1、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)Acute Infarction(hours)Infarct Expansion(hours to days)Global Remodeling(days to months)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血液動力學(xué)的變化 (CO、LVEDP)心力衰竭臨床癥狀的基礎(chǔ) 心室重塑 (心室結(jié)構(gòu)、功能的變化)心力衰竭發(fā)生發(fā)展的基礎(chǔ)ACEI治療心力衰竭病死率和病殘率05101520253035404550危險度降低（）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%

2、0.00131% 0.0420% Garg R,Yusuf S.JAMA.1995;237:1450-1456.-阻滯劑治療心力衰竭：無可辯駁的證據(jù)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風(fēng)險比值 0.85 (95% CI 0.75-0.96), p=0.011校正風(fēng)險比值 0.85, p=0.010483 (37.9%)538 (42.3%)%NNT = 231 年 HR 0.76P0.001CHARM - 合用組：首要終點心血管死亡或心衰住院的比例(%)安慰劑坎地

5、沙坦有危險的例數(shù)坎地沙坦127611761063948457安慰劑127211361013906422心率：心血管死亡的預(yù)測因子Fox K et al. Lancet Online August 31, 2008. 心率 402555-95787675606865年齡段平均年齡美國 (CHS)芬蘭(Helsinki)英國(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患病趨勢 Owan TE et al. N Engl J Med. 2006;3

8、55:251-259.SHF與HF-PEF的預(yù)后(5年生存率)OWAN TE et al. N Engl J Med 2006; 355: 251-259射血分數(shù)正常的患者射血分數(shù)降低的患者危險病例數(shù)危險病例數(shù)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: 血漿去甲腎上腺素水平與病死率的關(guān)系累計死亡率(%)月NE 900pg/mlNE 600-900 NE600pg/ml1008060402000122436486

13、0總 體P0.0001BNP(pg/ml)238BNP隨機化后時間 (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基線四分法全因死亡率亞組分析201030040Anand IS. Circulation. 2003;107:12781283.隨機化后時間 (月)Heart Failure after MI and HTNSystolic vs DiastolicN En

14、gl J Med 2003;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 = 心輸出量心肌細胞肥大，細胞外基質(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間間期縮短每搏量藥物對腎素血管緊張素系統(tǒng)的作用血管緊張素原腎素Ang IAT1 受體Ang IIACEIARBBBACEI (yes) BB (yes)Ang II (fmol/mL)(n = 11)ACEI (yes) BB (no)(n = 11)101510201510095Ang I (fmol/mL)510201510095血管緊張素 II 血管緊張素

15、 I105105ACEI + BB 在心力衰竭患者中顯著降低Ang II 水平00Campbell DJ et al. Lancet. 2001;358:16091610.腎上腺素系統(tǒng)活化腎素血管緊張素系統(tǒng)活化直接心臟毒性心率加快收縮力增強血管收縮容量負荷過重室壁張力增加心肌細胞損傷心肌氧耗增加心肌肥厚心肌收縮功能降低心力衰竭的神經(jīng)內(nèi)分泌機制CHARM-Added: 預(yù)設(shè)亞組, 心血管死亡或心力衰竭住院-阻滯劑 Yes 223/702 274/711 No260/574264/561ACE I.Yes232/643275/648推薦劑量No251/633263/624所有患者 483/1276538/1272Candesartan安慰劑Candesartan betterHazard ratioPlacebo better1.21.4P value