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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Clinical Pharmacology and
Epidemiology, and Surgen Ltd, Royal College of Surgeons in
Ireland; the Cardiovascular Division, Brigham and Women's
Hospital; and Harvard Medical School, Boston, MA.
This study examined the influence of the PlA
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 PlA 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, PlA2 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 PlA 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 PlA2 carriers (RR = 0.87,
0.46 to 1.64). There was no interaction between treatment (placebo and
orbofiban) and the PlA 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 PlA2 carriers compared with
noncarriers. In contrast, there was no evidence that PlA2
influenced the rate of recurrent events in placebo-treated patients. In
patients presenting with an acute coronary syndrome, the
PlA polymorphism of GPIIb/IIIa may explain some of the
variance in the response to an oral GPIIb/IIIa antagonist.
(Blood. 2001;98:3256-3260) Platelet 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 patients on sibrafiban.
Genetic factors are postulated to modulate drug response, either in
determining efficacy or the risk of side effects. Intuitively, this is
most likely where the genetic variation influences the drug target or
enzymes responsible for drug metabolism. In this study, we examined the
influence of the PlA polymorphism of GPIIIa on the response
to the GPIIb/IIIa antagonist, orbofiban, in patients with unstable
coronary syndromes.2 About 20% of the population are
carriers of the PlA2 polymorphism, which results in a
proline in place of a leucine at position 33 of GPIIIa.4
PlA2 has been associated with MI, coronary thrombosis, and
restenosis following coronary angioplasty and with
stroke.5-11 However, many studies have failed to confirm
any link between the PlA mutation and cardiovascular
disease.12-14 It is also unclear whether the
PlA2 variant alters receptor function. Several studies have
shown enhanced fibrinogen binding to and aggregation of platelets from individuals either heterozygous or homozygous for
PlA2.15-17 The PlA2 receptor also
exhibits enhanced "outside-in" signaling when expressed in Chinese
hamster ovary (CHO) cells.18 Finally, carriers of PlA2 receiving aspirin have a blunted bleeding time
response.19 However, other studies have failed to
show any enhanced effect.20-22
Study population
The protocol for the main study has been outlined in detail
elsewhere.2 Briefly, the inclusion criteria were ischemic
discomfort at rest for at least 5 minutes within the previous 72 hours
with one of the following: (1) new or presumably new
electrocardiographic changes (ST segment deviation Trial design
After randomization, patients received the drug as soon as possible, but within 72 hours of the index event. Treatment was to continue for a minimum of 6 months, and up to 24 months. The actual treatment period ranged from 1 month to a maximum of approximately 15 months. The primary end point was a composite of death, MI, recurrent ischemia at rest leading to rehospitalization or urgent revascularization, or stroke. A clinical events committee adjudicated all end points. Additional analyses were performed for MI and for all recorded coronary ischemic events. Severe or life-threatening bleeding was defined as an intracranial hemorrhage or bleeding associated with severe hemodynamic compromise; major bleeding was that associated with >15% absolute reduction in hematocrit or requiring a blood transfusion; minor bleeding was (nonmajor) bleeding that required medical treatment or laboratory evaluation.2 Genetic analysis Genetic analysis was performed at a mean of 157 days in 1014 patients, the majority of whom were from the USA (n = 537) and Canada (n = 276). Fifty-nine percent of the patients presented with acute MI as their index event and the remainder presented with unstable angina. Following DNA extraction,23 the PlA polymorphism was detected by capillary electrophoresis, as previously described.24Statistical analyses Means and proportions were compared using a t test or chi-square as appropriate. Survival analyses considered the time to the first primary end-point event, and also the time to the first severe, major, or minor bleeding event. All times were measured from the day of randomization. Kaplan-Meier survival curves were compared using the log-rank test. A Cox proportional hazards analysis was used when adjusting for the possible confounding effects of other prognostic factors. The nominal significance level of 0.05 was reduced to 0.025 for comparisons between each dose and placebo. Tests of interaction between genotype and treatment were performed by fitting terms within the survival analysis for genotype and treatment, and an interaction term. The P value of the interaction term was then calculated to interpret significance.Sixty-four patients were removed from the study due to poor health or due to the wishes of the patient or medical provider. Fifty of those removed had not had a previous primary event. A Cox proportional hazards analysis assumes that censoring is noninformative. Clearly this is not the case for those removed prior to their first event. To assess how sensitive our conclusions were to those patients lost to follow-up, we performed an analysis where we considered all those patients lost to follow-up as censored event-free and then repeated the analysis assuming that observations on those lost to follow-up were complete and represented time to first event. The results were comparable, so we report only the first analysis.
