CLINICAL STUDIES: INTERVENTIONAL CARDIOLOGY
PlA polymorphism of glycoprotein IIIa and risk of adverse events after coronary stent placement
Adnan Kastrati, MDa,
Werner Koch, PhDa,
Meinrad Gawaz, MDa,
Julinda Mehilli, MDa,
Corinna Böttiger, MDa,
Kathrin Schömig, MDa,
Nicolas von Beckerath, MDa and
Albert Schömig, MDa
a Deutsches Herzzentrum and 1. Medizinische Klinik rechts der Isar, Technische Universität München, Munich, Germany
Manuscript received June 22, 1999;
revised manuscript received December 30, 1999,
accepted March 24, 2000.
Reprint requests and correspondence: Dr. Adnan Kastrati, Deutsches Herzzentrum, Lazarettstr. 36, 80636 München, Germany
kastrati{at}dhm.mhn.de
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Abstract
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OBJECTIVE
We designed this prospective study to test the hypothesis that platelet antigen (PlA) polymorphism of glycoprotein (GP) IIIa is associated with an increased risk for adverse events after coronary stent placement.
BACKGROUND
Platelets play a central role in arterial thrombosis. The PlA polymorphism of GP IIIa, a constituent of the fibrinogen receptor, may influence the platelet function and, thereby, the early outcome of patients after coronary stent placement.
METHODS
The study included 1,759 consecutive patients with stable or unstable angina and successful coronary stent placement. Platelet antigen genotypes were determined by allele-specific restriction enzyme analysis. The end point of the study was a composite of death, myocardial infarction and urgent revascularization during the first 30 days after stent placement.
RESULTS
The PlA genotype of the patients included was: 70.2% were homozygous for platelet antigen 1 (PlA1), 2.6% homozygous for platelet antigen 2 (PlA2), and 27.2% were heterozygous (PlA1/A2). The incidence of the composite end point was 5.5% among PlA2 carriers and 5.4% in homozygous PlA1 subjects (p = 0.94). It was 5.4% in PlA1/A1 patients, 4.8% in PlA1/A2 patients and 13.0% in PlA2/A2 patients (p = 0.06). The combined incidence of death or myocardial infarction was 4.3% in PlA1/A1 patients, 4.2% in PlA1/A2 patients and 13.0% in PlA2/A2 patients (p = 0.02).
CONCLUSIONS
The isolated presence of the PlA2 allele in heterozygous patients is not associated with any detectable increase in the risk for an adverse 30-day outcome after coronary stenting. This study suggests also that an increased risk is likely to be present in homozygous carriers of the PlA2 allele, but this should be confirmed in a much larger series of patients.
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Abbreviations and Acronyms
| | CI | = confidence interval | | GP | = glycoprotein | | MI | = myocardial infarction | | MLD | = minimal lumen diameter | | PlA | = Platelet Antigen |
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Platelets play a central role in arterial thrombosis (1–4). Platelet activation by various agonists renders the major platelet integrin, glycoprotein (GP) IIb/IIIa, a functional adhesion receptor for binding fibrinogen, as the final pathway for platelet aggregation (2). Pharmacological GP IIb/IIIa blockade has resulted in reduction of early ischemic complications after percutaneous coronary interventions (4–8). Glycoprotein IIIa is a polymorphic protein with platelet antigen 1 (PlA1) and PlA2 as the most common allelic isoforms (9). In the PlA2 allele, cytosine is substituted for thymidine in exon 2, which is phenotypically translated in the substitution of proline for leucine at position 33 of the mature GP IIIa. The clinical significance of PlA polymorphism has been assessed in various pathologies in which an important role for arterial thrombosis is assumed. However, the finding of a significant association between PlA poly
morphism and coronary artery disease or myocardial infarction (MI) (10–13) has not been supported by other studies (14–17). This issue becomes even more encumbered by the controversial findings of in vitro studies concerning the activation and fibrinogen-binding affinity of platelets from PlA2 individuals (18–20). Recently, we demonstrated that the PlA polymorphism is associated with a higher risk for in-stent restenosis (21). Placement of coronary stents triggers a major stimulus for platelet activation (22), and stent thrombosis remains a complication for which no definitive solution has yet been found. This intervention is, therefore, thought to provide very suitable conditions for assessing the influence of platelet GP IIIa polymorphism (23). Initial findings show a strong link between this inherited factor and stent thrombosis (24), which could not be confirmed in another series of 280 stented patients (25). If studies in larger patient populations corroborate the association between PlA polymorphism and thrombotic events after stenting, this may have relevant therapeutic implications.
We designed this prospective study to test, in a large and consecutive series of patients, the hypothesis that PlA polymorphism of GP IIIa is associated with increased risk for adverse events after coronary stent placement.
