倍他受体阻滞剂在心力衰竭治疗中的指南和临床课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,倍他受体阻滞剂在心力衰竭治疗中的,指南和临床,中国医学科学院 北京协和医学院,心血管病研究所 阜外心血管病医院,心力衰竭诊治中心,张健 杨跃进,The Nobel Price Committee in recognition of Sir Blacks work declared 1988:,“,-blockers were the greatest breakthrough when it comes to pharmaceuticals against heart illness since the discovery of digitalis 200 years ago,”,“,自从,200,年前发现洋地黄以来，,-,受体阻滞剂是药物防治心脏疾病的最伟大突破,”,-,受体阻滞剂发展史,1894,年,-,发现肾上腺，肾上腺激素,1948,年,-,Ahlquist,发现,和,受体,1958,年,-,发现,受体阻滞剂,1962,年,-,pronethalol,（,丙萘洛尔,）治疗心绞痛，后因致癌性被淘汰,1964,年,-,心得安上市，治疗心绞痛和高血压，,发明者英国,James Black,爵士因此荣获,1988,年诺贝尔奖,1970,s,以来广泛用于治疗高血压、冠心病，近年心力衰竭,2004,年,-,欧洲,ESC,关于,受体阻滞剂专家共识,-,受体阻滞剂在心衰中的应用历史,Waagstein,于1975年第一次报告在7例病人中静注普萘洛尔改善心衰的症状,Ikram,于1981,年第一次进行了双盲交叉试验,观察了扩张性心肌病中,-,阻滞剂治疗的经验,80,年代初，在,B-HAT,试验中，首次观察到急性心肌梗死伴心衰的患者中普萘洛尔可减少死亡率和猝死率,ESC,共识,-,阻滞剂治疗慢性心力衰竭,有症状、稳定、,LVEF,降低,NYHA II,IV(,改善生存率,),I A,无症状，有心梗史、左室收缩功能不良,I A,无症状，无心梗史、左室收缩功能不良,I B,CHF,收缩功能尚好,（,降低心率,),IIa,C,AMI,后，急性，代偿性心力衰竭,IIa,B,CHF,急性失代偿后病情稳定,I A,European Heart Journal (2004),25, 1341,1362,2005,年,ESC,急性心力衰竭诊断治疗指南,在明确急性心力衰竭且肺部湿罗音较多的病人，使用,受体阻滞剂应当很小心。当这些病人伴有心肌缺血和心动过速时，可考虑静脉注射美托洛尔。,推荐强度,b,级，证据水平,C,然而，在急性心肌梗死病人发生急性心力衰竭而病情稳定后，应当尽早使用,受体阻滞剂。,推荐强度,a,级，证据水平,B,慢性心力衰竭病人在急性发作且病情稳定后（通常,4,天后） 应当开始使用,受体阻滞剂。,推荐强度,级，证据水平,A,-,阻滞剂抗心力衰竭机制,改善左室结构和功能，缩小,LV,容量，增加,EF,降低心率,延长舒张期充盈和冠脉舒张期灌注时间,降低心肌耗氧量,抑制儿茶酚胺介导的脂肪组织游离脂肪酸释放,改善心肌能量代谢,上调,受体密度和亲和力,减少氧化应激,有一定的抗心律失常的作用,CHF mechanism,Recognition Process,Treatment status,Clinical Benefit,Heart mechanical kinetics change,Cardiac &,diuresis,symptom Improving Mortality increase,Neuro-humoral,endocrine system,，,cell function change,ACEI,Mortality decrease,NA level in blood plasma increase,Add beta-blockade,Mortality decrease further,CHF,，,sympathetic nervous system activation is earlier than RAAS excitement,Using,beta-blockade,at first,sudden death decrease,The Evolving History - Beta-blockade in CHF,CIBIS-II,Lancet 1999,年;353:9-13,MERIT-HF,Lancet 1999,年;353:2001-07,COPERNICUS,N,Engl,J Med 2001,年;344:1651-8,受体阻滞剂治疗心衰的里程碑试验,-Blockers in Chronic Left Heart Failure,Drug,n,Mortality,Placebo,B-Blocker,Rel.Risk,Reduction,Mortality,Risk.Red,.,Sudden,Death,Metoprolol,MERIT-HF,Bisoprolol,CIBIS-II,Carvedilol,COPERNICUS,3991,2647,2289,11.0%,7.2%,17.3%,11.8%,18.5%,11.4%,-34%,-34%,-35%,-41%,-44%,-36%,The three landmark trials on,betablockers,in CHF,Beta-Blockers in Heart Failure,All-Cause Mortality,B-Blocker-Therapy in CHF,NYHA II,NYHA III,NYHA IV,Ischemic,Non ischemic,Effect of beta-blockade on survival