心力衰竭临床药物治疗面临的挑战会议课件教学幻灯

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,0 5 10 15 20 25 30 35 40 45 50,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,0.001 35%,0.001 23%,0.001 31%,0.04 20%,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 of Event-free Survival,Carvedilol (n=696),Placebo (n=398),Days,P.001,0.0,0,100,200,300,400,65% ,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-II3,0,600,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%),538 (42.3%),%,NNT = 23,1 年 HR 0.76 P0.001,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 1276 1176 1063 948 457 安慰剂 1272 1136 1013 906 422,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,-20,0,20,40,60,PROFILE,PROMISE,XAMOTEROL,VHeFT (Prazosin),VHeFT (HDZ/ISDN),CONSENSUS,SOLVD,US CARVEDILOL,MOCHA,CIBIS,NOR TIMOLOL,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=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 Study Group.,心率减慢,Incomplete follow-up 102 withdrew consent 3 randomisation irregularities,Incomplete follow-up 114 withdrew consent 1 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,12 138 screened,Study design,Ivabradine 5 mg 7.5 mg twice daily,Matching placebo,Visits,Am Heart J. 2006;152:860-66,Treatment Target HR60 bpm Reduce 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 August 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.,RRR 30,RRR 42,Olsson G et al. Am J Hypertens 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,RRR 41,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(Vasteras),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,EF 50%,EF 45%,EF 50%,EF 50%,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.,EF 50%,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-blind 2 weeks,W 2,W 4,W 8,M 6,M 10,M 14 to end Every 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 Endpoint Death or protocol specified CV hospitalization (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 (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 study,72,72,Adapted with permission from: Vasan RS, Levy D. Arch Intern Med. 1996;156:1790.,Progression From Hypertension to LVH, CAD, and Heart Failure,HTN,Smoking Lipids Diabetes,Obesity Diabetes Insulin Resistance,MI,LVH,Normal Left Ventricular (LV) Structure and Function,LV Remodeling,Subclinical LV Dysfunction,Overt HF,Diastolic Dysfunction,Systolic Dysfunction,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/ml NE 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,13.8,16.5,23.0,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 HTN Systolic 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