- Email: [email protected]
Antiarrhythmic Drugs in Atrial Fibrillation: Do They Have a Future?
Canadian Journal of Cardiology 29 (2013) 1158e1164
Review
Antiarrhythmic Drugs in Atrial Fibrillation: Do They Have a Future? Paul Angaran, MD, and Paul Dorian, MD Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
ABSTRACT
RESUM E
Atrial fibrillation (AF) is a common arrhythmia associated with significant morbidity and mortality. There has been much debate about the relative merits of rate vs rhythm control strategies, and studies to date have failed to show advantage with a rhythm-control strategy using antiarrhythmic drugs (AADs). This is likely because of the inadequacies of our current AADs and the limitations of study designs. However, there is evidence that AADs improve symptoms and quality of life (QOL). Until trials are performed with more appropriate patient selection, and end points and better AADs and strategies for their use, rhythm control should not be abandoned and may continue to be beneficial in selected patients.
quente associe e à La fibrillation auriculaire (FA) est une arythmie fre et une mortalite significatives. Les me rites relatifs des une morbidite gies sur la maîtrise de la fre quence vs la maîtrise du rythme ont strate bat, et les e tudes re alise es jusqu’à ce jour sur la fait l’objet d’un long de gie de la maîtrise du rythme par les me dicaments antistrate montrer d’avantages pour la survie. Cela arythmiques n’ont pas su de s’explique probablement par les lacunes actuelles (antiarythmisants) thodologies. Cependant, certains travaux et les limites des me rent que les me dicaments antiarythmiques soulagent les sugge liorent la qualite de vie (QV). Jusqu’à ce que des symptômes et ame alise s à partir d’une se lection de patients et de critères essais soient re s, ainsi que de meilleurs me dicaments de jugement plus approprie gies d’utilisation, la maîtrise du antiarythmiques et de meilleures strate e et peut continuer d’être rythme ne devrait pas être abandonne ne fique chez certains patients. be
Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence of 1%-2%. The prevalence of AF is strongly associated with age, affecting < 1% of persons younger than 60 years and > 9% of persons older than 80 years.1 The number of affected individuals in the United States is expected to double in the next 40 years to about 5 million. In Canada, it is estimated that 350,000 Canadians are living with AF, and this number is expected to increase because of the aging population.2 AF is also the most common arrhythmia seen in the emergency department and accounts for up to one-third of arrhythmia-related hospitalizations.3 AF is associated with increased mortality and morbidity, particularly heart failure, stroke, and hospitalization.1,4-11 Patients with AF also have impaired quality of life (QOL), often similar to or worse than patients after myocardial infarction or those with heart failure.12 Furthermore, AF imposes significant costs on an increasingly constrained health care system.13
There has been considerable focus recently on improvement of risk stratification for stroke and therapies for prevention of thromboembolism in AF. Beyond the undoubted value of stroke prevention, debate and discussion have also included the relative merits of rate vs rhythm control in AF. The guidelines of all the major medical societies recommend the use of antiarrhythmic drugs (AADs) to improve symptoms in patients with symptomatic AF; however, there are detailed restrictions for patient selection.3,14-18 The purpose of this review is to discuss the goals of treatment of AF, the role of oral AADs in achieving and maintaining sinus rhythm and improving symptoms, and the limitations of the rate- vs rhythm-control trials. Conventional atrioventricular (AV) node blocking agents and nonpharmacologic strategies to maintain sinus rhythm, namely, catheter ablation therapy, will not be specifically addressed.
Received for publication March 19, 2013. Accepted April 26, 2013. Corresponding author: Dr Paul Dorian, Division of Cardiology, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. Tel.: þ1-416-864-5104; fax: þ1-416-864-5348. E-mail: [email protected] See page 1162 for disclosure information.
Goals of AF Management The 3 potential reasons to treat AF are to reduce mortality, reduce morbidity, and improve symptoms and QOL. Mortality AF has been associated with increased mortality, even after adjusting for other comorbidities.7 What remains unclear,
0828-282X/$ - see front matter 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.04.033
Angaran and Dorian Antiarrhythmic Drugs in Atrial Fibrillation
1159
however, is whether the relationship between AF and mortality is causal or AF simply is a marker of underlying disease. Several clinical trials comparing rate vs rhythm controldPharmacological Intervention in Atrial Fibrillation (PIAF),19 Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM),20 Rate Control vs Electrical Cardioversion (RACE),21 Strategies of Treatment of Atrial Fibrillation (STAF),22 How to Treat Chronic Atrial Fibrillation (HOT CAFE)23 and Atrial Fibrillation and Congestive Heart Failure (AF-CHF)24dhave failed to demonstrate that treatment of AF with the AADs available at the time resulted in improved mortality, and in fact in some trials AADs had a tendency to increase mortality. In contrast, secondary “on-treatment” analyses of the AFFIRM trial and other observational data suggest that rhythm control may be associated with lower long-term mortality.25-27 Based on studies to date, there is currently no strong evidence supporting the use of AADs to treat AF with the goal of improving mortality.
Symptoms and QOL One of the most important goals in treating AF is to minimize symptoms and improve QOL. Symptoms vary considerably and may include palpitations, dyspnea, dizziness, chest pain, weakness, and fatigue. Patients with AF have poorer QOL compared with healthy controls and those with coronary artery disease.12,28,29 Moreover, in 1 study, female patients with AF reported significantly more impaired QOL than did men, specifically related to physical and functional health.30 The Canadian Cardiovascular Society Severity in Atrial Fibrillation (CCS-SAF) scale is a bedside scale for assessing QOL in patients with AF. It is analogous to the New York Heart Association heart failure and CCS angina scores, ranging from class 0 (no effect on QOL) to class 4 (severe effect on QOL). The CCS-SAF scale has been assessed and validated in patients with paroxysmal and persistent AF and correlates well with symptom severity but not frequency and duration of AF episodes. It also correlates with health care resource consumption, with higher scores representing more frequent and longer hospitalizations, emergency department. and specialist visits, and increasing cardioversions31 (Fig. 1). This scale is particularly practical because it not only classifies symptom severity but also clearly demonstrates the correlation between health care resource consumption and symptoms, namely, that as health care consumption increases, QOL is adversely affected. It stands to reason that treating AF by restoring sinus rhythm should improve symptoms and thus QOL. However, this has not been completely borne out in the major trials of rate vs rhythm control. Four randomized controlled trials (STAF,22 PIAF,19 RACE,21 and AFFIRM20) comparing a strategy of rate control and rhythm control with AADs and/ or cardioversion have consistently shown improvement in QOL with both rate- and rhythm-control therapy. In intention-to-treat analyses, the rate-control strategy demonstrated greater improvement in QOL, except in the AFFIRM trial, which showed similar improvements in QOL between both groups. However, in the PIAF and HOT CAFE trials, 6-minute walk time and maximal treadmill workload were better in the rhythm-control groups, respectively.23,32
Figure 1. Canadian Cardiovascular Society Severity in Atrial Fibrillation (CCS-SAF) scale and health care use. As SAF class increased, a greater proportion of patients had (A) more emergency room visits and (B) more hospitalizations in the previous 1-year period (P < 0.001). AFSS, Atrial Fibrillation Severity Scale; ER, emergency room. Modified from Dorian et al.31 with permission from Wolters Kluwer Health.
