Risk of Intracranial Hemorrhage, Mortality Lower with Dabigatran in A-fib Patients

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Among patients with atrial fibrillation (A-fib), the novel anticoagulant dabigatran significantly reduces the risk of intracranial hemorrhage and associated mortality compared with warfarin. An analysis from the large, randomized RE-LY trial, published online April 5, 2012, ahead of print in Stroke, also confirms previous suggestions that concomitant warfarin and aspirin use increases certain types of bleeding.

The main RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin (adjusted dose) in 18,113 patients who were at risk of stroke from nonvalvular A-fib. Published in the New England Journal of Medicine in 2009, the results showed that the higher dose of dabigatran was superior to warfarin with regard to stroke or systemic embolism (1.11% vs. 1.71% per year; P < 0.001) and equivalent with regard to major bleeding (3.32% vs. 3.57% per year; P = 0.32). The lower dose, meanwhile, was noninferior to warfarin for stroke or systemic embolism (1.54% per year; P < 0.001 for noninferiority) and superior for major bleeding (2.87% per year; P = 0.003). Both doses more than halved the rate of intracranial hemorrhage compared with warfarin.

For the new analysis, researchers led by Robert G. Hart, MD, of McMaster University (Hamilton, Canada), examined the 154 cases of intracranial hemorrhage that occurred in the RE-LY trial. Among these, 46% were intracerebral bleeds, 45% were subdural hematomas, and 8% were subarachnoid hemorrhages. Mortality after hemorrhage was approximately 52%, with no significant differences between the 3 treatment arms.

All Types of Intracranial Hemorrhage Lower with Dabigatran

Intracranial hemorrhage rates were significantly lower in patients assigned to either dabigatran dose compared with those assigned to warfarin. Dabigatran patients also had fewer fatal intracranial hemorrhages and fewer traumatic intracranial hemorrhages (table 1).

Table 1. Intracranial Hemorrhage Rates and Types at 2-Year Follow-up

^a For either dabigatran dose vs. warfarin.

Most of the 71 intracerebral hemorrhages that occurred (89%) were spontaneous. Among the few traumatic intracerebral hemorrhages (n = 8), almost all were associated with major head trauma.

The researchers identified several factors that independently predicted intracranial hemorrhage (table 2).

Table 2. Independent Risk Factors for Intracranial Hemorrhage

Similarly, more subdural hematomas occurred among those assigned to warfarin compared with dabigatran 150 mg and 110 mg (0.31% per year vs. 0.20% and 0.08%, respectively; P < 0.001), although the rate was more than doubled in the higher-dose dabigatran group compared with the lower-dose group (RR 2.4; P = 0.02). Fatal subdural bleeding occurred in 10 patients assigned to warfarin compared with 5 patients and 2 patients on dabigatran 150 mg and 110 mg, respectively (P < 0.05 for dabigatran 110 mg vs. warfarin).

Mechanism Not Fully Understood

According to the study authors, it has been hypothesized that warfarin interferes with tissue factor VIIa-mediated thrombosis, which may be especially important for hemostasis within the brain. Dabigatran, on the other hand, does not have this effect because the direct thrombin inhibitor has a more selective mechanism of action.

One concern with dabigatran is the lack of an agent to reverse its antithrombotic effects. But the authors point out that mortality from intracranial hemorrhage was not increased in dabigatran-treated patients compared with those given warfarin. “This observation, coupled with the substantially lower absolute rates of intracranial hemorrhage with dabigatran, explains why the likelihood of dying from intracranial bleeding is significantly lower (P < 0.01) during anticoagulation with dabigatran versus warfarin,” they conclude.

Dr. Hart and colleagues add that the underlying mechanisms for why not only dabigatran but other oral anticoagulants produce low levels of intracranial bleeding “are critical to understand, but remain to be fully elucidated.”

 

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Source:
Hart, RG, Diener H-C, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: The RE-LY trial. Stroke. 2012;Epub ahead of print.

 

 

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