【文档说明】事与愿违的大型临床试验结果告诉了我们什麽课件.ppt，共(40)页，1.324 MB，由小橙橙上传

转载请保留链接：https://www.ichengzhen.cn/view-253244.html

以下为本文档部分文字说明：

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,China北京阜外医院高血压中心主任编辑课件•prioriti

zestargetlevelsofsomeriskfactors:plasmasugarbloodpresurecholestrol编辑课件•Women'sHealthInitiativeRCTrevealedthathormone-replacementtherapy,whichreduc

esLDLcholesterollevels,increasedtheriskofcardiovasculardisease.(Andersonetal.Effectsofconjugatedequineestrogeninpostm

enopausalwomenwithhysterectomy:theWomen'sHealthInitiativeRandomizedControlledTrial.JAMA2004;291:1701-1712)编辑课件ENHANCE•ENHANCE:EffectofCombination

EzetimibeandHigh-DoseSimvastatinversusSimvastatinAloneontheAtheroscleroticProcessinPatientswithHeterozygousFamili

alHypercholesterolemiaKasteleinetal:NEJM2008,358:1431-1443;Correction:NEJM2008,358:1977编辑课件ENHANCEshowedthate

zetimibedidnotreducetheprogressionofarteriosclerosiswhencombinedwithsimvastatin,ascomparedwithsimvastatinalon

e,eventhoughthecombinationdidresultinagreaterreductionofLDLcholesterol.Kasteleinetal:NEJM2008,358:1431-1443;Correction:

NEJM2008,358:1977编辑课件Post-trialStudy•UKPDS(UKProtectiveDiabetesStudy)Type-2DM:lowplasmaglucose,Reductioninmicrovascularcomplications.

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，death

fromhyperglycemia,hypoglycemia,fatal,non-fatalMI,angina,heartfailure,fatal,non-fatalStroke,renalfailure,amputation,vitreoushemorrhage,ret

inalphoto-coagulation,blindnessinoneeye,hyperglycemia,Hypoglycemia.Microvasculardisease:vitreous(玻璃体)

hemorrhage,retinalphoto-Coagulation(视网膜光凝术),renalfailure,编辑课件Follow-up10yearsSulfonylurea-InsulinMetoforminAnyDM-relatedEn

dpoints9%(P=0.04)21%(P=0.01)MicrovasDis24%(P=0.001)MI15%(P=0.01)33%(P=0.005)DeathfromAnycause13%(P=0.007)2

7%(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ADVANCE•TheADVANCE：actionindiabetesandvascul

ardisease--preteraxanddiamicronMRcontrolledevaluation.Diabetologia2001;44:1118-1120CollaborativeGroupNEJM2008,35

8:2560-2572编辑课件ADVANCE•11,140patientswithtype2diabetes;Grouped:1.standardglucosecontrol2.intensiveglucosecontrol:g

liclazide(格列齐特,达美康modifiedrelease)plusotherdrugsasrequiredtoachieveaglycatedhemoglobinvalueof6.5%orless.•Primaryendpoints:1.compositesofmajo

rmacrovascularevents:deathfromcardiovascularcauses,nonfatalmyocardialinfarction,ornonfatalstroke2.majormicrovascevents:neworworseningnephropathyorre

tinopathy编辑课件ADVANCEAfteramedianof5yearsoffollow-up,IntensiveStandardHR95%CIPGlycatedhemoglobin6.5%7.3%Combinedmajormacrovascular&microvascularevent

s:18.1%,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ADVANCENosignificanteffectonretinopathy(P=0.50).Nosignificanteffectsofthetypeofglucosecontrolon：majormacrovasc.eventsdea

thfromcardiovasc.causesdeathfromanycauseSevrehypoglycemiaHR95%CIPIntensive2.7%,1.861.42-2.40<0.001Standard:1.5%编辑课件Me

ta-analysis：Rosiglitazone（Avandia）•Rosiglitazoneiswidelyusedtotreatpatientswithtype2diabetesmellitus,butitseffectoncardiovascularmorbi

dityandmortalityhasnotbeendetermined.•Methods：Theauthorssearchedthepublishedliterature,WebsiteofFDA,andaclinical

