FDA Advisors Approve Dabigatran for Stroke Prevention in Afib

SEPTEMBER 21, 2010
The cardiology community is abuzz with the news that 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.”

Larry Husten at CardioBrief says “The panel was split on whether both doses (150 mg bid and 110 mg bid) used in the RE-LY trial should gain approval, though in an informal straw poll a majority appeared to favor approval for both doses. (The FDA reviewers had recommended approval for only the higher dosage.) Most panel members also supported language on the label summarizing the superiority of the 150 mg dose over warfarin in RE-LY.”

A news release from Boehringer Ingelheim Pharmaceuticals, Inc, notes that this is good news for the approximately 2.3 million Americans who have AFib. This patient population is expected to grow significantly; the release claims that “the prevalence [of Afib] is expected to increase 2.5 fold to 5.6 million by 2050, reflecting the growing population of elderly individuals.”

The RE-LY trial involved more than 18,000 patients enrolled in more than 900 centers in 44 countries. Researchers compared the efficacy of dabigatran etexilate to warfarin in the prevention of stroke in “patients with non-valvular AFib and at least one other risk factor for stroke (ie, previous ischemic stroke, transient ischemic attack, or systemic embolism, left ventricular dysfunction, age greater than or equal to 75 years, age greater than or equal to 65 years with either diabetes mellitus, history of coronary artery disease, or hypertension)."

The FDA briefing information for the Cardiovascular and Renal Drugs Advisory Committee says that the official recommendation on regulatory action is that “Dabigatran should be approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation. The 150 mg dose of dabigatran should be approved but not the 110 mg dose. A superiority claim over warfarin should not be granted.”

The reviewers wrote that “With respect to the two doses of dabigatran, no clear and consistent differences are seen between the 150 mg and 110 mg dose” under the definition of “net benefit” being used for the review. Thus “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 one, raising questions about which dabigatran dose better balances safety against efficacy.”

Noting that “bleeding was the only important safety concern” that they identified in RE-LY, the FDA reviewers also wrote that “Relative to warfarin, dabigatran 150 mg was not associated with an increased risk of adjudicated major bleeds… whereas dabigatran 110 mg was associated with fewer major bleeding events.” They also noted that how a “major bleed” as defined in the RE-LY trial “compares in clinical significance to a stroke is questionable,” calling for “a finer classification of both types of events” in order to “assess the net benefit of dabigatran (relative to warfarin, and the two doses relative to one another).”

Philip B. Gorelick, MD, MPH, FACP, University of Illinois College of Medicine at Chicago, said that the results of the RE-LY trial “are likely to substantially change the treatment paradigm for stroke prevention in atrial fibrillation.” Gorelick also told TheHeart.org that “If approved for use by major regulatory agencies, higher-dose dabigatran may be used for AF patients at high risk of stroke who are in need of oral anticoagulation, and lower-dose dabigatran may be used in those AF patients not as high risk for stroke or those who physicians believe may have an increased risk of major bleeding but who qualify for oral anticoagulation therapy.”

This may be particularly beneficial to patients with atrial fibrillation who are at risk of stroke but who do not receive oral anticoagulation because “dabigatran therapy is not encumbered by limitations related to food-drug interaction or frequent blood-test monitoring, shows very little in the way of drug-drug interactions, and will likely turn out to be a welcome addition to our treatment strategies for AF patients in need of oral anticoagulation,” said Gorelick.

More information on the RE-LY trial

RELY-ABLE Long Term Multi-center Extension of Dabigatran Treatment in Patients With Atrial Fibrillation Who Completed the RE-LY Trial and a Cluster Randomised Trial to Assess the Effect of a Knowledge Translation Intervention on Patient Outcomes

Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) Comparing the Efficacy and Safety of Two Blinded Doses of Dabigatran Etexilate With Open Label Warfarin for the Prevention of Stroke and Systemic Embolism in Patients With Non-valvular Atrial Fibrillation: Prospective, Multi-centre, Parallel-group, Non-inferiority Trial (RE-LY Study)

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