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编辑课件WhatWehaveLearnedfromtheFailureofLargeClinicalTrials?事与愿违的大型临床试验结果告诉了我们什麽?HUIRutai惠汝太BeijingFuWaiHospital,Chi

na北京阜外医院高血压中心主任编辑课件•prioritizestargetlevelsofsomeriskfactors:plasmasugarbloodpresurecholestrol编辑课件•Women'sHealthInitiativeRCTrevealed

thathormone-replacementtherapy,whichreducesLDLcholesterollevels,increasedtheriskofcardiovasculardisease.(Andersonetal.Effect

sofconjugatedequineestrogeninpostmenopausalwomenwithhysterectomy:theWomen'sHealthInitiativeRandomizedCont

rolledTrial.JAMA2004;291:1701-1712)编辑课件ENHANCE•ENHANCE:EffectofCombinationEzetimibeandHigh-DoseSimvastatinversusSimv

astatinAloneontheAtheroscleroticProcessinPatientswithHeterozygousFamilialHypercholesterolemiaKasteleinetal:NEJM2008,35

8:1431-1443;Correction:NEJM2008,358:1977编辑课件ENHANCEshowedthatezetimibedidnotreducetheprogressionofarteriosclerosiswhencombi

nedwithsimvastatin,ascomparedwithsimvastatinalone,eventhoughthecombinationdidresultinagreaterreductionofLDLcholesterol.Ka

steleinetal:NEJM2008,358:1431-1443;Correction:NEJM2008,358:1977编辑课件Post-trialStudy•UKPDS(UKProtectiveDiabetesStudy)Type-2DM:lowplasmaglucose,Reduct

ioninmicrovascularcomplications.Whetherthetherapycanreducemacrovascularcomplications?降糖治疗试验停止后，持续随访10年的结果HolmanetalNEJM2008:359:

编辑课件AnyDM-relatedEndpoints：suddendeath，deathfromhyperglycemia,hypoglycemia,fatal,non-fatalMI,angina,heartfailure,f

atal,non-fatalStroke,renalfailure,amputation,vitreoushemorrhage,retinalphoto-coagulation,blindnessinonee

ye,hyperglycemia,Hypoglycemia.Microvasculardisease:vitreous(玻璃体)hemorrhage,retinalphoto-Coagulation(视网膜光凝术),renalfailure

,编辑课件Follow-up10yearsSulfonylurea-InsulinMetoforminAnyDM-relatedEndpoints9%(P=0.04)21%(P=0.01)MicrovasDis24%(P=0.00

1)MI15%(P=0.01)33%(P=0.005)DeathfromAnycause13%(P=0.007)27%(P=0.002)与传统限制饮食治疗比较，药物强化治疗HolmanetalNEJM2008:359:编辑课件ADVAN

CE•TheADVANCE：actionindiabetesandvasculardisease--preteraxanddiamicronMRcontrolledevaluation.Diabetologia2001;44:1118-1120CollaborativeGrou

pNEJM2008,358:2560-2572编辑课件ADVANCE•11,140patientswithtype2diabetes;Grouped:1.standardglucosecontrol2.intensiv

eglucosecontrol:gliclazide(格列齐特,达美康modifiedrelease)plusotherdrugsasrequiredtoachieveaglycatedhemoglobinvalueof

6.5%orless.•Primaryendpoints:1.compositesofmajormacrovascularevents:deathfromcardiovascularcauses,nonfatalm

yocardialinfarction,ornonfatalstroke2.majormicrovascevents:neworworseningnephropathyorretinopathy编辑课件ADVANCEAf

teramedianof5yearsoffollow-up,IntensiveStandardHR95%CIPGlycatedhemoglobin6.5%7.3%Combinedmajormacrovascular&microvascularevents:1

8.1%,20.0%0.900.82-0.980.01Majormicrovascularevents9.4%10.9%0.860.77-0.970.01Incidenceofnephropathy4.1%5.2%0.790.66-0.930.006编辑课件ADV

ANCENosignificanteffectonretinopathy(P=0.50).Nosignificanteffectsofthetypeofglucosecontrolon：majormacrovasc.eventsdeathfromcardiovasc.caus

esdeathfromanycauseSevrehypoglycemiaHR95%CIPIntensive2.7%,1.861.42-2.40<0.001Standard:1.5%编辑课件Meta-analysis：Rosiglitazone（Avandia

