Clinical Therapeutics/Volume 36, Number 9, 2014

Efficacy of Dronedarone Versus Propafenone in the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation After Electrical Cardioversion Kwang Jin Chun, MD; Kyeongmin Byeon, MD; Sung Il Im, MD; Kyoung-Min Park, MD, PhD; Seung-Jung Park, MD, PhD; June Soo Kim, MD, PhD; and Young Keun On, MD, PhD Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea ABSTRACT Purpose: Our objective was to compare the efficacy of dronedarone and propafenone in maintaining sinus rhythm in patients with atrial fibrillation (AF) after electrical cardioversion. Methods: In this single-center, open-label, randomized trial, we randomly assigned patients with AF after electrical cardioversion to receive dronedarone 400 mg BID or propafenone 150 mg TID. Follow-up clinical evaluations were conducted at 1, 2, 3, and 6 months of treatment. The primary end point was the time to the first recurrence of AF. Findings: A total of 98 patients were enrolled (79 men; mean age, 59.2 years; n ¼ 49 per group). The median times to first recurrence of AF were 31 days in the dronedarone group and 32 days in the propafenone group (P ¼ 0.715). The median (interquartile range) ventricular rates at first recurrence of AF were 76.5 (67.3–86.5) beats/min in the dronedarone group and 83.0 (71.0–96.0) beats/min in the propafenone group (P ¼ 0.059). Implications: Dronedarone and propafenone had similar efficacies in maintaining sinus rhythm in patients with AF after electrical cardioversion. The ventricular rate at the first recurrence of AF was numerically but not statistically significantly lower in the dronedarone group than in the propafenone group. ClinicalTrials.gov identifier: NCT01991119. (Clin Ther. 2014;36:1169–1175) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: atrial fibrillation, dronedarone, electrical cardioversion, propafenone.

INTRODUCTION

Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy.1–4 The prevalence

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of AF was 0.95% in persons aged 20 years or older (4). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older (4). There are 2 treatment options for the management of AF. One is rhythm control and the other is rate control, but the optimal strategy remains unclear.5,6 Because the maintenance of sinus rhythm is often associated with an improvement in health-related quality of life and exercise capacity, the restoration and maintenance of sinus rhythm remain the major goals in patients with AF.7 But the optimal long-term drug strategy is controversial. Dronedarone is a benzofuran derivative with an electropharmacologic profile closely resembling that of amiodarone, but with structural differences intended to eliminate the adverse effects of amiodarone on thyroid and pulmonary function.8,9 Propafenone, a class IC antiarrhythmic drug, has been widely used for the prevention of AF recurrence.10 However, based on a literature search, there are no studies available that have compared the efficacy of dronedarone and propafenone in maintaining sinus rhythm. Our objective was to compare the efficacy of dronedarone and propafenone in maintaining sinus rhythm in patients with AF after electrical cardioversion.

PATIENTS AND METHODS This single-center, open-label, randomized trial was conducted in men and women who were aged Z18 years and who had persistent AF nonresponsive to chemical cardioversion. The patients were admitted Accepted for publication July 23, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.07.013 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics and underwent electrical cardioversion. After conversion to sinus rhythm, eligible patients were randomly assigned to receive dronedarone or propafenone. Exclusion criteria were an acute myocardial infarction within the 3 months before screening, New York Heart Association functional class IV heart failure, New York Heart Association functional class II or III decompensated heart failure requiring hospitalization, echocardiographic ejection fraction o35%, previous treatment with amiodarone, bradycardia at o50 beat/ min, second- or third-degree atrioventricular block or sick sinus syndrome without a permanent pacemaker, severe hepatic dysfunction, pregnancy, QT prolongation of Z500 msec or PR interval 4280 msec, and/or hypersensitivity to the study drugs. Patients were enrolled Between May 2011 and April 2013. The dronedarone regimen was 400 mg BID, and the propafenone regimen was 150 mg TID. If AF recur during follow-up period, the patients were prescribed another antiarrhythmic drug, for example, amiodarone or conducted radiofrequency catheter ablation. Follow-up visits were scheduled at 1, 2, 3, and 6 months of treatment and included a clinical evaluation and 12-lead ECG. If symptoms that suggested recurrence of AF were noted, additional visits were scheduled and evaluations performed. All patients were followed up for 6 months after randomization. The primary end point was the time to first recurrence of AF after sinus rhythm had been restored. The secondary end point was the ventricular rate at first recurrence and the risk factors for the recurrence of AF. All patients provided informed consent for inclusion in the study. The protocol was approved by the institutional review board at Samsung Medical Center, Seoul, South Korea.

