DIRECT THROMBIN INHIBITORS FOR TREATMENT OF ARTERIAL THROMBOSIS - POTENTIAL DIFFERENCES BETWEEN BIVALIRUDIN AND HIRUDIN

Given the central role of thrombin in arterial thrombogenesis, most tr eatment strategies for acute coronary syndromes are aimed at inhibitin g its generation or blocking its activity. Although heparin has been w idely used, it has limitations in the setting of arterial thrombosis. These limitations reflect the inability of heparin to inactivate throm bin bound to fibrin, a major stimulus for thrombus growth. In addition , the anticoagulant response to heparin varies from patient to patient , and heparin is neutralized by platelet Factor IV, large quantities o f which are released from platelets activated at sites of plaque ruptu re. Consequently, heparin requires careful laboratory monitoring to en sure an adequate anticoagulant effect. Direct thrombin inhibitors, suc h as hirudin and bivalirudin, overcome the limitations of heparin. The se agents inhibit fibrin-bound thrombin, as well as fluid-phase thromb in, and produce a predictable anticoagulant response. Bivalirudin has both safety and potential efficacy advantages over hirudin. Bivalirudi n appears to have a wider therapeutic window than hirudin, possibly be cause bivalirudin only transiently inhibits the active site of thrombi n. The better safety profile of bivalirudin permits administration of higher doses, which may give it an efficacy advantage. Hirudin prevent s thrombin from activating protein C, thereby suppressing this natural anticoagulant pathway. In contrast, bivalirudin may promote protein C activation by transiently inhibiting thrombin until it can be bound b y thrombomodulin. Differences between bivalirudin and hirudin, as well as other direct thrombin inhibitors, highlight the pitfalls of consid ering all direct thrombin inhibitors to hove equivalent risk-benefit p rofiles. (C) 1998 by Excerpta Medica, Inc.