Dabigatran Carries Higher Risk of Major Bleeds, Lower Risk of Intracranial Hemorrhage

Dabigatran is associated with a higher risk of major bleeding and gastrointestinal (GI) hemorrhage compared with warfarin in Medicare beneficiaries with nonvalvular atrial fibrillation (A-fib), a finding consistent across high-risk subgroups, according to a study published online November 3, 2014, ahead of print in JAMA Internal Medicine. The risk of intracranial hemorrhage, however, is lower with dabigatran.

“Before more evidence is available, dabigatran should be prescribed with caution in high-risk patients,” Yuting Zhang, PhD, of the University of Pittsburgh (Pittsburgh, PA), and colleagues write. “Our study also indicates the importance of comparing the safety profiles of newer and traditional drugs using postmarketing real-world data.”

Methods
The researchers performed a retrospective cohort study using pharmacy and medical claims from a nationally representative 5% sample of Medicare beneficiaries. The analysis included patients newly diagnosed with A-fib from October 2010—when dabigatran (Pradaxa; Boehringer Ingelheim) was approved by the US FDA based on the results of the RE-LY trial—through October 2011 who initiated either dabigatran (n = 1,302) or warfarin (n = 8,102) within 60 days of diagnosis. Mean follow-up was 177 days for dabigatran users and 228 days for warfarin users.

After adjustment for demographics and clinical characteristics with inverse propensity-score weighting, the risks of most types of bleeding were higher with dabigatran relative to warfarin. However, the risks of intracranial bleeding, epistaxis, and hemorrhage not otherwise specified were lower with dabigatran (table 1).

Table 1. Adjusted Bleeding Risks


Rates of any bleeding, major bleeding, and GI bleeding were elevated in dabigatran users across 4 high-risk subgroups—age 75 years or older, black race, chronic kidney disease (CKD), and the presence of at least 7 comorbidities—although major bleeding risk was particularly high in black patients and those with CKD.

In the subgroup analysis, the risk of intracranial hemorrhage did not differ between dabigatran and warfarin in black patients or in those younger than 75.

Conflicting Results Across Studies

Multiple studies have examined bleeding risks associated with dabigatran starting with the RE-LY trial, which showed no difference between the dabigatran and warfarin arms in major bleeding. However, RE-LY also found the 150-mg dose of dabigatran to be associated with a higher rate of GI bleeding and a lower rate of intracranial hemorrhage.

After dabigatran was approved, reports of excess bleeding with the drug prompted the FDA to review the issue. An initial study from the agency concluded that dabigatran did not increase the rate of GI bleeding or intracranial hemorrhage compared with warfarin, although the analysis did not adjust for patient characteristics, Dr. Zhang and colleagues note.

A later meta-analysis showed that dabigatran was associated with a higher rate of GI bleeding, whereas a Danish registry study demonstrated similar rates of major and GI bleeding between dabigatran and warfarin.

The study by Dr. Zhang’s group adds to the mixed evidence surrounding the bleeding risks of dabigatran but carries limitations of its own. It could not account for unobserved factors related to the choice between dabigatran or warfarin, did not have long enough follow-up to evaluate the risk of stroke and assess the risk-benefit ratio associated with dabigatran, and lacked detailed information on laboratory findings.

Individualized Decision Making for Dabigatran

But the study still has implications for practice in that it highlights that “physicians should prescribe dabigatran with caution, especially among African Americans and patients with renal impairment,” Dr. Zhang and colleagues write.

The study, however, only looks at one side of the story, Dr. Zhang told TCTMD in a telephone interview, pointing out that clinicians need to balance the bleeding risks with the stroke prevention benefit of dabigatran in individual patients.

“Dabigatran has more bleeding, especially GI bleeding, but less intracranial bleeding,” she said. “So clinicians might need to be more cautious about prescribing it in patients with a higher risk of bleeding. Maybe start with a low dose, monitoring the patient carefully, and then increase to the high dose.”

In an accompanying editor’s note, Rita F. Redberg, MD, MSc, of the University of California, San Francisco, says the findings “give us cause for concern because it appears that the bleeding risk for dabigatran is higher than for warfarin and significantly greater than originally appeared at the time of the FDA approval.”

In addition, she continues, “this study reminds us of the importance of postmarketing data and of having adequate data on risks and benefits to advise our patients accurately.”

 


Sources:
1. Hernandez I, Baik SH, Piñera A, Zhang, Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2014;Epub ahead of print.

2. Redberg RF. The importance of postapproval data for dabigatran [editor’s note]. JAMA Intern Med. 2014;Epub ahead of print.

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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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Disclosures
  • The study was supported by the Commonwealth Foundation and Agency for Healthcare Research and Quality.
  • Drs. Redberg and Zhang report no relevant conflicts of interest.

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