Statistical Analysis The hypothesis for determining the number of patients needed for the study was derived from data from efficacy trials of antiarrhythmic drugs for the maintenance of sinus rhythm in patients with AF.11,12 On the basis of these studies, the estimated rates of sustained sinus rhythm at 6 months were 75% in the dronedarone group and 45% in propafenone group. To obtain a statistical power of 80% at the 5% level of significance, a sample size of 100 patients (50 in the dronedarone group and 50 in the propafenone group) was needed, assuming a 20% dropout rate and 6-month follow-up period. All reported P values are

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2-sided, and P values of o0.05 were considered to indicate statistical significance. Continuous data are expressed as means (SD) or medians (interquartile range [IQR]). Categorical data are expressed as frequencies and percentages. To evaluate the difference between the study groups, we used the unpaired t test for normally distributed data and the Mann-Whitney U test for skewed data. Categorical data were analyzed with the χ2 test or the Fisher exact test. The Kaplan-Meier method and log-rank test were used to compare the probability of remaining in sinus rhythm between the 2 study groups.

RESULTS A total of 100 patients were enrolled; data from 1 patient were omitted due to a protocol violation, and another patient withdrew informed consent, leaving 49 patients randomly assigned to receive dronedarone and 49 to receive propafenone. Table I presents the baseline characteristics of the patients in the 2 study groups. The mean age was 58.6 years and 81.6% were male in the dronedarone group, and the mean age was 59.8 years and 79.6% were male in the propafenone group. The prevalences of hypertension, diabetes, dyslipidemia, and a history of congestive heart failure did not differ significantly between the 2 study groups. The mean left ventricular ejection fraction was 58.86%, and the mean left atrial diameter by transthoracic echocardiography was 44.8 mm in the dronedarone group; corresponding values were 59.12% and 42.9 mm, respectively, in the propafenone group. The mean (SD) duration of follow-up in the non– end point patients was 172.4 (39.6) days; the median was 177.0 days. At 6 months, 73.5% of the patients in the dronedarone group and 75.5% of the patients in the propafenone group had a recurrence of AF (hazard ratio in the dronedarone group, 0.898 [95% CI, 0.362–2.229) (P ¼ 0.817). The median times to the first documented recurrence of AF were 31 days in the dronedarone group and 32 days in propafenone group (P ¼ 0.715) (Table II). The median (IQR) ventricular rates at the first documented recurrence of AF were 76.5 (67.3–86.5) beats/min in the dronedarone group and 83.0 (71.0–96.0) beats/min in the propafenone group (P ¼ 0.059). The Figure shows the Kaplan-Meier estimates of the probability of remaining in sinus rhythm. The

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Table I. Baseline characteristics of the groups in this study of the effects of treatment with dronedarone or propafenone in patients with atrial fibrillation (AF) after electrical cardioversion. Characteristic Age, mean (SD), y Male, no. (%) Body mass index, mean (SD), kg/m2 Weight, mean (SD), kg Risk factors, no. (%) Smoking status Current Former Never Disease history Hypertension Dyslipidemia Diabetes mellitus History of thyroid disease History of cerebrovascular disease History of congestive heart failure PAOD Duration of AF, no. (%) r1 y 41 y Cardiac parameters on admission Ventricular rate, median (IQR), beats/min LA diameter, mean (SD), mm LA volume index, median (IQR), mL/m2 Left ventricular ejection fraction, mean (SD), % Concurrent cardiovascular therapy, no. (%) Warfarin NOAC ARB CCB β-Blocker Diuretic Statin Aspirin ACE inhibitor Clopidogrel Digoxin Previous antiarrhythmic treatment, no. (%) Class Ic Class III Pilsicainide

