| Objective:Our study aimed to establish and validate the risk scores for highon-treatment platelet reactivity(HTPR) and cardiovascular events in Chinese Hanpatients with acute coronary syndrome (ACS) treated with stable clopidogrel.Methods: Consecutive patients admitted for ACS were enrolled from September2011to June2013. Light transmittance aggregometry (LTA) examination was applied toevaluate the platelet aggregation.Polymerase chain reaction-ligase detection reaction(PCR-LDR)was applied to genotype candidate single nucleotidepolymorphisms(SNP), including CYP2C19*2、CYP2C19*3、CYP2C19*17、PON1Q192R and ABCB1C3435T for each patient. The occurrence of adversecardiovascular events was followed up forone year. Relationships between the SNPsand HTPR, as well as theadverse cardiovascular events were analyzed. Patients werethen allocated randomly into model derivation group and validation group,respectively.In the derivation group, independent risk factors for HTPR and compositecardiovascular events were evaluatedby multivariate logistic regression.Model A wasset up based on both genetic and clinical factors, and Model B based merely onclinical factors.In the validation group, receiver operator characteristic curve(ROC)and Hosmer-Lemeshow testing were utilized to assess the performance of theconstructed models in comparision with a previous published PREDICT model.Results:(1) A total of589cases were enrolled in the present study, with500of themcompleting the one-year follow-up.Compared with non-carriers, CYP2C19loss-of-function (LOF) allele(*2and*3) carriers had both higher risk for HTPR andcomposite cardiovascular events [HTPR：adjusted OR1.79,95%CI:1.33–2.4, P=0.003.Composite cardiovascular events: adjusted OR2.4;95%CI1.47-3.9, P<0.001].(2)To establish the risk score system for HTPR, patients were then allocated randomlyinto model derivation group (n=300)and validation group(n=289).In the derivationgroup, Model A was constructed with score3for CYP2C19*2（OR：3.07,95%CI：1.96-4.81，P<0.001）, diabetes（OR：2.69,95%CI：1.49-4.84，P=0.001）, and high LDL（OR：2.78,95%CI：1.34-5.76，P=0.006）respectively, and score1forco-medication of calcium channel blocker (OR：1.3,95%CI：1.12-1.53，P=0.001).In the validation group, area under the curve(AUC) of ROC was0.73. The sensitivityand specificity was68%and71%, respectively. The threshold of the score for theincreased risk of HTPR wasscore4. No significant difference was found between theModel A predicted and actual risk for HTPR (P=0.18). In comparision with ModleB(including only clinical factors) and the previous published PRIDICT score, modelA couldpredict the risk for HTPR more accurately.(3) To establish the risk score system for composite cardiovascular events, patientswere then allocated randomly into model derivation group (n=300)and validationgroup(n=153). In the derivation group, Model A was constructed withscore3forCYP2C19LOF（OR：2.6,95%CI1.62-4.1，P<0.001）, score2for HTPR（OR：2.04,95CI1.07-3.90，P=0.03）and hyperlipidemia（OR：1.99,95%CI：1.05-3.77，P=0.03）respectively, and score1for age≥65（OR：1.07,95%CI1-1.21，P=0.03）and smoking（OR1.4，95%CI：1.02-1.93，P=0.04）respectively. In the validation group,AUC ofROC was0.76. The sensitivity and specificity was64%and75%, respectively. Thethreshold of the score for the increased risk of composite cardiovasculareventswasscore5. No significant difference was found between the Model A predictedand actual risk for composite cardiovascular events (P=0.12). In comparision withModle B(including only clinical factors) and the previous published PRIDICT score,model A couldpredict the risk for composite cardiovascular events more accurately.Conclusion:CYP2C19LOF polymorphismsare the main genetic risk factors forHTPR and composite cardiovascular events in Chinese-Han ACS patients treated withstable clopidogrel. The risk score systems, based on CYP2C19LOF polymorphismsand related clinical factors,could improve the prediction of the risks for HTPR andcomposite cardiovascular events. |
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