）•Rosiglitazoneiswidelyusedtotreatpatientswithtype2diabetesmellitus,butitseffectoncardiovascularmorbid

ityandmortalityhasnotbeendetermined.•Methods：Theauthorssearchedthepublishedliterature,WebsiteofFDA,andaclinical-trialsregist

rymaintained.Criteriaforinclusioninthemeta-analysisincludedastudydurationofmorethan24weeks,theuseofarandomizedcontrolgroupnotreceiv

ingrosiglitazone,andtheavailabilityofoutcomedataformyocardialinfarctionanddeathfromcardiovascularcauses.Of116potentiallyrelevantstudies,42trial

smettheinclusioncriteria.alloccurrencesofmyocardialinfarctionanddeathfromcardiovascularcausesweretabulated.编辑课件Meta-analysis：Rosiglitazone（Avandia）•R

esults：Inthe42trials,themeanageofthesubjectswasapproximately56years,andthemeanbaselineglycatedhemoglobinlevelwasapproximately8.2%.•Intherosi

glitazonegroup,ascomparedwiththecontrolgroup,theoddsratioformyocardialinfarctionwas1.43(95%CI,1.03to1.98;P=0.03),andtheoddsratioforde

athfromcardiovascularcauseswas1.64(95%CI,0.98to2.74;P=0.06).编辑课件Meta-analysis：Rosiglitazone（Avandia）Rosiglitazoneimprovesglucoseco

ntrol,butitmayalsobeassociatedwithincreasedcardiovascularrisk.(Nissenetal.Effectofrosiglitazoneonther

iskofmyocardialinfarctionanddeathfromcardiovascularcauses.NEnglJMed2007;356:2457-2471)编辑课件ONTARGET•OngoingTelmisartanAloneandinCombinatio

nwithRamipril(雷米普利)GlobalEndpointTrial/TelmisartanRandomizedAssessmentStudyinACEIntolerantSubjectswithCardio

vascularDisease(ONTARGET/TRANSCEND)trials.AmHeartJ2004;148:52-61.•ACEIreducemortalityandmorbidityfromcardiovascularcaus

es,buttheroleofARBsinsuchpatientsisunknown.•TheaimofthestudywastocomparetheACEIramipril,ARBtelmisartan,andthecombinationofthetwodrugsinpatientswithv

asculardiseaseorhigh-riskdiabetes.TheONTARGETInvestigators,NEJM358:1547-1559编辑课件ONTARGETGroups:1.ramipril10mgqd2.telmisartan80mgqd

3.CombinationofthetwodrugsPrimarycompositeoutcome:1.deathfromcardiovascularcauses,myocardialinfarction,stroke,2.hospital

izationforheartfailure.编辑课件ResultsAmedianfollow-upof56months,vs.ramipriltelmisartancombination1.Meanbloodressure0.9/0.6mmHg2.

4/1.4mmHggreatergreater2.outcomeramipril:1412(16.5%),telmisartan:1423(16.7%;RR1.01;95%CI,0.94-1.09vs.ramipril).combination:1386(16.3%;RR0.99;

95%CI,0.92-1.07vs.ramipril);3.sideeffects:telmisartan:cough(1.1%vs.4.2%,P<0.001vs.ramipril)angioedema(0.1%vs.0.3%,P=0.01vs.ramipril)hypot

ensivesymptoms(2.6%vs.1.7%,P<0.001vs.ramipril);syncope:thesameinthetwogroups(0.2%vs.ramipril).combination:hypotensivesymptoms(4.8%vs.1.7%,P

<0.001vs.ramipril),syncope(0.3%vs.0.2%,P=0.03vs.ramipril),renaldysfunction(13.5%vs.10.2%,P<0.001vs.ramipril).编辑课件Kaplan–MeierCurvesforthePrima

ryOutcomeintheThreeStudyGroups.编辑课件•Telmisartanwasequivalenttoramiprilinpatientswithvasculardiseaseorhigh

-riskdiabetesandwasassociatedwithlessangioedema.•Addinganangiotensin-receptorblockertoanangiotensin-converting–enzymeinhibitormayproduceagr

eaterreductioninbloodpressure,butitmaynotreducecardiovascularriskanditincreasestheriskofotheradverseevents.•The

ONTARGETInvestigators.Telmisartan,ramipril,orbothinpatientsathighriskforvascularevents.NEnglJMed2008;358:1547-1559.ONTARGET编辑课件ACCORD•ACCORD(Actionto

ControlCardiovascularRiskinDiabetes)NEJM2008，358:2545-2559•Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimproveo

utcomesinpatientswithtype2diabetesmellitus.编辑课件ACCORD•MethodsInthisrandomizedstudy,10,251patients(meanage,62.2years)withamedianglycatedhemoglo

binlevelof8.1%wereassignedtoreceivetargetingglycatedhemoglobinIntensivetherapy：below6.0%；Standardtherapy：7.0to7.9%.Primaryoutcome：compos

iteofnonfatalmyocardialinfarction,nonfatalstroke,ordeathfromcardiovascularcauses.Thefindingofhighermortalityintheintensive-therapygroupledtoadis

continuationofintensivetherapyafterameanof3.5yearsoffollow-up.编辑课件ACCORDAt1yearResultsIntensiveStandardHR，95%CIPStableme

dianGlycatedhemoglobin6.4%7.5%Primaryoutcome（n）3523710.900.78-1.04;0.16Death（n）2572031.22;1.01-1.460.04Hypoglycemiarequiringas

sistanceandweightgainofmorethan10kgweremorefrequentintheintensive-therapygroup(P<0.001).编辑课件ACCORD•Ascomparedwithstandardther

apy,theuseofintensivetherapytotargetnormalglycatedhemoglobinlevelsfor3.5yearsincreasedmortalityanddidnotsignificantlyreducemajorcardiovascularevents

