Meta-analysis: Good Bleeding Profile with Dabigatran vs. Warfarin for A-fib, VTE

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Compared with warfarin, use of the direct thrombin inhibitor dabigatran results in less overall and intracranial bleeding, but at the expense of increased gastrointestinal (GI) bleeding in patients with atrial fibrillation (A-fib) or venous thromboembolism (VTE). Results of the meta-analysis were published online December 26, 2013, ahead of print in the American Journal of Cardiology.

Researchers led by Mark J. Eisenberg, MD, MPH, of McGill University (Montreal, Canada), analyzed data from 4 multicenter randomized controlled trials comparing dabigatran with warfarin in 17,466 patients.

The included trials were:

  • RE-LY (n = 12,098)
  • PETRO (n = 236)
  • RE-COVER (n = 2,564)
  • RE-COVER II (n = 2,568)

RE-LY and PETRO consisted of A-fib patients, while the other 2 trials consisted of patients with VTE. A fifth trial, RE-MEDY (n = 2,866), which also consisted of a VTE population, was included in a systematic review but not the meta-analysis.

Less Overall Bleeding vs. Warfarin

When data were pooled across the 4 trials with non-overlapping patients, dabigatran was not associated with an increased risk of major bleeding. Compared with warfarin, dabigatran was associated with a decreased risk of overall bleeding, driven largely by decreased risk among VTE patients (RR 0.72; 95% CI 0.64-0.81) and a decreased risk of intracranial bleeding. However, dabigatran was associated with an increased risk of GI bleeding. Additionally, there was a trend toward decreased all-cause mortality with dabigatran, but this was only found in the RE-LY trial (table 1).

Table 1. Bleeding, Mortality for Dabigatran vs. Warfarin

 

Relative Risk

95% CI

Bleeding
Any
Major
GI
Intracranial

 
0.77
0.92
1.51
0.40

 
0.64-0.93
0.81-1.05
1.23-1.84
0.27-0.59

Mortality

0.90

0.80-1.01


Dabigatran patients in RE-COVER also demonstrated a lower risk of intraarticular or intramuscular bleeding (RR 0.29; 95% CI 0.13-0.65).

‘A Major Advantage’

Dr. Eisenberg and colleagues say the decreased risk in intracranial bleeding with dabigatran “constitutes a major advantage relative to [vitamin K antagonists] because intracranial bleeding is a complication that is not easily treatable. Future trials of anticoagulants should assess this outcome as part of their safety analyses to allow for the continued assessment of this clinically important outcome.”

Due to the 50% increase in the risk of GI bleeding with dabigatran reported in the meta-analysis, the study authors suggest that warfarin may be best for those at high risk of GI bleeding. “In addition, future studies should examine if patients at risk of GI bleeding may benefit from prophylactic protective therapy when using dabigatran,” they note.

In a telephone interview with TCTMD, Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), agreed that the findings, while not surprising, demonstrate consistent and “dramatic” reduction in intracranial bleeding across doses and indications.

One inconsistency, however, is the dabigatran dose itself, which Dr. Ezekowitz said varied widely in PETRO and RE-COVER. This is potentially important, he added, since GI bleeding is dose related. “It occurs with the 150-mg twice daily dose, but does not occur with the 110-mg twice daily dose,” he noted.

As far as the authors’ suggestions for dealing with patients at high risk for GI bleeding, Dr. Ezekowitz said the higher rate of intracranial bleeding makes warfarin an unattractive option, while the use of prophylactic agents such as proton-pump inhibitors is unproven in prospective studies of patients on dabigatran or vitamin K antagonists.

But an even bigger problem, he observed, is the uncertainty regarding who is or is not at risk for GI bleeding. “We have not been able to characterize who these patients are,” Dr. Ezekowitz said, adding that attempts at mounting a study to investigate the issue have been unsuccessful due to funding issues.

Study Details

Patients were predominantly male, with a mean age ranging from 55 to 71 years. In the A-fib trials, the primary efficacy endpoints were thromboembolic events or a composite of stroke or systemic embolism. In the VTE trials, the primary efficacy endpoints were recurrent or fatal VTE. Safety endpoints were examined using as-treated analyses in all included RCTs except for the RE-LY trial, which used an intention-to-treat analysis.

 


Source:
Bloom BJ, Filion KB, Atallah R, et al. Meta-analysis of randomized controlled trials on the risk of bleeding with dabigatran. Am J Cardiol. 2013;Epub ahead of print.

 

 

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Disclosures
  • Dr. Eisenberg reports no relevant conflicts of interest.
  • Dr. Ezekowitz reports serving as co-principal investigator for RE-LY; receiving consulting fees, lecture fees, and grant support from Aryx Therapeutics and Boehringer-Ingelheim; consulting fees from Sanofi-Aventis; and lecture fees and grant support from Portola Pharmaceuticals.

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