医学资料 慢性心力衰竭临床试验的回顾 学习课件

慢性心力衰竭临床试验的回顾北京大学第三医院心内科张福春导致心血管死亡事件之链心肌梗死心律失常猝死肌肉丢失神经激素激活重塑心室扩大心力衰竭死亡冠脉血栓心肌缺血CAD动脉硬化LVH危险因素

高脂蛋白血症

高血压

糖尿病

胰岛素抵抗AdaptedfromDzauV.BraunwaidE.AmHeartJ1991:121:1244-1263心力衰竭病生理机制的认识转变心力衰竭

神经内分泌失调

血流动力学紊乱心肌损害后神经激素激活心肌受损刺激交感中枢性NE释放血管收缩水潴留前负荷血管充血刺激血管加压素血浆血管加压素AdoptedfromGoldmithSR,KuboSH,inDrugTreatmentofHeartFailure,1988;50后负荷心肌功能刺激肾素血浆血管紧张素-II醛固酮钠潴留长期的交感神经系统激活NE水平升高ab

受体兴奋细胞钙超载氧化应急心率心缩力及负荷增加心肌肥厚低血钾肾灌注压降低心肌细胞凋亡坏死心肌需氧增加心肌缺血心律失常肾素血管紧张素系统激活阻断RAS系统局部的血管紧张素II分泌不依赖于血管紧张素转换酶血管紧张素原肝脏血管紧张素I血管紧张素IIAT1AT2胃促胰酶肾素抑制剂血管紧张素转换酶抑制剂缬沙坦AT1受体拮抗剂缓激肽羧氨酸AT1和AT2受体的作用血管收缩血管增殖醛固酮分泌心肌细胞增殖交感神经活性增加血管紧张素IIAT1AT2血管舒张抗增殖细胞凋亡MyocardialInsultMyocardialDysfunctionRenin-Angiotensin-AldosteroneSystemActivation

SympatheticSystemActivationReducedSystemPerfusion

AlteredGene ExpressionApoptosis

RemodelingComplexcascadePathogenesisofHeartFailure心肌梗死后左室重塑急性心肌梗死(数小时)梗死扩张(数小时数天)球型重塑(数天数月)b1

受体a1

受体心室重塑b2

受体交感的激活比索洛尔美托洛尔心得安达利全（卡维地洛）

受体阻断剂的抗肾上腺素治疗

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达利全显著降低轻中度慢性心衰病人的死亡率达65%达利全（n=696）对照组（n=398）

1.00.90.80.70.60.5050100150200250300350400

治疗时间(天)降低死亡危险65%

P<0.001USCarvedilolProgram生存率CarvedilolProspectiveRandomizedCumulativeSurvivalTrial达利全（卡维地洛）前瞻性随机累计生存研究哥白尼研究，COPERNICUS目标及临床设计目标：与安慰剂对比，达利全（卡维地洛）在严重慢性心衰患者中对总死亡率的影响设计：随机、安慰剂对比、平行多中心研究，研究对象为缺血性及非缺血性心脏病导致的严重慢性心衰患者随机性2289名患者按1:1的比例随机分配

安慰剂

达利全（卡维地洛）起始剂量为3.125mgbid，每2周增加一倍剂量直至25

mgbid的目标剂量。患者接受能够耐受的最高剂量。哥白尼研究，COPERNICUS00%存活率36912151821月10090806070p=0.0001335%危险性降低卡维地洛安慰剂哥白尼研究，COPERNICUS所有原因的死亡率Packer,AHA2000

治疗益处

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达利全(卡维地洛)心梗后左室功能不全生存对照研究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.NEJM200100.20.40.60.81MildtoModerateSevereß-blockersimprovesurvivalinpatientswithmildtomoderate(andperhapsadvanced)heartfailureß-blockersreducehospitalizationß-blockersimproveQOLandreducesymptomsConclusionsAreThereDifferencesBetweenbBlockers?bblockersareaheterogeneousclassmorethan15agentsavailableOnlythreehaveshownsignificantsurvivalbenefitsinmildtomoderateCHF carvedilolmetoprololbisoprolol达利全(n=696)对照组(n=398)0501001502002503003504001.00.90.80.70.60.5降低死亡危险65%p<0.001Packeretal(1996)Lancet(1999)0200400 600 8001.0