.•Thesefindingsidentifyapreviouslyunrecognizedharmofintensiveglucoseloweringinhigh-riskpatientswithtype2diabetes编辑

课件ADVANCE•ADVANCE(ActioninDiabetesandVascularDisease:Preterax(复方:配德利锭:PERINDOPRIL培哚普利1.669mg+吲哚帕胺INDAPAMIDE0.625mg)andDia

micronModifiedReleaseControlledEvaluation.Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimproveoutcomesin

patientswithtype2diabetesmellitus.编辑课件ADVANCE•TheADVANCEstudy'sfindingsindicatethatitsstrategymayreducetheriskofworseningrenalfunctionatthecost

ofanexcessriskofhypoglycemicevents.编辑课件•torcetrapib：apromisingagentthatloweredLDLcholesterollevelsandraise

dhigh-densitylipoprotein(HDL)cholesterollevels.•thetendencyoftorcetrapibtocausebloodpressuretoriseandpotassiumlevelstofallattr

actedmuchmoreattentionafterDecember2006thanithadpreviously.编辑课件•ILLUMINATETrial(InvestigationofLipidLevelManagementtoUnderstandItsIm

pactinAtheroscleroticEvents)编辑课件•Patientsreceivingtorcetrapibplusatorvastatinhadahighermortalityratethanthosereceivingat

orvastatinalone—despite72%increasesinHDLlevelsand25%decreasesinLDLlevels.（NissenSE,TardifJC,NichollsSJ,etal.Effectoftorcetrapibontheprogress

ionofcoronaryatherosclerosis.NEnglJMed2007;356:1304-1316）•onDecember2,2006,thedayPfizerstoppedILLUMI

NATEtrialandallothertrialsinvolvingtorcetrapib.编辑课件•Somestrategiesareknowntoimprovepatientoutcomes,•wherea

sothersareknowntoaffectonlyrisk-factorlevelsorotherintermediateoutcomes.•Wearenowbeginningtoappreciatethatastrategy'seffectonariskfactormayn

otpredictitseffectonpatientoutcomes.编辑课件•Lifestyleinterventionsmayhavefewrisks,butwecannotassumethesamefordrugs—anddrug-relatedrisksarenotalwa

ysknownorappreciated.•considerationsoftherisksofdisease•adverseconsequencesposedbytheintervention.编辑课件•aninterventiondesignedtoprotecta

gainstthatoutcomeisunlikelytoprovidesubstantialbenefit—soiftheinterventioncarriesevenasmallrisk,thisriskcanoffsetorevenoutweighthebenefit.•

Insickerpatientsandthosewithmorecomplexconditions,certaininterventions(suchasmaintenanceoftightglucosecontrol)maybemorelikelytoproduceadverseeffectst

hantheywouldinhealthierpatients,eitherdirectlyorthroughtheireffectonadherence.编辑课件•Focusonpatientoutcomes,improvement,notjustintermediate

outcomes,notjustonsurrogateendpoints.编辑课件•IndividualizedMedicine3PMedicine：personalizedpredictivepreventive编辑

课件•“Betweenthehealthcarewehaveandthecarewecouldhaveliesnotjustagap,•butachasm(大峡谷）.”•“Thelagbetweenthediscoveryofmoreefficaciousformsoftreatmentandth

eirincorporationintoroutinepatientcareisunnecessarilylong,intherangeofabout15-20years.”MajorChallenge:ApplyingWhatWeKnow编辑课件Studydesignbase

donPharmacogenomicsEpigenetics/epigenomicsTelomere:shortorlonger编辑课件•在人群的遗传素质是相对稳定的情况下，我国疾病谱和发病率发生巨大改变。这种变化表明环境对疾病有着巨大的影响。•对结肠癌

、脑中风、冠心病和II型糖尿病等多种复杂性疾病的研究发现，至少70％的患者受不良的“环境因素”影响，如偏食、超重、不运动和抽烟。而且，如果改变不良生活习惯，可大大地降低这些疾病。编辑课件表观遗传学定义：“在基因组序列不变的情况下，可以决定基

因表达与否并可稳定遗传下去的调控密码”。•表遗传学内容包括：DNA甲基化、基因组印记、染色质组蛋白修饰、隔离蛋白非编码RNA(包括microRNA)等DNA序列以外的各种调控方式，任何一方面的异常都将影响染色质结构和

基因表达，导致复杂综合征、多因素疾病。环境因素的影响短期内或许难以造成基因序列的改变，但却可以改变表观遗传密码，并将这种“烙印”传递给下一代。编辑课件科技部中德分子医学研究室暨教育部基因与临床重点室科技部/国家外专局

国家级国际合作研究中心编辑课件