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Background Amiodarone is effective in maintaining sinus rhythm in atrial fibrillation but is associated with potentially serious toxic effects. Dronedarone is a new antiarrhythmic agent pharmacologically related to amiodarone but developed to reduce the risk of side effects.
Methods In two identical multicenter, double-blind, randomized trials, one conducted in Europe (ClinicalTrials.gov number, NCT00259428
[ClinicalTrials.gov]
) and one conducted in the United States, Canada, Australia, South Africa, and Argentina (termed the non-European trial, NCT00259376
[ClinicalTrials.gov]
), we evaluated the efficacy of dronedarone, with 828 patients receiving 400 mg of the drug twice daily and 409 patients receiving placebo. Rhythm was monitored transtelephonically on days 2, 3, and 5; at 3, 5, 7, and 10 months; during recurrence of arrhythmia; and at nine scheduled visits during a 12-month period. The primary end point was the time to the first recurrence of atrial fibrillation or flutter.
Results In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002). At the recurrence of arrhythmia in the European trial, the mean (±SD) ventricular rate was 117.5±29.1 beats per minute in the placebo group and 102.3±24.7 beats per minute in the dronedarone group (P<0.001); the corresponding rates in the non-European trial were 116.6±31.9 and 104.6±27.1 beats per minute (P<0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group.
Conclusions Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.
Amiodarone is an especially potent atrial antifibrillatory agent,7 but it induces potentially serious side effects in some patients.7,8,9,10 Thus, compounds that are devoid of such effects but that retain the antiarrhythmic potential of amiodarone are therapeutically desirable.7,11 Dronedarone is a benzofuran derivative with an electropharmacologic profile closely resembling that of amiodarone12,13,14,15,16,17,18,19,20 but with structural differences intended to eliminate the effects of amiodarone on thyroid and pulmonary functions.17,18 In addition, the elimination half-life of dronedarone is 1 to 2 days, as compared with 30 to 55 days for amiodarone.20 We investigated the hypothesis that dronedarone is superior to placebo for maintaining sinus rhythm after electrical, pharmacologic, or spontaneous conversion from atrial fibrillation or atrial flutter.
Methods
Study Design
The European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS, NCT00259428 [ClinicalTrials.gov] ) and the American–Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS, NCT00259376 [ClinicalTrials.gov] ) were two identical, placebo-controlled, multicenter, double-blind, parallel-group trials sponsored by Sanofi-Aventis. The European trial was conducted in 12 European countries, and the non-European trial was conducted in the United States, Canada, Australia, South Africa, and Argentina.
The study protocols were approved by the human-research review boards at each participating institution. A single common steering committee designed the studies and the data analysis plans in collaboration with the sponsor. An independent data and safety monitoring board oversaw the safety of patients. All data-management activities were the responsibility of the sponsor. Data entry, verification, and validation were performed with the use of standard computer software (Clintrial 4.3), and data were stored in an Oracle database on a Sun Solaris computer. At study termination, the database was locked and transferred to the biostatistics department at Sanofi-Aventis for analysis. The academic investigators had independent access to the raw data. Dr. Singh, who wrote the manuscript with input from the other steering-committee members and from Sanofi-Aventis personnel, vouches for the accuracy and completeness of the data and the analysis.
Patients
Patients qualifying for enrollment were of either sex and at least 21 years of age, had had at least one episode of atrial fibrillation (as seen on electrocardiography) in the preceding 3 months, and were in sinus rhythm for at least 1 hour before randomization. Excluded from the study were patients with permanent atrial fibrillation (i.e., a duration of at least 12 months); women who could become pregnant and who were not using birth control; patients who had had torsades de pointes; patients with persistent bradycardia of less than 50 beats per minute, a PR interval of 0.28 second or more on electrocardiography, second-degree (or higher) atrioventricular block, and clinically significant sinus-node disease without an implanted pacemaker; patients who were taking class I or III antiarrhythmic agents; patients with New York Heart Association class III or IV congestive heart failure; and patients with a serum creatinine level of 1.7 mg per deciliter (150 µmol per liter) or more, severe electrolyte abnormalities, and clinically significant hepatic, pulmonary, endocrine, or other disorders associated with atrial fibrillation. Previous treatment with amiodarone was permitted, and patients who had received the drug could be enrolled immediately after its discontinuation. Written informed consent was obtained from all patients.
