HAMILTON, ONTARIO, CANADA. In July 2009 the US Food and Drug Administration approved the antiarrhythmic drug dronedarone (Multaq) for the treatment of atrial fibrillation (AF) in patients without severe systolic heart failure. The approval was based on three clinical trials (EURIDIS, ADONIS, ANDROMEDA) involving almost 2000 patients with AF and various comorbidities. The ANDROMEDA trial involving 600 patients with advanced congestive heart failure. In the 2 months the trial lasted, 8% of the patients receiving dronedarone died vs. 3.8% in the placebo group.

Nevertheless, in July 2010, an international group of researchers decided to go ahead with a new trial (PALLAS) designed to determine if treatment with dronedarone (400 mg twice daily) would reduce the rate of major cardiovascular events and associated hospitalizations in high risk patients with permanent AF. In July 2011 a total of 3236 patients had been enrolled. The average age of the patients was 75 years, 64% were male, 41% had coronary artery disease, 85% had hypertension, 35% diabetes, and about two-thirds of them had a history of heart failure. One-third of the patients were on digoxin and 84% received warfarin, but were only within the proper INR range 57% of the time. On July 15, 2011 when the trial was prematurely halted twice as many patients in the dronedarone group had died or suffered a stroke or heart attack when compared to the placebo group. The rate of unplanned hospitalizations for heart failure and other cardiovascular causes was 31%/year in the dronedarone group and 16%/year in the placebo group. Arrhythmia-related mortality was 3 times higher in the dronedarone group than in the placebo group indicating that dronedarone can cause dangerous ventricular arrhythmias in high-risk permanent afibbers. The use of dronedarone was found to be particularly dangerous in patients with diabetes.

The researchers conclude that dronedarone increases the rate of heart failure, stroke and death from cardiovascular causes in high-risk patients with permanent AF and consequently should not be prescribed for this patient population.
Connolly, SJ, et al. Dronedarone in high-risk permanent atrial fibrillation. New England Journal of Medicine, November 14, 2011 [Epub ahead of print]
Nattel, S. Dronedarone in atrial fibrillation – Jekyll and Hyde? New England Journal of Medicine, November 14, 2011 [Epub ahead of print]

Editor's comment: Unfortunately, this report is not the first pointing to a less than sterling safety profile for dronedarone. On September 22, 2011 the European Medicines Agency (EMA) issued a bulletin recommending restricting the use of dronedarone to cases where no other drugs had proven effective. This recommendation was partly based on the results of the prematurely-halted PALLAS trial. The EMA recommends that dronedarone use should be restricted to patients with paroxysmal or persistent AF when they are in normal sinus rhythm. It should not be used when patients are in AF, nor in those with permanent AF or heart failure. In any case, patients on the drug should be monitored by a specialist and have their lung, liver and heart rhythm function checked regularly.

Several electrophysiologists have expressed their misgivings about the drug. Dr. Steven Nissen of the Cleveland Clinic believes dronedarone is outright dangerous and Dr. Sanjay Kaul of Cedar-Sinai Medical Center in Los Angeles says that the drug does not even appear to be safe in intermediate-risk patients. It seems to me that giving paroxysmal afibbers a drug that becomes dangerous whenever they actually experience AF is a less than smart move. I think dronedarone deserves a place, alongside digoxin and sotalol, as the most useless pharmaceutical drug for lone AF patients.