Thursday, September 06, 2007

Dronedarone - A Safer Amiodarone?

Today, the New England Journal of Medicine reports on the safety and efficacy of dronedarone (Sanofi-Adventis (SNY) from the identically-designed EURIDIS and ADONIS (American-Australian-African trial with DronedarONe In atrial fibrillation or flutter patients for the maintenance of Sinus rhythm) trials. Dronedarone was effective at reducing the time to recurrent atrial fibrillation compared to placebo.

From this press release:
The ADONIS study showed that the median time from randomization to a first adjudicated AF/AFL recurrence was 2.7-fold longer in the dronedarone group than in the placebo group. Dronedarone significantly decreased the risk of a first recurrence of AF/AFL within the 12-month study period by 27.5% compared to placebo (log-rank test p=0.0017).

Most initial AF/AFL recurrences were symptomatic in both groups of patients. Overall incidence of adverse events was comparable in the two groups (73% in the placebo arm and 80% in the dronedarone group, (p = ns)) and dronedarone also displayed good cardiac tolerability, with no cases of torsades de pointes.
This trial was so reaffirmed earlier reporting of the trials from 2004 regardings to the long-term efficacy of the drug. As in the earlier 2004 reporting, this trial still demonstrated a disappointing recurrence rate of atrial fibrillation in the treatment group:
At 1 year of follow-up, the risk for AF recurrence in the European arm of the study was 67% with dronedarone, compared with 77% with placebo; in the non-European arm, the risk for AF recurrence was 61% with dronedarone, compared with 73% with placebo.
It was important to note the following about the use of dronedarone in patients with congestive heart failure (from the NEJM article):
A previous study, the Antiarrhythmic Trial with Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA), was discontinued early because an interim safety analysis suggested a potential increase in the risk of death with dronedarone therapy. The discontinued trial involved patients with moderate-to-severe congestive heart failure and ventricular dysfunction, and thus investigated a different (and higher-risk) population than the patients we studied. In our trials, the rates of death from any cause and sudden death in the dronedarone group did not differ significantly from those in the placebo group. Nonetheless, the experience with the ANDROMEDA trial indicates that dronedarone may be associated with an increased risk of death in patients with advanced congestive heart failure and that the drug should not be used in such patients until appropriate data are gathered.
This is an important distinction between dronedarone and its cousin amiodarone (which can be used in these higher risk patients). Still, given the limited number of effective medicines available for treatment of atrial fibrillation these days, the drug may still fill an important niche.



Bramah N. Singh, M.D., D.Sc., Stuart J. Connolly, M.D., Harry J.G.M. Crijns, M.D., Denis Roy, M.D., Peter R. Kowey, M.D., Alessandro Capucci, M.D., Ph.D., David Radzik, M.D., Etienne M. Aliot, M.D., Stefan H. Hohnloser, M.D., for the EURIDIS and ADONIS Investigators. "Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter" New Engl J Med, September 6, 2007, 357 (10):987-999.

Medscape (free registration required).

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