选择性醛固酮封锁需与瞬态或永久心脏的急性心肌梗死住院期间衰竭患者

NeedforSelectiveAldosteroneBlockadeforPatientswithTransientorPersistentHeartFailureDuringHospitalisationforAMIHospitalEventsinNRMIAMIPatientsEVENTAMI+CHF(%)AMI(%)Stroke2.21.4AVblock5.74.6VTorVF11.99.09Rupture/EMD1.81.0Unexpectedcardiacarrest8.34.4LOS7.15.3RecurrentMI3.02.7Death21.47.2AMIandHFConclusionsfromNMRICHFandAMIisahighrisksituationDespitethehighrisk,thesepatientsarelessfrequentlytreatedwithmedicationswithprovenmortalitybenefitorwithprimaryreperfusionstrategiesNoneofthesepatientsweretreatedwithaldactoneoreplerenoneCardiacEchoperformedwithin24hrsafterAMIPrognosisafterMyocardialInfarctionGRACE:ImpactofHeartFailure

onCumulativeMortalityFromACSACS=acutecoronarysyndromes.StegPGetal.Circulation.2004;109:494-499.TimetoDeathWithin6Months(n=10,771)0.0012346HR=3.8(95%CI,3.33to4.36)

HeartfailureatadmissionNoheartfailureatadmissionProportionDead5ACE-I=angiotensin-convertingenzymeinhibitor;

AngI=angiotensinI;ARB=angiotensinIIblocker.Pathophysiologic

effectson

cardiovascular

systemAngIIAngIAngiotensinogenReninNa+/H2O

retention

K+,Mg++lossAldosteroneACEACE-iNon-RAASStimulatorsARBARBAldosterone

BlockersAldosteroneNon-RAASstimulatorsAlternativePathwaysAldosterone:ImportantComponentof

Renin-Angiotensin-AldosteroneSystemFibrosisFibrosisNofibrosisAdaptedfromWeberKT,BrillaCG.Circulation1991;83:1849-1865.UnilateralRenalArteryStenosisAldosteroneInfusioninUninephricRatInfrarenalAorticBandingPlasmaHBPLVHFibrosisAngiotensinIIAldosteroneAngiotensinIIAldosteroneAngiotensinIIAldosteroneYesYesYesYesYesYesYesYesNoHBP=highbloodpressure;LVH=leftventricularhypertrophyAldosteroneStimulatesMyocardialFibrosisMyocardialFibrosisinHypertensionandCHF:TheAldosteroneHypothesisAldosteroneCardiacfibroblasts

Collagensynthesis

CollagendepositionMyocardialFibrosisLVstiffnessLVDCHFAldosteroneReceptorAntagonistsAdaptedfromHameediandChadow.CurrHypertensRep.2000;2:378-383PathophysiologicMechanismsofAldosteroneinHeartFailureVSMC=vascularsmoothmusclecell;NO=nitricoxide;ET-1=endothelin-1.RajagopalanandPitt.MedClinNorthAm.2003;87:441-457.AdrenalMyocardial/VascularAngiotensinII,K+,ACTHAldosteroneFibroblastCollagenSynthesisVSMCHypertrophyFreeRadicalProductionNO(inadrenal)AT1RBindingofAngIIACEActivityPAI-1ET-1McKelvieetal.Circulation1999;100:1056-645040302010

0-20-10-30-40DAldosterone(pg/mL)17weeks43weeksCandesartan4mgCandesartan8mgCandesartan16mgCandesartan

+Enalapril4mg/20mgCandesartan

+Enalapril8mg/20mgEnalapril20mgAldosteroneReboundOccursEvenwithCombinedACE-IandAIIBlocker(RESOLVD)11AIRE:ACEInhibitionforPost-MI

LVDysfunctionTheAcuteInfarctionRamiprilEfficacy(AIRE)StudyInvestigators.Lancet.1993;342:821-828.PlaceboRamiprilTime(months)353025201510500612182430HR0.73(95%CI,0.60to0.89)

P=.002CumulativeMortality(%)RR:27%LV=leftventricular;HR=hazardratio;RR=riskreduction.12CAPRICORN:Beta-blockadefor

Post-MILVDysfunction

(OnlyEvent-freeforAll-causeMortality)HR=hazardratio;RR=riskreduction.TheCAPRICORNInvestigators.Lancet.2001;357:1385-1390.PlaceboCarvedilolProportionEvent-FreeYears1.00.000.51.01.52.02.5HR0.77(95%CI,0.60to0.98)