Among the 1014 patients for whom genetic material was available
(Table 1), primary end-point events were
recorded in 165 patients. Of these patients, 33 had a recurrent MI, 55 underwent urgent revascularization, and 72 were rehospitalized for
recurrent ischemia. Six patients experienced a stroke and there were 3 deaths. Bleeding occurred in 187 patients.
In studying effects of both treatment and genotype in a population, it is important to consider possible interactions between genotype and treatment. In the absence of an interaction between genotype and treatment, analysis of independent effects are appropriate. However, when there is evidence of an interaction, subpopulations should be analyzed separately. For this reason, we present first the independent genotypic effects, and then consider possible interactions, presenting genotypic effects in treated and untreated subpopulations. Prevalence of the PlA polymorphism The frequency of the PlA2 allele in all 1014 patients was similar to that found in several previous studies,14,15 although lower than the 50% reported in young patients with acute MI.6 The frequencies of the PlA1 and the PlA2 allele were 0.86 and 0.14, respectively. Thus, 26.3% of patients carried at least one PlA2 allele and 2.2% of patients were homozygous for PlA.2 The PlA2 allele was evenly distributed among the racial groups (data not shown). A higher proportion of the PlA2 carriers were male (80.5% vs 73.8% for noncarriers; P = .03). PlA2 carrier frequency varied between countries (P = .03), with the most notable difference between Canadian (21.9% of 265 patients) and US Caucasians (30.0% of 477 patients). Among the 30 blacks in the study, the PlA2 frequency was similar to that of Caucasians (18.3%).Primary end point and MI: genotypic effects The median follow-up time for patients without a primary end point was 203 days with lower and upper quartiles of 150 and 303 days, respectively. There were 165 patients (16.5%) who had a primary event. This is lower than the 22.9% observed in the overall study of 10 288 patients followed to 10 months,2 possibly as the subpopulation studied had a lower risk profile, being younger and less often diabetic. Alternatively, some patients with serious events may have been removed from the study prior to genetic sampling.The time to first primary event was analyzed using a proportional hazards model, which adjusted for age and sex. Considering the total population, there was no significant association between PlA carrier status and the risk of a primary event (relative risk [RR], 1.26; 95% confidence interval [CI], 0.91 to 1.76; P = .17). However, the rate of MI was significantly higher among PlA2 carriers (RR = 2.71; 95% CI, 1.37 to 5.38; P = .004). This remained true even after adjusting for possible confounding effects of treatment, country of origin, and/or race. The risk of a primary end-point event increased slightly with the number of PlA alleles carried: 15.4% of PlA1/PlA1 patients had events, compared with 18.4% of the 245 PlA1/PlA2 heterozygotes and 22.7% of the 22 PlA2/PlA2 genotypes, although this trend was not statistically significant. Interaction between the PlA polymorphism and treatment: primary end point and MI Overall, treatment with orbofiban did not affect the primary end point or the rate of MI irrespective of the genotype (Tables 2 and 3). The interaction between the effects of genotype and treatment (Tables 3 and 4) approached significance for the primary end point (P = .10) and for MI (P = .08). The RR of a primary end-point event on orbofiban compared with placebo among PlA2 carriers was 1.37 (95% CI, 0.75 to 2.51) (Table 3), and among noncarriers RR was 0.73, (95% CI, 0.51 to 1.06) (Figure 1). Although among PlA2 carriers on orbofiban there was a trend toward a higher RR (2.46) of MI (95% CI, 0.70 to 8.67) (Table 3), this did not achieve statistical significance. In addition to examining the effect of treatment (placebo and orbofiban), we also examined the genotypic effects separately in the placebo and active treatment arms. When PlA2 carriers and PlA2 noncarriers were compared while on orbofiban, PlA2 carriers had an RR of a primary event of 1.55 (95% CI, 1.03 to 2.34, P = .04) (Table 4). In contrast, the primary event rate was not influenced by genotype in patients on placebo. There was also a significantly higher risk of MI in PlA2 carriers on active orbofiban, but not in those on placebo (Table 4).
