ACE研究将指导心血管疾病全面防治的新策略

RationaleforACETrialAccumulatingevidencesuggeststhereisacloseassociationbetween“prediabetes”andcardiovasculardisease(CVD)Treatingconventionalriskfactorsintype2diabetesdoesnotreduceCVDrisktothesamelevelasinanon-diabeticpopulationPostprandialhyperglycaemiamayexplaintheexcessriskseenindiabetesand“prediabetes”Acarbosehasbeenreported*toreduceCVDriskinindividualswith“prediabetes”,butitsimpactonnewCVDeventsinindividualswith“prediabetes”andexistingCVDandisunknown*ChiassonJLetal.JAMA2003;290(4):486-94ACETrialManagementCoordinatingCentreDiabetesTrialsUnit,UniversityofOxfordACEChineseProjectOfficeOxfordUniversity(Beijing)Science&TechnologyLimitedFunding&StudyMedicationBayerHealthCareChina&BayerScheringPharmaStudyDesignDouble-blind,multi-centre,randomised,controlled,clinicaloutcometrialcomparingacarboseversusplacebo

InvestigatordesignedandledacademictrialIndependentdatacollection,analysisandreportingConductedinMainlandChinaandHongKong7,500patientsin~150cardiovascularcentresMinimumpatientfollowupfouryearsEventdriven(904adjudicatedprimaryevents)RuryHolman UK Diabetologist (Chair)DaYiHu China Cardiologist (Co-Chair)ChangYuPan China Diabetologist (Co-Chair)JiaLunChen China Diabetologist (Honouredadviser)JulianaChan HongKong DiabetologistJean-LouisChiasson Canada DiabetologistJunBoGe China CardiologistHertzelGerstein Canada DiabetologistJohnMcMurray UK CardiologistLarsRydén Sweden CardiologistMichalTendera Poland CardiologistJaakkoTuomilehto Finland EpidemiologistWenYingYang China DiabetologistJoanneKeenan UK DTUProjectManagerDieterNeuser Germany BayerProjectManagerThorstenPetruschke Germany BayerProjectManagerACESteeringCommitteeMajorInclusionCriteriaConfirmedcardiovasculardisease(CVD)HistoryofmyocardialinfarctionPreviousunstableanginaCurrentstableanginaImpairedglucosetolerance(IGT)onanoralglucosetolerancetestwith:Fastingplasmaglucose<7.0mmol/l2-hourplasmaglucose≥7.8and≤11.1mmol/lMaleorfemale,aged50yearsormoreStabledrugtherapyforCVDwithnoplannedcoronary,cerebrovascularorperipheralarterialrevascularisationWritteninformedconsentMajorExclusionCriteriaHistoryofdiabetes(exceptgestationaldiabetes)Myocardialinfarction,unstableangina,strokeoraTIAintheprevious3monthsNYHAclassIIIorIVheartfailureHepaticdisease(ALT>3xULN)Severerenalimpairment

(eGFR<30ml/min/1.73m2)GastrointestinalproblemsoralphaglucosidaseinhibitorintolerancePregnancyorpossibilityofpregnancyThoughtbytheinvestigatortobeunsuitableACEPrimaryEndpointComposite“hard”CVDendpointDefinedasthetimetothefirstoccurrenceafterrandomisationofanyof:CardiovasculardeathResuscitatedcardiacarrestNon-fatalmyocardialinfarctionNon-fatalstrokeAnEndpointAdjudicationCommittee,maskedtotherapyallocation,willreviewallpotentialCVDendpointsindependently.New-onsettype2diabetes,confirmedbytwosuccessivediagnosticplasmaglucosevaluesFPG≥7.0mmol/l

and/or2HPG≥11.1mmol/lACESecondaryEndpointAllcausemortalityExtendedCVDendpointofcardiovasculardeath,resuscitatedcardiacarrest,non-fatalmyocardialinfarction,fatalornon-fatalstrokeandhospitalisationforheartfailureorforunstableangina.EachcomponentwillalsobeanalysedindividuallyEvidenceofnon-alcoholicfattyliverdisease(NAFLD)asjudgedbyALTchangesDevelopmentofimpairedrenalfunction(eGFR<60ml/minute/1.73m2)ordoublingofbaselinecreatinineHealthEconomicevaluationOtherSecondaryOutcomesSampleSizeEstimationAssumesAprimaryeventrateof3.5%peryearA20%relativereductioncomparedwithplaceboAn18monthaccrualperiodAlphaof5%For90%PowerThestudyrequires7,268patientswithaminimumof904adjudicatedprimaryeventsAtotalof7,500patientswillberecruitedtoallowforanoverall3%loss-to-followupDoubleBlindInterventionInadditiontooptimisedCVDtherapy:Randomisedto:Acarbose,50mgthreetimesaday

orMatchingplacebo,threetimesadayTabletstobetakenwithmealsUse‘Startlow,goslow’dosetitrationACEStudyFlowChartMinimumof904adjudicatedprimaryeventsrequired7,500CVD

orACSOptimisationofCardiovascularTherapyCVDtherapywillbeoptimisedduringthefour-week,single-blind,placeborun-inperiodtoensureitconformswithinternationalguidelinesfortreatingpatientswithestablishedCVDThatis:Antiplatelettherapy,unlesscontraindicatedornottoleratedAstatin,unlesscontraindicatedornottoleratedACEinhibitor,beta-blocker,and/orantihypertensivetherapyifconsideredindicatedbytheinvestigatorSafetyTheACEtrialwillbeconductedtoICH-GCPstandardsLiverfunctionwillbemonitoredannuallySeriousUnexpectedSuspectedAdverseReactions(SUSARs)willundergoexpeditedreportingAnIndependentDataSafetyMonitoringBoard(DSMB)willreviewunblindedsafetydataatleastsix-monthlyTheACEtrialisenrolling~150cardiovascularcentresinMainlandChinaandHongKingEachcentreisexpectedtorecruitapproximately50patients(minimumof35patients)Recruitmentiscompetitiveandwillclosewhen7,500patientshavebeenrandomisedTheACEtrialresultsareexpectedin2014ScheduleClinicalCentr