Moreover, intention-to-treat analyses, which are appropriate for the primary end point, do not account for “treatment success.” If analysis is performed according to rhythm achieved, a slightly different picture emerges. In a substudy of the Canadian Trial of Atrial Fibrillation (CTAF) trial, in which patients were randomized to either amiodarone or sotalol/propafenone, QOL significantly improved from baseline to 3 months.33 QOL improved the most in patients in whom therapy prevented AF recurrence. In a substudy of the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFET) study, patients with persistent AF who underwent successful restoration and maintenance of sinus rhythm with AADs (amiodarone or sotalol) cardioversion had improved exercise performance measures and QOL34 (Figs. 2 and 3). In another study, patients with symptomatic AF were treated with open-label flecainide, and QOL was assessed by the SF36 and Atrial Fibrillation Severity Scale scores. The investigators found that (1) patients with uncontrolled symptomatic paroxysmal AF (PAF), but not those with controlled symptomatic PAF, had inferior QOL compared with healthy matched controls and that (2) patients treated with flecainide had improvement in their QOL to a level that was similar to that in patients with controlled symptomatic AF.35 These studies must be interpreted with caution because they are post-hoc analyses, but there is a consistent pattern of QOL improvement in patients who achieve sinus rhythm with an AAD. Further evidence to support this theory comes from
1160
Canadian Journal of Cardiology Volume 29 2013
Figure 2. Improvement in maximal exercise duration in patients with sinus rhythm (SR) vs atrial fibrillation (AF). Mean increase in maximal exercise duration from baseline to 8 weeks and 1 year in patients with sinus rhythm vs AF. Exercise tolerance in patients with sinus rhythm was significantly higher than in patients with AF at both 8 weeks (81.5 seconds vs 33.5 seconds; P ¼ 0.01) and 1 year (74.6 seconds vs 15.2 seconds; P ¼ 0.02). y SR group: n = 213; AF group: n = 145. z SR group: n = 219; AF group: n = 113. Reprinted from Singh et al.34 with permission from the American College of Cardiology Foundation.
“real world” practice. In the Real-life Global Survey Evaluating Patients With Atrial Fibrillation (REALISE-AF) registry, QOL was highest for patients in sinus rhythm, followed by patients with AF with heart rates 80 bpm and lowest in patients with AF with heart rates > 80 bpm.36 Perhaps the best proof-of-concept evidence comes from the radiofrequency catheter ablation literature. Several studies have demonstrated improved QOL after achieving and maintaining sinus rhythm through successful ablation.37-41 Patients treated with catheter ablation, compared with AADs, had improved symptoms, exercise capacity, QOL, and in 1 study, even fewer hospitalizations. This likely results from the much lower recurrence rate and burden of AF with catheter ablation, supporting the notion that restoration of sinus rhythm may in fact be beneficial.
Limitations of the Current Trials If AF causes substantial symptoms and impaired QOL, why is it that most major trials of rate vs rhythm control have failed to show improved outcomes with a rhythm control strategy? There are several potential explanations. First, clinical trials comparing rhythm control vs rate control typically included older patients (AFFIRM, mean age w70 years) and likely under-represented the younger and typically more symptomatic patients. Second, in most trials, conclusions were based on the “strategy” of either rhythm or rate control, irrespective of whether sinus rhythm was actually achieved and maintained. In AFFIRM, 37.4% of patients in the rhythm-control group remained in AF, and in the rate-control group, 34.6% of patients were in sinus rhythm at the 5-year visit.20 Results
Figure 3. Improvement in quality of life (QOL) in symptomatic patients with sinus rhythm (SR) vs atrial fibrillation (AF). Mean improvement in QOL scores from baseline to 1 year in patients with symptomatic AF. Patients in sinus rhythm are denoted by blue bars and patients with AF are denoted by red bars. Patients in sinus rhythm had a greater improvement in physical functioning, general health, vitality, and social functioning compared with patients in AF. SCL, symptom checklist. Reprinted from Singh et al.34 with permission from the American College of Cardiology Foundation.