Dronedarone (n ¼ 49) 58.6 40 25.7 71.7

(8.0) (81.6) (3.3) (11.1)

Propafenone (n ¼ 49) 59.8 39 25.7 72.3

(11.2) (79.6) (3.1) (10.5)

P 0.535 0.798 0.978 0.794 0.787

6 (12.2) 8 (16.3) 35 (71.4)

8 (16.3) 9 (18.4) 32 (65.3)

22 7 6 5 3 2 1

25 4 7 6 1 1

(44.9) (14.3) (12.2) (10.2) (6.1) (4.1) (2.0)

34 (69.4) 15 (30.6) 77 44.8 46.0 58.86 32 14 14 10 9 9 8 3 2 2

(67–90) (5.8) (38.1–55.0) (7.27) (65.3) (28.6) (28.6) (20.4) (18.4) (18.4) (16.3) (6.1) (4.1) (4.1) 0

15 (30.6) 2 (4.1) 14 (28.6)

(51.0) (8.2) (14.3) (12.2) (2.0) (2.0) 0

0.544 0.337 0.766 0.749 0.617 1.000 1.000 0.145

27 (55.1) 22 (44.9) 80 42.9 44.6 59.12 34 12 10 12 18 9 7 5 1 1 1

(71–88) (5.3) (38.2–50.8) (5.90)

0.771 0.091 0.693 0.843

(69.4) (24.5) (20.4) (24.5) (36.7) (18.4) (14.3) (10.2) (2.0) (2.0) (2.0)

0.667 0.647 0.347 0.628 0.042 1.000 0.779 0.715 1.000 1.000 1.000 0.155

8 (16.3) 0 18 (36.7)

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin II receptor blocker; CCB ¼ calcium channel blocker; IQR ¼ interquartile range; LA ¼ left atrial; PAOD, peripheral arterial occlusive disease; NOAC, new oral anticoagulant.

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Table II. Outcomes in this study of the effects of treatment with dronedarone or propafenone in patients with atrial fibrillation (AF) after electrical cardioversion. Variable Recurrence of AF, no. (%) Time to first recurrence, median, d Ventricular rate at first recurrence, median (IQR), bests/min Duration of AF r1 y, no. Median, d 41 y, no. Median, d

Dronedarone (n ¼ 49)

Propafenone (n ¼ 49)

P

36 (73.5) 31 76.5 (67.3–86.5)

37 (75.5) 32 83.0 (71.0–96.0)

0.817 0.715 0.059

24 31 12 31

18 32 19 31

0.809 0.668

IQR ¼ interquartile range.

Probability of Remaining in Sinus Rhythm (%)

difference between the 2 groups was not significant (P ¼ 0.990 [log-rank test]). The age, sex, left atrial size, left atrial volume index, a history of congestive heart failure, and left ventricular ejection fraction did not appear as predictors of the recurrence of AF (Table III). We conducted a subgroup analysis according to the duration of atrial fibrillation. On the basis of 41 year, we stratified the patients into 2 groups (r1 vs 41 year). In the r1-year subgroup, the median times to the first documented recurrence of AF were 31 days with dronedarone and 32 days with propafenone (P ¼ 0.809). In the 41-year subgroup,

100

Dronedarone Propafenone p=0.990

50

0 0

50

150

100

200

250

Days

Figure. Kaplan-Meier estimates of the probability of remaining in sinus rhythm during follow-up after electrical cardioversion (n ¼ 49 per group).

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these values were 31 days with both treatments (P ¼ 0.668) (Table II).

