1、1,心力衰竭临床治疗进展,首都医科大学附属北京友谊医院 沈潞华,流行病学,美国FRAMINGHAM心脏研究2000,发病率,年均心衰死亡率:3050%,流行病学,美国FRAMINGHAM心脏研究2000,5年存活率,中国心衰的发病率,3574岁居民，15518人（10个省市20个城乡抽样调查）心率发病率0.9% 男性0.7% 女性1.0% 北方1.4% 南方0.5% 城市1.1% 农村0.8%随着年龄的增高，患病率显著上升,心力衰竭的形成过程,各种原因所致的心脏损害,心脏结构的改变,心肌重量,心室容量,心室形态,心室重构,心脏功能减退,心力衰竭,AMI 后神经内分泌激活界导左室重构的结果,AM
2、I,血液动力学异常 (SV EF CO LVEDP 心室扩张, 室壁张力增加）,神经内分泌激活(RAAS SNS细胞因子),心肌细胞肥厚心肌间质纤维化 心肌细胞坏死 心肌毛细血管生长不足,心功能受损,心肌缺血,心律失常,左室重构进展,心力衰竭,心衰时神经内分泌激活的危害性,循环和组织中NE, ANG II, 醛固酮, 内皮素, 加压素等,钠水潴留, 血管收缩,室壁张力升高, 心脏毒性作用, 刺激心肌纤维化,促进心室重构, 加速心衰进展,肾上腺素超负荷,血液动力学超负荷,心室重构心肌细胞肥大收缩功能异常细胞凋亡,交感神经系统兴奋,心力衰竭,Cir 93;87(SVI):VI-40-48,Plas
3、ma noradrenaline and mortality in congestive heart failure,CHF过程,心衰恶化可能机制,心衰病情加重,心衰,血肾素水平升高血管紧张素升高,交感神经系统长期激活,心脏处于极度氧化应激状态,对心脏产生毒性作用于心肌需氧增加,心脏交感神经活性,血管紧张素 II,心肌肥厚， 凋亡， 缺血，心律失常，心肌重构，纤维化,心室重塑,1受体 2受体 1受体,血管收缩,衰竭心肌-受体密度，非胞内重新分布 受体总数 表面受体反应性（脱敏）主要下调为1， 2密度正常或相对提高主要部位为内膜下选择性 衰竭时其受体密度为外膜的63 5% （正常时应为115 6
4、%） 非均一下调的机制：血CA、局部NE释放 心内膜外膜血流量代谢不同,衰竭心肌受体的改变,SNA增强是心衰的主要原因,衰竭时的心肌1受体激酶mRNA水平减少,*P0.05,正常,肥厚性心肌病,缺血性心脏病,*,*,Ref: Circulation 1993,87:454-463.,1 receptor mRNA, cpm,SNA增强是心衰的主要原因,2 receptor mRNA, cpm,正常,肥厚性心肌病,缺血性心脏病,Ref: Circulation 1993,87:454-463.,衰竭时的心肌2受体激酶mRNA水平不变,儿茶酚胺激活外周1受体引起外周血管收缩，而外周2受体使释放入突
5、触间隙的儿茶酚胺再摄取。心力衰竭时，外周肾上腺素受体未下调，而其反应可能被增加。心脏存在受体（几乎全部为1受体），受刺激导致磷酯酰肌醇水解，生成三磷酸肌醇酯，释放细胞内贮存的钙离子。正常状态下，心脏总肾上腺素受体中受体所占的比例很小，但在衰竭心脏，其比例升高。能介导心肌肥厚和增加心脏的兴奋性。,心力衰竭时血管和心脏的受体,1. 使衰竭心肌受体密度，恢复对CA敏感性2. 纠正交感支配不匀引起室壁局部异常运动 恢复舒缩协调、改善心肌迟缓、充盈与顺应性3. 抑制交感神经介导血管收缩、RAA释放和继发效应4. 降低血CA，改善CA长期 所致代谢和心血管损害5. 降低心肌耗氧、乳酸释放及心脏作功 纠正衰
6、竭心肌中异常细胞内Ca+的作用,受体阻断剂治疗充血心衰可能机制,抑制NE促使心脏肥大的作用，改善心肌供血。减轻因NE增加心肌细胞自律性、触发心脏电活动，低血钾所致心律失常。减轻因NE增加所致细胞凋亡。增加金属蛋白酶组织型抑制剂（TIMP-I）的活性而不影响基质金属蛋白酶（MMP-3）活性，因而减少细胞外重塑，减少缺血心肌纤维化。 阻滞剂通过降低心肌耗氧，降低CA水平，降低AngII水平及氧化损伤，扩张血管作用而改善心功能，延缓心衰进程。,受体阻断剂治疗充血心衰可能机制（续）,-受体阻滞剂,降低心肌需氧,降低血浆儿茶酚胺水平,降低肾素血管紧张素,抗氧化损伤扩张血管,改善心功能,延缓心衰进程,受体
7、阻断剂治疗充血性心衰,Interactions between betablockers and promoters of congestive heart failure and arrhythmias in CHF,How can betablockers improve myocardial energy balance in heart failure?,Heart rateDiastolic flow time Relaxation Myocardial restriction Perfusion pressure Filing pressure Hypertrophy Free f
8、atty acids Remodeling,目的：评估Bisoprolol对心衰死亡率影响设计：随机、双盲、安慰剂对照、多中心病人：641例各种病因心衰，1875岁，/级（EF0.4） （除外：限制、肥厚心、瓣膜病、3月内AMI）、 Biso,1.25mg/d5mg/d随访：1.90.1年 对照：常规（强心、利尿、CCB）结果： 治疗组 安慰剂组 死亡率 53/320(16.6%) 67/321(20.9%) p =0.22,CIBIS(cardiac Insufficiency Bisoprolol Study)(Lencet 1994;90:1765),CIBIS -心功能不全比索洛尔研究
