A 2-year noninferiority trial has shown dabigatran to be not inferior to warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation. And the higher, 150 mg dose of dabigatran was shown to be superior to warfarin in preventing these outcomes.
Stuart J. Connolly, MD, at the Population Health Research Institute in Hamilton, Ontario, Canada, and colleagues report the results on behalf of the RE-LY Study Group in the August 30 edition of The New England Journal of Medicine.
The investigators enrolled 18,113 patients with atrial fibrillation from 951 clinical centers in 44 countries between December 2005 and December 2007. Patients were a mean age of 71 years, and 63.6% were men.
The investigators randomly assigned the patients to receive 110 mg or 150 mg of dabigatran twice daily, or to receive 1, 3, or 5 mg of warfarin to an INR of 2 to 3.
The investigators administered dabigatran in a blinded fashion and warfarin in an unblinded fashion.
After a median follow-up of 2 years, 182 patients on 110 mg dabigatran, 134 patients on 150 mg dabigatran, and 199 patients on warfarin had a stroke or embolism.
The investigators determined that both doses of dabigatran were noninferior to warfarin (P<0.001). And the 150 mg dose was superior to warfarin (P<0.001). However, the lower dose of dabigatran was not superior to warfarin.
Warfarin, however, produced a lower rate of myocardial infarction than dabigatran: 0.53% per year, compared to 0.72% per year in the 110 mg dabigatran group (P=0.07) and 0.74% in the 150 mg group (P=0.048). The investigators attribute this to the superior protection warfarin provides against coronary ischemic events.
The rate of major bleeding was lower with the 150 mg dose of dabigatran and significantly lower with the 110 mg dose compared to warfarin.
And rates of life-threatening bleeding, intracranial bleeding, and major or minor bleeding were all significantly lower with either dose of dabigatran than warfarin. However, the 150 mg dose of dabigatran produced a significantly higher rate of gastrointestinal bleeding than warfarin.
The investigators also compared the 2 doses of dabigatran and found the 150 mg dose significantly reduced the risk of stroke or systemic embolism compared to the 110 mg dose (P=0.005).
The investigators correlated the higher dose of dabigatran with a trend toward an increased risk of major, gastrointestinal, minor, and any bleeding. They calculated that “the net clinical benefit was almost identical for the two doses.”
Dyspepsia was the only adverse event that was significantly more common with dabigatran than with warfarin.
The investigators concluded that because dabigatran achieved a rate of intracranial hemorrhage a third less than the rate with warfarin without a reduction in stroke protection, this “suggests an important advantage of dabigatran.”
Dabigatran is a new oral direct thrombin inhibitor. It was approved in 2008 by the European Medicines Agency, the National Health Service in Britain, and Health Canada for hip and knee surgery patients.
RE-LY stands for Randomized Evaluation of Long-Term Anticoagulation Therapy.
The study was funded by Boehringer Ingelheim and was coordinated by the Population Health Research Institute in Hamilton, Ontario, Canada.
