醫(yī)學(xué)資料 慢性心力衰竭臨床試驗的回顧 學(xué)習(xí)課件

慢性心力衰竭臨床試驗的回顧北京大學(xué)第三醫(yī)院心內(nèi)科張福春導(dǎo)致心血管死亡事件之鏈心肌梗死心律失常猝死肌肉丟失神經(jīng)激素激活重塑心室擴(kuò)大心力衰竭死亡冠脈血栓心肌缺血CAD動脈硬化LVH危險因素

高脂蛋白血癥

高血壓

糖尿病

胰島素抵抗AdaptedfromDzauV.BraunwaidE.AmHeartJ1991:121:1244-1263心力衰竭病生理機(jī)制的認(rèn)識轉(zhuǎn)變心力衰竭

神經(jīng)內(nèi)分泌失調(diào)

血流動力學(xué)紊亂心肌損害后神經(jīng)激素激活心肌受損刺激交感中樞性NE釋放血管收縮水潴留前負(fù)荷血管充血刺激血管加壓素血漿血管加壓素AdoptedfromGoldmithSR,KuboSH,inDrugTreatmentofHeartFailure,1988;50后負(fù)荷心肌功能刺激腎素血漿血管緊張素-II醛固酮鈉潴留長期的交感神經(jīng)系統(tǒng)激活NE水平升高ab

受體興奮細(xì)胞鈣超載氧化應(yīng)急心率心縮力及負(fù)荷增加心肌肥厚低血鉀腎灌注壓降低心肌細(xì)胞凋亡壞死心肌需氧增加心肌缺血心律失常腎素血管緊張素系統(tǒng)激活阻斷RAS系統(tǒng)局部的血管緊張素II分泌不依賴于血管緊張素轉(zhuǎn)換酶血管緊張素原肝臟血管緊張素I血管緊張素IIAT1AT2胃促胰酶腎素抑制劑血管緊張素轉(zhuǎn)換酶抑制劑纈沙坦AT1受體拮抗劑緩激肽羧氨酸AT1和AT2受體的作用血管收縮血管增殖醛固酮分泌心肌細(xì)胞增殖交感神經(jīng)活性增加血管緊張素IIAT1AT2血管舒張抗增殖細(xì)胞凋亡MyocardialInsultMyocardialDysfunctionRenin-Angiotensin-AldosteroneSystemActivation

SympatheticSystemActivationReducedSystemPerfusion

AlteredGene ExpressionApoptosis

RemodelingComplexcascadePathogenesisofHeartFailure心肌梗死后左室重塑急性心肌梗死(數(shù)小時)梗死擴(kuò)張(數(shù)小時數(shù)天)球型重塑(數(shù)天數(shù)月)b1

受體a1

受體心室重塑b2

受體交感的激活比索洛爾美托洛爾心得安達(dá)利全（卡維地洛）

受體阻斷劑的抗腎上腺素治療

NeuroendocrineImbalancein

HeartFailureGrowth-promoting:SympatheticactivationAngiotensin

(AT1receptor)AldosteroneEndothelinArginineVasopressinAnti-proliferativesubstances:NatriureticpeptidesBradykininNitricoxideAdrenomedullinACEInhibitionPreventsRemodelling:

SOLVD–Echocardiographic

Substudy2202102001904120MonthEnd-diastolicVolume(cc)P=0.0251601551501404120MonthP=0.019145End-systolicVolume(cc)0.400.300.200.104120MonthEjectionFraction0GreenbergBetal.Circulation1995Placebon= 130 130 142Enalapriln= 128 127 137ACEInhibitionvs

Carvedilol:

ComparativePharmacology

Carvedilol ACEinhibition

(b+ablockade)Neurohormonalmodulation SNS>>RAS RAS>SNSCardiacantiadrenergic + ±

2blockade + -

1blockade + -Bradykinin/NO - ++Antioxidant ++ +Apoptosis + +?Anti-ischaemic ++ +?Heartratereduction + -Remodellingeffects?SNS=SympatheticNervousSystem;RAS=Renin

AngiotensinSystemCARMEN:Rationale&BackgroundCarvedilolmayhaveasimilarorbetterprofilethanACEinhibitioninreversingremodellingandpreventingprogressionofCHFTochallengetheparadigmofACEinhibitionasmandatoryfirst-linetreatmentinmildCHFAfirststeptowardsareductioninpolypharmacyinthetreatmentofCHFToallowforamoreindividualisedapproachinselectedpatientsBaseline/screeningUp-titrationPhaseA0wkUp-titrationPhaseBMaintenancePhaseGroup1Ealapril(blinded)Group2Group39183612150Placebo(blinded)Down-titrationPhasePlacebo(blinded)Carvedilol(blinded)Carvedilol(blinded)Enalapril(blinded)Enalapril(blinded)Follow-up(months)Echoassessments572patientswithmildCHFonstabledosesofdiuretics,digoxin,nitrateswereincludedCARMEN:StudyDesign

