title: 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.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, and Surgen Ltd, Royal College of Surgeons in Ireland.
authors.forename: F F
authors.initials: FF
authors.lastname: O'Connor
authors.forename: D C
authors.initials: DC
authors.lastname: Shields
authors.forename: A
authors.initials: A
authors.lastname: Fitzgerald
authors.forename: C P
authors.initials: CP
authors.lastname: Cannon
authors.forename: E
authors.initials: E
authors.lastname: Braunwald
authors.forename: D J
authors.initials: DJ
authors.lastname: Fitzgerald
mesh_terms: D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000789:Angina, Unstable / Q000188:drug therapy / Q000235:genetics; D016824:Antigens, Human Platelet / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000235:genetics; D010919:Placebos; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011110:Polymorphism, Genetic; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D016824:Antigens, Human Platelet; D010919:Placebos; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; C083451:human platelet antigen 1b; C120234:orbofiban; D000409:Alanine; D001241:Aspirin