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PPT课件.ppt

选择选择性性醛醛固固酮酮封封锁锁需与瞬需与瞬态态或永久心或永久心脏脏的急性心肌梗死住院期的急性心肌梗死住院期间间衰竭患者衰竭患者Hospital Events in NRMI AMI Patients EVENTAMI+CHF(%)AMI(%)Stroke 2.21.4A V block5.74.6VT or VF11.99.09Rupture/EMD1.81.0Unexpected cardiac arrest8.34.4LOS7.15.3Recurrent MI3.02.7Death21.47.2AMI and HFConclusions from NMRICHF and AMI is a high risk situationDespite the high risk,these patients are less frequently treated with medications with proven mortality benefit or with primary reperfusion strategiesNone of these patients were treated with aldactone or eplerenoneCardiac Echo performed within 24 hrs after AMIPrognosis after Myocardial InfarctionGRACE:Impact of Heart Failure on Cumulative Mortality From ACSACS=acute coronary syndromes.Steg PG et al.Circulation.2004;109:494-499.Time to Death Within 6 Months(n=10,771)0.30.20.10.0012346HR=3.8(95%CI,3.33 to 4.36)Heart failure at admissionNo heart failure at admissionProportion Dead5ACE-I=angiotensin-converting enzyme inhibitor;Ang I=angiotensin I;ARB=angiotensin II blocker.PathophysiologicPathophysiologiceffects oneffects oncardiovascularcardiovascularsystemsystemAng IIAng IIAng IAng IAngiotensinogenAngiotensinogenReninReninNaNa+/H/H2 2O OretentionretentionK K+,Mg,Mg+loss lossAldosteroneAldosteroneACEACEACE-iACE-iNon-RAAS StimulatorsNon-RAAS StimulatorsARBARBARBARBAldosteroneAldosteroneBlockersBlockersAldosteroneAldosteroneNon-RAAS stimulatorsNon-RAAS stimulatorsAlternative PathwaysAldosterone:Important Component of Renin-Angiotensin-Aldosterone SystemFibrosisFibrosisFibrosisFibrosisNo fibrosisNo fibrosisAdapted from Weber KT,Brilla CG.Circulation 1991;83:1849-1865.UnilateralUnilateralRenalRenalArteryArteryStenosisStenosisAldosteroneAldosteroneInfusion inInfusion inUninephricUninephricRatRatInfrarenalInfrarenalAorticAorticBandingBandingPlasmaHBP LVHFibrosisAngiotensin II Aldosterone Angiotensin IIAldosteroneAngiotensin IIAldosteroneYesYesYesYesYesYesYesYesNoHBP=high blood pressure;LVH=left ventricular hypertrophyAldosterone Stimulates Myocardial FibrosisMyocardial Fibrosis in Hypertension and CHF:The Aldosterone Hypothesis AldosteroneCardiac fibroblasts Collagen synthesis Collagen depositionMyocardial Fibrosis LV stiffnessLVDCHFAldosterone Receptor AntagonistsAdapted from Hameedi and Chadow.Curr Hypertens Rep.2000;2:378-383Pathophysiologic Mechanisms of Aldosterone in Heart FailureVSMC=vascular smooth muscle cell;NO=nitric oxide;ET-1=endothelin-1.Rajagopalan and Pitt.Med Clin North Am.2003;87:441-457.AdrenalAdrenalMyocardial/VascularMyocardial/VascularAngiotensin II,KAngiotensin II,K+,ACTH,ACTH FibroblastFibroblastCollagenCollagenSynthesisSynthesisVSMCVSMCHypertrophyHypertrophy Free Free Radical Radical ProductionProduction NONO(in adrenal)(in adrenal)AT1R Binding AT1R Binding of Ang IIof Ang II ACE ACE ActivityActivity PAI-1 PAI-1 ET-1 ET-1McKelvie et al.Circulation 1999;100:1056-64 5040302010 0-20-10-30-40D D Aldosterone(pg/mL)17 weeks43 weeksCandesartan 4 mgCandesartan 8 mgCandesartan 16 mgCandesartan+Enalapril 4 mg/20mgCandesartan+Enalapril 8 mg/20mgEnalapril 20 mgAldosterone Rebound Occurs Even with Combined ACE-I and AII Blocker(RESOLVD)AIRE:ACE Inhibition for Post-MILV DysfunctionThe Acute Infarction Ramipril Efficacy(AIRE)Study Investigators.Lancet.1993;342:821-828.PlaceboRamiprilTime(months)353025201510500612182430HR 0.7395%CI,0.60 to 0.89)P=.002Cumulative Mortality(%)RR:27%LV=left ventricular;HR=hazard ratio;RR=risk reduction.11CAPRICORN:Beta-blockade for Post-MI LV Dysfunction(Only Event-free for All-cause Mortality)HR=hazard ratio;RR=risk reduction.The CAPRICORN Investigators.Lancet.2001;357:1385-1390.PlaceboCarvedilolProportion Event-FreeYears1.00.90.80.70.60.50.40.30.20.10.000.51.01.52.02.5HR 0.77(95%CI,0.60 to 0.98)P=.031RR:23%12VALIANT:ARB and/or ACEI Post MIAdapted from Pfeffer MA et al.N Engl J Med.2003;349:1893-1906.Probability of Event0.40.30.20.10.0061218243036MonthsProbability of Event12Months0.40.30.20.10.00618243036CaptoprilValsartanValsartan and CaptoprilDeath From Any CauseCombined Cardiovascular Endpoint13EPHESUS:Study DesignPrimary endpoints:Secondary endpoints:Total mortalityCV