Clopidogrel resistance response in patients with coronary artery disease and metabolic syndrome： the role of hyperglycemia and obesity

Background Despite the proven benefits of clopidogrel combined aspirin therapy for coronary artery disease （CAD）, CAD patients with metabolic syndrome （MS） still tend to have coronary thrombotic events. We aimed to investigate the influence of metabolic risk factors on the efficacy of clopidogrel treatment in patients with CAD undergoing percutaneous coronary intervention （PCI）. Methods Cohorts of 168 MS and 168 non-MS subjects with CAD identified by coronary angiography （CAG） were enrolled in our study. MS was defined by modified Adult Treatment Panel Ⅲ criteria. All subjects had taken 100 mg aspirin and 75 mg clopidogrel daily for more than 1 month, and administered loading doses of 600 mg clopidogrel and 300 mg aspirin before PCI. Blood samples were taken 24 h after the loading doses of clopidogrel and aspirin. Platelet aggregation was measured using light transmittance aggregometry （LTA） and thrombelastography （TEG）. Clopidogrel resistance was defined as more than 50% adenosine diphosphate （ADP） induced platelet aggregation as measured by TEG. Re- sults Platelet aggregation inhibition rate by ADP was significantly lower in patients with MS as measured both by TEG （55% ＋ 31% vs. 68% ± 32%; P 〈 0.001） and LTA （29% ± 23% vs. 42% ± 29%; P 〈 0.001）. In the multivariate analysis, elderly [OR （95% CI）： 1.483 （1.047±.248）; P = 0.002], obesity [OR （95% CI）： 3.608 （1.241-10.488）; P = 0.018], high fasting plasma glucose level [OR （95% CI）： 2.717 （1.176±.277）; P = 0.019] and hyperuricemia [OR （95% CI）： 2.583 （1.095-6.094）; P = 0.030] were all statistically risk factors for clopido- grel resistance. CAD patients with diabetes and obesity were more likely to have clopidogrel resistance than the CAD patients without dia- betes and obesity [75% （61/81） vs. 43% （67/156）; P 〈 0.001]. Conclusions CAD patients with MS appeared to have poorer antiplatelet response to clopidogrel compared to those without MS. Obesity, diabetes and hyperuricemia were all significantly associated with clopido- grel resistance.

Relation of cytochrome P450 2C19 gene 681G>A single nucleotide polynmrphism to clopidogrel resistance after PCI in Chinese

Objectives Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450(CYP) isoenzymes to inhibit platelet aggregation.Individualvariability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness.In this study,we sought to determine the association between the single nucleotide polymorphism of CYP 2C19 681G】A and the occurrence of clopidogrel resistance(CR) in Chinese.Methods The study enrolled 614 hospitalized patients who underwentsuccessful percutaneouscoronary intervention with drug-eluting stents were received the treatmentwith dual antiplatelet regimen(aspirin plus clopidogrel).All patients received loading doses of 600 mg clopidogrel and 300 mg aspirin.20μmol/L ADP-induced platelet aggregation ratio(PAR ) was assessed 24 h after clopi- dogrel administration.The maximum residual PAR≥70%was defined as CR.Genomic DNA was extracted from whole blood samples according to standard protocols,the single nucleotide polymorphism of the CYP2C19 681G】A was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in all the patients.Results CR was found in 126 patients(20.5%).There was CYP2C19 681G】A polymorphism in the study population.The frequencies of the three kinds of genotypes(GG,GA,A A) in CR group and non-CR (NCR)group were 32.5%,47.6%,19.8%and 48.0%, 45.0%,7.0%,respectively.The frequency of AA genotype was significantly higher in NCR group than that in CR group (OR =3.03,95%CI:1.889～5.784,P=0.003).The A allele carriers were more likely to develop clopidogrel resistance compared with that of G allele carriers(OR=1.85,95%CI: 1.392～2.459,P=0.002).Conclusions CYP2C19 681G/A polymorphism is associated with the risk of CR,and the A allele carriers may be a possible genetic susceptibility factor for patients with CR.

CYP2C19＊2, CYP2C19＊3, CYP2C19＊17 Allele and Genotype Frequencies in Clopidogrel-Treated Patients with Coronary Heart Disease in Russian

Individual variation in the response to drug therapy has been mainly attributed to the genetic polymorphism of cytochrome P 450 isoenzymes. Mutation in the gene CYP2C19 （cytochrome P450 2C19） has been shown to influence the clinical efficiency of clopidogrel. The aim is to investigate the frequencies of CYP2C19＊2 （c.G681A; rs4244285）, CYP2C19＊3 （c.G636A; rs4986893）, CYP2C19＊17 （c.C806T; rs12248560） and to compare the allele and genotype frequencies of CYP2C19＊2 in patients with CHD （coronary heart disease） to healthy volunteers. We examined 53 patients with CHD received clopidogrel and 146 healthy volunteers. CYP2C19＊2, CYP2C19＊3, CYP2C19＊17 carriages were determined by a polymerase-chain reaction. The observed genotype distribution did not deviate from Hardy-Weinberg equilibrium, it was determined by a Chi-square test with Yates correction. The frequency of CYP2C19＂2 allele reported in patients with CHD and in the healthy volunteers was 16.6% and 13.3%, respectively （P = 0.584）. The results of the present study may be helpful in developing current and future directions for its management.

