in detail elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Atrial fibrillation: Catheter ablation", section on 'Complications' and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Drug-related arrhythmias and mortality'.) Prior to 2020, catheter ablation (CA) was generally not offered as first-line therapy given the complexity of the procedure and the potential for complications. It was typically offered to patients who had failed AAD therapy. However, evidence suggests that CA is superior to AAD for control of symptoms. While CA appears superior to AAD for the prevention of AF recurrence, there is no evidence that the rates of cardiovascular death, myocardial infarction, or stroke differ between the two interventions. In addition, in the studies demonstrating superiority of CA, the procedure was performed by highly expert electrophysiologists. Thus, for most patients, we start with AAD. CA by an experienced operator may be considered as first-line therapy for symptomatic patients who, after a full discussion of the benefits and risks of both approaches, prefer an invasive approach. In a meta-analysis of six studies in 1200 patients comparing CA with AAD as first-line treatment for paroxysmal AF, CA was associated with [8]: Lower rates of recurrent atrial arrhythmias (35 versus 53 percent; risk ratio [RR] 0.64, 95% CI 0.51-0.80) [8]. Similar risks of serious adverse events (18 versus 21 percent; RR 0.87, 95% CI 0.58-1.30). Adverse events were defined differently across studies and included stroke, tamponade, and death. Lower rates of symptomatic atrial arrhythmias. Lower healthcare resource utilization. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 4/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate Lower rates of crossover to alternative treatment (RR 0.21, 95% CI 0.13-0.32). Limitations of this study include a moderate degree of heterogeneity among the included studies; one study in particular accounted for most of the heterogeneity (the RAAFT 2 trial) [9]. PATIENTS WITH PRIOR ANTIARRHYTHMIC DRUG TREATMENT For patients with either paroxysmal or persistent (see 'Classification' above) AF who are interested in decreasing their symptom burden and have received treatment with at least one antiarrhythmic drug, either catheter ablation or long-term antiarrhythmic drug therapy is a reasonable approach. The patient's choice will be guided by advantages and burdens of each approach. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) This section will review the studies that have directly compared the two approaches. These studies suggest that although catheter ablation and antiarrhythmic drug therapy lead to similar rates of all-cause mortality and other serious morbidities, there may be a greater improvement in quality of life with the former. This topic is not intended to address management in patients who have failed rhythm control with two or more antiarrhythmic drugs or those who have already received catheter ablation. Failure of an antiarrhythmic drug is defined as a drug trial that results in a reduction in AF burden that is not satisfactory to the patient, or results in side effects that are intolerable to the patient, proarrhythmia, or organ toxicity. (See "Atrial fibrillation: Catheter ablation" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Long-term issues'.) Three early meta-analyses of studies comparing catheter ablation and antiarrhythmic drug therapy found that recurrence of AF occurred less often in patients who received catheter ablation in the 12 months after initiation of therapy [10-12]. The following three randomized trials directly compared catheter ablation with antiarrhythmic drug therapy: The ThermoCool AF study randomly assigned 167 symptomatic patients with paroxysmal AF (no episodes lasting more than 30 days) who did not respond to at least one AAD and who experienced at least three episodes of paroxysmal AF within six months before randomization to either catheter ablation (with RFA) or AAD therapy in a 2:1 fashion [13]. Patients with significant left ventricular dysfunction, persistent AF, and advanced heart failure were excluded. Catheter ablation included pulmonary vein isolation with confirmation of entrance block, and AAD therapy included flecainide (36 percent), https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 5/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate propafenone (41 percent), dofetilide, sotalol, or quinidine at the investigator's discretion. After nine months, there were significantly fewer patients with documented symptomatic paroxysmal AF in the catheter ablation group (16 versus 66 percent; hazard ratio 0.30, 95% CI 0.19-0.47). In addition, major treatment-related adverse events occurred more often with AAD therapy (9 versus 5 percent) at 30 days. Mean quality-of-life scores improved significantly with catheter ablation compared to AAD therapy. The STOP AF trial randomly assigned 245 paroxysmal AF patients (in a 2:1 manner) to cryoballoon ablation or drug therapy [14]. Patients had previously failed drug therapy; paroxysmal and early persistent AF were present in 78 and 22 percent, respectively. Treatment success was defined as freedom from chronic treatment failure, as defined by the absence of: any detectable AF after the blanking period; use of a non-study antiarrhythmic drug; and any non-protocol intervention for AF. At 12 months, the primary end point was present in 69.9 and 7.3 percent of the two groups (p<0.001). Serious adverse procedure-related events occurred in 3.1 percent. Phrenic nerve palsy occurred in 11.2 percent, but resolved in the majority. The Catheter ABlation vs ANtiarrhythmic Drug Therapy in Atrial Fibrillation (CABANA) trial randomly assigned 2204 patients with paroxysmal (43 percent) or persistent AF (57 percent) to catheter ablation or antiarrhythmic drug therapy [15]. Patients were excluded if they had a prior catheter ablation or had failed two or more antiarrhythmic drugs. The following findings were noted: Among the patients who received antiarrhythmic drug therapy, 27.5 percent crossed over to the ablation group. The primary composite end point (death, disabling stroke, serous bleeding, or cardiac arrest) occurred in 8.0 and 9.2 percent of the two groups, respectively (hazard ratio [HR] 0.86, 95% CI 0.65-1.15), during a median follow-up of about four years. There was no difference in all-cause mortality (5.2 versus 6.1 percent; HR 0.85, 95% CI 0.60-1.21). The end point of death or cardiovascular hospitalization occurred less often with catheter ablation (51.7 versus 58.1 percent; HR 0.83, 95% CI 0.74-0.93), as did the rate for AF recurrence (49.9 versus 69.5 percent; HR 0.52, 95% CI 0.45-0.60). Both patient groups achieved significant improvement in quality-of-life scores, and the improvement in the catheter ablation group was significantly greater than in the drug therapy group. Using one quality-of-life tool, the mean score at baseline was approximately 63 points. At 12 months, the scores were 80.9 and 86.4 points, respectively [16]. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 6/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate The Catheter Ablation compared with optimized Pharmacological Therapy for Atrial Fibrillation (CAPTAF) trial randomly assigned 155 patients with symptomatic persistent or paroxysmal AF to catheter ablation or antiarrhythmic drug therapy [17]. The primary end point, SF-36 General Health score, improved more in the ablation group than the drug therapy group from baseline to 12 months (mean baseline score, 61.8 versus 62.7; mean change 11.9 versus 3.1, respectively; p = 0.003). Patients with heart failure Mortality and morbidity are higher among patients with atrial fibrillation and heart failure than among those with heart failure alone. Catheter ablation for atrial fibrillation has been proposed as a means of improving outcomes among patients with heart failure who are otherwise receiving appropriate treatment. This issue is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Catheter ablation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of catheter ablation are available in societal guidelines. The 2016 European Society of Cardiology guideline recommends catheter ablation for patients with symptomatic, paroxysmal, persistent, and probably long-standing persistent atrial fibrillation who have failed (or are intolerant to) treatment with at least one antiarrhythmic drug [18]. The 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation makes the following recommendations regarding catheter ablation (CA) to maintain sinus rhythm [19] CA is useful for symptomatic paroxysmal AF refractory or intolerant to at least one class I or III antiarrhythmic medication when a rhythm control strategy is desired. CA is reasonable for selected patients with symptomatic persistent AF refractory or intolerant to at least one class I or III antiarrhythmic medication. CA may be considered for symptomatic long-standing (>12 months) persistent AF refractory or intolerant to at least one class I or III antiarrhythmic medication, when a rhythm control strategy is desired. CA may be considered prior to initiation of antiarrhythmic drug therapy with a class I or III antiarrhythmic medication for symptomatic paroxysmal AF when a rhythm control strategy is desired. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 7/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) SUMMARY AND RECOMMENDATIONS For most patients with new-onset symptomatic paroxysmal atrial fibrillation (AF) who have chosen a rhythm rather than a rate control strategy, we suggest antiarrhythmic drug (AAD) therapy rather than catheter ablation (CA) as initial therapy (Grade 2C). Patients who may reasonably prefer CA as initial therapy include those who are concerned about the potential complications of AAD or the higher rate of AF recurrence with it. (See 'Patients without prior antiarrhythmic drug treatment' above.) For patients with symptomatic paroxysmal or persistent AF and who have failed or become intolerant to one or more AAD, we recommend CA (Grade 1A). (See 'Patients with prior antiarrhythmic drug treatment' above.) For patients with symptomatic persistent or longstanding persistent AF who have failed or become intolerant of one or more AAD or who choose not to start antiarrhythmic therapy, we suggest CA (Grade 2B). (See 'Patients with prior antiarrhythmic drug treatment' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Wilber DJ. Pursuing sinus rhythm in patients with persistent atrial fibrillation: when is it too late? J Am Coll Cardiol 2009; 54:796. 2. European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369. 3. Andrade JG, Champagne J, Dubuc M, et al. Cryoballoon or Radiofrequency Ablation for Atrial Fibrillation Assessed by Continuous Monitoring: A Randomized Clinical Trial. Circulation 2019; 140:1779. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 8/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate 4. Teunissen C, Velthuis BK, Hassink RJ, et al. Incidence of Pulmonary Vein Stenosis After Radiofrequency Catheter Ablation of Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:589. 5. Samuel M, Almohammadi M, Tsadok MA, et al. Population-Based Evaluation of Major Adverse Events After Catheter Ablation for Atrial Fibrillation. JACC Clin Electrophysiol 2017; 3:1425. 6. Kuck KH, F rnkranz A, Chun KR, et al. Cryoballoon or radiofrequency ablation for symptomatic paroxysmal atrial fibrillation: reintervention, rehospitalization, and quality-of- life outcomes in the FIRE AND ICE trial. Eur Heart J 2016; 37:2858. 7. Buiatti A, von Olshausen G, Barthel P, et al. Cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: an updated meta-analysis of randomized and observational studies. Europace 2017; 19:378. 8. Imberti JF, Ding WY, Kotalczyk A, et al. Catheter ablation as first-line treatment for paroxysmal atrial fibrillation: a systematic review and meta-analysis. Heart 2021; 107:1630. 9. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA 2014; 311:692. 10. Noheria A, Kumar A, Wylie JV Jr, Josephson ME. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: a systematic review. Arch Intern Med 2008; 168:581. 11. Terasawa T, Balk EM, Chung M, et al. Systematic review: comparative effectiveness of radiofrequency catheter ablation for atrial fibrillation. Ann Intern Med 2009; 151:191. 12. Chen HS, Wen JM, Wu SN, Liu JP. Catheter ablation for paroxysmal and persistent atrial fibrillation. Cochrane Database Syst Rev 2012; :CD007101. 13. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 2010; 303:333. 14. Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic Front (STOP AF) pivotal trial. J Am Coll Cardiol 2013; 61:1713. 15. Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1261. 16. Mark DB, Anstrom KJ, Sheng S, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321:1275. https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 9/10 7/5/23, 9:14 AM Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy - UpToDate 17. Blomstr m-Lundqvist C, Gizurarson S, Schwieler J, et al. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA 2019; 321:1059. 18. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 19. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2017; 14:e275. Topic 93920 Version 30.0 Contributor Disclosures Rod Passman, MD, MSCE Grant/Research/Clinical Trial Support: Abbott [Ablation]; AHA [Ablation]; NIH [Stroke prevention]. Consultant/Advisory Boards: Abbott [Ablation]; iRhythm [Monitoring]; Janssen [Atrial fibrillation detection]; Medtronic [Implantable cardiac monitors]. Speaker's Bureau: iRhythm [Monitoring]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. N A Mark Estes, III, MD Consultant/Advisory Boards: Boston Scientific [Arrhythmias]; Medtronic [Arrhythmias]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/maintenance-of-sinus-rhythm-in-atrial-fibrillation-catheter-ablation-versus-antiarrhythmic-drug-therapy/print 10/10
7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Management of atrial fibrillation: Rhythm control versus rate control : Kapil Kumar, MD, Warren J Manning, MD : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 26, 2023. INTRODUCTION Atrial fibrillation (AF) is the most common sustained arrhythmia. It may cause significant symptoms that impair both functional status and quality of life. A key decision in the treatment of patients with AF is whether to institute a strategy primarily aimed at keeping the ventricular rate within a goal range or to do rhythm control in order to achieve and maintain sinus rhythm. Advantages, disadvantages, and our preferences for rhythm and rate control, as well as whether there are subgroups of patients for whom one or the other should be preferred, will be discussed here. The methods to achieve rhythm or rate control and the management of patients with AF and heart failure are discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) DEFINITIONS Rhythm control A rhythm-control strategy typically employs one or more of the following therapies to maintain sinus rhythm: Antiarrhythmic drug therapy (see "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations") https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 1/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Electrical cardioversion (see "Atrial fibrillation: Cardioversion") Radiofrequency catheter ablation of the left atrium (see "Atrial fibrillation: Catheter ablation") Surgical ablation procedure performed at the time of open-heart surgery (see "Atrial fibrillation: Surgical ablation") The following are reasons that rhythm control can fail, at least in the short term: Unsuccessful cardioversion This includes failure to achieve sinus rhythm or immediate recurrence of AF after sinus rhythm has been restored (from an electrical cardioversion or catheter ablation of AF). AF recurrence When AF recurs sometime after initial successful rhythm control. Rate control A rate-control strategy uses one or more of the following strategies to keep the ventricular rate within a goal range: Medications that block (slow conduction through) the atrioventricular (AV) node such as beta blockers, rate-slowing nondihydropyridine calcium channel blockers, or digoxin. AV nodal ablation plus ventricular pacing to control symptoms is also considered when pharmacologic therapy is ineffective. This is used more rarely. (See "Atrial fibrillation: Atrioventricular node ablation".) Rate control goals are discussed elsewhere. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) Definitions for different subtypes of AF, including paroxysmal and persistent, are described in detail separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'.) . GOALS OF THERAPY Preventing adverse cardiac remodeling Although AF is not usually an acute life-threatening illness, it does cause a loss of the regular and effective left atrial contraction, short- and long- term deterioration in hemodynamics secondary to this increased heart rate, and loss of atrial contribution to cardiac output. These changes can lead to left atrial dilation and progressive dysfunction, as well as possible left ventricular dysfunction, which can reverse with restoration https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 2/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate of sinus rhythm. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm" and "Arrhythmia-induced cardiomyopathy".) Thus, both rate- and rhythm-control strategies are aimed at alleviating these pathophysiologic consequences or AF and alleviating a patient s symptoms of AF. For patients with AF, the long-term choice between rhythm or rate control should be made after a detailed shared decision-making discussion between patient and their provider(s) regarding the benefits and risks of each approach. Prevention of cardiovascular disease and mortality AF is associated with increased mortality and other sequelae. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Sequelae'.) Among high-cardiovascular-risk patients who are treated early in the course of their disease, rhythm control has been shown to improve cardiovascular outcomes and survival when compared with rate control. This is discussed in detail separately. (See 'High cardiovascular risk' below.) Alleviation of symptoms Symptoms of AF can include palpitations, dyspnea, lightheadedness, angina, decreased exercise tolerance, and near syncope. These can occur in patients with rate-controlled AF and those with rapid AF. Many patients with AF who are symptomatic will have a strong desire to be in sinus rhythm. For instance, among some physically active patients, being in AF rather than sinus rhythm can lower their exercise capacity [1]. Many active individuals or those who need to carry out activities requiring optimal cardiac performance generally do not tolerate AF. Even patients who are not physically active can be very symptomatic from AF and/or report low AF-related quality of life [2]. For many such patients, the benefits of achieving and maintaining sinus rhythm outweigh the risks of a rhythm-control strategy. Still, not every patient will feel better when in sinus rhythm compared with AF. Thromboembolic risk While thromboembolism, especially stroke, is the most important adverse outcome of AF, prevention of thromboembolism is not a reason for choosing a rhythm- versus a rate-control strategy. Regardless of which strategy is chosen, patients remain at risk for thromboembolism, and each must undergo risk stratification to determine their thromboembolic and bleeding risks and whether antithrombotic therapy is indicated. This is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Studies are somewhat inconsistent in their findings as to whether rhythm-control therapy reduces embolic risk. Both the AFFIRM and RACE trials demonstrated that embolic events https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 3/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate occurred with similar frequency regardless of whether a rate- or rhythm-control strategy was pursued. Furthermore, most embolic events (113 of 157 ischemic strokes in AFFIRM and 29 of 35 embolic events in RACE) occurred after warfarin had been stopped or when the international normalized ratio was subtherapeutic (less than 2) [3,4]. In contrast, the EAST-AF NET trial showed a lower risk of stroke for patients assigned to rhythm versus rate control; stroke risk was elevated in both groups compared with baseline stroke risk in patients without AF. These findings are discussed below. (See 'High cardiovascular risk' below.) One reason that a rhythm-control approach may not reduce the embolic risk is that AF frequently recurs after treatment in 35 to 60 percent at one year with intermittent monitoring ( figure 1) [5,6] and in up to 88 percent of those with continuous monitoring for more than 18 months on antiarrhythmic therapy [7]. In the AFFIRM trial described below, there was a high crossover rate from rhythm to rate control (17 and 38 percent of patients at one and five years), due primarily to an inability to maintain sinus rhythm and drug intolerance [3]. URGENT MANAGEMENT The clinical decision regarding whether to employ a rate- versus rhythm-control strategy in the urgent setting is required for patients who are clinically unstable. Unstable patients with AF include those with hypotension, altered mental status, ischemia, heart failure, cardiogenic shock, or very rapid ventricular rates (eg, patients with preexcitation and anterograde conduction of AF through an accessory pathway). (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Unstable patients' and "Wolff- Parkinson-White syndrome: Anatomy, epidemiology, clinical manifestations, and diagnosis" and "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome".) In most patients who require urgent management, we first employ a rate-control strategy. Exceptions are if the patient is hemodynamically unstable and successful ventricular rate control cannot be achieved. The decision about rate or rhythm control may change once the patient becomes stable and requires long-term management of AF. (See 'Elective and long-term management' below.) ELECTIVE AND LONG-TERM MANAGEMENT Rhythm control Indications for initial rhythm control https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 4/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Symptomatic patients Alleviation of symptoms from AF despite adequate ventricular rate control is a major pillar of management of the patient with AF. Therefore, we try an initial rhythm-control strategy. For some patients who are highly symptomatic, AF can limit activity and adversely affect quality of life even for those without a rapid heart rate. For such patients, it is reasonable to attempt a long-term rhythm-control strategy. Typically, a rate-control strategy may alleviate some of the symptoms of AF, especially at rest, but commonly a decline in exercise tolerance remains, often due to rapid rise of heart rate with exertion. In addition, for some patients, loss of atrial contribution to cardiac output can play a major role in symptoms. (See 'Alleviation of symptoms' above.) Quality-of-life scores have been assessed as substudies of some randomized AF trials. The Canadian Trial of Atrial Fibrillation (CTAF) randomized persistent AF patients to either amiodarone or propafenone [8]. The authors found that by three months, global well-being was significantly worse for patients who had recurrent AF compared with those who did not. In addition, they noted the main clinical variable that correlated with improved subjective quality of life was restoration and maintenance of sinus rhythm. The RACE study randomized patients to rate versus rhythm control. The quality-of-life substudy demonstrated that patients with AF had worse quality of life compared with healthy controls [9]. The treatment strategy did not affect quality of life. However, the presence of sinus rhythm at the end of the follow-up interval (instead of the assigned strategy) was associated with an improvement in quality of life. Age 80 years Younger patients generally have fewer side effects with pharmacologic rhythm control and catheter ablation compared with older patients. Younger patients are also less likely to have permanent AF, which increases the likelihood of a successful cardioversion and maintenance of sinus rhythm. Also, in younger patients, there is concern that being in AF for longer may lead to adverse long-term consequences such as adverse cardiac remodeling. High cardiovascular risk We prefer rhythm control for any patient, regardless of symptoms, who is at high risk for cardiovascular disease. High risk for cardiovascular disease is defined age >80 years, prior transient ischemic attack or stroke, or two of the following criteria: age >65 years, female sex, heart failure, hypertension, diabetes, severe coronary artery disease, chronic kidney disease, and left ventricular hypertrophy (diastolic septal wall width >15 mm). It is important to mention that these age cutoffs provide guidance but are not meant to be absolute. The management of AF in patients with heart failure is discussed in detail separately (See "The management of atrial fibrillation in patients with heart failure", section on 'Preference for rhythm over rate control' and 'Patient preference' below.) Higher survival with early (within 12 months of initial AF diagnosis) rhythm control in patients who are at high risk for cardiovascular disease outcome in the EAST-AF NET https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 5/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate trial The EAST-AFNET 4 trial demonstrated slightly improved survival with rhythm control in 2789 high-cardiovascular-risk patients if this strategy is employed within 12 months of the initial diagnosis [10]. High risk was defined as >75 years of age, prior transient ischemic attack or stroke, or two of the following criteria: age >65 years, female sex, heart failure, hypertension, diabetes, severe coronary artery disease, chronic kidney disease, and left ventricular hypertrophy (diastolic septal wall width >15 mm). This study randomly assigned patients with early AF (diagnosed 12 months before enrollment; median time since diagnosis, 36 days) to either early rhythm control with antiarrhythmic drugs or ablation or to usual care, which limited rhythm control to patients with unacceptable symptoms after rate control. The trial was stopped early for efficacy after a median of 5.1 years of follow- up. The following findings were reported: The primary composite outcome (eg, cardiovascular death, stroke, or serious adverse events related to rhythm-control therapy) occurred less often with rhythm control versus usual care (249 versus 316 events; 3.9 versus 5 events per 100 person-years; hazard ratio [HR] 0.79; 95% CI 0.66-0.94). Death from cardiovascular causes occurred less often in the rhythm-control group (67 versus 94 events; 1 versus 1.3 percent; HR 0.72; 95% CI 0.52-0.98). Stroke occurred less often in the rhythm-control group (40 versus 62 events; 0.6 versus 0.9 percent; HR 0.65; 95% CI 0.44-0.97). Causal mediation analysis in this study showed that sinus rhythm at 12 months explained 81 percent of the treatment benefit of early rhythm control therapy on stroke reduction during the remainder of follow-up. More than 70 percent of patients were asymptomatic in both treatment groups at one and two years. There was no significant difference between the two groups in the rate of the primary safety outcome (eg, death, stroke, and serious adverse event related to the rhythm- control strategy). Serious adverse events related to rhythm-control therapy were uncommon but were more frequent in the rhythm-control group (4.9 versus 1.4 percent). EAST-AF NET trial results did not differ according to the presence of symptoms In a post-hoc analysis of EAST-AFNET4, rates of the primary composite outcome did not differ between asymptomatic and symptomatic patients [11]. Among asymptomatic patients, patients randomized to early rhythm control had lower risk of the primary composite outcome compared with those assigned to usual care (HR 0.76; 95% CI 0.6-1.03) that was https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 6/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate not statistically significant. Among symptomatic patients, a similar benefit from early rhythm control was seen (HR 0.79; 95% CI 0.6-0.98). The study was not powered to detect a difference between patients with and without symptoms. However, this does suggest that symptoms may be underreported by patients with AF, and there is some clinical improvement with maintaining sinus rhythm. Early studies suggested a higher mortality with pharmacologic rhythm versus rate control, whereas later meta-analyses show equivalent outcomes This is discussed separately. (See '>80 years, asymptomatic, and low cardiovascular disease risk' below.) Heart failure This is discussed in detail separately. (See "The management of atrial fibrillation in patients with heart failure".) Treatment approach Initial cardioversion For the majority of patients with persistent AF, we try rhythm control with early cardioversion as the initial elective or long-term management strategy ( algorithm 1) [12]. Many patients undergoing rhythm control may still require long-term rate- slowing drugs (in the event of return to AF), as well as chronic antithrombotic therapy. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Rhythm control can also be achieved with pharmacologic (ie, antiarrhythmic drug therapy and/or pharmacologic cardioversion) or nonpharmacologic methods (ie, electrical cardioversion, catheter, or surgical ablation). These approaches are discussed in detail separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Atrial fibrillation: Catheter ablation".) (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) Unsuccessful initial cardioversion or AF recurrence A minority of patients will have an unsuccessful cardioversion, and some can experience early AF recurrence. If a patient does not convert successfully to sinus rhythm after cardioversion, further treatment strategy depends on the patient s symptom burden, age, and comorbidities. Age >80 years and low cardiovascular disease risk We switch to rate control in these patients. This is discussed in detail separately. (See '>80 years, asymptomatic, and low cardiovascular disease risk' below.) https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 7/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Age 80 years and/or high cardiovascular disease risk In these patients, we will continue with a rhythm-control strategy and add an antiarrhythmic medication or pursue a catheter ablation. These are discussed in detail separately. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) (See "Maintenance of sinus rhythm in atrial fibrillation: Catheter ablation versus antiarrhythmic drug therapy".) (See "Atrial fibrillation: Catheter ablation".) We reassess patient comorbidities, age, and preferences during routine follow-up. This will inform continuation with rhythm control versus switching to a rate-control strategy. Rate control This can be done with oral beta blocker, rate-slowing nondihydropyridine calcium channel blocker, or with use of digoxin. This is discussed in detail separately. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) For selected patients who do not respond to pharmacologic rate control, AV node ablation with pacing is another option for rate control of AF. This is discussed in detail separately. (See "Atrial fibrillation: Atrioventricular node ablation".) >80 years, asymptomatic, and low cardiovascular disease risk In this group of patients with AF, we pursue a rate-control strategy; this is particularly true if the patient has long- standing or recurrent AF. Patients over age 80 account for approximately 35 percent of patients with AF, and the prevalence of AF in this group is about 10 percent ( figure 2) [13]. In the group of patients >80 years of age who are asymptomatic and at low risk of cardiovascular disease, we choose rate control for the following reasons: Less side effects with rate control There are more potential side effects from rhythm than with rate control. Patients >80 years of age are more sensitive to the proarrhythmic effects of antiarrhythmics. These include proarrhythmia that can occur with antiarrhythmic drugs [14,15] and vascular and other procedural complications that can result from catheter ablation. (See "Major side effects of class I antiarrhythmic drugs".) (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) (See "Atrial fibrillation: Catheter ablation", section on 'Complications'.) Early studies suggested a lower mortality with rate versus pharmacologic rhythm control, whereas later meta-analyses show equivalent outcomes Two trials that were https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 8/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate conducted prior to the widespread use of catheter ablation suggested that pharmacologic rhythm control was associated with higher mortality than rate control. Among patients with long-standing AF, the results from AFFIRM and RACE show at least equivalent and possibly better outcomes with rate compared with rhythm control with antiarrhythmic medications ( figure 3 and figure 4) [3,4]. Half of the patients in AFFIRM had a low symptom burden, with symptoms of AF occurring less than once a month [3]. A subsequent meta-analysis of five trials comparing rate versus pharmacologic rhythm control, in which AFFIRM accounted for 77 percent of the patients, showed a trend toward a reduction in all-cause mortality with rate control (13 versus 14.6 percent with rhythm control; odds ratio 0.87; 95% CI 0.74-1.02) [16]. The proportion of patients who had an ischemic stroke was similar with the two approaches (3.5 versus 3.9 percent). An important caveat is that these studies were conducted prior to the widespread use of catheter ablation as a rhythm-control method. At least seven randomized trials have compared rate and rhythm control using antiarrhythmic drug therapy in a broad population of patients with AF [3,4,17-19]. In the aggregate, these studies demonstrated equivalent health outcomes (such as the rates of death or embolism) in both arms. One trial demonstrated improved quality-of-life scores with rhythm control [20]. Unsuccessful pharmacologic rate control In selected patients who do not respond adequately and/or cannot tolerate pharmacologic rate control, we consider switching to either a rhythm-control strategy or ablation of the AV node with pacemaker implant. We generally prefer use of antiarrhythmics or catheter ablation of AF to maintain sinus rhythm over an ablate-and- pace strategy for younger patients or those without a long history of AF. For older patients or those with significant comorbidities, long history of AF, or very large atria, AV node ablation and physiologic pacing (His bundle or left bundle pacing) may be preferable given the lower likelihood of being able to maintain sinus rhythm. (See "Atrial fibrillation: Atrioventricular node ablation" and "Atrial fibrillation: Catheter ablation" and 'Failure of rate control' below.) Changing management strategies In patients with AF, there are several reasons we may make a switch from rate to rhythm control or vice versa. Patient preference One reason for making a switch is if the patient expresses a strong preference for trying another approach. For example, some patients will have a strong preference to be in sinus rhythm due to persistent symptoms with a rate-control strategy. Long- term monitoring to assess the adequacy of rate control is useful to confirm adequacy of ventricular rate control and/or that symptoms correlate with rapid ventricular rates. It is https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 9/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate reasonable to try a given approach for a few months and no longer than one year prior to considering switching approaches. (See 'Alleviation of symptoms' above.) Failure of rhythm control Rhythm control has the highest chance of success if the patient has been in AF for less than one year continuously. This is because the AF-related atrial structural and electrical cardiac remodeling are less pronounced if the duration of AF is <1 year. If a patient does not respond to rhythm control after a reasonable attempt, we may decide to pursue rate control instead. Another reason to switch to rate control would be due to medication side effects or intolerances (eg, antiarrhythmics). (See "Major side effects of class I antiarrhythmic drugs", section on 'Flecainide'.) (See "Major side effects of class I antiarrhythmic drugs", section on 'Propafenone'.) (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Drug-related arrhythmias and mortality'.) There is a substantial rate of recurrent AF and frequent crossover to a rate-control strategy when antiarrhythmic drugs are used for maintenance therapy after conversion to sinus rhythm. Recurrence is detected clinically in 20 to 60 percent at one year ( figure 1) [21]. Furthermore, a study of patients who had continuous electrocardiographic monitoring found that recurrent episodes occurred in approximately 90 percent of people; many of these episodes were asymptomatic, including some lasting more than 48 hours [7]. The risk of recurrent AF is highest in patients who have hypertension, an enlarged left atrium, AF for more than one year, or heart failure [22]. Failure of rate control In patients who do not respond adequately to initial rate control, we may switch to a rhythm-control strategy. Clinical scenarios that signal the failure of rate control are described below: Bothersome symptoms Some patients have persistent palpitations, dyspnea, lightheadedness, angina, and near syncope despite adequate rate control. In these patients we often try a rhythm-control strategy. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Inability to achieve adequate rate control In patients who cannot achieve low enough resting or exertional heart rates despite therapy, we prefer rhythm control in order to prevent tachycardia-mediated cardiomyopathy). (See "Arrhythmia-induced cardiomyopathy" and "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy", section on 'Evaluation and goal ventricular rate'.) https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 10/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate RECOMMENDATIONS OF OTHERS Recommendations regarding the choice between rate and rhythm control are available from the American Heart Association/American College of Cardiology (2014, 2019) and the European Society of Cardiology (2016) [23-26]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Rationale and goals of therapy Both rate- and rhythm-control strategies are aimed at alleviating pathophysiologic consequences or symptoms and atrial fibrillation (AF). Patients with AF are at increased risk for stroke and other embolic events from left atrial thrombi; however, neither rate nor rhythm control has great efficacy at preventing this consequence. (See 'Goals of therapy' above.) https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 11/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Urgent management We prefer to use rate rather than rhythm control for the acute management of new-onset AF, acute episodes of paroxysmal AF, and for long-standing AF with rapid ventricular rates. (See 'Urgent management' above.) Elective and long-term management Goals of therapy For patients with AF, the long-term choice between rhythm or rate control should be made after a detailed shared decision-making discussion between the patient and their provider(s) regarding the benefits and risks of each approach. Important factors to consider in this discussion are patient symptoms, quality of life, and any potential cardiovascular, mortality and safety benefits associated with the chosen strategy. In many cases, the benefits and risks will be closely balanced, and either strategy will be a reasonable choice. All patients with AF, irrespective of rate versus rhythm control, must undergo risk stratification for their thromboembolic and bleeding risks and be considered for antithrombotic therapy; this is discussed in detail separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Preference for rhythm control For patients who are at high risk for cardiovascular disease and especially if the patient is symptomatic, we suggest a rhythm- rather than a rate-control strategy, provided it can be initiated within 12 months of AF onset ( algorithm 1) (Grade 2C). High risk is defined as >80 years of age, prior transient ischemic attack or stroke, or two of the following criteria: age >65 years, female sex, heart failure, hypertension, diabetes, severe coronary artery disease, chronic kidney disease, and left ventricular hypertrophy (diastolic septal wall width >15 mm). (See 'High cardiovascular risk' above.) We also suggest initial cardioversion in patients with symptoms (for symptom relief) and in patients who are <80 years of age (since they have a higher likelihood of maintaining sinus rhythm after a cardioversion). (See 'Symptomatic patients' above and 'Age 80 years' above.) For patients who have an unsuccessful initial cardioversion, if they are 80 years of age and at high cardiovascular disease risk, we will continue with a rhythm-control strategy and add an antiarrhythmic medication or pursue a catheter ablation to maintain sinus rhythm. If they are >80 years of age and at low cardiovascular disease risk, we switch to rate control. (See 'Unsuccessful initial cardioversion or AF recurrence' above.) Preference for rate control https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 12/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate We generally prefer long-term rate control for asymptomatic patients age >80 years old who are asymptomatic and have a low cardiovascular disease risk ( algorithm 1). (See 'Rate control' above.) In selected patients who do not respond adequately and/or cannot tolerate pharmacologic rate control, we consider switching to a rhythm-control strategy. (See 'Unsuccessful pharmacologic rate control' above.) Changing management strategies If a patient has a strong preference to pursue another management strategy, or if there is a failure of the initial chosen strategy after a reasonable attempt, we often switch to another approach. (See 'Changing management strategies' above.) 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Randomized trial of rate-control versus rhythm- control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003; 41:1690. 19. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest 2004; 126:476. 20. Ogawa S, Yamashita T, Yamazaki T, et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ J 2009; 73:242. 21. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 14/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate 22. Dittrich HC, Erickson JS, Schneiderman T, et al. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:193. 23. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 24. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 25. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 26. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1045 Version 39.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 15/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate GRAPHICS The rate of recurrent atrial fibrillation is lowest with amiodarone
and at high cardiovascular disease risk, we will continue with a rhythm-control strategy and add an antiarrhythmic medication or pursue a catheter ablation to maintain sinus rhythm. If they are >80 years of age and at low cardiovascular disease risk, we switch to rate control. (See 'Unsuccessful initial cardioversion or AF recurrence' above.) Preference for rate control https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 12/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate We generally prefer long-term rate control for asymptomatic patients age >80 years old who are asymptomatic and have a low cardiovascular disease risk ( algorithm 1). (See 'Rate control' above.) In selected patients who do not respond adequately and/or cannot tolerate pharmacologic rate control, we consider switching to a rhythm-control strategy. (See 'Unsuccessful pharmacologic rate control' above.) Changing management strategies If a patient has a strong preference to pursue another management strategy, or if there is a failure of the initial chosen strategy after a reasonable attempt, we often switch to another approach. (See 'Changing management strategies' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Atwood JE, Myers JN, Tang XC, et al. Exercise capacity in atrial fibrillation: a substudy of the Sotalol-Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T). Am Heart J 2007; 153:566. 2. Spertus J, Dorian P, Bubien R, et al. Development and validation of the Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) Questionnaire in patients with atrial fibrillation. Circ Arrhythm Electrophysiol 2011; 4:15. 3. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 4. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 5. Zarembski DG, Nolan PE Jr, Slack MK, Caruso AC. Treatment of resistant atrial fibrillation. A meta-analysis comparing amiodarone and flecainide. Arch Intern Med 1995; 155:1885. 6. Antonielli E, Pizzuti A, P link s A, et al. Clinical value of left atrial appendage flow for prediction of long-term sinus rhythm maintenance in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2002; 39:1443. 7. Israel CW, Gr nefeld G, Ehrlich JR, et al. Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optimal patient care. J Am Coll Cardiol 2004; 43:47. 8. Dorian P, Mangat I. Quality of life variables in the selection of rate versus rhythm control in patients with atrial fibrillation: observations from the Canadian Trial of Atrial Fibrillation. Card Electrophysiol Rev 2003; 7:276. https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 13/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate 9. Hagens VE, Ranchor AV, Van Sonderen E, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol 2004; 43:241. 10. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1305. 11. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial. Eur Heart J 2022; 43:1219. 12. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial fibrillation: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Intern Med 2003; 139:1009. 13. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. 14. Heijman J, Hohnloser SH, Camm AJ. Antiarrhythmic drugs for atrial fibrillation: lessons from the past and opportunities for the future. Europace 2021; 23:ii14. 15. Mankad P, Kalahasty G. Antiarrhythmic Drugs: Risks and Benefits. Med Clin North Am 2019; 103:821. 16. de Denus S, Sanoski CA, Carlsson J, et al. Rate vs rhythm control in patients with atrial fibrillation: a meta-analysis. Arch Intern Med 2005; 165:258. 17. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000; 356:1789. 18. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm- control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003; 41:1690. 19. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest 2004; 126:476. 20. Ogawa S, Yamashita T, Yamazaki T, et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ J 2009; 73:242. 21. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913. https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 14/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate 22. Dittrich HC, Erickson JS, Schneiderman T, et al. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:193. 23. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 24. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:2071. 25. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 26. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1045 Version 39.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 15/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate GRAPHICS The rate of recurrent atrial fibrillation is lowest with amiodarone The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the median time to recurrence was longer (>468 versus 98 days). Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913. Graphic 69285 Version 3.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 16/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Long-term management of patients with atrial fibrillation: Selection of rhythm versus rate control In some patients who strongly prefer to be in SR, regardless of age or comorbidities, we pursue a rhythm control strategy. Regardless of strategy, it is important to assess need for anticoagulation based on patient's risk factors for thromboembolic events and bleeding risk (ie, CHADS2-VASCc score). Refer to related UpToDate content for further information. AF: atrial fibrillation; SR: sinus rhythm. High risk for cardiovascular disease includes >75 years of age, prior transient ischemic attack or stroke, or two of the following criteria: age >65 years, female sex, heart failure, hypertension, diabetes, severe coronary artery disease, chronic kidney disease, and left ventricular hypertrophy (diastolic septal wall width >15 mm). A patient at low risk for cardiovascular disease includes everyone else not at high risk. https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 17/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate An unsuccessful cardioversion will not result in conversion to SR or only short duration in SR. AF recurrence occurs later, not immediately after cardioversion Refer to related UpToDate content for further information. Graphic 141597 Version 1.