心力衰竭臨床藥物治療面臨的挑戰(zhàn)-會(huì)議課件教學(xué)幻燈

李勇復(fù)旦大學(xué)華山醫(yī)院心臟科心力衰竭臨床藥物治療面臨的挑戰(zhàn)AcuteInfarction

(hours)InfarctExpansion

(hourstodays)GlobalRemodeling

(daystomonths)心肌梗死后左心室重構(gòu)交感神經(jīng)RAAS交感神經(jīng)RAAS交感神經(jīng)RAAS血液動(dòng)力學(xué)的變化(CO↓、LVEDP↑)心力衰竭臨床病癥的根底心室重塑(心室結(jié)構(gòu)、功能的變化)心力衰竭發(fā)生開(kāi)展的根底ACEI治療心力衰竭

病死率和病殘率05101520253035404550危險(xiǎn)度降低〔％〕心衰死亡率或住院率總死亡率心衰死亡率致命性/非致命性心梗<0.00135%↓<0.00123%↓<0.00131%↓<0.0420%↓GargR,YusufS.JAMA.1995;237:1450-1456.-阻滯劑治療心力衰竭：無(wú)可辯駁的證據(jù)34%CumulativeMortality(%)Days20155010P=.0062(adjusted)MetoprololCR/XL(n=1990)Placebo(n=2001)USCarvedilolTrials1Probabilityof

Event-freeSurvivalCarvedilol(n=696)Placebo(n=398)DaysP<.0010.0010020030040065%1.00.80.70.9MERIT-HF2Survival(%ofPatients)1009080607006000400300200100DaysCarvedilol(n=1156)Placebo(n=1133)500600040030020010050035%P=.00013COPERNICUS4Days0.02004008001.00.80.6P<.000134%Bisoprolol(n=1327)Placebo(n=1320)CIBIS-II30600Survival1.PackerMetal.NEnglJMed.1996;334:1349–1355.

2.MERIT-HFStudyGroup.Lancet.1999;253:2001–2007.

3.CIBIS-IIInvestigators.Lancet.1999;353:9–13.

4.PackerMetal.NEnglJMed.2001;344:1651–1658.0123年010203040503.5風(fēng)險(xiǎn)比值0.85(95%CI0.75-0.96),p=0.011

校正風(fēng)險(xiǎn)比值0.85,p=0.010483(37.9%)538(42.3%)%NNT=231年HR0.76P<0.001CHARM

-

合用組：首要終點(diǎn)心血管死亡或心衰住院的比例(%)撫慰劑坎地沙坦有危險(xiǎn)的例數(shù)坎地沙坦 1276 1176 1063 948 457撫慰劑 1272 1136 1013 906 422心率：心血管死亡的預(yù)測(cè)因子FoxKetal.LancetOnlineAugust31,2021.心率<70bpm心率≥70bpm心血管死亡率（%）P=0.0041風(fēng)險(xiǎn)率=1.34(1.10–1.63)時(shí)間（年）00.511.52051015Changeinheartrate(bpm)Changeinmortality(%)-20-16-12-8-404812-100-80-60-40-200204060PROFILEPROMISEXAMOTEROLVHeFT(Prazosin)VHeFT(HDZ/ISDN)CONSENSUSSOLVDUSCARVEDILOLMOCHACIBISNORTIMOLOLBHATANZ**GESICAChangeinHeartRateandCHFMortalityKjekshus&Gullestad(1999)總死亡率隨訪月百分比036912151820151050撫慰劑美托洛爾p=0.0096降低危險(xiǎn)=44%撫慰劑美托洛爾p=0.0067降低危險(xiǎn)=36%百分比低劑量組每3個(gè)月隨訪

(n=1016)高劑量組每3個(gè)月隨訪

(n=2635)隨訪月MERIT-HF:3個(gè)月后劑量相關(guān)的回憶性亞組分析201510500369121518WikstrandJetal.fortheMERIT-HFStudyGroup.4周(41mg)6周(80mg)8周(151mg)基線基線2周(21mg)2周(17mg)4周(32mg)6周(64mg)8周與3月(76mg)(次/分)美托洛爾控釋片劑量6570758085050100150200MERIT-HF:3個(gè)月后劑量相關(guān)的回憶性亞組分析3月(192mg)小劑量組大劑量組WikstrandJetal.fortheMERIT-HFStudyGroup.心率減慢

