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A Randomized Trial

SPORTIF Executive Steering Committee for the SPORTIF V Investigators^*

JAMA. 2005;293:690-698.

Context  In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use.

Objective  To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism.

Design, Setting, and Participants  Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors.

Interventions  Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily.

Main Outcome Measures  The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model.

Results  During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, –0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, –0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, –14% to –6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred.

Conclusions  The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.

Authors/SPORTIF Executive Steering Committee: Stanford Stroke Center, Palo Alto, Calif (Gregory W. Albers, MD); Department of Neurology, University of Essen, Essen, Germany (Hans-Christoph Diener, MD); Department of Biostatistics, AstraZeneca Research and Development Mölndal, Mölndal, Sweden (Lars Frison, PhD); Departments of Clinical Science (Margaretha Grind, MD, PhD), Clinical Project Management (Mark Nevinson, BPharm), and Clinical Development (Stephen Partridge, PhD), AstraZeneca Research and Development Charnwood, Charnwood, England; Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (Jonathan L. Halperin, MD); Department of Clinical Development, AstraZeneca LP, Wilmington, Del (Jay Horrow, MD); Department of Cardiology, University Hospital, Lund, Sweden (S. Bertil Olsson, MD, PhD); Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark (Palle Petersen, MD, DMSc); and Department of Cardiology, Hospital Tenon, Paris, France (Alec Vahanian, MD).

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