Baseline Evaluation, Randomization, and Therapy
All study patients underwent a baseline evaluation that included a medical history, symptom review, cardiovascular examination, assessment of vital signs, 12-lead electrocardiography, chest radiography, and laboratory tests, including a complete blood count and tests of serum electrolytes, urea, creatinine, and cholesterol and thyroid and liver function. Left atrial size and left ventricular ejection fraction were determined by two-dimensional echocardiography. Eligible patients who were not in sinus rhythm during screening could be enrolled if they underwent successful cardioversion and remained in sinus rhythm for at least 1 hour.
After a 7-day screening period, eligible patients were randomly assigned in a 2:1 ratio to receive either 400 mg of oral dronedarone twice daily or a matching placebo. A stochastic randomization procedure suggested by Pocock and Simon21 and revised by Freedman and White22 was used. On the first day of the study, symptoms were evaluated, vital signs were assessed, the assigned study drug was administered, and 12-lead electrocardiography was performed.
Follow-up
We scheduled follow-up visits that included a review of symptoms, assessment of vital signs, and performance of electrocardiography on days 7, 14, and 21 and at 2, 4, 6, 9, and 12 months. The above-mentioned blood tests were repeated on day 21 and at months 4, 9, and 12. Chest radiography was repeated in the case of pulmonary symptoms.
All enrolled patients were given a transtelephonic electrocardiographic monitor and were instructed in its use. Patients transmitted electrocardiograms on days 2, 3, and 5; at months 3, 5, 7, and 10; and whenever they had symptoms. On each occasion, two electrocardiograms were recorded approximately 10 minutes apart and were evaluated at a central core laboratory (MDS Pharma Services, Paris) by investigators who were unaware of study-group assignments to confirm the recurrence of atrial fibrillation. Each time an electrocardiogram was recorded, the patient was contacted to confirm the occurrence of one or more of the following symptoms: palpitations, dizziness, fatigue, chest pain, and dyspnea. Reported symptoms were taken into account if they were accompanied by atrial fibrillation. If oral anticoagulation therapy was administered, the international normalized ratio was monitored locally.
Study End Points
The primary end point was the time from randomization to the first documented recurrence of atrial fibrillation, defined as an episode lasting for at least 10 minutes and confirmed by two consecutive recordings taken 10 minutes apart on 12-lead electrocardiography or transtelephonic monitoring. The main secondary end points were symptoms related to atrial fibrillation during recordings of 12-lead electrocardiography or transtelephonic monitoring and the mean ventricular rate during the first recurrence.
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 treatment of atrial fibrillation.23,24,25 It was presumed that 60% of patients in the placebo group would have a recurrence of arrhythmia within 12 months; a relative decrease in this rate of at least 25% was expected in the dronedarone group (i.e., a 45% recurrence rate).
With a sample size of 552 patients (368 in the dronedarone group and 184 in the placebo group), each trial would have a power of 90% to detect a between-group difference, assuming a 20% dropout rate and a 1-year follow-up period. The primary analysis was performed according to a modified intention-to-treat principle, with all randomized patients who received at least one dose of a study drug included. A secondary on-treatment analysis was also performed. A two-sided Fisher's exact test was used for qualitative measures. The event-free probability curves were estimated by the nonparametric Kaplan–Meier technique, with 95% confidence intervals. A standard log-rank technique was used to test the null hypothesis of identical Kaplan–Meier curves in the two study groups. All reported P values are two-sided, and P values of less than 0.05 were considered to indicate statistical significance.
