心力衰竭临床药物治疗面临的挑战会议课件教学幻灯PPT.ppt

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1、李 勇复旦大学华山医院心脏科,心力衰竭临床药物治疗面临的挑战,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,心室重塑(心室结构、功能的变化),心力衰竭发生发展的基础,ACEI治疗心力衰竭病死率和病残率,05101520253035404550,危险度降低（）,心衰死亡率或住院率,总死亡率,心衰死亡率,致命性/非致命性心梗,0

2、.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(%),Days,20,15,5,0,10,P=.0062(adjusted),Metoprolol CR/XL(n=1990),Placebo(n=2001),US Carvedilol Trials1,Probability ofEvent-free Survival,Carvedilol(n=696),Placebo(n=398),Days,P.001,0.

3、0,0,100,200,300,400,65%,1.0,0.8,0.7,0.9,MERIT-HF2,Survival(%of Patients),100,90,80,60,70,0,600,0,400,300,200,100,Days,Carvedilol(n=1156),Placebo(n=1133),500,600,0,400,300,200,100,500,35%,P=.00013,COPERNICUS4,Days,0.0,200,400,800,1.0,0.8,0.6,P.0001,34%,Bisoprolol(n=1327),Placebo(n=1320),CIBIS-II3,0,6

4、00,Survival,1.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.,0,1,2,3,年,0,10,20,30,40,50,3.5,风险比值 0.85(95%CI 0.75-0.96),p=0.011校正风险比值 0.85,p=0.010,483(37.9%),53

5、8(42.3%),%,NNT=23,1 年 HR 0.76P0.001,CHARM-合用组：首要终点,心血管死亡或心衰住院的比例(%),安慰剂,坎地沙坦,有危险的例数坎地沙坦127611761063948457安慰剂127211361013906422,心率：心血管死亡的预测因子,Fox K et al.Lancet Online August 31,2008.,心率 70 bpm,心率 70 bpm,Change in heart rate(bpm),Change in mortality(%),-20,-16,-12,-8,-4,0,4,8,12,-100,-80,-60,-40,-20,

6、0,20,40,60,PROFILE,PROMISE,XAMOTEROL,VHeFT(Prazosin),VHeFT(HDZ/ISDN),CONSENSUS,SOLVD,US CARVEDILOL,MOCHA,CIBIS,NORTIMOLOL,BHAT,ANZ,*,*,GESICA,Change in Heart Rate and CHF Mortality,Kjekshus&Gullestad(1999),总死亡率,随访月,百分比,安慰剂,美托洛尔,p=0.0096,安慰剂,美托洛尔,p=0.0067,降低危险=36%,百分比,低剂量组每3个月随访(n=1016),高剂量组每3个月随访(n=

7、2635),随访月,MERIT-HF:3个月后剂量相关的回顾性亚组分析,Wikstrand 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,65,70,75,80,85,0,50,100,150,200,MERIT-HF:3个月后剂量相关的回顾性亚组分析,3 月(192mg),小剂量组,大剂量组,Wikstrand J et al.for the MERIT-HF Stu

8、dy Group.,心率减慢,Incomplete follow-up102 withdrew consent3 randomisationirregularities,Incomplete follow-up114 withdrew consent1 lost to follow-up,Patients and follow-up,10 917 randomised,5479 to ivabradine,5438 to placebo,Median study duration:19 months;maximum:35 months,5438 analysed,5479 analysed,1

9、2 138 screened,Study design,Ivabradine 5 mg 7.5 mg twice daily,Matching placebo,Visits,Am Heart J.2006;152:860-66,Treatment Target HR60 bpmReduce dosage or discontinue when HR50bpm or/and symptomatic bradycardia,选择性窦房结If通道阻滞剂对心率的影响,总体人群,HR 70 bpm人群,伊伐布雷定平均剂量：6.18 mg bid,Fox K et al.Lancet Online Aug

10、ust 31,2008.,伊伐布雷定平均剂量：6.64 mg bid,心肌梗死后静息心率减慢与临床获益,Cucherat M.Euro Heart J,2007;28:30123019.,选择性窦房结If通道阻滞剂对主要终点的影响,主要复合终点：心血管死亡、因急性心肌梗死住院、因心力衰竭新发或恶化而住院,Fox K et al.Lancet Online August 31,2008.,总体人群,HR 70 bpm人群,患者基线时的治疗,Fox K et al.Lancet Online August 31,2008.,RRR30,RRR42,Olsson G et al.Am J Hyper

11、tens 1991;4(2 Pt 1):151-158.Olsson G et al.Eur Heart J 1992;13:28-32.The MERIT-HF Study Group.Lancet 1999;353:2001-2007.,1阻滞剂：有效降低心脏性猝死危险,RRR41,心力衰竭患病率,66-103,75-86,70-84,75,50,40,25,55-95,78,76,75,60,68,65,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(V

