A significant increase in cardiovascular events in patients with permanent atrial fibrillation who are taking dronedarone in the PALLAS trial has led the drug’s manufacturer to suspend the phase IIIb study.
Dronedarone (Multaq), a benzofuran derivative that is a an analogue of amiodarone, is approved in the United States and the European Union for a different population of patients with AF, not those with permanent AF, and "the benefit-risk of Multaq remains unchanged in its approved indication in nonpermanent AF," the company said in a press release issued on July 7.
The Food and Drug Administration approved dronedarone in 2009 for reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors who are in sinus rhythm or who will be cardioverted. (In the EU, it is indicated for clinically stable adults with a history of nonpermanent AF or with current nonpermanent AF, to prevent the recurrence of AF or to lower the ventricular rate.)
PALLAS (Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy) was discontinued for enrolled patients with permanent AF.
The international phase IIIb study compared dronedarone 400 mg twice daily (the approved dose) to placebo in about 3,000 patients with permanent AF, who were over age 65 and had comorbidities such as previous myocardial infarction, documented coronary artery disease, previous stroke, symptomatic heart failure, or diabetes. Patients with New York Heart Association class IV or unstable NYHA class III heart failure were excluded.
The company stopped the study in response to recommendations made by the study’s operations and data monitoring committees, after a significant increase in cardiovascular events was observed among those in the dronedarone arm, according to the statement.
In the statement, the study’s coprincipal investigator, Dr. Stuart Connolly, director of the cardiology division and professor of medicine at McMaster University, Hamilton, Ont., said that the committee members were "very disappointed to discover that the hypothesis that dronedarone would improve major outcomes for this high-risk patient population has been refuted."
Patients enrolled in PALLAS had permanent AF and were more likely to have advanced vascular disease than patients in whom the drug is currently indicated, who have intermittent AF and most often do not have advanced vascular disease, Dr. Connolly said in an interview.
"The results of PALLAS do not bear directly on the patients on dronedarone for the approved indication," he noted. "So it is reasonable to continue those patients on dronedarone, and I would expect that they will still benefit from it in terms of reduced cardiovascular hospitalization."
About 70% of the patients enrolled in PALLAS had had permanent AF for more than 2 years, and about 70% had NYHA class I-III heart failure at baseline, which the Sanofi statement listed as other differences between these patients and the patients enrolled in the ATHENA study that supported the currently approved indication. (In the ATHENA study, fewer than 30% of patients had NYHA class I-III heart failure and none had permanent AF, the statement said).
This is not the first indication that dronedarone may not be suitable for sicker patients. Its label already includes a black box warning that says the drug is contraindicated in patients with NYHA class IV heart failure or NYHA class II-III heart failure with a recent decompensation requiring hospitalization or referral to a heart failure clinic. This warning was based on the results of another dronedarone study that was stopped early – the ANDROMEDA study – which found that mortality was increased among such patients who were given dronedarone, when compared with placebo.
Dr. Connolly said he has received grant support and consulting and lecture fees from Sanofi.