LVESVI=leftventricularend-systolicvolumeindexLVEDVI=leftventricularend-diastolicvolumeindexEndpointsPrimaryendpointChangefrombaselinetomonth18inLVESVIassessedbyechocardiographybetweenCarvedilol&EnalaprilversusEnalaprilCarvedilolversusEnalaprilMajorsecondaryendpointschangesfrombaselineinLVESVIwithintreatmentgroupchangesfrombaselineinLVEDVI,LVEFMortalityandhospitalisationsNT-proBNP

LVESVI(biplane)[ml/m2]PvaluesforBLtoM6,M12,M18PrimaryEndpoint:LVESVI

ComparisonBetweenTreatmentsCarvedilol&EnalaprilCarvedilolEnalapril-7Month6Month12Month18BaselineNSP<0.002-6-5-4-3-2-10P<0.05LVESVI:ChangeFromBaseline

WithinTreatment-armComparison*P<0.05,**P<0.001EnalaprilCarvedilol-10-8-6-4-2024*********

LVESVI(ml/m2)M6M12M18M6M18M12M6M12M18Carvedilol&

EnalaprilLVEF:ChangeFromBaseline

WithinTreatment-armComparison*P<0.05;**P<0.01;***P<0.001EnalaprilCarvedilol&

EnalaprilCarvedilol-1012345

LVEF(%)******************M6M12M18M6M18M12M6M12M18CarvedilolCombination(C+E)Enalapril013253952657891104117130WeeksinStudyEventFree0.60.81.00.40.200.5875C+Evs.E0.8403Cvs.E0.7322C+Evs.CAll-causeMortalityorHospitalisationConclusionsThecombinationofcarvedilolandanACEinhibitortherapyresultedinahighlysignificantimprovementofLVremodellingandfunctionPatientsreceivingcarvedilol,eitherasmonotherapyorincombinationwithenalapril,showedareversalofLVremodelling-resultsnotobservedwithenalapril

monotherapyAllthreetreatmentarmsshowedaverysimilarsafetyandtolerabilityprofileIncontrasttocommonperception,therewasnodifferenceintolerabilitybetweencarvedilolandenalapril0200400600800Timeafterinclusion(days)1.00.80.60BisoprololPlaceboSurvivalp<0.0001CIBIS-IIInvestigatorsandCommittees,Lancet1999;353:9-13AnnualMortalityBisoprolol=9.0%Placebo=13.3%Averagefollow-up1.3yearsn=2647CIBISII-44%-26%-36%SuddenDeathPumpFailureMIOtherCVNonCVDeathsHospforCHFp=0.0011p=0.17p=NSp=NSp=NSp=0.0001PlaceboBisoprolol%ofgroup01020155CIBIS-II,Lancet1999;353:9-13CIBISII0102030405060AllCauseHospCVDeathsCombinedEndpointPermTxWithdrawalp=0.0006p=0.0049p=0.0004p=0.98PlaceboBisoprolol-20%-29%-21%%ofgroupCIBISIICIBIS-II,Lancet1999;353:9-1320151050036912151821Cumulativemortality(%)p=0.0062(adjusted)p=0.00009(nominal)PlaceboMetoprololCR/XLLancet1999;353:2001-7Follow-up(months)MERIT-HF-Mortality05010015020025034%49%41%38%DeathCVDeathSuddenDeathCHFDeathplacebo(n=2001)metoprolol

CR/XL(n=1990)p<0.00009p<0.00003p<0.0002p<0.0023DeathsMERIT-HFLancet1999;353:2001-7Hjalmarsonetal,JAMA2000;283:1295-302Monthsoffollow-up35302520151050Placebo

n=2001Metoprolol

CR/XL

n=199024681012PercentofpatientsEndoftitrationperiodRiskReduction:18%

P=0.0050All-CauseHospitalizationinMERIT-HF

(FirstYearofFollow-Up)HeartfailureP<0.00001-35%CVcauseP=0.00021-25%NumberofpatientsAll-causeP=0.0043-18%RR:6684942945813942000100200300400500600700PlaceboMetoprolol

CR/XLPatientsHospitalizedinMERIT-HFHjalmarsonetal,JAMA2000;283:1295-302*Patient’sself-assessment?72%consideredimprovementasimportant,veryimportant,

orextremelyimportanttocarryoutdailyactivities?AnegativevaluerepresentsimprovementNYHAclassimprovedNYHAclasssdeterioratedMcMasterOverallTreatmentEvaluationscore*(alittlebettertoagreatdealbetter)MinnesotaLivingwithHeartFailureQuestionnaireMetoprolol