Incompletefollow-up102withdrewconsent3randomisationirregularitiesIncompletefollow-up114withdrewconsent1losttofollow-upPatientsandfollow-up10917randomised5479toivabradine5438toplaceboMedianstudyduration:19months;maximum:35months5438analysed5479analysed12138screenedStudydesignIvabradine5mg7.5mgtwicedailyMatchingplaceboVisits3YEARSAmHeartJ.2006;152:860-66TreatmentTargetHR<60bpm

ReducedosageordiscontinuewhenHR<50bpmor/andsymptomaticbradycardia選擇性竇房結(jié)If通道阻滯劑對(duì)心率的影響——總體人群——HR≥70bpm人群伊伐布雷定平均劑量：6.18mgbid心率(bpm)50607080隨訪時(shí)間(天)0153090180360540720安慰劑選擇性竇房結(jié)If通道阻滯劑6961696472FoxKetal.LancetOnlineAugust31,2021.伊伐布雷定平均劑量：6.64mgbid6575736679506070800153090180360540720安慰劑選擇性竇房結(jié)If通道阻滯劑心率(bpm)隨訪時(shí)間(天)心肌梗死后靜息心率減慢與臨床獲益CucheratM.EuroHeartJ,2007;28:3012–3019.0.69(0.56-0.83)HetP=0.439（4項(xiàng)試驗(yàn)）0.78(0.68-0.90)HetP=0.036（6項(xiàng)試驗(yàn)）0.91(0.79-1.06)HetP=0.605（6項(xiàng)試驗(yàn)）全因死亡-15%0.60.70.81.0較大(16.2)平均(10.0)較小(4.7)風(fēng)險(xiǎn)率絕對(duì)心率降低（平均bpm）三分位分析趨向檢測(cè)P=0.017非致死性心肌梗死再發(fā)-18%0.60.70.81.0較大(15.3)平均(10.8)較小(4.4)風(fēng)險(xiǎn)率絕對(duì)心率降低（平均bpm）0.61(0.48-0.76)HetP=0.85（4項(xiàng)試驗(yàn)）0.79(0.66-0.94)HetP=0.61（4項(xiàng)試驗(yàn)）0.84(0.70-1.02)HetP=1.00（5項(xiàng)試驗(yàn)）三分位分析趨向檢測(cè)P=0.033選擇性竇房結(jié)If通道阻滯劑對(duì)主要終點(diǎn)的影響主要復(fù)合終點(diǎn)：心血管死亡、因急性心肌梗死住院、因心力衰竭新發(fā)或惡化而住院主要復(fù)合終點(diǎn)事件的發(fā)生率（%）選擇性竇房結(jié)If通道阻滯劑安慰劑P=0.94危害比=1.00(0.91–1.10)0510152025時(shí)間（年）00.511.52FoxKetal.LancetOnlineAugust31,2021.——總體人群——HR≥70bpm人群主要復(fù)合終點(diǎn)事件的發(fā)生率（%）選擇性竇房結(jié)If通道阻滯劑安慰劑P=0.17危害比=0.91(0.81–1.04)0510152025時(shí)間（年）00.511.52患者基線時(shí)的治療安慰劑n=5438選擇性竇房結(jié)If通道阻滯劑n=5479全部n=10917抗血栓治療(%)949494他汀(%)747474β受體阻滯劑(%)878787RAS阻斷劑(%)909090FoxKetal.LancetOnlineAugust31,2021.利尿劑倍他樂(lè)克隨訪（年）510(p=0.017,n=3,234)高血壓MAPHY研究50累積發(fā)生數(shù)安慰劑倍他樂(lè)克(p=0.002,n=5,474)123心肌梗死五項(xiàng)研究匯總分析61218(p=0.0002,n=3,991)慢性心衰MERIT-HF研究12120累積發(fā)生數(shù)累積發(fā)生百分率(%)安慰劑倍他樂(lè)克隨訪（年）隨訪（月）RRR30％RRR42％OlssonGetal.AmJHypertens1991;4(2Pt1):151-158.OlssonGetal.EurHeartJ1992;13:28-32.TheMERIT-HFStudyGroup.Lancet1999;353:2001-2007.β1阻滯劑：有效降低心臟性猝死危險(xiǎn)RRR41％心力衰竭患病率66-10375-8670-847550>40>2555-9578–7675–606865年齡段平均年齡美國(guó)(CHS)芬蘭(Helsinki)英國(guó)(Poole)丹麥.(Copen.)西班牙(Asturias)葡萄牙(EPICA)荷蘭(Rotter.)瑞典(Vasteras)左心室收縮功能降低的比例HF-PSF的比例5551684671593971PetrieM,McMurrayJ.Lancet.2001;358:423-434.HoggKetal.JAmCollCard.2004;43:317-327.CHF患病率(%)012345678910心力衰竭患者中HF-PEF的比例EF50%EF45%EF50%EF50%Framingham2(n=73)Olmstead1(n=137)CHS3

(n=269)NHFProject4(n=19,710)1.SenniMetal.Circulation.1998;98:2282-2289.2.

