Did PALLAS Deliver the Final Blow to Dronedarone?

Abstract

The Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) included patients aged over 65 years, who had at least 6-month history of permanent atrial fibrillation (AF) and risk factors for major vascular events. The latter comprised coronary artery disease, previous stroke or transient ischemic attack, symptomatic heart failure, which was defined as current New York Heart Association class II or III symptoms and admission to the hospital for heart failure in the previous year (but not in the most recent month), a left ventricular ejection fraction of <40%, peripheral arterial disease, or the combination of an age of 75 years or older, hypertension, and diabetes. They were randomized to receive either dronedarone at a dose of 400 mg twice daily or placebo. On July 5, 2011, the data monitoring committee recommended that the study be terminated for safety reasons. A total of 3236 patients had undergone randomization with median follow-up of 3.5 months. The investigators had defined as the first coprimary outcome: stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes; and as a second coprimary outcome: unplanned hospitalization for a cardiovascular cause or death.

The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio-HR, 2.29; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (HR, 2.11; P = 0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (HR, 3.26; P = 0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (HR, 2.32; P = 0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (HR, 1.81; P = 0.02). Thus, the authors concluded that dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent AF who were at risk for major vascular events and therefore this drug should not be used in such patients... (excerpt)