CR/XLPlaceboOveralltreatmenteffect(pvalue)564/1970118/1970179/434?-0.7?(n=331)512/1982148/1982146/3700.2(n=339)0.00270.0087NSImprovementinNYHAClassandQualityofLifeinMERIT-HFHjalmarsonetal,JAMA2000;283:1295-302Placebo達(dá)利全顯著降低輕中度慢性心衰病人的死亡率達(dá)65%達(dá)利全（n=696）對照組（n=398）

1.00.90.80.70.60.5050100150200250300350400

治療時間(天)降低死亡危險65%

P<0.001USCarvedilolProgram生存率CarvedilolProspectiveRandomizedCumulativeSurvivalTrial達(dá)利全（卡維地洛）前瞻性隨機(jī)累計生存研究哥白尼研究，COPERNICUS目標(biāo)及臨床設(shè)計目標(biāo)：與安慰劑對比，達(dá)利全（卡維地洛）在嚴(yán)重慢性心衰患者中對總死亡率的影響設(shè)計：隨機(jī)、安慰劑對比、平行多中心研究，研究對象為缺血性及非缺血性心臟病導(dǎo)致的嚴(yán)重慢性心衰患者隨機(jī)性2289名患者按1:1的比例隨機(jī)分配

安慰劑

達(dá)利全（卡維地洛）起始劑量為3.125mgbid，每2周增加一倍劑量直至25

mgbid的目標(biāo)劑量。患者接受能夠耐受的最高劑量。哥白尼研究，COPERNICUS00%存活率36912151821月10090806070p=0.0001335%危險性降低卡維地洛安慰劑哥白尼研究，COPERNICUS所有原因的死亡率Packer,AHA2000

治療益處

p-值

死亡或任何原因的住院率24%

<0.0001

死亡或心血管原因的住院率27%

<0.0001

死亡或心衰的住院率 31%

<0.0001

哥白尼研究，COPERNICUSPacker,AHA2000摩羯星研究

CAPRICORN達(dá)利全(卡維地洛)心梗后左室功能不全生存對照研究Carvedilol

PostInfarctSurvivalControl

inLeftVentricularDysfunction181ProportioneventfreeYears0.90.850.70.750.80.9500.511.522.5CarvedilolPlacebo23%

vs.placebo

P=0.031PrimaryEndpoint:

All-CauseMortalityTrial n HazardRatio(95%CI)USCarvedilol

Prog 1,094 0.35(0.20-0.61)CIBISII 2,647 0.66(0.54-0.81)MERIT-HF 3,991 0.66(0.53-0.81)COPERNICUS 2,289 0.65(0.52-0.81)BEST 2,708 0.90(0.78-1.02)ProspectiveOutcomesStudiesof

BlockersinCHFPackeretal.NEJM1996;CIBISIIInvest.Lancet1999;MERIT-HFStudyGp.Lancet1999BESTInvestigators.Lancet1999;Packeretal.NEJM200100.20.40.60.81MildtoModerateSevere?-blockersimprovesurvivalinpatientswithmildtomoderate(andperhapsadvanced)heartfailure?-blockersreducehospitalization?-blockersimproveQOLandreducesymptomsConclusionsAreThereDifferencesBetweenbBlockers?bblockersareaheterogeneousclassmorethan15agentsavailableOnlythreehaveshownsignificantsurvivalbenefitsinmildtomoderateCHF carvedilolmetoprololbisoprolol達(dá)利全(n=696)對照組(n=398)0501001502002503003504001.00.90.80.70.60.5降低死亡危險65%p<0.001Packeretal(1996)Lancet(1999)0200400 600 8001.0

0.8

0.6

0Bisoprolol對照組p<0.0001生存率降低死亡危險34%TheMERIT-HFStudyGroup(1999)死亡率03691215182120151050對照組MetoprololCR/XLp=0.0062降低死亡危險34%USCarvedilolStudyCIBIS-IIMERIT-HF生存率用藥時間（天）用藥時間（天）用藥時間（月）達(dá)利全比傳統(tǒng)β受體阻滯劑臨床療效比較表RPharmacologicalDifferencesWithinthebBlockerClassb1

b2

a1

Ancillaryblockade

blockade

blockadeISAeffects* Carvedilol +++ ++++++ -+++Metoprolol +++ - - - -Bisoprolol +++ - - - -*anti-oxidant,anti-endothelin,anti-proliferativeMetraMetal.AmHeartJ2000EffectsofDifferentbBlockingAgentsSympatheticactivationPharmacologicaldifferences

