Promising Early Results for Combination Treatment for Atrial Fibrillation

July 1, 2014
Andrew Smith

Phase II trial data suggest that a fixed-dose combination of ranolazine and low-dose dronedarone may significantly reduce disease burden among patients with atrial fibrillation.

Phase II trial data suggest that a fixed-dose combination of ranolazine and low-dose dronedarone may significantly reduce disease burden among patients with atrial fibrillation (AF).

The HARMONY trial randomized 134 patients among five treatment arms: placebo (n=26), 750 mg tablets of ranolazine taken twice daily (n=26), 225 mg capsules of dronedarone taken twice daily (n=26), a combination of 750 mg of ranolazine and 150 mg of dronedarone (RD150) taken twice daily (n=26), and a combination of 750 mg of ranolazine and 225 mg dronedarone (RD225) taken twice daily (n=27).

The primary endpoint was the change over a 12-week period in AF burden: the total time a patient was in atrial tachycardia/atrial fibrillation expressed as percentage of total recording time continuously from 0 to 12 weeks.

Neither of the groups assigned to take a single medication experienced a significantly greater change in AF burden compared with people who took the placebo. The RD150 group, on the other hand, experienced a 45% reduction in AF burden while the RD225 group experienced a 59% reduction.

Roughly 45% of RD225 patients achieved AF burden reductions from baseline of ≥70% over the 12-week study.

“There currently are a limited number of safe and effective anti-arrhythmic therapies for AF patients, underscoring the need to evaluate new treatment strategies,” said Peter R. Kowey, MD, in a news release that accompanied publication of the study results. Kowey is the William Wikoff Smith Chair in Cardiovascular Research at Lankenau Medical Center, and Professor of Medicine and Clinical Pharmacology at Thomas Jefferson University’s medical college.

“HARMONY suggests that a new therapeutic approach of combining ranolazine and low-dose dronedarone is more effective than either therapy alone in lowering AF burden. Pending larger phase III evaluation, a combination of ranolazine and low-dose dronedarone has the potential to help address a significant and growing unmet need for additional treatment options for people living with this serious disease,” said Kowey.

Adverse events were similar across all active treatment groups. The most frequent adverse events leading that led to discontinuation within each treatment group were atrial fibrillation (placebo group, 2 patients), vertigo and dizziness (ranolazine 750 mg, 2 patients each), dyspnea and pruritus (dronedarone 225 mg, 2 patients each), and hypotension (RD225, 2 patients). No adverse events led to discontinuation of more than one patient in the RD150 group.

Dronedarone is already approved for treatment in patients with a history of paroxysmal or persistent AF, but ranolazine is only approved right now for the treatment of chronic angina.

A preclinical study published four years ago in the Journal of the American College of Cardiology suggested the two drugs have synergistic effects and led Gilead to begin testing them in combination against AF.

Several subsequent small trials have supported the hypothesis that ranolazine may increase dronedarone’s efficacy against AF. Indeed, Gilead says results to date have been good enough to convince the company to begin planning a larger phase III trial of a fixed-dose combination on patients with paroxysmal/persistent AF.