12、asteras),左心室收缩功能降低的比例,HF-PSF的比例,55,51,68,46,71,59,39,71,Petrie M,McMurray J.Lancet.2001;358:423-434.Hogg K et al.J Am Coll Card.2004;43:317-327.,CHF患病率(%),0,1,2,3,4,5,6,7,8,9,10,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 e

13、t 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.Bhati

14、a 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,射血分数降低的患者,危险病例数,危险病例数,年,年,生存率,生存率,Placebo,Forced titration,Maintenance,Enrollment,Single-blind2 weeks,W 2,W 4,W 8,M 6,M 10,M 14

15、to endEvery 4 months,75 mg,150 mg,300 mg,Follow-up continued until 1,440 primary endpoints occurred,N=4,128,I-PRESERVE:Study Design,Irbesartan,R,Only 1/3 pts could enter on an ACEI,Randomized,double-blind,placebo controlled trial,I-PRESERVE:Primary EndpointDeath or protocol specified CV hospitalizat

16、ion(Mean follow-up 49.5 months),Months from Randomization,Cumulative Incidence of Primary Events(%),40-,0-,10-,20-,30-,0,6,12,18,24,36,42,30,48,60,54,2067,1929,1812,1730,1640,1513,1291,1569,1088,497,816,2061,1921,1808,1715,1618,1466,1246,1539,1051,446,776,No.at Risk,Irbesartan,Placebo,HR(95%CI)=0.95

17、(0.86-1.05)Log-rank p=0.35,I-PRESERVE:Baseline Treatments,32,30,Lipid lowering,59,58,Antiplatelet,40,39,Calcium channel blocker,59,58,Beta-blocker,14,13,Digoxin,26,25,ACE-inhibitor,15,15,Spironolactone,82,84,Treatment(%)Diuretic,Irbesartan(N=2067),Placebo(N=2061),38,39,27,28,Total exposed during the

18、 study,72,72,Adapted with permission from:Vasan RS,Levy D.Arch Intern Med.1996;156:1790.,Progression From Hypertensionto LVH,CAD,and Heart Failure,HTN,SmokingLipidsDiabetes,ObesityDiabetesInsulin Resistance,MI,LVH,Normal Left Ventricular(LV)Structureand Function,LV Remodeling,Subclinical LV Dysfunct

19、ion,Overt HF,DiastolicDysfunction,SystolicDysfunction,CHF,CAD,V-HeFT:血浆去甲肾上腺素水平与病死率的关系,累计死亡率(%),月,NE 900pg/mlNE 600-900 NE600pg/ml,100,80,60,40,20,0,0,12,24,36,48,60,总 体P0.0001,BNP(pg/ml),41,4197,98238,238,BNP,随机化后时间(月),生存率,9.7,14.3,20.7,32.4,%死亡率,NE,572,274,274394,395572,NE(pg/mL),24.2,%死亡率,13.8,16

20、.5,23.0,Val-HeFT:BNP和NE基线四分法全因死亡率亚组分析,20,10,30,0,40,Anand IS.Circulation.2003;107:12781283.,随机化后时间(月),Heart Failure after MI and HTNSystolic vs Diastolic,N 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,血管

21、紧张素原,肾素,Ang I,AT1 受体,Ang II,ACEI(yes)BB(yes),15.5,1.1,7.2,Ang II(fmol/mL),(n=11),ACEI(yes)BB(no),(n=11),101,5,10,20,15,100,95,Ang I(fmol/mL),5,10,20,15,100,95,血管紧张素 II,血管紧张素 I,105,105,ACEI+BB 在心力衰竭患者中显著降低Ang II 水平,0,0,Campbell DJ et al.Lancet.2001;358:16091610.,肾上腺素系统活化,肾素血管紧张素系统活化,直接心脏毒性,心率加快收缩力增强,

22、血管收缩,容量负荷过重,室壁张力增加,心肌细胞损伤,心肌氧耗增加,心肌肥厚,心肌收缩功能降低,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 Yes 223/702 274/711 No260/574264/561ACE I.Yes232/643275/648推荐剂量No251/633263/624所有患者 483/1276538/1272,Candesartan,安慰剂,Candesartan better,Hazard ratio,Placebo better,0.6,0.8,1.0,1.2,1.4,P value fortreatment interaction,0.14,0.26,McMurray JV et al.Lancet.2003.http:/,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,心血管病的进程,Volpe M,2007,（左室肥厚）,RAS抑制+阻滞剂：防治心力衰竭,