事與愿違的大型臨床試驗(yàn)結(jié)果告訴了我們什麼課件

WhatWehaveLearnedfromtheFailureofLargeClinicalTrials?事與愿違的大型臨床試驗(yàn)結(jié)果告訴了我們什麼?HUIRutai惠汝太BeijingFuWaiHospital,China北京阜外醫(yī)院高血壓中心主任編輯課件WhatWehaveLearnedfromth1prioritizestargetlevelsofsomeriskfactors:plasmasugarbloodpresurecholestrol編輯課件prioritizestargetlevelsofs2Women'sHealthInitiative

RCTrevealedthathormone-replacementtherapy,whichreducesLDLcholesterollevels,increasedtheriskofcardiovasculardisease.

(Andersonetal.Effectsofconjugatedequineestrogeninpostmenopausalwomenwithhysterectomy:theWomen'sHealthInitiativeRandomizedControlledTrial.JAMA2004;291:1701-1712)

編輯課件編輯課件3ENHANCEENHANCE:EffectofCombinationEzetimibeandHigh-DoseSimvastatinversusSimvastatinAloneontheAtheroscleroticProcessinPatientswithHeterozygousFamilialHypercholesterolemiaKasteleinetal:NEJM2008,358:1431-1443;Correction:NEJM2008,358:1977

編輯課件ENHANCEENHANCE:EffectofComb4

ENHANCE

showedthatezetimibedidnotreducetheprogressionofarteriosclerosiswhencombinedwithsimvastatin,ascomparedwithsimvastatinalone,eventhoughthecombinationdidresultinagreaterreductionofLDLcholesterol.

Kasteleinetal:NEJM2008,358:1431-1443;Correction:NEJM2008,358:1977編輯課件編輯課件5Post-trialStudyUKPDS(UKProtectiveDiabetesStudy)Type-2DM:lowplasmaglucose,Reductioninmicrovascularcomplications.Whetherthetherapycanreducemacrovascularcomplications?降糖治療試驗(yàn)停止后，持續(xù)隨訪10年的結(jié)果HolmanetalNEJM2008:359:編輯課件Post-trialStudyUKPDS(UKProt6AnyDM-relatedEndpoints：suddendeath，deathfromhyperglycemia,hypoglycemia,fatal,non-fatalMI,angina,heartfailure,fatal,non-fatalStroke,renalfailure,amputation,vitreoushemorrhage,retinalphoto-coagulation,blindnessinoneeye,hyperglycemia,Hypoglycemia.Microvasculardisease:vitreous(玻璃體)hemorrhage,retinalphoto-Coagulation(視網(wǎng)膜光凝術(shù)

),renalfailure,編輯課件AnyDM-relatedEndpoints：編輯課件7Follow-up10years

Sulfonylurea-InsulinMetoforminAnyDM-relatedEndpoints9%(P=0.04)21%(P=0.01)MicrovasDis24%(P=0.001)MI15%(P=0.01)33%(P=0.005)DeathfromAnycause13%(P=0.007)27%(P=0.002)與傳統(tǒng)限制飲食治療比較，藥物強(qiáng)化治療

HolmanetalNEJM2008:359:編輯課件Follow-up8ADVANCETheADVANCE：actionindiabetesandvasculardisease--preteraxanddiamicronMRcontrolledevaluation.Diabetologia2001;44:1118-1120

CollaborativeGroupNEJM2008,358:2560-2572

編輯課件ADVANCETheADVANCE：actionind9ADVANCE11,140patientswithtype2diabetes;Grouped:1.ensiveglucosecontrol:gliclazide(格列齊特,達(dá)美康modifiedrelease)plusotherdrugsasrequiredtoachieveaglycatedhemoglobinvalueof6.5%orless.Primaryendpoints:

1.compositesofmajormacrovascularevents:deathfromcardiovascularcauses,nonfatalmyocardialinfarction,ornonfatalstroke2.majormicrovascevents:neworworseningnephropathyorretinopathy

