Analysis Of Risk Factors Associated With Platelet Hyperresponsiveness After Interventional Therapy In Chinese Patients With Coronary Heart Disease

Background:Dual antiplatelet therapy with aspirin and clopidogrel is the corner stone of treatment for patients with acute coronary syndrome(ACS)or those undergoing percutaneous coronary intervention(PCI).However,platelet reactivity during antiplatelet therapy displays considerable inter-individual variability.Some patients do not acquire adequate platelet inhibition from antiplatelet drugs like aspirin and clopidogrel,resulting in high on-treatment platelet reactivity(HTPR).Genetics is known to contribute to such variability in drug response.Platelet endothelial aggregation receptor-1(PEAR1)is a recently reported platelet transmembrane protein which plays an important role in platelet aggregation.The aim of this study was to investigate whether PEAR1 genetic variations were associated with platelet reactivity as assessed by adenosine diphosphate(ADP)-induced platelet aggregation in Chinese patients treated with aspirin and clopidogrel.Methods:Patients with coronary heart disease who underwent percutaneous coronary intervention from November 2011 to March 2013 in our hospital were enrolled in the study.All patients were on dual antiplatelet therapy with aspirin and clopidogrel.ADP-induced platelet aggregation was measured by thromboelastography and defined as percent inhibition of platelet aggregation(I PA).Patients with I PA less than 30%were identified as high on-treatment platelet reactivity(HTPR).Patients with IPA greater than 70%were identified as low on-treatment platelet reactivity(LTPR).Based on previous reports and the results of HapMap(http://hapmap.ncbi.nlm.nih.gov/)Chinese Han Beijing Databank with the aid of Haploview 4.2 software,sixteen single nucleotide polymorphism(SNP)of PEAR1 were selected for analysis.SNPs of PEAR1 were determined by a method of improved multiple ligase detection reaction.Results:In our cohort,there were 204 patients with high on-treatment platelet reactivity and 201 patients with low on-treatment platelet reactivity.Among the 16 SNPs examined by univariate analysis,5 SNPs were significantly associated with ADP-induced platelet aggregation.In univariate analysis with dominant model,minor allele C at rs11264580(p=0.033),minor allele G at rs2644592(p=0.048),minor allele T at rs3737224(p=0.033),minor allele T at rs41273215(p=0.025)and haplotype C-G-T-T-C(p=0.034)were strongly associated with HTPR,whereas in recessive model,homozygous TT genotype at rs57731889(p=0.009)and haplotype T-A-C-C-T(p=0.009)were associated with LTPR.Multivariate logistic regression analysis further revealed that the minor allele T at rs41273215(p=0.038)was an independent predictor of HTPR and the homozygous TT genotype at rs57731889(p=0.003)was an independent predictor of LTPR.Conclusions:(1)PEAR1 genetic variations were strongly associated with ADP-induced platelet aggregation in Chinese patients with coronary heart disease treated with aspirin and clopidogrel;(2)Changes at different sites of PEAR1 gene differentially affect platelet reactivity;(3)rs41273215 related to HTPR whereas rs57731889 related to LTPR.Background:Thrombosis is a core cause of acute coronary syndrome.Platelet is the main composition of thrombus,and its adhesion,activation and aggregation plays an important role in thrombosis,so antiplatelet therapy has become the cornerstone of treatment for preventing thrombosis and reducing clinical adverse events.However,clinical practice found that antiplatelet efficacy in patients displays considerable inter-individual variability,some patients display resistance to aspirin and clopidogrel which may lead to poor curative effect and clinical adverse ischemic events.Platelet endothelial aggregation receptor 1(PEAR1)is a platelet transmembrane protein which plays an important role on platelet aggregation.The aim of our study is to investigate whether PEAR1 genetic variations associated with 1-year outcomes in the Chinese acute myocardial infarction patients after percutaneous coronary intervention.Methods:Patients with acute myocardial infarction underwent percutaneous coronary intervention from November 2011 to March 2013 in our hospital and under dual antiplatelet therapy with aspirin and clopidogrel were enrolled in the study.Single nucleotide polymorphism(SNP)of PEAR1 related to high on-treatment platelet reactivity(P<0.1)found by our previous study were enrolled for analyzing the association with clinical outcomes.SNPs were detected by the method of improved multiple ligase detection reaction.Clinical follow-up period was 12 months by the method of readmission records,outpatient records and telephone records.The follow-up events including all-cause death,cardiac death,myocardial infarction,unplanned revascularization and stent thrombosis.Composite ischemic events defined as the composite endpoint including cardiac death,myocardial infarction,unplanned revascularization and stent thrombosis.Results:A total of 647 patients with acute myocardial infarction were included