mortality/CV hospitalizationsCV mortalityTotal mortality/total hospitalizationsEplerenone 25 to 50 mg qd(n=3319)Placebo(n=3313)6632 Patients 3 to 14 DaysPost-MI1012 DeathsPitt B et al.N Engl J Med.2003;348:1309-1321.Acute MI,Heart Failure,LVEF 40%,Standard Therapy14RR:31%Pitt B et al.Abstract presented at:ESC Working Group on Acute Cardiac Care;2004.EPHESUS Co-Primary Endpoint:Total Mortality(30 Days)Eplerenone+standard care Placebo+standard care Cumulative Incidence(%)Days From RandomizationHR=0.69(95%CI,0.54 to 0.89)(4.6%)(3.2%)P=.004HR=hazard ratio.RR=risk reduction.EPHESUS Co-Primary Endpoint:Total Mortality(Duration of Study)Adapted from Pitt B et al.N Engl J Med.2003;348:1309-1321.Eplerenone+standard care(n=3319)Placebo+standard care(n=3313)Cumulative Incidence(%)2220181614121086420369121518212427Months Since RandomizationHR=0.85(95%CI,0.75 to 0.96)P=.0080RR:15%(16.7%)(14.4%)HR=hazard ratio.RR=risk reduction.HR=0.87(95%CI,0.74 to 1.01)EPHESUS Co-Primary Endpoint:CV Mortality/CV Hospitalization(30 Days)Pitt B et al.Abstract presented at:ESC Working Group on Acute Cardiac Care;2004.RR:13%Eplerenone+standard carePlacebo+standard careCumulative Incidence(%)Days From Randomization(9.9%)(8.6%)HR=hazard ratio.RR=risk reduction.P=.074EPHESUS Co-Primary Endpoint:CV Mortality/CV Hospitalization(Duration of Study)Adapted from Pitt B et al.N Engl J Med.2003;348:1309-1321.Eplerenone+standard care(n=3319)Placebo+standard care(n=3313)40Cumulative Incidence(%)35302520151050369121518212427HR=0.87(95%CI,0.79 to 0.95)P=.0020Months Since RandomizationRR:13%(30.0%)(26.7%)HR=hazard ratio.RR=risk reduction.EPHESUS:Sudden Death From Cardiac CausesAdapted from Pitt B et al.N Engl J Med.2003;348:1309-1321.Eplerenone+standard care(n=3319)Placebo+standard care(n=3313)10Cumulative Incidence(%)86543210369121518212427HR=0.79(95%CI,0.64 to 0.97)P=0.03097Months Since RandomizationRR:21%HR=hazard ratioRR=risk reduction.EPHESUS:Rates of Hyperkalemia and HypokalemiaEplerenonen(%)Placebon(%)P valueInvestigator reportedHyperkalemia113(3.4%)66(2.0%).001Hypokalemia15(0.5%)49(1.5%).001Laboratory assessed6.0 mEq/L180(5.5%)126(3.9%).0023.5 mEq/L273(8.4%)424(13.1%)5.5 mEq/L at initiationCreatinine clearance 30 mL/minConcomitant use with potent CYP3A4 inhibitors such as ketoconazole,itraconazole,nefazodone,troleandomycin,clarithromycin,ritonavir,nelfinavir,or other drugs described in their labeling as strong inhibitors of CYP3A423Eplerenone:Rates of Sex-Hormone-Related Adverse EventsEplerenonePlaceboMalesGynecomastia0.4%0.5%Mastodynia0.1%0.1%Females Abnormal vaginal bleeding0.4%0.4%24Eplerenone:Potassium MonitoringMeasure serum potassiumBefore initiating eplerenone therapyAt 1 dayAt 1 weekAt 1 monthPeriodically thereafterPatient characteristics and serum potassium levels may prompt additional monitoringUse caution when treating patients with renal insufficiency or diabetes,including those with proteinuria,due to increased risk of hyperkalemia25Eplerenone:Dose Adjustments After Initiating Therapy for Post-MI HFSerum Potassium(mEq/L)ActionDose Adjustment5.0Increase25 mg qod to 25 mg qd25 mg qd to 50 mg qd5.0-5.4MaintainNo adjustment5.5-5.9Decrease50 mg qd to 25 mg qd25 mg qd to 25 mg qod 25 mg qod to withhold6.0Withhold*Eplerenone can be restarted at 25 mg qod when the potassium level falls to 5.5 mmol/L):Elevated baseline serum creatinineLow baseline creatinine clearanceHistory of diabetes mellitusBaseline use of antiarrhythmicsThese risk factors were not associated with a significant differential adverse effect of eplerenone vs placebo for:All-cause mortalityCV death/CV hospitalizationCV death Sudden cardiac deathEPHESUS:Risk Factors for Hyperkalemia Bakris G et al.American Heart Association Scientific Sessions;2004.EPHESUS:Worst-Case Analysis:Hyperkalemia and MortalityBakris G et al.American Heart Association Scientific Sessions;2004.Pitt B et al.N Engl J Med.2003;348:1309-1321.EplerenonePlaceboP valueIncidence K(K+5.5 mmol/L)15.6%11.2%.001Incidence K(K+6.0 mmol/L)5.5%3.9%.002Study drug discontinuation due to K1%1%Deaths adjudicated to Kn=0n=1All deaths due to K+all sudden cardiac death+all deaths from unknown causes5.3%6.6%.016