Paris, France (updated) - Sanofi, maker of dronedarone (Multaq), has suspended its phase 3b trial of its antiarrhythmic drug due to an increase in cardiovascular events seen in patients randomized to dronedarone. The PALLAS trial was testing the drug in patients with permanent atrial fibrillation (AF) and at least one other cardiovascular disease risk factor; at present, dronedarone is approved in patients with nonpermanent AF.

The trial's operations and data monitoring committees made the decision to halt the study after seeing a significant increase in cardiovascular events among patients taking the study drug, as compared with patients on placebo, although details of just what those events are have not been released. In both arms of the trial, patients were also receiving antithrombotic and rate-control medications.

Co-primary investigator Dr Stuart Connolly (McMaster University, Hamilton, ON) said he could not provide details on the types of cardiovascular events seen. "Suffice it to say . . . there was a significant increase in major cardiovascular events, and in our study that was defined as a composite of stroke, MI, systemic embolism, or cardiovascular death. . . . These were pretty important events."

According to a press release issued by Sanofi today, the company has informed regulators about the decision to stop the trial and asked trial investigators to get in touch with patients to tell them to stop taking the drug. Patients taking Multaq outside of the trial, however, "should not stop their therapy and should consult their treating physician if they have any questions," the Sanofi release states.

To heartwire, Connolly stressed the differences between the nonpermanent-AF patient population studied in the ATHENA study and the permanent-AF population studied in PALLAS.

"The two studies are completely different. In ATHENA, the patients all had intermittent AF, and there was a reduction in AF recurrences with dronedarone. In PALLAS, they all had permanent AF, and there was no reduction in the AF in these patients. These patients remained in permanent AF."

In ATHENA, he adds, patients had to have intermittent AF as well as a risk factor for increased hospitalization, but these were "relatively mild risk factors," such as left atrial enlargement, age over 75, or history of hypertension. By contrast, in PALLAS, "patients had to have had either a major vascular event like a stroke or MI, or they had to have a low ejection fraction, or triple risk factors—so it was a much higher-risk group."

He continued, "There's very strong evidence from ATHENA that patients benefit from dronedarone—that is, the patients who are ATHENA-like patients, and clearly there is something very different about the permanent-AF patients. For patients who are currently on dronedarone and who have nonpermanent AF, I would say that it's reasonable to stay on the drug, and I don't think they should be worried."

Of note, the press release states that the "decision to terminate the study was not related to any hepatic adverse event." Liver injuries are a known side effect of the drug and have previously prompted warnings by both US and European regulators. Speaking with heartwire, Connolly said he was "not aware" of any signal of hepatic events and that he hadn't seen those numbers. "But certainly [hepatic events] were not a part of the discussion" that led to the decision to halt the trial.

PALLAS was launched in July 2010 and was designed to enroll 10 800 patients, with an estimated completion date of August 2013. Only 3149 patients had been enrolled at the time the study was stopped. The study was to include over 585 sites, and according to Connolly, those included 185 sites in the US and at least 20 in Canada.

Dronedarone has faced a range of criticisms since its approval in the US in July 2009, including questions about its safety/efficacy tradeoff and the design and execution of the ATHENA study. Just last week, newspapers in France reported that French health authorities had concluded that the efficacy of dronedarone was "insufficient"—an opinion that could lead to the drug being dropped from the country's drug reimbursement formulary.