Completion of an FDA safety review concluded that Sanofi-Aventis’ dronedarone (Multaq) increases the risk of cardiovascular events, including death, in permanent atrial fibrillation (AF) patients. Chatter about the drug’s potential to increase CVD risk began last June when Sanofi pulled its Phase IIIb PALLAS trial after during an increase of CV events in the dronedarone arm.

The FDA’s safety review focused on two clinical trials, the PALLAS trial and the ATHENA trial, thats results helped Sanofi-Aventis first gain regulatory approval for dronedarone. Whereas the PALLAS trial showed that the rate of CV hospitalization or death was almost doubled, ATHENA showed that a reduction of nearly 25 percent in the dronedarone arm, Stuart J. Connolly, MD, cardiologist with the Population Health Research Institute, both in Hamilton, Ontario, said at this year’s 2011 American Heart Association (AHA) meeting.

Also at AHA 2011, N.A. Mark Estes, III, MD, director of the New England Cardiac Arrhythmia Center at Tufts Medical Center in Boston, said, “The critical question that comes up based on the PALLAS study is, do the unfavorable results of the PALLAS study obtained in patients with permanent AF also apply to patients who are using dronedarone for the approved indication?” Additionally, he offered that the drug should not be administered to HF patients or those with permanent AF. He also said that patients who fit the ATHENA trial criteria should be monitored regularly, for at least six months, to ensure they remain within the approved indication.

After the safety review, the FDA put forth the following revisions:

• That dronedarone not be prescribed to patients with AF who cannot be converted into normal sinus rhythm. Dronedarone was found to double the rate of CV death, stroke and heart failure in these patients;
• Healthcare professionals should monitor cardiac rhythm via electrocardiogram at least once every three months. Patients with AF should stop taking the drug and, if clinically indicated, the patient should undergo cardioversion; and
• Dronedarone has been shown to reduce hospitalization for paroxysmal or persistent AF patients. Therefore, patients prescribed dronedarone should receive appropriate antithrombotic therapy.

The FDA said that it is still reviewing the risk evaluation and mitigation strategy (REMS) for Multaq to determine the changes necessary to review whether the drugs benefits outweigh its risks.

Back in September, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use recommended the restricted use of dronedarone and urged that the drug only be prescribed for maintaining heart rhythm in paroxysmal or persistent AF patients. The EMA even went as far as to say that the drug should only be prescribed to patients after other treatment options have been considered.