Results
Patients
In the European trial, 680 patients were screened, and 612 were randomly assigned to study groups to receive treatment (411 to the dronedarone group and 201 to the placebo group). In the non-European trial, 731 patients were screened, and 625 were randomly assigned to receive treatment (417 to the dronedarone group and 208 to the placebo group). Three patients in the European trial and four in the non-European trial did not receive a study drug (Figure 1).
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In the European trial, according to the modified intention-to-treat analysis, the median times from randomization to a documented recurrence of atrial fibrillation were 96 days in the dronedarone group and 41 days in the placebo group. At 12 months, 67.1% of patients in the dronedarone group and 77.5% of patients in the placebo group had had a recurrence of atrial fibrillation (hazard ratio for the dronedarone group, 0.78; 95% confidence interval [CI], 0.64 to 0.96; P=0.01) (Table 2). On-treatment analysis of the same population had similar results (P=0.01).
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For the two trials combined, the median times to a documented recurrence of atrial fibrillation were 116 days in the dronedarone group and 53 days in the placebo group. At 12 months, the rates of recurrence were 64.1% in the dronedarone group and 75.2% in the placebo group (hazard ratio, 0.75; 95% CI, 0.65 to 0.87; P<0.001) (Table 2). Figure 2 shows the Kaplan–Meier cumulative incidence curves for the adjudicated first recurrence in patients in the European trial and the non-European trial, separately and combined. The association of dronedarone with a reduction in the risk of recurrence of atrial fibrillation, as compared with placebo, was consistent for a series of clinically important subgroups (Figure 3).
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Heart Rate and QT Interval in Sinus Rhythm
In the combined European and non-European trials, the effects of dronedarone, as compared with those of placebo, on the mean heart rate, QT interval, and QT interval corrected for heart rate (QTc) were investigated in preplanned analyses (see the Supplementary Appendix, available with the full text of this article at www.nejm.org). As compared with baseline values, in the dronedarone group, heart rate was reduced by 6.8%, the QT interval was prolonged by 23.4 msec, and the QTc interval was prolonged by 9.0 msec (P<0.001 for all comparisons with the placebo group), without significant effects on the QRS duration.
Ventricular Rate at First Recurrence
In both trials, ventricular rates during the recurrence of atrial fibrillation were evaluated in preplanned analyses. In the European trial, the mean (±SD) ventricular rate during the first adjudicated recurrence was 102.3±24.7 beats per minute in the dronedarone group and 117.5±29.1 beats per minute in the placebo group (P<0.001). The corresponding numbers for the non-European trial were 104.6±27.1 beats per minute in the dronedarone group and 116.6±31.9 beats per minute in the placebo group (P<0.001) (Table 2).
Symptomatic First Recurrence
In another preplanned analysis, the rates of symptomatic recurrence of atrial fibrillation were compared between the study groups in each trial. The majority of documented first recurrences were symptomatic, and the pattern of symptoms did not differ between the dronedarone group and the placebo group. In the European trial, 37.1% of patients in the dronedarone group and 47.5% of those in the placebo group had symptomatic recurrences (P=0.006 by the log-rank test). In the non-European trial, symptomatic recurrences occurred in 38.3% of patients in the dronedarone group and 44.5% of those in the placebo group (P=0.02 by the log-rank test). The corresponding numbers for the pooled data were 37.7% and 46.0% (P<0.001 by the log-rank test) (Table 2). The Prentice cumulative incidence curves26 for a symptomatic first recurrence for the pooled data are shown in the Supplementary Appendix.
Hospitalization or Death
In the European Trial, a post hoc analysis revealed that 21.2% of patients in the dronedarone group had been hospitalized or had died at 12 months, as compared with 32.0% of those in the placebo group (hazard ratio, 0.66; 95% CI, 0.47 to 0.93; P=0.02). In the non-European trial, 24.5% of patients in the dronedarone group had been hospitalized or had died, as compared with 29.8% of those in the placebo group (hazard ratio, 0.80; 95% CI, 0.56 to 1.14; P=0.22). The corresponding numbers in the combined analysis were 22.8% and 30.9% (hazard ratio, 0.73; 95% CI, 0.57 to 0.93; P=0.01) (Table 2).