-trialsregistrymaintained.Criteriaforinclusioninthemeta-analysisincludedastudydurationofmorethan24weeks,theuseofarandomizedcontrolgroupnotr

eceivingrosiglitazone,andtheavailabilityofoutcomedataformyocardialinfarctionanddeathfromcardiovascula

rcauses.Of116potentiallyrelevantstudies,42trialsmettheinclusioncriteria.alloccurrencesofmyocardialinfarctionanddeat

hfromcardiovascularcausesweretabulated.编辑课件Meta-analysis：Rosiglitazone（Avandia）•Results：Inthe42trials,t

hemeanageofthesubjectswasapproximately56years,andthemeanbaselineglycatedhemoglobinlevelwasapproximately8.2%.•Intherosiglitazonegroup

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

ratiofordeathfromcardiovascularcauseswas1.64(95%CI,0.98to2.74;P=0.06).编辑课件Meta-analysis：Rosiglitazone（Avandia）Rosiglitazoneimprovesglucos

econtrol,butitmayalsobeassociatedwithincreasedcardiovascularrisk.(Nissenetal.Effectofrosiglitazoneontherisko

fmyocardialinfarctionanddeathfromcardiovascularcauses.NEnglJMed2007;356:2457-2471)编辑课件ONTARGET•OngoingTe

lmisartanAloneandinCombinationwithRamipril(雷米普利)GlobalEndpointTrial/TelmisartanRandomizedAssessmentStudyinACEIntole

rantSubjectswithCardiovascularDisease(ONTARGET/TRANSCEND)trials.AmHeartJ2004;148:52-61.•ACEIreducemortalityandmorbidityfromcardiovascularcauses,but

theroleofARBsinsuchpatientsisunknown.•TheaimofthestudywastocomparetheACEIramipril,ARBtelmisartan,andthecombinationofthetwodrugsinpatientswith

vasculardiseaseorhigh-riskdiabetes.TheONTARGETInvestigators,NEJM358:1547-1559编辑课件ONTARGETGroups:1.ramipril10mgqd2.telmisartan80mgqd3.Combinati

onofthetwodrugsPrimarycompositeoutcome:1.deathfromcardiovascularcauses,myocardialinfarction,stroke,2

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

mmHg2.4/1.4mmHggreatergreater2.outcomeramipril:1412(16.5%),telmisartan:1423(16.7%;RR1.01;95%CI,0.94-1.09vs.ramipril).co

mbination:1386(16.3%;RR0.99;95%CI,0.92-1.07vs.ramipril);3.sideeffects:telmisartan:cough(1.1%vs.4.2%,P<0.001vs.ra

mipril)angioedema(0.1%vs.0.3%,P=0.01vs.ramipril)hypotensivesymptoms(2.6%vs.1.7%,P<0.001vs.ramipril);syncope:thesameinthetwogrou

ps(0.2%vs.ramipril).combination:hypotensivesymptoms(4.8%vs.1.7%,P<0.001vs.ramipril),syncope(0.3%vs.0.2%,P=0.03vs.ramipri

l),renaldysfunction(13.5%vs.10.2%,P<0.001vs.ramipril).编辑课件Kaplan–MeierCurvesforthePrimaryOutcomeintheThreeStudyGroups.编辑课件•Telmisartanwasequivalentt

oramiprilinpatientswithvasculardiseaseorhigh-riskdiabetesandwasassociatedwithlessangioedema.•Addingana

ngiotensin-receptorblockertoanangiotensin-converting–enzymeinhibitormayproduceagreaterreductioninbloodpress

ure,butitmaynotreducecardiovascularriskanditincreasestheriskofotheradverseevents.•TheONTARGETInvestigators.Telmisartan,ramipril,orboth

inpatientsathighriskforvascularevents.NEnglJMed2008;358:1547-1559.ONTARGET编辑课件ACCORD•ACCORD(ActiontoControlCardiovascul

arRiskinDiabetes)NEJM2008，358:2545-2559•Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimprov

eoutcomesinpatientswithtype2diabetesmellitus.编辑课件ACCORD•MethodsInthisrandomizedstudy,10,251patients(meanage,62.2years)withamediang

lycatedhemoglobinlevelof8.1%wereassignedtoreceivetargetingglycatedhemoglobinIntensivetherapy：below6.0%；St