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 18/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Prevalence of atrial fibrillation with age In a cross-sectional study of almost 1.9 million men and women, the prevalence of atrial fibrillation increases with age, ranging from 0.1 for those <55 years of age to over 9 percent in those 85 years of age. At all ages, the prevalence is higher in men than women. Data from Go AS, Hylek EM, Phillips K, et al. Prevalence of diagnosed atrial brillation in adults: National implications for rhythm management and stroke prevention: The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. Graphic 77268 Version 5.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 19/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Rate control versus rhythm control in AFFIRM Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that was likely to be recurrent were randomly assigned to rhythm or rate control. The primary end point was overall mortality. There was an almost significant trend toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio 0.87, 95 percent CI 0.75 to 1.01). Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825. Graphic 61608 Version 3.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 20/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Rate control versus rhythm control in RACE Results of the RACE trial in which 522 patients with recurrent persistent atrial fibrillation (AF) were randomly assigned to rhythm or rate control. The primary end point was a composite of cardiovascular death, heart failure, thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug side effects. There was an almost significant trend toward a lower incidence of the primary end point with rate control (17.2 versus 22.6 percent with rhythm control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01). Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002; 347:1834. Graphic 74434 Version 3.0 https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 21/22 7/5/23, 9:15 AM Management of atrial fibrillation: Rhythm control versus rate control - UpToDate Contributor Disclosures Kapil Kumar, MD No relevant financial relationship(s) with ineligible companies to disclose. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/management-of-atrial-fibrillation-rhythm-control-versus-rate-control/print 22/22
7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Mechanisms of atrial fibrillation : Brian Olshansky, MD, Rishi Arora, MD : Bradley P Knight, MD, FACC, Hugh Calkins, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION Atrial fibrillation (AF) is a most common cardiac arrhythmia. The chance of developing AF is tied closely to age, with AF rare before the age of 50 years [1]. In addition to age, there are many types of cardiac and medical conditions that are also closely linked to AF. These include hypertension, coronary artery disease, heart failure, valvular heart disease, obesity [2], and sleep-apnea syndrome. It is well established that high levels of alcohol [3] can increase the probability of developing AF, and that hyperthyroidism can cause AF. Evidence for caffeine and energy drinks, while suspected, is questionable [4]. Furthermore, while exercise can be protective against atrial fibrillation, endurance athletics may be a cause for atrial fibrillation [5]. It is also well established that AF is more common in individuals who have a first-degree relative who developed AF at a young age. There is also a variety of acute conditions that can initiate AF such as cardiac surgery, pulmonary embolus, and inflammatory lung conditions. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) The precise mechanisms by which age and the other conditions listed above increase the propensity for development of AF are understood poorly ( figure 1). However, these conditions may impact the triggers for AF, which commonly arise in the pulmonary veins or the substrate for maintenance of AF, which broadly relates to atrial size and the extent of fibrosis. Some of the factors that may play a role in the mechanisms of AF include autonomic tone, inflammation, atrial pressure and wall stress, and genetics. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Other factors'.) https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 1/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate This topic will provide a broad overview of the current understanding of the mechanisms of AF. This discussion will provide a relatively simplistic approach to a complex topic. The reader will be referred to a rapidly growing literature on this topic, including some comprehensive reviews [6]. DEFINITIONS The following terms are defined to help the reader s understanding of the material below: Trigger a rapidly firing focus often arising in the pulmonary veins that can initiate atrial fibrillation (AF). Triggered activity One of three mechanisms of cardiac arrhythmias (including automaticity and reentry). Triggered activity refers to additional depolarizations, which occur during or immediately following a cardiac depolarization and may cause a sustained cardiac arrhythmia. Substrate Mechanical and anatomic structure of the atria in which AF can occur. Substrate remodeling Changes in the mechanical and anatomic macro, micro, and ultrastructure of the atrial substrate that result from the development of AF and increase the propensity for the development and maintenance of AF over time. Electrical remodeling Changes in the atrial electrical properties (refractoriness and conduction) that result from the development of AF and increase the propensity for the development and maintenance of AF over time. Dispersion of refractoriness A range of differences in the refractory period properties throughout the atrial tissue. Spatial heterogeneity of refractoriness Dispersion of refractoriness manifest as variability in refractoriness throughout the atrial anatomy. Complex fractionated electrograms Local electrograms obtained from areas of the atrium that are rapid, of low amplitude, and have multiple components. Reentry/reentrant mechanism One of three mechanisms of cardiac arrhythmias (including automaticity and triggered activity). Reentry is the most common mechanism of cardiac arrhythmias and refers to the presence of one or more electrical circuit(s) in which electrical activation proceeds in a circular fashion to complete a self-sustaining circuit. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 2/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Atrial anisotropy Conduction properties related to directionality of conduction through atrial tissue. BASIC ATRIAL ELECTROPHYSIOLOGY The electrophysiologic properties of normal and fibrillating atria have been studied extensively [7]. A basic understanding of these properties is necessary to understand the pathologic processes that play a role in initiating and perpetuating atrial fibrillation (AF). In the aggregate, these electrophysiologic properties permit the development of very complex patterns of conduction and an extremely rapid atrial rate as seen in AF. The atrial myocardium consists of so-called "fast-response" tissues that depend on the rapidly activating sodium current for phase 0 of the action potential. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Normal atrial myocardium has the following properties [7-9]: A short action-potential duration. Cellular reactivation can occur rapidly due to the short refractory period (in contrast to Purkinje fibers and ventricular muscle). Very rapid electrical conduction can occur. The refractory period shortens with increasing rate. In the aggregate, these electrophysiologic properties permit the development of very complex patterns of conduction and an extremely rapid atrial rate as seen in AF. CLINICAL FACTORS ASSOCIATED WITH AF The following are common clinical conditions associated with atrial fibrillation (AF) in developed countries, and the percent of AF cases in which they are found (see "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Chronic disease associations') [6]: Hypertension (60 to 80 percent). Cardiovascular disease, including cardiomyopathy, valvular and coronary artery disease (25 to 30 percent). New York Heart Association class II to IV heart failure (30 percent). https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 3/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Diabetes (20 percent). Age. Each of the first three is associated with left atrial dilatation, which is important in the development of a substrate for AF and also may increase the probability of electrical firing from the pulmonary veins. (See 'Mechanisms of atrial fibrillation: triggers and substrates' below.) The following section will discuss the link between these conditions and AF. MECHANISMS OF ATRIAL FIBRILLATION: TRIGGERS AND SUBSTRATES Atrial fibrillation (AF) may present as a paroxysmal (self-terminating AF within seven days), a persistent (one that lasts greater than seven days), or a long-standing persistent AF (continuous AF for 12 months or greater). The term permanent AF should be used when both the patient and physicians agree to not pursue strategies to restore or maintain sinus rhythm. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Classification and terminology'.) This wide range of clinical presentations is likely due to an interaction between a trigger and the substrate ( figure 1). AF is initiated by rapid firing (or triggers) from the pulmonary veins (PV). Early in the course of AF the atrium is relatively healthy and as a result sinus rhythm is spontaneously restored. As the substrate remodels further over time, AF no longer terminates spontaneously and becomes persistent. With more extensive remodeling of the atrium, it becomes increasingly difficult to maintain sinus rhythm and the patient and physician may agree no longer to attempt to maintain sinus rhythm, with the AF thereby being considered permanent [10]. Triggers of AF It has been known for many years that a single focus firing rapidly in the atria can be a trigger for fibrillatory conduction throughout the atria [11]. It is now well established that the most common site of the rapid atrial firing that triggers AF is the PVs. Catheter ablation of AF depends in large part on the electrical isolation of the PVs from the remainder of the atrium. Electrophysiologic evaluation of the PVs has identified myocardial tissue that can lead to repetitive firing or even the presence of episodic reentrant activation in the veins [6]. Additionally, stretch can increase the propensity for rapid firing from the PVs as a result of stretch sensitive ion channels. [12]. It has been speculated that the mechanism of atrial stretch may help explain the association between AF and mitral regurgitation as well as various types of heart failure. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 4/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Role of premature atrial complex and other arrhythmia triggers AF is initiated (triggered) predominantly by rapid firing from PVs. Much less commonly, AF can be triggered by non-PV sites of rapid firing (such as tissue near the PV including the Vein of Marshall, the superior vena cava, or coronary sinus) or by other types of supraventricular arrhythmias including atrioventricular nodal reentrant tachycardia (AVNRT), orthodromic AV reciprocating tachycardia, and atrial flutter [6,13-23]. In some patients, successful elimination of AF with catheter ablation requires both isolation of the PVs, as well as elimination of these non-PV triggers. (See "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) Role of atrial flutter and supraventricular tachycardias Atrial tachycardia, atrial flutter, and other supraventricular tachycardias can initiate AF in predisposed patients. The interaction between these arrhythmias and AF is not well understood, but atrial flutter and AF commonly coexist. In some instances, elimination of atrial flutter will diminish and/or eliminate episodes of AF. Nevertheless, elimination of the right atrial reentry circuit responsible for typical flutter frequently does not eliminate the predisposition to AF that is predominately a left-atrial problem in a large number of patients. Many studies have demonstrated that patients who undergo catheter ablation of typical atrial flutter have a very high probability of developing AF over the ensuing five years. This is true regardless of whether AF had been observed prior to development of typical atrial flutter. This has clinical implications when it comes to ablation, but also has implications for anticoagulation strategies and patient follow-up. Nevertheless, for most patients, it makes sense to try to eliminate the organized supraventricular tachycardia, especially if right-sided by ablation before considering PV isolation and/or other more extensive ablation procedures to eliminate AF, as the AF may be reduced or eliminated by eliminating the other tachycardia first. Role of the autonomic nervous system The autonomic nervous system plays an important role in the development and maintenance of AF [24-26]. Clinical studies using heart rate variability analysis in patients with AF suggest that fluctuation in autonomic tone may be a major determinant of AF in patients with focal ectopy originating from the PVs [27]. Studies have also demonstrated a change in heart rate variability after PV ablation [28], further suggesting that PV triggers may be at least partially modulated by autonomic activity. Another study showed that the occurrence of paroxysmal AF greatly depends on variations of the autonomic tone, with a primary increase in adrenergic tone followed by an abrupt shift toward vagal predominance [29]. Anatomic studies of the autonomic innervation of the atria also indicate that the PVs and posterior left atrium (PLA) have a unique autonomic profile with a rich innervation from sympathetic and parasympathetic nerves [30-35]. The autonomic nervous system may also be https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 5/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate playing a role in the genesis of AF in diseased hearts [30,36,37]. Studies suggest that the parasympathetic and sympathetic nervous system may also be playing a role in creation of AF substrate in the setting of heart failure [36,37]. Both the sympathetic and parasympathetic nervous systems have been implicated in the genesis [30,38,39] and maintenance of AF: Sympathetic effects Early studies suggested that exercise-induced AF may be sympathetically driven [30,40]. PV ectopic foci appear to be at least partially modulated by autonomic signaling, with sympathetic stimulation with isoproterenol frequently utilized to elicit these triggers in patients undergoing ablation for AF [41]. Parasympathetic (vagal) effects The parasympathetic nervous system may contribute to AF in young patients with no structural heart disease [42]. Animal studies show that vagal stimulation contributes to the genesis of AF by nonuniform shortening of atrial effective refractory periods, thereby setting up substrate for reentry. Vagal stimulation can also lead to the emergence of focal triggers in the atrium [43-45]. Bezold-Jarisch-like "vagal" reflexes can be elicited during radiofrequency ablation and occur in and around the PVs. It has been suggested that elimination of these vagal reflexes during ablation may improve efficacy of AF ablation procedures [46]. Vagal responsiveness also appears to decrease following ablation in the left atrium [47]. In some series, adding ganglionated plexi (GP) ablation to PV isolation appears to increase ablation success for AF [12]. Data suggest that areas in the atrium demonstrating complex fractionated atrial electrograms (CFAE) may represent a suitable target site for ablation; although several studies have reported that ablation at these sites may increase the efficacy of PV isolation procedures [48,49], enthusiasm for this approach has fallen over time. One possible explanation for the improvement in ablation success reported in these trials is that several CFAE sites anatomically overlie fat pads containing GPs [18,50]. As indicated above, autonomic denervation performed by GP ablation is thought to improve efficacy of AF ablation. (See "Atrial fibrillation: Catheter ablation" and "Catheter ablation for the treatment of atrial fibrillation: https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 6/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Technical considerations for non-electrophysiologists", section on 'Ablation techniques and targets'.) In a study of 40 patients with paroxysmal AF scheduled to undergo catheter ablation, individuals were randomly assigned to noninvasive transcutaneous low-level stimulation of the tragus (the anterior protuberance of the ear where the auricular branch of the vagus nerve is accessible) or to sham stimulation for one hour. Compared with control, low-level stimulation suppressed AF as measured by the decreased duration of atrial pacing-induced AF and an increased AF cycle length [51]. Maintenance of atrial fibrillation In patients with persistent AF, the prevailing understanding of the mechanism is that, once triggered, the arrhythmia is maintained (sustained) by one or more abnormalities in the atrial tissue. This process may explain why the failure rate of PV isolation is as high as 40 to 60 percent at one year: The trigger(s) may have been treated but not the abnormalities that sustain AF once triggered (initiated). The role of localized sources (electrical rotors and focal impulses) in the initiation and maintenance of AF was explored in the CONFIRM trial of 92 patients undergoing ablation procedures for paroxysmal or persistent (72 percent) AF [52]. Consecutive patients were prospectively treated (not randomly assigned) in a 1:2 case-cohort design with either conventional ablation at sources identified within the atria followed by conventional ablation or conventional ablation alone. Localized sources were identified in 97 percent of cases (70 percent rotors and 30 percent focal impulses) with sustained AF, each with an average of 2.1 sources. During a median of 273 days, patients treated with treatment of both sources and conventional ablation had a significantly higher freedom from AF (82.4 versus 44.9 percent). Similar information was reported, indicating that driver domains, located in specific areas of the atria, act as unstable re-entry circuits that perpetuate atrial fibrillation in patients who have persistent AF [53,54]. Murine cell cultures show a differential ion channel gene expression associated with atrial tissue remodeling (ie, decreased SCN5A, CACN1C, KCND3, and GJA1; and increased KCNJ2) [55]. Fibrillatory complexity, increased in late compared with early stage cultures, was associated with a decrease in rotor tip meandering and increase in wavefront curvature. Rotors are not the only explanation. In a study using high-density, simultaneous, biatrial, epicardial mapping of persistent and longstanding persistent AF in patients undergoing open heart surgery, several non-reentrant drivers were present in both atria in 11 or 12 patients with two to four foci per patient; foci were seen in both atria but generally in the lateral left atrial free wall, and likely acted as drivers. Reentry was not found to be the mechanism [56]. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 7/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Likely, the substrate to maintain AF is a combination of reentrant activity and focal triggers. In a study of biatrial epicardial mapping of AF in sheep, wave propagation patterns were passing wave (69 percent occurrence, 68.6 percent of total time), point source (20.4, 13.1 percent), wave collision (4, 2.8 percent), reentrant wave (0.7, 6.3 percent), half-rotation (2.9, 4.4 percent), wave splitting (2.7, 4.3 percent), conduction block (0.05, 0.03 percent) and figure of eight reentry (0.05, 0.05 percent) [57]. Periods of repetitive activity were detected in the left and right atria. The following sections describe factors that might contribute to the maintenance of AF. Atrial remodeling Atrial remodeling involves the concept that there are structural changes, such as fibrosis, or electrical changes, such as refractory-period dispersion or conduction display, in the atria that can predispose to the development and maintenance of AF. In some instances, structural and electrical changes occur simultaneously. These processes can facilitate or create electrical reentrant circuits or triggers that can lead to AF [13,58]. It is also well established that the presence of AF results in remodeling of the atrium over time [7]. This explains the well-established concept that AF begets AF ( figure 2). Thus, the longer a patient has been in continuous AF, the less likely it is to terminate spontaneously, and harder it is to restore and maintain sinus rhythm [59]. Electrical remodeling Paroxysmal AF commonly precedes chronic AF. It has been suggested even after only a few minutes, AF induces transient changes in atrial electrophysiology that promote its perpetuation [14]. This might occur through a tachycardiomyopathy or through "electrical remodeling" of the atria by AF, leading to a progressive decrease in atrial refractoriness [14,15]. Electrical remodeling results from the high rate of electrical activation, which stimulates the AF-induced changes in refractoriness [60]. Tachycardia-induced changes in refractoriness are spatially nonuniform and there is increased variability both within and among various atrial regions [61]. It is possible that the change in atrial refractory period observed after an episode of AF predisposes to the spontaneous recurrence of AF in the days following cardioversion. In addition to the shortening of the refractory period, chronic, rapid, atrial pacing-induced AF results in other changes within the atria, including an increase in the expression and distribution of connexin 43 and heterogeneity in the distribution of connexin 40, both of which are intercellular gap junction proteins ("gap junctional remodeling") [16,17]; cellular remodeling is due to apoptotic death of myocytes with myolysis, which may not be entirely reversible [18]; the induction of sinus node dysfunction, demonstrated by prolonged corrected sinus node recovery time, reduced maximal heart rate in response to isoproterenol, and lower intrinsic heart rate after administration of atropine and propranolol [19]; and an increase in P wave duration and intraatrial conduction time. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 8/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate A clinical study evaluated the hypothesis of electrical remodeling by the use of atrial pacing- induced AF in patients with a history of supraventricular tachycardia [20]. AF significantly shortened the right-atrial effective refractory period after only a few minutes, and temporal recovery of the refractory period occurred over about eight minutes. Upon termination of AF, there was an increased propensity for the induction of another episode of AF that decreased with increasing time after the initial AF reversion. The second also tends to last longer than the first. The time to recurrence was also evaluated in a review of 61 patients who had daily electrocardiogram (ECG) recordings using transtelephonic monitoring: 57 percent had recurrent AF during the first month after cardioversion, with a peak incidence during the first five days [21]. Among patients with recurrence, there was a positive correlation between the duration of the shortest coupling interval of premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) after cardioversion, which correlates with the refractory period and the timing of recurrence ( figure 3). (See "Atrial fibrillation: Cardioversion".) In contrast to the normal situation in which the atrial refractory period shortens with an increase in rate (as in AF) and prolongs when the rate decreases, the refractory period fails to lengthen appropriately at slow rates (eg, with return to sinus rhythm) in patients with acute or chronic AF. The duration of AF has no significant impact upon the extent of these electrophysiologic changes [22]. Atrial electrical remodeling is reversed gradually after the restoration of sinus rhythm [23,62]. This may be one of the explanations for the early or immediate return of AF after cardioversion. In one study of 25 patients, the atrial refractory period increased and the adaptation of atrial refractoriness to rate was normal by four weeks after cardioversion [23]. In another report of 38 patients, the atrial refractory period increased by one week, with some variation in different regions of the atrium [62]. This observation has important clinical implications. The mechanism for electrical remodeling and shortening of the atrial refractory period is not entirely clear; a possible explanation is ion-channel remodeling, with a decrease in the protein content of the L-type calcium channel [63]. Support for this comes from an animal study in which verapamil, an L-type calcium antagonist, prevented electric remodeling of short-duration AF (one day or less) and hastened complete recovery, without affecting inducibility of AF [64]. Similar findings have been noted in humans as verapamil, but not procainamide, prevented remodeling when given prior to the electrophysiologic induction of AF [65]. Oral diltiazem is also effective in some patients [66], while beta blockers had no effect on electrical remodeling in an animal model [60]. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 9/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate In comparison, cytosolic calcium overload, induced by hypercalcemia or digoxin, which increases the intracellular concentration of calcium by activating the sodium-calcium exchanger, enhances electrical remodeling [64,67,68]. The effect of digoxin, which is not due to its vagotonic activity, is associated with an increase in the inducibility and duration of AF [68]. Calcium leak from the sarcoplasmic reticulum may trigger and maintain AF. It is known that protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2), resulting in dissociation of the channel-stabilizing subunit calstabin2, causes sarcoplasmic reticulum (SR) calcium leak in failing hearts. This phenomenon seems to be involved in triggering ventricular arrhythmias. Using similar logic, these proteins were investigated in atrial tissues from both dogs and humans with AF [69]. Atrial tissue in those with AF showed a significant increase in PKA phosphorylation of RyR2 and a decrease in calstabin2 binding to the channel. Channels isolated from dogs with AF had an increased open probability under conditions simulating diastole compared with channels from control hearts, suggesting that these AF channels could predispose to a diastolic SR calcium leak. The conclusion was that SR calcium leak due to RyR2 PKA hyperphosphorylation may play a role in the initiation and/or maintenance of AF. Other studies also suggest that RyR2 receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model [70,71]. The effects of calcium overload are quite complex. It is likely that triggers and substrates initiate short episodes of AF that then lead to calcium overload and over a period of minutes there is activation of the I current that increases I , decreases I , increases I , and decreases CaL K1 Na KACh I . This can affect the action-potential duration and allow for more reentry to occur. As reentry TO occurs, the substrate changes and there is remodeling through calcium handling abnormalities as well as mRNA transcription [59], and ultimately perhaps with protein decrease, changes in connexons, including, Cx40, that can affect conduction. The calcium-handling abnormalities can also lead to hypocontractility and atrial dilatation, thereby affecting even more the possibility of developing AF [59]. Both animal and human studies suggest that angiotensin II is involved in electrical and atrial myocardial remodeling [72,73] (see "Pathophysiology of heart failure: Neurohumoral adaptations", section on 'Renin-angiotensin system'). In an animal model, inhibition of angiotensin II with captopril or candesartan prevented shortening of the atrial effective refractory period and atrial electrical remodeling during rapid atrial pacing [72], while atrial tissue obtained during open heart surgery from patients with AF revealed downregulation of AT1 receptor proteins and upregulation of AT2 receptor [73]. The potential clinical importance of these changes is illustrated by the observations that angiotensin converting enzyme (ACE) https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 10/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate inhibitors reduce the incidence of AF in patients with left ventricular dysfunction after myocardial infarction [74] and in patients with chronic left ventricular dysfunction due to ischemic heart disease [75]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".) Another possible contributor to electrical remodeling and shortening of the atrial refractory period is atrial ischemia, which activates the sodium/hydrogen exchanger. The intravenous administration of HOE 642, a selective inhibitor of this sodium proton pump, to dogs undergoing rapid atrial pacing resulted in the lengthening of atrial refractoriness after one hour, while control dogs showed effective refractory-period shortening greater than 10 percent [76]. Role of fibrosis The development of AF invokes atrial remodeling processes that involve electrophysiological and structural alterations that serve to maintain, promote, and propagate AF. In addition to electrophysiological alterations, such as shortening of the atrial action potential, increased dispersion of refractoriness, and conduction velocity shortening, morphological changes consist of fibrosis, hypertrophy, necrotic and apoptotic cell loss, and dilation [77]. Of these, fibrosis is considered especially important in the creation of AF substrate, especially in the setting of chronic atrial dilatation caused by heart failure. A canine model of heart failure has demonstrated a progressive increase in AF inducibility with increasing fibrosis [78]. An increase in conduction heterogeneity noted in this model is thought to play a major role in the creation of reentrant circuits in the dilated atria. Patients with AF also display increased atrial fibrous tissue content, along with increased expression of collagen I and III [79], as well as up-regulation of MMP-2 protein, and down-regulation of the tissue inhibitor of metalloproteinase, TIMP-1 [79]. Expression of the active form of MMP-9 and of monocyte chemoattractant protein-1, an inflammatory mediator, is increased in AF patients [80]. The left atrial free wall around the PV area presents particularly strong interstitial fibrotic changes [81-83]. Although the underlying molecular mechanisms that lead to the development of atrial fibrosis are complex, work suggests that the TGF- pathway may be an important contributor to the development of fibrosis (especially in the setting of increasing atrial stretch/dilatation resulting from congestive heart failure) [84-86]. Role of inflammation and oxidative stress Emerging evidence suggests a significant role of inflammation in the pathogenesis of AF [87]. Evidence includes elevated serum levels of inflammatory biomarkers in patients with AF, the expression of inflammatory markers in atrial tissue from AF patients, and beneficial effects of antiinflammatory drugs in the setting of experimental AF [88]. Inflammation is suggested to be linked to various pathological processes, https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 11/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate such as oxidative stress, apoptosis, and fibrosis that promote the creation and perpetuation of AF substrate. Several of the downstream effects of inflammation in the heart are thought to be mediated by oxidative stress [89]. Indeed, studies in patients with AF demonstrate increased generation of reactive oxygen species (ROS) in the fibrillating atrium compared with normal atria [90,91]. Several major enzymatic sources of ROS have been implicated in AF. Of these, NAPDH oxidase (specifically its NOX2 isoform) has been shown to be elevated in humans with AF in a variety of studies [92,93]. Other sources of ROS implicated in AF include uncoupled nitric oxide synthase [94] and xanthine oxidase [95]. In addition to the increase in ROS noted in tissue from patients with AF, experimental evidence suggests that ROS may be implicated not only in promoting AF but also in maintaining atrial arrhythmia. The administration of antioxidants such as vitamin C or statins (which are known to have pleiotropic antioxidant effects) decreased AF inducibility in canine models of tachypacing-induced AF [96,97]. Antioxidants such as vitamin C and n-acetylcysteine have been administered to patients undergoing cardiac surgery and have been shown to decrease postoperative AF [98,99]. These early results are encouraging and warrant further investigation of inflammation and oxidative stress as viable therapeutic targets in patients with AF. Reentrant mechanism Maps of AF in animals and humans suggest that this arrhythmia is caused by multiple wandering wavelets ( figure 4), and these may be due to heterogeneity of atrial refractoriness and conduction. In addition, the response of atrial activity to adenosine infusion suggests a reentrant rather than a focal mechanism [100]. Adenosine increases the inward potassium rectifier current, which shortens refractory periods and would accelerate reentrant circuits. In contrast, this effect would slow an automatic or triggered focus. In a series of 33 patients with AF undergoing electrophysiology study, adenosine increased the dominant frequencies, supporting reentrant rather than focal sources for the perpetuation of AF. It has been suggested that at least four to six independent wavelets are required to maintain AF [101]. These wavelets rarely reenter themselves but can re-excite portions of the myocardium recently activated by another wavefront, a process called random reentry [7,102-104]. As a result, there are multiple wavefronts of activation that may collide with each other, extinguishing themselves or creating new wavelets and wavefronts, thereby perpetuating the arrhythmia ( figure 5). The reentrant circuits are therefore unstable; some disappear, while others reform. These circuits have variable but short cycle lengths, resulting in multiple circuits to which atrial tissue cannot respond in a 1:1 fashion. As a result, functional block, slow conduction, and multiple wave fronts develop [104]. