Special Feature

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.

References

1. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994;330:956-961.

2. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The Epilog Investigators. N Engl J Med 1997;336:1689-1696.

3. van den Merkhof LF et al. Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty. Results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 1999; 33:1528-1532.

4. Ohman EM et al. Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators. Circulation 1997;95:846-854.

5. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT II. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II. Lancet 1997;349:1422-1428.

6. The Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338;1498-1505.

7. Zhao XQ et al. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet receptor inhibition for ischemic syndrome management in patients limited by unstable signs and symptoms). PRISM-PLUS Investigators. Circulation 1999;100:1609-1615.

8. Simmons ML, GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: The GUSTO IV-ACS randomised trial. Lancet 2001;357:1915-1924.

9. Boersma E et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002; 359:189-198.

10. Braunwald E et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—2002: Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2002;106:1893-1900.