Journal takes deep dive into dabigatran’s safety data

The journal BMJ took aim at the anticoagulant dabigatran and its manufacturer in a three-pronged package published online July 23 that cataloged the drug’s tumultuous pre-approval and post-approval journeys in the U.S. and Europe. Maker Boehringer Ingelheim called the stories unbalanced.

BMJ simultaneously published an analysis, an investigative piece and an editorial that reviewed concerns raised over bleeding risks with dabigatran (Pradaxa), which was developed as an alternative to warfarin for patients with nonvalvular atrial fibrillation who are at risk of stroke. Dabigatran at 150 mg dose was approved by the FDA in October 2010. Two doses—150 mg and 110 mg—were approved by the European Medicines Agency (EMA) in August 2011.

Thomas J. Moore, AB, of the Institute for Safe Medication Practices in Horsham, Penn., and colleagues focused on the different priorities of the two regulatory bodies in their analysis. The FDA appeared to value efficacy over safety, they wrote, while the EMA honed in on bleeding risk.

The authors recounted the drama that accompanied the FDA approval process: the agency’s initial rejection of the application because it questioned the data quality in the pivotal RE-LY trial; its decision to not consider the lower dosage in opposition of its advisory panel; and a panelist’s concerns about five-fold variability in blood plasma levels that might warrant monitoring.

“The cost of these decisions was sometimes doubling or tripling the risk of severe bleeding in older patients, patients with impaired kidney function, low body weight, those who were taking aspirin or who for other reasons ended up with excessively high plasma levels,” they wrote.

Moore et al argued the drug’s safety could be improved with dose adjustments, monitoring and approval of lower doses.

Editorial writers Blake Charlton and Rita Redberg, MD, MS, both of the University of California, San Francisco, dissected the RE-LY trial’s design and the FDA’s use of a single study in lieu of the standard requirement of two randomized trials. They also introduced information from internal documents that came to light with litigation, which Deborah Cohen, the journal’s investigation editor, expounds on in her feature.

Boehringer Ingelheim challenged the BMJ reports, saying their statements were misleading. The company wrote that it wanted to “set the record straight … as we are concerned that the reporting might put patients at risk of stopping their important stroke preventing medication.” It called dabigatran, which was the first anticoagulant to win approval since warfarin, a breakthrough.

Dabigatran is a direct thrombin inhibitor and warfarin is a vitamin K antagonist. The anticoagulants rivaroxaban (Xarelto, Janssen Pharmaceuticals/Bayer HealthCare) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) are direct factor Xa inhibitors.