FDA: Awareness, not excessive bleeds, hounds Pradaxa

An FDA analysis using its Mini-Sentinel program puts the anticoagulant dabigatran once again on equal footing with warfarin for bleeding risks. The report, published online March 14 as a perspectives article in the New England Journal of Medicine, attributes the high number of postmarket cases of bleeding to “stimulated reporting.”  

The findings were published by Mary Ross Southworth, PharmD, Marsha E. Reichman, PhD, and Ellis F. Unger, MD, of the FDA’s Center for Drug Evaluation and Research.

The agency conducted its analysis in response to reports in its FDA Adverse Event Reporting System of serious and fatal bleeding events in patients given dabigatran (Pradaxa, Boehringer Ingelheim). The drug was approved by the FDA in October 2010, as an alternative to warfarin to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. Approval was based on results from the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, in which dabigatran had lower rates of stroke and mortality compared with warfarin, with equal bleeding risks.

“We were concerned that postmarketing use of dabigatran might be different from its use in the RE-LY trial (e.g., different patient populations, dosing, concomitant medications and degree of renal impairment) or that adjustments for real failure had not been made correctly,” they wrote.

A case review failed to find any unrecognized risk factors or indications that physicians were not following label instructions.

They noted that newly approved drugs tend to garner more attention among physicians, patients and the press, which also might heighten awareness and prompt an increase in reports. To test that possibility, they compared bleeding rates for dabigatran and warfarin based on insurance claim data and administrative data (inpatient diagnosis codes) in the FDA Mini-Sentinel database. The analysis spanned the date of dabigatran’s approval (Oct. 19, 2010) to the end of 2011.

They concluded that bleeding rates for dabigatran did not appear to be higher than for warfarin. Their analysis did not adjust for confounding factors, though. They plan to conduct more assessments that include adjustments.

“We believe that the large number of cases of bleeding associated with dabigatran provides a salient example of stimulated reporting,” they concluded. “In this case, such reporting provided a distorted estimate of the comparative bleeding rates associated with dabigatran and warfarin in clinical practice.”