0.8

0.6

0Bisoprolol对照组p<0.0001生存率降低死亡危险34%TheMERIT-HFStudyGroup(1999)死亡率03691215182120151050对照组MetoprololCR/XLp=0.0062降低死亡危险34%USCarvedilolStudyCIBIS-IIMERIT-HF生存率用药时间（天）用药时间（天）用药时间（月）达利全比传统β受体阻滞剂临床疗效比较表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急性心梗仍然严重威胁生命

每年有110万心梗新发病例(65万为首次发作,45万为复发心梗)

每年有83万次心梗住院

每年死亡患者20万例每29秒即发生1例心梗,每分钟即有1例患者死于心梗美国危险因素动脉粥样硬化心梗心室重构心室扩大心衰终末期

心血管疾病死亡获得证据的高危心梗后患者的治疗药物左心室功能损害程度抗血小板药物β-阻滞剂他汀类药物已证实疗效的ACE-I醛固酮受体拮抗剂LVSD或急性心衰

LVSD

和急性心衰

AT1AT2胃促胰酶肾素抑制剂ARB血管紧张素转化酶抑制剂（ACEI）的作用机制血管紧张素原(肝脏)血管紧张素ⅠACEI血管紧张素Ⅱ缓激肽羧氨酸循证医学证据：ACEI治疗心力衰竭试验例数心功能治疗药物随访死亡率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*与肼屈嗪-硝酸异山梨酯治疗相比较*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*安慰剂

(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*心肌梗死复发ACEI降低心血管死亡和主要心血管事件危险25%死亡及主要心血管事件发生率(%)SAVE/AIRE/TRACE研究荟萃分析*:OR(oddRatio)LessonsfromACEinhibitortrialsinheartfailureACE-inhibitorsexerttheirmajoreffectsnotthroughvasodilationbutthroughblockingofneuroendocrineactivationNeuroendocrineactivationisassociatedwithimprovedprognosisandtherapeuticeffectACE-inhibitortherapyimprovessurvivalinpatientswithheartfailureandsystolicdysfunctionARB阻断RAS系统，可否具备同样心血管益处?血管紧张素原非ACE途径

(例如:糜蛋白酶)收缩血管细胞生长钠/水储留交感神经激活肾素血管紧张素I血管紧张素IIACE咳嗽血管性水肿益处

缓激肽非活性片段扩张血管抗增殖(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氯沙坦心力衰竭试验（ELITE-II）

假设和目的假设：在有症状心力衰竭患者中，与卡托普利相比，氯沙坦能更多地降低总死亡率（主要终点）、降低心脏猝死（包括复苏成功者）的发生率（第二终点）如果上述假设得到证实，氯沙坦将取代血管紧张素转换酶抑制剂作为治疗心力衰竭的标准PittB,etal.JCardFail1999,5(2):146-154ELITE-II试验：研究终点小结卡托普利组（n=1574）氯沙坦组（n=1578）校正后危险比（95%CI）P值主要终点总死亡率250(15.9%)280(17.7%)0.88(0.75~1.05)0.16二级终点猝死/复苏115(7.3%)142(9.0%)0.80(0.63~1.03)0.08三级终点

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

副作用停药228(14.5%)149(9.4%)<0.001心力衰竭患者

>18岁;EF<40%;NYHAII~IV906例死亡（记录事件）缬沙坦

40mgbid，上调至

160mg

bid安慰剂随机分组接受常规治疗包括ACE抑制剂、利尿剂、地高辛、

-阻滞剂（分层随机）Val-HeFT

试验设计Val-HeFT：主要终点分析终点事件数危险比（95%CI）P值缬沙坦组（n=2511）安慰剂组（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/病残率723(28.8%)801(32.1%)0.87(0.79~0.96)0.009ARBs:用于心梗后的证据OPTIMAAL

OPtimalTrialInMyocardialinfarctionwiththeAngiotensinIIAntagonistLosartan

血管紧张素II拮抗剂氯沙坦心肌梗死最佳试验VALIANTVALsartanInAcutemyocardialiNfarctionTrial缬沙坦急性心肌梗死试验急性心梗临床/放射学

心衰体征LVEF<35%orLVEDD>65mm新发Q波前壁心梗或

新发LBBB或既往前壁Q波梗死再发心梗OPTIMAAL:入选标准LVEDD:左室舒张末期内径LBBB:左束支传导阻滞随机分组(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:

疗程剂量OPTIMAAL:主要结果终点 氯沙坦(n) 卡托普利(n) 比数比

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

心跳骤停+猝死心梗 384 379 1.03(0.89–1.18) 0.72脑卒中 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住院治疗 1,806 1,774 1.03(0.97–1.10) 0.362