9、,双盲，安慰剂对照的随机实验2647例患者，包括（NYHA +）常规治疗（利尿剂+AECI）的基础上加比索洛尔,CIBIS-生存率,1.00.80.6,0,0,200,400,600,800,比索洛尔死亡156例(n=1327),安慰剂死亡228例(n=1320),P0.0001,入选后时间(天),比索洛尔组全因死亡率降低34%,MERIT-HF 结果,总死亡累积百分率的Kaplan-Meuer曲线经2次中期阶段分析校正的P值,下降34%,MERIT-HF结果,下降38%,心血管死亡致死的累积百分率的Kaplan-Meier曲线,猝死致死的累积百分率的Kaplan-Meier曲线,MERIT-
10、HF 结果,下降41%,心力衰竭恶化致死的累积百分率的Kaplan-Meier曲线,MERIT-HF 结果,下降49%,Carvedilol,同时阻滞1，2，1受体阻滞受体 心率，心缩力阻滞1受体 前，后负荷,抗自由基，抗氧化损伤直接清除氧自由基抑制氧自由基介导的脂质过氧化保护内源性抗氧化系统,对心率影响小阻滞受体心率阻滞1受体心率,心率变化小, 抑制心肌细胞凋亡,心肌需氧,改善心功能,Injury to heart,Sympathetic activation,Disease progression,Metoprolol,Bucindolol,Carvedilol,Sympathetic N
11、ervous System Activation in Heart Failure,Bisoprolol,2receptors,1 receptors,1receptors,Nebivolol,1 receptors,卡维地洛降低轻中度慢性心衰病人的死亡危险（NYHA-IIIII）,Carvedilol（n=696）,Placebo（n=398）,Survival 1.0,0.9,0.8,0.7,0.6,0.5,0 50 100 150 200 250 300 350 400,Days,死亡危险 65%,P0.001,US Carvedilol Program,COPERNICUS研究,随机分
12、组2289 例严重心力衰竭患者按 1:1 随机分组至安慰剂组卡维地洛组起始剂量为 3.125 mg 每日2次，每二周剂量加倍，直至达到目标剂量 25 mg 每日2次。患者服用所能耐受的最高剂量,卡维地洛降低重度心衰病人死亡危险 （ NYHA-IIIIV）,Placebo,% Survival,90,80,70,60,50,0 4 8 12 16 20 24 28,Months,Carvedilol,COPERNICUS Study,35% P=0.00014,100,卡维地洛降低极重心衰病人死亡率,100,80,60,40,20,3,9,0,6,21（月）,18,15,12,Carvedilo
13、l,Placebo,39% (P = 0.009),%生存,观察时间,哥白尼研究高危亚组,P=0.0017,300,900,700,500,安慰剂,卡维地洛,20%,任何原因,P=0.0002,0,600,400,200,28%,心血管原因,P=0.0001,0,450,300,150,33%,心力衰竭,安慰剂,卡维地洛,安慰剂,卡维地洛,COPERNICUS研究住院率,0,Packer et al (2000),CIBIS-II Investigators (1999),0 200 400 600 800,1.00.80.60,Bisoprolol,Placebo,Time after in
14、clusion (days),p0.0001,Survival,Risk reduction = 34%,The MERIT-HF Study Group (1999),Months of follow-up,Mortality %,0,3,6,9,12,15,18,21,20,15,10,5,0,Placebo,Metoprolol CR/XL,p=0.0062,Risk reduction = 34%, Blockade in systolic HF All-cause mortality,CIBIS-II,MERIT-HF,Months,8,4,12,16,20,24,28,70,80,
15、90,100,60,50,Placebo,Carvedilol,Nominal p=0.0001435% risk reduction,% Survival,COPERNICUS,0.2,0.4,0.6,0.8,1.0,1.2,Carvedilol (US trials)All cause mortalitySudden deathBisoprolol (CIBIS-II)All cause mortalitySudden deathMetoprolol (MERIT-HF)All cause mortalitySudden death,Risk ratio (95% CI),阻断剂降低心衰死
16、亡率和猝死率,重度心力衰竭,Myocardial function,Time,The two modes of death in heart failure,Sudden death,Progressive heart failure death,Antiremodeling effects of metoprolol CR/XL in congestive heart failure,-30,-25,-20,-15,-10,-5,0,5,10, LVEDVI ml/m2, LVESVI ml/m2, Ejection fraction units,Placebo,Metoprolol,ml/
17、m2 or EF units,Adapted from Groenning BA et al J Am Coll Cardiol 2000;36:2072,p=0.01,P=0.001,p=0.03,Beta-Blockers Are Underutilized in Heart Failure,Annual Prescriptions for Heart Failure (1000s),MDC (1993)CIBIS I (1994),U.S CarvedilolANZ,MERIT-HFCIBIS II,COPERNICUS,0,4,000,8,000,12,000,16,000,20,00