1receptors

2receptors

1receptorsCardiotoxicityBisoprololCarvedilolMetoprololEffectsof

2-ReceptorsDirectchronotropic,inotropic,lusitropic

cAMPmediatedCouplingtotheGs/cAMPpathwaygreaterthanvia

1-adrenoceptor,furtherenhancedbyselective

1-blockade

Newtonetal.Circ1999;Kaumannetal,Circ1999Halletal.CircRes1990Hypertrophy,fibrosis,remodellingDuetal.Circulation2000AntiapoptoticCommunaletal.Circulation1999ArrhythmogenicBillmanetal.Circulation1997Facilitationofnorepinephrinerelease(presynaptic)Boudreauetal.AmJPhysiol1993Effectsof

1ReceptorsMyocardialhypertrophy,fibrosis,remodelingSimpson&McGrath,JClinInvest1983Morgan&Baker,Circulation1991Cardiotoxicity(withreceptors)

Mannetal.,Circulation1992ArrhythmogenicMolina-Viamonteetal.,Circulation1991Peripheralvasoconstriction

Leieretal.,Circulation1990RenalhypoperfusionandsodiumretentionSmythetal.,CircRes1985Hesseetal.,BrJPharmacol1985RandomisedTrials

ComparingMetoprololandCarvedilolMetraetal.(Circulation,2000) n=150Di

Lenardaetal.(JAmColl

Cardiol,1999) n=30Kukinetal.(Circulation,1999) n=67Sandersonetal.(JAmColl

Cardiol,1999) n=51Dodifferentadrenergicblockingagentsexertequaleffectsinheartfailure?0246810121416Absolutechangefrombaseline-40-35-30-25-20-15-10-50ml/m2LVEjectionfractionLVEDVLVESVMetoprololCarvedilolLVEFunits(%)CarvedilolReversesLVRemodellingtoaGreaterExtentthanMetoprololMetraMetal.Circulation2000*************P<0.01;***P<0.001

vsbaseline******P=0.038PeakVO2AbsoluteChangefromBaseline

(ml/kg/min)SixminwalkMLHFNYHAclassMetoprololCarvedilolAbsoluteChangesinExerciseToleranceandSymptomsAfterLong-termTreatmentwithMetoprololorCarvedilolMetraMetal.Circulation2000MLHF=MinnesotaLivingwithHeartFailure020406080100Meters-16-14-12-10-8-6-4-20Score-1.5-1.2-0.9-0.6-0.30******************-1-0.500.511.52***RandomizedTrialsThatHaveDirectlyComparedMetoprololwithCarvedilolStudy Targetmetoprolol Targetcarvedilol IRdose(n=147) dose(n=151)DiLenardaetal., 100mgBID 50mgBID(JACC1999) (n=16) (n=14)Kukinetal., 25mgBID 25mgBID(Circulation1999) (n=30) (n=37)Metraetal., 50mgBID 25mgBID(Circulation2000) (n=75) (n=75)Sandersonetal., 50mgBID 25mgBID(JACC1999) (n=26) (n=25)Meantargetdose 50.3mgBID 27.3mgBIDRestingheartrate 65beats/min 65beats/minExerciseheartrate 119beats/min 116beats/minDiLenardaAetal.JAmColl

Cardiol1999.MetraMetal.Circulation2000

KukinMLetal.Circulation1999.SandersonJEetal.JAmColl

Cardiol1999PackerMetal.AmHeartJ2001LVEjectionFraction(%)0+2+4+6+8+10+12Metoprolol(n=123)Carvedilol(n=125)P=0.009Meta-analysisofDirectComparisonTrials

withMetoprololandCarvedilolinCHFCOMETHypothesisDotheantisympatheticactionsofcarvedilolbeyond

1-blockadehaveafavorableeffectonsurvival?COMETTrialTheCOMETtrialisnotsimplyacomparisonofthesurvivaleffectsofmetoprololandcarvedilolinpatientswithheartfailure.TheCOMETtrialisreallyatestofwhetherthepropertiesofcarvedilol

beyond

1-blockadehavefavorableeffectsonsurvival.

–

Thisistrueonlyifthedosesofmetoprolol andcarvedilolusedinCOMETtrial(50mg BIDand25mgBID,respectively)produce equivalentdegreesof

1-blockadeObjectivesandDesignTocomparetheeffectsofcarvedilolwiththoseofmetoprololonmortalityandmorbidityinpatientswithchronicheartfailureNorun-inperiod

Mild,moderateorsevereCHFMetoprolol(n=1,518)Carvedilol(n=1,511)ScreeningTitrationMaintenance(estimated4-6yrs)RandomisationTime(years)Mortality(%)010203040012345MetoprololCarvedilolhazardratio0.83,95%CI0.74-0.93,P=0.0017

NumberatriskCarvedilol 1511 1367 1259 1155 1002 383Metoprolol 1518 1359 1234 1105 933 352Primaryendpointofmortality0.500.751.001.251.50SexmalefemaleAge<65