Angaran and Dorian Antiarrhythmic Drugs in Atrial Fibrillation
were based on the strategy assigned and not whether sinus rhythm was actually achieved. However, analyzing data on the basis of whether sinus rhythm was achieved may point toward a different conclusion. In an AFFIRM substudy, using an “on-treatment analysis” sinus rhythm was significantly associated with improved survival (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39-0.72; P < 0.0001), but rhythm-control drug use was associated with increased mortality (HR, 1.49; 95% CI, 1.11-2.01; P ¼ 0.0005) after adjusting for the presence of sinus rhythm. This suggests that the beneficial effects of AADs were offset by their adverse events.26 In the small STAF pilot trial, patients with persistent AF were randomized to a rate- or rhythm-control strategy. Although there was no significant difference in the primary end point, 18 primary end points occurred during AF, whereas only 1 occurred in sinus rhythm (P ¼ 0.049).22 Similar results showing improved outcomes in patients who achieved and maintained sinus rhythm were also found in the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) trial42 and in AF studies with predominantly patients with heart failure, including a substudy of the Danish Investigations of Arrhythmia and Mortality on Dofetilide studies (DIAMOND)43 and Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (CHF-STAT).44 Conversely, in a RACE substudy, patients in sinus rhythm did not experience improved outcomes compared with those who remained in AF,45 and in an AF-CHF substudy, sinus rhythm was not associated with improved mortality but did show a trend toward improvement of heart failure (HR, 0.62; 95% CI, 0.37-1.02; P ¼ 0.050).46 Although these results support improved outcomes with sinus rhythm, they should be interpreted with caution because they are secondary analyses. Another possible explanation is that the ability to achieve sinus rhythm may just be a marker for less severe underlying disease and therefore a more favorable prognosis. Third, in the AFFIRM trial, crossover between the groups was moderately large: at 5 years, approximately 15% of ratecontrol patients and 38% of rhythm-control patients crossed over to the other treatment group.20 The patients in the ratecontrol strategy group who crossed over to rhythm control presumably did so on the basis of symptom severity, suggesting that their QOL was impaired. Conversely, patients who crossed from a rhythm- to a rate-control strategy presumably had drug intolerance or inability to maintain sinus rhythm, and thus were unlikely to be receiving a QOL benefit from the originally assigned therapy. Finally, another possible reason why trials have not demonstrated improved QOL outcomes with a rhythm approach is that AADs are not perfectly effective and may have side effects that can mask or even outweigh the benefits of these drugs. These considerations indicate that AADs, if effective in restoring and maintaining sinus rhythm in symptomatic patients, or at least reducing or eliminating symptomatic recurrences and not causing adverse effects, can indeed result in QOL improvement. Limitations of Current AADs Current AADs are moderately effective at restoring and maintaining sinus rhythm. In the CTAF trial, the probability
1161
of remaining in sinus rhythm after 1 year was 69% in the amiodarone group and 39% in the sotalol/propafenone group (P < 0.001).47 Amiodarone remains the most effective drug,20,47,48 but its use is associated with frequent adverse effects with long-term use, notably extracardiac side effects. This was perhaps not a major issue in older and sicker patients enrolled in the AFFIRM and AF-CHF trials, in which amiodarone was used in 63% and 82% of patients, respectively.20,46 However, in the typical younger patient with PAF, long-term amiodarone use certainly poses challenges and its use is limited. Nonetheless, in select patients, amiodarone remains a highly effective and safe drug if properly monitored. Class IC AADs such as flecainide and propafenone are moderately effective at achieving and maintaining sinus rhythm in patients with AF. Their main risks include proarrhythmia and paradoxical increase in ventricular rates as a result of 1:1 AV node conduction from the organization of AF to atrial flutter. However, these risks can be minimized with careful patient selection and concurrent use of AV node blocking agents, but avoiding their use in patients with coronary artery disease and structural heart disease.49-51 Unfortunately, these drugs have not been extensively studied in the rate vs rhythm trials owing to the high use of amiodarone, comorbidities, and presence of structural heart disease. Dronedarone is a benzofuran derivative with a pharmacologic profile similar to amiodarone, but without the iodine and the addition of a methane-sulfonyl group.52 These structural changes result in fewer extracardiac side effects and a shorter half-life; however, this is at the price of decreased efficacy. In early trials, dronedarone was moderately efficacious at maintaining sinus rhythm (25% reduction) and achieving reasonable ventricular rate control (12-15 bpm or 7% reduction).53 A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA) trial was a double-blinded, placebo-controlled parallel-arm study assessing the efficacy of dronedarone 400 mg twice daily in high-risk patients with AF or atrial flutter.52 Unlike earlier trials that examined the first recurrence of AF, the primary end point used was first hospitalization because of cardiovascular events or death, representing a shift toward more meaningful clinical outcomes. Dronedarone significantly reduced the incidence of hospitalization from cardiovascular events or death in patients with AF or atrial flutter over a mean period of 21 5 months (HR, 0.74; 95% CI, 0.69-0.84; P < 0.001) (Fig. 4). These results were mainly driven by a reduction in AF-related hospitalizations. Although strictly speaking, there was no QOL measurement in ATHENA, the end point of hospitalization likely reflects the patient’s QOL or at the very least the physician’s perception of patient’s QOL. Hospitalization was driven by either the patient’s or the treating physician’s perceptions of the severity of symptoms from AF and as a result, the need to admit them to the hospital. In essence, by reducing hospitalizations in patients with AF, dronedarone indirectly improved QOL. The main side effects from dronedarone include bradycardia, QT-interval prolongation, and gastrointestinal side effects, including diarrhea and nausea, and rash. Perhaps the greatest concern with dronedarone arose from the Antiarrhythmic Trial With Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating
1162
Figure 4. Kaplan-Meier cumulative incidence of primary outcome in the ATHENA (A Trial With Dronedarone to Prevent Hospitalization or Death In Patients With Atrial Fibrillation) trial. The primary outcome was a composite of first hospitalization resulting from cardiovascular events or death from any cause, which occurred in 31.9% of the dronedarone group and in 39.4% of the placebo group, with a hazard ratio for dronedarone of 0.76 (95% confidence interval [CI], 0.69-0.84; P < 0.001). Reproduced from Hohnloser et al.52 Copyright ª 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Morbidity Decrease (ANDROMEDA) and Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) studies, which randomized patients with symptomatic heart failure and severe left ventricular dysfunction and permanent AF, respectively.54,55 Both trials were stopped prematurely because of safety concerns resulting from increased mortality in the dronedarone group. As a result of these studies, dronedarone should not be administered to patients with acute or worsening heart failure, severe left ventricular dysfunction, or permanent AF. Although dronedarone has limitations as an AAD, the ATHENA study did demonstrate in a placebo-controlled, blinded, randomized paradigm, that an AAD can indeed lead to important patient benefit in patients with symptomatic AF. AAD Therapy Should Not Be Abandoned The failure of the rhythm strategy in the rate vs rhythm trials to show benefit does not mean that rhythm control should be completely abandoned. Development of new AADs with more favorable efficacy/side effect profiles may be one strategy to improve outcomes. Further research and advances in basic science mechanisms are needed to help achieve this goal.56 Alternatively, more careful patient selection combined with strategies to prescribe and continue AADs only if they are clinically effective have yet to be studied and could prove effective. The ideal patients who are eligible for a trial of AADs are those with highly symptomatic PAF or persistent AF, not including those patients with minimal or nonsymptomatic AF or permanent AF. A new paradigm for the design of clinical trials using AADs may prove more fruitful given the “disconnect” between
Canadian Journal of Cardiology Volume 29 2013
