Dronedarone is a class III antiarrhythmic which was approved in 2009.1 Positive effects of dronedarone were found when it was compared to placebo in the ATHENA trial; dronedarone decreased hospitalizations due to cardiovascular causes in patients with paroxysmal or persistent atrial fibrillation.2 A post-hoc analysis suggested that the benefits extended to patients who developed permanent atrial fibrillation during the ATHENA trial.3 Therefore, the large scale PALLAS (Permanent Atrial Fibrillation Outcome Study using Dronedarone on Top of Standard Therapy) trial was conducted to determine if dronedarone could reduce cardiovascular events in patients at high risk for major vascular events with permanent atrial fibrillation.
The PALLAS trial was a multicenter, randomized, double-blind, placebo-controlled trial evaluating dronedarone 400mg twice daily in patients at least 65 years old with permanent atrial fibrillation and at least one of the following risk factors: coronary artery disease, prior stroke or TIA, symptomatic heart failure, ejection fraction <40%, peripheral artery disease, or combination of 75 years or older, hypertension, or diabetes.4 The first co-primary endpoint was a composite of stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second co-primary endpoint was a composite of unplanned hospitalization for a cardiovascular cause or death.4
There were 3,236 patients randomized during the trial. The mean age was 75 years old, 69% had a history of permanent atrial fibrillation for at least 2 years, and about two thirds of patients had a history of heart failure. The trial ended early with a median follow-up of 3.5 months due to significantly more events in the dronedarone arm than placebo. For the first co-primary endpoint, the event rate/100 patient-years in the dronedarone arm was 8.2 compared to 3.6 in the placebo arm (HR 2.25, 95% CI 1.34-3.94, P=0.002). Dronedarone also had a higher event rate/100 patient-years of 25.3 compared to 12.9 for placebo with the second co-primary endpoint (HR 1.95, 95% CI 1.45-2.62, P<0.001). In addition to the co-primary endpoints, the dronedarone arm had statistically more deaths, deaths from cardiovascular causes, deaths associated with arrhythmias, strokes, unplanned hospitalizations for cardiovascular causes, hospitalizations for heart failure, and hospitalizations for heart failure or heart failure episodes.4
This large-scale trial showed that dronedarone is harmful for patients with permanent atrial fibrillation at risk for major vascular events. These results stand in contrast to results of the ATHENA trial where benefit was seen with dronedarone. There was a lower prevalence of heart failure in the ATHENA trial compared with the PALLAS trial; this may explain some of the differences between the two trials, particularly since dronedarone was shown to increase mortality due to worsening heart failure in the ANDROMEDA trial.5,6 Digoxin toxicity is another possible reason that has been suggested for the negative results seen in the PALLAS trial.4 Dronedarone interacts with digoxin and increased digoxin levels were observed during the trial; however, only 30% of patients were receiving digoxin and digoxin toxicity would not explain all of the adverse effects observed in the PALLAS trial.5 Based on the results of the PALLAS trial, dronedarone should only be prescribed for patients with paroxysmal or persistent atrial fibrillation and has no role in permanent atrial fibrillation. Patients receiving dronedarone need to be closely monitored for developing permanent atrial fibrillation or heart failure ...