in CHF,Level of Evidence A,0 0.5 1 1.5 2,relative Risk and 95%-Interval,CIBIS II,MERIT-HF,US,Carvedilol,-program,Established Therapy of Chronic Left Heart Failure,1.,Diuretics,2. ACE-Inhibitors or/and AT1-receptor antagonists,3.,blockers (,Bisoprolol,Carvedilol,Metoprolol,Nebivolol,),4.,Aldosterone,antagonists(spironolactone,eplerenone,),5.,Digital(low,doses),6.,Devices(CRT,ICD,),ESC,Guidelines,Eur,Heart J 2005,AHA/ACC,Guidelines,Circulation,(2005),2004,ESC,共识,阻滞剂治疗心力衰竭,“,小量开始,缓慢加量,”,美托洛尔控释制剂,12.5-25,mg QD,每,2,周剂量加倍至,200,mg QD,卡维地洛 （达利全）,3.125,mg BID,每2,周剂量加倍直至,25,mg BID,比索洛尔（康忻）,1.25,mg QD,每,2,周剂量加倍直至,10,mg QD,每,2-4,周增加一次剂量；达最大耐受剂量后维持，不按照患者的治疗反应来定剂量。,传统做法是开始使用一种,ACE,抑制剂，例如依那普利,1.25-2.5 mg,每日两次,通常每隔,2-4,周剂量加倍，直至,10 mg,每日两次,以后再开始使用,受体阻滞剂,若您将,受体阻滞剂（例如比索洛尔）作为起始药物，且将获得怎样的结果呢,?,心力衰竭的起始治疗,CIBIS-III,目的：用非劣效分析比较先用比索洛尔然后合用依那普利或相反用法在减少总死亡和总住院率的疗效,入选标准：,65,岁，,NYHA II-III,级，,EF0.35,是第一个也是迄今惟一一项在,CHF,病人,先使用,受体阻滞剂后使用,ACE,抑制剂,与先使用,ACE,抑制剂后使用,受体阻滞剂,比较安全性和疗效的临床研究,ACE,抑制剂和,受体阻滞剂，特别是后者，没有很好地使用或增加剂量,与,ACE,抑制剂相比，,受体阻滞剂使用的病人数量更少，而且使用的病人也往往达不到理想剂量,Cleland JG et al. IMPROVEMENT. Lancet 2002; 360: 1631-9.,Komajda,M et al. T,he MAHLER survey.,Eur,Heart J 2005; 26: 1653-59.,Komajda,M et al.,The,EuroHeart,Failure Survey,.,Eur,Heart J 2003; 24: 464-74.,CIBIS III,研究的合理性,新诊断的,CHF,病人，在早期具有较高的死亡率,主要是死于猝死,受体阻滞剂减少猝死的作用可能优于,ACE,抑制剂,受体阻滞剂与,ACE,抑制剂从未进行过直接比较,CIBIS III,研究的合理性,交感神经系统在疾病早期即被激活,RAAS,系统则在较晚时期被激活,在病理生理学方面，以,受体阻滞剂作为起始治疗药物是合理的,研究以,受体阻滞剂或,ACE,抑制剂作为治疗,CHF,起始药物具有重要价值,CIBIS III,研究的合理性,先使用比索洛尔,(,o.d.),先使用依那普利,(,b.i.d.),比索洛尔,o.d.,依那普利,b.i.d.,比索洛尔,o.d.,依那普利,b.i.d,周,研究结束,1 - 2.5,年,0 2 4 6 8 10,26 28 30 32 34 36,周,研究结束,1 - 2.5,年,第一种药剂量递增,第一种药剂量递增,第二种药剂量递增,维持治疗,第二种药维持治疗,22-100,周,16-94,周,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,* * * * * * * * * * * * * * * * . * * * * *,* =,随访,10.0 mg,10.0 mg,10.0 mg,10.0 mg,研究设计,比索洛尔,o.d.,依那普利,b.i.d,0 2 4 6 8 10,26 28 30 32 34 36,* * * * * * * * * * * * * * * * . * * * * *,Willenheimer,et al. Circulation. 2005;112:2426-2435.,维持治疗,第二种药剂量递增,第二种药维持治疗,意向治疗,(,ITT),人群,50,60,70,80,90,100,0,6,12,18,先使用比索洛尔,先使用依那普利,按方案治疗,(,PP),人群,50,60,70,80,90,100,0,6,12,18,主要联合终点,无终点事件,%,无终点事件,%,B/E,比,E/B,163,例 比,165,例,RR 0.97 (95% CI 0.78-1.21),非劣性,P=0.046,B/E,比,E/B,178,例 比,186,例,RR 0.94 (95% CI 0.77-1.16),非劣性,P=0.019,503,498,356,353,265,259,80,73,505,505,389,388,291,277,87,76,月,月,在按方案治疗人群，先使用比索洛尔不劣于先使用依那普利,在意向治疗人群，先使用比索洛尔不劣于先使用依那普利并具有显著性。,处于危险的例数,处于危险的例数,危险降低,3%,危险降低,6%,Willenheimer,et al.,Circulation. 