編輯課件ADVANCE11,140patientswithty10ADVANCEAfteramedianof5yearsoffollow-up,IntensiveStandardHR95%CIPGlycatedhemoglobin6.5%7.3%Combinedmajormacrovascularµvascularevents: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

編輯課件ADVANCEAfteramedianof5y11ADVANCENosignificanteffectonretinopathy(P=0.50).Nosignificanteffectsofthetypeofglucosecontrolon：majormacrovasc.eventsdeathfromcardiovasc.causesdeathfromanycause

SevrehypoglycemiaHR95%CIPIntensive2.7%,1.861.42-2.40<0.001Standard:1.5%編輯課件ADVANCENosignificanteff12Meta-analysis：

Rosiglitazone（Avandia）Rosiglitazoneiswidelyusedtotreatpatientswithtype2diabetesmellitus,butitseffectoncardiovascularmorbidityandmortalityhasnotbeendetermined.Methods：Theauthorssearchedthepublishedliterature,WebsiteofFDA,andaclinical-trialsregistrymaintained.Criteriaforinclusioninthemeta-analysisincludedastudydurationofmorethan24weeks,theuseofarandomizedcontrolgroupnotreceivingrosiglitazone,andtheavailabilityofoutcomedataformyocardialinfarctionanddeathfromcardiovascularcauses.Of116potentiallyrelevantstudies,42trialsmettheinclusioncriteria.alloccurrencesofmyocardialinfarctionanddeathfromcardiovascularcausesweretabulated.

編輯課件Meta-analysis：

Rosiglitazone13Meta-analysis：

Rosiglitazone（Avandia）Results：Inthe42trials,themeanageofthesubjectswasapproximately56years,andthemeanbaselineglycatedhemoglobinlevelwasapproximately8.2%.Intherosiglitazonegroup,ascomparedwiththecontrolgroup,theoddsratioformyocardialinfarctionwas1.43(95%CI,1.03to1.98;P=0.03),andtheoddsratiofordeathfromcardiovascularcauseswas1.64(95%CI,0.98to2.74;P=0.06).

編輯課件Meta-analysis：

Rosiglitazone14Meta-analysis：Rosiglitazone（Avandia）

Rosiglitazoneimprovesglucosecontrol,butitmayalsobeassociatedwithincreasedcardiovascularrisk.

(Nissenetal.Effectofrosiglitazoneontheriskofmyocardialinfarctionanddeathfromcardiovascularcauses.NEnglJMed2007;356:2457-2471)編輯課件Meta-analysis：Rosiglitazo15ONTARGETOngoingTelmisartanAloneandinCombinationwithRamipril(雷米普利)GlobalEndpointTrial/TelmisartanRandomizedAssessmentStudyinACEIntolerantSubjectswithCardiovascularDisease(ONTARGET/TRANSCEND)trials.AmHeartJ2004;148:52-61.

ACEIreducemortalityandmorbidityfromcardiovascularcauses,buttheroleofARBsinsuchpatientsisunknown.TheaimofthestudywastocomparetheACEIramipril,ARBtelmisartan,andthecombinationofthetwodrugsinpatientswithvasculardiseaseorhigh-riskdiabetes.

TheONTARGETInvestigators,NEJM358:1547-1559

編輯課件ONTARGETOngoingTelmisartanAl16ONTARGETGroups:1.ramipril10mgqd2.telmisartan80mgqd3.CombinationofthetwodrugsPrimarycompositeoutcome:1.deathfromcardiovascularcauses,myocardialinfarction,stroke,2.hospitalizationforheartfailure.編輯課件ONTARGETGroups:編輯課件17ResultsAmedianfollow-upof56months,vs.ramipriltelmisartancombination1.Meanbloodressure0.9/0.6mmHg2.4/1.4mmHggreatergreater2.

outcome

ramipril: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)hypotensivesymptoms(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).

編輯課件ResultsAmedianf18Kaplan–MeierCurvesforthePrimaryOutcomeintheThreeStudyGroups.

