Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. New anticoagulants have been developed that target a single coagulation factor and have predictable dose-response relationships. These include direct thrombin inhibitors and factor Xa inhibitors. Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia (HIT). Bivalirudin is a parenteral direct thrombin

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... itor that is licensed for patients undergoing percutaneous coronary interventions and for those with HIT who require percutaneous coronary interventions. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, showed efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. However, due to nonhematologic safety concerns, it did not receive FDA approval in the US. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux demonstrated efficacy compared to low-molecular-weight heparin in randomized clinical trials and is FDA approved for the prevention and treatment of venous thromboembolism. The OASIS 5 trial in non-ST-segment elevation acute coronary syndromes recently demonstrated that the fondaparinux dose approved for prophylaxis of deep venous thrombosis is as efficacious with respect to ischemic outcomes as therapeutic doses of enoxaparin; fondaparinux, however, was associated with a substantial reduction in major bleeding at 9 days and mortality at 1 and 6 months. A number of oral direct factor Xa inhibitors as well as other oral direct thrombin inhibitors are in clinical development for the prevention and treatment of thrombosis; the current status of these anticoagulants is reviewed along with the challenges faced in designing pivotal clinical trials of these agents in comparison to existing anticoagulants. The coagulation pathway is centrally involved in the formation of both arterial and venous thrombi and the development of molecules that inhibit its function is a major strategy for the design of new antithrombotic drugs. Until very recently, pharmacologic prophylaxis of venous thromboembolism was based on three types of anticoagulants: vitamin K antagonists (e.g., warfarin), unfractionated heparin, and low-molecular-weight heparins. Whereas these antithrombotic agents are multi-targeted, i.e., act on a number of coagulation factors, new antithrombotic drugs have been developed that are selective for one specific coagulation factor. The vitamin K antagonists, the only oral anticoagulants currently approved for use, have a number of limitations; these are shown along with their respective consequences in Table 1 . An "improved" oral anticoagulant that is at least as effective as warfarin in preventing thrombus formation and at least as safe with respect to bleeding risk would be highly desirable. The desired properties of such an agent are shown in Table 2 . Direct Thrombin Inhibition Thrombin plays a central role as a procoagulant by converting fibrinogen to fibrin as well as by activating its other substrates including factor V, factor VIII, factor XI, factor XIII, and the platelet protease-activated receptors (PAR-1 From the VA