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1、EffectsofCYP2C19genotypesonclopidogreltreatmentintheCUREandACTIVEtrialsGuillaumePareMDCanadaResearchChairinGeneticandMolecularEpidemiologyBackgroundAssumptionthatCYP2C19poormetabolizersdonotconvertthepro-drugintotheactivemetaboliteandthusdonotderiveclinicalbenefitoftreatment
2、“Blackbox”warningfromFDAofreducedeffectivenessofclopidogrelinpatientswhoarepoormetabolizersUseofahigherdoseofclopidogrelUseofanalternativeantiplateletagentCYP2C19Alleles3alleleclasses-“Wildtype”(*1):63%-Loss-of-function(*2,*3):13%-Gain-of-function(*17):24%5metabolizerphenoty
3、pes-Poor:2loss-of-functionalleles(2%)-Intermediate:1loss-of-functionand1wildtypealleles(16%)-Extensive:2wildtypesalleles(39%)-Ultra:1or2gain-of-functionalleles(37%)-Unknown:1gain-of-functionand1loss-of-functionalleles(6%)2carrierstatus-Loss-of-functioncarriers(1ormore*2,*3):
4、24%-Gain-of-functioncarriers(1ormore*17):41%CURETrial12,562ACSpatientswithoutST-segmentelevationRandomizedtoClopidogrel(75mg)orPlaceboOnabackgroundofASA(75mgto325mg)Averagefollow-upof9monthsOutcomesFirstPrimary:CVdeath,MI,StrokeSecondPrimary:Firstprimary,orrecurrentischemia,
5、orUASafety:Majorbleed(life-threateningornot)Yusufetal.NEJM2001;345:494-502CUREGeneticsBaselineCharacteristicsCharacteristicOVERALLCURE-GeneticsPlaceboClopidogrelTotalPlaceboClopidogrelTotalN6303625912562251025495059Female(%)38.338.738.540.941.241.0Age64.2(11.3)64.2(11.3)64.2
6、(11.3)63.9(11.1)63.8(11.0)63.8(11.0)BMI27.4(4.1)27.4(4.1)27.4(4.1)27.6(4.1)27.7(4.2)27.6(4.2)Diabetes(%)22.822.422.621.520.721.1Smoking(%)22.723.423.021.623.122.4SBP134.1(22.0)134.4(22.5)134.2(22.2)134.6(22.0)135.5(22.3)135.0(22.1)PCIwithoutstent4.03.73.93.93.23.5PCIwithsten
7、t17.317.317.313.515.514.5CABG16.816.216.516.315.916.1CUREOverall:582events,9.3%versus719events,11.4%;HR=0.8095%CI0.72-0.90,P<0.001CURE-Genetics:231events,9.1%versus316events,12.6%;HR=0.7195%CI0.60-0.84,P<0.001Thebenefitofclopidogreltreatmentonthefirstprimarycompositeefficacy
8、outcomewassimilartotheparentstudy:CURE–MetabolizerPhenotypesHeterogeneityP-
