Higher risk of bleeds with dabigatran but lower risk of brain hemorrhage

Blacks and patients with impaired kidney function may be particularly at risk of bleeding if given the anticoagulant dabigatran, according to an analysis of Medicare data. Compared with warfarin, dabigatran had higher bleeding risks overall but a lower risk of intracranial hemorrhage.

In 2010, the FDA approved the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation. But several studies since have reported results for major and gastrointestinal bleeding that differed from the drug’s pivotal trial, RE-LY.  The FDA came out with its own analysis using Mini Sentinel data that concurred with RE-LY findings but the agency failed to account for patient differences in the study.

Inmaculada Hernandez, PharmD, of the University of Pittsburgh, and colleagues went beyond the FDA’s approach by analyzing Medicare Part D data for patients with newly diagnosed atrial fibrillation who started either dabigatran or warfarin treatment in 2010 and 2011. They used a 5 percent random sampling that included 1,302 dabigatran users and 8,102 warfarin users and propensity score weighting to balance patient characteristics.

They published their results online Nov. 3 in JAMA Internal Medicine.

After propensity score weighting, the dabigatran group had a higher risk of major bleeding and any bleeding compared with the warfarin group and a higher incidence rate (9 percent vs. 5.9 percent). The hazard ratio for dabigatran compared with warfarin was 1.58 for major bleeding and 1.3 for any bleeding.

Age and race affected major bleeding risk. Being 75 years or older compared with younger than 65 years had a hazard ratio of 1.48 for major bleeding and being black compared with white had a hazard ratio of 2.09.

The hazard ratio for gastrointestinal bleeding for dabigatran vs. warfarin was 1.41. But dabigatran had a lower rate of intracranial bleeding, at 0.6 percent vs. 1.8 percent, and a hazard ratio of 0.32 percent.

“[I]ntracranial hemorrhage is the most feared complication associated with warfarin; thus, patients at high risk of intracranial hemorrhage may be willing to accept the higher risk of other bleeding events associated with dabigatran for a lower likelihood of intracranial bleeding,” they wrote. “Arguably, this is the subgroup in which dabigatran is most likely to be a favorable choice in terms of safety.”

In a subgroup analysis that included age, whether patients were black, had renal impairment or had seven concomitant comorbidities, Hernandez et al determined that the risk of any bleeding and gastrointestinal bleeding was higher for all subgroups. The hazard ratio for blacks was 2.12 and for patients with chronic kidney disease it was 2.07.  

Warfarin use increased the risk of intracranial hemorrhage in patients older than 75. Dabigatran compared with warfarin had a hazard ratio of 0.1 for this group.

“[P]hysicians should prescribe dabigatran with caution, especially among African Americans and patients with renal impairment,” they suggested.

They added that their follow-up was only 14 months. Consequently, they could not evaluate stroke incidence to provide a risk-benefit analysis.