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课件

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HospitalEventsinNRMIAMIPatientsEVENTAMI+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)0.30.20.10.0012346HR=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:TheAldosteroneHypothesis

AldosteroneCardiacfibroblasts

Collagensynthesis

CollagendepositionMyocardialFibrosis

LVstiffnessLVDCHFAldosteroneReceptorAntagonistsAdaptedfromHameediandChadow.CurrHypertensRep.2000;2:378-383PathophysiologicMechanismsofAldosteroneinHeartFailureVSMC=vascularsmoothmusclecell;NO=nitricoxide;ET-1=endothelin-1.RajagopalanandPitt.MedClinNorthAm.2003;87:441-457.AdrenalMyocardial/VascularAngiotensinII,K+,ACTH

Aldosterone

FibroblastCollagenSynthesisVSMCHypertrophy

FreeRadicalProduction

NO(inadrenal)

AT1RBindingofAngII

ACEActivity

PAI-1

ET-1McKelvieetal.Circulation1999;100:1056-645040302010

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

+Enalapril4mg/20mgCandesartan

+Enalapril8mg/20mgEnalapril20mgAldosteroneReboundOccursEvenwithCombinedACE-IandAIIBlocker(RESOLVD)AIRE: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.11CAPRICORN:Beta-blockadefor

Post-MILVDysfunction

(OnlyEvent-freeforAll-causeMortality)HR=hazardratio;RR=riskreduction.TheCAPRICORNInvestigators.Lancet.2001;357:1385-1390.PlaceboCarvedilolProportionEvent-FreeYears1.00.90.80.70.60.50.40.30.20.10.000.51.01.52.02.5HR0.77(95%CI,0.60to0.98)

P=.031RR:23%12VALIANT:ARBand/orACEIPostMIAdaptedfromPfefferMAetal.NEnglJMed.2003;349:1893-1906.ProbabilityofEvent0.40.30.20.10.0061218243036MonthsProbabilityofEvent12Months0.40.30.20.10.00618243036CaptoprilValsartanValsartanandCaptoprilDeathFromAnyCauseCombinedCardiovascular

Endpoint13EPHESUS:StudyDesignPrimaryendpoints:Secondaryendpoints:TotalmortalityCVmortality/CVhospitalizationsCVmortalityTotalmortality/totalhospitalizationsEplerenone25to50mgqd(n=3319)Placebo

(n=3313)6632Patients

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

StandardTherapy14RR: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.Eplerenone:Post-MIHeartFailureIndicationandDosingIndicatedtoimprovesurvivalofstablepatientswithLeftventricularsystolicdysfunction(LVEF40%)ClinicalevidenceofHFafteracuteMIStartat25mgqdandtitrateinasinglesteptotargetdosageof50mgqd,preferablywithin4weeks,astoleratedNointeractionswithACEinhibitors,ARBs,beta-blockers,diuretics,aspirin,statins,orreperfusiontherapyMaybeadministeredwithorwithoutfoodPittBetal.NEnglJMed.2003;348:1309-1321.22Eplerenone:Post-MIHeartFailureContraindicationsSerumpotassium>5.5mEq/LatinitiationCreatinineclearance30mL/minConcomitantusewithpotentCYP3A4inhibitorssuchasketoconazole,itraconazole,nefazodone,troleandomycin,clarithromycin,ritonavir,nelfinavir,orotherdrugsdescribedintheirlabelingasstronginhibitorsofCYP3A423Eplerenone:RatesofSex-Hormone-RelatedAdverseEventsEplerenonePlaceboMalesGynecomastia0.4%0.5%Mastodynia0.1%0.1%FemalesAbnormalvaginalbleeding0.4%0.4%24Eplerenone:PotassiumMonitoringMeasureserumpotassiumBeforeinitiatingeplerenonetherapyAt1dayAt1weekAt1monthPeriodicallythereafterPatientcharacteristicsandserumpotassiumlevelsmaypromptadditionalmonitoringUsecautionwhentreatingpatientswithrenalinsufficiencyordiabetes,includingthosewithproteinuria,duetoincreasedriskofhyperkalemia25Eplerenone:DoseAdjustmentsAfterInitiatingTherapyforPost-MIHFSerumPotassium(mEq/L)ActionDoseAdjustment<5.0Increase25mgqodto25mgqd25mgqdto50mgqd5.0-5.4MaintainNoadjustment5.5-5.9Decrease50mgqdto25mgqd25mgqdto25mgqod25mgqodtowithhold6.0Withhold**Eplerenonecanberestartedat25mgqodwhenthepotassiumlevelfallsto<5.5mEq/L..26ConclusionsHeartfailurepostMIisamajorpublichealthproblemNeurohormonalblockersimprovetheclinicalcourseofpost-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.EPHESUS:

HospitalizationsforHeartFailurePittBetal.NEnglJMed.2003;348:1309-1321.0100