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 12/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Patients with AF may have increased dispersion of refractoriness. This correlates with enhanced inducibility of AF and spontaneous episodes [105] likely related to unstable reentry circuits. Some patients have site-specific dispersion of atrial refractoriness and intraatrial conduction delays resulting from nonuniform atrial anisotropy [106]. This appears to be a common property of normal atrial tissue, but there are further conduction delays to and within area surrounding the AV node in patients with induced AF, suggesting an important role for the low right atrium in the genesis of AF. Abnormalities in restitution as well as the spatial distribution of such abnormalities can be related to the persistence of AF. In one study, monophasic action potential recordings were evaluated in patients with AF [107]. The action potential duration was plotted as a function of the preceding diastolic interval, and the slope of the action potential duration versus the diastolic interval (the restitution curve) was determined. If the slope was greater than one, oscillations occurred that may cause localized conduction delay or block resulting in a wave break giving rise to atrial fibrillation. These different patterns of conduction are reflected in the morphology of electrograms recorded with mapping during induced AF. Single potentials were indicative of rapid uniform conduction, short double potentials indicated collision, long double potentials were indicative of conduction block, while fragmented potentials were markers for pivoting points or slow conduction ( figure 6) [108,109]. Sites of fragmented potentials or complex fractionated atrial electrograms are potential targets for radiofrequency ablation to terminate AF as they may represent critical areas from which AF originates and perpetuates. (See "Atrial fibrillation: Catheter ablation".) This phenomenon has been termed microreentry to distinguish it from classic reentry in which the same reentrant pathway is repetitively traversed. The impulse may circulate around a central line of functional block, so-called leading circle reentry; this type of reentry tends not to be stable but rather to drift through the atria until it is extinguished. The perpetuation of AF may also depend importantly upon macroreentry around natural orifices and structures in the atrium, which provides a rationale and anatomic landmarks for ablative treatment. The collision of wavefronts cancels many atrial depolarizations that might otherwise reach the AV node, resulting in a slower heart rate than might otherwise have occurred ( figure 7A-B). Although multiple wandering wavelets probably account for the majority of AF, one study reported nine patients in whom a single, rapidly firing focus was identified with electrophysiologic mapping [110]. Organized and rapid atrial activity with a centrifugal and consistent pattern of atrial activation resulted from this focus, but it fired irregularly with striking https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 13/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate and abrupt changes in atrial cycle lengths. In most of the patients, the focus was near the ostia of great vessels and was amenable to radiofrequency ablation ( figure 8 and figure 9). Small reentrant sources, called rotors, may drive or maintain AF in some cases. These rotors result in a hierarchical distribution of frequencies throughout the atria that may be identified with spectral analysis of intracardiac recordings. Ablation of such sites has terminated paroxysmal AF, suggesting that they may play an important role [111], but it is not clear that the rotors are responsible for AF or are fixed in most instances. AF may be chaotic and have wavelets and rotors that are secondary rather than the predominant cause of AF [112]. However, antral pulmonary venous reentrant and focal drivers may be responsible for AF [54]. The complexity of such drivers increase with prolonged AF. These sites are often localized near the PV orifices in patients with paroxysmal AF, and are more often localized to the left or right atria in patients with chronic AF [100]. The fibrillating atrium cannot be captured by pacing when the atrial electrograms are disorganized. This observation supports the presence of microreentry, since there is no excitable gap (or it is very small) to permit capture. However, when type I ( figure 9) AF (which has organized atrial electrograms) is induced by rapid atrial pacing, the fibrillating atrium can be captured with rapid atrial pacing, suggesting the presence of an excitable gap [113]. ROLE OF THE ATRIOVENTRICULAR NODE The atrioventricular (AV) node regulates the number of atrial impulses that reach the ventricle. The ventricular rate in atrial fibrillation (AF) is typically irregularly irregular, with a ventricular rate that may be slow, moderate, or rapid depending on the capacity of the AV node to conduct impulses. The rate of AV nodal conduction is dependent upon multiple factors, including electrical properties of the node and the influence of the autonomic nervous system [114]. In addition, the use drugs such as digoxin, calcium channel blockers, or beta blockers may influence AV nodal function. There also may be a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [115]. AV nodal tissue consists of so-called "slow response" fibers, which depend on a mixed
experimental evidence suggests that ROS may be implicated not only in promoting AF but also in maintaining atrial arrhythmia. The administration of antioxidants such as vitamin C or statins (which are known to have pleiotropic antioxidant effects) decreased AF inducibility in canine models of tachypacing-induced AF [96,97]. Antioxidants such as vitamin C and n-acetylcysteine have been administered to patients undergoing cardiac surgery and have been shown to decrease postoperative AF [98,99]. These early results are encouraging and warrant further investigation of inflammation and oxidative stress as viable therapeutic targets in patients with AF. Reentrant mechanism Maps of AF in animals and humans suggest that this arrhythmia is caused by multiple wandering wavelets ( figure 4), and these may be due to heterogeneity of atrial refractoriness and conduction. In addition, the response of atrial activity to adenosine infusion suggests a reentrant rather than a focal mechanism [100]. Adenosine increases the inward potassium rectifier current, which shortens refractory periods and would accelerate reentrant circuits. In contrast, this effect would slow an automatic or triggered focus. In a series of 33 patients with AF undergoing electrophysiology study, adenosine increased the dominant frequencies, supporting reentrant rather than focal sources for the perpetuation of AF. It has been suggested that at least four to six independent wavelets are required to maintain AF [101]. These wavelets rarely reenter themselves but can re-excite portions of the myocardium recently activated by another wavefront, a process called random reentry [7,102-104]. As a result, there are multiple wavefronts of activation that may collide with each other, extinguishing themselves or creating new wavelets and wavefronts, thereby perpetuating the arrhythmia ( figure 5). The reentrant circuits are therefore unstable; some disappear, while others reform. These circuits have variable but short cycle lengths, resulting in multiple circuits to which atrial tissue cannot respond in a 1:1 fashion. As a result, functional block, slow conduction, and multiple wave fronts develop [104]. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 12/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Patients with AF may have increased dispersion of refractoriness. This correlates with enhanced inducibility of AF and spontaneous episodes [105] likely related to unstable reentry circuits. Some patients have site-specific dispersion of atrial refractoriness and intraatrial conduction delays resulting from nonuniform atrial anisotropy [106]. This appears to be a common property of normal atrial tissue, but there are further conduction delays to and within area surrounding the AV node in patients with induced AF, suggesting an important role for the low right atrium in the genesis of AF. Abnormalities in restitution as well as the spatial distribution of such abnormalities can be related to the persistence of AF. In one study, monophasic action potential recordings were evaluated in patients with AF [107]. The action potential duration was plotted as a function of the preceding diastolic interval, and the slope of the action potential duration versus the diastolic interval (the restitution curve) was determined. If the slope was greater than one, oscillations occurred that may cause localized conduction delay or block resulting in a wave break giving rise to atrial fibrillation. These different patterns of conduction are reflected in the morphology of electrograms recorded with mapping during induced AF. Single potentials were indicative of rapid uniform conduction, short double potentials indicated collision, long double potentials were indicative of conduction block, while fragmented potentials were markers for pivoting points or slow conduction ( figure 6) [108,109]. Sites of fragmented potentials or complex fractionated atrial electrograms are potential targets for radiofrequency ablation to terminate AF as they may represent critical areas from which AF originates and perpetuates. (See "Atrial fibrillation: Catheter ablation".) This phenomenon has been termed microreentry to distinguish it from classic reentry in which the same reentrant pathway is repetitively traversed. The impulse may circulate around a central line of functional block, so-called leading circle reentry; this type of reentry tends not to be stable but rather to drift through the atria until it is extinguished. The perpetuation of AF may also depend importantly upon macroreentry around natural orifices and structures in the atrium, which provides a rationale and anatomic landmarks for ablative treatment. The collision of wavefronts cancels many atrial depolarizations that might otherwise reach the AV node, resulting in a slower heart rate than might otherwise have occurred ( figure 7A-B). Although multiple wandering wavelets probably account for the majority of AF, one study reported nine patients in whom a single, rapidly firing focus was identified with electrophysiologic mapping [110]. Organized and rapid atrial activity with a centrifugal and consistent pattern of atrial activation resulted from this focus, but it fired irregularly with striking https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 13/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate and abrupt changes in atrial cycle lengths. In most of the patients, the focus was near the ostia of great vessels and was amenable to radiofrequency ablation ( figure 8 and figure 9). Small reentrant sources, called rotors, may drive or maintain AF in some cases. These rotors result in a hierarchical distribution of frequencies throughout the atria that may be identified with spectral analysis of intracardiac recordings. Ablation of such sites has terminated paroxysmal AF, suggesting that they may play an important role [111], but it is not clear that the rotors are responsible for AF or are fixed in most instances. AF may be chaotic and have wavelets and rotors that are secondary rather than the predominant cause of AF [112]. However, antral pulmonary venous reentrant and focal drivers may be responsible for AF [54]. The complexity of such drivers increase with prolonged AF. These sites are often localized near the PV orifices in patients with paroxysmal AF, and are more often localized to the left or right atria in patients with chronic AF [100]. The fibrillating atrium cannot be captured by pacing when the atrial electrograms are disorganized. This observation supports the presence of microreentry, since there is no excitable gap (or it is very small) to permit capture. However, when type I ( figure 9) AF (which has organized atrial electrograms) is induced by rapid atrial pacing, the fibrillating atrium can be captured with rapid atrial pacing, suggesting the presence of an excitable gap [113]. ROLE OF THE ATRIOVENTRICULAR NODE The atrioventricular (AV) node regulates the number of atrial impulses that reach the ventricle. The ventricular rate in atrial fibrillation (AF) is typically irregularly irregular, with a ventricular rate that may be slow, moderate, or rapid depending on the capacity of the AV node to conduct impulses. The rate of AV nodal conduction is dependent upon multiple factors, including electrical properties of the node and the influence of the autonomic nervous system [114]. In addition, the use drugs such as digoxin, calcium channel blockers, or beta blockers may influence AV nodal function. There also may be a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [115]. AV nodal tissue consists of so-called "slow response" fibers, which depend on a mixed calcium/sodium current. This current is often called the inward calcium current, since in a normal physiologic environment, the ions are almost exclusively calcium. The mixed current uses a kinetically slow channel and is responsible for phase 0 depolarization. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 14/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate These characteristics lead to properties that are quite different from "fast-response" tissue in the atria, which as noted above, depend on an inward sodium current that uses a kinetically fast channel for phase 0 depolarization [8,116]: Partial and complete reactivation returns only 100 ms or more after return to the diastolic potential (versus 10 to 50 ms in the atria). The refractory period changes little as a function of rate. Conduction velocity is relatively slow, ranging from 0.01 to 0.1 m/s. Unlike tissue generating a fast action potential that has an all-or-none response (ie, the velocity of impulse conduction is similar at all stimulation rates until block occurs), tissue that generates a slow action potential exhibits a graded or decremental response, in which the velocity of impulse conduction slows as the stimulation rate increases. As noted above, the ventricular rate usually ranges 90 and 170 beats/min. Ventricular rates below 60 beats/min are seen with AV nodal disease, drugs that affect conduction, and high vagal tone as can occur in a well-conditioned athlete. Ventricular rates above 200 beats/min suggest catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract as occurs in the preexcitation syndrome. The QRS complexes are widened in the last setting and must be distinguished from a rate-related or underlying bundle branch block. In the classical view, the AV node is bombarded by impulses from the fibrillating atria. Some impulses traverse the AV node and reach the specialized infranodal conduction system and then the ventricles. However, most atrial impulses penetrate the AV node from varying distances and then are extinguished when they encounter the refractoriness of an earlier wavefront; this phenomenon of concealed conduction in turn creates a refractory wave that affects succeeding impulses. The failure of the refractory period to shorten with increasing rate (as occurs in the atria) further decreases the likelihood of an impulse traversing the AV node. Anatomically distinct AV nodal inputs, called the slow and fast pathways, are involved in the ventricular response to AF. The importance of these pathways has been demonstrated in radiofrequency ablation studies in which ablation reduced the number of beats that successfully reached the infranodal conduction system and the ventricles [117-120]. (See "Atrioventricular nodal reentrant tachycardia".) In addition to its intrinsic properties, the AV node is richly supplied and affected by both components of the autonomic nervous system. AV conduction is enhanced and refractoriness https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 15/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate reduced by the sympathetic fibers, and conduction reduced and refractoriness prolonged by the parasympathetic fibers. The net effect of the electrophysiologic properties of the AV node is that the rate of conduction into the specialized infranodal conduction system is (fortunately) much slower than the rate of the fibrillating atria. In some cases, the high degree of refractoriness in the AV node with AF results in high-grade or third-degree block. In this setting, the pacemaker that controls the ventricles is below the AV node. (See "The electrocardiogram in atrial fibrillation".) In patients with the preexcitation syndrome, the AV node is bypassed by "fast-response" tracts, which activate and reactivate much faster than the AV node and are therefore capable of rapid conduction. The development of AF in such a patient can result in very rapid transmission of atrial impulses to the ventricles [120] and can rarely cause ventricular fibrillation [15]. (See "The electrocardiogram in atrial fibrillation".) It is also important to recognize that the presence of an accessory pathway can increase the propensity for development of AF. In patients with AF who have Wolff-Parkinson-White (WPW) syndrome, catheter ablation of the accessory pathway is indicated to lower the sudden death risk but also to decrease the probability of recurrent AF. Unexpected ventricular rates The ventricular response to AF characteristically is irregularly irregular although it may appear regular in the presence of complete AV block. The usual ventricular rate in AF is between 90 and 170 beats per minute in the absence of AV node disease, drugs that affect conduction, or enhanced vagal inputs. Ventricular rates that are clearly outside this range suggest some concurrent problem: A ventricular rate below 60 beats per minute, in the absence of AV nodal blocking agents, suggests AV nodal disease that may be associated with the sinus node dysfunction. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".) A ventricular rate above 170 beats per minute suggests thyrotoxicosis, catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract in the preexcitation syndrome. (See "Epidemiology, risk factors, and prevention of atrial fibrillation".) SPECIFIC CLINICAL SITUATIONS Late recurrent AF after catheter ablation The etiology of late recurrent atrial fibrillation (AF) following pulmonary vein isolation (PVI) has been debated. In some cases, triggering foci outside of the PVs may initiate AF [121-124]. Alternatively, persistence of the substrate for https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 16/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate maintaining AF (abnormal electrical properties of the atria themselves) may be more important than the triggering foci, especially in chronic AF. However, there is increasing evidence that when AF does recur late after PVI, it often represents incomplete electrical isolation of the PVs, either due to resumption of conduction across the ablation scar or to residual conduction in PVs that were not successfully ablated. Most [125-128], but not all [129], studies of the former mechanism support the hypothesis that resumption of PV-left atrial (LA) conduction is associated with an increased risk of recurrent AF. However, recurrent conduction across ablated lesions is more common than clinically evident recurrent AF [127,130]. Pre-existing LA scarring may predispose patients to late recurrence. In a series of 700 consecutive patients undergoing first-time PVI, scarring was detected in 6 percent [131]. These patients had a much higher rate of recurrence than those without scarring (57 versus 19 percent). Possible causes of scarring include atrial remodeling and inflammation. The patients with scarring had significant elevations in serum C-reactive protein (CRP) compared to those without scarring (5.9 versus 0.31 mg/L). This is consistent with other studies showing a relationship between serum CRP and AF [132]. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Inflammation and infection'.) After cardiac surgery AF occurs frequently (approximately one of four patients) after cardiac surgery. Nonuniform atrial conduction is greatest on days two and three in this setting, and the longest atrial conduction time is greatest on day three after open heart surgery; these abnormalities coincide with the time of greatest risk for AF [133]. The degree of atrial inflammation after surgery in dogs was associated with a proportional increase in the inhomogeneity of atrial conduction and in the duration of AF; antiinflammatory therapy decreased the inhomogeneity [134]. Nevertheless, the mechanism of AF in the postoperative period is likely multifactorial. It is important to note that in most of the patients, especially those without a prior history of AF, that the AF is self-limited, and antiarrhythmic drug therapy can usually be stopped two to three months following surgery when the inflammation has subsided. (See "Atrial fibrillation and flutter after cardiac surgery".) Hyperthyroidism It is well established that hyperthyroidism can increase susceptibility to development of AF. As a consequence, all patients with new onset AF should have some measure of thyroid function tested. Successful treatment of the hyperthyroidism often results in elimination of the AF. https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 17/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Obesity Obesity has been associated with AF and it is possible that both are related mechanistically [135]. In a sheep model, weight gain was associated with increased left atrial volume, fibrosis, inflammatory infiltrates, and lipidosis. There was reduced conduction velocity in atrial tissue and increased inducible and spontaneous AF with obesity. Atrial endothelin-A and -B receptors, endothelin-1, atrial interstitial and cytoplasmic transforming growth factor beta1, and platelet-derived growth factor were higher with obesity. In a clinical study of 110 patients undergoing AF ablation versus 20 reference patients without AF, pericardial fat volumes were associated with AF, its chronicity, and its symptom burden. Pericardial fat predicted AF recurrence post-ablation [136]. Associations persisted after adjusting for body weight but body mass index was not associated with these outcomes in multivariate-adjusted models. In another report [137], weight management with subsequent weight loss was associated with improved AF symptom burden scores, symptom severity scores, number of episodes, and cumulative duration of AF. This preliminary information does not yet prove that obesity causes AF by any specific mechanism. In a study of atrial sheep myocytes, acute, short-term incubation in free fatty acids resulted in no differences in passive or active properties of isolated left atrial myocytes but stearic acid reduced membrane capacitance and abbreviated the action potential duration, likely due to a reduction of the L-type calcium and of the transient outward potassium currents [138]. GENETICS OF AF Over the last decade, a preponderance of evidence suggests a large genetic contribution to atrial fibrillation (AF) [139,140]. Having a family member with AF is associated with a 40 percent increased risk for the arrhythmia [141]. Initially, traditional genetic techniques such as linkage analysis led to the discovery of rare, monogenic causes of AF. The first such study identified a genetic locus for AF using a series of related families with early onset AF [142]. A later study identified the first gene for familial AF [143]. Using a large Chinese kindred with autosomal dominant AF, they found a gain-of-function mutation in KCNQ1 (the gene encoding the subunit of the potassium channel current, I ). Since then, several additional gain-of-function variants Ks have been identified in KCNQ1 [144,145]. In addition to KCNQ1, mutations have been identified in other potassium channels genes, including KCNA5 [146], KCND3 [147], and KCNJ2 [148], and accessory subunits KCNE1 [149], KCNE2 [150], KCNE3 [151], and KCNE5 [152,153]. The majority of these functionally validated, AF-associated potassium channel variants have a gain-of-function channel, with an expected shortening of the atrial action potential duration and atrial refractory period. Variation in sodium channel subunits has also been identified as an important factor in the development of familial AF, with AF-causing variants observed in both the https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 18/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate major cardiac sodium channel alpha subunit SCN5A [154] and its associated beta subunits [155,156]. Several variants have also been identified in genes that do not directly alter the atrial action potential, but instead would be expected to cause AF through alternative mechanisms, eg, somatic mutations in GJA5, which encodes the gap junctional protein; connexin 40, a frameshift mutation that resulted in early truncation of NPPA [157], which encodes for the precursor for atrial natriuretic peptide; and genetic variation in several developmentally related cardiac transcription factors, ie, NKX2.5, PITX2, GATA4, GATA5, and GATA6 [156,158,159]. Genome-wide association studies (GWAS) have been used to identify genetic loci associated with AF. GWAS rely on the unbiased comparison of common single-nucleotide polymorphisms (SNPs) throughout the genome, with SNPs occurring with different frequency in individuals with a disease versus controls being used to localize disease-related genetic loci. The first GWAS performed for AF identified a region on chromosome 4q25, which was associated with AF in those of European and Asian descent [160]. Subsequently, these findings were broadly replicated in individuals of European, Asian, and African descent [161,162]. Genetic variants on chromosome 4q25 that are most significantly associated with AF reside about 150 kilobases upstream of the nearest gene PITX2. PITX2 encodes the paired-like homeodomain transcription factor 2, which helps determine cardiac laterality, suppresses the default expression of a sinoatrial nodal gene programme in the left atrium, and encodes the pulmonary venous myocardium [163]. In addition, PITX2 is associated with formation of the pulmonary veins. These findings are particularly interesting in light of the fact that AF triggers frequently arise in the pulmonary veins. In addition to the role of PITX2 in development, studies demonstrate a role for the PitX2c transcript in expression of gene-encoding ion channels, calcium cycling proteins, and gap junctions; these direct electrophysiological influences likely lead to formation of substrate for triggered activity as well as reentry [164]. Related analysis identified the same genomic region as being associated with an increased risk of cardioembolic stroke [156,165] and a prolonged PR interval [166]. To date, GWAS have identified 14 genomic regions of susceptibility for AF, with 17 independent signals at these loci [167]. These include the ZFHX3 gene that encodes a zinc finger homeobox transcription factor [168], the KCNN3 gene that encodes the SK3 potassium channel [169], and the PRRX1 gene that encodes a member of the paired-related homeobox gene family [168]. Whole exome and genome sequencing has been increasingly used to identify rare variants associated with AF [156]. For example, Oleson et al reported a much higher prevalence of rare variants in genes associated with AF (KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5) in early onset, lone AF patients than in the background population [170]. This approach is beginning to identify rare candidate variants in genes not previously linked to other types of https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 19/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Mendelian disease and thus may offer new insights into AF pathogenesis and disease pathways that could ultimately provide novel therapeutic targets for this common condition. A 2018 meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than 500,000 individuals, sought to identify AF-associated genes at the GWAS loci by performing RNA sequencing and expression quantitative trait locus analyses in 101 left atrial samples (which is the most relevant tissue for AF) [171]. A transcriptome-wide analysis was also performed; this analysis identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci-implicated genes enriched within cardiac developmental, electrophysiological, contractile, and structural pathways. SUMMARY The precise mechanisms by which age and other risk factors such as hypertension, coronary artery or valvular heart disease, or heart failure increase the propensity for development of atrial fibrillation (AF) are poorly understood ( figure 1). These conditions may affect the triggers of or the substrate for the maintenance of AF. (See 'Introduction' above.) These mechanisms are complex and involve a dynamic interplay between the triggers and substrate abnormalities. It is likely that short-lived episodes are due to specific triggers, including autonomic perturbations, focal discharges, specific reentry circuits in the pulmonary veins (PVs), and effects of stretch, whereas inflammation, dilatation, fibrosis, repolarization abnormalities, and conduction disturbances allow for perpetuation of episodes of AF. (See 'Mechanisms of atrial fibrillation: triggers and substrates' above.) AF is most often initiated (triggered) by rapid firing from the PV. (See 'Triggers of AF' above.) Paroxysmal AF commonly precedes chronic AF. This suggests that, in addition to other predisposing factors, AF may play a role in its own natural history. (See 'Electrical remodeling' above.) The autonomic nervous system likely influences the initiation and perpetuation of AF. (See 'Role of the autonomic nervous system' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 20/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate 1. Wasmer K, Eckardt L, Breithardt G. Predisposing factors for atrial fibrillation in the elderly. J Geriatr Cardiol 2017; 14:179. 2. Goudis CA, Korantzopoulos P, Ntalas IV, et al. Obesity and atrial fibrillation: A comprehensive review of the pathophysiological mechanisms and links. 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Circulation 1997; 95:1945. 65. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans. Circulation 1997; 96:1542. 66. Tse HF, Lau CP, Wang Q, et al. Effect of diltiazem on the recurrence rate of paroxysmal atrial fibrillation. Am J Cardiol 2001; 88:568. 67. Tieleman RG, Blaauw Y, Van Gelder IC, et al. Digoxin delays recovery from tachycardia- induced electrical remodeling of the atria. Circulation 1999; 100:1836. 68. Sticherling C, Oral H, Horrocks J, et al. Effects of digoxin on acute, atrial fibrillation-induced changes in atrial refractoriness. Circulation 2000; 102:2503. 69. Vest JA, Wehrens XH, Reiken SR, et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 2005; 111:2025. 