An overview of platelet GP IIb/IIIa receptor antagonists trials

Newer strategies for profound inhibition of platelet activity at the coronary plaque focus on the integrin glycoprotein (GP) IIb/IIIa receptor on the platelet surface membrane, which binds circulating fibrinogen or von Willebrand factor and cross-links adjacent platelets as the final common pathway to platelet aggregation. Parenteral agents directed against GP IIb/IIIa include the chimeric 7E3 Fab monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and the non-peptide mimetics tirofiban and lamifiban. Initial clinical experience with GP IIb/IIIa blockade involved patients undergoing percutaneous coronary revascularization. The EPIC trial reported that administration of abciximab for 12 h in high-risk patients during and after coronary intervention, in addition to conventional therapy with heparin and aspirin, reduced 30-day incidence of death, myocardial infarction (MI) or urgent revascularization compared with conventional therapy (35% reduction, P<0.008). The subsequent EPILOG study showed that the additional risk for bleeding complications with abciximab observed in EPIC may be eliminated by reduction of heparin dosing, and that the benefits of GP IIb/IIIa blockade could be extended to all risk strata of patients (56% reduction in composite endpoint, P=0.001). In addition, the RAPPORT trial confirmed a benefit for abciximab in the setting of primary angioplasty. Eptifibatide and tirofiban have also been tested in large-scale phase III studies of coronary intervention (IMPACT II and RESTORE, respectively). In contrast to some of the abciximab findings, these reversible, specific inhibitors were associated with a 16-18% reduction in ischaemic endpoints at 30 days. Potential explanations for differences in clinical efficacy between these agents and abciximab include inadequate dosages of eptifibatide or tirofiban, or prolonged GP IIb/IIIa receptor occupancy or receptor non-specificity of abciximab. The GP IIb/IIIa antagonists have also been evaluated in large-scale, placebo-controlled trials involving patients with unstable angina, including PURSUIT (eptifibatide), PRISM and PRISM-PLUS (tirofiban), and PARAGON (lamifiban). In the PURSUIT trial, a 72-96 h regimen of eptifibatide reduced the risk of death or myocardial (re)infarction from 15.7% to 14.2% (P=0.042). The other three unstable angina trials similarly indicated reductions in the risk of death or MI ranging from 10% to 27%. In the interventional setting, the recently completed EPI-STENT trial extended the adjunct benefit of GP IIb/IIIa blockade to stent implantation, for which abciximab reduced the endpoint event rate by 51% (P<0.001) with no increase in major bleeding events. Early phase II trial experience with the GP IIb/IIIa inhibitors in patients with acute MI also suggests a benefit from these agents in enhancing the speed and completeness of thrombolytic reperfusion.