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Methods
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This study includes all patients with stable or unstable angina pectoris who received successful stent implantation in the period from April 1996 through January 1998. During this period, coronary stent implantation was attempted in 2,235 consecutive patients. Procedural failure (defined as failure to place the stent at the desired position or to achieve a final diameter stenosis of less than 30% by visual inspection) was recorded in 47 patients (2.1%). Of the 2,188 successfully treated patients, 429 underwent stenting in the setting of acute MI and were excluded from this study. Thus, our study population comprised 1,759 patients. Each participant gave written informed consent for the study, which was approved by the institutional Ethics Committee.
Implantation of various slotted-tube stents was performed as previously described (26). More than 95% of the stents were hand-crimped on conventional angioplasty balloons and delivered under fluoroscopic guidance. Postprocedural therapy consisted of aspirin (100 mg twice a day, indefinitely) and ticlopidine (250 mg twice a day for four weeks, Tiklyd, Sanofi-Winthrop, Munich, Germany). Patients with suboptimal results due to residual thrombus or dissection with flow impairment after stent implantation received additional therapy with abciximab given as bolus injection during stent insertion procedure and as a 12-h continuous infusion thereafter. The decision to give abciximab was left to the operator’s discretion. Patients with symptoms or signs of recurrent ischemia after the intervention underwent repeat angiography.
Determination of PlA genotypes.
High molecular weight DNA was extracted from 200 µl of peripheral blood with the QIAamp blood kit (QIAGEN, Hilden, Germany). Platelet antigen genotypes were determined by allele-specific restriction enzyme analysis (27–29). Briefly, a 268 base pair sequence containing exon 2 of the GP IIIa gene was amplified by polymerase chain reaction using specific oligonucleotide primers: the sense primer 5'-TTCTGATTGCTGGACTTCTCTT-3' and the reverse primer 5'-TCTCTCCCCATGGCAAAGAGT-3'. After allele-specific restriction-enzyme digestion of the amplified DNA with MspI (Boehringer Mannheim, Mannheim, Germany), the PlA genotype was identified on a 6% polyacrylamide gel. For all homozygous patients for PlA2 allele and those with stent thrombosis, PlA genotype determination was repeated using DNA from a separate preparation. Similarly, PlA genotype determination was also repeated in 20% of the other patients selected at random.
Angiographic assessment.
Lesions were classified according to the modified American College of Cardiology/American Heart Association grading system (30). Lesions of grade B2 and C were considered to be complex. The diagnosis of reduced left ventricular function was established in the presence of at least two hypokinetic segments in the contrast angiogram. Postprocedural final angiogram was evaluated for the presence of substantial residual dissections defined as dissections >5 mm (31). The diagnosis of stent thrombosis was established angiographically in the presence of a Thrombolysis in Myocardial Infarction flow of grade 0 or 1 (32). Quantitative analysis was performed off-line for angiograms obtained before and immediately after stent placement using the automated edge-detection system CMS (Medis Medical Imaging Systems, Nuenen, the Netherlands). Identical projections of the target lesion were used for all assessed angiograms. Minimal lumen diameter (MLD), reference diameter, percent diameter stenosis and the diameter of the maximally inflated balloon were obtained with this analysis system.
Definitions and end point of the study.
This study assessed the possible relation between PlA polymorphism and adverse events after coronary stent placement. The end point of adverse events was a combination of death from any cause, MI and severe myocardial ischemia requiring urgent revascularization by means of coronary bypass surgery or percutaneous intervention within 30 days of intervention. Myocardial infarction was defined as new abnormal Q waves on the electrocardiogram (Q wave MI) or a value of creatine kinase or its MB isoenzyme at least three times the upper limit of normal (non-Q wave). Cardiac enzymes were systematically determined after the intervention.
Walter et al. (24) have found a more than five-fold increase of the risk for stent thrombosis in patients with the PlA2 allele. Assuming that about 30% of patients are carriers of the PlA2 allele, the sample size in our study was estimated to provide 80% power for detecting an increase in the risk for adverse events from 6% in PlA1/A1 patients to 10% in those who carry the PlA2 allele.
Statistical analysis.
Discrete variables are expressed as counts and compared with chi-square or Fisher’s exact test as appropriate. Continuous variables are expressed as mean ± SD and compared by means of the unpaired, two-sided t test or analysis of variance for comparisons of more than two groups. The independent association between the presence of the PlA2 allele and adverse events was assessed after adjusting for other factors using a multiple logistic regression analysis. The risk associated with each factor was assessed on the basis of the respective odds ratio and the corresponding 95% confidence interval (CI). All statistical analyses were performed using S-Plus software (Mathsoft, Inc., Seattle, Washington). Statistical significance was assumed for p values <0.05.
