心力衰竭藥物治療 新證據(jù)與新視野

心力衰竭藥物治療

新證據(jù)與新視野治療心力衰竭的藥物1、強心苷類藥物2、利尿劑3、ACE抑制劑及血管緊張素II（AT1）受體拮抗劑4、受體阻斷劑5、其他治療CHF的藥物：（1）鈣拮抗劑（2）磷酸二酯酶抑制劑

（3）其他血管擴張劑：長效硝酸酯類，肼苯噠嗪

DIG研究50403020100Placebon=3403Digoxinn=3397480122436Mortality%NEnglJMed1997;336:525Monthsp=0.8DigitalisN=6800NYHAII-III

0.6ProbabilityofDeath0Placebo(273)

Prazosin(183)

Hz+ISDN(186)Months0.70.50.30.40.20.1NEnglJMed1986;314:1547Nitrates06121824303642V-HeFT-I研究combinationofhydralazine(300mg/day)andisosorbidedinitrate(160mg/day23%reductioninmortalityPlaceboEnalapril12111098765ProbabiilityofDeathMonths0.10.800.20.30.70.40.50.6p<0.001p<0.002NEnglJMed1987;316:142943210CONSENSUS研究253patientswithclassIVheartfailureEnalapril：2.5-40mg/day31%reductioninmortality50403020100Months0612p=0.0036%Mortality241830364248Enalapriln=1285Placebon=1284

NEnglJM1991;325:293n=2589CHF-NYHAII-III-EF<35SOLVD(Treatment)研究11.3%reductioninmortality0,540,480122448600.750.500.2500.470.360.250.130.090.310.180.4236Monthsp=0.08NEnglJMed1991;325:303EnalaprilHZ+ISDNn=804p=0.016ProbabilityofdeathNitrate+HydralazineVsEnalaprilV-HeFTII研究

YearsProbabilityofEvent00.050.10.150.20.250.301230.350.44ACE-IPlacebo

ACE-I 2995 2250 1617 892 223

Placebo 2971 2184 1521 853 138FlatherMD,etal.Lancet.2000;355:1575–1581OR:0.74(0.66–0.83)

ACE-I:702/2995(23.4%)

Placebo:866/2971(29.1%)TRACE

Echocardiographic

EF￡35%AIRE

Clinicaland/orradiographicsignsofHFSAVE

Radionuclide

EF￡40%卡維地洛n=696安慰劑n=398存活天050100150200250300350400危險度下降=65%p<0.001Packeretal(1996)CIBIS-IIInvestigators(1999)比索洛爾安慰劑接收后的時間(天)p<0.0001存活危險度下降=34%TheMERIT-HFStudyGroup(1999)美國卡維地洛計劃CIBIS-II0.81.00.60隨訪月03691215182120151050安慰劑美托洛爾

CRp=0.0062危險度下降=34%MERIT-HF月003691215182110090806070卡維地洛安慰劑危險度下降=35%存活Packeretal(2001)哥白尼（COPERNICUS）研究p=0.000130.50.60.70.80.91.00200400600800死亡率(%)AldactonePlaceboSurvival1.00.90.80.70.60.5061218243036monthsp<0.0001AnnualMortalityAldactone18%;Placebo23%RR－21.7%N=1663NYHAIII-IVMeanfollow-up2yNEJM1999;341:709SpironolactoneRALES研究心力衰竭藥物治療Asymptomatic Mildtomoderate ModerateLVdysfunction CHF tosevereCHFACEinhibitor Digoxin DigoxinBetablocker Diuretics Diuretics ACEinhibitor ACEinhibitor Betablocker Betablocker Spironolactone心力衰竭治療指南：常規(guī)治療所有收縮性心力衰竭患者必需應用ACE抑制劑，包括無癥狀性心力衰竭，LVEF<45%者，除非有禁忌證或不能耐受。所有慢性收縮性心衰，NYHAI～IV級患者，病情穩(wěn)定，無禁忌癥，均必須服用受體阻滯劑應在ACE抑制劑，利尿劑（地高辛）基礎上加用

受體阻滯劑不能用于危重搶救（需靜脈用藥，有體液潴留）從小劑量開始，2周倍增。改善常在2～3月后出現(xiàn)腎素－血管緊張素系統(tǒng)血管緊張素原非ACE途徑

(tonin,chymase,CAGE)血管收縮細胞生長水、鈉潴留交感神經活化腎素血管緊張素I血管緊張素IIAT1ACEAT2咳嗽,血管性水腫臨床獲益?

