Stroke: Fewer fatal bleeds with dabigatran than warfarin

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stroke, brain imaging - 40.65 Kb
Sites of intracranial bleeding in the RE-LY trial. Source: Stroke, online April 5, 2012

The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran (Pradaxa, Boehringer Ingelheim); however, the absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin, based on an analysis of the RE-LY trial, published online April 5 in Stroke. In addition, concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.

“Intracranial hemorrhage is the most feared complication of warfarin anticoagulation in older patients with atrial fibrillation and is responsible for the bulk of disability and death from anticoagulation-associated bleeding,” with mortality rates exceeding 50 percent in most studies (52 percent in RE-LY), wrote the study authors. “About two-thirds of intracranial hemorrhages during warfarin anticoagulation are intracerebral hemorrhages, and most of the remainder are subdural hematomas.” However, outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined.

Robert G. Hart, MD, from the Population Health Research Institute in Hamilton, Ontario, and colleagues conducted an analysis of the 18,113 participants with atrial fibrillation in the RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial, assigned to adjusted-dose warfarin (target international normalized ratio, 2 to 3) or dabigatran (150 mg or 110 mg, both twice daily).

During a mean of two years follow-up, the researchers reported that 154 intracranial hemorrhages occurred in 153 participants: 46 percent intracerebral (49 percent mortality), 45 percent subdural (24 percent mortality) and 8 percent subarachnoid (31 percent mortality). The rates of intracranial hemorrhage were 0.76 percent, 0.31 percent and 0.23 percent per year among those assigned to warfarin, dabigatran 150 mg and dabigatran 110 mg, respectively.

Thus, fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg (13 patients and 11 patients, respectively) versus warfarin (32 patients), according to Hart et al. Also, they found that fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran (11 patients with each dose) compared with warfarin (24 patients).

Independent predictors of intracranial hemorrhage were assigned to warfarin (relative risk, 2.9), aspirin use (relative risk, 1.6), age (relative risk, 1.1 per year) and previous stroke/transient ischemic attack (relative risk, 1.8).

“It has been hypothesized that warfarin interferes with tissue factor VIIa-mediated thrombosis that may be especially important for hemostasis within the brain, whereas novel oral anticoagulants do not because of their more selective mechanisms of action,” Hart and colleagues wrote. “Any explanation for the lower rates of intracranial hemorrhage seen with dabigatran must account for reduced rates associated with all sites of intracranial hemorrhage and with traumatic versus atraumatic hemorrhages.

“The underlying mechanism(s) accounting for the low risk of all sites of intracranial bleeding with dabigatran and other novel oral anticoagulants are critical to understand, but remain to be fully elucidated,” the researchers concluded.

Boehringer Ingelheim funded the study.