Novel Antithrombotic Strategies for the Treatment of Coronary Artery Thrombosis: A Critical Appraisal

Abstract

Large-scale clinical trials have demonstrated that treatment of patients with acute myocardial infarction and unstable angina with antithrombotic agents significantly improves outcome. Despite the proven benefit of current therapies, there is a widespread perception that outcome could be enhanced further with novel antithrombotic agents. Enthusiasm for novel antithrombotic strategies has been stimulated by recent advances in the understanding of the mechanisms responsible for coronary artery thrombosis, which has led to the development of diverse inhibitors of platelet function and coagulation factors. In experimental models of coronary artery thrombosis, aspirin and heparin have been ineffective in preventing recurrent thrombosis after coronary thrombolysis and in preventing the progression of thrombosis in response to strong thrombogenic stimuli. In contrast, inhibitors of the platelet fibrinogen receptor, direct-acting thrombin inhibitors, and inhibitors of coagulation factors that promote elaboration of thrombin have been shown to be effective in attenuating arterial thrombosis in a variety of experimental preparations. Initial clinical trials with these agents have also documented efficacy in attenuating thrombotic events in patients treated with coronary thrombolysis and in those with unstable angina. However, optimal doses of novel antithrombotic agents, the degree to which combination antiplatelet and anticoagulant therapies are needed, and the risk/benefit ratio associated with specific novel antithrombotic drugs are still relatively undefined. With regard to the latter, it is possible that the large-scale clinical trials now in progress may show an increase in bleeding complications with novel anticoagulants compared with conventional therapy. Nonetheless, there are considerable data that suggest that treatment with aspirin and heparin is not completely effective in preventing the progression of thrombosis or its recurrence after interventions in high-risk subgroups of patients with coronary artery thrombosis and unstable coronary artery disease. Accordingly, continued investigation of a large variety of antithrombotic agents, both currently available and in development, should improve the treatment of high-risk patients with coronary disease if regimens with appropriate efficacy but without serious hemorrhagic effects can be designed.