| BackgroundSeveral studies have demonstrated wide inter-individual variability in the pharmacodynamic response to clopidogrel. Observational studies have linked a poor pharmacodynamic response to cardiovascular events after percutaneous coronary intervention (PCI), including death, recurrent myocardial infarction, stroke, or stent thrombosis. Genetic factors were considered as one of the mechanisms for clopidogrel hyporesposiveness. Effect of the ABCB1, CYP2C19, CYP3A4, CYP3A5, and P2Y12variants on platelet reactivity and clinical outcomes of clopidogrel has not been reported in Chinese patients undergoing PCI.ObjectivesThe aim of this study was to investigate the effect of the ABCB1, CYP3A4, CYP3A5, and P2Y12variants on clopidogrel pharmacodynamics and clinical outcomes in these patients.Methods1408patients undergoing stent implantation were enrolled in a single-center registry. The ABCB1, CYP2C19, CYP3A4, CYP3A5, and P2Y12genotypes were detected by the improved multiple ligase detection reaction, and the antiplatelet effect of clopidogrel were assessed by thrombelastography. Primary clinical endpoint was defined as major adverse cardiovascular events (MACE), which included the composite of all-cause death, nonfatal myocardial infarction, target vessel revascularization, or stent thrombosis. The secondary clinical endpoints were all-cause death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis during12-month follow-up.ResultsThe carriage of the CYP2C19loss-of-function alleles was relatively high (59.3%).62(4.4%) patients had MACE during12-month follow-up. The lowest risk of response to clopidogrel (55.4±30.5vs.52.0±30.0vs.44.6±31.1; P=0.001) and the highest incidence of MACE (2.8%vs.4.9%vs.7.5%; P=0.016) increased with the number of CYP2C19loss-of-function alleles. In the multivariate Cox regression analysis, two CYP2C19LOF alleles (HR=2.962,95%CI:1.426-6.152, P=0.004) were associated with MACE compared with noncarriers; the carriers of one CYP2C19LOF allele (HR=1.833;95%CI:0.986-3.406; P=0.055) were not associated with MACE compared with noncarriers. However, there were no significant differences in clopidogrel pharmacodynamics and adverse ischemic events across the ABCB1, CYP3A4, CYP3A5and P2Y12genotype groups (P>0.05).ConclusionsThe CYP2C19loss-of-function alleles had a gene dose effect on the clopidogrel pharmacodynamics and major adverse cardiovascular events in our population. The carrage of two CYP2C19LOF alleles was an independent predictor of major adverse cardiovascular events in patients undergoing PCI during follow-up period. The antiplatelet effect and adverse clinical outcomes of clopidogrel were not significantly influenced by ABCB1, CYP3A4, CYP3A5and P2Y12genotype in these patients. BackgroundPatients exhibiting heightened platelet reactivity to adenosine diphosphate (ADP) might be at increased risk for recurrent ischemic events after coronary stenting. Several platelet function tests are currently used to measure responsiveness to antiplatelet therapy.However, which test can be best to detect platelet function specifically and predict clincial outcomes was still uncertain. High on-treatment platelet reactivity of Chinese patients is still no uniform diagnostic criteria.ObjectivesThe aim of our study was to whether patients receiving clopidogrel undergoing stenting who display high on-treatment platelet reactivity measured by light transmittance aggregometry (LTA) and thrombelastography (TEG) will be at increased risk for poststenting ischemic events.MethodsProspective, observational, single-center study of789Chinese patients underwent stent implantation. This study was investigated the correlations between the2tests (LTA and TEG) and performed receiver operating characteristic curve (ROC) analysis for major adverse cardiovascular events (MACE), a composite of death, myocardial infarction (MI), stent thrombosis, or target vessel revascularization, at1-year follow-up.ResultsMajor adverse cardiovascular events occurred in32patients (4.1%), including5patients with recurrent MI,3patients with stent