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Results
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Baseline characteristics.
Of the 1,759 patients included in this study, 1,234 (70.2%) were PlA1/A1, 479 (27.2%) were PlA1/A2 and 46 (2.6%) were PlA2/A2 patients. The genotype distribution was in Hardy-Weinberg equilibrium (33). The allele frequency was 83.8% for PlA1 and 16.2% for PlA2. Table 1 shows the baseline clinical characteristics of the patients according to the PlA genotype. There was only a trend for PlA2/A2 patients to be older than patients of other genotypes, with all other characteristics being similarly distributed. Ticlopidine could not be given or was prematurely discontinued only in <1% of the patients. Of note, abciximab was given in a comparable proportion among the three groups. Table 2 shows the angiographic and procedural characteristics of the study patients. Except for a trend in PlA2/A2 patients to have a slightly less severe diameter stenosis before the intervention, all other parameters were similar between patients with different PlA genotype. In addition, there was no significant difference related to the type of stent inserted into the coronary artery (p = 0.29), and the postprocedural results were also comparable as shown by the final MLD and diameter stenosis and the proportion of substantial residual dissections.
PlA genotype and outcome after stenting.
The first analysis consisted in comparing the adverse event rates between PlA2 carriers and homozygous individuals for the PlA1 allele. There were no significant differences for the parameters analyzed. The composite end point of death, MI and urgent revascularization was observed in an almost identical proportion of patients: 5.5% of PlA2 carriers and 5.4% of homozygous PlA1 subjects, p = 0.94. Death or MI was observed in 5.0% of PlA2 carriers and 4.3% of PlA1/A1 individuals, p = 0.54. Platelet antigen 2 allele carriers had an incidence of angiographic stent thrombosis of 2.1%, which was not significantly different from that of 1.7% observed among homozygous carriers of the PlA1 allele (p = 0.57). Table 3 contains more detailed information about the incidence of adverse events according to PlA genotype. For all parameters shown in this table, homozygous PlA2 patients had either a clear trend or a significantly higher adverse event rate as compared with patients of the other two genotypes. Highlighting the main results shown in Table 3, the primary end point was reached in 5.4% of the PlA1/A1 patients, 4.8% of the heterozygotes and 13.0% of the PlA2 homozygotes (p = 0.06). The combined incidence of death or MI was 4.3% in PlA1/A1 patients, 4.2% in heterozygotes and 13.0% among PlA2 homozygotes (p = 0.02). The most significant difference was observed in the incidence of angiographic stent thrombosis, which was 1.7% in PlA1/A1 patients, 1.5% in heterozygotes and 8.7% among PlA2 homozygotes (p = 0.002). None of the PlA2 homozygotes with stent thrombosis had a substantial residual dissection after the procedure. The patients with stent thrombosis who carried the PlA2 allele tended to be younger than those PlA1 homozygotes who also incurred stent thrombosis (61.3 ± 10.5 vs. 67.3 ± 8.1 years, respectively, p = 0.08).
Two subset analyses were also performed for patients who did not receive abciximab therapy and for women. The main results of these analyses are displayed in Table 4 and are concordant with the results observed in the entire population (Table 3).
To adjust for potential influences of other clinical, angiographic and procedural factors, we constructed two multivariate models for our end point of an adverse 30-day outcome. All variables that in the univariate analysis differed with a p < 0.20 among patients with different PlA genotype (Tables 1 and 2: age, active smoking, MLD and diameter stenosis before the intervention) were entered into these models. Because of the strong predictive role of the antithrombotic therapy and final procedural results for early major adverse events (31), we also included the antithrombotic treatment (ticlopidine, abciximab) and the presence or absence of substantial residual dissection after the procedure. In addition, the first model contained the presence or absence of PlA2 allele. No increased risk for an adverse outcome was associated with the presence of PlA2 allele since the model yielded an odds ratio of 1.02 (95% CI, 0.65–1.60) for this factor. The second model contained the genotype of patients. The model identified the PlA2/A2 genotype to be independently associated with an adverse outcome after stenting with an odds ratio of 2.55 (1.03–6.34) as compared with the PlA1/A1 genotype.
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Discussion
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Previous evidence.