clinical trials to date and “real world” practice. In most trials of rhythm control, patients randomized to the rhythm-control group continued to receive AADs regardless of their effectiveness. This is not in keeping with everyday practice in which drugs are titrated, changed, or stopped depending on the patient’s clinical response and side effects. Indeed, “chasing sinus rhythm” may be a fool’s errand whereby we use too many AADs at doses that are too high and are never able to demonstrate the effectiveness of AADs. The better strategy may perhaps be to aim for symptomatic improvement even if the rhythm is sometimes AF, and not strive for complete rhythm control (which may in fact not be achievable). Although time to first recurrence of AF and AF burden has been used as an efficacy end point in many studies, these outcomes are less meaningful for several reasons, including clustering of AF episodes, limitations of monitoring strategies, and poor correlation with symptoms and cardiovascular outcomes. If we can decrease the severity or number of symptomatic AF episodes, this would be a clinical success, but it has largely been ignored in clinical trials using an end point of recurrence or mortality. An alternative trial design, which has not been performed to date, would be structured so that AADs are continued only if patient QOL improves and are stopped otherwise. The ATHENA protocol came closer to this than any other study because the end point was not rhythm control with any electrocardiographic mandated definitions of success. Simply “prescribing the drug” and following patients clinically, ie, “treating the patient and not the electrocardiogram” is what we do, or should be doing, in clinical practice. The ATHENA trial therefore supports the concept that AADs can benefit patients but that dronedarone may not be the ideal drug to do so. We thus need studies comparing strategies of “symptom control” using AADs and AV node blockers. Effectiveness trials, instead of efficacy trials, whereby therapies are not necessarily discontinued at recurrence but rather are continued if the therapy continues to be helpful, may be the better way to finally demonstrate the potential benefits of rhythm control on QOL. Conclusions Trials to date have largely failed to consistently demonstrate that rhythm control to maintain sinus rhythm in patients with AF is superior to rate control with respect to improving QOL, but they do not disprove it either. This is likely a result of the inherent limitations of the study designs combined with current inadequacies of AADs. The ideal trials have yet to be conducted and until they are, the issue of whether rhythm control is superior for improving QOL will remain unresolved. Disclosures Dr Dorian has received honoraria and consulting fees from Bristol-Myers Squibb, Merck, and Sanofi. Dr Angaran has no conflicts of interest to disclose. References 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and
Angaran and Dorian Antiarrhythmic Drugs in Atrial Fibrillation stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370-5. 2. Heart and Stroke Foundation. Statistics:atrial fibrillation. Available at http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/ Statistics.htm#atrialfib. Accessed June 10, 2013. 3. 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): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114: e257-354. 4. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98:476-84. 5. Go AS. The epidemiology of atrial fibrillation in elderly persons: the tip of the iceberg. Am J Geriatr Cardiol 2005;14:56-61. 6. 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;113:359-64. 7. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229-34. 8. Wattigney WA, Mensah GA, Croft JB. Increased atrial fibrillation mortality: United States, 1980-1998. Am J Epidemiol 2002;155:819-26. 9. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8. 10. 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: 946-52. 11. Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation 2003;108:711-6. 12. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36: 1303-9. 13. Wodchis WP, Bhatia RS, Leblanc K, Meshkat N, Morra D. A review of the cost of atrial fibrillation. Value Health 2012;15:240-8. 14. Gillis AM, Verma A, Talajic M, Nattel S, Dorian P. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: rate and rhythm management. Can J Cardiol 2011;27:47-59. 15. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36. 16. Camm AJ, Kirchhof P, Lip GY, 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: 2369-429. 17. 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. Eur Heart J 2012;33:2719-47.
1163
18. 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. Circulation 2011;123:104-23. 19. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillationdPharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789-94. 20. 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;347:1825-33. 21. 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;347:1834-40. 22. 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;41:1690-6. 23. 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;126:476-86. 24. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-77. 25. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch Intern Med 2012;172: 997-1004. 26. 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;109:1509-13. 27. Steinberg JS, Sadaniantz A, Kron J, et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1973-80. 28. Howes CJ, Reid MC, Brandt C, et al. Exercise tolerance and quality of life in elderly patients with chronic atrial fibrillation. J Cardiovasc Pharmacol Ther 2001;6:23-9. 29. van den Berg MP, Hassink RJ, Tuinenburg AE, et al. Quality of life in patients with paroxysmal atrial fibrillation and its predictors: importance of the autonomic nervous system. Eur Heart J 2001;22:247-53. 30. Paquette M, Roy D, Talajic M, et al. Role of gender and personality on quality-of-life impairment in intermittent atrial fibrillation. Am J Cardiol 2000;86:764-8. 31. Dorian P, Guerra PG, Kerr CR, et al. Validation of a new simple scale to measure symptoms in atrial fibrillation: the Canadian Cardiovascular Society Severity in Atrial Fibrillation scale. Circ Arrhythm Electrophysiol 2009;2:218-24. 32. Hohnloser SH, Kuck KH. Randomized trial of rhythm or rate control in atrial fibrillation: the Pharmacological Intervention in Atrial Fibrillation Trial (PIAF). Eur Heart J 2001;22:801-2. 33. 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: 276-9. 34. Singh SN, Tang XC, Singh BN, et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial
1164 fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol 2006;48:721-30. 35. Guedon-Moreau L, Capucci A, Denjoy I, et al. Impact of the control of symptomatic paroxysmal atrial fibrillation on health-related quality of life. Europace 2010;12:634-42. 36. Steg PG, Alam S, Chiang CE, et al. Symptoms, functional status and quality of life in patients with controlled and uncontrolled atrial fibrillation: data from the RealiseAF cross-sectional international registry. Heart 2012;98:195-201. 37. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure (ARC-HF). J Am Coll Cardiol 2013;61: 1894-903. 38. 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;303:333-40. 39. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118: 2498-505.
Canadian Journal of Cardiology Volume 29 2013 45. Rienstra M, Van Gelder IC, Hagens VE, et al. Mending the rhythm does not improve prognosis in patients with persistent atrial fibrillation: a subanalysis of the RACE study. Eur Heart J 2006;27:357-64. 46. Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2010;55:1796-802. 47. 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;342:913-20. 48. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861-72. 49. 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;324:781-8. 50. 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;64:1317-21.
40. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634-40.
51. Clementy J, Dulhoste MN, Laiter C, Denjoy I, Dos Santos P. Flecainide acetate in the prevention of paroxysmal atrial fibrillation: a nine-month follow-up of more than 500 patients. Am J Cardiol 1992;70:44A-9A.
41. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367:1587-95.
52. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360: 668-78.
42. Ogawa S, Yamashita T, Yamazaki T, et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ J 2009;73:242-8. 43. 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 investigation of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001;104:292-6. 44. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHFSTAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation 1998;98:2574-9.
53. 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: 987-99. 54. Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358: 2678-87. 55. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268-76. 56. Nattel S. From guidelines to bench: implications of unresolved clinical issues for basic investigations of atrial fibrillation mechanisms. Can J Cardiol 2011;27:19-26.
