Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes

This study examined the influence of the PIA polymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the PIA polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, PIA2 carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P = .004). There was a significant interaction between treatment (placebo and orbofiban) and the PIA polymorphism for bleeding (n = 187; P = .05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71; P < .001) in a dose-dependent fashion, it did not increase bleeding events in PIA2 carriers (RR = 0.87, 0.46 to 1.64). There was no Interaction between treatment (placebo and orbofiban) and the PIA polymorphism for the primary end point (P = .10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P = .04) and MI (RR 4.27, 1.82 to 10.03; P < .001) in PIA2 carriers compared with noncarriers. In contrast, there was no evidence that PIA2 influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the PIA polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist. (Blood. 2001;98:3256-3260) (C) 2001 by The American Society of Hematology.