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.
Atrial ﬁbrillation (AF) is the most common cardiac arrhythmia requiring medical therapy.1–4 The prevalence
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.
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
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.
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)
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
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,
Dronedarone Propafenone p=0.990
Figure. Kaplan-Meier estimates of the probability of remaining in sinus rhythm during follow-up after electrical cardioversion (n ¼ 49 per group).
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)
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
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
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
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.
CONFLICTS OF INTEREST The authors have indicated that they have no conﬂicts of interest with regard to the content of this article.
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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]