CYP2C19＊2 and Other Allelic Variants Affecting Platelet Response to Clopidogrel Tested by Thrombelastography in Patients with Acute Coronary Syndrome

Background：To investigate the contributions ofCYP2C 19 polymorphisms to the various clopidogrel responses tested by thrombelastography （TEG） in Chinese patients with the acute coronary syndrome （ACS）.Methods：Patients were screened prospectively with ACS diagnose and were treated with clopidogrel and aspirin dual antiplatelet therapy.CYP2C 19 loss of function （LOF） and gain of function （GOF） genotype,adenosine 5＇-diphosphate （ADP）-channel platelet inhibition rate （PIR） tested by TEG and the occurrence of 3-month major adverse cardiovascular events and ischemic events were assessed in 116 patients.Results：High on-treatment platelet reactivity （HTPR） prevalence defined by PIR 〈30% by TEG in ADP-channel was 32.76% （38/116）.With respect to the normal wild type,CYP2C 19＊2,and ＊3 LOF alleles,and ＊ 17 GOF alleles,patients were classified into three metabolism phenotypes：41.38% were extensive metabolizers （EMs）,56.90% were intermediate metabolizers （IMs）,and 1.72% were poor metabolizers （PMs）.Of the enrolled patients,31.47%,5.17%,and 0.43%,respectively,were carriers of ＊2,＊3,and ＊ 17 alleles.The HTPR incidence differed significantly according to CYP2C 19 genotypes,accounting for 18.75%,41.54%,and 100.00% in EMs,IMs,and PMs,respectively.Eighteen （17.24%） ischemic events occurred during the 3-month follow-up,and there was a significant difference in ischemic events between HTPR group and nonhigh on-treatment platelet reactivity group.Conclusions：Genetic CYP2C 19 polymorphisms are relative to the inferior,the antiplatelet activity after clopidogrel admission and may increase the incidence of ischemic events in patients with ACS.

Earlier application of loading doses of aspirin and clopidogrel decreases rate of recurrent cardiovascular ischemic events for patients undergoing percutaneous coronary intervention

Background Aspirin and clopidogrel resistance plays a significant role in the development of cardiovascular ischemic events for ninety patients undergoing percutaneous coronary intervention.Recent studies have indicated that increasing the dose of antiplatelet drugs maybe a potent method to improve the inhibition of platelet aggregation.Methods Thrombelastograph （TEG） determinations were used to evaluate the effect of antiplatelet therapy.According to the results,90 patients were divided into three groups and given different doses of aspirin and clopidogrel.Thirty patients with both an inhibition rate of aspirin 〉50% and an inhibition rate of clopidogrel 〉50% were defined as the control group.Sixty patients with an inhibition rate for aspirin 〈50% and an inhibition rate for clopidogrel 〈50% were defined as the resistance group.Patients in resistance group were randomly assigned to be given a routine dose （100 mg aspirin plus 75 mg clopidogrel per day,which we called a resistance plus routine dose group,R＋R） and a loading dose （200 mg aspirin and 150 mg clopidogrel per day,which we called resistance plus loading dose group,R＋L） of antiplatelet therapy.A 12-month follow-up was observed to examine the change of inhibition rate of antiplatelet therapy and to estimate the relationship between inhibition rate and the occurrence of cardiovascular ischemic events.Results After 6 months of antiplatelet therapy,the inhibition rate of aspirin in the R＋L group increased from （31.4±3.7）% to （68.6±7.1）%,which was significantly higher than that in R＋R group,（51.9±8.2）% （P 〈0.01）.The inhibition rate of clopidogrel in the R＋L group increased from （22.1±3.8）% to （60.2±7.4）%,which was significantly higher than in the R＋R group,（45.9±4.3）% （P 〈0.01）.The occurrence rates of cardiovascular ischemic events,stent thrombosis,recurrent unstable angina and myocardial infarction in the R＋R group were 20%,36% and 17%,respectively.Occurrence was significantly increased compared with that in the control group,3%,10% and 1%,respectively （P 〈0.01）.In contrast,the occurrence rates in the R＋L group （10%,23% and 6%,respectively） were attenuated compared with those in the R＋R group （P 〈0.01 ）,although still higher than in the control group （P 〈0.01）.Conclusions Almost all of the cardiovascular ischemic events occurred in the first six months after percutaneous coronary intervention.According to the result of TEG determinations,earlier application of a loading dose of aspirin and clopidogrel can decrease the rate of recurrent cardiovascular ischemic events.

Subacute coronary stent thrombosis in a patient with angina treated with double antiplatelet drugs for six days

Stent implantation has been a great advance in percutaneous coronary intervention （PCI）, decreasing the frequency of acute closure and restenosis. But stent thrombosis is a severe complication of this therapy regardless of the stent type： bare-metal stent （BMS） and drug-eluting stent （DES）. According to the timing after initial PCI, stent thrombosis is considered as acute when occurring between 0 hour and 24 hours after stent implantation, subacute between 24 hours and 30 days,