Direct thrombin inhibitors

Thrombin plays a central role in thrombosis. Consequently, most current antithrombotic treatment strategies are aimed at blocking the activity of thrombin, or preventing its generation. Although heparin has been a cornerstone of treatment, it has limitations. Thus, the anticoagulant response to heparin is unpredictable, the heparin/antithrombin complex is unable to inhibit fibrin-bound thrombin, an important trigger of thrombus growth, and heparin is neutralized by platelet factor 4. Direct thrombin inhibitors were developed to overcome these limitations. Unlike heparin, direct thrombin inhibitors produce a predictable anticoagulant response that is unaffected by platelet factor 4, and they inhibit fibrin-bound thrombin. Three parenteral direct thrombin inhibitors--hirudin, bivalirudin and argatroban--are currently licensed for use in North America, and orally available direct thrombin inhibitors are under investigation. This review summarizes the clinical trial data with direct thrombin inhibitors and provides perspective on the role of direct thrombin inhibitors in the face of other new anticoagulants currently under development.