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Background Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor.
Methods In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran — 110 mg or 150 mg twice daily — or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism.
Results Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051).
Conclusions In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600
[ClinicalTrials.gov]
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Source Information
From the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada (S.J.C., S.Y., J.E., J.P., E.T.); Lankenau Institute for Medical Research and the Heart Center, Wynnewood, PA (M.D.E., A.P.); Uppsala Clinical Research Center, Uppsala, Sweden (J.O., L.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (P.A.R., J.V., S.W.); Working Group on Cardiovascular Research the Netherlands, Utrecht, the Netherlands (M.A.); St. John's National Academy of Health Sciences, Bangalore, India (D.X.); FuWai Hospital, Beijing (J.Z.); Estudios Clínicos Latinoamérica, Rosario, Argentina (R.D.); Lady Davis Carmel Medical Center, Haifa, Israel (B.S.L.); Vivantes Klinikum Neukölln, Berlin (H.D.); University Duisburg-Essen, Essen, Germany (H.-C.D.); and Sunnybrook Health Sciences Centre, Toronto (C.D.J.).
Drs. Connolly, Ezekowitz, Yusuf, and Wallentin contributed equally to this article.
This article (10.1056/NEJMoa0905561) was published on August 30, 2009, and updated on September 16, 2009, at NEJM.org.
Address reprint requests to Dr. Connolly at the Population Health Research Institute, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at connostu{at}phri.ca.
Related Letters:
Dabigatran versus Warfarin in Patients with Atrial Fibrillation
Houston D. S., Zarychanski R., Tomoda H., Moia M., Mannucci P. M., Worthington J. M., Gattellari M., Poller L., Jespersen J., Ibrahim S., Barry M., Connolly S. J., Ezekowitz M. D., Gage B. F.
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N Engl J Med 2009;
361:2671-2675, Dec 31, 2009.
Correspondence
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