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Dronedarone vs. Amiodarone in Atrial Fibrillation
Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco receives grant/research support from St. Jude Medical, Astellas, and Novartis, is a consultant for Medtronic and Sanofi-Aventis, and is a speaker for St. Jude Medical and Boston Scientific.
Source: Le Heuzey J-Y, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: The DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21:597-605.
Dronedarone is an antiarrhythmic drug with structural and electrophysiologic similarities to amiodarone that was released in 2009. Dronedarone's structure includes a benzofuranyl ring but, unlike amiodarone, the ring is not iodinated. This, and a side chain modification, give dronedarone a shorter half-life and reduced tissue accumulation. The study reported here was designed to compare the short-term efficacy and safety of dronedarone and amiodarone in patients with atrial fibrillation.
Patients in atrial fibrillation of at least three days duration were eligible for inclusion. The main exclusion criteria were: prior treatment with amiodarone, thyroid disease, severe congestive heart failure, severe bradycardia or AV block, or use of other antiarrhythmic drugs. Patients underwent a screening period of 30 days and then were randomly assigned to either dronedarone 400 mg twice daily or amiodarone 600 mg daily for 28 days. Electrical cardioversion was scheduled between days 10 and 28 if the patient had not converted spontaneously to sinus rhythm. The study duration was six months. Heart rhythm assessment was performed by 12-lead ECGs during scheduled clinic visits. The main endpoints included recurrence of atrial fibrillation, premature study discontinuation for lack of efficacy, and premature drug discontinuation for intolerance. Other endpoints included unsuccessful electrical cardioversion and no spontaneous cardioversion with no electrical cardioversion.
The study enrolled and randomized 504 patients. The mean age was 64 + 11 years, with 20% of the population older than 75 years. The most common cardiovascular diagnosis was hypertension (66.9%); 18% had coronary artery disease. At baseline, the majority of patients were treated with oral anticoagulants (96%) and beta adrenergic blocking agents (63%).
Amiodarone appeared to be more effective than dronedarone. Overall, atrial fibrillation recurrence or persistence was documented in 64% of dronedarone patients compared to 42% of the amiodarone patients. Documented atrial fibrillation was seen after conversion in 37% of the dronedarone patients vs. 24% of the amiodarone patients. Unsuccessful electrical cardioversion was noted in 12% of the dronedarone patients vs. only 6% of the amiodarone patients. There was no spontaneous cardioversion and no electrical cardioversion in 15% of the dronedarone patients vs. 11% of the amiodarone patients. Study drug was prematurely discontinued in 10% of the dronedarone patients and 13% of the amiodarone patients.
Side effects were more common during amiodarone treatment. Thyroid disorders, neurologic events, and skin reactions were all more common with amiodarone. Diarrhea, nausea, and vomiting were more frequently seen in the dronedarone group. Hepatic enzyme elevations were seen with a similar frequency in both groups. Both groups experienced a moderate increase in creatinine plasma levels. There were more supratherapeutic INR levels in the amiodarone group. A higher incidence of hemorrhagic events was also seen in amiodarone. No pulmonary toxicity was noted in either group in this short-term study. Study drug was discontinued early due to an adverse event in 11% of the amiodarone patients compared to 5% of the dronedarone patients.
The authors conclude that dronedarone was less effective than amiodarone for preventing AF recurrence but had a better safety profile due to a reduced frequency of thyroid and neurologic adverse reactions and a lessened potential for interaction with oral anticoagulants.
Dronedarone was released in the United States for treatment of atrial fibrillation in 2009. Approval was largely based on the results of the ATHENA trial. ATHENA enrolled more than 4,600 patients, who were randomized to either dronedarone or placebo. The primary outcome was mortality and cardiovascular hospitalization, which were decreased by dronedarone treatment. Atrial fibrillation recurrence, however, was not carefully tracked in ATHENA, and DIONYSOS was performed to give a comparative look at the relative efficacies of dronedarone and amiodarone. In this study, dronedarone appears to be less effective an antiarrhythmic agent compared to amiodarone. The side-effect profile is somewhat better. Physicians starting patients on rhythm-control therapy for atrial arrhythmias will have to consider this risk-benefit profile when choosing between dronedarone and amiodarone.