在非ST段抬高的急性冠状动脉综合征(NSTACS)

在非ST段抬高的急性冠状动脉综合征(NSTACS)

中早期应用血小板糖蛋白IIbIIIa受体拮抗剂：

一项评估NSTACS治疗中早期应用依替巴肽

临床效果的随机、双盲、安慰剂对照试验

EarlyGlycoproteinIIb/IIIaInhibitioninNon-ST-segmentElevationAcuteCoronarySyndrome:ARandomized,Double-blind,Placebo-ControlledTrialEvaluatingtheClinicalBenefitsofEarlyFront-loadedEptifibatideintheTreatmentofPatientswithNon-ST-segmentElevationAcuteCoronarySyndromesEarlyGlycoproteinIIb/IIIaInhibitioninNon-ST-segmentElevationAcuteCoronarySyndrome:ARandomized,Double-blind,Placebo-ControlledTrialEvaluatingtheClinicalBenefitsofEarlyFront-loadedEptifibatideintheTreatmentofPatientswithNon-ST-segmentElevationAcuteCoronarySyndromesDisclosuresFundedbyMillenniumPharmaceuticalsandScheringPloughIndividualdisclosuresArmstrongBraunwaldCaliffGibsonGiuglianoHarringtonMontalescotNewbyStronyVandeWerfStudyStructure—figurewiththebelowcomponentsExecCommSteeringCommitteeSponsorCoordinatingCenters—DCRI,TIMI,CVCDSMBSitesCECPrimaryObjectiveTodemonstratethesuperiorityofastrategyofearly,routineeptifibatidebegunshortlyafterpresentationcomparedwithastrategyofdelayed,provisionaluseofeptifibatidepre-PCIinreducingthecompositeofdeath,MI,recurrentischemia,andthromboticbail-outwithin96hoursinpatientswithhigh-riskNSTEACSmanagedwithaninvasivestrategyStudyDesignHigh-riskNSTEACSn=10,500(9500)1Endpoint:96-hrDeath/MI/UrgentRevasc/Thromboticbailout2Endpoint:30-dDeath/MIFadeinsafetyendpointsat120hours(bleeding(GUSTOandTIMIscales),transfusions,stroke,non-hemorrhagicSAEsPlacebo/provisionaleptifibatidepre-PCIEarly,routineeptifibatide(180/2/180)Randomizewithin12hoursofpresentationInvasivestrategy:12to96hoursafterrandomization2of3high-riskcriteria:1.Age>60years2.+CKMBorTnT/I3.STortransientST(Orage50-59,h/oCVDand+CKMBorTnT/I)KeyExclusionCriteriaIncreasedbleedingriskactivebleedingorrecentbleedRecentsurgeryortraumaPriorICHorrecentischemicstrokeSeriousconcomitantillnessorpregnancyESRDwithdialysis<30daysRecentorplanneduseofdirectthrombininhibitor,fXainhibitor,abciximab/tirofibanamendment1:bivalirudinatPCIamendment2:acutefondaparinuxorbivalirudinBlindedStudyDrugAdministrationDoublebolusandinfusionregimen180ug/KgIVeptifibatide(ormatchingplacebo)bolusassoonaspossibleafterrandomizationImmediateinitiationof2ug/Kg/mineptifibatide(ormatchingplacebo)infusion(1ug/Kg/minifCrCl<50cc/min)Second180ug/KgIVeptifibatide(ormatchingplacebo)bolus10minutesafterinitialbolusProvisional,blindedtransitiontoopenlabeleptifibatideattimeofPCIusingblindedboluskitPCIactiveiftransitionbeforewirecrossedlesionPCIbailoutifafterwirecrossedthelesionStatisticalMethodsPower=85%todetecta22.5%reductionintheprimaryquadruplecompositeassuminganeventrateof5.8%withplaceboatalpha0.048aftersingleinterimefficacyanalysisPower=85%forthekeysecondaryefficacyendpointofdeathorMIat30days(15%RRR,placeborate12.7%);alsoatalpha0.048,usingstepdowntestingprocedurewhereformallytestedonlyifprimaryendpointsignificantPoweraftersamplesizereductionto9500patients98%for96-hourprimarycompositeendpoint81%for30-daykeysecondaryendpointofdeathorMI

