Key result
In patients with unstable coronary syndromes treated with orbofiban, Pl(A2) carriers had a higher risk of the primary composite ischemic endpoint than noncarriers (RR 1.55; 95% CI 1.03-2.34; P=0.04).
Why the study?
Does the Pl(A) polymorphism of GPIIIa determine the response to the oral GPIIb/IIIa antagonist orbofiban in patients with unstable coronary syndromes?
RCT (n=1,014)
randomized
Does the Pl(A) polymorphism of GPIIIa determine the response to the oral GPIIb/IIIa antagonist orbofiban in patients with unstable coronary syndromes?
The Pl(A) polymorphism of GPIIIa may explain variance in response to oral GPIIb/IIIa antagonists in ACS patients, with Pl(A2) carriers experiencing higher ischemic risk and noncarriers experiencing higher bleeding risk with orbofiban.
May warrant avoiding orbofiban in Pl(A2) carriers; extends pharmacogenetic evidence for GPIIb/IIIa response in ACS.
This study examined the influence of the Pl(A) 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 Pl(A) 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, Pl(A2) 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 Pl(A) 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 Pl(A2) carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the Pl(A) 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 Pl(A2) carriers compared with noncarriers. In contrast, there was no evidence that Pl(A2) influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the Pl(A) polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.
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O'Connor et al. (2001) conducted an RCT in unstable coronary syndromes (n=1,014). Orbofiban (stratified by Pl(A) polymorphism) vs. placebo was evaluated on composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke (RR 1.55, 95% CI 1.03-2.34, p=0.04). In patients with unstable coronary syndromes treated with orbofiban, Pl(A2) carriers had a higher risk of the primary composite ischemic endpoint than noncarriers (RR 1.55; 95% CI 1.03-2.34; P=0.04).
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