心力衰竭临床药物治疗面临的挑战-会议课件-教学幻灯.ppt

心力衰竭临床药物治疗面临的挑战-会议课件，教学幻灯Acute Infarction(hours)Infarct Expansion(hours to days)Global Remodeling(days to months)心肌梗死后左心室重构交感神经RAAS交感神经RAAS交感神经RAAS血液动力学的变化(CO、LVEDP)心力衰竭临床症状的基础心力衰竭临床症状的基础 心室重塑(心室结构、功能的变化)心力衰竭发生发展的基础心力衰竭发生发展的基础ACEI治疗心力衰竭治疗心力衰竭病死率和病残率病死率和病残率0 05 5101015152020252530303535404045455050危险度降低（）危险度降低（）心衰死亡率心衰死亡率或住院率或住院率总死亡率总死亡率心衰死亡率心衰死亡率致命性致命性/非致非致命性心梗命性心梗0.00135%0.00123%0.00131%0.0420%Garg R,Yusuf S.JAMA.1995;237:1450-1456.-阻滞剂治疗心力衰竭：无可辩驳的证据34%Cumulative Mortality(%)Days20155010P=.0062(adjusted)Metoprolol CR/XL(n=1990)Placebo(n=2001)US Carvedilol Trials1Probability ofEvent-free Survival Carvedilol(n=696)Placebo(n=398)DaysP.0010.0010020030040065%1.00.80.70.9MERIT-HF2Survival(%of Patients)1009080607006000400300200100DaysCarvedilol(n=1156)Placebo(n=1133)500600040030020010050035%P=.00013COPERNICUS4Days0.02004008001.00.80.6P.000134%Bisoprolol(n=1327)Placebo(n=1320)CIBIS-II30600Survival1.Packer M et al.N Engl J Med.1996;334:13491355.2.MERIT-HF Study Group.Lancet.1999;253:20012007.3.CIBIS-II Investigators.Lancet.1999;353:913.4.Packer M et al.N Engl J Med.2001;344:16511658.70123年年010203040503.5风险比值 0.85 (95%CI 0.75-0.96),p=0.011校正风险比值 0.85,p=0.010483(37.9%)538(42.3%)%NNT=231 年 HR 0.76P0.001CHARM-合用合用组：首要：首要终点点心血管死亡或心衰住院的比例(%)安慰剂安慰剂坎地沙坦坎地沙坦有危险的例数有危险的例数坎地沙坦坎地沙坦127611761063948457安慰剂安慰剂12721136101390642210心率：心血管死亡的心率：心血管死亡的预测预测因子因子Fox K et al.Lancet Online August 31,2008.心率心率 70 bpm心率心率 70 bpm心血管死亡率（心血管死亡率（%）P=0.0041风险率风险率=1.34(1.10 1.63)时间（年）时间（年）00.511.52051015Change in heart rate(bpm)Change in heart rate(bpm)Change in mortality(%)Change in mortality(%)-20-20-16-16-12-12-8-8-4-40 04 48 81212-100-100-80-80-60-60-40-40-20-200 0202040406060PROFILEPROFILEPROMISEPROMISEXAMOTEROLXAMOTEROLVHeFTVHeFT(Prazosin)(Prazosin)VHeFTVHeFT(HDZ/ISDN)(HDZ/ISDN)CONSENSUSCONSENSUSSOLVDSOLVDUS CARVEDILOLUS CARVEDILOLMOCHAMOCHACIBISCIBISNORNORTIMOLOLTIMOLOLBHATBHATANZANZ*GESICAGESICAChange in Heart Rate and CHF MortalityKjekshus&Gullestad(1999)Kjekshus&Gullestad(1999)总死亡率总死亡率随访月百分比036912151820151050安慰剂美托洛尔p=0.0096降低危险=44%安慰剂美托洛尔p=0.0067降低危险=36%百分比低剂量组低剂量组每每3 3个月随访个月随访(n=1016)高剂量组高剂量组每每3 3个月随访个月随访(n=2635)随访月MERIT-HF:3个月后剂量相关的回顾性亚组分析个月后剂量相关的回顾性亚组分析201510500369121518Wikstrand J et al.for the MERIT-HF Study Group.4周(41mg)6周(80mg)8周(151mg)基线基线2周(21mg)2周(17mg)4周(32mg)6周(64mg)8周与 3月(76mg)(次/分)美托洛尔控释片剂量6570758085050100150200MERIT-HF:3个月后剂量相关的回顾性亚组分析个月后剂量相关的回顾性亚组分析3 月(192mg)小剂量组小剂量组大剂量组大剂量组Wikstrand J et al.for the MERIT-HF Study Group.心率减慢 Incomplete follow-up102 withdrew consent3 randomisationirregularitiesIncomplete follow-up114 withdrew consent1 lost to follow-upPatients and follow-upPatients and follow-up10 917 randomised5479 to ivabradine5438 to placeboMedian study duration:19 months;maximum:35 months5438 analysed5479 analysed12 138 screenedStudy designIvabradine 5 mg 7.5 mg twice dailyMatching placeboVisits3 YEARSAm Heart J.2006;152:860-66Treatment Target HR60 bpmReduce dosage or discontinue when HR402555-95787675606865年龄段平均年龄美国(CHS)芬兰(Helsinki)英国(Poole)丹麦.(Copen.)西班牙(Asturias)葡萄牙(EPICA)荷兰(Rotter.)