緩激肽失活片段血管舒張抗增殖

(kinins)醛固酮CAGE=chymostatin-sensitiveangiotensinII-generatingenzyme.ACE抑制劑ARBsRAS抑制對于心力衰竭患者：

ARBs>ACE抑制劑？

ARBs＋ACE抑制劑>ACE抑制劑？PlaceboValsartanTimeSinceRandomization(mo)P=0.81.000.900.800.702724211815129630SurvivalProbability0.950.850.750Val-HeFT:All-CauseMortalityCohnJNetal.NEnglJMed.2001;345:1667-1675.

EffectofValsartanonCombinedMortalityandMorbidityEndPoint*inOverallPopulationMonths369121518212427065707580859095100ProbabilityofEvent-FreeSurvival

0*All-causemortality,suddendeathwithresuscitation,hospitalizationforworseningheartfailure,ortherapywithIVinotropesorvasodilators.CohnJNetal.NEnglJMed.2001;345:1667-1675.30ValsartanPlaceboP=0.00913.2%riskreductionCHARM

AddedCHARM

PreservedCHARM研究3componenttrialscomparingcandesartantoplaceboinpatientswithsymptomaticheartfailureCHARM

Alternativen=2028

LVEF￡40%

ACEinhibitor

intolerantn=2548LVEF￡40%

ACEinhibitor

treatedn=3025LVEF>40%

ACEinhibitor

treated/nottreatedPrimaryoutcomeforOverallProgram:All-causedeathPrimaryoutcomeforeachtrial:CVdeathorCHFhospitalizationSwedbergKetal.JCardFail.1999;5:276-282.CHARM-Overall:總死亡率0123years3.50102030PlaceboCandesartan5152535%HR0.91(95%CI0.83-1.00),p=0.055AdjustedHR0.90,p=0.032945(24.9%)886(23.3%)CHARM研究:死亡率和病殘率0.70.80.91.01.11.20.60.70.80.91.01.11.2所有原因的死亡心血管死亡或心力衰竭住院HazardratioHazardratioPheterogeneity=0.33AlternativeAddedPreservedOverallPheterogeneity=0.37PfefferMAetal.Lancet.2003./extras/03art7416web.pdf主要終點:

所有原因死亡率次級終點: 心血管死亡、心?；蛐乃テ渌K點: 安全性和耐受性卡托普利

50mgtid(n=4,909)纈沙坦

160mgbid(n=4,909)卡托普利50mgtid+纈沙坦80mgbid(n=4,885)急性心梗

(0.5–10天)—符合SAVE,AIRE或TRACE入選標準(同時具有心衰或左室收縮功能障礙的臨床/放射學證據(jù))主要排除標準:血清肌酐>2.5mg/dL血壓<100mmHg既往對ARB或ACEI不耐受不同意參加研究雙盲活性對照平均隨訪時間:24.7月

事件驅動:2,700次事件VALIANT:研究設計卡托普利00.050.10.150.20.250.3061218243036事件概率VALIANT:治療死亡率 纈沙坦 4909 4464 4272 4007 2648 1437 357月纈沙坦vs.卡托普利:風險比=1.00;P=0.982纈沙坦+卡托普利vs.卡托普利:風險比=0.98;P=0.726 卡托普利 4909 4428 4241 4018 2635 1432 364

纈沙坦+卡托普利 4885 4414 4265 3994 2648 1435 382纈沙坦纈沙坦+卡托普利PfefferMetal.NEnglJMed2003;349:1893-9060.20.40.60.8No.of

PatientsFavorsValsartanFavorsPlaceboCombinedendpointACE-Iy,BBn3034ACE-Iy,BBy1610ACE-In,BBn226ACE-In,BBy140MortalityACE-Iy,BBn3034ACE-Iy,BBy1610ACE-In,BBn226ACE-In,BBy1401.21.41.61.81.0Val-HeFT:CombinedMorbidity/MortalityinSubgroupsBB=-blocker;y=yes;n=no.CohnJetal.NEnglJMed.2001;345:1667-1675.CHARM-Added:預設亞組,心血管死亡或心力衰竭住院?-阻滯劑 Yes 223/702 274/711 No 260/574 264/561ACEI. Yes 232/643 275/648