Adverse Events
Table 3 shows the incidence of selected adverse events in the two study groups. Most of these specific adverse events are shown because they include many of the known side effects of amiodarone. In addition, there was a higher incidence of elevated serum creatinine levels in the dronedarone group than in the placebo group (2.4% vs. 0.2%, P=0.004).
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Discussion
The European trial and the non-European trial were large, double-blind, placebo-controlled trials, each comparing the efficacy of dronedarone with that of placebo for the maintenance of sinus rhythm in patients with atrial fibrillation. We found that dronedarone reduced the incidence of a first recurrence, as well as a symptomatic first recurrence, within 12 months after randomization. Dronedarone also significantly reduced the ventricular rate during the recurrence of arrhythmia. In addition, in a post hoc analysis, dronedarone significantly reduced the rate of hospitalization or death.
In both the European and non-European trials, dronedarone prolonged the time to the recurrence of atrial fibrillation by a factor of more than 2, as compared with placebo. This finding is consistent with the drug's propensity for markedly prolonging the atrial effective refractory period18,27 by inducing multiple ion-channel blockade.15 However, the effectiveness of dronedarone in maintaining sinus rhythm in atrial fibrillation cannot be reliably compared with that of amiodarone or sotalol on the basis of these data. The latter agents have been evaluated in studies that may have differed markedly from our trials with respect to the trial design, study population, and pattern of atrial fibrillation (paroxysmal or persistent).3,24,28,29 In our trials, patients were in sinus rhythm at the time of randomization, but the trial design did not permit a clear distinction between patients who had persistent atrial fibrillation and those with paroxysmal atrial fibrillation. It is likely that most of the patients in our trials who did not require direct-current cardioversion during the 5 days preceding randomization (71%) had paroxysmal atrial fibrillation or flutter. The results of the subgroup analyses underscore the consistent effectiveness of dronedarone in maintaining sinus rhythm in patients with atrial fibrillation encompassing a wide range of covariates.
In our trials, the effectiveness of 400 mg of dronedarone twice daily in maintaining sinus rhythm without major prolongation of either the QT or the QTc interval suggests a measure of atrial selectivity of the drug action, as reported in studies involving rabbit ventricular and atrial cells.17,18 Amiodarone and dronedarone both limit the risk of torsades de pointes by attenuating after-depolarization activity in the M cell and Purkinje fiber activity30,31,32,33,34,35,36,37,38 in the ventricular myocardium. In the case of amiodarone, torsades de pointes is rare,32,33 and to date an unequivocal case of torsades induced by dronedarone has not been noted despite the lengthening of the QT and QTc intervals by 23 and 9 msec, respectively, in our combined trials.
In neither of the trials did we directly compare dronedarone with amiodarone. Therefore, we cannot be certain that the efficacy of dronedarone is similar to that of amiodarone, nor can we state with certainty that the rate of adverse events is significantly lower. On the basis of experience with amiodarone in other trials, our findings suggest these conclusions, but a definitive answer will require a trial that directly compares the two drugs. Furthermore, the low rate of adverse events (especially pulmonary toxic effects) may be explained in part by the relatively short duration of our trials and by the fact that chest radiography and assessment of pulmonary function were not performed unless symptoms were present.
As in many other trials examining the efficacy of treatments for atrial fibrillation, it is likely that we were not able to detect every episode of recurrent arrhythmia in our study patients. Follow-up electrocardiograms were obtained at frequent intervals and in the case of symptoms. The fact that the majority of first documented recurrences were symptomatic strongly suggests that not all episodes were detected, since the majority of episodes of atrial fibrillation in the general population may be asymptomatic. Continuous monitoring of all study patients over the long term was beyond the scope of these trials and typically has not been considered essential for the interpretation of such studies.
