Dronedarone hydrochloride is used to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm who have a history of paroxysmal or persistent atrial fibrillation. Current evidence from a comparative trial suggests that dronedarone is less effective than amiodarone in preventing recurrence of atrial fibrillation but has an improved safety profile (based on short-term follow-up) with regard to certain serious adverse effects (e.g., thyroid, neurologic) and potential for drug interactions (e.g., with warfarin). However, long-term data and experience are needed to fully elucidate the relative safety and tolerability of dronedarone versus amiodarone because some adverse effects of amiodarone (e.g., pulmonary toxicity) have been reported to occur up to 2-3 years after initiation of therapy.
Dronedarone should not be used in patients with permanent atrial fibrillation (i.e., patients in whom normal sinus rhythm will not or cannot be restored); results of a clinical trial indicate an increased risk of cardiovascular events and death in such patients.
(See Cardiovascular Death and Heart Failure in Patients with Permanent Atrial Fibrillation under Warnings/Precautions: Warnings, in Cautions.)
The efficacy of retreatment with dronedarone in patients who relapse after initial successful treatment or in those who fail therapy with amiodarone remains to be determined. Some clinicians suggest that based on current data, dronedarone should be considered alternative (e.g., second- or third-line) therapy in selected patients in whom control of ventricular rate alone is not feasible or successful and who do not have advanced (i.e., New York Heart Association [NYHA] class IV or recently decompensated class II or III) heart failure and are not receiving drugs that prolong QT interval or strongly inhibit cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4).
(See Cautions: Contraindications.)Treatment of atrial fibrillation/flutter should be individualized, with consideration given to the relative benefits and risks of various therapies (e.g., rhythm versus rate control, nondrug therapies such as ablation and pacemaker implantation), patient age, as well as patient preference and tolerance of the arrhythmia.
In a multicenter, placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone for the prevention of hospitalization for cardiovascular events or death from any cause in patients with atrial fibrillation/flutter (ATHENA study), the incidence of the combined primary outcome (first hospitalization due to cardiovascular events or death from any cause) was reduced with dronedarone compared with placebo. In this study, 4628 patients with a recent history of paroxysmal or persistent atrial fibrillation/flutter were randomized to receive dronedarone (400 mg twice daily) or placebo in addition to conventional therapy for cardiovascular diseases (i.e., β-adrenergic blocking agents, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, digoxin, calcium-channel blocking agents, HMG-CoA reductase inhibitors, oral anticoagulants, aspirin, other maintenance antiplatelet therapy, and diuretics). Eligible patients included those who were at least 75 years of age or those at least 70 years of age who had one or more risk factors (i.e., hypertension, diabetes, prior cerebrovascular accident, left atrial diameter of 50 mm or greater, left ventricular ejection fraction of 40% or less) and who were in sinus rhythm or were to undergo cardioversion to sinus rhythm. Patients ineligible for participation in the study included, but were not limited to, patients with NYHA class IV heart failure. The median duration of follow-up was 22 months (range: 12-30 months).
In the ATHENA study, the combined primary outcome of first hospitalization due to cardiovascular events or death from any cause occurred in 31.9% of patients who received dronedarone (individual event rates of 29.3 and 2.6% were reported for cardiovascular hospitalization and death from any cause, respectively) compared with 39.4% of patients who received placebo (individual event rates of 36.9 and 2.5% were reported for cardiovascular hospitalizations and death from any cause, respectively). The reduction in the rate of the combined primary outcome with dronedarone was mainly attributable to a reduction in the rate of first hospitalization due to cardiovascular events, principally hospitalization related to atrial fibrillation; the incidence of death from any cause was not substantially reduced. The numbers of first hospitalizations for congestive heart failure (CHF), ventricular arrhythmia, nonfatal cardiac arrest, or syncope were similar for patients who received dronedarone or placebo; however, there were fewer first hospitalizations for acute coronary syndromes in the dronedarone group.
In 2 other multicenter, double-blind, placebo-controlled trials in outpatients with atrial fibrillation/flutter receiving dronedarone for the maintenance of sinus rhythm (the EURIDIS study in 12 European countries and the ADONIS study in the US, Canada, Australia, South Africa, and Argentina), patients who received dronedarone had a longer median time to first recurrence of atrial fibrillation/flutter (116 versus 53 days) and a lower rate of recurrence at 12 months (64.1 versus 75.2%) than those who received placebo. In these studies, a total of 1237 patients 21 years of age or older who had at least one episode of atrial fibrillation/flutter (as documented by electrocardiogram [ECG]) during the previous 3 months and were in sinus rhythm for at least 1 hour were randomized to receive dronedarone (400 mg twice daily) or placebo, in addition to conventional therapy, for 12 months. Patients ineligible for participation in the studies included, but were not limited to, patients with NYHA class III or IV congestive heart failure. The primary outcome was time from randomization to first documented recurrence of atrial fibrillation/flutter, which was defined as an episode lasting for at least 10 minutes and confirmed by 2 consecutive ECG or transtelephonic recordings taken 10 minutes apart.