PrespecifiedsubgroupsProper:Age,baselinetroponin,hospitaltype,diabetes,earlyclopidogrel,UFHvsenoxaparin,TIMIRiskScorePost-randomization(improper):Bymanagementstrategy(PCI,CABG,medical)EnrollmentUsemapofworldwithenrollmentbycountryonthemapRecognizetop20(?30)enrollersworldwide—couldbea“build”ontopofthemapStudyConductPatientsrandomized 9492Patientsexcludedforsiteconduct 64Patientswithoutinformedconsent 22Intent-to-treatpopulation 9406Patientswhoreceivednostudydrug 77As-treatedsafetypopulation 9329Losttofollow-up 11BaselineCharacteristics

ERE(n=4722) DPE(n=4684)Age(years) 67(60,75) 68(60,75)Female(%) 32.0 31.2Region(%) MostofWorld 69.2 69.4NorthAmerica 30.8 30.6Diabetesmellitus(%) 30.1 30.7Hypertension(%) 70.5 71.9Dyslipidemia(%) 57.9 57.8PriorMI (%) 27.0 28.2PriorPCI(%) 24.3 25.0PriorCABG(%) 13.1 14.2 CreatinineClearance(cc/min) 75(56,96) 74(56,96)TroponinorCKMBpositive(%) 85.9 87.0ST-segmentshifts(%) 61.6 62.0Presentationtorand(hours) 5.4(3.3,8.8) 5.7(3.4,8.8)In-hospitalManagement

ERE(n=4722)DPE(n=4684)CardiacCatheterization(%) 97.5 97.6 Randomizationtocath(hours) 21.4(16.9,34.2)21.4(16.7,31.0)PCI(%) 58.5 59.7Activeprovisional(%) 24.9 26.8Bailout(%) 11.3 12.0CABG(%) 13.2 12.9MedicallyTreatedonly(%) 30.3 31.4UseofEvidence-basedRx(%)ASA 97.5 97.3UFHorenoxaparin 94.3 94.2Beta-blocker 87.7 87.7

Statin 86.4 86.9ACEI/ARB 78.4 78.5Clopidogrel(intendedearly) 74.8 75.2Clopidogrel(any) 90.4 90.696-HourPrimaryEfficacyResults

ERE DPE OR P (n=4722) (n=4684)(95%CI)Death,MI,RIUR,TBO 9.3 10.0 0.92 0.23 (0.80-1.06)Death 0.8 0.9 0.96 0.87 (0.62-1.50)Death/MI 7.5 8.3 0.89 0.13 (0.77-1.04)Death/MI/RIUR 8.4 9.4 0.89 0.11 (0.77-1.03 )Kaplan-MeierCurvesforPrimaryEndpointDeath,MI,RIURorTBO(%)051015TimeSinceRandomization(Hours)0481216202428323640444852566064687276808488929610.0%9.3%Delayedprovisionaleptifibatide468446925.9(18.7,48.4)Earlyroutineeptifibatide472243931.1(18.8,62.2)P=0.23(stratifiedforintendedearlyclopidogreluse)N#EventsHourstoEventDelayedprovisionaleptifibatideEarlyroutineeptifibatide30-DaySecondaryEfficacyResults

ERE DPE OR P (n=4722) (n=4684)(95%CI) DeathorMI 11.2 12.3 0.89 0.079 (0.79-1.01)Death 2.8 2.6 1.10 0.46 (0.86-1.41)Death,MI,RIUR 12.5 13.8 0.89 0.065 (0.79-1.01)Kaplan-MeierCurvesfor30-dayDeathorMIDeathorMI(%)051015TimeSinceRandomization(Days)012345678910111213141516171819202122232425262728293012.4%11.2%P=0.079(stratifiedforintendedearlyclopidogreluse)Delayedprovisionaleptifibatide46845782.1(1.0,5.8)Earlyroutineeptifibatide47225282.7(1.0,4.9)N#EventsDaystoEventDelayedprovisionaleptifibatideEarlyroutineeptifibatide96-hourPrimaryEfficacyResults