Interaction between the PlA polymorphism and treatment: bleeding Severe, major, recurrent, or minor bleeding occurred in 18.4% of patients during the study (Tables 2 and 3). For the total cohort studied, bleeding was increased with orbofiban relative to placebo (P < .002). A Cox analysis of the time to first bleeding was performed, adjusting for age and sex and stratified by country (Table 3). The risk of bleeding relative to placebo (RR and 95% CI) was 1.35 (0.94 to 1.93) and 1.88 (1.33 to 2.67) for the low dose and high dose orbofiban groups, respectively. The interaction between genotype and treatment (placebo and orbofiban) on the risk of bleeding was significant. Thus, while there was a highly significant, dose-dependent increase in bleeding events in PlA1 homozygous patients, there was no increase in PlA2 carriers (Table 3, Figure 2). As with the efficacy end points, we also examined the genotypic effects separately in the placebo and active treatment arms. When PlA2 carriers and PlA2 noncarriers while on orbofiban were compared, the risk of bleeding was lower for PlA2 carriers relative to PlA2 noncarriers (RR, 0.59; 95% CI, 0.39 to 0.92; P = .02, Table 4). PlA2 carriers were protected against bleeding most clearly in the high dose group, since their bleeding rate was no higher than that of placebo, whereas PlA1/A1 homozygotes had a large increase in bleeding risk (Table 2). The results may be explained by a partial agonist effect of the drug in carriers of PlA2.
Previous studies have implicated PlA2 in acute MI, even among patients who are heterozygous for the mutation.5-10 This might be expected if the mutation enhanced the function of the receptor and indeed several studies demonstrate a modest increase in platelet activity as a consequence of the PlA polymorphism.15-19 Thus, there is an increase in fibrinogen binding to platelets of patients homozygous for the PlA2 allele and enhanced platelet aggregation to low concentrations of agonists.15-17 PlA2 carriers are also reported to have increased thrombin generation when on aspirin compared with noncarriers.25 However, other studies have failed to show any functional effect of the PlA2 polymorphism.20-22 In this substudy of the OPUS trial of orbofiban, the frequency of the PlA2 allele was no higher in patients presenting with an unstable coronary syndrome compared with that reported by several investigators in stable coronary syndromes or noncardiac patients.14,16 Moreover, there was no association between the PlA polymorphism and the subsequent occurrence of the primary end point of the study, a composite of death, MI, recurrent ischemia at rest leading to rehospitalization or urgent revascularization, or stroke. However, of these only MI has been consistently linked to coronary thrombosis and our data demonstrated an association between the PlA polymorphism and subsequent MI. In previous studies,5,9 PlA2 has shown an interaction with age (an increased risk of developing MI at a young age) and smoking. We found no significant interaction with age, although the combination of the PlA2 allele and smoking or diabetes mellitus was weakly associated with an increased event rate (data not shown). The underlying hypothesis for the study was that the PlA genotype would influence the response to a GPIIb/IIIa antagonist. Orbofiban had no significant impact on the frequency of primary events in the subset of patients studied. Although the overall interaction of genotype with treatment was not quite significant, among patients on active treatment there was an increase in events among PlA2 carriers that was particularly striking for MI, with an RR of 4.27. In contrast, within the placebo group PlA2 carriers were not at a higher risk. The results of the analyses for bleeding and for MI are internally consistent and suggest that at the very least the PlA2 variant blunts response to treatment. The results are also consistent with the hypothesis that PlA2 is a prothrombotic variant, increasing events and reducing bleeding, although in this study such effects are absent in the placebo arm and only observed in the treated groups. The OPUS-TIMI-16 trial showed an increase in death that was evident in both active treatment arms.2 Subsequent analysis has shown that many of the deaths reflected new coronary events. Two other large-scale clinical trials of oral GPIIb/IIIa antagonists in patients with unstable coronary syndromes confirm these findings (SYMPHONY I and II).3 Our study shows that it is possible that the increase in