andardtherapy：7.0to7.9%.Primaryoutcome：compositeofnonfatalmyocardialinfarction,nonfatalstroke,ordeathfromcardiovascularcauses.Thef

indingofhighermortalityintheintensive-therapygroupledtoadiscontinuationofintensivetherapyafterameanof3.5yearsoffollow-up.编辑课件ACCORDAt1yearResultsInte

nsiveStandardHR，95%CIPStablemedianGlycatedhemoglobin6.4%7.5%Primaryoutcome（n）3523710.900.78-1.04;0.16Death（n）2572031.22;1.01-1.460.04Hypoglycemiare

quiringassistanceandweightgainofmorethan10kgweremorefrequentintheintensive-therapygroup(P<0.001).编辑课件

ACCORD•Ascomparedwithstandardtherapy,theuseofintensivetherapytotargetnormalglycatedhemoglobinlevelsfor3.5yearsincreasedmortalityandd

idnotsignificantlyreducemajorcardiovascularevents.•Thesefindingsidentifyapreviouslyunrecognizedharmofintensiveglucoselowerin

ginhigh-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I

NDAPAMIDE0.625mg)andDiamicronModifiedReleaseControlledEvaluation.Strategy：theuseofmultiplemedicationsto

achievetightglucosecontrolwouldimproveoutcomesinpatientswithtype2diabetesmellitus.编辑课件ADVANCE•TheADVANCEstudy'sfin

dingsindicatethatitsstrategymayreducetheriskofworseningrenalfunctionatthecostofanexcessriskofhypoglycemicevents.

编辑课件•torcetrapib：apromisingagentthatloweredLDLcholesterollevelsandraisedhigh-densitylipoprotein(HDL)cholesterollev

els.•thetendencyoftorcetrapibtocausebloodpressuretoriseandpotassiumlevelstofallattractedmuchmoreattentionafterDecember2006thanithadpreviously.编辑

课件•ILLUMINATETrial(InvestigationofLipidLevelManagementtoUnderstandItsImpactinAtheroscleroticEvents)编辑课件•Patientsreceivingtorcetrapibplusatorvastatin

hadahighermortalityratethanthosereceivingatorvastatinalone—despite72%increasesinHDLlevelsand25%decreasesinLDLlevels.（NissenSE

,TardifJC,NichollsSJ,etal.Effectoftorcetrapibontheprogressionofcoronaryatherosclerosis.NEnglJMed2007;356:1304-1316）•o

nDecember2,2006,thedayPfizerstoppedILLUMINATEtrialandallothertrialsinvolvingtorcetrapib.编辑课件•Somestrategiesareknowntoimp

rovepatientoutcomes,•whereasothersareknowntoaffectonlyrisk-factorlevelsorotherintermediateoutcomes.•Wearenowbeginningtoappreciatet

hatastrategy'seffectonariskfactormaynotpredictitseffectonpatientoutcomes.编辑课件•Lifestyleinterventionsmayhavef

ewrisks,butwecannotassumethesamefordrugs—anddrug-relatedrisksarenotalwaysknownorappreciated.•considerationsoftherisksofdisease•adverse

consequencesposedbytheintervention.编辑课件•aninterventiondesignedtoprotectagainstthatoutcomeisunlikelytoprovidesubs

tantialbenefit—soiftheinterventioncarriesevenasmallrisk,thisriskcanoffsetorevenoutweighthebenefit.•Insickerpatientsandthos

ewithmorecomplexconditions,certaininterventions(suchasmaintenanceoftightglucosecontrol)maybemorelikelytoproduceadverseeffectsthan

theywouldinhealthierpatients,eitherdirectlyorthroughtheireffectonadherence.编辑课件•Focusonpatientoutcomes,improvement,notjustinter

mediateoutcomes,notjustonsurrogateendpoints.编辑课件•IndividualizedMedicine3PMedicine：personalizedpredictivepreventive编辑课件•“Betweenthehealthc

arewehaveandthecarewecouldhaveliesnotjustagap,•butachasm(大峡谷）.”•“Thelagbetweenthediscoveryofmoreefficacious

formsoftreatmentandtheirincorporationintoroutinepatientcareisunnecessarilylong,intherangeofabout15-20years.”MajorChallenge:ApplyingWhatWeKnow编辑课

件StudydesignbasedonPharmacogenomicsEpigenetics/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