Journal of Invasive Cardiology

The primary pathophysiologic mechanism for myocardial ischemia secondary to ACS or as an acute complication of PCI is thrombotic occlusion of a coronary artery in response to vascular injury.1 Endothelial denudation caused by disruption or erosion of atherosclerotic plaque or mechanical injury during PCI promotes deposition of platelets and the formation of a hemostatic plug. Platelet adhesion, mediated primarily through binding of platelet GP Ib and IIb receptors to subendothelial von Willebrand factor, is rapidly followed by platelet activation.2 Local biochemical and mechanical stimuli activate signal transduction pathways within platelets that induce a conformational change in the platelet GP IIb/IIIa receptor, making it capable of binding adhesive plasma proteins, primarily fibrinogen or von Willebrand factor. These proteins cross-link activated GP IIb/IIIa receptors on adjacent platelets, leading to platelet aggregation and coronary thrombus formation.3 Platelet aggregates form the partly occlusive “white” thrombus, which has been shown to be the cause of ischemia in patients with non-ST segment elevation ACS.4 Conversely, in patients with ST-segment elevation myocardial infarction, the culprit thrombi are more often completely occlusive and contain a network of cross-linked fibrin and entrapped red blood cells (“red thrombus”) superimposed on the underlying platelet-rich thrombus.4
Based on the above aforementioned pathophysiologic mechanisms, aspirin and heparin have traditionally formed the cornerstones of antithrombotic therapy for patients with non-ST segment elevation ACS. Clinical trials of aspirin and heparin therapy for ACS have demonstrated improved clinical outcomes in patients who receive these agents in combination.5 Despite such combination therapy, significant morbidity and mortality persists among patients with non-ST segment elevation ACS due to the limitations of aspirin and heparin based on their mechanisms of action. For example, aspirin is a relatively weak antiplatelet agent that blocks only one of several pathways for platelet activation. In addition, heparin is limited by its requirement for antithrombin III, its ineffectiveness against clot-bound thrombin, and the fact that it binds to cellular and plasma proteins, which leads to an unpredictable anticoagulant effect. Recognition of these limitations, along with an improved understanding of the vascular biology underlying coronary thrombosis, has provided the impetus for the development of better anti-thrombotic agents.

GP IIb/IIIa receptor inhibitors. The advent of competitive inhibitors for fibrinogen binding to the platelet GP IIb/IIIa receptor has further expanded the therapeutic options available for treating thrombotic disorders. To date, only 3 intravenous GP IIb/IIIa inhibitors have been approved for clinical use: abciximab (ReoPro, Centocor/Eli Lilly), tirofiban (Aggrastat, Merck) and eptifibatide (Integrilin, COR Therapeutics). Although this class of therapeutic agents has been defined by a common affinity for the platelet GP IIb/IIIa receptor, the 3 currently available agents differ in pharmacodynamic and pharmacokinetic profile.6,7 Differences in the duration of action at the platelet target receptor, specific receptor affinity, as well as differential binding sites on the GP IIb/IIIa receptor have been demonstrated for the monoclonal antibody, abciximab, compared with both the cyclic heptapeptide eptifibatide and the nonpeptide tyrosine derivative tirofiban.7,8