DicksteinK,etal.Lancet2002;

360:752-60.急性心梗后高危患者死亡率30%20%10%10%卡托普利较好氯沙坦较好

OPTIMAAL:所有原因死亡率OPTIMAAL:结论本研究显示氯沙坦并不比卡托普利占优势，而且也未显示出其与卡托普利等效根据OPTIMAAL研究:

-对这组人群不推荐使用氯沙坦

-ACEI仍是有并发症的急性心梗患者的一线治疗

ARB急需新的证据证实对高危心梗患者的疗效左心室功能损害程度抗血小板药物β-阻滞剂他汀类药物已证实疗效的ACE-I

氯沙坦50mgqd

其他ARB?ACE-I+ARB?醛固酮拮抗剂LVSD

或急性心衰

LVSD

和急性心衰

OPTIMAAL研究失败的可能原因

Losartan

剂量不足

ELITEII，OPTIMAL均为50mg/日

LIFE为100mg/日

Losartan

为ARBs

中作用最弱者

心梗后试验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评价心梗后患者心脏保护作用的大型研究

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

(4909)50mgtid4871(99.2%)Vitalstatusunknown:38(0.8%)VALIANT:入选和随访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总死亡率—非劣效性检验0.811.2危险比(97.5%可信区间)1.13P值(非劣效性)0.002方案治疗患者群体

(n=14,285)0.004意向治疗患者群体(n=14,703)非劣效性成立缬沙坦优于卡托普利卡托普利优于缬沙坦非劣效性不成立非劣效性检验界值非劣效性检验首次证实ARB与ACEI作用相当代文可降低心肌梗死高危患者死亡率达25%死亡率危险比利于有效药物利于安慰剂Pfeffer,McMurray,Velazquez,etal.NEnglJMed2003;3490.512三项研究的联合死亡率TRACESAVEAIREVALIANT(归因分析)缬沙坦可保留卡托普利99.6%的生存利益25%非劣效性成立缬沙坦优于卡托普利卡托普利优于缬沙坦非劣效性不成立缬沙坦降低心血管死亡和主要心血管事件危险与ACEI相当0.811.2危险比(97.5%可信区间)1.13P值(非劣效性)非劣效性检验界值心血管死亡(1657例事件)0.001心血管死亡或心衰

(2661例事件)0.0001心血管死亡或心梗复发

(2234例事件)0.00001心血管死亡、心梗复发或心衰

(3096例事件)0.000001心血管死亡率和并发症率心血管死亡、心肌梗死或心衰的危险比(95%可信区间)Pfeffer,McMurray,Velazquez,etal.NEnglJMed2003;349:1893–1906利于联合

用药组利于卡托普利组平均年龄 <65 ≥65性别

Male

Female既往 No

心肌梗死

Yes

糖尿病

No

Yes收缩压 ≤median

>median血清肌酐 ≤median

>medianKillip分级

I

II

III

IVβ受体 No

阻滞剂

Yes

0.512利于缬沙坦组利于卡托普利组#患者人数P值0.512#患者人数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亚组分析显示各亚组患者应用缬沙坦均受益心血管死亡、心肌梗死或心衰的危险比(95%可信区间)缬沙坦VS.卡托普利:未服用β受体阻滞剂(n=2907)服用β受体阻滞剂(n=6911)联合用药VS.卡托普利:未服用β受体阻滞剂(n=2910)服用β受体阻滞剂(n=6882)0.512利于卡托普利组利于缬沙坦组利于卡托普利组利于联合用药组0.560.48P值(非劣效性)ARB可与β阻滞剂和ACEI安全地合用Pfeffer,McMurray,Velazquez,etal.NEnglJMed2003;349:1893–1906研究结论针对合并心力衰竭和/或左室功能障碍的心肌梗死患者:

缬沙坦与证实剂量的卡托普利可同样有效地降低下列事件的发生危险:死亡心血管死亡、非致死性心肌梗死、心衰住院归因分析缬沙坦可降低心肌梗死高危患者死亡率达25%

缬沙坦与证实剂量的卡托普利联合用药未能进一步降低死亡率,同时可能增加不良反应。临床意义:VALIANT研究首次证实，ARB(缬沙坦)对心肌梗死后高危患者的治疗作用与ACEI相当.降低心肌梗死高危患者死亡率达25%缬沙坦与心血管事件链动脉粥样硬化左室肥厚重构心室扩张充血性心衰终末期心脏病心肌梗死危险因素高血压吸烟血脂水平糖尿病年龄等…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