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STATE-OF-THE-ART PAPER

Ximelagatran: Oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation

Mount Sinai School of Medicine, New York, New York

Manuscript received July 19, 2004; revised manuscript received August 31, 2004, accepted September 6, 2004.

^* Reprint requests and correspondence: Dr. Jonathan L. Halperin, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, New York 10029-6574 (Email: jonathan.halperin{at}msnyuhealth.org).

Atrial fibrillation (AF) causes 50,000 to 100,000 ischemic strokes annually in the U.S., most of which could be prevented by oral anticoagulant treatment of the highest-risk patients. The greatest barrier to such treatment is the narrow therapeutic index of the vitamin K antagonists ([VKAs]: warfarin and related coumarin derivatives), the only oral anticoagulant agents currently available. Safe and effective treatment with the VKAs requires careful monitoring, because they interact with many other drugs and foods, and their anticoagulant action is unpredictable. Besides vitamin K, candidate targets for anticoagulant therapy include thrombin, a key prothrombotic mediator. Ximelagatran, the oral direct thrombin inhibitor at the most advanced stage of clinical development, is rapidly absorbed and bioconverted to its active moiety, melagatran—a potent, competitive inhibitor of both free and clot-bound thrombin. Two large clinical trials have demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily, administered without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin (international normalized ratio 2.0 to 3.0). The overall risk of bleeding was lower with ximelagatran than warfarin, although differences in rates of major hemorrhage were not statistically significant. Elevation of serum alanine aminotransferase levels above 3x the upper limit of normal occurred in approximately 6% of ximelagatran-treated patients but typically returned toward pretreatment levels without associated symptoms. In terms of preventing thromboembolism without hemorrhage, ximelagatran may have a more favorable benefit:risk profile than warfarin for patients with AF.

Abbreviations and Acronyms   AF = atrial fibrillation   DTI = direct thrombin inhibitor   INR = international normalized ratio   ITT = intention-to-treat   RRR = relative risk reduction   SEE = systemic embolic event   SPORTIF = Stroke Prevention with an ORal Thrombin Inhibitor in Atrial Fibrillation   TIA = transient ischemic attack   VKA = vitamin K antagonist   VTE = venous thromboembolism

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