心力衰竭药物治疗新证据与新视野ppt课件

Click to edit Master title style,Click to edit Master text styles kbb,Second level,Third level,Fourth level,Fifth level,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,心力衰竭药物治疗新证据与新视野李勇,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,（AT,1,）,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,治疗心力衰竭的药物1、强心苷类药物,DIG,研究,50,40,30,20,10,0,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,DIG 研究50403020100PlaceboDigox,0.6,Probability 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,0.6Probability of Death0Place,Placebo,Enalapril,12,11,10,9,8,7,6,5,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,PlaceboEnalapril12111098765Pro,50,40,30,20,10,0,Months,0,6,12,p = 0.0036,% Mortality,24,18,30,36,42,48,Enalapril,n=1285,Placebo,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,50403020100Months0612p = 0.00,0,54,0,48,0,12,24,48,60,0.75,0.50,0.25,0,0.47,0.36,0.25,0.13,0.09,0.31,0.18,0.42,36,Months,p = 0.08,N Engl J Med 1991; 325:303,Enalapril,HZ + ISDN,n = 804,p = 0.016,Probability of death,Nitrate + Hydralazine,Vs,Enalapril,V-HeFT II,研究,0,540,480122448600.750.500.250,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,0,3,6,9,12,15,18,21,20,15,10,5,0,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,(%),卡维地洛安慰剂存活天05010015020025030035,Aldactone,Placebo,Survival,1.0,0.9,0.8,0.7,0.6,0.5,0,6,12,18,24,30,36,months,p 0.0001,Annual Mortality,Aldactone 18%; Placebo 23%,RR,21.7%,N = 1663,NYHA III-IV,Mean follow-up 2 y,NEJM 1999;341:709,Spironolactone,RALES,研究,AldactonePlaceboSurvival1.00.9,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,心力衰竭药物治疗AsymptomaticMild to,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，,LVEF ACE,抑制剂？,ARBs,ACE,抑制剂, ACE,抑制剂？,RAS抑制对于心力衰竭患者：ARBs ACE抑制剂？,CHARM Added,CHARMPreserved,CHARM,研究,3 component trials comparing candesartan,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 CHF hospitalization,Swedberg K et al.,J Card Fail,. 1999;5:276-282.,CHARM AddedCHARMPreservedCHA,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. 研究: 死亡率和病残率0.70.80.91.01,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: 2,700次事件,VALIANT:,研究设计,主要终点: 所有原因死亡率卡托普利 50 mg,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: Combined Morbidity/Mortality in Subgroups,BB =,-blocker; y = yes; n = no.,Cohn J et al.,N Engl J Med.,2001;345:1667-1675.,0.20.40.60.8No. of PatientsFa,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 ratio,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. 预设亚组, 心血管死亡或心力衰竭住,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,ESC Guidelines on the diagnosi,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 CHF,EHJ 2005,坎地沙坦,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？,RAS抑制阻滞剂治疗心力衰竭患者： ACE抑制剂,Stable doses,of diuretics,digoxin, nitrates,Baseline/,screening,Up-titration,Phase A,0,wk,Up-titration,Phase B,Maintenance,Phase,9,18,3,6,12,15,0,Down-titration,Phase,Follow-up (months),CARMEN,研究设计,Group 2,Placebo (blinded),Carvedilol (blinded),Group 1,Carvedilol (blinded),Ealapril (blinded),Enalapril (blinded),Group 3,Enalapril (blinded),Placebo (blinded),Stable dosesof diuretics,digox,CARMEN Primary Endpoint: Comparison of LVESVI Between Treatments,Month 6,Month 12,Month 18,NS,P0.002,Baseline,LVESVI (biplane) ml/m,2,LVESVI = left ventricular endsystolic volume index,CARMEN Primary Endpoint: Comp,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-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 III,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,Bisoprolol-first (o.d.)Enalapr,不同,-,受体阻断剂的药理学差异,1,2,1,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,+,-,(+)-,不同-受体阻断剂的药理学差异121 blo,心力衰竭药物治疗新证据与新视野ppt课件,-,受体阻断剂治疗心力衰竭,1-,受体阻断是,-,受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？,-受体阻断剂治疗心力衰竭1-受体阻断是-受体阻断剂治疗,0.50,0.75,1.00,1.25,1.50,Sex,M,ale,F,emale,Age,25%,Heart rate,80 beats/min,80 beats/min,Systolic BP,3 months,LV function,35% (,40% if LV dilated per echo),90% receiving diuretics, 69% ACE-inhibitor, 17% angiotensin receptor blocker, 74% beta-blocker,Isosorbide dinitrate (ISDN) pl,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).,A-Heft Trial: Primary Endpoint,