編輯課件Kaplan–MeierCurvesforthePr19Telmisartanwasequivalenttoramiprilinpatientswithvasculardiseaseorhigh-riskdiabetesandwasassociatedwithlessangioedema.

Addinganangiotensin-receptorblockertoanangiotensin-converting–enzymeinhibitormayproduceagreaterreductioninbloodpressure,butitmaynotreducecardiovascularriskanditincreasestheriskofotheradverseevents.TheONTARGETInvestigators.Telmisartan,ramipril,orbothinpatientsathighriskforvascularevents.NEnglJMed2008;358:1547-1559.

ONTARGET編輯課件Telmisartanwasequivalentto20ACCORDACCORD(ActiontoControlCardiovascularRiskinDiabetes)

NEJM2008，358:2545-2559Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimproveoutcomesinpatientswithtype2diabetesmellitus.編輯課件ACCORDACCORD(ActiontoContro21ACCORDMethodsInthisrandomizedstudy,10,251patients(meanage,62.2years)withamedianglycatedhemoglobinlevelof8.1%wereassignedtoreceive

targetingglycatedhemoglobin

Intensivetherapy：below6.0%；

Standardtherapy：7.0to7.9%.Primaryoutcome：compositeofnonfatalmyocardialinfarction,nonfatalstroke,ordeathfromcardiovascularcauses.Thefindingofhighermortalityintheintensive-therapygroupledtoadiscontinuationofintensivetherapyafterameanof3.5yearsoffollow-up.編輯課件ACCORDMethodsInthisrandomiz22ACCORDAt1yearResultsIntensiveStandardHR，95%CIPStablemedianGlycatedhemoglobin6.4%7.5%

Primaryoutcome（n）3523710.900.78-1.04;0.16

Death（n）2572031.22;1.01-1.460.04

Hypoglycemiarequiringassistanceandweightgainofmorethan10kgweremorefrequentintheintensive-therapygroup(P<0.001).編輯課件ACCORDAt1yearResults23ACCORDAscomparedwithstandardtherapy,theuseofintensivetherapytotargetnormalglycatedhemoglobinlevelsfor3.5yearsincreasedmortalityanddidnotsignificantlyreducemajorcardiovascularevents.Thesefindingsidentifyapreviouslyunrecognizedharmofintensiveglucoseloweringinhigh-riskpatientswithtype2diabetes編輯課件ACCORDAscomparedwithstandar24ADVANCEADVANCE(ActioninDiabetesandVascularDisease:Preterax(復(fù)方:配德利錠:PERINDOPRIL培哚普利1.669mg+吲哚帕胺INDAPAMIDE0.625mg)andDiamicronModifiedReleaseControlledEvaluation.Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimproveoutcomesinpatientswithtype2diabetesmellitus.編輯課件ADVANCEADVANCE(ActioninDiab25ADVANCETheADVANCEstudy'sfindingsindicatethatitsstrategymayreducetheriskofworseningrenalfunctionatthecostofanexcessriskofhypoglycemicevents.

編輯課件ADVANCETheADVANCEstudy'sfin26torcetrapib：apromisingagentthatloweredLDLcholesterollevelsandraisedhigh-densitylipoprotein(HDL)cholesterollevels.thetendencyoftorcetrapibtocausebloodpressuretoriseandpotassiumlevelstofallattractedmuchmoreattentionafterDecember2006thanithadpreviously.編輯課件torcetrapib：apromisingagent27ILLUMINATETrial(InvestigationofLipidLevelManagementtoUnderstandItsImpactinAtheroscleroticEvents)編輯課件ILLUMINATETrial(Investigatio28Patientsreceivingtorcetrapibplusatorvastatinhadahighermortalityratethanthosereceivingatorvastatinalone—despite72%increasesinHDLlevelsand25%decreasesinLDLlevels.（NissenSE,TardifJC,NichollsSJ,etal.Effectoftorcetrapibontheprogressionofcoronaryatherosclerosis.NEnglJMed2007;356:1304-1316）onDecember2,2006,thedayPfizerstoppedILLUMINATEtrialandallothertrialsinvolvingtorcetrapib.編輯課件Patientsreceivingtorcetrapib29Somestrategiesareknowntoimprovepatientoutcomes,whereasothersareknowntoaffectonlyrisk-factorlevelsorotherintermediateoutcomes.Wearenowbeginningtoappreciatethatastrategy'seffectonariskfactormaynotpredictitseffectonpatientoutcomes.