A previous study, the Antiarrhythmic Trial with Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA), was discontinued early because an interim safety analysis suggested a potential increase in the risk of death with dronedarone therapy. The discontinued trial involved patients with moderate-to-severe congestive heart failure and ventricular dysfunction, and thus investigated a different (and higher-risk) population than the patients we studied. In our trials, the rates of death from any cause and sudden death in the dronedarone group did not differ significantly from those in the placebo group. Nonetheless, the experience with the ANDROMEDA trial indicates that dronedarone may be associated with an increased risk of death in patients with advanced congestive heart failure and that the drug should not be used in such patients until appropriate data are gathered.
In conclusion, our trials showed that the rates of the first recurrence of atrial fibrillation and of the first symptomatic recurrence at 1 year were significantly reduced with dronedarone, as compared with placebo. Dronedarone also reduced the ventricular rate in atrial fibrillation during recurrences of arrhythmia. The available data are not directive with respect to the rates of adverse effects, as compared with those of amiodarone.
Supported by Sanofi-Aventis.
Dr. Singh reports receiving consulting and lecture fees from CV Therapeutics, Sanofi-Aventis, GlaxoSmithKline, Astellas, and Procter & Gamble Pharmaceuticals; Dr. Hohnloser, consulting fees from Sanofi-Aventis, St. Jude Medical, Boehringer Ingelheim, Procter & Gamble Pharmaceuticals, and Solvay Pharmaceuticals and lecture fees from Sanofi-Aventis and St. Jude Medical; Dr. Connolly, consulting and lecture fees from Sanofi-Aventis and grant support from Sanofi-Aventis, Boehringer Ingelheim, and St. Jude Medical; Dr. Crijns, consulting fees from Sanofi-Aventis, AstraZeneca, Cardiome, and Meda Pharma, lecture fees from Sanofi-Aventis, AstraZeneca, St. Jude Medical, and Meda Pharma, and grant support from Medtronic, St. Jude Medical, and Sanofi-Aventis; Dr. Roy, consulting and lecture fees from Sanofi-Aventis, Astellas, and Cardiome and grant support from the Canadian Institutes of Health Research; Dr. Kowey, consulting fees from Sanofi-Aventis, Reliant, Cardiome, Astellas, Procter & Gamble Pharmaceuticals, and Solvay Pharmaceuticals and lecture fees from Sanofi-Aventis; Dr. Capucci, consulting fees from CV Therapeutics and St. Jude Medical and lecture fees from Sanofi-Aventis, Meda Pharma, and Pfizer; Dr. Radzik, being employed by Sanofi-Aventis and having equity interest in the company; and Dr. Aliot, consulting and lecture fees from Sanofi-Aventis, Meda Pharma, and Sorin-Ela. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Veterans Affairs Greater Los Angeles Healthcare System and the David Geffen School of Medicine at UCLA — both in Los Angeles (B.N.S.); the University of Hamilton, Hamilton, ON, Canada (S.J.C.); the University of Maastricht, Maastricht, the Netherlands (H.J.G.M.C.); the University of Montreal, Montreal (D. Roy); Lankenau Hospital and Institute of Medical Research, Philadelphia (P.R.K.); Ospedale Clinical, Taverna, Italy (A.C.); Sanofi-Aventis, Paris (D. Radzik); Hôpital Central, Nancy, France (E.M.A.); and Goethe University, Frankfurt, Germany (S.H.H.).
Address reprint requests to Dr. Singh at Veterans Affairs Greater Los Angeles Healthcare System, Cardiology Division, 11301 Wilshire Blvd., Los Angeles, CA 90073, or at bsingh{at}ucla.edu.
References
The following authors and other investigators participated in the European trial and the non-European trial: Steering Committee: B.N. Singh (chair), E. Aliot, A. Capucci, S.J. Connolly, H.J.G.M. Crijns, S. Hohnloser, P. Kowey, L.D. Roy, and D. Radzik. Data and Safety Monitoring Board: Lyon, France — A. Leizorovicz (chair); London — J. Camm; Miami — R. Myerburg.
