After discussions with dabigatran’s sponsor, Boehringer Ingelheim GMBH, and further study of pivotal trial data submitted with new drug application for the oral direct thrombin inhibitor, the Food and Drug Administration has revised the anticoagulant’s labeling to note that it demonstrated superiority in prevention of ischemic and hemorrhagic stroke over warfarin.
Dabigatran (Pradaxa) obtained FDA approval for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) in October 2010. The label change, in the Clinical Studies section, is not because of any additional post-NDA or postmarketing data but reflects a fuller review by FDA of the data from the phase III pivotal RE-LY trial, Boehringer Ingelheim’s senior vice president for clinical development and medical affairs, John Smith, noted.
"We’ve maintained an ongoing dialogue with [the FDA’s] cardiorenal division since the approval of Pradaxa," Smith added. "What this does is ... reiterate the significant reduction of stroke that we saw in the RE-LY trial, 35% reduction of stroke, including significant 25% reduction in the risk of ischemic stroke, which is the most common stroke type in patients with atrial fibrillation." RE-LY also demonstrated significant reduction of risk for hemorrhagic stroke.
Dabigatran currently is the only approved anticoagulant drug with efficacy data superior to warfarin. It was approved with a Risk Evaluation and Mitigation Strategy, including a Medication Guide, which notes that it "can cause bleeding which can be serious, and sometimes lead to death.
AE Reporting Suggests Safety Trouble for Dabigatran
Dabigatran is safety challenged, however, especially if one gives credence to adverse event (AE) reporting. In a May 31 report, the Institute for Safe Medication Practices noted that dabigatran and warfarin ranked first and second in 2011 in serious adverse event reports to FDA by companies, clinicians, and patients. The Institute cautioned, however, that its data are not scientific – direct reporting of serious AEs to FDA is a valuable index of drug-safety risk but should not be seen as a reliable indicator of the frequency of AEs with a specific drug. FDA estimates that less than 1% of serious AEs are directly reported.
In its Quarter Watch report, the Institute noted that dabigatran accounted for 3,781 domestic serious AEs in 2011, including 542 patient deaths. These reports included 2,367 cases of hemorrhage, 291 cases of acute renal failure, and 644 of stroke. Meanwhile, warfarin was linked to 1,106 serious AEs and 72 deaths.
Later this year, Boehringer Ingelheim plans to unveil data from its long-term safety study of Pradaxa called RELY-ABLE, while it also is establishing the GLORIA-AF patient registry to study NVAF patients being treated with oral anticoagulants.
"We anticipate enrolling almost up to 10,000 patients [in GLORIA-AF], approximately a sixth of the patients globally," Mr. Smith said. "This is an opportunity to observe the use of oral anticoagulants in a real-world setting and again globally, and also allows for the serial collection of data that aren’t necessarily available from spontaneous reports."
Editor’s note: This story appears courtesy of "The Pink Sheet," a weekly Elsevier publication covering pharmaceutical business and policy issues. To learn more, contact customer care at 800-332-2181 or sign up for a free trial.