Dronedarone in high-risk permanent atrial fibrillation

N Engl J Med. 2011 Dec 15;365(24):2268-76. doi: 10.1056/NEJMoa1109867. Epub 2011 Nov 14.

Abstract

Background: Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation.

Methods: We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death.

Results: After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02).

Conclusions: Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amiodarone / adverse effects
  • Amiodarone / analogs & derivatives*
  • Amiodarone / therapeutic use
  • Anti-Arrhythmia Agents / adverse effects
  • Anti-Arrhythmia Agents / blood
  • Anti-Arrhythmia Agents / therapeutic use*
  • Atrial Fibrillation / blood
  • Atrial Fibrillation / drug therapy*
  • Atrial Flutter / drug therapy
  • Cardiovascular Diseases / chemically induced
  • Cardiovascular Diseases / mortality
  • Chronic Disease
  • Digoxin / blood
  • Digoxin / therapeutic use
  • Double-Blind Method
  • Dronedarone
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Heart Failure / chemically induced
  • Heart Failure / epidemiology
  • Heart Rate / drug effects
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Risk Factors
  • Stroke / chemically induced
  • Stroke / epidemiology

Substances

  • Anti-Arrhythmia Agents
  • Digoxin
  • Dronedarone
  • Amiodarone

Associated data

  • ClinicalTrials.gov/NCT01151137