編輯課件Somestrategiesareknowntoi30Lifestyleinterventionsmayhavefewrisks,butwecannotassumethesamefordrugs—anddrug-relatedrisksarenotalwaysknownorappreciated.considerationsoftherisksofdiseaseadverseconsequencesposedbytheintervention.編輯課件Lifestyleinterventionsmayha31aninterventiondesignedtoprotectagainstthatoutcomeisunlikelytoprovidesubstantialbenefit—soiftheinterventioncarriesevenasmallrisk,thisriskcanoffsetorevenoutweighthebenefit.Insickerpatientsandthosewithmorecomplexconditions,certaininterventions(suchasmaintenanceoftightglucosecontrol)maybemorelikelytoproduceadverseeffectsthantheywouldinhealthierpatients,eitherdirectlyorthroughtheireffectonadherence.

編輯課件aninterventiondesignedtopr32Focusonpatientoutcomes,improvement,notjustintermediateoutcomes,notjustonsurrogateendpoints.編輯課件Focusonpatientoutcomes,imp33IndividualizedMedicine3PMedicine：personalizedpredictivepreventive編輯課件IndividualizedMedicine編輯課件34 “Betweenthehealthcarewehaveandthecarewecouldhaveliesnotjustagap,butachasm(大峽谷）.”“Thelagbetweenthediscoveryofmoreefficaciousformsoftreatmentandtheirincorporationintoroutinepatientcareisunnecessarilylong,intherangeofabout15-20years.”MajorChallenge:ApplyingWhatWeKnow編輯課件MajorChallenge:ApplyingWh35StudydesignbasedonPharmacogenomicsEpigenetics/epigenomicsTelomere:shortorlonger編輯課件Studydesignbasedon編輯課件36在人群的遺傳素質(zhì)是相對(duì)穩(wěn)定的情況下，我國(guó)疾病譜和發(fā)病率發(fā)生巨大改變。這種變化表明環(huán)境對(duì)疾病有著巨大的影響。對(duì)結(jié)腸癌、腦中風(fēng)、冠心病和II型糖尿病等多種復(fù)雜性疾病的研究發(fā)現(xiàn)，至少70％的患者受不良的“環(huán)境因素”影響，如偏食、超重、不運(yùn)動(dòng)和抽煙。而且，如果改變不良生活習(xí)慣，可大大地降低這些疾病。編輯課件在人群的遺傳素質(zhì)是相對(duì)穩(wěn)定的情況下，我國(guó)疾病譜和發(fā)病率發(fā)生巨37

表觀遺傳學(xué)定義：“在基因組序列不變的情況下，可以決定基因表達(dá)與否并可穩(wěn)定遺傳下去的調(diào)控密碼”。表遺傳學(xué)內(nèi)容包括：DNA甲基化、基因組印記、染色質(zhì)組蛋白修飾、隔離蛋白非編碼RNA(包括microRNA)等DNA序列以外的各種調(diào)控方式，任何一方面的異常都將影響染色質(zhì)結(jié)構(gòu)和基因表達(dá)，導(dǎo)致復(fù)雜綜合征、多因素疾病。環(huán)境因素的影響短期內(nèi)或許難以造成基因序列的改變，但卻可以改變表觀遺傳密碼，并將這種“烙印”傳遞給下一代。編輯課件表觀遺傳學(xué)定義：“在基因組序列不變的情況下，可以決定基因38科技部中德分子醫(yī)學(xué)研究室暨教育部基因與臨床重點(diǎn)室

