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Glycoprotein IIb-IIIa Receptor Inhibitors: Applications in the ED
By William J. Brady, MD
The glycoprotein IIb-IIIa receptor inhibitor (GPI) agents represent a relatively recent addition to the therapeutic armamentarium employed in the treatment of the patient with acute coronary syndrome (ACS). During platelet stimulation, surface receptors are activated, particularly the membrane glycoprotein IIb-IIIa receptors. Those receptors represent the final common pathway for platelet activation and ultimate aggregation. Once activated, the glycoprotein IIb-IIIa receptors allow the various circulating factors (von Willebrand factor and fibrinogen) to link into a chain-like arrangement; this linked-chain formation ultimately results in platelet adhesion and clot.
Three agents in this class currently are used widely: abciximab, eptifibatide, and tirofiban. Abciximab was the first such GPI to be studied in large clinical trials. As a monoclonal antibody specific for the glycoprotein IIb-IIIa receptor, it provides prolonged inhibition of platelet aggregation even after cessation of drug infusion. Numerous trials have demonstrated its effectiveness in ACS patients. Yet, only a subset of these patients actually derives benefit from its application—the patient who is managed with percutaneous coronary intervention (PCI) with or without intracoronary stent. The EPIC trial investigated the effect of the drug in high-risk unstable angina and acute myocardial infarction (AMI) patients scheduled for PCI. Results demonstrated a 35% reduction in mortality rate, recurrent MI, and need for unplanned rescue therapies (e.g., surgical revascularization, repeat PCI, and intraaortic balloon pump placement), balanced by an increase in hemorrhagic complications.1 The EPILOG trial further evaluated the effect of abciximab in ACS patients who had undergone invasive coronary interventions; the investigators noted a 68% reduction in death or nonfatal MI in the treatment group with a lower incidence of major bleeding episodes than in the EPIC study.2 In the GRAPE study, which investigated the use of GPI in patients scheduled for urgent PCI, increased rates of thrombolysis in myocardial infarction (TIMI) grade 3 flow were noted in the abciximab group.3
Eptifibatide, a synthetic peptide, prevents binding of fibrinogen to the glycoprotein IIb-IIIa receptor; that antagonism blocks platelet aggregation and subsequent thrombus formation. The IMPACT-AMI investigators reported the results in acute MI patients who had received fibrinolytic agents and varying doses of eptifibatide (i.e., non-mechanical means of reperfusion).4 The investigators noted an increase in TIMI grade 3 flow at 90 minutes with similar rates of death, recurrent MI, and the need for revascularization procedures. In the IMPACT-II trial, ACS patients scheduled for PCI demonstrated a modest reduction in the rate of revascularization, acute MI, or death at 30 days; that modest benefit was lost at six months.5 Tirofiban is a synthetic, nonpeptide, shorter-acting GPI with a similar mechanism of action to eptifibatide. Recent trials did not demonstrate significant benefit in unstable angina patients in cardiac ischemic events at 30 days (PRISM trial),6 and found benefit limited to angiographic variables (e.g., intracoronary thrombus burden, improved perfusion grade, and decreased severity of obstruction) in the PRISM-PLUS trial.7
Recent work has confirmed the most appropriate use of GPI in the AMI patient—the patient scheduled for PCI with or without intracoronary stenting. Results from the GUSTO IV trial revealed that abcixamab did not alter the rate of death or recurrent MI at one month in patients with ACS, although hemorrhagic complications occurred more often in the active treatment groups.8 A meta-analysis of GPI use in ACS patients reinforces this conclusion—patients who undergo PCI benefit markedly from glycoprotein inhibitor administration, although other ACS groups do not derive significant benefit from its application.9 As such, the American College of Cardiology/American Heart Association has provided the following guidelines: Class I (evidence and/or general consensus treatment is effective) — GPI should be given, in addition to aspirin and heparin, to patients in whom PCI is planned; Class IIa (conflicting evidence and/or a divergence of opinion regarding effectiveness, but weight of evidence/opinion favors efficacy)—GPI should be given to patients already receiving heparin, aspirin, and clopidogrel in whom PCI is planned; Class IIa (conflicting evidence and/or a divergence of opinion regarding effectiveness, but weight of evidence/opinion favors efficacy) — eptifibatide or tirofiban should be given to patients with continuing ischemia, an elevated troponin, or with other high-risk features (in addition to aspirin and heparin) in whom an invasive management approach is not planned; and Class IIb (conflicting evidence and/or a divergence of opinion regarding effectiveness, and efficacy less well established by evidence and/or opinion) — eptifibatide or tirofiban, in addition to aspirin and heparin, may be given to patients without continuing ischemia who have no other high-risk features and in whom PCI is not planned.10
Dr. Brady, Associate Professor of Emergency Medicine and Internal Medicine, Vice Chair, Emergency Medicine, University of Virginia, Charlottesville, is on the Editorial Board of Emergency Medicine Alert.
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