Dronedarone in Atrial Fibrillation

Summary

The ATHENA trial 1 included 4 628 patients (mean age 72 years) with paroxysmal or persistent atrial fibrillation or flutter and additional risk factors for death. Patients with permanent atrial fibrillation were excluded. Twenty-five percent of patients had atrial fibrillation at randomization.The mean follow-up period was 21±5 months; the study drug was discontinued prematurely in 30.2% of patients receiving dronedarone and in 30.8% of receiving placebo, mostly because of adverse events. Dronedarone 400 mg twice a day decreased the primary outcome (first hospitalization due to cardiovascular events or death) (31.9% vs. 39.4%; HR 0.76, 95% CI 0.69 to 0.84) compared with placebo. There were 116 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (HR 0.84, 95% CI 0.66 to 1.08). There were 63 deaths from cardiovascular causes (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (HR 0.71, 95% CI 0.51 to 0.98), largely due to a reduction in the rate of death from arrhythmia with dronedarone.

In a post hoc analysis 2, it was shown that dronedarone also reduced the rate of stroke in patients with atrial fibrillation who were receiving usual care, which included antithrombotic therapy and heart rate control. Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (HR 0.66, 95% CI 0.46 to 0.96). The effect of dronedarone was similar whether or not patients were receiving oral anticoagulant therapy, and there was a significantly greater effect of dronedarone in patients with higher CHADS(2) scores.

The ANDROMEDA trial 3 planned to randomize 1000 patients who were hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction to receive 400 mg of dronedarone twice a day or placebo. A history of atrial fibrillation (chronic, persistent, or paroxysmal) was reported by almost 40% of the patients, whereas atrial fibrillation at the time of randomization (as detected on an electrocardiogram) was present in 23.2% of the patients in the dronedarone group and 26.8% in the placebo group.The trial was prematurely terminated for safety reasons after inclusion of 627 patients. During a median follow-up of 2 months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (HR 2.13, 95% CI 1.07 to 4.25). The excess mortality was predominantly related to worsening of heart failure. The primary end point (the composite of death from any cause or hospitalization for heart failure) did not differ significantly between the two groups (dronedarone 17.1% vs. placebo 12.6%; HR 1.38, 95% CI 0.92 to 2.09). More increases in the creatinine concentration were reported as serious adverse events in the dronedarone group than in the placebo.

The PALLAS trial 4 included patients who were at least 65 years of age (mean age 75 years) with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The study was stopped for safety reasons after the enrollment of 3 236 patients. The first coprimary outcome (stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes) occurred in 43 patients receiving dronedarone and 19 receiving placebo (HR 2.29, 95% CI 1.34 to 3.94). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (HR 2.11, 95% CI 1.00 to 4.49), including death from arrhythmia in 13 patients and 4 patients, respectively (HR 3.26, 95% CI 1.06 to 10.00). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (HR 2.32, 95% CI 1.11 to 4.88). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (HR 1.81, 95% CI 1.10 to 2.99).