70. Li N, Chiang DY, Wang S, et al. Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model. 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Physiol 2008; 294:H134. 34. Ulphani JS, Arora R, Cain JH, et al. The ligament of Marshall as a parasympathetic conduit. Am J Physiol Heart Circ Physiol 2007; 293:H1629. 35. Arora R, Ng J, Ulphani J, et al. Unique autonomic profile of the pulmonary veins and posterior left atrium. J Am Coll Cardiol 2007; 49:1340. 36. Ogawa M, Zhou S, Tan AY, et al. Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure. J Am Coll Cardiol 2007; 50:335. 37. Ng J, Villuendas R, Cokic I, et al. Autonomic remodeling in the left atrium and pulmonary veins in heart failure: creation of a dynamic substrate for atrial fibrillation. Circ Arrhythm Electrophysiol 2011; 4:388. 38. Chou CC, Chen PS. New concepts in atrial fibrillation: neural mechanisms and calcium dynamics. Cardiol Clin 2009; 27:35. 39. Yamaguchi Y, Kumagai K, Nakashima H, Saku K. Long-term effects of box isolation on sympathovagal balance in atrial fibrillation. Circ J 2010; 74:1096. 40. Coumel P. Autonomic influences in atrial tachyarrhythmias. J Cardiovasc Electrophysiol 1996; 7:999. 41. Crawford T, Chugh A, Good E, et al. Clinical value of noninducibility by high-dose isoproterenol versus rapid atrial pacing after catheter ablation of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2010; 21:13. 42. Chen PS, Tan AY. Autonomic nerve activity and atrial fibrillation. Heart Rhythm 2007; 4:S61. 43. Nemirovsky D, Hutter R, Gomes JA. The electrical substrate of vagal atrial fibrillation as assessed by the signal-averaged electrocardiogram of the P wave. Pacing Clin Electrophysiol https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 23/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate 2008; 31:308. 44. Sharifov OF, Fedorov VV, Beloshapko GG, et al. Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs. J Am Coll Cardiol 2004; 43:483. 45. Hirose M, Carlson MD, Laurita KR. Cellular mechanisms of vagally mediated atrial tachyarrhythmia in isolated arterially perfused canine right atria. J Cardiovasc Electrophysiol 2002; 13:918. 46. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004; 109:327. 47. Verma A, Saliba WI, Lakkireddy D, et al. Vagal responses induced by endocardial left atrial autonomic ganglion stimulation before and after pulmonary vein antrum isolation for atrial fibrillation. Heart Rhythm 2007; 4:1177. 48. Arruda M, Natale A. Ablation of permanent AF: adjunctive strategies to pulmonary veins isolation: targeting AF NEST in sinus rhythm and CFAE in AF. J Interv Card Electrophysiol 2008; 23:51. 49. Porter M, Spear W, Akar JG, et al. Prospective study of atrial fibrillation termination during ablation guided by automated detection of fractionated electrograms. J Cardiovasc Electrophysiol 2008; 19:613. 50. Katritsis D, Giazitzoglou E, Sougiannis D, et al. Complex fractionated atrial electrograms at anatomic sites of ganglionated plexi in atrial fibrillation. Europace 2009; 11:308. 51. Stavrakis S. Low-level transcutaneous electrical vagus nerve stimulation. J Am Coll Cardiol 2015; :867. 52. Narayan SM, Krummen DE, Shivkumar K, et al. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol 2012; 60:628. 53. Haissaguerre M, Hocini M, Denis A, et al. Driver domains in persistent atrial fibrillation. Circulation 2014; 130:530. 54. Lim HS, Hocini M, Dubois R, et al. Complexity and Distribution of Drivers in Relation to Duration of Persistent Atrial Fibrillation. J Am Coll Cardiol 2017; 69:1257. 55. Climent AM, Guillem MS, Fuentes L, et al. Role of atrial tissue remodeling on rotor dynamics: an in vitro study. Am J Physiol Heart Circ Physiol 2015; 309:H1964. 56. Lee S, Sahadevan J, Khrestian CM, et al. Simultaneous Biatrial High-Density (510-512 Electrodes) Epicardial Mapping of Persistent and Long-Standing Persistent Atrial Fibrillation https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 24/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate in Patients: New Insights Into the Mechanism of Its Maintenance. Circulation 2015; 132:2108. 57. Kuklik P, Lau DH, Ganesan AN, et al. High-density mapping of atrial fibrillation in a chronic substrate: evidence for distinct modes of repetitive wavefront propagation. Int J Cardiol 2015; 199:407. 58. Allessie MA. Atrial fibrillation-induced electrical remodeling in humans: what is the next step? Cardiovasc Res 1999; 44:10. 59. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol 2008; 1:62. 60. Wijffels MC, Kirchhof CJ, Dorland R, et al. Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulation 1997; 96:3710. 61. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation 1998; 98:2202. 62. Raitt MH, Kusumoto W, Giraud G, McAnulty JH. Reversal of electrical remodeling after cardioversion of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2004; 15:507. 63. Brundel BJ, Van Gelder IC, Henning RH, et al. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation 2001; 103:684. 64. Tieleman RG, De Langen C, Van Gelder IC, et al. Verapamil reduces tachycardia-induced electrical remodeling of the atria. Circulation 1997; 95:1945. 65. Daoud EG, Knight BP, Weiss R, et al. Effect of verapamil and procainamide on atrial fibrillation-induced electrical remodeling in humans. Circulation 1997; 96:1542. 66. Tse HF, Lau CP, Wang Q, et al. Effect of diltiazem on the recurrence rate of paroxysmal atrial fibrillation. Am J Cardiol 2001; 88:568. 67. Tieleman RG, Blaauw Y, Van Gelder IC, et al. Digoxin delays recovery from tachycardia- induced electrical remodeling of the atria. Circulation 1999; 100:1836. 68. Sticherling C, Oral H, Horrocks J, et al. Effects of digoxin on acute, atrial fibrillation-induced changes in atrial refractoriness. Circulation 2000; 102:2503. 69. Vest JA, Wehrens XH, Reiken SR, et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 2005; 111:2025. 70. Li N, Chiang DY, Wang S, et al. 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Roselli C, Chaffin MD, Weng LC, et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet 2018; 50:1225. Topic 16402 Version 27.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 33/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate GRAPHICS AF mechanisms Overview of mechanisms of AF. Four different positive-feedback loops are proposed as 2 the main driving forces for the atrial remodeling process. Enhanced Ca + loading during AF is believed to underlie most of the cellular proarrhythmic mechanisms (trigger loop). The main process in the electrical loop is an altered contribution of ion channels to the 2 action potential configuration that protects atrial myocytes against excessive Ca + loading. Abbreviation of the action potential facilitates re-entry and thereby promotes AF. In the structural loop, chronic atrial stretch activates numerous signaling cascades that produce alterations of the extracellular matrix and conduction disturbances, also facilitating re-entrant mechanisms. The main changes of the contractile properties of the heart are loss of atrial contractility which increases atrial compliance and the development of a ventricular tachycardiomyopathy, both of which increase stretch in the atrial wall. The circular positive-feedback enhancement of these pathophysiological changes explains the general tendency of AF to become more stable with time. It should be noted that the different loops are interconnected by mechanisms that are part of more than one loop. For example, increased Ca + loading enhances trigger activity 2 (trigger loop) and also results in a change in the ion channel population and activity (electrical loop). Re-entrant mechanisms are promoted by both shortening of refractoriness (electrical loop) as well as by conduction disturbances resulting from https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 34/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate tissue fibrosis (structural loop). Like in a system of meshing gear wheels, one loop will drive the other, leading to progression of the arrhythmia. However, the proposed system of gear wheels does not start to move spontaneously. Structural heart diseases, arrhythmias, aging, or inherited diseases are required to initiate movement of one or more of these wheels. When the pathophysiological alterations eventually reach a certain threshold, AF will ensue. Ulrich Schotten, Sander Verheule, Paulus Kirchhof, and Andreas Goette. Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal. Physiol Rev January 2011 91:265-325 [PRV1/2011]. Reproduced with permission. Copyright 2011 The American Physiological Society. Graphic 63675 Version 5.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 35/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate AF remodeling 2+ Mechanisms underlying ATR. Rapid atrial rates increase potentially cytotoxic Ca loading. Autoprotective I changes (I reductions occur via rapidly developing functional Ca,L inactivation) and more slowly developing changes in gene and protein Ca,L expression. Decreased I shortens refractoriness and reduces the wavelength (WL), which allows for smaller and 2+ reduces Ca loading but decreases APD. Diminished APD Ca,L more atrial reentry circuits, thus making AF unlikely to terminate. Atrial tachycardia also increases inward-rectifier currents such as I APD and promotes AF. and I , which further reduces K1 K,ACh,c RP: refractory period; WL: wavelength. Reproduced with permission from: Nattel S, Burstein B, Dobrev D. Atrial Remodeling and Atrial Fibrillation: Mechanisms and Implications. Circ Arrhythm Electrophysiol 2008; 1:62. Copyright 2008 Lippincott Williams & Wilkins. Graphic 51670 Version 8.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 36/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Signal averaged electrocardiogram predicts atrial fibrillation after coronary artery bypass graft (CABG) surgery The incidence of atrial fibrillation (AF) after coronary artery bypass graft surgery is directly related to the duration of the P wave on a signal averaged ECG. Data from Zaman AG, Archbold RA, Helft G, et al. Circulation 2000; 101:1403. Graphic 60431 Version 4.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 37/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Atrial activation in atrial fibrillation Spread of activation through right (upper half) and left (lower half) atria during stable atrial fibrillation. These activation maps show propagation of impulse through the atria, as visualized by color isochrones of 10 milliseconds (ms). White arrows indicate general direction of wavelets. Asterisks represent sites of impulse fragmentation and development of new wavelets. Redrawn from Allissie MA, Lammers WJEP, Bonke FIM, et al. In: Cardiac Arrhythmias, Grane &Stratton, Orlando, 1985, p. 265. Graphic 59310 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 38/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Two types of reentry in atrial fibrillation The isochronal activation maps demonstrate two types of reentry in atrial fibrillation. Map A shows random reentry with three simultaneous wavefronts (black arrows) activating most of the recording area. Map B also shows three simultaneous wavefronts, but they are coming from different directions than those in map A. Maps C and D show two consecutive cycles of complete reentry. The wave of activation (black arrow) spreads clockwise in a circular fashion around a line of unexcited tissue. Reproduced with permission from Holm M, Johansson R, Brandt J, et al. Eur Heart J 1997; 18:290. Graphic 73931 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 39/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Atrial electogram morphology in atrial fibrillation The morphology of unipolar electrograms recorded during atrial fibrillation reflect different patterns of conduction, as demonstrated by the isochrone maps. Black arrows indicate the direction of activation. Single potentials are indicative of rapid uniform conduction. Short doubles result from collision of the wavefronts along a line of collision (map A). Long doubles are due to conduction block (Map B). Fragmented electrograms refect multiple discrete deflections that may result from impulse conduction around a pivotal point (map C) or from slow or delayed conduction (map D). Reproduced with permission from Konings KTS, Smeets JLRM, Penn OC, et al. Circulation 1997; 95:1231. Graphic 52152 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 40/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Schema of normal impulse conduction in the heart The sinoatrial node (SAN) generates an action potential that is conducted through the right and left atria, resulting in atrial contraction. The impulse is then conducted through the atrioventricular node (AVN), activating the ventricular myocardium, resulting in contraction of the right and left ventricle. SVC: superior vena cava; IVC: inferior vena cava; PV: pulmonary veins; LAA: left atrial appendage; RAA: right atrial appendage. Graphic 57781 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 41/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Electrical activity in atrial fibrillation During atrial fibrillation there are multiple reentrant circuits within the right and left atrium, resulting in nonuniform activitation of the atrial myocardium. These circuits, which produce multiple wavelets, often occur around the normal structures of the atrial including the orifices of the superior (SVC) and inferior (IVC) vena cavae, the orifice of the pulmonary veins (PVs), and the right (RAA) and left (LAA) atrial appendages. Graphic 58689 Version 1.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 42/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Noncontact endocardial activation map of focal atrial fibrillation The noncontact endocardial activation map of the half-open left atrium shows that the initial depolarization from an ectopic focus spreads centrifugally from the ostium of the right upper pulmonary vein (RUP), indicated by the white-blue color. LUP: left upper pulmonary vein. Reproduced with permission from Schneider MA, Ndrepepa G, Zrenner B, et al. Noncontact mapping-guided catheter ablation of atrial brillation associated with left atrial ectopy. J Cardiovascular Electrophysiol 2000; 11:475. Copyright 2000 Futura Publishing Company, Inc. Graphic 55997 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 43/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Activation patterns in atrial fibrillation Isochronal activation maps obtained from the right atrial free wall during atrial fibrillation show four distinct patterns of myocardial activation, indicated by black arrows. Activation from a localizable site which spreads in all directions away from the site is termed focal atrial activation (upper left). Type I activation is a single broad wavefront that propagates without conduction delay (upper right). Type II activation is a single wavefront that is associated with conduction slowing or block, or with two wavefronts (lower left). Type III activation results from the presence of three or more wave fronts associated with areas of slow and blocked conduction (lower right). Reproduced with permission from Holm M, Johansson R, Brandt J, et al. Eur Heart J 1997; 18:290. Graphic 66498 Version 2.0 https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 44/45 7/5/23, 9:15 AM Mechanisms of atrial fibrillation - UpToDate Contributor Disclosures Brian Olshansky, MD Other Financial Interest: AstraZeneca [Member of the DSMB for the DIALYZE trial]; Medtelligence [Cardiovascular disease]. All of the relevant financial relationships listed have been mitigated. Rishi Arora, MD No relevant financial relationship(s) with ineligible companies to disclose. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Hugh Calkins, MD Grant/Research/Clinical Trial Support: Adagio Medical [Atrial fibrillation]; Boston Scientific [ARVC]; Farapulse [Atrial fibrillation]; Medtronic [Atrial fibrillation]. Consultant/Advisory Boards: Abbott [Atrial fibrillation]; Atricure [Atrial fibrillation]; Biosense Webster [Catheter ablation]; Boston Scientific [ARVC and atrial fibrillation]; Medtronic [Atrial fibrillation]; Sanofi [Atrial fibrillation]. Other Financial Interest: Atricure [Lecture honoraria]; Biosense Webster [Lecture honoraria]; Boston Scientific [Lecture honoraria]; Medtronic [Lecture honoraria]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/mechanisms-of-atrial-fibrillation/print 45/45