Platelet Glycoprotein IIb/IIIa Inhibition and Percutaneous Coronary Intervention in the Elderly
Cynthia M. Westerhout, MSc and Eric Boersma, PhD
From the Department of Cardiology, Erasmus Medical Centre,
Rotterdam, The Netherlands and the University of Alberta, Edmonton, AB, Canada.
Introduction
The introduction of balloon angioplasty in the early 1980s and stents in the mid-1990s has revolutionized mechanical reperfusion therapy in patients with stenotic coronary arteries.1,2 In fact, percutaneous coronary interventions (PCI) are one of most frequently performed procedures, with more than 1.3 million performed worldwide in 1999.3 However, an important limitation of PCI is the risk of inducing platelet aggregation. As a result of the disruption of the culprit plaque and injury to the coronary vessel during the procedure, the periprocedural risk of reocclusion of the vessel and myocardial infarction (MI) is high, and there is a 20-40% incidence of restenosis at 6-12 months after the index procedure.3
In an attempt to reduce the risk of these complications, several new strategies have been explored. Glycoprotein IIb/IIIa receptor inhibitors (GPIs), for example, have been enthusiastically tested in over 25,000 patients undergoing PCI over the last decade (Table 1). Gp IIb/IIIa receptors are found in great abundance on the surface of platelets and blocking these receptors obstructs the final common pathway leading to platelet aggregation.
In the following review, the efficacy and safety issues associated with these agents will be evaluated with particular emphasis on the elderly (as defined in the trials). Specifically, this appraisal is based on large-scale, phase III, randomized clinical trials and meta-analyses evaluating intravenous agents (abciximab, eptifibatide and tirofiban) in the setting of PCI, and xemilofiban, an oral agent that has been aimed at extending the benefits of intravenous agents after PCI. In the second part of this article (to be published in the July/August issue of Geriatrics & Aging) intravenous and oral GPIs will also be reviewed in the context of medical management of elderly patients suffering from non-ST-segment elevation acute coronary syndromes.
Intravenous GPIs
Abciximab
Based on the results of the groundbreaking trial, EPIC, abciximab (ReoPro) was the first GPI to be approved for use in the United States in 1994, and in Canada in 1996, as an adjunct therapy to PCI (Table 2). In the EPIC trial, high-risk patients who were scheduled to undergo PCI were randomized to abciximab bolus, abciximab bolus plus infusion or placebo bolus plus infusion (Table 3). Patients who received abciximab bolus plus infusion benefited from a 35% relative reduction in death, MI or unplanned revascularization at 30 days compared to those who received the placebo (8.3% versus 12.8%, p=0.008), and these benefits were homogeneous across all age groups (Figure 1).4 In the long-term evaluation of abciximab's efficacy, similar benefits were maintained at six months, and one and three years.5,6 However, abciximab therapy was also associated with an increase in bleeding events and transfusions (Table 4, page 36).
To address these concerns further, a pilot trial modified the heparin regimen and vascular access sheath removal time, as these factors were suspected contributors to the excess bleeding complications seen in the EPIC trial.7 Subsequently, the EPILOG investigators tested these modifications in 2,792 patients undergoing PCI (Table 3).8 The design of EPILOG also allowed for the effects of abciximab to be evaluated in patients of all risk profiles. Both the standard- and low-dose heparin regimens, in conjunction with abciximab, resulted in a significantly lower incidence of the primary composite endpoint (death, MI or urgent revascularization) at 30 days (placebo, 11.7%, versus abciximab plus standard-dose heparin, 5.4%, p<0.001, 54% relative risk reduction; versus abciximab plus low-dose heparin, 5.2%,