Elsevier

The Lancet

Volume 359, Issue 9302, 19 January 2002, Pages 189-198
The Lancet

Articles
Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials

https://doi.org/10.1016/S0140-6736(02)07442-1Get rights and content

Summary

Background

Platelet glycoprotein IIb/IIIa inhibitors have been shown to reduce cardiac complications in patients undergoing percutaneous coronary intervention. The clinical efficacy of these drugs in acute coronary syndromes, however, is still unclear. We did a meta-analysis of all large randomised trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularisation.

Methods

Inclusion criteria were: randomisation of patients with acute coronary syndromes but without persistent ST elevation; comparison of a glycoprotein IIb/IIIa inhibitor with placebo or control therapy; non-recommendation of early coronary revascularisation during study-drug infusion; and enrolment of at least 1000 patients. Data on individual patients were obtained from all participants in these trials.

Findings

Six trials, enrolling 31402 patients, fulfilled the inclusion criteria. 30 days after randomisation, 3530 (11·2%) patients died or developed a myocardial infarction. At 30 days, a 9% reduction in the odds of death or myocardial infarction was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10·8% [1980/18297] vs 11·8% [1550/13105] events; odds ratio 0·91 [95% CI 0·84–0·98]; p=0·015). The relative treatment benefit was similar in subgroups of patients according to important clinical baseline characteristics; hence, the absolute treatment benefit was largest in high-risk patients. An unexpected and significant interaction was seen between sex and allocated treatment, with a treatment benefit in men (0·81 [0·75–0·89] but not in women (1·15 [1·01–1·30]). However, once patients were stratified according to troponin concentration, there was no evidence of a sex difference in treatment response, and a risk reduction was seen in men and women with raised troponin concentrations. Major bleeding complications were increased by glycoprotein IIb/IIIa inhibitors (2·4% [445/18297] vs 1·4% [180/13105]; p<0·0001), but intracranial bleeding was not (16 [0·09%] vs 8 [0·06%]; p=0·40).

Interpretation

Glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or myocardial infarction in patients with acute coronary syndromes not routinely scheduled for early revascularisation. The event reduction is greatest in patients at high risk of thrombotic complications. Treatment with a glycoprotein IIb/IIIa inhibitor might therefore be considered especially in such patients early after admission, and continued until a decision about early coronary revascularisation has been made.

Introduction

Disruption of atherosclerotic plaque, which either occurs spontaneously in patients with acute coronary syndromes or during a percutaneous coronary intervention (PCI), triggers platelet aggregation and intracoronary thrombus formation, and can result in myocardial infarction or death. Activation of the platelet glycoprotein IIb/IIIa receptor is the final common pathway in the process leading to platelet aggregation, and inhibitors of this receptor have been shown to protect against periprocedural death or myocardial infarction in patients undergoing PCI for various indications.1, 2, 3, 4

Randomised clinical trials have indicated that glycoprotein IIb/IIIa inhibitors reduce the occurrence of these events by 38% compared with placebo or control therapy.5, 6 However, the results of trials in acute coronary syndromes in which coronary revascularisation during study-drug infusion was not part of the protocol, have been less conclusive. Glycoprotein IIb/IIIa inhibitors did reduce cardiac endpoints in most of these trials,7, 8, 9, 10, 11 but not in all.12 In the trials with a positive trend, the event reduction was often lower than expected, and significance was not always reached. In fact, most trials in acute coronary syndromes were powered for the detection of a large treatment effect (>20% risk reduction), but were underpowered for more modest, but potentially clinically important, effects. In this situation, a meta-analysis of the combined trial data can be useful to estimate more reliably the overall effect of glycoprotein IIb/IIIa inhibitors. If based on data from individual patients, such meta-analyses can also provide reliable estimates of treatment effects in clinically meaningful subgroups of patients.13 In case of an overall beneficial effect, analysis of subgroups can help identify the target population to be treated preferentially. We did a meta-analysis of all large randomised trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who were not routinely scheduled for early coronary revascularisation.

Section snippets

Methods

The methodological principles that lie behind a meta-analysis of randomised clinical trials based on data from individual patients have been described in detail.13 We therefore only briefly describe the applied methods of trial selection, data-management, endpoint definitions, and statistical analysis.

Patients' characteristics

The six trials altogether enrolled 31402 patients in 41 countries. There were no important differences in baseline characteristics between patients randomly assigned glycoprotein IIb/IIIa inhibitors (n=18297) and those assigned placebo or control (n=13105). The mean age of the population was 64 years, 65% were men, and 76% had a history of cardiovascular disease. 56% of the patients presented with ST-segment depression, 46% with raised creatine kinase MB concentrations, and 80% with either one

Discussion

Inhibitors of the platelet glycoprotein IIb/IIIa receptor were associated with an absolute reduction in the 30-day rate of death or myocardial infarction of 1% compared with control therapy. This risk reduction was achieved after completion of study medication, and was maintained throughout 30-day follow-up. The treatment benefit was seen in patients treated with and without heparin. Sex differences were apparent, with a treatment benefit in men (two-thirds of the population), but not in women.

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