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

NeedforSelectiveAldosteroneBlockadeforPatientswithTransientorPersistentHeartFailureDuringHospitalisationforAMI ProfessorCRichardCONTIUniversityofFloridaCollegeofMedicine Gainsville Florida USA HospitalEventsinNRMIAMIPatients AMIandHF ConclusionsfromNMRICHFandAMIisahighrisksituationDespitethehighrisk thesepatientsarelessfrequentlytreatedwithmedicationswithprovenmortalitybenefitorwithprimaryreperfusionstrategiesNoneofthesepatientsweretreatedwithaldactoneoreplerenone CardiacEchoperformedwithin24hrsafterAMI PrognosisafterMyocardialInfarction GRACE ImpactofHeartFailureonCumulativeMortalityFromACS ACS acutecoronarysyndromes StegPGetal Circulation 2004 109 494 499 TimetoDeathWithin6Months n 10 771 0 3 0 2 0 1 0 0 0 1 2 3 4 6 HR 3 8 95 CI 3 33to4 36 HeartfailureatadmissionNoheartfailureatadmission ProportionDead 5 ACE I angiotensin convertingenzymeinhibitor AngI angiotensinI ARB angiotensinIIblocker Pathophysiologiceffectsoncardiovascularsystem AngII AngI Angiotensinogen Renin Na H2OretentionK Mg loss Aldosterone ACE ACE i Non RAASStimulators ARB ARB AldosteroneBlockers Aldosterone Non RAASstimulators AlternativePathways Aldosterone ImportantComponentofRenin Angiotensin AldosteroneSystem Fibrosis Fibrosis Nofibrosis AdaptedfromWeberKT BrillaCG Circulation1991 83 1849 1865 UnilateralRenalArteryStenosis AldosteroneInfusioninUninephricRat InfrarenalAorticBanding Plasma HBP LVH Fibrosis AngiotensinIIAldosteroneAngiotensinIIAldosteroneAngiotensinIIAldosterone Yes Yes Yes Yes Yes Yes Yes Yes No HBP highbloodpressure LVH leftventricularhypertrophy AldosteroneStimulatesMyocardialFibrosis MyocardialFibrosisinHypertensionandCHF TheAldosteroneHypothesis Aldosterone Cardiacfibroblasts Collagensynthesis Collagendeposition MyocardialFibrosis LVstiffness LVD CHF AldosteroneReceptorAntagonists AdaptedfromHameediandChadow CurrHypertensRep 2000 2 378 383 PathophysiologicMechanismsofAldosteroneinHeartFailure VSMC vascularsmoothmusclecell NO nitricoxide ET 1 endothelin 1 RajagopalanandPitt MedClinNorthAm 2003 87 441 457 Adrenal Myocardial Vascular AngiotensinII K ACTH Aldosterone FibroblastCollagenSynthesis VSMCHypertrophy FreeRadicalProduction NO inadrenal AT1RBindingofAngII ACEActivity PAI 1 ET 1 McKelvieetal Circulation1999 100 1056 64 50 40 30 20 10 0 20 10 30 40 DAldosterone pg mL 17weeks 43weeks Candesartan4mg Candesartan8mg Candesartan16mg Candesartan Enalapril4mg 20mg Candesartan Enalapril8mg 20mg Enalapril20mg AldosteroneReboundOccursEvenwithCombinedACE IandAIIBlocker RESOLVD 11 AIRE ACEInhibitionforPost MILVDysfunction TheAcuteInfarctionRamiprilEfficacy AIRE StudyInvestigators Lancet 1993 342 821 828 PlaceboRamipril RR 27 LV leftventricular HR hazardratio RR riskreduction 12 CAPRICORN Beta blockadeforPost MILVDysfunction OnlyEvent freeforAll causeMortality HR hazardratio RR riskreduction TheCAPRICORNInvestigators Lancet 2001 357 1385 1390 Placebo Carvedilol ProportionEvent Free Years 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 0 0 5 1 0 1 5 2 0 2 5 HR0 77 95 CI 0 60to0 98 P 031 RR 23 13 VALIANT ARBand orACEIPostMI AdaptedfromPfefferMAetal NEnglJMed 2003 349 1893 1906 ProbabilityofEvent 0 4 0 3 0 2 0 1 0 0 0 6 12 18 24 30 36 Months ProbabilityofEvent 12 Months 0 4 0 3 0 2 0 1 0 0 0 6 18 24 30 36 Captopril Valsartan ValsartanandCaptopril DeathFromAnyCause CombinedCardiovascularEndpoint 14 EPHESUS StudyDesign Primaryendpoints Secondaryendpoints TotalmortalityCVmortality CVhospitalizationsCVmortalityTotalmortality totalhospitalizations Eplerenone25to50mgqd n 3319 Placebo n 3313 6632Patients3to14DaysPost MI1012Deaths PittBetal NEnglJMed 2003 348 1309 1321 AcuteMI HeartFailure LVEF 40 StandardTherapy RR 31 PittBetal Abstractpresentedat ESCWorkingGrouponAcuteCardiacCare 2004 EPHESUSCo PrimaryEndpoint TotalMortality 30Days Eplerenone standardcare Placebo standardcare CumulativeIncidence DaysFromRandomization HR 0 69 95 CI 0 54to0 89 4 6 3 2 P 004 HR hazardratio RR riskreduction EPHESUSCo PrimaryEndpoint TotalMortality DurationofStudy AdaptedfromPittBetal