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Studies conflict over bleeding risk with dabigatran, warfarin
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Two new studies that compared outcomes in Medicare beneficiaries who initiated dabigatran or warfarin for the treatment of atrial fibrillation reported a higher risk for gastrointestinal bleeding for patients receiving dabigatran and a higher risk for intracranial hemorrhage for those receiving warfarin.
However, one study by Inmaculada Hernandez, PharmD, and colleagues published in JAMA Internal Medicine found a higher risk for any bleeding among patients receiving dabigatran (Pradaxa, Boehringer Ingelheim) compared with warfarin, while the other study, conducted by FDA and CMS officials and published in Circulation, found no difference in hospitalization for any bleeding between the groups. The FDA-CMS study reported that dabigatran was associated with reduced risk for ischemic stroke and death compared with warfarin; the study by Hernandez and colleagues did not compare outcomes not related to bleeding.
Inmaculada Hernandez
The University of Pittsburgh-Lapaz University study
Hernandez and colleagues analyzed pharmacy and medical claims from a 5% random sample of Medicare beneficiaries. They followed those newly diagnosed with AF from Oct. 1, 2010, to Oct. 31, 2011, who initiated treatment with dabigatran (n=1,302) or warfarin (n=8,102) within 60 days of diagnosis. Follow-up continued until death, discontinuation, switch of anticoagulants or Dec. 31, 2011.
Major bleeding events were defined as intracranial hemorrhage, hemoperitoneum, and inpatient or emergency stays for hematuria, gastrointestinal or other hemorrhage. All bleeding events were characterized by site and as major or minor.
Relative to warfarin, dabigatran was associated with a higher risk for any bleeding event (HR=1.3; 95% CI, 1.2-1.41), major bleeding (HR=1.58; 95% CI, 1.36-1.83) and gastrointestinal bleeding (HR=1.85; 95% CI, 1.64-2.07). Dabigatran was also associated with lower risk for intracranial hemorrhage compared with warfarin (HR=0.32; 95% CI, 0.2-0.5).
The elevated risk for major bleeding and gastrointestinal hemorrhage associated with dabigatran was consistent across all subgroups analyzed, and the elevated risk for major bleeding associated with dabigatran was especially high in black adults (HR=2.12; 95% CI, 1.39-3.24) and those with chronic kidney disease (HR=2.07; 95% CI, 1.66-2.58). The elevated risk for intracranial hemorrhage associated with warfarin relative to dabigatran was especially pronounced in patients aged older than 75 years (HR=0.1; 95% CI, 0.04-0.24), according to the researchers.
“Before more evidence is available, dabigatran should be prescribed with caution in high-risk patients,” Hernandez, from the department of health policy and management at the University of Pittsburgh’s Graduate School of Public Health, and colleagues concluded.
Rita F. Redberg
In an editor’s note published in JAMA Internal Medicine along with this study, Rita F. Redberg, MD, MSc, said the study prompts “cause for concern because it appears that the bleeding risk for dabigatran is higher than for warfarin and significantly greater than [it] originally appeared at the time of the FDA approval.”
“The haste to approve novel drugs places an increasing importance on postapproval data to help better understand risks and benefits. This study reminds us of the importance of postmarketing data and of having adequate data on risks and benefits to advise our patients accurately,” Redberg, chief editor of JAMA Internal Medicine, professor of medicine at University of California, San Francisco, and Cardiology Today Editorial Board member, wrote.
The FDA-CMS study
David J. Graham, MD, MPH, and colleagues studied new-user cohorts of propensity score-matched patients aged 65 years and older enrolled in Medicare who initiated dabigatran or warfarin for the treatment of nonvalvular AF between October 2010 and December 2012 (n=134,414).
The primary outcomes included ischemic stroke, major bleeding (with focus on intracranial and gastrointestinal bleeding) and acute MI. Secondary outcomes were all hospitalized bleeding events and mortality.
During 37,587 person-years of follow-up, the researchers observed 2,715 primary outcome events.
Compared with warfarin, patients taking dabigatran had a lower risk for ischemic stroke (HR=0.8; 95% CI, 0.67-0.96), intracranial hemorrhage (HR=0.34; 95% CI, 0.26-0.46) and death (HR=0.86; 95% CI, 0.77-0.96); no difference in risk for acute MI (HR=0.92; 95% CI, 0.78-1.08) or all hospitalized bleeds (HR=1; 95% CI, 0.92-1.09); and a higher risk for major gastrointestinal bleeding (HR=1.28; 95% CI, 1.14-1.44).
For those taking dabigatran 150 mg twice daily, the magnitude of effect was greater, and for those taking dabigatran 75 mg twice daily, there was no difference in risk compared for warfarin for any outcome except for intracranial hemorrhage, except for a lower risk associated with dabigatran, Graham, from the Office of Surveillance and Epidemiology, FDA Center for Drug Evaluation and Research, and colleagues wrote.
The increased risk for gastrointestinal bleeding associated with dabigatran appeared to be restricted to women aged 75 years and older and men aged 85 years and older, while the decreased risk for mortality associated with dabigatran was no present in women aged 85 years and older.
For more information:
Graham DJ. Circulation. 2014;doi:10.1161/CIRCULATIONAHA.114.012061.
Hernandez I. JAMA Intern Med. 2014;doi:10.1001/jamainternmed.2014.5398.
Redberg RF. JAMA Intern Med. 2014;doi:10.1001/jamainternmed.2014.6265.
Disclosure: The study by Hernandez and colleagues was supported in part by a grant from the Commonwealth Foundation and Agency for Healthcare Research and Quality. Both sets of researchers and Redberg report no relevant financial disclosures.