Approval of dronedarone imminent?

WYNNEWOOD, PENNSYLVANIA. Amiodarone (Cordarone) is supposedly the most effective antiarrhythmic drug on the market today, although a recent trial found that its efficacy in keeping atrial fibrillation patients afib-free for a year was only 34%. Apart from questionable efficacy, amiodarone also has a long list of potentially very serious side effects including thyrotoxicosis, hypothyroidism, pulmonary toxicity (fatal in 10% of cases), liver toxicity, optic neuropathy (including loss of vision), and blurred vision.

The amiodarone molecule contains 37.5% by weight of iodine and it is widely believed that it is the iodine that causes most of the adverse effects of the drug. Thus, it is not surprising that much research has been devoted to finding a drug similar to amiodarone (a benzofuran derivative), but without the iodine component. This search has now resulted in the development of dronedarone (Multaq). Dronedarone has undergone several large-scale clinical trials, which, with the exception of one (ANDROMEDA) involving patients with severe congestive heart failure, have found it to be safe and with no significant adverse effects after one year of use. However, an increase in serum creatinine level (an indicator of possible kidney toxicity) has been observed in some trials, as have gastrointestinal problems like diarrhea, nausea and vomiting.

Two large clinical trials (EURIDIS and ADONIS) evaluated the effect of 400 mg twice a day on 1237 patients with atrial fibrillation. About half of the trial participants had hypertension, 25% had coronary heart disease, and just over 20% had a history of heart failure. The main results of the two trials (data combined) were:

  • The median time to the first documented recurrence of AF was 116 days in the dronedarone group and 53 days in the placebo group.

  • At the end of the trial (12 months from the start) 24.8% of the placebo group were still in normal sinus rhythm as compared to 35.9% in the dronedarone group.

  • A pre-specified secondary end-point showed that 62.3% of dronedarone-treated patients were free of symptomatic AF recurrences versus 54% in the placebo group. Symptoms were defined as palpitations, dizziness, fatigue, chest pain, and breathing difficulties.

  • Patients in the dronedarone group had a slightly lower heart rate (average 103 bpm) during their first recurrence than did those in the placebo group (average 117 bpm).

  • Rates of thyroid, liver and lung dysfunction observed over the 12-month trial period were not significantly increased in the dronedarone group. However, there was a substantially higher incidence of elevated serum creatinine levels in the dronedarone group (2.4% vs. 0.2%), perhaps indicating potential problems with kidney function.

  • At the end of the trial 22.8% in the dronedarone and 30.9% in the placebo group had been hospitalized or had died (death accounted for 1% in the dronedarone group and 0.7% in the placebo group).

There were some early indications that dronedarone might not be suitable for patients with moderate to severe heart failure and ventricular dysfunction. The ANDROMEDA trial involving over 600 patients with advanced congestive heart failure proved these suspicions to be correct. In the 2 months that the trial lasted, 8% of the patients receiving dronedarone died versus 3.8% in the placebo group. Another trial (ATHENA) involving patients with less severe heart failure noted, however, that those patients treated with dronedarone had a 16% reduced risk of death from any cause (over a 21-month period) than did those on placebo. Thus, dronedarone would seem to be generally safe, but not highly effective, in afib patients not suffering from advanced congestive heart failure. Dronedarone, of course, also has a marked advantage over amiodarone in that its half-life is only 1 to 2 days as compared to 30 to 55 days for amiodarone.

NOTE: The Cardiovascular and Renal Drugs Advisory Committee on March 18, 2009 voted 10 to 3 to recommend that the FDA approve this drug for the treatment of atrial fibrillation in patients without severe systolic heart failure. Interestingly, the 3 dissenting voices on the panel were the representatives of the patient and the consumer, and the toxicology expert.

Laughlin, JC and Kowey, PR. Dronedarone: a new treatment for atrial fibrillation. Journal of Cardiovascular Electrophysiology, Vol. 19, November 2008, pp. 1220-26

Editor’s comment: Keeping only 36% of afibbers involved in the trials afib-free for 12 months is hardly an overwhelming success, especially when viewed in the context of the 25% “success rate” of placebo treatment. However, if dronedarone also proves safe in actual day-to-day use (as opposed to the strictly supervised use in clinical trials) then it should be a welcome replacement for amiodarone.