Hirudin in Acute Myocardial Infarction

Abstract

The central role of thrombosis in the pathogenesis of acute myocardial infarction has led to intense interest in developing more effective thrombolytic-antithrombotic regimens. Hirudin is 65 amino acid polypeptide that binds in a 1:1 relationship with thrombin, thereby inhibiting the final step in the coagulation cascade. Hirudin has several potential advantages over the current antithrombin agent heparin: It is a direct inhibitor that does not require a cofactor, it has no known inhibitors that would attentuate its anticoagulant effects, and it can inhibit clot-bound thrombin, thereby achieving an antithrombotic effect at the site of potential rethrombosis. Initial clinical trials have shown promising results: Hirudin, as compared with heparin, provided a more consistent level of anticoagulation, as gauged by the activated partial thromboplastin time. As an adjunct to thrombolytic therapy in acute myocardial infarction, hirudin improved indices of coronary reperfusion and patency. Initial results with clinical end points, including death or myocardial infarction, also have shown favorable results for hirudin compared with heparin. In the first phases of the larger phase III trials, the rate of hemorrhagic events, including intracranial hemorrhage, was higher than expected in both the hirudin and heparin arms, indicating that a safety ceiling had been reached. The TIMI 9B and GUSTO IIb trials are using lower doses of intravenous hirudin and heparin, which should allow testing of the "thrombin hypothesis": that more potent inhibition of thrombin will translate into improved clinical outcome for patients with acute MI.