Upstream use of small-molecule glycoprotein iib/iiia inhibitors in patients with non-ST-segment elevation acute coronary syndromes: a systematic overview of randomized clinical trials

Background— The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non–ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials. Methods and Results— Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63). Conclusions— In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding.