Anticoagulants in acute coronary syndromes.

Antithrombotic and antiplatelet agents, particularly unfractionated heparin and aspirin, are longstanding therapeutic mainstays for acute coronary syndromes such as unstable angina and non-Q-wave myocardial infarction (MI). Early studies demonstrated that aspirin reduces the risk of mortality or nonfatal MI by 50-70% in patients presenting with unstable angina or non-Q-wave MI. Added to aspirin, heparin regimens further diminish the incidence of these myocardial ischemic events in the acute setting. Three major clinical studies demonstrated that such enhanced risk reductions can be achieved without significant increases in bleeding complications. The low-molecular-weight (LMW) heparin, dalteparin, proved superior to placebo but not unfractionated heparin in diminishing the incidence of (1) death or MI; (2) death, MI, or recurrence of angina; or (3) frequency of revascularization procedures. On the other hand, another LMW heparin, enoxaparin, did reduce these events at 14 and 30 days, as well as 1 year after treatment. The principal biophysical limitation of heparins, however, is that they cannot inactivate clot-bound thrombin, which probably contributes to morbidity and mortality in acute coronary syndromes. The natural leech-derived polypeptide hirudin and its derivatives (e.g., lepirudin) inactivate both fibrin-bound and free thrombin. Lepirudin has been approved in certain countries for the treatment of heparin-induced thrombocytopenia and is now being evaluated in the clinical management of acute myocardial ischemic syndromes. The well-documented pathophysiologic foundation for acute coronary syndromes is partial or intermittent thrombotic occlusion of a coronary artery as the result of atherosclerosis. Although a stable atherosclerotic plaque may not be clinically problematic, plaque rupture, which occurs under a variety of stimuli, touches off a cascade of enzymatic and cellular responses that frequently culminate in thrombotic occlusion. In the coronary circulation, such an occlusion may cause transmural MI, unstable angina, or non-Q-wave MI. Because the pathogenetic mechanisms of atherosclerosis with thrombotic complications have been elucidated, this knowledge can be translated into a rational clinical approach using antithrombotic therapies.