65NYHAIIIIIIVCauseOtherIHDLVEF

25%>25%Heartrate<80

80SystolicBP<110110-139

140DiabetesyesnoOverallCarvedilolbetterMetoprololbetter4101200 5001217 0.80175730 228736 0.75309732 324716 0.912849 4866 0.68102311 100301 0.97207834 231803 0.84305677 369715 0.84198735 219703 0.83314776 381815 0.85270706 285630 0.79221743 287819 0.84234693 284733 0.86277816 314783 0.80120245 132235 0.80121447 158434 0.71153360 178371 0.853591151 4221147 0.82512151160015180.83270817 310849 0.89

deathsn deathsnHR

Carvedilol

MetoprololMortalityinsub-groupsSummaryandconclusionCOMETisthelongestandlargeststudyinCHFFirsthead-to-headmortalitystudycomparingtwobeta-blockingagentsinCHFCarvedilolsavedsignificantlymorelivesthanmetoprolol(by17%,P=0.0017)Carvedilolcomparedtometoprololreducedannualmortalityfrom10.0%to8.3%andprolongedmediansurvivalby1.4yearsCarvedilolisthepreferredbeta-blockerforthetreatment ofchronicheartfailure急性心梗仍然嚴(yán)重威脅生命

每年有110萬心梗新發(fā)病例(65萬為首次發(fā)作,45萬為復(fù)發(fā)心梗)

每年有83萬次心梗住院

每年死亡患者20萬例每29秒即發(fā)生1例心梗,每分鐘即有1例患者死于心梗美國危險因素動脈粥樣硬化心梗心室重構(gòu)心室擴(kuò)大心衰終末期

心血管疾病死亡獲得證據(jù)的高危心梗后患者的治療藥物左心室功能損害程度抗血小板藥物β-阻滯劑他汀類藥物已證實(shí)療效的ACE-I醛固酮受體拮抗劑LVSD或急性心衰

LVSD

和急性心衰

AT1AT2胃促胰酶腎素抑制劑ARB血管緊張素轉(zhuǎn)化酶抑制劑（ACEI）的作用機(jī)制血管緊張素原(肝臟)血管緊張素ⅠACEI血管緊張素Ⅱ緩激肽羧氨酸循證醫(yī)學(xué)證據(jù)：ACEI治療心力衰竭試驗例數(shù)心功能治療藥物隨訪死亡率P值CONSENSUS253IV依那普利

6m–40%0.002V-HeFTII*804II~III依那普利

30m–28%0.016SOLVD-T2569II~IV依那普利41m–16%0.0036AIRE2006II~III雷米普利15m–27%0.002AIREX603II~III雷米普利

59m–36%0.002*與肼屈嗪-硝酸異山梨酯治療相比較*OR(95%CI)FlatherMD,etal.Lancet.2000;355:1575–1581因心衰再次住院n=

460n=

355(0.63–0.85)0.73*n=

324n=

391(0.69–0.95)0.80*安慰劑

(n=2971)ACEI(n=2995)心血管死亡/心肌梗死/因心衰再次住院010203040n=

1049n=

1244(0.67–0.83)0.75*心肌梗死復(fù)發(fā)ACEI降低心血管死亡和主要心血管事件危險25%死亡及主要心血管事件發(fā)生率(%)SAVE/AIRE/TRACE研究薈萃分析*:OR(oddRatio)LessonsfromACEinhibitortrialsinheartfailureACE-inhibitorsexerttheirmajoreffectsnotthroughvasodilationbutthroughblockingofneuroendocrineactivationNeuroendocrineactivationisassociatedwithimprovedprognosisandtherapeuticeffectACE-inhibitortherapyimprovessurvivalinpatientswithheartfailureandsystolicdysfunctionARB阻斷RAS系統(tǒng)，可否具備同樣心血管益處?血管緊張素原非ACE途徑

(例如:糜蛋白酶)收縮血管細(xì)胞生長鈉/水儲留交感神經(jīng)激活腎素血管緊張素I血管緊張素IIACE咳嗽血管性水腫益處

緩激肽非活性片段擴(kuò)張血管抗增殖(激肽)醛固酮AT2AT1ACEIARBAT1-receptorblockersinheartfailureAT1-receptorblockermonotherapyisbetterthanplaceboBenefitofACEinhibitorsisduetoreducedangiotensinIIproduction2ACEinhibitorandAT1-

receptorblockercombinationtherapyisbetterthanACEinhibitormonotherapyARB:moreeffectiveRAASinhibitionACEinhibitor:BKis“good”31Non-ACEangiotensinIIgenerationSelectiveblockadeofAT1receptor/

stimulationofAT2receptorBKis“bad”ARBsbettertoleratedAT1-receptorblockermonotherapyisbetterthanACEinhibitormonotherapyHypothesisTheoreticalbasisAT1-receptorblockermonotherapyisbetterthanplacebo?2ACEinhibitorandAT1-receptorblockercombinationtherapyisbetterthanACEinhibitormonotherapy?31AT1-receptorblockermonotherapyisbetterthanACEinhibitormonotherapy?QuestionTrial

AnswerCHARM ?