in the study.On the basis of our previous findings,6 PEAR1 SNPs related to high on-treatment platelet reactivity with P value<0.1 were included in the study for analysis,including rs11264580,rs2644592,rs3737224,rs41273215,rs56260937 and rs822442.In the 1 year follow-up,66(10.2%)adverse clinical events occurred:8 cases(1.2%)of all-cause death,4 cases(0.6%)of cardiac death,6 cases(0.9%)of myocardial infarction,61 cases(9.4%)of unplanned reascularization,there were no stent thrombosis occured.In recessive model analysis,when compared to major allele carriers,minor allele homozygote TT genotype at rs56260937 had a significantly higher incidences of unplanned reascularization(16.7%vs 8.6%,P=0.034).Further multivariate Cox regression analysis showed that carriage of rs56260937 minor allele homozygote TT genotype was a independent risk factor of unplanned reascularization(HR=2.09,95%CI 1.07-4.06,p=0.031)after adjusting confound factors.Conclusions:(1)PEAR1 genetic polymorphisms were significantly associated with 1-year clinical outcomes in the Chinese patients with acute myocardial infarction after percutaneous coronary intervention;(2)Minor allele homozygote TT genotype at rs56260937 was a independent risk factor of unplanned reascularization;(3)The genetic testing of PEAR1 variants can be valuable in guiding clinical individualized antiplatelet therapy,so as to improve the clinical prognosis.Background:Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome.However,a considerable number of patients display poor response to antiplatelet drugs,which lead to a higher risk of high on-treatment platelet reactivity(HTPR).By now,there has been cumulative evidence pointed out that clinical factors are known to contribute to variability in drug response.So our study aim to analyze clinical factors associated with HTPR and construct a risk score for predicting HTPR based on clinical variables that are easily available in daily routine.The present risk score may help to do a comprehensive assessment about the platelet reactivity and indicate patients who tend to have HTPR quickly and conveniently without taking additional tests and cost,so as to guide individualized antiplatelet therapy.Methods:Patients admitted to Fuwai Hospital between January 2013 and December 2013 with acute coronary syndrome underwent percutaneous coronary intervention and on dual antiplatelet therapy with aspirin and clopidogrel were enrolled in the study.Adenosine diphosphate(ADP)induced platelet reactivity was measured by Thromboelastography(TEG),the definition of HTPR was ADP-induced platelet-fibrin clot strength(MAADP)>47mm.Clinical factors available in daily routine were analyzed in univariate and multivariate logistic regression analysis to determine the independent risk factors associated with HTPR.For continuous variables,we converted them to categorical variables based on cut-off values accepted by clinical practice.Clinical factors with a significance level of P<0.05 independently related to HTPR were included in risk score model and scoring variables based on odds ratio(OR)values,thus established a clinical risk sore.Patients were followed up 24-month after percutaneous coronary intervention by the method of readmission records,outpatient records and telephone records.The follow-up clinical events including all-cause mortality,cardiac death,myocardial infarction,unplanned revascularization,stent thrombosis and stroke.Results:A total of 2511 patients with acute coronary syndrome underwent percutaneous coronary intervention and on dual antiplatelet therapy with aspirin and clopidogrel were enrolled in the study.There were 781(31.10%)patients with HTPR in our cohort.After univariate and multivariate logistic regression analysis,five clinical factors were independently associated with HTPR and scoring them according to their OR values:reduced renal function(Scr>133umol/L,OR=3.06,95%C11.28-7.32)was weighted by score 3;female(OR=2.84,95%CI 2.24-3.59)by score 2;diabetes mellitus(OR=1.61,95%CI 1.33-1.95)by socre 1,elevated platelet count(>300×109,OR=1.55,95%CI 1.07-2.25)by socre 1,proton pump inhibitor use(OR=1.25.95%CI 1.02-1.53)by score 1,thus a score ranging from 0-8 was developed to predict HTPR.Patients were divided to three groups according to scores:low risk group(0-2 score),medium risk group(3-5 score),high risk group(6-8 score).The platelet reactivity(TEG-MAADP)were 33.88 ±17.75 mm,45.69±17.05 mm and 50.90±17.80 mm for each group(P<0.001);the rates of HTPR were 587(26.95%),192(58.18%)and 2(66.67%)for each group(P<0.001).There were no statistical differences of clinical events incidences among three groups no matter single events or the composite endpoints.Conclusion:(1)Clinical factors have a significant effect on HTPR,patients with a higher clinical risk score were significantly more likely to present HTPR;(2)Clinical risk score might help to identify patient with high risk of HTPR,so as to guide intensified antiplatelet therapy without additional tests and cost;(3)The risk score established by our study can only predict HTPR,can not predict adverse clinical events.