Unmet Therapeutic Needs in the Management of Acute Ischemia

Abstract

Unstable angina and myocardial infarction (MI) continue to present a major challenge in clinical management. These acute ischemic coronary syndromes (AICS) are a spectrum of clinical presentations of the same pathophysiologic mechanism: thrombus formation superimposed on atherosclerotic plaque disruption or erosion. Current approaches to the management of AICS, which include both interventional and pharmacologic therapy, have been introduced to clinical practice during the past 20 years, and most of them have demonstrated efficacy in clinical studies. A common inadequacy of current therapies, however, is the lack of significant inhibition of platelet aggregation—the crucial event in the formation of coronary thrombi and the pathogenesis of AICS. The final common pathway to platelet aggregation is the activation of the platelet glycoprotein (GP) IIb-IIIa receptor, which allows the cross-linking of adjacent platelets by the adhesive plasma proteins fibrinogen and von Willebrand’s factor. The emergence of the GP IIb-IIIa receptor as a potential treatment target has led to the development of several inhibitors of its function. The inhibitors most advanced in clinical development are the chimeric monoclonal antibody abciximab (ReoPro) and the cyclic peptide eptifibatide (INTEGRILIN). In phase III clinical trials, both abciximab and eptifibatide have been shown to reduce the incidence of cardiac events in patients at risk for abrupt vessel closure after coronary angioplasty. Inhibition of the GP IIb-IIIa receptor is the most promising novel approach to the treatment of unstable angina and MI, and it may soon be an indispensable component of the management of patients with AICS.