瑞典(Vasteras)左心室收缩功能降低的比例HF-PSF的比例5551684671593971Petrie M,McMurray J.Lancet.2001;358:423-434.Hogg K et al.J Am Coll Card.2004;43:317-327.CHF患病率患病率(%)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)NHF Project4(n=19,710)1.Senni M et al.Circulation.1998;98:2282-2289.2.Vasan RS et al.J Am Coll Card.1999;33:1948-1955.3.Gottdiener JS et al.Ann Intern Med.2002;137:631-639.EF50%EF 50%Owan5(n=4,596)Bhatia6(n=2,802)Patients(%)4.Masoudi FA et al.J Am Coll Card.2003;41-217-223.5.Owan TE et al.N Engl J Med.2006;355:251-259.6.Bhatia RS et al.N Engl J Med.2006;355:260-269.HF-PEF患病趋势 Owan TE et al.N Engl J Med.2006;355:251-259.SHF与HF-PEF的预后(5年生存率)OWAN TE et al.N Engl J Med 2006;355:251-259射血分数正常的患者射血分数正常的患者射血分数正常的患者射血分数正常的患者射血分数降低的患者射血分数降低的患者射血分数降低的患者射血分数降低的患者危险病例数危险病例数年年生存率生存率PlaceboForced titrationMaintenanceEnrollmentSingle-blind2 weeksW 2W 4W 8M 6M 10M 14 to endEvery 4 months75 mg150 mg300 mgFollow-up continued until 1,440 primary endpoints occurredN=4,128I-PRESERVE:Study DesignIrbesartanROnly 1/3 pts could enter on an ACEIRandomized,double-blind,placebo controlled trialI-PRESERVE:Primary EndpointDeath or protocol specified CV hospitalization(Mean follow-up 49.5 months)Months from RandomizationCumulative Incidence of Primary Events(%)40-0-10-20-30-06121824364230486054206719291812173016401513129115691088497816206119211808171516181466124615391051446776No.at RiskIrbesartanPlaceboHR(95%CI)=0.95(0.86-1.05)Log-rank p=0.35PlaceboIrbesartanI-PRESERVE:Baseline Treatments3230 Lipid lowering59 58 Antiplatelet4039 Calcium channel blocker5958 Beta-blocker1413 Digoxin2625 ACE-inhibitor1515 Spironolactone 8284Treatment(%)DiureticIrbesartan(N=2067)Placebo(N=2061)38392728Total exposed during the study7272Adapted with permission from:Vasan RS,Levy D.Arch Intern Med.1996;156:1790.Progression From Hypertensionto LVH,CAD,and Heart FailureHTNSmokingLipidsDiabetesObesityDiabetesInsulin ResistanceMILVHNormal Left Ventricular(LV)Structureand FunctionLV RemodelingSubclinical LV DysfunctionOvert HFDiastolicDysfunctionSystolicDysfunctionCHFCADV-HeFT:血浆去甲肾上腺素水平与病死率的关系累计死亡率累计死亡率(%)(%)月月NE 900pg/mlNE 900pg/mlNE 600-900NE 600-900 NE600pg/mlNE600pg/ml10080604020001224364860总总 体体P0.0001BNP(pg/ml)238BNP随机化后时间随机化后时间(月月)生存率生存率2010300400.50.60.70.81.00.99.714.320.732.4%死亡率死亡率NE572274274394395572NE(pg/mL)0.50.60.70.81.00.924.2%死亡率死亡率13.816.523.0Val-HeFT:BNP和和NE基线四分法全因死亡率亚组分析基线四分法全因死亡率亚组分析201030040Anand IS.Circulation.2003;107:12781283.随机化后时间随机化后时间(月月)Heart Failure after MI and HTNSystolic vs DiastolicN Engl J Med 2003;348:2007-18高血压-左心室肥厚-交感神经活性高血压交感神经活性RAAS活性心率 X 每搏量=心输出量心肌细胞肥大，细胞外基质堆积心输出量左心室壁肥厚，室腔容积减小每搏量舒张时间间期缩短每搏量药物对肾素血管紧张素系统的作用药物对肾素血管紧张素系统的作用血管紧张素原血管紧张素原肾素肾素Ang IAT1 受体受体Ang IIACEIARBBBACEI (yes)BB (yes)15.51.17.2Ang II(fmol/mL)(n=11)ACEI(yes)BB(no)(n=11)101510201510095Ang I(fmol/mL)510201510095血管紧张素血管紧张素 II 血管紧张素血管紧张素 I105105ACEI+BB 在心力衰竭患者中显著降低在心力衰竭患者中显著降低Ang II 水平水平00Campbell DJ et al.Lancet.2001;358:16091610.肾上腺素系统肾上腺素系统活化活化肾素血管紧张素系统肾素血管紧张素系统活化活化直接心脏毒性直接心脏毒性心率加快心率加快收缩力增强收缩力增强血管收缩血管收缩容量负荷过重容量负荷过重室壁张力增加室壁张力增加心肌细胞损伤心肌细胞损伤心肌氧耗增加心肌氧耗增加心肌肥厚心肌肥厚心肌收缩功能降低心肌收缩功能降低心力衰竭的神经内分泌机制心力衰竭的神经内分泌机制CHARM-Added:预设亚组,心血管死亡或心力衰竭住院-阻滞剂阻滞剂 Yes 223/702 274/711 No260/574264/561ACE I.Yes232/643275/648推荐剂量推荐剂量 No251/633263/624所有患者所有患者 483/1276 538/1272Candesartan安慰剂安慰剂Candesartan betterHazard ratioPlacebo better0.60.81.01.21.4P value fortreatment interaction0.140.26McMurray JV et al.Lancet.From Risk Factors to Heart FailureTo treat heart failure,the BEST WAYis to PREVENT heart failure血压靶器官损害心血管事件心血管病的心血管病的进程程Volpe M,2007（左室肥厚）（左室肥厚）RAS抑制+阻滞剂：防治心力衰竭