Oral direct thrombin inhibition: an effective and novel approach for venous thromboembolism

Abstract

Venous thromboembolism is a serious illness that affects patient morbidity and mortality and presents a significant management challenge to healthcare providers world-wide. Despite major achievements in the significant reduction of thromboembolic complications, the most common therapies currently used for prevention and treatment of venous thromboembolism--heparins and vitamin K antagonists such as warfarin--have several limitations. In particular, unfractionated heparin and warfarin show significant inter-patient variability in pharmacokinetics and pharmacodynamics, which makes regular coagulation monitoring necessary. Furthermore, only warfarin is suitable for long-term use, as it is administered orally. A new class of anticoagulants has been developed that directly target thrombin, a key enzyme in the blood coagulation cascade. Unlike warfarin and heparin, these direct thrombin inhibitors are able to inhibit fibrin-bound thrombin and so produce more effective inhibition of coagulation. Importantly, some members of this class of drugs have been developed for oral administration. Ximelagatran, which is converted to its active form melagatran, has predictable pharmacokinetics and pharmacodynamics. Therefore, ximelagatran can be administered in fixed doses with no need for coagulation monitoring. Its efficacy and safety profile have been demonstrated in preclinical and clinical studies. As the first oral agent in the new class, direct thrombin inhibitors, ximelagatran has significant potential for improving the prevention and treatment of venous thromboembolism.