DISCUSSION We compared the efficacy of maintaining sinus rhythm after electrical cardioversion between dronedarone and propafenone, and efficacy was similar between the 2 groups. Based on a literature search, there have been no studies that have directly compared the efficacy between dronedarone and propafenone to date. In our study, the rates of remaining in sinus rhythm after 6 months were 26.5% in the dronedarone group and 24.5% in the propafenone group. Previous studies reported rates of remaining in sinus rhythm ranging from 35% to 75% with dronedarone and 39% to 70% with propafenone at 6 months.11–19 The rates of remaining in sinus rhythm in our study with dronedarone and propafenone were lower than those in other studies. The other studies enrolled patients with paroxysmal AF as well as persistent AF, but our study excluded patients with paroxysmal AF. This difference may explain the difference in rates between our study and those studies. One study reported that the use of intracellular calcium-lowering medications (β-blockers and calcium channel blockers) during AF, but not after conversion to sinus rhythm, may lower the recurrence rate of AF in the first month after cardioversion, especially during the first 5 days.20 In our study, the rates of

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Table III. Risk factors for the recurrence of atrial fibrillation (AF) under treatment with dronedarone or propafenone in patients with AF after electrical cardioversion. Data are given as no. (%) of patients unless otherwise noted. Parameter Age group r65 y 465 y Male History of congestive heart failure Cardiac parameters LA diameter r44 mm 444 mm LA volume r34 mL/m2 434 mL/m2 Left ventricular ejection fraction, mean (SD), %

Recurrence of AF (n ¼ 73)

No Recurrence of AF (n ¼ 25)

P 0.564

54 19 60 3

(74.0) (26.0) (82.2) (4.1)

17 (68.0) 8 (32.0) 19 (76.0) 0

41 (56.2) 32 (43.8)

14 (56.0) 11 (44.0)

7 (9.6) 66 (90.4) 59.4 (6.7)

4 (16.0) 21 (84.0) 57.7 (6.3)

0.561 0.568 0.989

0.464

0.251

LA ¼ left atrial.

use of β-blockers and calcium channel blockers before cardioversion were similar between the 2 groups. The ventricular rate during the recurrence of AF was evaluated. In our study, the median (IQR) ventricular rates were 76.5 (67.3–86.5) beats/min in the dronedarone group and 83.0 (71.0-96.0) beats/ min in the propafenone group (P ¼ 0.059). There was numerically but not statistically significantly greater control of the heart rate in the dronedarone group. There have been 2 studies that evaluated the ventricular rate during the first recurrence of AF after the restoration of sinus rhythm.12,19 In both trials, the effects of dronedarone were compared with those of placebo, and dronedarone was more effective than placebo in controlling the heart rate at the time of the recurrence of AF (P o 0.001). The mean (SD) ventricular rates during the first documented recurrence were 102.3 (24.7) beats/min and 104.6 (27.1) beats/min, respectively, in the dronedarone group in one study (European and non-European trials, respectively).19 In another study, the mean (SD) ventricular rate during the first documented recurrence was 78.5 (18.2) beats/min and the median ventricular rate was 75 beats/min in the dronedarone group.12 The ventricular rate during the recurrence of AF in our

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study was numerically similar or lower. In the present study, we allowed the use of β-blockers or calcium channel blockers after the electrical cardioversion. The β-blockers were used more often in the propafenone group (36.7% vs 18.4% in the dronedarone group; P ¼ 0.042), and calcium channel blocker was similarly used (24.5% vs 20.4%, respectively; P ¼ 0.628). So if the difference in the use of β-blockers between the 2 groups had been modified, different results might have been reported. Some studies have reported that the left atrial diameter and underlying heart disease are predictors of the recurrence of AF, but another study failed to show the same results.14,21–23 Our study demonstrated that the age, sex, left atrial diameter, left atrial volume index, a history of congestive heart failure, and left ventricular ejection fraction were not predictors of AF recurrence.

Study Limitations A relatively small number of patients were enrolled in our study. We investigated only the efficacy of the study drugs, so any adverse events with use of the study drugs, and health-related quality of life, were not assessed. In our study, follow-up visits were scheduled

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Clinical Therapeutics at 1, 2, 3, and 6 months, and we did not use transtelephonic ECG monitors. In some studies on the maintenance of sinus rhythm in patients with AF, recurrence of AF develops within the first month after the restoration of sinus rhythm. Although we educated the patients that if at any time they felt any symptoms of a recurrence they should visit the hospital, there was the possibility of missing asymptomatic occurrences.

