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New RE-LY data on brain bleeds favor dabigatran

Reuters Health • The Doctor's Channel Daily Newscast

NEW YORK (Reuters Health) – The clinical spectrum of intracranial hemorrhage was similar in patients treated with warfarin or dabigatran in the pivotal RE-LY trial, a new analysis of data from the trial shows.

However, absolute rates of bleeding in the brain at all sites and both fatal and traumatic hemorrhages were lower with dabigatran than with warfarin, the researchers report.

According to the analysis, reported online April 5 in Stroke, concomitant use of aspirin with warfarin or dabigatran was the most important modifiable independent risk factor for intracranial hemorrhage.

The RE-LY trial compared dabigatran (110 mg and 150 mg twice daily) with warfarin in more than 18,000 patients with AF and at least one other risk factor for stroke. It was the basis for the U.S. Food and Drug Administration approval of dabigatran in October 2010.

The trial showed that for stroke prevention, the higher dose of dabigatran was superior to warfarin and the lower dose was noninferior to dose-adjusted warfarin (target INR 2-3). Rates of major bleeding were comparable with the higher dose of dabigatran and warfarin (3.32% and 3.57% per year, respectively) and lower with the lower dabigatran dose (2.87% per year). There was no difference in mortality with dabigatran compared with warfarin.

The FDA approved the 150-mg twice daily dose for patients with a creatinine clearance > 30 mL/min and a 75-mg twice daily dose for patients with severe renal impairment (creatinine clearance 15 to 30 mL/min). The FDA did not approve the 110-mg twice daily dose studied in RE-LY.

A 2011 “focused update” to existing guidelines on the management of patients with AF states that dabigatran is a useful alternative to warfarin for stroke risk reduction in patients with nonvalvular AF. (see Reuters Health story of Feb. 23, 2011).

The goal of the new analysis of RE-LY data was to investigate outcomes associated with different sites of intracranial bleeding occurring with warfarin vs dabigatran – something that has not been defined, according to Dr. Robert G. Hart from Hamilton, Ontario’s McMaster University and colleagues.

They report that during an average of 2 years follow-up, 154 intracranial hemorrhages occurred in 153 RE-LY participants: 46% intracerebral (with 49% mortality rate), 45% subdural (often due to trauma, with a 24% mortality rate), and 8% subarachnoid (with a 31% mortality rate).

The rates of intracranial hemorrhage per year was 0.76% with warfarin versus 0.31% and 0.23% with dabigatran 150 mg and 110 mg (p<0.001 for either dabigatran dose vs warfarin). Fatal intracranial hemorrhages were substantially less frequent with dabigatran 150 mg and 100 mg (13 and 11, respectively) than with warfarin (32 total; p<0.01 for both). The top independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk 2.9; p<0.001) and use of aspirin (RR 1.6; p=0.01). “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 authors conclude. The RE-LY study and this analysis were funded by Boehringer Ingelheim. One author on the new analysis is an employee of the company and all but one of the other co-authors has served as consultants to the company. SOURCE: Intracranial Hemorrhage in Atrial Fibrillation Patients During Anticoagulation With Warfarin or Dabigatran

Stroke 2012.