VasanRSetal.JAmCollCard.1999;33:1948-1955.3.GottdienerJSetal.AnnInternMed.2002;137:631-639.EF50%EF>50%Owan5(n=4,596)Bhatia6(n=2,802)Patients(%)4.MasoudiFAetal.JAmCollCard.2003;41-217-223.5.OwanTEetal.NEnglJMed.2006;355:251-259.6.BhatiaRSetal.NEnglJMed.2006;355:260-269.HF-PEF患病趨勢(shì)

OwanTEetal.NEnglJMed.2006;355:251-259.SHF與HF-PEF的預(yù)后(5年生存率)

OWANTEetal.NEnglJMed2006;355:251-259射血分?jǐn)?shù)正常的患者射血分?jǐn)?shù)降低的患者危險(xiǎn)病例數(shù)危險(xiǎn)病例數(shù)年年生存率生存率PlaceboForcedtitrationMaintenanceEnrollmentSingle-blind2weeksW2W4W8M6M10M14toendEvery4months75mg150mg300mgFollow-upcontinueduntil1,440primaryendpointsoccurredN=4,128I-PRESERVE:StudyDesignIrbesartanROnly1/3ptscouldenteronanACEIRandomized,double-blind,placebocontrolledtrialI-PRESERVE:PrimaryEndpoint

DeathorprotocolspecifiedCVhospitalization

(Meanfollow-up49.5months)MonthsfromRandomizationCumulativeIncidenceof

PrimaryEvents(%)40-0-10-20-30-06121824364230486054206719291812173016401513129115691088497816206119211808171516181466124615391051446776No.atRiskIrbesartanPlaceboHR(95%CI)=0.95(0.86-1.05)Log-rankp=0.35PlaceboIrbesartanI-PRESERVE:BaselineTreatments3230Lipidlowering5958Antiplatelet4039Calciumchannelblocker5958Beta-blocker1413Digoxin2625ACE-inhibitor1515Spironolactone8284Treatment(%)DiureticIrbesartan(N=2067)Placebo(N=2061)38392728Totalexposedduringthestudy7272Adaptedwithpermissionfrom:VasanRS,LevyD.ArchInternMed.1996;156:1790.ProgressionFromHypertension

toLVH,CAD,andHeartFailureHTNSmokingLipidsDiabetesObesityDiabetes

InsulinResistanceMILVHNormalLeftVentricular(LV)Structure

andFunctionLVRemodelingSubclinicalLVDysfunctionOvertHFDiastolicDysfunctionSystolicDysfunctionCHFCADV-HeFT:血漿去甲腎上腺素水平與病死率的關(guān)系累計(jì)死亡率(%)月NE>900pg/mlNE600-900

NE≤600pg/ml10080604020001224364860總體P<0.0001BNP(pg/ml)<4141–9798–238>238BNP隨機(jī)化后時(shí)間(月)生存率2010300400.50.60.70.81.00.99.714.320.732.4%死亡率NE>572<274274–394395–572NE(pg/mL)0.50.60.70.81.00.924.2%死亡率13.816.523.0Val-HeFT:BNP和NE基線四分法全因死亡率亞組分析201030040AnandIS.Circulation.2003;107:1278?1283.隨機(jī)化后時(shí)間(月)HeartFailureafterMIandHTNSystolicvsDiastolicNEnglJMed2003;348:2007-18高血壓-左心室肥厚-交感神經(jīng)活性高血壓交感神經(jīng)活性 RAAS活性心率X每搏量=心輸出量心肌細(xì)胞肥大，細(xì)胞外基質(zhì)堆積心輸出量左心室壁肥厚，室腔容積減小每搏量舒張時(shí)間間期縮短每搏量藥物對(duì)腎素血管緊張素系統(tǒng)的作用血管緊張素原腎素AngIAT1受體AngIIACEIARB