Review
Antiarrhythmic Drugs in Atrial Fibrillation: Do They Have a Future? Paul Angaran, MD, and Paul Dorian, MD Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
ABSTRACT
RESUM E
Atrial fibrillation (AF) is a common arrhythmia associated with significant morbidity and mortality. There has been much debate about the relative merits of rate vs rhythm control strategies, and studies to date have failed to show advantage with a rhythm-control strategy using antiarrhythmic drugs (AADs). This is likely because of the inadequacies of our current AADs and the limitations of study designs. However, there is evidence that AADs improve symptoms and quality of life (QOL). Until trials are performed with more appropriate patient selection, and end points and better AADs and strategies for their use, rhythm control should not be abandoned and may continue to be beneficial in selected patients.
quente associe e à La fibrillation auriculaire (FA) est une arythmie fre et une mortalite significatives. Les me rites relatifs des une morbidite gies sur la maîtrise de la fre quence vs la maîtrise du rythme ont strate bat, et les e tudes re alise es jusqu’à ce jour sur la fait l’objet d’un long de gie de la maîtrise du rythme par les me dicaments antistrate montrer d’avantages pour la survie. Cela arythmiques n’ont pas su de s’explique probablement par les lacunes actuelles (antiarythmisants) thodologies. Cependant, certains travaux et les limites des me rent que les me dicaments antiarythmiques soulagent les sugge liorent la qualite de vie (QV). Jusqu’à ce que des symptômes et ame alise s à partir d’une se lection de patients et de critères essais soient re s, ainsi que de meilleurs me dicaments de jugement plus approprie gies d’utilisation, la maîtrise du antiarythmiques et de meilleures strate e et peut continuer d’être rythme ne devrait pas être abandonne ne fique chez certains patients. be
Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence of 1%-2%. The prevalence of AF is strongly associated with age, affecting < 1% of persons younger than 60 years and > 9% of persons older than 80 years.1 The number of affected individuals in the United States is expected to double in the next 40 years to about 5 million. In Canada, it is estimated that 350,000 Canadians are living with AF, and this number is expected to increase because of the aging population.2 AF is also the most common arrhythmia seen in the emergency department and accounts for up to one-third of arrhythmia-related hospitalizations.3 AF is associated with increased mortality and morbidity, particularly heart failure, stroke, and hospitalization.1,4-11 Patients with AF also have impaired quality of life (QOL), often similar to or worse than patients after myocardial infarction or those with heart failure.12 Furthermore, AF imposes significant costs on an increasingly constrained health care system.13
There has been considerable focus recently on improvement of risk stratification for stroke and therapies for prevention of thromboembolism in AF. Beyond the undoubted value of stroke prevention, debate and discussion have also included the relative merits of rate vs rhythm control in AF. The guidelines of all the major medical societies recommend the use of antiarrhythmic drugs (AADs) to improve symptoms in patients with symptomatic AF; however, there are detailed restrictions for patient selection.3,14-18 The purpose of this review is to discuss the goals of treatment of AF, the role of oral AADs in achieving and maintaining sinus rhythm and improving symptoms, and the limitations of the rate- vs rhythm-control trials. Conventional atrioventricular (AV) node blocking agents and nonpharmacologic strategies to maintain sinus rhythm, namely, catheter ablation therapy, will not be specifically addressed.
Received for publication March 19, 2013. Accepted April 26, 2013. Corresponding author: Dr Paul Dorian, Division of Cardiology, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. Tel.: þ1-416-864-5104; fax: þ1-416-864-5348. E-mail: [email protected] See page 1162 for disclosure information.
Goals of AF Management The 3 potential reasons to treat AF are to reduce mortality, reduce morbidity, and improve symptoms and QOL. Mortality AF has been associated with increased mortality, even after adjusting for other comorbidities.7 What remains unclear,
0828-282X/$ - see front matter 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.04.033
Angaran and Dorian Antiarrhythmic Drugs in Atrial Fibrillation
1159
however, is whether the relationship between AF and mortality is causal or AF simply is a marker of underlying disease. Several clinical trials comparing rate vs rhythm controldPharmacological Intervention in Atrial Fibrillation (PIAF),19 Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM),20 Rate Control vs Electrical Cardioversion (RACE),21 Strategies of Treatment of Atrial Fibrillation (STAF),22 How to Treat Chronic Atrial Fibrillation (HOT CAFE)23 and Atrial Fibrillation and Congestive Heart Failure (AF-CHF)24dhave failed to demonstrate that treatment of AF with the AADs available at the time resulted in improved mortality, and in fact in some trials AADs had a tendency to increase mortality. In contrast, secondary “on-treatment” analyses of the AFFIRM trial and other observational data suggest that rhythm control may be associated with lower long-term mortality.25-27 Based on studies to date, there is currently no strong evidence supporting the use of AADs to treat AF with the goal of improving mortality.
Symptoms and QOL One of the most important goals in treating AF is to minimize symptoms and improve QOL. Symptoms vary considerably and may include palpitations, dyspnea, dizziness, chest pain, weakness, and fatigue. Patients with AF have poorer QOL compared with healthy controls and those with coronary artery disease.12,28,29 Moreover, in 1 study, female patients with AF reported significantly more impaired QOL than did men, specifically related to physical and functional health.30 The Canadian Cardiovascular Society Severity in Atrial Fibrillation (CCS-SAF) scale is a bedside scale for assessing QOL in patients with AF. It is analogous to the New York Heart Association heart failure and CCS angina scores, ranging from class 0 (no effect on QOL) to class 4 (severe effect on QOL). The CCS-SAF scale has been assessed and validated in patients with paroxysmal and persistent AF and correlates well with symptom severity but not frequency and duration of AF episodes. It also correlates with health care resource consumption, with higher scores representing more frequent and longer hospitalizations, emergency department. and specialist visits, and increasing cardioversions31 (Fig. 1). This scale is particularly practical because it not only classifies symptom severity but also clearly demonstrates the correlation between health care resource consumption and symptoms, namely, that as health care consumption increases, QOL is adversely affected. It stands to reason that treating AF by restoring sinus rhythm should improve symptoms and thus QOL. However, this has not been completely borne out in the major trials of rate vs rhythm control. Four randomized controlled trials (STAF,22 PIAF,19 RACE,21 and AFFIRM20) comparing a strategy of rate control and rhythm control with AADs and/ or cardioversion have consistently shown improvement in QOL with both rate- and rhythm-control therapy. In intention-to-treat analyses, the rate-control strategy demonstrated greater improvement in QOL, except in the AFFIRM trial, which showed similar improvements in QOL between both groups. However, in the PIAF and HOT CAFE trials, 6-minute walk time and maximal treadmill workload were better in the rhythm-control groups, respectively.23,32
Figure 1. Canadian Cardiovascular Society Severity in Atrial Fibrillation (CCS-SAF) scale and health care use. As SAF class increased, a greater proportion of patients had (A) more emergency room visits and (B) more hospitalizations in the previous 1-year period (P < 0.001). AFSS, Atrial Fibrillation Severity Scale; ER, emergency room. Modified from Dorian et al.31 with permission from Wolters Kluwer Health.
