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Maintenance of sinus rhythm with dronedarone in patients with atrial fibrillation or flutter - EURIDIS and ADONIS
Description:
The goal of the trials were to evaluate the safety and efficacy of dronedarone, a novel antiarrhythmic agent that is a derivative of amiodarone, compared with placebo among patients with atrial fibrillation (AF) or atrial flutter (AFL).
Study Design
Study Design:
Patients Enrolled: 1,237
Mean Follow Up: One year
Mean Patient Age: Mean age 63 years
Female: 30
Patient Populations:
Age ≥21 years; sinus rhythm for at least one hour at time of randomization and at least one ECG-documented AF in the prior three months
Exclusions:
History of torsades de pointes; severe bradycardia; New York Heart Association class III or IV; creatinine >1.7 mg/dl; permanent AF/AFL; or previous aminodarone therapy discontinued for ineffectiveness
Primary Endpoints:
Time from randomization to first documented AF/AFL recurrence
Secondary Endpoints:
Mean ventricular rate during AF/AFL at first recurrence
AF/AFL related symptoms at time of recording of first recurrence
Drug/Procedures Used:
The EURIDIS (n=612) and the sister trial ADONIS (n=625), randomized patients with AF or AFL in a 2:1 manner to either dronedarone (400 mg twice per day, n=828) or placebo (n=409). Patients were followed for one year.
Principal Findings:
Time from randomization to recurrence of AF/AFL was longer in the dronedarone arm compared with placebo in both the EURIDIS trial (96 days vs. 41 days, relative risk [RR] 0.78, p=0.0138) and the ADONIS trial (158 days vs. 59 days, RR 0.72, p=0.0017). Recurrence had occurred in 67.1% of the dronedarone arm and 77.5% of the placebo arm in the EURIDIS trial, and in 61.1% of the dronedarone arm and 72.8% of the placebo arm in the ADONIS trial. The majority of recurrent events were symptomatic. Time to first symptomatic AF/AFL recurrence was longer in the dronedarone group versus placebo in both the EURIDIS trial (p=0.0055) and ADONIS trial (p=0.021). Ventricular rate at first recurrence was lower in the dronedarone group compared with placebo in both the EURIDIS trial (102.3 vs. 117.5 bpm, p<0.001) and ADONIS trial (104.6 vs. 116.6, p<0.001). Findings were consistent in the prespecified subgroups, including patients with recent cardioversion (within five days) and amiodarone prior to randomization.
There was no difference in the combined trials for the safety endpoints of death (1.0% for dronedarone vs. 0.7% for placebo), serious adverse events (19.8% vs. 24.4%), or any adverse events (69.8% vs. 65.8%). Permanent discontinuation of the study drug following a treatment emergent adverse event occurred in 7.1% in the placebo group compared with 9.7% in the dronedarone group. There were no cases of torsades de pointes during the 12-month follow-up period.
Interpretation:
Among patients with AF or AFL, treatment with the novel antiarrhythmic agent dronedarone was associated with a reduction in time to recurrent AF/AFL compared with placebo at one-year follow-up. The reduction was also observed for time to first symptomatic AF/AFL with no evidency of toxicity.
Dronedarone is a novel derivative of amiodarone designed to lower the adverse effects. The present trial demonstrates the safety and efficacy of dronedarone compared with placebo, but additional studies are required to evaluate efficacy of dronedarone therapy with amiodarone. In an earlier trial of dronedarone in patients with moderate-to-severe congestive heart failure and ventricular dysfunction, the ANDROMEDA trial, an interim safety analysis showed an increase in the risk of death with dronedarone, prompting the early discontinued of that trial. No excess of mortality was observed in the present trial, although the death rate was very low in the trial of patients with AF or AFL.
References:
Singh BN, et al. Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter. N Engl J Med 2007;357:987-99.
Hohnloser SH. EURIDIS and ADONIS: maintenance of sinus rhythm with dronedarone in patients with atrial fibrillation or flutter. Paper presented at the European Society of Cardiology Congress 2004, 29 August-1 September, Munich, Germany.
Keywords: Risk, Ventricular Dysfunction, Follow-Up Studies, Electric Countershock, Electrocardiography, Torsades de Pointes, Recurrence, Heart Failure, Siblings, Atrial Flutter
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