心力衰竭药物治疗新证据与新视野

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,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IIAT1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,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,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,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,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,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,卡维地,洛,n=696,抚慰剂,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,抚慰剂,接收后的时间(天),p0.0001,存活,危险度下降=34%,The MERIT-HF Study Group(1999),美国卡维地洛方案,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,抚慰剂,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,抚慰剂,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,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,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，包括无病症性心力衰竭，LVEF ACE,抑制剂？,ARBs,ACE,抑制剂,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,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.,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:平安性和耐受性,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,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.,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,抚慰剂,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.,ESC Guidelines on the diagnosis and treatment of CHF,EHJ 2005,对ACE抑制剂有不能耐受病症的患者，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抑制剂治疗有病症的患者，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 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？,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),CARMEN Primary Endpoint:Comparison of LVESVI Between Treatments,Month 6,Month 12,Month 18,NS,P0.002,Baseline,LVESVI(biplane)ml