European trial: Belgium — J. Boland, P. Brugada, L. De Roy, G. Mairesse; Czech Republic — J. Bytesnik, M. Herold, J. Hradec, B. Semrad; France — J. Davy, P. Defaye, P. Djiane, S. Kacet, A. Leenhardt, E. Quiring; Germany — D. Andresen, G. Baumann, S. Felix, E. Hoffmann, S.H. Hohnloser, J. Kiehn, C. Karle, T. Lewalter, V. Mitrovic, A. Schirdewan, S. Spitzer; Hungary — M. Mezofi, L. Regos, K. Simon, J. Tomcsanyi; Italy — P. Rizzon, J. Salerno-Uriarte, M. Santini, P. Schwartz; Poland — T. Kawka-Urbanek, T. Marczyk, P. Miekus, W. Musial, G. Opolski, M. Piepiorka, W. Tracz, M. Trusz-Gluza; Spain — J. Alzueta-Rodriquez, G. Baron, P. Blanch, C. Moro, A. Salvador, J. Vilaplana; the Netherlands — A. Anneveldt, F.A.L.E. Bracke, C. Burgersdijk, H.J.G.M. Crijns, J.A. Kragten, D.J.A. Lok, J.G. Meeder, L.H. Savalle, A.J.M. Timmermans, I.C. Van Gelder, L.H.J. Van Kempen, E.P. Viergever; Denmark: P. Grande, B. Sigurd, C. Torp-Pedersen; Finland: H. Huikuri, K. Peuhkurinen, A. Ylitalo; United Kingdom — E. Rowland. Non-European trial: Argentina — M. Elizari, A. Gambarte, J. Gonzalez, J. Krauss, J. Vallejos; Australia — J. Amerena, J. Counsell, M. Davis, J. Hill, J. Leitch, J. Sampson, B. Singh, D. Whalley, A. Whelan; Canada — P. Auger, J. Bedard, R. Bhargava, P. Bolduc, D. Borts, G. Boutros, J. Champagne, Y. Chan, L. Charles, S. Connolly, P. Costi, P. Dorian, C. Fortin, M. Green, S. Kouz, R. Leather, P. Ma, B. Mitchell, A. Mukherjee, D. Quimet, D. Roy, M. Senaratne, Z. Wulffhart; South Africa — S. Hardcastle, J. Du Toit, D. Milne, D. Naidoo, I. Obel, R. Scott-Millar, N. Van Der Merwe, H. Dutoit Theron; United States — W. Abraham, C. Kuo, M. Berk, R. Bryg, M. Carlson, J. Mackall, C. Chen, A. Chu, H. Colfer, G. Crossley, L. Dreifus, K. Ellenbogen, G. Emlein, R. Falk, G. Feld, C. Fellows, R. Filart, J. Fleischhauer, D. Gilligan, J. Glass, M. Goldberg, C. Goren, D. Gottlieb, G. Grewal, J. Herre, S. Hessen, A. Jacobson, S. Keim, S. Kim, R. Klein, M. Koren, P. Kowey, J. Krantzler, R. Leman, T. Lessmeier, L. Lewkowiez, B. McGovern, C. Albert, B. McLaurin, G. San, G. Naccarelli, I. Niazi, P. O'Neill, B. Peart, M. Platt, S. Promisloff, A. Quick, J. Reiffel, E. Roth, S. Rothbart, J. Sacco, B.N. Singh, N. Smiley, J. Steinberg, M. Tonkon, N. Vijay, K. Vijayaraghavan, P. Vijayaraman, H. Weiner, R. Weiss, B. Williamson, J. Baker, and G. Wong.
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Related Letters:
Dronedarone in Atrial Fibrillation
Arlet J.-B., Chouchana L., Capron L., Fink A. H. Jr., Singh B. N., Hohnloser S. H., Ezekowitz M. D.
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N Engl J Med 2007;
357:2403-2405, Dec 6, 2007.
Correspondence
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