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Glycoprotein IIb-IIIa Antagonists in Non-ST Elevation Acute Coronary Syndromes and Percutaneous Interventions: from Pharmacology to Individual Patient's Therapy: Part 1: The Evidence of Benefit

Zimarino, Marco MD; De Caterina, Raffaele MD, PhD

Journal of Cardiovascular Pharmacology:
Review Article
Abstract

Antagonists of platelet glycoprotein IIb/IIIa (abciximab, tirofiban, eptifibatide) have now an approved role in reducing the extent of thrombotic complications leading to myocardial damage during percutaneous coronary interventions (PCI). This effect likely here translates into a long-term survival benefit. However, the question of their usefulness in different clinical scenarios (stable or unstable coronary disease, without PCI) has not been fully answered on the basis of considerations of dosing and cost-effectiveness. These agents seem most useful in high-risk patients with unstable coronary syndromes especially in the presence of co-morbidities such as diabetes or renal insufficiency. This article summarizes reasons for the ongoing debate on their efficacy and highlights areas of uncertainty.

Platelet adhesion is triggered by damage to the vessel wall and local exposure of the subendothelial matrix. Coverage of the exposed site by platelets depends on the recognition of adhesive proteins by specific platelet-membrane glycoproteins (GP), most being integrins. 1 The integrin family consists of heterodimeric molecules composed of a series of α and β subunits: α2β1 (GP Ia/IIa), α5β1 (GP Ic/IIa), α6β1, αIIbβ3 (GP IIb/IIIa), αvβ3. The GP IIb/IIIa (αIIbβ3) integrin receptor is the pivotal mediator of platelet aggregation, but has a secondary role also in platelet adhesion; it becomes abundant on the platelet surface, in the active form, when platelets are activated by a variety of agonists (ie, thrombin, ADP, collagen, thromboxane A2, and serotonin). 2 The binding of fibrinogen and other adhesive proteins, such as von Willebrand factor, by means of GP IIb/IIIa receptor on adjacent platelets allows the first formation of a platelet thrombus, and can be effectively attenuated by GP IIb/IIIa antagonists. 3,4

In percutaneous coronary interventions (PCI), the use of GP IIb/IIIa antagonists has been associated with a uniform reduction of ischemic events in several trials. However their use in acute coronary syndromes (ACS) without ST-segment elevation (ie, the combination of unstable angina and non-ST segment elevation acute myocardial infarction (NSTEMI) (otherwise collectively termed “unstable coronary syndromes”)) is a mix of lights and shadows. These uncertainties cause substantial differences in patient treatment according to the type of hospital and geographical location. 5,6 For example, in the Global Registry of Acute Coronary Events (GRACE), which collected data from 95 hospital in 14 countries, contrary to the use of aspirin, which was similar across all hospital types and geographical regions, the use of GP IIb/IIIa inhibitors and of PCI was significantly higher in teaching hospitals compared with non-teaching hospitals (19% vs. 11% and 33% vs. 19%, respectively, P < 0.01 for both comparisons) and was also substantially higher in the United States compared with Europe (32% vs. 14% and 38% vs. 29%, respectively, P < 0.001). 5 During the duration of the registry (July 1999–December 2001), the presentation and publication of major international guidelines was not associated with a measurable change in the pattern of practice. 7

In a spontaneous observational registry of patients hospitalized in the United States, GP IIb/IIIa inhibitors were administered only to a 25% of the 60,770 eligible patients admitted for NSTEMI. 8 Treated patients had lower unadjusted in-hospital mortality compared with untreated patients (3.3% vs. 9.6%, P < 0.0001) and were more likely to undergo PCI (45% vs. 15%, P < 0.0001). The survival benefit conferred by early GP IIb/IIIa inhibition was consistent even after adjustment for patient risk, treatment propensity, and hospital characteristics.

GP IIb/IIIa blockers are however expensive and potentially harmful agents, and the benefit/risk ratio associated with their use needs to be carefully evaluated. We will herein review the evidence for the benefit of such drugs in unstable coronary syndromes with or without PCI, aiming at reaching conclusions about current indications, the solidity of their basis, and areas where further research is needed. This article will deliberately not address the use of these drugs in ST-segment elevation acute myocardial infarction (MI), where controversy still exists on dosages and on the usefulness of combination with other drugs and the different types of revascularization strategies currently possible.

Author Information

From the Institute of Cardiology and Center of Excellence on Aging, “G. d'Annunzio” University, Chieti, Italy.

Received for publication November 5, 2003; accepted January 5, 2004.

Reprints: Dr. Marco Zimarino, Institute of Cardiology, “G. D'Annunzio” University Chieti, C/o Ospedale S. Camillo de Lellis, Via Forlanini, 50 66100 Chieti, Italy (e-mail: m.zimarino@unich.it).

© 2004 Lippincott Williams & Wilkins, Inc.