科技部/國(guó)家外專(zhuān)局國(guó)家級(jí)國(guó)際合作研究中心

編輯課件科技部中德分子醫(yī)學(xué)研究室暨教育部基因與臨床重點(diǎn)室

科技部/國(guó)39編輯課件編輯課件40WhatWehaveLearnedfromtheFailureofLargeClinicalTrials?事與愿違的大型臨床試驗(yàn)結(jié)果告訴了我們什麼?HUIRutai惠汝太BeijingFuWaiHospital,China北京阜外醫(yī)院高血壓中心主任編輯課件WhatWehaveLearnedfromth41prioritizestargetlevelsofsomeriskfactors:plasmasugarbloodpresurecholestrol編輯課件prioritizestargetlevelsofs42Women'sHealthInitiative

RCTrevealedthathormone-replacementtherapy,whichreducesLDLcholesterollevels,increasedtheriskofcardiovasculardisease.

(Andersonetal.Effectsofconjugatedequineestrogeninpostmenopausalwomenwithhysterectomy:theWomen'sHealthInitiativeRandomizedControlledTrial.JAMA2004;291:1701-1712)

編輯課件編輯課件43ENHANCEENHANCE:EffectofCombinationEzetimibeandHigh-DoseSimvastatinversusSimvastatinAloneontheAtheroscleroticProcessinPatientswithHeterozygousFamilialHypercholesterolemiaKasteleinetal:NEJM2008,358:1431-1443;Correction:NEJM2008,358:1977

編輯課件ENHANCEENHANCE:EffectofComb44

ENHANCE

showedthatezetimibedidnotreducetheprogressionofarteriosclerosiswhencombinedwithsimvastatin,ascomparedwithsimvastatinalone,eventhoughthecombinationdidresultinagreaterreductionofLDLcholesterol.

Kasteleinetal:NEJM2008,358:1431-1443;Correction:NEJM2008,358:1977編輯課件編輯課件45Post-trialStudyUKPDS(UKProtectiveDiabetesStudy)Type-2DM:lowplasmaglucose,Reductioninmicrovascularcomplications.Whetherthetherapycanreducemacrovascularcomplications?降糖治療試驗(yàn)停止后，持續(xù)隨訪10年的結(jié)果HolmanetalNEJM2008:359:編輯課件Post-trialStudyUKPDS(UKProt46AnyDM-relatedEndpoints：suddendeath，deathfromhyperglycemia,hypoglycemia,fatal,non-fatalMI,angina,heartfailure,fatal,non-fatalStroke,renalfailure,amputation,vitreoushemorrhage,retinalphoto-coagulation,blindnessinoneeye,hyperglycemia,Hypoglycemia.Microvasculardisease:vitreous(玻璃體)hemorrhage,retinalphoto-Coagulation(視網(wǎng)膜光凝術(shù)

),renalfailure,編輯課件AnyDM-relatedEndpoints：編輯課件47Follow-up10years

Sulfonylurea-InsulinMetoforminAnyDM-relatedEndpoints9%(P=0.04)21%(P=0.01)MicrovasDis24%(P=0.001)MI15%(P=0.01)33%(P=0.005)DeathfromAnycause13%(P=0.007)27%(P=0.002)與傳統(tǒng)限制飲食治療比較，藥物強(qiáng)化治療

HolmanetalNEJM2008:359:編輯課件Follow-up48ADVANCETheADVANCE：actionindiabetesandvasculardisease--preteraxanddiamicronMRcontrolledevaluation.Diabetologia2001;44:1118-1120

CollaborativeGroupNEJM2008,358:2560-2572

編輯課件ADVANCETheADVANCE：actionind49ADVANCE11,140patientswithtype2diabetes;Grouped:1.ensiveglucosecontrol:gliclazide(格列齊特,達(dá)美康modifiedrelease)plusotherdrugsasrequiredtoachieveaglycatedhemoglobinvalueof6.5%orless.Primaryendpoints:

1.compositesofmajormacrovascularevents:deathfromcardiovascularcauses,nonfatalmyocardialinfarction,ornonfatalstroke2.majormicrovascevents:neworworseningnephropathyorretinopathy

編輯課件ADVANCE11,140patientswithty50ADVANCEAfteramedianof5yearsoffollow-up,IntensiveStandardHR95%CIPGlycatedhemoglobin6.5%7.3%Combinedmajormacrovascularµvascularevents: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

編輯課件ADVANCEAfteramedianof5y51ADVANCENosignificanteffectonretinopathy(P=0.50).Nosignificanteffectsofthetypeofglucosecontrolon：majormacrovasc.eventsdeathfromcardiovasc.causesdeathfromanycause

SevrehypoglycemiaHR95%CIPIntensive2.7%,1.861.42-2.40<0.001Standard:1.5%編輯課件ADVANCENosignificanteff52Meta-analysis：

Rosiglitazone（Avandia）Rosiglitazoneiswidelyusedtotreatpatientswithtype2diabetesmellitus,butitseffectoncardiovascularmorbidityandmortalityhasnotbeendetermined.Methods：Theauthorssearchedthepublishedliterature,WebsiteofFDA,andaclinical-trialsregistrymaintained.Criteriaforinclusioninthemeta-analysisincludedastudydurationofmorethan24weeks,theuseofarandomizedcontrolgroupnotreceivingrosiglitazone,andtheavailabilityofoutcomedataformyocardialinfarctionanddeathfromcardiovascularcauses.Of116potentiallyrelevantstudies,42trialsmettheinclusioncriteria.alloccurrencesofmyocardialinfarctionanddeathfromcardiovascularcausesweretabulated.

編輯課件Meta-analysis：

Rosiglitazone53Meta-analysis：

Rosiglitazone（Avandia）Results：Inthe42trials,themeanageofthesubjectswasapproximately56years,andthemeanbaselineglycatedhemoglobinlevelwasapproximately8.2%.Intherosiglitazonegroup,ascomparedwiththecontrolgroup,theoddsratioformyocardialinfarctionwas1.43(95%CI,1.03to1.98;P=0.03),andtheoddsratiofordeathfromcardiovascularcauseswas1.64(95%CI,0.98to2.74;P=0.06).

編輯課件Meta-analysis：

Rosiglitazone54Meta-analysis：Rosiglitazone（Avandia）

Rosiglitazoneimprovesglucosecontrol,butitmayalsobeassociatedwithincreasedcardiovascularrisk.

(Nissenetal.Effectofrosiglitazoneontheriskofmyocardialinfarctionanddeathfromcardiovascularcauses.NEnglJMed2007;356:2457-2471)編輯課件Meta-analysis：Rosiglitazo55ONTARGETOngoingTelmisartanAloneandinCombinationwithRamipril(雷米普利)GlobalEndpointTrial/TelmisartanRandomizedAssessmentStudyinACEIntolerantSubjectswithCardiovascularDisease(ONTARGET/TRANSCEND)trials.AmHeartJ2004;148:52-61.

ACEIreducemortalityandmorbidityfromcardiovascularcauses,buttheroleofARBsinsuchpatientsisunknown.TheaimofthestudywastocomparetheACEIramipril,ARBtelmisartan,andthecombinationofthetwodrugsinpatientswithvasculardiseaseorhigh-riskdiabetes.

TheONTARGETInvestigators,NEJM358:1547-1559

編輯課件ONTARGETOngoingTelmisartanAl56ONTARGETGroups:1.ramipril10mgqd2.telmisartan80mgqd3.CombinationofthetwodrugsPrimarycompositeoutcome:1.deathfromcardiovascularcauses,myocardialinfarction,stroke,2.hospitalizationforheartfailure.編輯課件ONTARGETGroups:編輯課件57ResultsAmedianfollow-upof56months,vs.ramipriltelmisartancombination1.Meanbloodressure0.9/0.6mmHg2.4/1.4mmHggreatergreater2.

outcome

ramipril: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)hypotensivesymptoms(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).

