The FDA’s Cardiovascular and Renal Drug advisory committee has unanimously voted nine to zero in favor of Boehringer Ingelheim Pharmaceuticals’ dabigatran etexilate mesylate (Pradaxa) capsules, an anticoagulant indicated for use in atrial fibrillation (AF) patients to prevent stroke.

According to FDA briefing documents, the review was based on results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which compared the use of dabigatran in 150 mg and 110 mg doses to warfarin (Coumadin, Bristol-Myers Squibb/Sanofi-Aventis), a commonly used anticoagulant.

The RE-LY trial results showed that a 110 mg dose of dabigatran was associated with 90 MIs, while warfarin was associated with 74 MIs. Additionally, the 150 mg dose of dabigatran was linked to 102 MIs. 

“Whether or not the higher rate of MI with dabigatran represents the play of chance, an adverse effect of dabigatran or beneficial effects of warfarin on infarction risk remains unclear,” the FDA's clinical review documents stated. It also said that “a superiority claim over warfarin should not be granted.”

During the trial, results showed that rates of the primary outcome were 1.69 percent per year in the warfarin group, compared with 1.53 percent per year in the group that received 110 mg of dabigatran, and 1.11 percent per year in the group that received 150 mg of dabigatran. Additionally, the mortality rate was 4.13 percent per year in the warfarin arm, compared with 3.75 percent per year with 110 mg of dabigatran and 3.64 percent per year with 150 mg of dabigatran.

FDA researchers who assessed the RE-LY trial, a multicenter, randomized study of more than 18,000 patients, found the only safety concern to be bleeding.

According to the researchers, 150 mg doses of dabigatran was not associated with an increased risk of major bleeding events, but the 110 mg dose of the drug was linked to fewer major bleeding events. With these results, the researchers said that “how a major bleed, as defined in RE-LY, compared in clinical significance to stroke is questionable,” and said that a “finer classification of both types of events is perhaps needed.”

The panelists wrote, “With respect to the two doses of dabigatran, no clear and consistent differences are seen between the 150 mg and 110 mg dose using these definitions of ‘net benefit.’ As shown below, net benefit does not strongly or consistently favor one or the other dabigatran arm; the confidence intervals for the 150 mg to 110 mg comparisons are also, for the most part, broad and cross 1.0, raising questions about which dabigatran dose better balances safety against efficacy.”

The researchers reported that stroke events or life threatening bleeds occurred in 302 cases in patients administered dabigatran 110 mg, 288 for patients administered 150 mg dose of dabigatran and 364 cases with warfarin. 

“We believe dabigatran etexilate will offer patients and doctors the first new treatment option for stroke prevention in atrial fibrillation in more than 50 years,” said Christopher Corsico, MD, U.S. medical director of Boehringer. “We look forward to working with the FDA as it finalizes its review of dabigatran.”

Dabigatran etexilate is approved in the European Union for indications to prevent venous thromboembolic events in patients who have underwent total hip and knee replacements. The current FDA approval is the first of its kind for the indication of stroke prevention in AF patients. The drug competes with other anticoagulants that aim to be indicated for the prevention of stroke including rivaroxaban (Xarelto, Bayer) and apixaban (Bristol-Myers Squibb/Pfizer).

While the FDA often upholds the recommendations of the clinical reviewers, it can accept or reject the recommendations. A decision on Pradaxa by the FDA is expected by October 19.