Moreover, intention-to-treat analyses, which are appropriate for the primary end point, do not account for “treatment success.” If analysis is performed according to rhythm achieved, a slightly different picture emerges. In a substudy of the Canadian Trial of Atrial Fibrillation (CTAF) trial, in which patients were randomized to either amiodarone or sotalol/propafenone, QOL significantly improved from baseline to 3 months.33 QOL improved the most in patients in whom therapy prevented AF recurrence. In a substudy of the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFET) study, patients with persistent AF who underwent successful restoration and maintenance of sinus rhythm with AADs (amiodarone or sotalol) cardioversion had improved exercise performance measures and QOL34 (Figs. 2 and 3). In another study, patients with symptomatic AF were treated with open-label flecainide, and QOL was assessed by the SF36 and Atrial Fibrillation Severity Scale scores. The investigators found that (1) patients with uncontrolled symptomatic paroxysmal AF (PAF), but not those with controlled symptomatic PAF, had inferior QOL compared with healthy matched controls and that (2) patients treated with flecainide had improvement in their QOL to a level that was similar to that in patients with controlled symptomatic AF.35 These studies must be interpreted with caution because they are post-hoc analyses, but there is a consistent pattern of QOL improvement in patients who achieve sinus rhythm with an AAD. Further evidence to support this theory comes from
1160
Canadian Journal of Cardiology Volume 29 2013
Figure 2. Improvement in maximal exercise duration in patients with sinus rhythm (SR) vs atrial fibrillation (AF). Mean increase in maximal exercise duration from baseline to 8 weeks and 1 year in patients with sinus rhythm vs AF. Exercise tolerance in patients with sinus rhythm was significantly higher than in patients with AF at both 8 weeks (81.5 seconds vs 33.5 seconds; P ¼ 0.01) and 1 year (74.6 seconds vs 15.2 seconds; P ¼ 0.02). y SR group: n = 213; AF group: n = 145. z SR group: n = 219; AF group: n = 113. Reprinted from Singh et al.34 with permission from the American College of Cardiology Foundation.
“real world” practice. In the Real-life Global Survey Evaluating Patients With Atrial Fibrillation (REALISE-AF) registry, QOL was highest for patients in sinus rhythm, followed by patients with AF with heart rates 80 bpm and lowest in patients with AF with heart rates > 80 bpm.36 Perhaps the best proof-of-concept evidence comes from the radiofrequency catheter ablation literature. Several studies have demonstrated improved QOL after achieving and maintaining sinus rhythm through successful ablation.37-41 Patients treated with catheter ablation, compared with AADs, had improved symptoms, exercise capacity, QOL, and in 1 study, even fewer hospitalizations. This likely results from the much lower recurrence rate and burden of AF with catheter ablation, supporting the notion that restoration of sinus rhythm may in fact be beneficial.
Limitations of the Current Trials If AF causes substantial symptoms and impaired QOL, why is it that most major trials of rate vs rhythm control have failed to show improved outcomes with a rhythm control strategy? There are several potential explanations. First, clinical trials comparing rhythm control vs rate control typically included older patients (AFFIRM, mean age w70 years) and likely under-represented the younger and typically more symptomatic patients. Second, in most trials, conclusions were based on the “strategy” of either rhythm or rate control, irrespective of whether sinus rhythm was actually achieved and maintained. In AFFIRM, 37.4% of patients in the rhythm-control group remained in AF, and in the rate-control group, 34.6% of patients were in sinus rhythm at the 5-year visit.20 Results
Figure 3. Improvement in quality of life (QOL) in symptomatic patients with sinus rhythm (SR) vs atrial fibrillation (AF). Mean improvement in QOL scores from baseline to 1 year in patients with symptomatic AF. Patients in sinus rhythm are denoted by blue bars and patients with AF are denoted by red bars. Patients in sinus rhythm had a greater improvement in physical functioning, general health, vitality, and social functioning compared with patients in AF. SCL, symptom checklist. Reprinted from Singh et al.34 with permission from the American College of Cardiology Foundation.
Angaran and Dorian Antiarrhythmic Drugs in Atrial Fibrillation
were based on the strategy assigned and not whether sinus rhythm was actually achieved. However, analyzing data on the basis of whether sinus rhythm was achieved may point toward a different conclusion. In an AFFIRM substudy, using an “on-treatment analysis” sinus rhythm was significantly associated with improved survival (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39-0.72; P < 0.0001), but rhythm-control drug use was associated with increased mortality (HR, 1.49; 95% CI, 1.11-2.01; P ¼ 0.0005) after adjusting for the presence of sinus rhythm. This suggests that the beneficial effects of AADs were offset by their adverse events.26 In the small STAF pilot trial, patients with persistent AF were randomized to a rate- or rhythm-control strategy. Although there was no significant difference in the primary end point, 18 primary end points occurred during AF, whereas only 1 occurred in sinus rhythm (P ¼ 0.049).22 Similar results showing improved outcomes in patients who achieved and maintained sinus rhythm were also found in the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) trial42 and in AF studies with predominantly patients with heart failure, including a substudy of the Danish Investigations of Arrhythmia and Mortality on Dofetilide studies (DIAMOND)43 and Congestive Heart Failure: Survival Trial of Antiarrhythmic Therapy (CHF-STAT).44 Conversely, in a RACE substudy, patients in sinus rhythm did not experience improved outcomes compared with those who remained in AF,45 and in an AF-CHF substudy, sinus rhythm was not associated with improved mortality but did show a trend toward improvement of heart failure (HR, 0.62; 95% CI, 0.37-1.02; P ¼ 0.050).46 Although these results support improved outcomes with sinus rhythm, they should be interpreted with caution because they are secondary analyses. Another possible explanation is that the ability to achieve sinus rhythm may just be a marker for less severe underlying disease and therefore a more favorable prognosis. Third, in the AFFIRM trial, crossover between the groups was moderately large: at 5 years, approximately 15% of ratecontrol patients and 38% of rhythm-control patients crossed over to the other treatment group.20 The patients in the ratecontrol strategy group who crossed over to rhythm control presumably did so on the basis of symptom severity, suggesting that their QOL was impaired. Conversely, patients who crossed from a rhythm- to a rate-control strategy presumably had drug intolerance or inability to maintain sinus rhythm, and thus were unlikely to be receiving a QOL benefit from the originally assigned therapy. Finally, another possible reason why trials have not demonstrated improved QOL outcomes with a rhythm approach is that AADs are not perfectly effective and may have side effects that can mask or even outweigh the benefits of these drugs. These considerations indicate that AADs, if effective in restoring and maintaining sinus rhythm in symptomatic patients, or at least reducing or eliminating symptomatic recurrences and not causing adverse effects, can indeed result in QOL improvement. Limitations of Current AADs Current AADs are moderately effective at restoring and maintaining sinus rhythm. In the CTAF trial, the probability