18、0,Total prescriptions for heart failure,Diuretics,ACEs,Digoxin,Beta-blockers,IMS NPA, NDTI,2000年上海16家二三级医院心力衰竭药物使用率调查,中华心血管病杂志。 2001，29（11）：644-648,国内心力衰竭药物使用率调查显示： 受体阻滞剂仅为27.20%,Komajda M et al. Eur Heart J 2003,Utilisation of -Blockade for CHFin Clinical Practice,33,21,21,17,62,37,36,87,0%,50%,100
19、%,Diuretics,ACE Inhibitors,-blockers,Digoxin,Nitrates,Calcium antagonists,Spironolactone,ACEi, B, diuretics,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient has BP which is too lowPatient has EF which is to
20、o lowBeta-blockers cause impotence, claudication and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,MERIT-HF: Risk reduction with Beta-blockade in the Elderly,Deedwania P et al. Circulation 104 (Suppl II):II-753,65 yearsn=1982,30%,
21、37%,38%,43%,8%,61%,22%,38%,All Cause Mortality,Sudden Death,Death/Worsening HF,Hosp for worsening HF,Risk reduction (%),-60,-50,-40,-30,-20,-10,0,10,20,-70,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient h
22、as BP which is too lowPatient has EF which is too lowBeta-blockers cause impotence, claudication and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,Meto CR/XL PlaceboNet differenceAdverse event1 (Meto CR/XL-Placebo) n=1990n=2001 On
23、e year of treatment,Infection25874-0.8%Dyspnoea30270.1%Pulmonary oedema89-0.1%Bronchospasm68-0.1%COPD367-0.1%Haemoptysis17-0.3%Any respiratory AE108121-0.7%,The MERIT-HF Study Group,Respiratory System Disorders: All AE/SAE Reported,1One patient may have more than one AE in a system organ class2Pneum
24、onia, Bronchitis or Respiratory infection3Chronic obstructive pulmonary disease,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient has BP which is too lowPatient has EF which is too lowBeta-blockers cause imp
25、otence, claudication and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,MERIT-HF: Risk Reductions in Diabetics Patients,Deedwania P et al. ACC 2002,-30,-20,-10,0,10,All Deaths,All deaths/All Hosp,All Deaths/ HF Hosp, 21%, 15%, 29%,
26、Risk reduction* vs placebo (%),n=984,* Time to first event,5,-5,-15,-25,Meto CR/XL PlaceboNet differenceAdverse event (Meto CR/XL-Placebo) n=1990n=2001 One year of treatment,Hyperglycaemic reaction24200.2%Hypoglycaemic reaction430.1%Diabetic ulcer44 - New onset diabetes mellitus34-0.1%Total number o
27、f patients35310.2%,The MERIT-HF Study Group, JAMA 2000;283:1295-1302,Diabetes Mellitus: All AE/SAE Reported,The MERIT-HF Study Group,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient has BP which is too lowP