(0003study)Val-HeFT ?CHARM ?

(0006study)ELITE-II NoAT1-receptorblockersinheartfailure氯沙坦心力衰竭試驗（ELITE-II）

假設(shè)和目的假設(shè)：在有癥狀心力衰竭患者中，與卡托普利相比，氯沙坦能更多地降低總死亡率（主要終點(diǎn)）、降低心臟猝死（包括復(fù)蘇成功者）的發(fā)生率（第二終點(diǎn)）如果上述假設(shè)得到證實(shí)，氯沙坦將取代血管緊張素轉(zhuǎn)換酶抑制劑作為治療心力衰竭的標(biāo)準(zhǔn)PittB,etal.JCardFail1999,5(2):146-154ELITE-II試驗：研究終點(diǎn)小結(jié)卡托普利組（n=1574）氯沙坦組（n=1578）校正后危險比（95%CI）P值主要終點(diǎn)總死亡率250(15.9%)280(17.7%)0.88(0.75~1.05)0.16二級終點(diǎn)猝死/復(fù)蘇115(7.3%)142(9.0%)0.80(0.63~1.03)0.08三級終點(diǎn)

總死亡/住院707(44.9%)752(47.7%)0.94(0.85~1.04)0.21

副作用停藥228(14.5%)149(9.4%)<0.001心力衰竭患者

>18歲;EF<40%;NYHAII~IV906例死亡（記錄事件）纈沙坦

40mgbid，上調(diào)至

160mg

bid安慰劑隨機(jī)分組接受常規(guī)治療包括ACE抑制劑、利尿劑、地高辛、

-阻滯劑（分層隨機(jī)）Val-HeFT

試驗設(shè)計Val-HeFT：主要終點(diǎn)分析終點(diǎn)事件數(shù)危險比（95%CI）P值纈沙坦組（n=2511）安慰劑組（n=2499）所有原因死亡495(19.7%)484(19.4%)1.02(0.90~1.15)0.800所有原因死亡/病殘率723(28.8%)801(32.1%)0.87(0.79~0.96)0.009ARBs:用于心梗后的證據(jù)OPTIMAAL

OPtimalTrialInMyocardialinfarctionwiththeAngiotensinIIAntagonistLosartan

血管緊張素II拮抗劑氯沙坦心肌梗死最佳試驗VALIANTVALsartanInAcutemyocardialiNfarctionTrial纈沙坦急性心肌梗死試驗急性心梗臨床/放射學(xué)

心衰體征LVEF<35%orLVEDD>65mm新發(fā)Q波前壁心梗或

新發(fā)LBBB或既往前壁Q波梗死再發(fā)心梗OPTIMAAL:入選標(biāo)準(zhǔn)LVEDD:左室舒張末期內(nèi)徑LBBB:左束支傳導(dǎo)阻滯隨機(jī)分組(N=5,004)氯沙坦12.5mgqd氯沙坦25mgqd氯沙坦50mgqd卡托普利12.5mgtid卡托普利25mgtid卡托普利50mgtidDicksteinK,KjekshusJ.AmJCardiol

1999;

83(4):477-81.OPTIMAAL:

療程劑量OPTIMAAL:主要結(jié)果終點(diǎn) 氯沙坦(n) 卡托普利(n) 比數(shù)比

p值死亡率 499 447 1.13(0.99–1.28) 0.069復(fù)蘇 239 203 1.19(0.99–1.34) 0.073

心跳驟停+猝死心梗 384 379 1.03(0.89–1.18) 0.72腦卒中 140 132 1.07(0.84–1.36) 0.587心血管死亡 420 363 1.17(1.01–1.34) 0.032住院治療 1,806 1,774 1.03(0.97–1.10) 0.362

DicksteinK,etal.Lancet2002;

360:752-60.急性心梗后高?；颊咚劳雎?0%20%10%10%卡托普利較好氯沙坦較好

OPTIMAAL:所有原因死亡率OPTIMAAL:結(jié)論本研究顯示氯沙坦并不比卡托普利占優(yōu)勢，而且也未顯示出其與卡托普利等效根據(jù)OPTIMAAL研究:

-對這組人群不推薦使用氯沙坦

-ACEI仍是有并發(fā)癥的急性心?；颊叩囊痪€治療

ARB急需新的證據(jù)證實(shí)對高危心梗患者的療效左心室功能損害程度抗血小板藥物β-阻滯劑他汀類藥物已證實(shí)療效的ACE-I

氯沙坦50mgqd

其他ARB?ACE-I+ARB?醛固酮拮抗劑LVSD

或急性心衰

LVSD

和急性心衰

OPTIMAAL研究失敗的可能原因

Losartan

劑量不足

ELITEII，OPTIMAL均為50mg/日

LIFE為100mg/日

Losartan

為ARBs

中作用最弱者

心梗后試驗Lancet.2002;360:752–760.AmJCardiol.1991;68:70D–79D.Lancet.1993;342:821–828.