1161
of remaining in sinus rhythm after 1 year was 69% in the amiodarone group and 39% in the sotalol/propafenone group (P < 0.001).47 Amiodarone remains the most effective drug,20,47,48 but its use is associated with frequent adverse effects with long-term use, notably extracardiac side effects. This was perhaps not a major issue in older and sicker patients enrolled in the AFFIRM and AF-CHF trials, in which amiodarone was used in 63% and 82% of patients, respectively.20,46 However, in the typical younger patient with PAF, long-term amiodarone use certainly poses challenges and its use is limited. Nonetheless, in select patients, amiodarone remains a highly effective and safe drug if properly monitored. Class IC AADs such as flecainide and propafenone are moderately effective at achieving and maintaining sinus rhythm in patients with AF. Their main risks include proarrhythmia and paradoxical increase in ventricular rates as a result of 1:1 AV node conduction from the organization of AF to atrial flutter. However, these risks can be minimized with careful patient selection and concurrent use of AV node blocking agents, but avoiding their use in patients with coronary artery disease and structural heart disease.49-51 Unfortunately, these drugs have not been extensively studied in the rate vs rhythm trials owing to the high use of amiodarone, comorbidities, and presence of structural heart disease. Dronedarone is a benzofuran derivative with a pharmacologic profile similar to amiodarone, but without the iodine and the addition of a methane-sulfonyl group.52 These structural changes result in fewer extracardiac side effects and a shorter half-life; however, this is at the price of decreased efficacy. In early trials, dronedarone was moderately efficacious at maintaining sinus rhythm (25% reduction) and achieving reasonable ventricular rate control (12-15 bpm or 7% reduction).53 A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA) trial was a double-blinded, placebo-controlled parallel-arm study assessing the efficacy of dronedarone 400 mg twice daily in high-risk patients with AF or atrial flutter.52 Unlike earlier trials that examined the first recurrence of AF, the primary end point used was first hospitalization because of cardiovascular events or death, representing a shift toward more meaningful clinical outcomes. Dronedarone significantly reduced the incidence of hospitalization from cardiovascular events or death in patients with AF or atrial flutter over a mean period of 21 5 months (HR, 0.74; 95% CI, 0.69-0.84; P < 0.001) (Fig. 4). These results were mainly driven by a reduction in AF-related hospitalizations. Although strictly speaking, there was no QOL measurement in ATHENA, the end point of hospitalization likely reflects the patient’s QOL or at the very least the physician’s perception of patient’s QOL. Hospitalization was driven by either the patient’s or the treating physician’s perceptions of the severity of symptoms from AF and as a result, the need to admit them to the hospital. In essence, by reducing hospitalizations in patients with AF, dronedarone indirectly improved QOL. The main side effects from dronedarone include bradycardia, QT-interval prolongation, and gastrointestinal side effects, including diarrhea and nausea, and rash. Perhaps the greatest concern with dronedarone arose from the Antiarrhythmic Trial With Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating
1162
Figure 4. Kaplan-Meier cumulative incidence of primary outcome in the ATHENA (A Trial With Dronedarone to Prevent Hospitalization or Death In Patients With Atrial Fibrillation) trial. The primary outcome was a composite of first hospitalization resulting from cardiovascular events or death from any cause, which occurred in 31.9% of the dronedarone group and in 39.4% of the placebo group, with a hazard ratio for dronedarone of 0.76 (95% confidence interval [CI], 0.69-0.84; P < 0.001). Reproduced from Hohnloser et al.52 Copyright ª 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
Morbidity Decrease (ANDROMEDA) and Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) studies, which randomized patients with symptomatic heart failure and severe left ventricular dysfunction and permanent AF, respectively.54,55 Both trials were stopped prematurely because of safety concerns resulting from increased mortality in the dronedarone group. As a result of these studies, dronedarone should not be administered to patients with acute or worsening heart failure, severe left ventricular dysfunction, or permanent AF. Although dronedarone has limitations as an AAD, the ATHENA study did demonstrate in a placebo-controlled, blinded, randomized paradigm, that an AAD can indeed lead to important patient benefit in patients with symptomatic AF. AAD Therapy Should Not Be Abandoned The failure of the rhythm strategy in the rate vs rhythm trials to show benefit does not mean that rhythm control should be completely abandoned. Development of new AADs with more favorable efficacy/side effect profiles may be one strategy to improve outcomes. Further research and advances in basic science mechanisms are needed to help achieve this goal.56 Alternatively, more careful patient selection combined with strategies to prescribe and continue AADs only if they are clinically effective have yet to be studied and could prove effective. The ideal patients who are eligible for a trial of AADs are those with highly symptomatic PAF or persistent AF, not including those patients with minimal or nonsymptomatic AF or permanent AF. A new paradigm for the design of clinical trials using AADs may prove more fruitful given the “disconnect” between
Canadian Journal of Cardiology Volume 29 2013
clinical trials to date and “real world” practice. In most trials of rhythm control, patients randomized to the rhythm-control group continued to receive AADs regardless of their effectiveness. This is not in keeping with everyday practice in which drugs are titrated, changed, or stopped depending on the patient’s clinical response and side effects. Indeed, “chasing sinus rhythm” may be a fool’s errand whereby we use too many AADs at doses that are too high and are never able to demonstrate the effectiveness of AADs. The better strategy may perhaps be to aim for symptomatic improvement even if the rhythm is sometimes AF, and not strive for complete rhythm control (which may in fact not be achievable). Although time to first recurrence of AF and AF burden has been used as an efficacy end point in many studies, these outcomes are less meaningful for several reasons, including clustering of AF episodes, limitations of monitoring strategies, and poor correlation with symptoms and cardiovascular outcomes. If we can decrease the severity or number of symptomatic AF episodes, this would be a clinical success, but it has largely been ignored in clinical trials using an end point of recurrence or mortality. An alternative trial design, which has not been performed to date, would be structured so that AADs are continued only if patient QOL improves and are stopped otherwise. The ATHENA protocol came closer to this than any other study because the end point was not rhythm control with any electrocardiographic mandated definitions of success. Simply “prescribing the drug” and following patients clinically, ie, “treating the patient and not the electrocardiogram” is what we do, or should be doing, in clinical practice. The ATHENA trial therefore supports the concept that AADs can benefit patients but that dronedarone may not be the ideal drug to do so. We thus need studies comparing strategies of “symptom control” using AADs and AV node blockers. Effectiveness trials, instead of efficacy trials, whereby therapies are not necessarily discontinued at recurrence but rather are continued if the therapy continues to be helpful, may be the better way to finally demonstrate the potential benefits of rhythm control on QOL. Conclusions Trials to date have largely failed to consistently demonstrate that rhythm control to maintain sinus rhythm in patients with AF is superior to rate control with respect to improving QOL, but they do not disprove it either. This is likely a result of the inherent limitations of the study designs combined with current inadequacies of AADs. The ideal trials have yet to be conducted and until they are, the issue of whether rhythm control is superior for improving QOL will remain unresolved. Disclosures Dr Dorian has received honoraria and consulting fees from Bristol-Myers Squibb, Merck, and Sanofi. Dr Angaran has no conflicts of interest to disclose. References 1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and
