EMA Adds CV Events to Review of Dronedarone

July 12, 2011

July 12, 2011 (London, United Kingdom) — The European Medicines Agency (EMA) is to review the cardiovascular risk of the antiarrhythmic dronedarone (Multaq, Sanofi-Aventis), following the decision last week to suspend the phase 3 PALLAS trial of the drug in patients with permanent atrial fibrillation, because of an increase in CV events in those randomized to dronedarone [1].

The EMA "will determine the need for any further action" at its July meeting, to be held next week. The EMA, along with the US FDA, is already reviewing the overall risk/benefit profile of dronedarone following reports of severe liver injury, a process begun in January, and the scope of the review has now been extended to assess new information from the PALLAS study following a request from the European Commission.

The decision to halt PALLAS was made by the trial's operations and data monitoring committees after seeing a significant increase in cardiovascular events among patients taking dronedarone, as compared with patients on placebo, but details of just what those events are have not been released.

AF expert Dr John Camm (St George's Hospital, London, UK) told heartwire : "There is obviously some concern, but we must wait for details before the ramifications of this will become apparent." However, he stressed, "The PALLAS trial is in permanent AF, an indication that is not currently held by dronedarone." This point is also underscored by EMA, which notes that the population for which Multaq is currently approved is those who have or have had nonpermanent AF.

One of the PALLAS co–primary investigators, Dr Stuart Connolly (McMaster University, Hamilton, ON)--speaking with heartwire last week about the decision to halt the trial--also stressed the differences between those two patient populations. He said he believes there is strong evidence from the trial on which approval of dronedarone was based, ATHENA, that patients with nonpermanent AF benefit from the drug, and he does not think this type of patient should be worried.

Nevertheless, dronedarone has faced a range of criticisms since its approval in the US in July 2009, including questions about its safety/efficacy trade-off and the design and execution of the ATHENA study. Most recently, French health authorities have also reportedly concluded that the efficacy of dronedarone is "insufficient"--an opinion that could affect the drug's reimbursement status there [2]. Following the halting of PALLAS last week, French drug-oversight agency AFSSAPS (French Agency for Safety of Health Products) issued an alert to doctors telling them to use the "highest vigilance" in prescribing the drug and telling them to suspend all prescriptions for dronedarone in permanent AF.