A Replacement for Warfarin

Abstract

Vitamin K antagonists (VKAs) such as warfarin are the only oral anticoagulants currently available for clinical use. Warfarin has numerous limitations, including slow onset and offset of action, a narrow therapeutic window, and a metabolism that is affected by diet, drugs, and genetic polymorphisms.1 Because of its unpredictable dose response, warfarin requires careful coagulation monitoring to ensure that a therapeutic anticoagulant effect is achieved.2 Variable dose requirements, concern about the risk of bleeding, and the need for frequent coagulation monitoring have prompted the development of new oral anticoagulants to replace warfarin. With a predictable anticoagulant response and little potential for food or drug interactions, these new agents have been designed to be administered in fixed doses without coagulation monitoring. Consequently, these drugs have the potential to simplify long-term anticoagulant therapy. Article p 180 The features of the new oral anticoagulants in the most advanced stages of clinical development are listed in the Table and are compared with those of warfarin. Unlike warfarin, which reduces the functional levels of factors II (prothrombin), VII, IX, and X, these novel agents are directed against the active site of factor Xa or thrombin, the enzymes responsible for thrombin generation and fibrin formation, respectively (see the Figure). Rivaroxaban and apixaban target factor Xa, whereas dabigatran etexilate inhibits thrombin. View this table: Comparison of Warfarin to New Oral Anticoagulants in Advanced Stages of Clinical Development Targets of new oral anticoagulant drugs. Oral factor Xa inhibitors (rivaroxaban, apixaban) bind directly to factor Xa and prevent thrombin generation. Dabigatran etexilate, an orally active direct thrombin inhibitor, undergoes metabolic activation to dabigatran, which binds to the active site of thrombin (factor IIa) and blocks its capacity to convert fibrinogen to fibrin, to activate platelets, and to amplify its own generation by activating factors V, VIII, and XI. By blocking the …