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. IntroductionPlatelet activation and subsequent aggregation play major roles in initiating coronary thrombosis, the underlying event in acute coronary syndromes such as unstable angina and myocardial infarction (MI). Platelet aggregation is mediated by glycoprotein (GP) IIb/IIIa, the receptor for fibrinogen and von Willebrand factor (vWf). GPIIb/IIIa antagonists bind to the receptor and prevent platelet aggregation to all known agonists. Yet oral GPIIb/IIIa antagonists have proven ineffective and may be harmful when administered chronically to patients presenting with acute coronary syndromes. 1 Three large-scale clinical trials have reported an increase in death and MI in patients on active treatment compared with placebo. In the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16) trial of orbofiban, the study was terminated due to an increase in mortality. 2 In the SYMPHONY II (sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes II) trial, 3 there was an increase in MI and death in patien...

The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists

“…However, with 45 possible pairwise interactions there is insufficient statistical power, so we limited our investigation to one gene-gene interaction. Much of the evidence concerning the role of inflammation (and infection) in thrombosis 4 is obscured by concerns whether the inflammation is the cause or consequence of the coronary disease process. We tested whether pro-inflammatory variants interact with platelet pro-thrombotic factors in the population.…”

“…These patients participated in the OPUS TIMI-16 clinical trial of oral glycoprotein GPIIb/IIIa antagonists, 3 and were followed prospectively to determine the incidence of recurrent events and of bleeding complications. Our initial analyses of the PLA2 polymorphism 4 and the GPIb␣ T-5C variant 5 in this population suggested that these individual factors appeared to modulate disease risk. However, no single common genetic variant confers a very large risk of coronary ischemia, so that a particular association is unlikely to be consistently found without very large sample sizes.…”

Gene mutations of platelet glycoproteins and response to tirofiban in acute coronary syndrome

“…Aggregation data and incidence of death among 50 patients with unstable angina and non-ST-segment elevation myocardial infarction be an association between this mutation and coronary thrombosis. 25 Wheeler et al showed that there was less platelet inhibition through using abciximab in patients with the PlA2 mutation who underwent percutaneous coronary intervention. 26 Weber et al…”

Pharmacogenetics of Antiplatelet Drugs

“…A subgroup of 1,014 patients, the majority of whom were from the U.S. and Canada, donated a genetic sample at a mean of 157 days. These patients were genotyped for the Pl A2 polymorphism and its effect on response to orbofiban was examined [53]. The rate of MI was significantly higher among all Pl A2 carriers (RR = 2.71, 95%CI 1.37-5.38, p = 0.004).…”