編輯課件ResultsAmedianf58Kaplan–MeierCurvesforthePrimaryOutcomeintheThreeStudyGroups.

編輯課件Kaplan–MeierCurvesforthePr59Telmisartanwasequivalenttoramiprilinpatientswithvasculardiseaseorhigh-riskdiabetesandwasassociatedwithlessangioedema.

Addinganangiotensin-receptorblockertoanangiotensin-converting–enzymeinhibitormayproduceagreaterreductioninbloodpressure,butitmaynotreducecardiovascularriskanditincreasestheriskofotheradverseevents.TheONTARGETInvestigators.Telmisartan,ramipril,orbothinpatientsathighriskforvascularevents.NEnglJMed2008;358:1547-1559.

ONTARGET編輯課件Telmisartanwasequivalentto60ACCORDACCORD(ActiontoControlCardiovascularRiskinDiabetes)

NEJM2008，358:2545-2559Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimproveoutcomesinpatientswithtype2diabetesmellitus.編輯課件ACCORDACCORD(ActiontoContro61ACCORDMethodsInthisrandomizedstudy,10,251patients(meanage,62.2years)withamedianglycatedhemoglobinlevelof8.1%wereassignedtoreceive

targetingglycatedhemoglobin

Intensivetherapy：below6.0%；

Standardtherapy：7.0to7.9%.Primaryoutcome：compositeofnonfatalmyocardialinfarction,nonfatalstroke,ordeathfromcardiovascularcauses.Thefindingofhighermortalityintheintensive-therapygroupledtoadiscontinuationofintensivetherapyafterameanof3.5yearsoffollow-up.編輯課件ACCORDMethodsInthisrandomiz62ACCORDAt1yearResultsIntensiveStandardHR，95%CIPStablemedianGlycatedhemoglobin6.4%7.5%

Primaryoutcome（n）3523710.900.78-1.04;0.16

Death（n）2572031.22;1.01-1.460.04

Hypoglycemiarequiringassistanceandweightgainofmorethan10kgweremorefrequentintheintensive-therapygroup(P<0.001).編輯課件ACCORDAt1yearResults63ACCORDAscomparedwithstandardtherapy,theuseofintensivetherapytotargetnormalglycatedhemoglobinlevelsfor3.5yearsincreasedmortalityanddidnotsignificantlyreducemajorcardiovascularevents.Thesefindingsidentifyapreviouslyunrecognizedharmofintensiveglucoseloweringinhigh-riskpatientswithtype2diabetes編輯課件ACCORDAscomparedwithstandar64ADVANCEADVANCE(ActioninDiabetesandVascularDisease:Preterax(復(fù)方:配德利錠:PERINDOPRIL培哚普利1.669mg+吲哚帕胺INDAPAMIDE0.625mg)andDiamicronModifiedReleaseControlledEvaluation.Strategy：theuseofmultiplemedicationstoachievetightglucosecontrolwouldimproveoutcomesinpatientswithtype2diabetesmellitus.編輯課件ADVANCEADVANCE(ActioninDiab65ADVANCETheADVANCEstudy'sfindingsindicatethatitsstrategymayreducetheriskofworseningrenalfunctionatthecostofanexcessriskofhypoglycemicevents.

編輯課件ADVANCETheADVANCEstudy'sfin66torcetrapib：apromisingagentthatloweredLDLcholesterollevelsandraisedhigh-densitylipoprotein(HDL)cholesterollevels.thetendencyoftorcetrapibtocausebloodpressuretoriseandpotassiumlevelstofallattractedmuchmoreattentionafterDecember2006thanithadpreviously.編輯課件torcetrapib：apromisingagent67ILLUMINATETrial(InvestigationofLipidLevelManagementtoUnderstandItsImpactinAtheroscleroticEvents)編輯課件ILLUMINATETrial(Investigatio68Patientsreceivingtorcetrapibplusatorvastatinhadahighermortalityratethanthosereceivingatorvas