NEnglJMed.1995;333:1670–1676.Dataonfile.NovartisPharmaceuticals.SAVEAIRETRACEOPTIMAALVALIANT2,2311,9861,7495,47714,70302,0004,0006,0008,00010,00016,00012,00014,000評價心梗后患者心臟保護(hù)作用的大型研究

OPTIMAAL左心室功能不全急性心衰VALIANT研究中入選的患者比OPTIMAAL研究更高危Captopril

(4909)50mgtid4871(99.2%)Vitalstatusunknown:38(0.8%)VALIANT:入選和隨訪Medianfollow-up:24.7monthsValsartan

(4909)160mgbid4856(98.9%)Vitalstatusunknown:53(1.1%)14808PatientsRandomized4837(99.0%)Vitalstatusunknown:48(1.0%)Combination

(4885)50mgbid+80mgbidInformedconsentnotensured:105patientsVitalstatusascertainedin14564patients(99.05%)Vitalstatusnotascertainedin139patients(0.95%)14703Patients總死亡率—非劣效性檢驗0.811.2危險比(97.5%可信區(qū)間)1.13P值(非劣效性)0.002方案治療患者群體

(n=14,285)0.004意向治療患者群體(n=14,703)非劣效性成立纈沙坦優(yōu)于卡托普利卡托普利優(yōu)于纈沙坦非劣效性不成立非劣效性檢驗界值非劣效性檢驗首次證實(shí)ARB與ACEI作用相當(dāng)代文可降低心肌梗死高危患者死亡率達(dá)25%死亡率危險比利于有效藥物利于安慰劑Pfeffer,McMurray,Velazquez,etal.NEnglJMed2003;3490.512三項研究的聯(lián)合死亡率TRACESAVEAIREVALIANT(歸因分析)纈沙坦可保留卡托普利99.6%的生存利益25%非劣效性成立纈沙坦優(yōu)于卡托普利卡托普利優(yōu)于纈沙坦非劣效性不成立纈沙坦降低心血管死亡和主要心血管事件危險與ACEI相當(dāng)0.811.2危險比(97.5%可信區(qū)間)1.13P值(非劣效性)非劣效性檢驗界值心血管死亡(1657例事件)0.001心血管死亡或心衰

(2661例事件)0.0001心血管死亡或心梗復(fù)發(fā)

(2234例事件)0.00001心血管死亡、心梗復(fù)發(fā)或心衰

(3096例事件)0.000001心血管死亡率和并發(fā)癥率心血管死亡、心肌梗死或心衰的危險比(95%可信區(qū)間)Pfeffer,McMurray,Velazquez,etal.NEnglJMed2003;349:1893–1906利于聯(lián)合

用藥組利于卡托普利組平均年齡 <65 ≥65性別

Male

Female既往 No

心肌梗死

Yes

糖尿病

No

Yes收縮壓 ≤median

>median血清肌酐 ≤median

>medianKillip分級

I

II

III

IVβ受體 No

阻滯劑

Yes

0.512利于纈沙坦組利于卡托普利組#患者人數(shù)P值0.512#患者人數(shù)P值4618

52006738

30807088

27307564

22545632

41824970

48372718

4747

1687

6190.96

0.55

0.93

0.12

0.71

0.67

0.844675

51196768

30267085

27097528

22665642

41494908

48782805

4675

1655

6181.00

0.47

0.26

0.85

0.68

0.92

0.112907

69110.482910

68820.56亞組分析顯示各亞組患者應(yīng)用纈沙坦均受益心血管死亡、心肌梗死或心衰的危險比(95%可信區(qū)間)纈沙坦VS.卡托普利:未服用β受體阻滯劑(n=2907)服用β受體阻滯劑(n=6911)聯(lián)合用藥VS.卡托普利:未服用β受體阻滯劑(n=2910)服用β受體阻滯劑(n=6882)0.512利于卡托普利組利于纈沙坦組利于卡托普利組利于聯(lián)合用藥組0.560.48P值(非劣效性)ARB可與β阻滯劑和ACEI安全地合用Pfeffer,McMurray,Velazquez,etal.NEnglJMed2003;349:1893–1906研究結(jié)論針對合并心力衰竭和/或左室功能障礙的心肌梗死患者:

纈沙坦與證實(shí)劑量的卡托普利可同樣有效地降低下列事件的發(fā)生危險:死亡心血管死亡、非致死性心肌梗死、心衰住院歸因分析纈沙坦可降低心肌梗死高危患者死亡率達(dá)25%

纈沙坦與證實(shí)劑量的卡托普利聯(lián)合用藥未能進(jìn)一步降低死亡率,同時可能增加不良反應(yīng)。臨床意義:VALIANT研究首次證實(shí)，ARB(纈沙坦)對心肌梗死后高?；颊叩闹委熥饔门cACEI相當(dāng).降低心肌梗死高危患者死亡率達(dá)25%纈沙坦與心血管事件鏈動脈粥樣硬化左室肥厚重構(gòu)心室擴(kuò)張充血性心衰終末期心臟病心肌梗死危險因素高血壓吸煙血脂水平糖尿病年齡等…死亡AT1-receptorblockers:mechanism

ofactionAngiotensinIItype1(AT1)receptorblockers–pharmacologicallydistinctmechanismofinhibitingRAASAT1-receptorinhibition–morecompleteblockadeofangiotensinIIactionExistenceofalternative,non-ACEenzymaticpathways–angiotensinIIcanbegeneratedfromangiotensinIeveninpresenceofACEinhibitor[1]ReflexincreaseinangiotensinIinducedbyACE

inhibitionmayovercomecompetitiveblockadeofACEenablingangiotensinII(andaldosterone)‘escape’BlockadeofAT1-receptor,ratherthanACE,could

bebetteratinhibitingadverseeffectsofRAAS1.

Wolnyetal.CircRes1997;80(2):219–27Candesartan:potentandlong-acting

AT1-receptorblockerHighlypotent[1]Long-acting[1]10,000greateraffinityforAT1-receptorthanAT2-receptor[1]‘Insurmountable’antagonist[1]Antihypertensiveagent[2]Welltolerated[3–6]Effectonmorbidityandmortality?1. Ojimaetal.EurJPharmacol1997;319:137–46.2. Anderssonetal.JHumHypertens1997;11(Supp2):S63–4.3. McKelvieetal.Circulation1999;100:1056–64.4. Grangeretal.AmHeartJ2000139(4):609–17.5. Rieggeretal.Circulation1999;100:2224–30.6. Mitrovicetal.AmHeartJ2003;145:E14.Clinicalexperiencewithcandesartan

inCHFRESOLVDpilotstudy:candesartancombinedwithenalaprilimprovedLVfunctionmorethaneitherofagentsalone,andsuppressedaldosteronelevelstoagreaterextent[1]SPICEpilotstudy:inpatientswithhistoryofACEinhibitorintolerance,similarpercentageofpatientscompleted12-weektreatmentperiodoncandesartanvsplacebo[2]STRETCHstudy:maximalexercisecapacityincreaseddose-dependentlywithcandesartancomparedtoplacebo[3]Mitrovicetal.study:candesartandemonstrated

significantshort-andlong-termimprovementsinhaemodynamic,neurohormonalandsymptomatic

status[4]1.

McKelvieetal.Circulation1999;100:1056–642.

Grangeretal.AmHeartJ2000139(4):609–173.

Rieggeretal.Circulation1999;100:2224–304.

Mitrovicetal.AmHeartJ2003;145:E14Background(1)ACEinhibitors,beta-blockersandspironolactonehavebeendemonstratedtobelife-savinginpatientswithCHFHowever,thesepatientsstillremainathighriskforcardiovasculardeathandrecurrenthospitaladmissionsforheartfailure

Background(2)AngiotensinIItype1(AT1)receptorblockers(ARBs)provideapharmacologicallydistinctmechanismofinhibitingtherenin-angiotensin-aldosteronesystemARBsofferthepotentialtoproducefurtherclinicalimprovementsaboveandbeyondACEinhibitorsaswellasanalternativeforthosepreviouslyintoleranttoanACEinhibitorCHARM

AddedCHARM

PreservedCHARMProgramme3componenttrialscomparingcandesartan

toplaceboinpatientswithsymptomaticheartfailureCHARM

Alternativen=2028

LVEF￡40%

ACEinhibitor

intolerantn=2548LVEF￡40%

ACEinhibitor

treatedn=3025LVEF>40%

ACEinhibitor

treated/nottreatedPrimaryoutcomeforOverallProgramme:All-causedeathPrimaryoutcomeforeachtrial:CVdeathorCHFhospitalisationCHARM-Alternative

PatientdispositionMedianfollow-upof34