The Food and Drug Administration is satisfied that dabigatran’s bleeding risk is no greater than that of warfarin and will not change the drug’s label.
The rates of gastrointestinal and intracranial bleeding among patients who have been prescribed the anticoagulant dabigatran "do not appear to be higher" than the rates among patients who have been prescribed warfarin, according to an analysis of insurance claims and administrative data conducted by the agency.
The results of this analysis, conducted in response to postmarketing reports of bleeding among people treated with dabigatran, are "consistent with observations" in the RE-LY trial, the study of 18,000 patients that was the basis of the approval of the anticoagulant for reducing the risk of stroke and blood clots in patients with nonvalvular atrial fibrillation (AF), the FDA said in the MedWatch safety alert, released on Nov. 2. In the RE-LY study, the rates of serious bleeding was similar among those treated with dabigatran and those with warfarin (N. Engl. J. Med. 2009;361:1139-51).
The agency is evaluating different sources of data in its review of this safety issue, which is ongoing. Dabigatran, an orally administered direct thrombin inhibitor, was approved in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and is marketed as Pradaxa by Boehringer Ingelheim.
The FDA’s analysis found that the rates of bleeding were actually higher among those on warfarin, although the statement does not point this out. The FDA analyzed data from a database of nearly 100 million patients and determined that the combined incidence of intracranial and gastrointestinal hemorrhages per 100,000 days at risk was 1.8-2.6 times higher for new users of warfarin than for new users of dabigatran. When they analyzed the two events separately, they found that the incidence rate of gastrointestinal hemorrhage events per 100,000 days at risk was 1.6-2.2 times higher for new users of warfarin than for new users of dabigatran. The incidence rate of intracranial hemorrhage events per 100,000 days at risk was 2.1-3.0 times higher for new users of warfarin than for those on dabigatran.
These estimates do not account for age, medical conditions, or other differences between the patients on warfarin and dabigatran that could affect bleeding outcomes, according to the FDA. In addition, although a "large" number of reports of bleeding in treated patients were submitted to the FDA’s Adverse Events Reporting System (FAERS) after dabigatran was approved, the agency believes that a "simple comparison" between the number of postmarketing bleeding events associated with dabigatran and warfarin is "misleading" because it is likely that bleeding events associated with warfarin are under reported, since the drug has been available for so long and bleeding is a well-recognized consequence of warfarin treatment.
At this time, the FDA is not changing any recommendations on the dabigatran label and is continuing to monitor postmarketing reports of bleeding in patients on dabigatran "for evidence of inappropriate dosing, use of interacting drugs, and other clinical factors that might lead to a bleeding event," according to the statement. The recommendations in the statement include advice to clinicians that they evaluate a patient’s renal function before prescribing dabigatran, which is eliminated by the kidneys, and the dosing regimens for patients with severe renal impairment and those with a creatinine clearance above 30 mL/min.
Click here for the Medwatch safety alert. Adverse events associated with dabigatran should be reported here or to the FDA at 800-332-0178.
