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SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs Warfarin for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation: A Randomized Trial. JAMA. 2005;293(6):690–698. doi:10.1001/jama.293.6.690
Authors/SPORTIF Executive Steering Committee:
Stanford Stroke Center, Palo Alto, Calif
(Gregory W.AlbersMD); Department
of Neurology, University of Essen, Essen, Germany
Department of Biostatistics, AstraZeneca Research and Development Mölndal,
(LarsFrisonPhD); Departments of Clinical Science
Clinical Project Management
(MarkNevinsonBPharm), and Clinical Development
(StephenPartridgePhD), AstraZeneca Research and Development Charnwood,
Charnwood, England; Cardiovascular Institute, Mount Sinai Medical Center,
New York, NY
(Jonathan L.HalperinMD); Department of Clinical Development, AstraZeneca
LP, Wilmington, Del
Department of Cardiology, University Hospital,
(S. BertilOlssonMD, PhD); Department of Neurology, Copenhagen University
Hospital, Copenhagen, Denmark
(PallePetersenMD, DMSc); and Department
of Cardiology, Hospital Tenon, Paris, France
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
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
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