NEnglJMed 2003 348 1309 1321 Eplerenone standardcare n 3319 Placebo standardcare n 3313 RR 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 standardcare Placebo standardcare CumulativeIncidence DaysFromRandomization 9 9 8 6 HR hazardratio RR riskreduction P 074 EPHESUSCo PrimaryEndpoint CVMortality CVHospitalization DurationofStudy AdaptedfromPittBetal NEnglJMed 2003 348 1309 1321 Eplerenone standardcare n 3319 Placebo standardcare n 3313 40 CumulativeIncidence 35 30 25 20 15 10 5 0 3 6 9 12 15 18 21 24 27 HR 0 87 95 CI 0 79to0 95 P 002 0 MonthsSinceRandomization RR 13 30 0 26 7 HR hazardratio RR riskreduction EPHESUS SuddenDeathFromCardiacCauses AdaptedfromPittBetal NEnglJMed 2003 348 1309 1321 Eplerenone standardcare n 3319 Placebo standardcare n 3313 10 CumulativeIncidence 8 6 5 4 3 2 1 0 3 6 9 12 15 18 21 24 27 HR 0 79 95 CI 0 64to0 97 P 0 03 0 9 7 MonthsSinceRandomization RR 21 HR hazardratio RR riskreduction EPHESUS RatesofHyperkalemiaandHypokalemia PittBetal NEnglJMed 2003 348 1309 1321 ACC AHAGuidelinesforManagementofST ElevationMIwithLVDysfunctionandHF AspirinClopidogrel BlockerACEinhibitorAldosteroneantagonistHeparin UFHorLMWH GPIIb IIIainhibitor ifreceivingPCI AspirinClopidogrel BlockerACEinhibitorAldosteroneantagonistStatinSmokingcessationCardiacrehabilitation In hospitalTherapy DischargeTherapy LV leftventricular UFH unfractionatedheparin LMWH low molecular weightheparin GP glycoprotein PCI percutaneouscoronaryintervention 22 Eplerenone Post MIHeartFailureIndicationandDosing IndicatedtoimprovesurvivalofstablepatientswithLeftventricularsystolicdysfunction LVEF 40 ClinicalevidenceofHFafteracuteMIStartat25mgqdandtitrateinasinglesteptotargetdosageof50mgqd preferablywithin4weeks astoleratedNointeractionswithACEinhibitors ARBs beta blockers diuretics aspirin statins orreperfusiontherapyMaybeadministeredwithorwithoutfood PittBetal NEnglJMed 2003 348 1309 1321 23 Eplerenone Post MIHeartFailureContraindications Serumpotassium 5 5mEq LatinitiationCreatinineclearance 30mL minConcomitantusewithpotentCYP3A4inhibitorssuchasketoconazole itraconazole nefazodone troleandomycin clarithromycin ritonavir nelfinavir orotherdrugsdescribedintheirlabelingasstronginhibitorsofCYP3A4 24 Eplerenone RatesofSex Hormone RelatedAdverseEvents 25 Eplerenone PotassiumMonitoring MeasureserumpotassiumBeforeinitiatingeplerenonetherapyAt1dayAt1weekAt1monthPeriodicallythereafterPatientcharacteristicsandserumpotassiumlevelsmaypromptadditionalmonitoringUsecautionwhentreatingpatientswithrenalinsufficiencyordiabetes includingthosewithproteinuria duetoincreasedriskofhyperkalemia 26 Eplerenone DoseAdjustmentsAfterInitiatingTherapyforPost MIHF Eplerenonecanberestartedat25mgqodwhenthepotassiumlevelfallsto 5 5mEq L Conclusions HeartfailurepostMIisamajorpublichealthproblemNeurohormonalblockersimprovetheclinicalcourseofpost MIpatientswithLVdysfunctionEplerenoneimprovessurvivalandreducesCVmortality CVhospitalizationsinpatientswithpost MILVdysfunctionandevidenceofHF thesebenefitsareadditivetothosefromothercardiacdrugsConsiderearlyuseofeplerenoneforstablepatientswithLVEF 40 andpastorpresentsignsorsymptomsofheartfailureafteracuteMI WhoisaGoodCandidateforAldosteroneBlockadeafteraMyocardialInfarction HeartFailurePatients Rales S3 ChestX rayCongestion Symptoms HypokalemiaHypertensionLeftVentricularHypertrophyDilatedCardiomyopathy TakehomemessagePatientspost MIwithheartfailureareathighriskofdeath evenwhentreatedwithprimaryPCIearlyafterpresentation Earlyinitiationoftherapy i e beforehospitaldischarge cansavelives Weber NEnglJMed 1999 341 752 755 Aldosterone escapes ACE inhibitorsuppressionMaybecausedbyInabilityofstandarddosestofullysuppressangiotensin regulatedadrenalproductionofaldosteronePatientlifestylemaycounter bystimulatingreninrelease Uprightposture physicalactivity restrictionofdietarysodiumAldosteronesecretioncanbeindependentofRAASPotassium dependentaldosteronesecretionReducedmetabolicclearanceofaldosteroneandbiologicactivityofitsmetabolites Aldosterone Escape andIndependenceofRAAS EPHESUS BaselineTherapy Atrandomiz