***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: BACKGROUND It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite . METHODS We genotyped patients from two large , r and omized trials that showed that clopidogrel , as compared with placebo , reduced the rate of cardiovascular events ( the primary efficacy outcome ) among patients with acute coronary syndromes and among patients with atrial fibrillation . Patients were genotyped for three single-nucleotide polymorphisms ( * 2 , * 3 , * 17 ) that define the major CYP2C19 alleles . RESULTS Among 5059 genotyped patients with acute coronary syndromes , clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome , irrespective of the genetically determined metabolizer phenotype ( P=0.12 for heterogeneity ) . The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles ( rate among carriers , 8.0 % with clopidogrel vs. 11.6 % with placebo ; hazard ratio with clopidogrel , 0.69 ; 95 % confidence interval [ CI ] , 0.49 to 0.98 ; rate among noncarriers , 9.5 % vs. 13.0 % ; hazard ratio , 0.72 ; 95 % CI , 0.59 to 0.87 ) . In contrast , gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers ( rate of primary outcome among carriers , 7.7 % vs. 13.0 % ; hazard ratio , 0.55 ; 95 % CI , 0.42 to 0.73 ; rate among noncarriers , 10.0 % vs. 12.2 % ; hazard ratio , 0.85 ; 95 % CI , 0.68 to 1.05 ; P=0.02 for interaction ) . The effect of clopidogrel on bleeding did not vary according to genotypic subgroups . Among 1156 genotyped patients with atrial fibrillation , there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype , loss-of-function carrier status , or gain-of-function carrier status . CONCLUSIONS Among patients with acute coronary syndromes or atrial fibrillation , the effect of clopidogrel as compared with placebo is consistent , irrespective of CYP2C19 loss-of-function carrier status . ( Funded by Sanofi-Aventis and Bristol-Myers Squibb ; Clinical Trials.gov number , NCT00249873 . ) Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite . The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors , but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear . Using in vitro metabolomic profiling techniques , we identified paraoxonase-1 ( PON1 ) as the crucial enzyme for clopidogrel bioactivation , with its common Q192R polymorphism determining the rate of active metabolite formation . We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy .  PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis , lower PON1 plasma activity , lower plasma concentrations of active metabolite and lower platelet inhibition . Thus , we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel . These findings have therapeutic implication s and may be exploited to prospect ively assess the clinical efficacy of clopidogrel CONTEXT Despite dual antiplatelet therapy , stent thrombosis remains a devastating and unpredictable complication of percutaneous coronary intervention ( PCI ) . OBJECTIVE To perform a sequential analysis of clinical and genetic factors associated with definite early stent thrombosis . DESIGN , SETTING , AND PARTICIPANTS Case-control study conducted in 10 centers in France between January 2007 and May 2010 among 123 patients undergoing PCI who had definite early stent thrombosis and DNA sample s available , matched on age and sex with 246 stent thrombosis-free controls . MAIN OUTCOME MEASURE Accuracy of early stent thrombosis prediction by 23 genetic variants . RESULTS Among the 23 genetic variants investigated in 15 different genes , the significant determinants of early stent thrombosis were CYP2C19 metabolic status ( adjusted odds ratio [ OR ] , 1.99 ; 95 % CI , 1.47 - 2.69 ) , ABCB1 3435 TT genotype ( adjusted OR , 2.16 ; 95 % CI , 1.21 - 3.88 ) , and ITGB3 PLA2 carriage ( adjusted OR , 0.52 ; 95 % CI , 0.28 - 0.95 ) . Nongenetic independent correlates were acuteness of PCI ( adjusted OR , 3.05 ; 95 % CI , 1.54 - 6.07 ) , complex lesions ( American College of Cardiology/American Heart Association type C ) ( adjusted OR , 2.33 ; 95 % CI , 1.40 - 3.89 ) , left ventricular function less than 40 % ( adjusted OR , 2.25 ; 95 % CI , 1.09 - 4.70 ) , diabetes mellitus ( adjusted OR , 1.82 ; 95 % CI , 1.02 - 3.24 ) , use of proton pump inhibitors ( adjusted OR , 2.19 ; 95 % CI , 1.29 - 3.75 ) , and higher clopidogrel loading doses ( adjusted OR , 0.73 ; 95 % CI , 0.57 - 0.93 ) . The discriminative accuracy of the clinical -only model was similar to that of a genetic-only model ( area under the curve , 0.73 [ 95 % CI , 0.67 - 0.78 ] vs 0.68 [ 95 % CI , 0.62 - 0.74 ] , respectively ; P = .34 ) . A combined clinical and genetic model led to a statistically significant increase in the discriminatory power of the model compared with the clinical -only model ( area under the curve , 0.78 [ 95 % CI , 0.73 - 0.83 ] vs 0.73 [ 95 % CI , 0.67 - 0.78 ] ; P = .004 ) . CONCLUSIONS This case-control study identified 3 genes ( CYP2C19 , ABCB1 , and ITGB3 ) and 2 clopidogrel-related factors ( loading dose and proton pump inhibitors ) that were independently associated with early stent thrombosis . Future studies are needed to vali date the prognostic accuracy of these risk factors in prospect i ve cohorts AIMS Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases . Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response . We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events . METHODS AND RESULTS A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management , and Avoidance ( CHARISMA ) trial who consented to genotyping was analysed . Patients with clinical ly evident cardiovascular disease or multiple risk factors were enrolled in the trial . The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients r and omized to clopidogrel vs. placebo .  A total of 4819 patients were genotyped and available for the analysis . Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events . However , clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers : 36.1 % ( 240/665 ) vs. 42.5 % ( 681/1601 ) in non-carriers , HR : 0.80 , 95 % CI : 0.69 - 0.93 , P = 0.003 ( genotype/treatment interaction , P-value = 0.023 ) . The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints . CONCLUSION No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with  clopidogrel .  There was , however , significantly less bleeding with clopidogrel in carriers of the loss-of-function allele , suggesting less anti-platelet response . Although several prior studies , including mainly stented patients , have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel , this study of stable patients establishes a potential link with reduced bleeding complications . CLINICAL TRIAL REGISTRATION This study is registered with Clinical Trials.gov number , NCT00050817 Background and objectives A large number of clinical studies have well demonstrated that the loss-of-function variant allele CYP2C19 * 2 is associated with attenuated response to clopidogrel and increased risk of developing stent thrombosis ( ST ) in white or black patients with stenting . However , similar association studies on the effect of the CYP2C19 * 2 and * 3 variants on maximum platelet aggregation ( MPA ) and the risk of cardiovascular events are currently unavailable for the Chinese patients . This work was aim ed at assessing the impact of the CYP2C19 * 2 and * 3 variants on the antiplatelet effects and adverse cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention ( PCI ) . Methods The study population consisted of 617 patients undergoing PCI .  Genotypes were determined using MALDI/TOF-MS . MPA was measured by light transmittance aggregometry . The clinical end-point was the 1-year incidence of adverse cardiovascular events , including ST . Results Carriers of CYP2C19 heterozygous ( * 1/*2 , or * 1/*3 ; n = 278 ) and mutant homozygous ( * 2/*2 , * 2/*3 , or * 3/*3 , n = 80 ) genotypes had significantly higher MPA values than noncarriers ( * 1/*1 ; n = 259 ; P = 0.036 and 0.007 respectively ) . Moreover , the presence of the CYP2C19 * 2 or * 3 mutant allele was significantly associated with an increased risk of developing ST , with the higher risk of ST being seen in patients homozygous for the CYP2C19 * 2 or * 3 variant allele than in noncarriers ( OR , 13.58 ; 95 % CI , 1.49–123.31 ; P = 0.012 ) . Furthermore , multivariate analysis revealed an independent association of the presence of CYP2C19 * 2 and /or * 3 variant alleles with greater MPA values ( P = 0.001 ) and increased risk of ST ( OR , 11.67 ; 95 % CI , 1.21–78.83 ; P = 0.022 ) . However , there was no significant influence of CYP2C19 * 2 and * 3 on the risk of developing other adverse cardiovascular events . Conclusions Carriage of the loss-of-function genetic variants CYP2C19 * 2 and * 3 is significantly associated with attenuated platelet response to clopidogrel and an increased risk of ST in Chinese patients treated with stenting OBJECTIVES The goal of this study was to evaluate the effect of smoking on the pharmacokinetics and pharmacodynamics ( PD ) of clopidogrel and prasugrel therapy . BACKGROUND Major r and omized trial data demonstrated that nonsmokers experience less or no benefit from clopidogrel treatment compared with smokers ( i.e. , the " smokers ' paradox " ) . METHODS PARADOX was a prospect i ve , r and omized , double-blind , double-dummy , placebo-controlled , crossover study of objective ly assessed nonsmokers ( n = 56 ) and smokers ( n = 54 ) with stable coronary artery disease receiving aspirin therapy . Patients were r and omized to receive clopidogrel ( 75 mg daily ) or prasugrel ( 10 mg daily ) for 10 days and crossed over after a 14-day washout . PD was ass 
    Output:
    
Minimal heterogeneity was apparent between studies of Asian population s. CONCLUSIONS The reported association between CYP2C19 LoF allele carriage and major cardiovascular outcomes differs based on the ethnic population of the study and , to a lesser extent , the clopidogrel indication .