P=.031RR:23%13VALIANT:ARBand/orACEIPostMIAdaptedfromPfefferMAetal.NEnglJMed.2003;349:1893-1906.ProbabilityofEvent0.10.0061218243036MonthsProbabilityofEvent12Months0.10.00618243036CaptoprilValsartanValsartanandCaptoprilDeathFromAnyCauseCombinedCardiovascular

Endpoint14EPHESUS:StudyDesignPrimaryendpoints:Secondaryendpoints:TotalmortalityCVmortality/CVhospitalizationsCVmortalityTotalmortality/totalhospitalizationsEplerenone25to50mgqd(n=3319)Placebo

(n=3313)6632Patients

3to14DaysPost-MI1012DeathsPittBetal.NEnglJMed.2003;348:1309-1321.AcuteMI,HeartFailure,LVEF40%,

StandardTherapyRR:31%PittBetal.

Abstractpresentedat:

ESCWorkingGrouponAcuteCardiacCare;2004.EPHESUSCo-PrimaryEndpoint:

TotalMortality(30Days)Eplerenone+standardcarePlacebo+standardcareCumulativeIncidence(%)DaysFromRandomizationHR=0.69(95%CI,0.54to0.89)(4.6%)(3.2%)P=.004HR=hazardratio.RR=riskreduction.EPHESUSCo-PrimaryEndpoint:

TotalMortality(DurationofStudy)AdaptedfromPittBetal.NEnglJMed.2003;348:1309-1321.Eplerenone+standardcare

(n=3319)Placebo+standardcare

(n=3313)CumulativeIncidence(%)2220181614121086420369121518212427MonthsSinceRandomizationHR=0.85(95%CI,0.75to0.96)

P=.0080RR:15%(16.7%)(14.4%)HR=hazardratio.RR=riskreduction.HR=0.87(95%CI,0.74to1.01)EPHESUSCo-PrimaryEndpoint:

CVMortality/CVHospitalization(30Days)PittBetal.

Abstractpresentedat:ESCWorkingGrouponAcuteCardiacCare;2004.RR:13%Eplerenone+standardcarePlacebo+standardcareCumulativeIncidence(%)DaysFromRandomization(9.9%)(8.6%)HR=hazardratio.RR=riskreduction.P=.074EPHESUSCo-PrimaryEndpoint:

CVMortality/CVHospitalization

(DurationofStudy)AdaptedfromPittBetal.NEnglJMed.2003;348:1309-1321.Eplerenone+standardcare

(n=3319)Placebo+standardcare

(n=3313)40CumulativeIncidence(%)35302520151050369121518212427HR=0.87(95%CI,0.79to0.95)

P=.0020MonthsSinceRandomizationRR:13%(30.0%)(26.7%)HR=hazardratio.RR=riskreduction.EPHESUS:

SuddenDeathFromCardiacCausesAdaptedfromPittBetal.NEnglJMed.2003;348:1309-1321.Eplerenone+standardcare

(n=3319)Placebo+standardcare

(n=3313)10CumulativeIncidence(%)86543210369121518212427HR=0.79(95%CI,0.64to0.97)

P=0.03097MonthsSinceRandomizationRR:21%HR=hazardratio.RR=riskreduction.EPHESUS:RatesofHyperkalemia

andHypokalemiaEplerenonen(%)Placebon(%)PvalueInvestigatorreportedHyperkalemia113(3.4%)66(2.0%)<.001Hypokalemia15(0.5%)49(1.5%)<.001Laboratoryassessed6.0mEq/L180(5.5%)126(3.9%).002<3.5mEq/L273(8.4%)424(13.1%)<.001PittBetal.NEnglJMed.2003;348:1309-1321.ACC/AHAGuidelinesforManagementof

ST-ElevationMIwithLVDysfunctionandHFAspirinClopidogrel-BlockerACEinhibitorAldosteroneantagonistHeparin(UFHorLMWH)GPIIb-IIIainhibitor(ifreceivingPCI)AspirinClopidogrel-BlockerACEinhibitorAldosteroneantagonistStatinSmokingcessationCardiacrehabilitationIn-hospitalTherapyDischargeTherapyLV=leftventricular;UFH=unfractionatedheparin;LMWH=low-molecular-weightheparin;

