心力衰竭药物治疗新证据与新视野

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1、心力衰竭药物治疗新证据与新视野,李勇 复旦大学附属华山医院心脏科 上海 200040,治疗心力衰竭的药物,1、强心苷类药物 2、利尿剂 3、ACE抑制剂及血管紧张素II（AT1）受体拮抗剂 4、受体阻断剂 5、其他治疗CHF的药物： （1）钙拮抗剂 （2）磷酸二酯酶抑制剂 （3）其他血管扩张剂：长效硝酸酯类，肼苯哒嗪,DIG 研究,Placebo n=3403,Digoxin n=3397,48,0,12,24,36,Mortality %,N Engl J Med 1997;336:525,Months,p = 0.8,Digitalis,N=6800 NYHA II-III,0.6,Pro

2、bability of Death,0,Placebo (273)Prazosin (183)Hz + ISDN (186),Months,0.7,0.5,0.3,0.4,0.2,0.1,N Engl J Med 1986;314:1547,Nitrates,0,6,12,18,24,30,36,42,V-HeFT-I研究,combination of hydralazine (300mg/day) and isosorbide dinitrate (160mg/day,23% reduction in mortality,Placebo,Enalapril,12,11,10,9,8,7,6,

3、5,Probabiility of Death,Months,0.1,0.8,0,0.2,0.3,0.7,0.4,0.5,0.6,p 0.001,p 0.002,N Engl J Med 1987;316:1429,4,3,2,1,0,CONSENSUS 研究,253 patients with class IV heart failure Enalapril： 2.5-40mg/day,31% reduction in mortality,Months,0,6,12,p = 0.0036,% Mortality,24,18,30,36,42,48,Enalapril n=1285,Place

4、bo n=1284,N Engl J M 1991;325:293,n = 2589 CHF - NYHA II-III - EF 35,SOLVD (Treatment) 研究,11.3% reduction in mortality,0,54,0,48,0,12,24,48,60,0.75,0.50,0.25,0,0.47,0.36,0.25,0.13,0.09,0.31,0.18,0.42,36,Months,p = 0.08,N Engl J Med 1991; 325:303,Enalapril,HZ + ISDN,n = 804,p = 0.016,Probability of d

5、eath,Nitrate + Hydralazine Vs Enalapril,V-HeFT II研究,卡维地洛 n=696,安慰剂 n=398,存活,天,0,50,100,150,200,250,300,350,400,危险度下降=65%,p0.001,Packer et al (1996),CIBIS-II Investigators (1999),比索洛尔,安慰剂,接收后的时间 (天),p0.0001,存活,危险度下降=34%,The MERIT-HF Study Group (1999),美国卡维地洛计划,CIBIS-II,0.8,1.0,0.6,0,随访月,0,3,6,9,12,15

6、,18,21,20,15,10,5,0,安慰剂,美托洛尔 CR,p=0.0062,危险度下降=34%,MERIT-HF,月,0,0,3,6,9,12,15,18,21,100,90,80,60,70,卡维地洛,安慰剂,危险度下降=35%,存活,Packer et al (2001),哥白尼（COPERNICUS）研究,p=0.00013,0.5,0.6,0.7,0.8,0.9,1.0,0,200,400,600,800,死亡率 (%),Aldactone,Placebo,Survival,months,p 0.0001,Annual Mortality Aldactone 18%; Place

7、bo 23% RR 21.7%,N = 1663 NYHA III-IV Mean follow-up 2 y,NEJM 1999;341:709,Spironolactone,RALES研究,心力衰竭药物治疗,AsymptomaticMild to moderateModerate LV dysfunctionCHFto severe CHF ACE inhibitorDigoxinDigoxin Beta blockerDiureticsDiuretics ACE inhibitorACE inhibitor Beta blockerBeta blocker Spironolactone,

8、心力衰竭治疗指南：常规治疗,所有收缩性心力衰竭患者必需应用ACE抑制剂，包括无症状性心力衰竭，LVEF45%者，除非有禁忌证或不能耐受。 所有慢性收缩性心衰，NYHA IIV级患者，病情稳定，无禁忌症，均必须服用受体阻滞剂 应在ACE抑制剂，利尿剂（地高辛）基础上加用 受体阻滞剂不能用于危重抢救（需静脉用药，有体液潴留） 从小剂量开始，2周倍增。改善常在23月后出现,RAS抑制对于心力衰竭患者：ARBs ACE抑制剂？ARBsACE抑制剂 ACE抑制剂？,CHARM Added,CHARMPreserved,CHARM 研究,3 component trials comparing cande