28、atient has EF which is too lowBeta-blockers cause impotence, claudication and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,SBP: 120 (mean 142 mm Hg),144/213167/226,Total mortality/hospitalization for heart failureEffect of systoi
29、lic blood pressure,Favours metoprolol,Favours placebo,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient has BP which is too lowPatient has EF which is too lowBeta-blockers cause impotence, claudication and d
30、epressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,EF: 0.25 (mean 0.32),146/231165/208,Favours metoprolol,Favours placebo,Total mortality/hospitalization for heart failureEffect of ejection fraction,EF: 0.25 (mean 0.32),Total mortality/
31、hospitalization for heart failureEffect of ejection fraction,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient has BP which is too lowPatient has EF which is too lowBeta-blockers cause impotence, claudicatio
32、n and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,Depression59-0.2%Impotence630.1%Anxiety25-0.2%Other psychiatric AE1623-0.4%Any psychiatric AE2837-0.5%,The MERIT-HF Study Group, JAMA 2000;283:1295-1302,Psychiatric Disorders: Al
33、l AE/SAE Reported,*One patient may have more than one AE in a system organ class,The MERIT-HF Study Group,Meto CR/XL PlaceboNet differenceAdverse event* (Meto CR/XL-Placebo) n=1990n=2001 One year of treatment,Why Do Physicians Not Give Beta-blockers to Patients?,Patient is too old for beta-blockersP
34、atient has COPDPatient has Diabetes mellitusPatient has BP which is too lowPatient has EF which is too lowBeta-blockers cause impotence, claudication and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about side effects and tolerability:,Why Do Physicians Not Give Bet
35、a-blockers to Patients?,Patient is too old for beta-blockersPatient has COPDPatient has Diabetes mellitusPatient has BP which is too lowPatient has EF which is too lowBeta-blockers cause impotence, claudication and depressionCan only tolerate low doseToo expensive drugs -no cost-benefit,Myths about
36、side effects and tolerability:,Hospitalizations in MERIT-HF trial,514,349,362,379,424,441,0,200,400,600,800,1000,1200,1400,Standard Rx,Metoprolol,Hospitalizations per 1000 Patients,Non-CVD Hosp,Other CVD Hosp,HF Hosp,Total Number of Days in Hospital,Heart failure,p0.00001,-36%,All-cause,p=0.0042,-17
37、%,The MERIT-HF Study Group, JAMA 2000;283:1295-1302,ACE inhibitor,Fluid retention,Diuretics,No fluid retention,Beta-blocker,Digoxin,Spironolactone,Nitrates + hydralazine,Algorithm for treatment ofsystolic heart failure,所有慢性收缩性心力衰竭，NYHA心功能II、III级患者，LVEF40%，病情稳定者均必须应用受体阻滞剂，除非有紧急或不能耐受。应告知患者：（1）症状改善常在治疗