推薦劑量

No 251/633 263/624

所有患者

483/1276 538/1272Candesartan安慰劑Candesartan

betterHazardratioPlacebo

better0.60.81.01.21.4Pvaluefortreatment

interaction0.140.26McMurrayJVetal.Lancet.2003./extras/03art7417web.pdfESCGuidelinesonthediagnosisandtreatmentofCHF,EHJ2005對ACE抑制劑有不能耐受癥狀的患者，ARBs可以很好的替代ACE抑制劑，可以降低發(fā)病率和死亡率(證據(jù)水平B,I級)ARBs和ACE抑制劑在治療CHF方面，有相似的功能(證據(jù)水平B,I級)急性心肌梗死后有心衰或左室功能障礙征兆，ARBs與ACE抑制劑有相似的療效(證據(jù)水平B,I級)聯(lián)合使用ARBs與ACE抑制劑治療有癥狀的患者，能夠降低死亡率(證據(jù)水平B,IIa級)和心衰的入院治療率(證據(jù)水平A,I級)

TheRoleofARBsinHeartFailure坎地沙坦4-32纈沙坦

80-320依普沙坦400-800氯沙坦50-100依貝沙坦150-300替米沙坦40-80通常被用來治療心衰的ARBs可降低死亡率/發(fā)病率的ARB

每日劑量（mg)ESCGuidelinesonthediagnosisandtreatmentofCHF,EHJ2005RAS抑制＋β阻滯劑治療心力衰竭患者：

ACE抑制劑或ARBs

必須先于β阻滯劑？Stabledosesofdiuretics,digoxin,nitratesBaseline/screeningUp-titrationPhaseA0wkUp-titrationPhaseBMaintenancePhase9183612150Down-titrationPhaseFollow-up(months)CARMEN研究設計Group2Placebo(blinded)Carvedilol(blinded)Group1Carvedilol(blinded)Ealapril(blinded)Enalapril(blinded)Group3Enalapril(blinded)Placebo(blinded)CARMENPrimaryEndpoint:

ComparisonofLVESVIBetweenTreatmentsMonth6Month12Month18NSP<0.002BaselineLVESVI(biplane)[ml/m2]LVESVI=leftventricularendsystolicvolumeindexBisoprolol-first(o.d.)Enalapril-first(b.i.d.)Bisoprololo.d.Enalaprilb.i.d.Bisoprololo.d.Enalaprilb.i.d

weekStudyend1-2.5years0246810

262830323436

weekStudyend1-2.5yearsFirstup-titrationFirstup-titrationSecondup-titrationSecondup-titrationMaintenanceperiodMaintenanceperiodSecondmaintenanceperiod22-100weeksSecondmaintenanceperiod16-94weeks1.252.53.755.07.51.252.53.755.07.52.55.02.55.0****************……….…….*****

*=visits10.0mg10.0mg10.0mg10.0mgCIBISIII研究設計Bisoprololo.d.Enalaprilb.i.d0246810

262830323436****************……….…….*****DOI:10.1161/CIRCULATIONAHA.105.582320Intention-to-treat(ITT)population5060708090100061218Bisoprolol-firstEnalapril-firstPer-protocol(PP)population5060708090100061218Combinedprimaryendpoint%withoutendpoint%withoutendpointB/EvsE/B163vs165ptsHR0.97(95%CI0.78-1.21)non-inferiorityP=0.046B/EvsE/B178vs186ptsHR0.94(95%CI0.77-1.16)non-inferiorityP=0.01950349835635326525980735055053893882912778776monthsmonthsBisoprolol-firstsignificantlynon-inferiortoenalapril-firstifupperlimitof95%CIbelowhazardratio(HR)1.17,P<0.025.(=RR1.125,AR+5%)InthePPpopulation,bisoprolol-firstwasnotsignificantlynon-inferiortoenalapril-firstIntheITTpopulation,bisoprolol-firstwassignificantlynon-inferiortoenalapril-firstNumbersatriskNumbersatrisk3%riskreduction6%riskreductionDOI:10.1161/CIRCULATIONAHA.105.582320All-causehospitalizationthroughoutstudy(ITT)50607080901000612182777638728985386%withouthospitalization505505m