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)與新視野李勇復(fù)旦大學(xué)附屬華山醫(yī)院心臟科上海200040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(kuò)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

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

CRp=0.0062危險度下降=34%MERIT-HF月003691215182110090806070卡維地洛撫慰劑危險度下降=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(yīng)用ACE抑制劑，包括無病癥性心力衰竭，LVEF<45%者，除非有禁忌證或不能耐受。所有慢性收縮性心衰，NYHAI～I(xiàn)V級患者，病情穩(wěn)定，無禁忌癥，均必須服用受體阻滯劑應(yīng)在ACE抑制劑，利尿劑〔地高辛〕根底上加用受體阻滯劑不能用于危重?fù)尵取残桁o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)RAS抑制對于心力衰竭患者：

ARBs>ACE抑制劑？

ARBs＋ACE抑制劑>ACE抑制劑？CHARM

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.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: 平安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(biāo)準(zhǔn)(同時具有心衰或左室收縮功能障礙的臨床/放射學(xué)證據(jù))主要排除標(biāo)準(zhǔn):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(qū)動:2,700次事件VALIANT:研究設(shè)計0.20.40.60.8No.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(yù)設(shè)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撫慰劑Candesartan

betterHazardratioPlacebo

better0.60.81.01.21.4Pvaluefortreatment

interaction0.140.26McMurrayJVetal.Lancet.ESCGuidelinesonthediagnosisandtreatmentofCHF,EHJ2005對ACE抑制劑有不能耐受病癥的患者，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抑制劑治療有病癥的患者，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(shè)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.

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(shè)計Bisoprololo.d.0246810

262830323436****************……….…….*****

不同-受體阻斷劑的藥理學(xué)差異 1

2

1blockade antioxidant

blockade blockade (vasodilat.) effects美托洛爾 +++ - - -比索洛爾 +++ - - -阿替洛爾 +++ - - -卡維地絡(luò) +++ +++ ++ ++布辛洛爾 +++ +++ (+) -奈比洛爾 +++ - (+) --受體阻斷劑治療心力衰竭1-受體阻斷是-受體阻斷劑治療獲益的主要來源在獲得等同的1-受體阻斷作用下，其他作用1阻斷胰島素敏感性血脂代謝

可否帶來進(jìn)一步的獲益？0.500.751.001.251.50SexMaleFemaleAge<65≥65NYHA

classIIIIIIVCauseOtherIHDLVEF≤25%>25%Heartrate<80beats/min≥80beats/minSystolicBP<110110-139≥140DiabetesYesNoOverallCarvedilolbetterMetoprololbetter4101200 5001217 0.80175730 228736 0.75309732 324716 0.912849 4866 0.68102311 100301 0.96207834 231803 0.84305677 369715 0.84198735 219703 0.83314776 381815 0.85270706 285630 0.79221743 287819 0.84234693 284733 0.86277816 314783 0.80120245 132235 0.80121447 158434 0.71153360 178371 0.853591150 4191143 0.82512151160015180.83270817 310849 0.89Deathsn DeathsnHR

CarvedilolMetoprololHazardRatioCOMET研究：亞組分析2005年最新資料:醛固酮拮抗劑醛固酮拮抗劑是否證明對II級心衰或尚未出現(xiàn)病癥的左心室收縮功能障礙患者具有益處，還有待進(jìn)一步證實當(dāng)病癥加重時,是否需要加大醛固酮拮抗劑的劑量還難以確定比較SOLVD-T、CIBIS-II和CHARM-參加試驗的一年后死亡率死亡率(%)05101520利尿劑洋地黃利尿劑洋地黃ACE-I利尿劑洋地黃ACE-I利尿劑洋地黃ACE-I-阻滯劑利尿劑洋地黃ACE-I-阻滯劑利尿劑洋地黃ACE-I-阻滯劑坎地沙坦SOLVD-T(1991)CIBIS-II(1999)RR-33%CHARM-參加試驗(2003)RR-33%RR

－20%RR

－33%RR

－33%治療慢性心力衰竭和降低左心室射血分?jǐn)?shù)病癥的嚴(yán)重性NYHAIII/IVNYHAII-IV-阻滯劑ACE抑制劑或ARB如果

ACE不耐受或ACE-I和

ARB?醛固酮拮抗劑

CIBIS2MERIT-HFCOPERNICUSCONSENSUSSOLVD-TV-HeFTIIELITE-2CHARM-選擇試驗Val-HeFTCHARM-參加試驗RALESEPHERSUS++ImpactofISDN-hydralazineonmortalityandmorbidityofAfrican-AmericanpatientswithHeartFailureA-HeftTrialIsosorbidedinitrate(ISDN)plushydralazineTabletcontaining