9、sartan to placebo in patients with symptomatic heart failure,CHARMAlternative,n=2028 LVEF 40%ACE inhibitor intolerant,n=2548 LVEF 40%ACE inhibitor treated,n=3025 LVEF 40%ACE inhibitor treated/not treated,Primary outcome for Overall Program: All-cause death,Primary outcome for each trial: CV death or

10、 CHF hospitalization,Swedberg K et al. J Card Fail. 1999;5:276-282.,CHARM 研究: 死亡率和病残率,0.7,0.8,0.9,1.0,1.1,1.2,0.6,0.7,0.8,0.9,1.0,1.1,1.2,所有原因的死亡,心血管死亡或 心力衰竭住院,Hazard ratio,Hazard ratio,P heterogeneity = 0.33,Alternative,Added,Preserved,Overall,P heterogeneity = 0.37,Pfeffer MA et al. Lancet. 2003.

11、,主要终点: 所有原因死亡率 次级终点: 心血管死亡、心梗或心衰 其他终点: 安全性和耐受性,卡托普利 50 mg tid (n = 4,909),缬沙坦 160 mg bid (n = 4,909),卡托普利 50 mg tid + 缬沙坦 80 mg bid (n = 4,885),急性心梗 (0.510 天)符合SAVE, AIRE 或 TRACE 入选标准(同时具有心衰或左室收缩功能障碍的临床/放射学证据),主要排除标准: 血清肌酐 2.5 mg/dL 血压 100 mm Hg 既往对 ARB 或 ACEI不耐受 不同意参加研究,双盲活性对照,平均随访时间: 24.7 月事件驱动: 2

12、,700次事件,VALIANT: 研究设计,0.2,0.4,0.6,0.8,No. of Patients,Favors Valsartan,Favors Placebo,Combined end point,ACE-I y, BB n 3034,ACE-I y, BB y 1610,ACE-I n, BB n 226,ACE-I n, BB y 140,Mortality,ACE-I y, BB n 3034,ACE-I y, BB y 1610,ACE-I n, BB n 226,ACE-I n, BB y 140,1.2,1.4,1.6,1.8,1.0,Val-HeFT: Combine

13、d Morbidity/Mortality in Subgroups,BB = -blocker; y = yes; n = no. Cohn J et al. N Engl J Med. 2001;345:1667-1675.,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 No260/574264/561 ACE 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 rat

14、io,Placebo better,0.6,0.8,1.0,1.2,1.4,P value for treatment interaction,0.14,0.26,McMurray JV et al. Lancet. 2003. ,ESC Guidelines on the diagnosis and treatment of CHF, EHJ 2005,对ACE抑制剂有不能耐受症状的患者， ARBs 可以很好的替代ACE抑制剂，可以降低发病率和死亡率 (证据水平 B, I级) ARBs 和 ACE抑制剂在治疗CHF方面，有相似的功能 (证据水平 B, I级) 急性心肌梗死后有心衰 或左室功能

15、障碍征兆 ，ARBs 与 ACE 抑制剂有相似的疗效 (证据水平 B, I级) 联合使用ARBs与ACE抑制剂治疗有症状的患者，能够降低死亡率 (证据水平 B, IIa级) 和心衰的入院治疗率 (证据水平 A, I级),The Role of ARBs in Heart Failure,坎地沙坦 4-32 缬沙坦 80-320 依普沙坦 400-800 氯沙坦 50-100 依贝沙坦 150-300 替米沙坦 40-80,通常被用来治疗心衰的ARBs,可降低死亡率/发病率的ARB 每日剂量（mg),ESC Guidelines on the diagnosis and treatment of

16、 CHF, EHJ 2005,RAS抑制阻滞剂治疗心力衰竭患者： ACE抑制剂 或 ARBs 必须先于阻滞剂？,0 wk,Follow-up (months),CARMEN 研究设计,Group 2,Placebo (blinded),Carvedilol (blinded),Group 3,Placebo (blinded),CARMEN Primary Endpoint: Comparison of LVESVI Between Treatments,Month 6,Month 12,Month 18,NS,P0.002,Baseline,LVESVI (biplane) ml/m2,LV

17、ESVI = left ventricular endsystolic volume index,Bisoprolol-first (o.d.),Enalapril-first (b.i.d.),Bisoprolol o.d.,Enalapril b.i.d.,Bisoprolol o.d.,Enalapril b.i.d,week,Study end,1 - 2.5 years,0 2 4 6 8 10,26 28 30 32 34 36,week,Study end,1 - 2.5 years,First up-titration,First up-titration,Second up-

18、titration,Second up-titration,Maintenance period,Maintenance period,Second maintenance period,22-100 weeks,Second maintenance period,16-94 weeks,1.25,2.5,3.75,5.0,7.5,1.25,2.5,3.75,5.0,7.5,2.5,5.0,2.5,5.0,* * * * * * * * * * * * * * * * . * * * * *,* = visits,10.0 mg,10.0 mg,10.0 mg,10.0 mg,CIBIS II

