BROOKLYN, NEW YORK. Dronedarone (Multaq) is a benzofuran derivative similar to amiodarone but without the iodine moiety, which is believed to be responsible for the toxic effects of amiodarone, notably on the thyroid and lungs. The US Food and Drug Administration (FDA) has approved dronedarone for preventing rehospitalisation in patients in sinus rhythm with cardiovascular risk factors. A pretty narrow scope indeed! Nevertheless, 27 trials have been carried out to evaluate the efficacy and safety of using the drug in other populations.
A group of researchers from three American medical centers now report the results of a meta-analysis carried out to determine the safety of dronedarone across the spectrum of patient populations in which it has been tested. The analysis included 7 randomized, controlled clinical trials involving a total of 10,676 subjects. Six of the trials involved patients with atrial fibrillation (AF), whilst one (the ANDROMEDA trial) involved patients with heart failure, but no AF. All trials but one used a dose of 400 mg twice daily and follow-up ranged from 3.5 to 21 months. Considering the combined outcome of the 7 trials, there was a trend for increased cardiovascular and all-cause mortality amongst patients randomized to receive dronedarone. However, when the results of a trial (ATHENA) involving only paroxysmal afibbers (with non-lone AF) were omitted, dronedarone was associated with a highly significant increase in both cardiovascular and all-cause mortality. Excluding a trial (ANDROMEDA) involving heart failure patients still resulted in dronedarone use being significantly associated with increased cardiovascular mortality. Similarly, excluding a trial (PALLAS) involving permanent afibbers only from the analysis maintained a statistically significant increase of cardiovascular mortality in the dronedarone group. However, when limiting the analysis to patients with paroxysmal or persistent AF, dronedarone use was associated with a slight decrease in cardiovascular mortality and a decrease in rehospitalisation rate. Cardiovascular and all-cause mortality were independent of the duration of dronedarone use.
L The researchers conclude that treatment with dronedarone across a wide spectrum of cardiovascular conditions resulted in a trend toward an increase in mortality. They recommend caution in using dronedarone, especially in patients with cardiovascular risk factors.
Chatterjee, S, et al. Meta-analysis of cardiovascular outcomes with dronedarone in patients with atrial fibrillation or heart failure. American Journal of Cardiology, May 18, 2012 [Epub ahead of print]
Editor's comment: Two trials are of particular interest to lone afibbers. NOTE: Both trials were sponsored by Sanofi-Aventis, the manufacturer of dronedarone.
ADONIS-EURIDIS (2007) – This trial involved 1237 patients with paroxysmal AF of whom 59% had no structural heart disease. The trial found that 400 mg twice daily use of dronedarone significantly decreased the frequency of AF episodes and reduced the ventricular (pulse) rate during an episode. All-cause mortality in the dronedarone group was 1.0% versus 0.7% in the placebo group over the 12-month follow-up.
DAFNE (2003) – this trial involved 270 patients who had undergone electrical cardioversion for persistent AF. Thirty-five percent of trial participants had valve disease, 20% had coronary artery disease, and 14% had heart failure. A dronedarone dose of 400 mg twice daily significantly extended the time to AF relapse and reduced the ventricular rate at relapse. There was no difference in all-cause mortality between the 800-mg/day dronedarone group and the placebo group over the 6-month follow-up, but 3.9% of dronedarone users discontinued the drug mostly due to gastrointestinal side effects. Thus, it would seem that, although dronedarone is contraindicated in AF patients with heart failure or other cardiovascular disease, it would be reasonably safe for lone afibbers with paroxysmal or persistent AF.