GP=glycoprotein;PCI=percutaneouscoronaryintervention.22Eplerenone:Post-MIHeartFailureIndicationandDosingIndicatedtoimprovesurvivalofstablepatientswithLeftventricularsystolicdysfunction(LVEF40%)ClinicalevidenceofHFafteracuteMIStartat25mgqdandtitrateinasinglesteptotargetdosageof50mgqd,preferablywithin4weeks,astoleratedNointeractionswithACEinhibitors,ARBs,beta-blockers,diuretics,aspirin,statins,orreperfusiontherapyMaybeadministeredwithorwithoutfoodPittBetal.NEnglJMed.2003;348:1309-1321.23Eplerenone:Post-MIHeartFailureContraindicationsSerumpotassium>5.5mEq/LatinitiationCreatinineclearance30mL/minConcomitantusewithpotentCYP3A4inhibitorssuchasketoconazole,itraconazole,nefazodone,troleandomycin,clarithromycin,ritonavir,nelfinavir,orotherdrugsdescribedintheirlabelingasstronginhibitorsofCYP3A424Eplerenone:RatesofSex-Hormone-RelatedAdverseEventsEplerenonePlaceboMalesGynecomastia0.4%0.5%Mastodynia0.1%0.1%FemalesAbnormalvaginalbleeding0.4%0.4%25Eplerenone:PotassiumMonitoringMeasureserumpotassiumBeforeinitiatingeplerenonetherapyAt1dayAt1weekAt1monthPeriodicallythereafterPatientcharacteristicsandserumpotassiumlevelsmaypromptadditionalmonitoringUsecautionwhentreatingpatientswithrenalinsufficiencyordiabetes,includingthosewithproteinuria,duetoincreasedriskofhyperkalemia26Eplerenone:DoseAdjustmentsAfterInitiatingTherapyforPost-MIHFSerumPotassium(mEq/L)ActionDoseAdjustment<5.0Increase25mgqodto25mgqd25mgqdto50mgqd5.0-5.4MaintainNoadjustment5.5-5.9Decrease50mgqdto25mgqd25mgqdto25mgqod25mgqodtowithhold6.0Withhold**Eplerenonecanberestartedat25mgqodwhenthepotassiumlevelfallsto<5.5mEq/L..ConclusionsHeartfailurepostMIisamajorpublichealthproblemNeurohormonalblockersimprovetheclinicalcourseofpost-MIpatientswithLVdysfunctionEplerenoneimprovessurvivalandreducesCVmortality/CVhospitalizationsinpatientswithpost-MILVdysfunctionandevidenceofHF;thesebenefitsareadditivetothosefromothercardiacdrugsConsiderearlyuseofeplerenoneforstablepatientswithLVEF40%andpastorpresentsignsorsymptomsofheartfailureafteracuteMIWhoisaGoodCandidateforAldosteroneBlockadeafteraMyocardialInfarction?HeartFailurePatients(Rales,S3,ChestX-rayCongestion,Symptoms)HypokalemiaHypertensionLeftVentricularHypertrophyDilatedCardiomyopathyTakehomemessage

Patientspost-MIwithheartfailureareat

highriskofdeath,evenwhentreatedwithprimaryPCIearlyafterpresentation.

Earlyinitiationoftherapy,i.e.beforehospitaldischarge,cansavelives!Weber.NEnglJMed.1999;341:752-755.Aldosterone“escapes”ACE-inhibitorsuppressionMaybecausedbyInabilityofstandarddosestofullysuppressangiotensin-regulatedadrenalproductionofaldosteronePatientlifestylemaycounter(bystimulatingreninrelease)Uprightposture,physicalactivity,restrictionofdietarysodiumAldosteronesecretioncanbeindependentofRAASPotassium-dependentaldosteronesecretionReducedmetabolicclearanceofaldosteroneandbiologicactivityofitsmetabolitesAldosterone“Escape”andIndependenceofRAASEPHESUS:BaselineTherapy*Eplerenone

(n

=

3319)Placebo

(n

=

3313)ACEinhibitor/ARB86%87%Beta-blockers75%75%Diuretics60%61%Aspirin88%89%Statins47%47%Reperfusiontherapyorrevascularization45%45%*Atrandomization(3to14daysafterMI).PittBetal.NEnglJMed.2003;348:1309-1321.33EPHESUS:

HospitalizationsforHeartFailurePittBetal.NEnglJMed.2003;348:1309-132