心力衰竭临床药物治疗面临的挑战-会议教学幻灯课件

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0.00135% 0.00123%

2、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 SurvivalCarvedilol (n=696)Placebo (n=398)DaysP.0010.0010020030040065% 1.0

3、MERIT-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

4、Study Group. Lancet. 1999;253:20012007. 3. CIBIS-II Investigators. Lancet. 1999;353:913.4. Packer M et al. N Engl J Med. 2001;344:16511658.0123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 - 合用组：首要终点心血管死亡或心衰住院的比例(%)安慰剂坎地

5、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 402555-95787675606865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;

6、358:423-434. Hogg K et al. J Am Coll Card. 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)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. Gottdiene

7、r 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;3

8、55:251-259.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

9、-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 -

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 blocker59

11、58 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

12、 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(%)月NE 900pg/mlNE 600-900 NE600pg/ml1008060402000122436486

13、0总 体P0.0001BNP(pg/ml)238BNP随机化后时间 (月)生存率2010300400.81.00.99.714.320.732.4% 死亡率NE572274274394395572NE(pg/mL)0.81.00.924.2% 死亡率13.816.523.0Val-HeFT: BNP和NE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 (月)Heart Failure after MI and HTNSystolic vs DiastolicN En

14、gl 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 IAT1 受体Ang IIACEIARBBBACEI (yes) BB (yes)Ang II (fmol/mL)(n = 11)ACEI (yes) BB (no)(n = 11)101510201510095Ang I (fmol/mL)510201510095血管紧张素 II 血管紧张素

15、 I105105ACEI + BB 在心力衰竭患者中显著降低Ang II 水平00Campbell 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 483/1276538/1272Candesartan安慰剂Candesartan betterHazard ratioPlacebo better1.21.4P value