38、2-3个月后才出现，即使症状不改善，也可防止疾病的进展。（2）不良反应常发生在治疗的早期，一般不妨碍长期用药。受体阻滞剂不能应用于“抢救”急性心衰患者，包括难治性心衰需静脉给药者。NYHA心功能IV级心衰患者，需待病情稳定（4天内未静脉给药；已无液体潴留并体重稳定）后，在严密监护下由专科医生指导应用。应在ACEI和利尿剂基础上加用受体阻滞剂、地高辛也可应用。,中华医学会心衰治疗指南,受体阻滞剂的应用要点：,受体阻滞剂的禁忌症:支气管痉挛性疾病心动过缓（心率小于60次/分）二度以上房室传导阻滞（除非已安装起博器）有明显液体潴留，需大量利尿剂者，暂时不能应用。受体阻滞剂的起始和维持起始治疗前患者已
39、无明显液体潴留，体重恒定，利尿剂已维持在最合适剂量。受体阻滞剂必须从极小量开始，每2-4周剂量加倍。达到最大耐受量或目标剂量后长期维持，不按照患者的治疗反应来确定剂量。,受体阻滞剂的应用要点：,中华医学会心衰治疗指南,受体阻滞剂应用时的监测低血压：特别是有-受体阻滞作用的制剂易于发生，一般在首剂或加量的24-48小时内发生。可将ACEI或血管扩张剂与受体阻滞剂在每日不同时间应用，一般不将利尿剂减量。液体潴留和心衰恶化：常在起始治疗3-5天出现体重增加，如不处理，1-2周后常致心衰恶化。应告知患者每日秤体重，如有增加，立即加大利尿剂用量。心动过缓和房室阻滞：与受体阻滞剂剂量大小成正比，如心率小于
40、55次/分，或出现二、三度房室传导阻滞，应将受体阻滞剂减量或停用。,受体阻滞剂的应用要点：,中华医学会心衰治疗指南,对心力衰竭患者合理加用受体阻滞剂治疗-稳定、逆转左室功能不全改善生存率减轻症状提高生活质量成为心功能不全患者规范治疗的一个重要组成部分,最大耐受量以清醒静息时心率55次/分,如何使用受体阻断剂（1）,55,中华心血管病杂志。 2002，30（1),如何使用受体阻断剂（2）,靶剂量后应避免突然撤药，以防引起病情恶化如患者不能耐受，亦可用较低剂量即最大耐受量,中华心血管病杂志。 2002，30（1),在用药期间如心衰有加重,首先调整利尿剂和ACEI剂量，以达到临床稳定,中华心血管病杂
41、志。 2002，30（1),如何使用受体阻断剂（3）,如病情恶化需静脉用药，可减量或停用,中华心血管病杂志。 2002，30（1),如何使用受体阻断剂（4）,CAPRICORN研究目的 / 设计,在现代治疗的基础上，评价卡维地洛对急性心肌梗死后左心室功能障碍的患者的临床转归的影响在左心室射血分数 40%合并或不合并心力衰竭患者中，进行多中心, 随机, 平行，安慰剂对照试验,CAPRICORN研究,各研究者的最佳治疗,一般 3 5 天但是MI后可长达 21天,卡维地洛 (n=975),安慰剂 (n=984),递增,递减,起始剂量为 6.25 mg 或 3.125 mg 每日2次在2-4周内递增至
42、最大耐受剂量目标剂量为 25 mg 每日2次,(n=1959),维持,直到发生 633 次事件的时间 平均随访: 1.3 年,1,无事件比例,年,0.9,0.85,0.7,0.75,0.8,0.95,0,0.5,1,1.5,2,2.5,卡维地洛,安慰剂,与安慰剂相比，降低23% P = 0.031,CAPRICORN研究主要终点: 所有原因的死亡,CAPRICORN: 降低复发性心梗,无事件百分率,卡维地洛,安慰剂,年,0,0.92,0.2,0.4,0.6,0.8,1.0,1.2,1.4,1.6,1.8,0.94,0.96,0.98,1,CAPRICORN: 抗心律失常作用,房颤/房扑,相对危
43、险降低%,所有SVA,所有VA,VF/VT,59%P=0.0003,63%P0.0001,76%P0.0001,52%P=0.0015,0,-10,-20,-30,-40,-50,-60,-70,-80,CAPRICORN: 明显降低心梗后心律失常,无事件比值,年,无事件比值,年,卡维地洛,安慰剂,卡维地洛,安慰剂,P=0.0003,P0.0001,房扑或房颤,室性心动过速或心室颤动,0,0.5,1.0,1.5,2.0,2.5,0.90,0.92,0.94,0.96,0.98,1.00,0,0.5,1.0,1.5,2.0,2.5,0.90,0.92,0.94,0.96,0.98,1.00,CA
44、PRICORN研究,是目前唯一的评价 阻滞剂治疗急性心肌梗死后出现左心室功能障碍的大规模临床试验在已获目前心肌梗死最佳治疗(溶栓、血运重建、ACE抑制剂)的基础上，卡维地洛仍显示出其显著的临床益处如果不存在特异的反指证，应考虑给予所有急性心肌梗死后左心室功能障碍的患者卡维地洛治疗对心肌梗死后的患者，卡维地洛应及早使用并长期维持,0 wk,随访 (月),CARMEN 研究设计,组 2,安慰剂 (双盲),卡维地洛 (双盲),组 3,安慰剂 (双盲),首要终点: 不同治疗组间 LVESVI 的比较,第 6 月,第 12 月,第 18 月,NS,P0.002,基线,LVESVI = left vent
45、ricular endsystolic volume index,LVESVI (biplane) ml/m2,4,2,0,-2,-4,-6,-8,-10,+,+,+,+,+,+,M6,M12,M18,M6,M12,M18,M6,M12,M18,+P0.05, +P0.001,CARMEN: 卡维地洛改善轻度CHF的左心室功能,CARMEN研究,对心力衰竭患者，在ACE抑制剂之前应用卡维地洛是安全的，并能逆转左心室肥厚。这将对长期以来ACE抑制剂先于 受体阻滞剂应用的观点提出挑战在ACE抑制剂之前能将卡维地洛安全用于心力衰竭治疗CARMEN 结果印证了目前的治疗指南。并且，CARMEN研究为轻度心力衰竭患者及早联合应用ACE抑制剂和卡维地洛提供另外的证据,
