Platelet Glycoprotein IIb/IIIa Inhibitors in the Treatment of Non-ST-segment Elevation Acute Coronary Syndromes in the Elderly: Part 2 of 2
Cynthia M. Westerhout, MSc1,2 and Eric Boersma, PhD1
From the 1Department of Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands and the 2University of Alberta, Edmonton, AB.
Introduction
The chain of events leading to acute coronary syndromes (ACS), including unstable angina (UA) and non-ST-segment elevation (NSTE) or ST-segment elevation myocardial infarction (STEMI), is triggered by the disruption of an atherosclerotic plaque, which leads to the formation of a platelet-rich thrombus within a coronary artery.1,2 The inhibition of platelet aggregation is fundamental to the treatment of these patients; however, standard antiplatelet agents such as aspirin do not completely obstruct this activity. Advances in understanding the pathophysiology of ACS have to the recognition of the activation of the glycoprotein IIb/IIIa (Gp IIb/IIIa) receptors on platelets as the final common pathway leading to platelet aggregation. With this target in mind, pharmacological treatment of ACS has been propelled into a new era with agents that completely inhibit platelet aggregation.3
In this second of two reviews examining the impact of platelet glycoprotein IIb/IIIa receptor inhibitor (GPI) therapy on patients suffering from ischemic heart disease, the efficacy and safety issues associated with these agents in the medical management of non-ST-segment elevation ACS (NSTE-ACS) will be discussed. Specifically, this appraisal is based on large-scale, phase III, randomized clinical trials and meta-analyses evaluating intravenous (abciximab, eptifibatide, tirofiban and lamifiban) and oral agents (sibrafiban and orbofiban), with particular emphasis on the elderly (as defined in the trials) (Table 1).
Intravenous GPIs
Abciximab
Although it was the first GPI to be tested in patients undergoing percutaneous coronary intervention (PCI), abciximab is one of the most recent to be tested in the front-line medical treatment of NSTE-ACS. The investigators of the GUSTO-IV ACS (see Table 1 for full trial names) trial compared the effect of two different lengths of abciximab infusion (24-hour and 48-hour) against a placebo bolus and infusion in NSTE-ACS patients who were not undergoing early PCI (Table 2).4 In patients with either a positive troponin T or I test, or transient or persistent ST-segment depression (= 0.5mm), there was no benefit from the administration of abciximab, regardless of the length of infusion, at 30 days ((death or MI at 30 days) 8.0% placebo versus 8.2% 24-hour abciximab, odds ratio (OR) 1.0, 95% confidence interval (CI) (0.83-1.24); and 9.1% 48-hour abciximab, OR 1.1, 95% CI(0.94, 1.39)). This lack of effect was also evident in both younger (<65 years) and older ((= 65 years) patients (Figure 1). Unlike the investigations of abciximab in patients with refractory angina and in those undergoing PCI, it seems that no additional benefit was derived from the use of abciximab in the medical management of NSTE-ACS.
Eptifibatide
On the heels of the success of Gp IIb/IIIa receptor inhibition in patients undergoing PCI, it was suspected that eptifibatide, a small-molecule GPI, could reduce ischemia in UA patients. To follow-up on the promising results of Schulman's dose-finding trial, the PURSUIT trial investigators tested the hypothesis that eptifibatide could significantly reduce death and MI beyond standard therapy, such as aspirin and heparin, in ACS patients without persistent ST-segment elevation (Table 2).5,6 A unique feature of this trial was its practice-based protocol, which mandated that decisions on treatment strategies, including cardiac catheterization and revascularization, were made at the discretion of the treating physicians.
Overall, the use of eptifibatide in these patients led to a significant reduction in death or non-fatal MI at each time point. On the fourth day after randomization, a 1.5% absolute reduction was achieved and was consistently