Angaran and Dorian Antiarrhythmic Drugs in Atrial Fibrillation stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001;285:2370-5. 2. Heart and Stroke Foundation. Statistics:atrial fibrillation. Available at http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3483991/k.34A8/ Statistics.htm#atrialfib. Accessed June 10, 2013. 3. 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): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114: e257-354. 4. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995;98:476-84. 5. Go AS. The epidemiology of atrial fibrillation in elderly persons: the tip of the iceberg. Am J Geriatr Cardiol 2005;14:56-61. 6. 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;113:359-64. 7. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158:229-34. 8. Wattigney WA, Mensah GA, Croft JB. Increased atrial fibrillation mortality: United States, 1980-1998. Am J Epidemiol 2002;155:819-26. 9. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-8. 10. 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: 946-52. 11. Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation 2003;108:711-6. 12. Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol 2000;36: 1303-9. 13. Wodchis WP, Bhatia RS, Leblanc K, Meshkat N, Morra D. A review of the cost of atrial fibrillation. Value Health 2012;15:240-8. 14. Gillis AM, Verma A, Talajic M, Nattel S, Dorian P. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: rate and rhythm management. Can J Cardiol 2011;27:47-59. 15. Skanes AC, Healey JS, Cairns JA, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 2012;28:125-36. 16. Camm AJ, Kirchhof P, Lip GY, 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: 2369-429. 17. 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. Eur Heart J 2012;33:2719-47.
1163
18. 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. Circulation 2011;123:104-23. 19. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillationdPharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789-94. 20. 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;347:1825-33. 21. 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;347:1834-40. 22. 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;41:1690-6. 23. 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;126:476-86. 24. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-77. 25. Ionescu-Ittu R, Abrahamowicz M, Jackevicius CA, et al. Comparative effectiveness of rhythm control vs rate control drug treatment effect on mortality in patients with atrial fibrillation. Arch Intern Med 2012;172: 997-1004. 26. 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;109:1509-13. 27. Steinberg JS, Sadaniantz A, Kron J, et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109:1973-80. 28. Howes CJ, Reid MC, Brandt C, et al. Exercise tolerance and quality of life in elderly patients with chronic atrial fibrillation. J Cardiovasc Pharmacol Ther 2001;6:23-9. 29. van den Berg MP, Hassink RJ, Tuinenburg AE, et al. Quality of life in patients with paroxysmal atrial fibrillation and its predictors: importance of the autonomic nervous system. Eur Heart J 2001;22:247-53. 30. Paquette M, Roy D, Talajic M, et al. Role of gender and personality on quality-of-life impairment in intermittent atrial fibrillation. Am J Cardiol 2000;86:764-8. 31. Dorian P, Guerra PG, Kerr CR, et al. Validation of a new simple scale to measure symptoms in atrial fibrillation: the Canadian Cardiovascular Society Severity in Atrial Fibrillation scale. Circ Arrhythm Electrophysiol 2009;2:218-24. 32. Hohnloser SH, Kuck KH. Randomized trial of rhythm or rate control in atrial fibrillation: the Pharmacological Intervention in Atrial Fibrillation Trial (PIAF). Eur Heart J 2001;22:801-2. 33. 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: 276-9. 34. Singh SN, Tang XC, Singh BN, et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial
1164 fibrillation: a Veterans Affairs Cooperative Studies Program Substudy. J Am Coll Cardiol 2006;48:721-30. 35. Guedon-Moreau L, Capucci A, Denjoy I, et al. Impact of the control of symptomatic paroxysmal atrial fibrillation on health-related quality of life. Europace 2010;12:634-42. 36. Steg PG, Alam S, Chiang CE, et al. Symptoms, functional status and quality of life in patients with controlled and uncontrolled atrial fibrillation: data from the RealiseAF cross-sectional international registry. Heart 2012;98:195-201. 37. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure (ARC-HF). J Am Coll Cardiol 2013;61: 1894-903. 38. 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;303:333-40. 39. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation 2008;118: 2498-505.
Canadian Journal of Cardiology Volume 29 2013 45. Rienstra M, Van Gelder IC, Hagens VE, et al. Mending the rhythm does not improve prognosis in patients with persistent atrial fibrillation: a subanalysis of the RACE study. Eur Heart J 2006;27:357-64. 46. Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol 2010;55:1796-802. 47. 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;342:913-20. 48. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861-72. 49. 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;324:781-8. 50. 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;64:1317-21.
40. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA 2005;293:2634-40.
51. Clementy J, Dulhoste MN, Laiter C, Denjoy I, Dos Santos P. Flecainide acetate in the prevention of paroxysmal atrial fibrillation: a nine-month follow-up of more than 500 patients. Am J Cardiol 1992;70:44A-9A.
41. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012;367:1587-95.
52. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360: 668-78.
42. Ogawa S, Yamashita T, Yamazaki T, et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ J 2009;73:242-8. 43. 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 investigation of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 2001;104:292-6. 44. Deedwania PC, Singh BN, Ellenbogen K, et al. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHFSTAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation 1998;98:2574-9.
53. 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: 987-99. 54. Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358: 2678-87. 55. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268-76. 56. Nattel S. From guidelines to bench: implications of unresolved clinical issues for basic investigations of atrial fibrillation mechanisms. Can J Cardiol 2011;27:19-26.