2005;112:2426-2435.,整个研究期总住院率,(,ITT,分析,),50,60,70,80,90,100,0,6,12,18,277,76,387,289,85,386,无住院比例,%,505,505,月,处于危险,的例数,先使用比索洛尔,先使用依那普利,t,B/E,比,E/B,151,比,157,例病人住院治疗,RR 0.95 (95% CI 0.76-1.19),P=0.66,危险下降,5%,Willenheimer,et al. Circulation. 2005;112:2426-2435.,整个研究期总死亡率,(,ITT,分析,),75,80,85,90,95,100,0,6,12,18,368,125,470,379,117,475,B/E,比,E/B,65,例 比,73,例 死亡,RR 0.88 (95% CI 0.63-1.22),P=0.44,存活率,%,月,505,505,先使用比索洛尔,先使用依那普利,处于危险,的例数,危险降低,12%,Willenheimer,et al. Circulation. 2005;112:2426-2435.,单药治疗期末总死亡率,(,ITT,分析,),80,85,90,95,100,0,1,2,3,4,5,6,492,473,458,448,434,254,495,481,463,453,446,234,505,505,B/E,比,E/B,23,例 比,32,例 死亡,RR 0.72 (95% CI 0.42-1.24),P=0.24,存活率,%,月,处于危险,的例数,先使用比索洛尔,先使用依那普利,危险下降,28%,Willenheimer,et al. Circulation. 2005;112:2426-2435.,随访,1,年的总死亡率,(,ITT,分析,),75,80,85,90,95,100,0,6,12,470,368,475,379,505,505,B/E,比,E/B,42,例 比,60,例 死亡,RR 0.69 (95% CI 0.46-1.02),P=0.06,存活率,%,月,处于危险,的例数,先使用比索洛尔,先使用依那普利,危险降低,31%,Willenheimer,et al. Circulation. 2005;112:2426-2435.,CIBIS-III,结论：,在总死亡和住院的联合终点方面，先用比索洛尔不劣于先用依那普利,2,组安全性比较无明显差别，先用比索洛尔不应成为问题,随访,1,年总死亡率较先用依那普利显著下降,CIBIS-III,提示医生可以根据患者的情况选择先用比索洛尔或依那普利,阜外心血管病医院心力衰竭监护病房,144,例中重度心力衰竭患者有创血液动力学监测下的治疗与临床资料的浅析,144,例中重度心力衰竭患者基本临床特征,例数,144,年龄,51.3 13.6,性别 男,112 （77.8,）,女,32 （22.2,）,诊断 扩张型心肌病,73 50.7,缺血性心肌病,32 22.2,瓣膜性心脏病术后,17 11.8,其他,22 15.3%,144,例中重度心力衰竭患者基本临床特征,NYHA,分级,II 8.3 %,III 37.5%,IV 54.2%,血压 收缩压,108.4, 19,mmHg,舒张压,71.5, 17,mmHg,心率,82.8, 17.3,bpm,144,例中重度心力衰竭患者基本临床特征,胸片肺淤血或水肿,64.6%,心脏超声,LA,45.3,10.7 mm,LV,67.0,13.0 mm,EF,33.8,12.4 mm,PAP,39.0,17.2 mmHg,项目,右房压（,RAP,mmHg,）,8.166.15,右室压（,RVP,mmHg,）,20.9,10.5,肺动脉压（,PAP,mmHg,）,31.9 13.5,肺动脉楔压（,PCWP,mmHg,）,22.4 12.4,心排血量（,CO L/min）,4.26 1.47,心排指数 （,CI）,2.34 0.77,肺动脉血管阻力（,PVR,dynes/sec/cm,-5,）,203.1 151.9,外周血管阻力（,SVR,dynes/sec/cm,-5,）,1514.2 524.9,144,例中重度心力衰竭患者基本临床特征,144,例中重度心力衰竭患者基本临床特征,治疗药物,利尿剂,100%,地高辛,100%,ACEI,72%,受体阻滞剂,（,131,例）,91%,安体舒通,100%,硝普钠或硝酸甘油,100%,多巴胺或多巴酚丁胺,100%,基线,12,h,后,24,h,后,RAP,8.15,7.38,6.52,RVP,20.9,8.18, ,10.2, ,PAP,31.9,28.1, ,26.5, ,PCWP,22.4,17.6, ,15.3, ,CI,2.34,2.34,2.32,PVR,203.1,212.7,232.9,SVR,1514.2,1416.7,1361.6, ,治疗前后有创血液动力学指标的变化,13,例未使用患者分析,风心病术前,2,例,房颤伴长间歇,1,例,III AVB 1,例,急性左心衰,2,例,哮喘,2,例,肺动脉高压,1,例,心动过缓,2,例,心脏移植术前,2,例,受体阻滞剂,使用情况,加量,维持,先加后减,减量,停用,未用,合计,DCM,20,40,4,5,2,2,73,CHD,10,13,0,4,0,5,32,瓣膜病术后,5,7,0,0,1,4,17,监护室中应用,-,受体阻滞剂的,经验监测,出入液量,严格保证使用,-,受体阻滞剂初期负平衡,必须出量,入量（每日多时间段统计）,体重,晨起体重的测量更为准确的反映了患者昨日全天的出入量情况。