CONCLUSIONS In the present trial in these patients with AF after electrical cardioversion, dronedarone and propafenone had similar efficacy in maintaining sinus rhythm. The ventricular rate at the time of the first recurrence of AF was numerically but not statistically significantly lower in the dronedarone group than in the propafenone group.

ACKNOWLEDGMENTS None.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.

REFERENCES

1. Tsang TS, Gersh BJ. Atrial fibrillation: an old disease, a new epidemic. Am J Med. 2002;113:432–435. 2. Singh BN. Atrial fibrillation: epidemiologic considerations and rationale for conversion and maintenance of sinus rhythm. J Cardiovasc Pharmacol Ther. 2003;8(Suppl 1):S13– S26. 3. Prystowsky EN, Benson DW Jr, Fuster V, et al. Management of patients with atrial fibrillation. A Statement for Healthcare Professionals. From the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation. 1996;93:1262–1277. 4. 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;285:2370–2375. 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;347:1834–1840. 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;347:1825–1833.

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7. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med. 2005;352:1861– 1872. 8. Sun W, Sarma JS, Singh BN. Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone. J Cardiovasc Pharmacol. 2002;39:677–684. 9. Sun W, Sarma JS, Singh BN. Electrophysiological effects of dronedarone (SR33589), a noniodinated benzofuran derivative, in the rabbit heart : comparison with amiodarone. Circulation. 1999;100:2276–2281. 10. Funck-Brentano C, Kroemer HK, Lee JT, Roden DM. Propafenone. N Engl J Med. 1990;322:518–525. 11. Pritchett EL, Page RL, Carlson M, Undesser K, Fava G. Efficacy and safety of sustained-release propafenone (propafenone SR) for patients with atrial fibrillation. Am J Cardiol. 2003;92:941–946. 12. Page RL, Connolly SJ, Crijns HJ, et al. Rhythm- and ratecontrolling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol. 2011;107:1019–1022. 13. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J. 2003;24: 1481–1487. 14. 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;88:640–645. 15. Kochiadakis GE, Igoumenidis NE, Hamilos MI, et al. Long-term maintenance of normal sinus rhythm in patients with current symptomatic atrial fibrillation: amiodarone vs propafenone, both in low doses. Chest. 2004;125:377–383. 16. Kochiadakis GE, Igoumenidis NE, Hamilos ME, et al. Sotalol versus propafenone for long-term maintenance of normal sinus rhythm in patients with recurrent symptomatic atrial fibrillation. Am J Cardiol. 2004;94:1563–1566. 17. Stroobandt R, Stiels B, Hoebrechts R. Propafenone for conversion and prophylaxis of atrial fibrillation. Propafenone Atrial Fibrillation Trial Investigators. Am J Cardiol. 1997;79:418–423. 18. Antman EM, Beamer AD, Cantillon C, McGowan N, Friedman PL. Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs. J Am Coll Cardiol. 1990;15:698–707. 19. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987–999. 20. Tieleman RG, Van Gelder IC, Crijns HJ, et al. Early recurrences of atrial fibrillation after electrical cardioversion: a result of fibrillation-induced electrical remodeling of the atria? J Am Coll Cardiol. 1998;31:167–173.

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21. 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;134:419–425. 22. Reimold SC, Lamas GA, Cantillon CO, Antman EM. Risk factors for the development of recurrent atrial fibrillation: role of pacing and clinical variables. Am Heart J. 1995;129: 1127–1132. 23. Ewy GA, Ulfers L, Hager WD, Rosenfeld AR, Roeske WR, Goldman S. Response of atrial fibrillation to therapy: role of etiology and left atrial diameter. J Electrocardiol. 1980;13: 119–123.

Address correspondence to: Young Keun On, MD, PhD, Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, #81 Irwon-ro Gangnam-gu, Seoul 135-710, South Korea. E-mail: [email protected]

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Efficacy of dronedarone versus propafenone in the maintenance of sinus rhythm in patients with atrial fibrillation after electrical cardioversion.

Our objective was to compare the efficacy of dronedarone and propafenone in maintaining sinus rhythm in patients with atrial fibrillation (AF) after e...
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