ByPrespecifiedSubgroups0.700.800.500.600.901.002.00BaselineCharacteristicOddsRatioforUpstreamEptifibatide(95%CI)EarlyRoutineEptifibatide,%DelayedProvisionalEptifibatide,%OverallMenWomenAge<75yrAge>75yrTroponinpositiveTroponinnegativeDiabetesNoDiabetesRandomized<4hoursRandomized>4hoursHighTIMIRiskScore(5-7)IntermediateTIMIRiskScore(3-4)LowTIMIRiskScore(0-2)UnfractionatedheparinonlyLowmolecularweightheparinonlyPrimaryCareHospitalTertiaryCareHospital9.310.09.19.89.710.48.69.511.411.49.510.67.76.88.910.69.59.88.910.59.59.810.410.89.410.16.88.09.111.09.99.99.09.79.410.1EarlyEptifibatideBetterDelayedProvisionalEptifibatideBetterUpfrontclopidogrelintendedNoupfrontclopidogrelintended8.89.510.811.5NorthAmericaWesternEuropeEasternEurope10.310.67.38.611.211.2MiddleEast,AfricaandAsia10.911.530-dayDeathorMI

ByPrespecifiedSubgroups0.700.800.500.600.901.002.00Overall11.212.3Men11.412.0Women10.713.0Age<75yr10.211.6Age>75yr14.014.6Troponinpositive11.613.0Troponinnegative8.18.4Diabetes11.713.8NoDiabetes10.911.7Randomized<4hours11.112.8Randomized>4hours11.212.1HighTIMIRiskScore(5-7)13.213.3IntermediateTIMIRiskScore(3-4)10.912.8LowTIMIRiskScore(0-2)8.19.1Unfractionatedheparinonly11.313.0Lowmolecularweightheparinonly11.312.8PrimaryCareHospital10.712.3TertiaryCareHospital11.312.4Upfrontclopidogrelintended10.312.0Noupfrontclopidogrelintended13.713.4BaselineCharacteristicOddsRatioforUpstreamEptifibatide(95%CI)EarlyRoutineEptifibatide,%DelayedProvisionalEptifibatide,%EarlyEptifibatideBetterDelayedProvisionalEptifibatideBetterNorthAmericaWesternEuropeEasternEurope13.214.510.28.814.515.2MiddleEast,AfricaandAsia11.011.6SafetyResults(through120hours)

ERE DPE OR(95%CI) P (n=4686) (n=4643)Bleeding(overall) TIMIMajor 2.6 1.81.42(1.07-1.89) 0.015 TIMImajororminor 5.8 3.41.75(1.43-2.14) <0.001 GUSTOSevere 0.8 0.90.99(0.64-1.55) 0.97 GUSTOModerateorSevere 7.6 5.11.52(1.28-1.80) <0.001 PRBCtransfusion 8.6 6.71.31(1.12-1.53) 0.001Bleeding(CABG) Re-operationforbleeding 6.0 8.40.70(0.39-1.27) 0.24 Chesttubeoutput(mL/24H)720 770 -- 0.41Thrombocytopenia(nadir<100K)3.3 2.8 Stroke 0.6 0.80.79(0.48-1.30) 0.36Amonghigh-riskNSTEACSpatients,astrategyofearly,routineeptifibatidecomparedwithdelayedprovisionaleptifibatideatPCIdidnotsignificantlyreducetheprimarycompositeofD/MI/RIUR/TBOat96h(9.3%vs.10.0%,OR0.92;0.80-1.06;p=0.234)resultedinatrendtowardreductionindeathorMIat