coronary events occurs largely in PlA2 carriers. Why oral GPIIb/IIIa antagonists increase cardiac events is unknown. GPIIb/IIIa is not a passive receptor, but upon fibrinogen binding it transmits signals that amplify platelet activation, so-called "outside-in" signaling. This signaling is critical for platelet activity, as defects in outside-in signaling prevent platelets from aggregating despite fibrinogen binding.26 There is evidence that GPIIb/IIIa antagonists may also trigger outside-in signaling and so act as partial agonists.27,28 Thus, increased platelet activity, detected as expression of CD62 (P selectin), has been reported in patients on orbofiban.29,30 Compared with the PlA1 variant, the PlA2 variant of GPIIb/IIIa exhibits greater outside-in signaling detected as phosphorylation of focal adhesion kinase when cells expressing the mutated receptor are exposed to fibrinogen.18 Whether the PlA2 variant of GPIIb/IIIa is also more susceptible to the partial agonist activityinduced by smaller ligands, such as GPIIb/IIIa antagonists, and whether this explains why the response to GPIIb/IIIa antagonists is modified in patients carrying the variant, has yet to be addressed. It is worth noting that primary events and MI were more common at the low dose of orbofiban (Table 3), where partial agonism would be more evident. In conclusion, the PlA genotype may modify the response to an oral GPIIb/IIIa antagonist and may in part explain the variance in the response to these drugs in humans. Whether this applies also to short-term intravenous administration of this class of drugs is as yet unknown.
We thank the OPUS-TIMI-16 investigators for their immense effort in the collection of the clinical data and blood samples for DNA used in this study.
Submitted April 30, 2001; accepted July 30, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Desmond J. Fitzgerald, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland; e-mail: dfitzgerald{at}rcsi.ie.
1.
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Goodall AH, Curzen N, Panesar M, et al.
Increased binding of fibrinogen to glycoprotein IIIa-proline33 (HPA-1b, PlA2, Zwb) positive platelets in patients with cardiovascular disease.
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Vijayan VK, Goldschmidt-Clermont PJ, Roos C, Bray PF.
The PlA2 polymorphism of integrin 19. Szczeklik A, Undas A, Sanak M, Frolow M, Wegrzyn W. Relationship between bleeding time, aspirin, and the PlA1/A2 polymorphism of platelet glycoprotein IIIa. Br J Haematol. 2000;110:965-967[CrossRef][Medline] [Order article via Infotrieve].
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© 2001 by The American Society of Hematology.
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  F. Marin, R. Gonzalez-Conejero, P. Capranzano, T. A. Bass, V. Roldan, and D. J. Angiolillo Pharmacogenetics in cardiovascular antithrombotic therapy. J. Am. Coll. Cardiol., September 15, 2009; 54(12): 1041 - 1057. [Abstract] [Full Text] [PDF]
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 S. T. Morozowich, B. S. Donahue, and I. J. Welsby Genetics of coagulation: considerations for cardiac surgery. Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2006; 10(4): 297 - 313. [Abstract] [PDF]
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 A. Lepantalo, K. S Virtanen, J. Heikkila, U. Wartiovaara, and R. Lassila Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions Eur. Heart J., March 2, 2004; 25(6): 476 - 483. [Abstract] [Full Text] [PDF]
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 D. E. Mager, M. A. Mascelli, N. S. Kleiman, D. J. Fitzgerald, and D. R. Abernethy Simultaneous Modeling of Abciximab Plasma Concentrations and ex Vivo Pharmacodynamics in Patients Undergoing Coronary Angioplasty J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 969 - 976. [Abstract] [Full Text] [PDF]
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 C. J Knight Antiplatelet treatment in stable coronary artery disease Heart, October 1, 2003; 89(10): 1273 - 1278. [Full Text] [PDF]
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 C. Muckian, A. Fitzgerald, A. O'Neill, A. O'Byrne, D. J. Fitzgerald, and D. C. Shields Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease Blood, July 30, 2002; 100(4): 1220 - 1223. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
0.5 mm,
T-wave inversion 
) and noncarriers (
) on placebo and
orbofiban.
448 polymorphism with myocardial infarction and extent of coronary artery disease.
Circulation.
1997;96:1424-1431
IIb