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Dabigatran raises major bleeding risk

Publish date: November 3, 2014
By
Mary Ann Moon

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Higher bleeding risk than warfarin’s

The bleeding risk for dabigatran appears to be higher than that for warfarin and significantly greater than it initially seemed at the time of FDA approval.

Hernandez et al. noted that the study on which the FDA based its approval failed to adjust for important differences in patient characteristics, which likely biased the results. They remind us that postmarketing data are crucial for us to advise our patients accurately.

Dr. Rita F. Redberg is the editor of JAMA Internal Medicine and director of women’s cardiovascular services at the Philip R. Lee Institute for Health Policy Studies at the University of California, San Francisco, Medical Center. She reported no financial conflicts of interest. Dr. Redberg made these remarks in an Editor’s Note accompanying Dr. Hernandez’s report (JAMA Intern. Med. 2014 Nov. 3).


 

FROM JAMA INTERNAL MEDICINE

References

Dabigatran significantly raises the risk of major bleeding and gastrointestinal bleeding across all subgroups of patients with atrial fibrillation, and particularly in African Americans and patients with chronic kidney disease, according to a report published online Nov. 3 in JAMA Internal Medicine.

Physicians should only prescribe dabigatran with caution, and should fully explain to patients who do take the drug how to identify abnormal bleeding so that it can be detected and controlled as early as possible, said Inmaculada Hernandez, Pharm.D., of the department of health policy and management, University of Pittsburgh, and her associates.

The FDA approved dabigatran in 2010 via an accelerated pathway after only 6 months of review, based largely on findings from a single clinical study, the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which did not adjust for patient characteristics (N. Engl. J. Med. 2009;361:1139-51). That study reported lower bleeding risks with dabigatran than with warfarin. Several months later, the agency’s Adverse Event Reporting System received “a large number” of reports of severe bleeding associated with dabigatran; and the relative bleeding risk associated with the two drugs is still unclear.

Dr. Hernandez and her colleagues examined the issue using data from a nationally representative random sample of 9,404 Medicare beneficiaries newly diagnosed as having nonvalvular atrial fibrillation during a 1-year period and treated in real-world practice. A total of 1,302 patients were given dabigatran and 8,102 were given warfarin to prevent stroke and systemic embolism. They were followed for a median of about 200 days, until discontinuing or switching their anticoagulant, dying, or reaching the study’s cutoff date. Nine categories of bleeding were assessed, and the data were adjusted to account for numerous demographic and clinical characteristics known to affect bleeding risk.

Compared with warfarin, dabigatran was associated with a significantly higher risk of major bleeding (9.0% vs 5.9%), with a hazard ratio of 1.58. Dabigatran also was associated with a significantly higher risk of GI bleeding (HR, 1.85), hematuria (HR, 1.41), vaginal bleeding (HR, 2.27), hemarthrosis (HR, 2.78), and hemoptysis (HR, 1.49). In contrast, dabigatran was associated with a slightly lower (0.6%) rate of intracranial bleeding, and also with lower rates of epistaxis and nonspecified bleeding, the investigators reported (JAMA Intern. Med. 2014 Nov. 3 [doi: 10.1001/jamainternmed.2014.5398]).

These differences were consistent across numerous subgroups of patients assessed, and were especially strong among African Americans and patients with chronic kidney disease.

This study was supported by the Commonwealth Foundation and the U.S. Agency for Healthcare Research and Quality. Dr. Hernandez and her associates reported having no financial conflicts of interest.

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