thrombosis, and26patients with target vessel revascularization. Correlations were strong between the2tests in the adenosine diphosphate induced platelet reactivity (Spearman r=0.733, P<0.001). ROC-curve analysis demonstrated that LTA (area under the curve [AUC],0.677;95%confidence interval [CI],0.643-0.710; P=0.0009), and TEG assay (AUC,0.684;95%CI,0.650-0.716; P=0.0001) had moderate ability to discriminate between patients with and without MACE at1-year follow-up. MACE occurred more frequently in patients with high on-treatment platelet reactivity (HTPR) when assessed by LTA (7.4%vs.2.7%; P=0.003), and by TEG (6.7%vs.2.6%; P=0.005). Kaplan-Meier analysis demonstrated that HTPR based on the LTA and modified TEG was associated with almost4-fold increased risk of MACE at1-year follow-up (HR:2.752,95%CI:1.360-5.569, P=0.005; HR:2.601;95%CI:1.279-5.290, P=0.008; respectively).Conclusions The ADP-induced platelet aggregation by LTA and TEG showed a strong correlation. Hypo-responsiveness to clopidogrel measured by light transmittance aggregometry, and modified thrombelastography were significantly associated with MACE in Chinese patients undergoing stenting. However, the predictive accuracy of these two tests was moderate. BackgroundRoutine assessment of CYP2C19genotyping or platelet function after clopidogrel, which can be used to risk-stratify patients with coronary artery disease receiving stenting implantation, is still debated. We hypothesized that an aggregate risk evaluated by CYP2C19genotyping combined with platelet reactivity by thrombelastograph (TEG) platelet-mapping assay would be a powerful predictor of recurrent cardiovascular ischemic events.ObjectiveThis study sought to determine an integrate results evaluated by CYP2C19genotyping combined with platelet reactivity by TEG for enhanced prediction of major adverse cardiovascular events in Chinese patients undergoing coronary stenting with clopidogrel.Methods1104Chinese patients undergoing coronary stenting were enrolled in a single-center registry. CYP2C19genotyping (s4244285and rs4986893) were detected by the improved multiple ligase detection reaction. Platelet function testing were performed by thrombelastograph platelet-mapping assay. High on-treatment platelet reactivity (HTPR) was defined as cutoff values of ADP inhibition≤30%assessed by the TEG. Major adverse cardiovascular events (MACE) included the composite of all-cause death, nonfatal myocardial infarction, target vessel revascularization, or stent thrombosis. The follow-up period was12months.Results47patients (4.3%) had major adverse cardiovascular events. In the multivariate Cox regression analysis, carriers of CYP2C19loss-of-function alleles (*1/*2,*1/*3,*2/*2,*2/*3, and*3/*3) were increased nearly2.2-fold risk of MACE compared with noncarriers (HR:2.195,95%CI:1.035-4.658, P=0.04); HTPR were increased almost2.2-fold risk of MACE compared with normal on-treatment platelet reactivity (HR:2.218,95%CI:1.131-4.351, P=0.02). In the multivariate Cox regression analysis after an integrate results evaluated by CYP2C19genotyping combined with platelet reactivity by TEG,2positive results (carriers of CYP2C19loss-of-function alleles and HTPR) were significantly increased almost3.8-fold of the risk of MACE compared with0positive results (noncarriers of CYP2C19loss-of-function alleles and normal on-treatment platelet reactivity)(HR:3.777,95%CI:1.508-9.461, P=0.005). Adding the integrate results to conventional clinical predictors improved prediction trend for1-year MACE as measured by the area under the ROC curve (AUC, from0.67to0.73; P=0.074), and the net reclassification improvement (NRI=27.7%; P=0.003)/integrated discrimination improvement (IDI=0.016; P=0.013).ConclusionsThe integrate results evaluated by CYP2C19genotyping combined with platelet reactivity by TEG is an independent and additive predictor of1-year MACE in Chinese patients undergoing stenting with clopidogrel, which is better than the either single testing (CYP2C19genotyping or platelet function testing). |
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