The presence of the PlA2 allele can potentially influence both platelet activation and aggregation (34). In fact, epinephrine and adenosine diphosphate-induced platelet aggregability was enhanced in patients with PlA2 allele (19,20). The first evidence of the potential clinical relevance of PlA polymorphism came from the study of Weiss et al. (10), in which a significant association between this inherited factor and the risk of acute coronary syndromes was found. Subsequently, conflicting results on this association were reported (11–15,17) indicating not only the complexity of this issue but also that of the mechanisms underlying plaque rupture and thrombosis. Considering the potential link between PlA polymorphism and platelet activation and the key role of platelet activation for the incurrence of stent thrombosis (22,35), investigation of the relationship between this polymorphism and the procedural risk of coronary stent implantation seems well motivated. The first study on this issue included 318 patients with coronary stenting (24). Eleven of the patients in the latter study incurred stent thrombosis, which was observed five times more frequently in carriers of PlA2 allele (24). On the basis of these findings, the authors concluded that the presence of PlA2 allele in patients undergoing coronary stent placement provides a rationale for selectively starting aggressive antiplatelet therapy despite the risk of increased bleeding complications (24). Two issues should, however, be taken into consideration with regard to this recommendation: first, the limited number of patients, particularly in view of the expected rare occurrence of the end point in the study above (24), second, Walter et al. (24) report findings in a population that present an unusual PlA genotype distribution characterized by the complete absence of homozygote PlA2. A more recent study on the same issue found no association between the presence of PlA2 allele and the risk for an adverse 30-day outcome in 653 patients with various percutaneous interventions (25). The incidence of the composite end point of death, MI and revascularization in the 280 stented patients in the latter study was 7.6% among the 184 homozygous carriers of the PlA1 allele and 10.8% among the 74 carriers of the PlA2 allele; the 42% risk increase in the presence of the PlA2 allele did not reach statistical significance (25). Summarizing the above findings, the issue of the potential influence of PlA polymorphism on the early outcome of patients with coronary stent placement has remained largely not clarified.
Present study.
We evaluated the impact of PlA polymorphism on the procedural risk in a large consecutive series of patients undergoing coronary stent placement for stable or unstable angina pectoris. Genotype distribution complied with Hardy-Weinberg equilibrium and was similar to that reported previously (14,15,28,29). The main finding of this study was that the isolated presence of PlA2 allele in heterozygous patients was not associated with an increase in the risk for an adverse 30-day outcome. We recognize the potential influence of the antithrombotic poststenting therapy in this negative finding. The combination of ticlopidine and aspirin has been effective in reducing the risk of stent thrombosis (36) and may have attenuated a possible impact originating from the presence of only one PlA2 allele in the gene coding for GP IIIa. Abciximab was administered only in a small number of high risk patients ( 12%) and might not be considered responsible for the lack of association; the results obtained in patients who did not receive abciximab were in line with the overall findings of our study.
Another finding of this study is the strong trend toward an association between PlA2 homozygosity and risk of an adverse outcome after stenting. Epinephrine and adenosine diphosphate induced aggregation was more enhanced for platelets of homozygous carriers than for platelets of heterozygous carriers of the PlA2 allele (19). Thus, we can speculate that, although the antithrombotic poststenting therapy may have been able to suppress the negative effect of a single PlA2 allele, the additive impact of two PlA2 alleles in homozygous patients may have surpassed this ability and resulted in the increase in stent thrombosis rate. Platelet antigen polymorphism has been associated with a differential responsiveness to antithrombotic drugs (37) so that differences in poststenting therapy should be taken into consideration before comparing the results of the studies that assessed the relation between PlA polymorphism and thrombotic events after stenting. The standard antithrombotic therapy in the study of Walter et al. (24) comprised daily doses of 100 mg aspirin and 250 mg ticlopidine for four weeks after stenting, and oral anticoagulants were given in 6% of the patients. Laule et al. (25) treated all their stented patients with a daily regime of 100 mg aspirin plus 500 mg ticlopidine for four weeks as well. We used an antiplatelet therapy similar to that of Laule et al. (25) except for an aspirin dose twice as high and the provisional administration of abciximab in 12% of the cases.
In interpreting the association between PlA2 homozygosity and thrombotic events after stenting, we should take into account the rare frequency of this genotype in the general population. This limits not only the power of this study but also the clinical significance of PlA2 homozygosity for patients undergoing coronary stent placement. With only 46 PlA2 homozygote patients encompassed in our study, we should be very cautious in drawing any conclusion for this specific genotype. In addition, we should also emphasize here that, although this study includes the largest series of patients with stent implantation and PlA genotyping, our study design gave sufficient power only to detect a relatively large difference of 67% in the adverse event rates between PlA2 carriers (heterozygotes and homozygotes) and PlA1/A1 patients.
Conclusions.
The isolated presence of the PlA2 allele in heterozygous patients is not associated with any detectable increase in the risk for an adverse 30-day outcome in patients undergoing coronary stent placement and treated with a combined therapy of ticlopidine plus aspirin. This study suggests also that an increased risk is likely to be present in homozygous carriers of the PlA2 allele, but this should be confirmed in a much larger series of patients. The low frequency with which PlA2 homozygosity is encountered in the general population attenuates, however, its clinical significance as a risk factor for thrombotic events after coronary stent implantation.
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Abstract
Methods