19、I 研究设计,Bisoprolol o.d.,Enalapril b.i.d,0 2 4 6 8 10,26 28 30 32 34 36,* * * * * * * * * * * * * * * * . * * * * *,DOI: 10.1161/CIRCULATIONAHA.105.582320,不同-受体阻断剂的药理学差异,121 blockadeantioxidant blockade blockade (vasodilat.)effects 美托洛尔+- 比索洛尔+- 阿替洛尔+- 卡维地络+ 布辛洛尔+(+)- 奈比洛尔+-(+)-,-受体阻断剂治疗心力衰竭,1-受体阻断是-受

20、体阻断剂治疗获益的主要来源 在获得等同的1-受体阻断作用下，其他作用 1阻断 胰岛素敏感性 血脂代谢 可否带来进一步的获益？,0.50,0.75,1.00,1.25,1.50,Sex,Male,Female,Age,65,65,NYHAclass,II,III,IV,Cause,Other,IHD,LVEF,25%,25%,Heart rate,80 beats/min,80 beats/min,Systolic BP,110,110-139,140,Diabetes,Yes,No,Overall,Carvedilol better,Metoprolol better,410 1200 500

21、 1217 0.80,175 730 228 736 0.75,309 732 324 716 0.91,28 49 48 66 0.68,102 311 100 301 0.96,207 834 231 803 0.84,305 677 369 715 0.84,198 735 219 703 0.83,314 776 381 815 0.85,270 706 285 630 0.79,221 743 287 819 0.84,234 693 284 733 0.86,277 816 314 783 0.80,120 245 132 235 0.80,121 447 158 434 0.71

22、,153 360 178 371 0.85,359 1150 419 1143 0.82,512 1511 600 1518 0.83,270 817 310 849 0.89,Deaths n Deaths n HR,Carvedilol Metoprolol,Hazard Ratio,COMET研究：亚组分析,2005年最新资料: 醛固酮拮抗剂,醛固酮拮抗剂是否证明对II 级心衰或尚未出现症状的左心室收缩功能障碍患者具有益处，还有待进一步证实 当症状加重时,是否需要加大醛固酮拮抗剂的剂量还难以确定,比较SOLVD-T、CIBIS-II 和 CHARM-加入试验的 一年后死亡率,死亡率 (%

23、),0,5,10,15,20,利尿剂 洋地黄,利尿剂 洋地黄 ACE-I,利尿剂 洋地黄 ACE-I,利尿剂 洋地黄 ACE-I -阻滞剂,利尿剂 洋地黄 ACE-I -阻滞剂,利尿剂 洋地黄 ACE-I -阻滞剂 坎地沙坦,SOLVD-T (1991),CIBIS-II (1999) RR-33%,CHARM-加入试验 (2003) RR-33%,RR 20%,RR 33%,RR 33%,治疗慢性心力衰竭和降低左心室射血分数,症状的 严重性,NYHA III/IV,NYHA II-IV, -阻滞剂,ACE 抑制剂 或 ARB 如果 ACE不耐受 或 ACE-I 和 ARB?,醛固酮拮抗剂,C

24、IBIS 2 MERIT-HF COPERNICUS,CONSENSUS SOLVD-T V-HeFT II ELITE-2 CHARM-选择试验 Val-HeFT CHARM-加入试验,RALES EPHERSUS,+,+,Impact of ISDN-hydralazine on mortality and morbidity of African-American patients with Heart Failure,A-Heft Trial,Isosorbide dinitrate (ISDN) plus hydralazine Tablet containing 20 mg ISD

25、N and 37.5 mg hydralazine (BiDil, NitroMed) 3X daily. Dosage could be doubled by enrolling physician. n=518 44.2% female 44.8% diabetic,Primary Endpoint: Weighted composite of all-cause death, first hospitalization for heart failure, and change in quality of life at a mean follow-up of 10 months,A-H

26、eft Trial,Presented at AHA 2004,Placebo n=532 36.1% female 37.0% diabetic,1,050 African-American patients with advanced heart failure New York Heart Association (NYHA) class 3-4 for 3 months LV function 35% ( 40% if LV dilated per echo) 90% receiving diuretics, 69% ACE-inhibitor, 17% angiotensin rec

27、eptor blocker, 74% beta-blocker,A-Heft Trial: Primary Endpoint,Presented at AHA 2004,All individual components of the primary composite endpoint were significantly improved with ISDN-hydralazine therapy, namely death, first hospitalization for heart failure, and change in the quality-of-life score (a larger negative score indicates a better quality of life).,