In another double-blind, placebo-controlled trial of dronedarone therapy in patients with moderate to severe CHF (ANDROMEDA study), the study was terminated prematurely (after enrollment of 627 of 1000 planned patients and a median follow-up of 63 days) because of excess mortality, mainly as a result of worsening heart failure, in the dronedarone group (8.1%) compared with the placebo group (3.8%). However, at study termination, the combined primary end point of death from any cause or hospitalization for worsening heart failure was not significantly different between patients who received dronedarone or placebo (crude estimate: 17.1 versus 12.6%). After an additional 6 months of follow-up without study treatment, the rate of mortality and the percentage of patients who had reached the combined primary end point were not significantly different between the 2 groups.
In the ANDROMEDA study, patients 18 years of age or older who were hospitalized with new or worsening heart failure and who had at least one episode of shortness of breath on minimal exertion or at rest (NYHA class III or IV heart failure) or paroxysmal nocturnal dyspnea within the previous month and a wall-motion index of 1.2 or less (ejection fraction of about 35% or less) were randomized to receive dronedarone (400 mg twice daily) or placebo. Outcomes were assessed up to the day active treatment was discontinued, 1 month after the date of cessation of the active-treatment phase, and at the end of a 6-month follow-up phase following completion of the study. The study was originally scheduled to last for 2 years and each patient was to be treated for a minimum of 12 months; however, 7 months after the first patient was assigned to a study group, enrollment and treatment were discontinued for safety reasons on the recommendation of the data and safety monitoring board. Dronedarone is contraindicated in patients with NYHA class IV heart failure or heart failure with recent decompensation requiring hospitalization.
(See Cautions: Contraindicationsand also see Cardiovascular Death in Decompensated Heart Failure under Warnings/Precautions: Warnings, in Cautions.)
Dronedarone appears to be less effective than amiodarone in preventing recurrence of atrial fibrillation but may be less likely to cause serious adverse effects, at least in the short term. In a randomized, double-blind study (DIONYSOS) in 504 amiodarone-naive patients (mean age: 64 years) with persistent atrial fibrillation, the primary composite (efficacy/safety) end point (time to first ECG-documented recurrence of atrial fibrillation or premature discontinuance of the study drug due to lack of efficacy or intolerance) was reached in 75.1% of patients receiving dronedarone (400 mg twice daily) compared with 58.8% of those receiving amiodarone (600 mg daily for 28 days, then 200 mg daily) at 12 months; the median duration of treatment was 7 months (maximum treatment duration of 13.8 months in both groups).
Patients enrolled in the DIONYSOS study had documented atrial fibrillation of more than 72 hours' duration, and almost all (95.6%) were receiving concomitant oral anticoagulant therapy. Recurrence of atrial fibrillation (including documented atrial fibrillation after successful conversion, unsuccessful electrical cardioversion, and no spontaneous conversion and no electrical cardioversion on days 10-28) accounted for the largest component of the composite primary end point (63.5 or 42% for dronedarone or amiodarone, respectively) compared with the premature drug discontinuance component (10.4 or 13.3% for dronedarone or amiodarone, respectively). Recurrence of atrial fibrillation after successful conversion was more frequent with dronedarone than with amiodarone (36.5 versus 24.3%, respectively). The incidence of the predefined main safety end point, which included thyroid, hepatic, pulmonary, neurologic, skin, ocular, and GI adverse effects as well as premature drug discontinuance, was similar for dronedarone and amiodarone at 12 months. Bradycardia and QTc (QT interval corrected for rate, Bazett's formula) prolongation, thyroid and neurologic events, and premature drug discontinuance due to adverse effects were less frequent with dronedarone; however, GI events, none of which were serious (mainly diarrhea), occurred at a higher incidence in the dronedarone group. However, when GI events were excluded, the relative risk of the main safety end point was reduced by 39% with dronedarone. In addition, the proportion of patients with supratherapeutic INR levels (exceeding 4.5) was smaller and the incidence of hemorrhagic events was reduced with dronedarone compared with amiodarone therapy.
In the PALLAS study, patients with permanent atrial fibrillation (defined as the presence of atrial fibrillation or atrial flutter for at least 6 months prior to randomization and patient and clinician decision not to make further efforts to restore sinus rhythm) and additional cardiovascular risk factors who received dronedarone had a higher incidence of heart failure, stroke, and cardiovascular death than those receiving placebo, and the study was terminated early for safety reasons. In this study, patients received dronedarone (400 mg twice daily) or placebo in addition to standard therapy (e.g., drugs to control heart rate, digoxin, anticoagulation with a vitamin K antagonist [e.g., warfarin]). Patients were at least 65 years of age and considered at high risk for vascular events because of the presence of at least one of the following risk factors: coronary artery disease, previous stroke or transient ischemic attack (TIA); symptomatic heart failure, left ventricular ejection fraction of 40% or less; peripheral arterial disease; or the combination of age exceeding 75 years, hypertension, and diabetes. Dronedarone therapy was associated with a more-than-twofold increase in the rate of the first coprimary outcome (stroke, myocardial infarction, systemic embolism, or cardiovascular death) and a near-doubling of the second coprimary outcome (unplanned hospitalization for cardiovascular causes or death). Dronedarone is contraindicated in patients with permanent atrial fibrillation. (
See Cautions: Contraindicationsand see Cardiovascular Death and Heart Failure in Patients with Permanent Atrial Fibrillation under Warnings/Precautions: Warnings, in Cautions.)