Learning from the recently completed oral glycoprotein IIb/IIIa receptor antagonist trials

Although parenteral therapy with glycoprotein (GP) IIb/IIIa inhibitors has resulted in a reduced risk of death or myocardial infarction in patients with acute coronary syndromes and in patients undergoing percutaneous coronary intervention, the benefit is achieved only during the infusion period. Oral GP IIb/IIIa inhibitors may offer an opportunity to expand the application of this therapy to additional vascular indications and to extend therapy beyond the in-hospital period. A number of oral GP IIb/IIIa inhibiting agents have been evaluated; however, no benefit has been observed. Oral GP IIb/IIIa inhibitors have been associated with an increased incidence of bleeding, but additional experience may permit the design of dosing regimens that decrease this risk. The recent Orbofiban in Patients with Unstable Coronary Syndromes (OPUS/TIMI-16) trial showed a small but significant increase in mortality in orbofiban-treated patients. It appears that this agent, and perhaps other oral GP IIb/IIIa inhibitors including sibrafiban and xemilofiban, may have a pro-aggregatory effect. This may be caused by the drug dissociating from the GP IIb/IIIa receptor, leaving an activated receptor that can then bind fibrinogen and form a platelet aggregate. Further studies are needed to elucidate the mechanism of this effect and to evaluate whether the second-generation of oral GP IIb/IIIa inhibitors, which have tight binding and a longer duration of antiplatelet effect, will be of clinical benefit.