Dronedarone is the latest antiarrhythmic drug to be developed for atrial fibrillation. In their search for a safe and effective drug for atrial fibrillation, pharmaceutical companies have long imagined their "Holy Grail:" A drug that is as effective as amiodarone, but without its unique toxicity profile. Dronedarone (Multaq) was developed by Sanofi (the makers of amiodarone) specifically in the hopes of creating that holy grail.
Dronedarone is indeed a derivative of amiodarone -- the most effective, but the most toxic, antiarrhythmic drug yet developed. Unlike amiodarone, dronedarone does not contain idodine atoms, and the iodine within amiodarone has been postulated to produce some of the drug's striking toxic effects, especially the thyroid toxicity seen with the drug, and perhaps the lung toxicity. Encouragingly, during the clinical trials with dronedarone, amiodarone-like toxicity so far has not been seen.
Several clinical trials with dronedarone have been reported. Two of these trials (the EURIDIS and ADONIS trials) assessed the effectiveness of dronedarone for treating atrial fibrillation. In these trials, 64% of patients treated with dronedarone had recurrent atrial fibrillation during the first year after beginning treatment, as compared with 75% of patients treated with placebo. This improvement is statistically significant, but is by no means striking -- and indeed is little better than the reduction in atrial fibrillation seen with many other antiarrhythmic drugs.
More recently, however, the ATHENA trial reported that patients treated with dronedarone for atrial fibrillation for 21 months had a signficantly reduced risk of death or cardiac hospitalization, compared to patients treated with placebo. This study is the first clinical study to suggest that treating patients who have atrial fibrillation with any antiarrhythmic drug can improve survival or reduce hospitalizations.
While the results of the ATHENA trial have caused quite a stir, the mechanism for reduced mortality with dronedarone is unclear. Since dronedarone may not be remarkably effective in reducing recurrences of atrial fibrillation, perhaps the drug may have some other, undefined, benefit aside from actually preventing atrial fibrillation.
Keep in mind that in 2003, Sanofi had to prematurely halt a clinical trial using dronedarone in patients with significant heart failure and atrial fibrillation, at the urging of the independent Data Safety and Monitorning Board, because those treated with dronedarone appeared to have an increased risk of death. Notably, patients enrolled in the ATHENA trial were significantly healthier than in that earlier, more alarming, study.
Side effects with dronedarone so far appear to be relatively benign. The most common reported side effects are diarrhea or nausea, slow heart rate, and rash. The unique side effects seen with amiodarone (such as lung toxicity, thyroid disorders, visual disturbances, or neurological disorders) have not been seen with dronedarone. However, it should be noted that none of the clinical trials with dronedarone have lasted for more than two years -- and some of the unusual toxicities seen with amiodarone may not appear until the drug has been taken for for several years. So, while dronedarone at this point looks reasonably safe, its true safety profile will not be known until it has been in use for a substantial period of time.
The FDA approved the use of dronedarone for the treatment of atrial fibrillation in the summer of 2009. The FDA specified that dronedarone should be limited to patients who (like those enrolled in the ATHENA trial) do not have significant heart failure.
Sources:
Hohnloser SH, Crijns HJGM, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668-678.
Singh BN, Connolly SJ, Crijns HJGM, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007; 357:987-99.
Ezekowitz MD. Maintaining sinus rhythm—making treatment better than the disease. N Engl J Med 2007; 357:1039.