,血压和心率,心率,55次/,min ，,血压,90/60,mmHg (,特别注意较基础血压和心率下降的程度,),二、三度房室传导阻滞,应将,-,受体阻滞剂减量或停用,恰当掌握,受体阻滞剂,心衰加重 心衰减轻,受体阻滞剂加重心衰,静脉血管活性药物,利尿剂,ACEI,新近的,受体阻滞剂评价生存试验（,BEST）,并未观察到,受体阻滞剂 布新洛尔对严重心力衰竭患者降低死亡率有效，,可能与布新洛尔（和美托洛尔及卡维地洛不同）有内在拟,交感活性作用有关,在,MERITHF,研究中，,NYHA IV,级心衰患者的病死率虽然,在美托洛尔组显著低于安慰剂组（,15.9,对,21.1,），但死亡,和住院率的综合终点在美托洛尔组却 比安慰剂组更高（,47.8,对,43.4,）,受体阻滞剂治疗严重心衰的疗效尚不肯定,-,阻滞剂治疗严重心衰,Background:,Vicious Circle of Ischemia and an AHF attack,Ischemic heart disease,Acute heart failure,Ischemia attack,Chronic Heart Failure,Objective,To investigate whether the treatment,of,introvenous,beta-blocker infusion on the improvement of cardiac ischemia may further improve the acute heart failure so as to find a method in the management of this severe condition,Selection of Patients,patients with IHF and LVEF 45%.,The patients are undergoing an acute aggravation,Typical symptoms of acute left heart failure with or without pulmonary edema.,Each patients must has an ischemic evidence of ECG changes. The BP and HR are increasing during the AHF onset.,Not well responded to the routine treatment of AHF, including diuretic and vasodilatation agents,Methods,Metoprolol,intravenous infusion,Dosage,：,Titrate from low dose,1-5mg per time，up titrate to 20mg,Oral administration after,symptoms were relieved,Pay close attention to the HR, BP, ST segment changes,Gender,Male (9 cases),female (6 cases),Age,61,18 (yrs),63,15 (yrs),Weight,65,16 (kg),62,12 (kg),Height,168,9 (cm),159,8 (cm),SBP,113,24 (mmHg),116,19 (mmHg),DBP,68,11 (mmHg),66,9 (mmHg),HR,66,14 (,bpm,),64,13 (,bpm,),LVDd,60.4,5.3 (mm),57.6,7.5 (mm),LVEF,38%,14%,40%,11%,NYHA class,II(2)-III(7),II(1)-III(5),Characteristic before AHF attack,Basic diseases of Patients,Gender,Male (9 cases),female (6 cases),Hypertension,6,3,Diabetes,3,3,angina,9,6,OMI,5,4,AMI attack,1,1,Characteristics at onset of AHF,Gender,Male (9 cases),female (6cases),SBP,132,23 (mmHg),125,22 (mmHg),DBP,71,13 (mmHg),67,10 (mmHg),HR,87,21 (,bpm,),89,18 (,bpm,),Short breath,severe,severe,Cough/expectoration,mild 6 / severe 3,mild 3 / severe 3,orthopnea,yes,yes,CXR,Pul.cong.7/edema2,Pul.cong.4/edema2,ST segment,Depres.8/elevated1,Depre.4/elevated2,The characteristic after AHF attack,Gender,male (9 cases),female (6cases),SBP,106,20 (mmHg),101,17 (mmHg),DBP,61,9 (mmHg),63,8 (mmHg),HR,64,11 (,bpm,),62,13 (,bpm,),Short breath,marked relieve,marked relieve,Cough/ expectoration,marked relieve,marked relieve,Orthopnea,marked relieve,marked relieve,CXR,Pul.cong,./edema,marked relieve,marked relieve,ST segment changes,recovery (7),recovery (5),Improve time,40,35 (min),39,38 (min),Safety,Among the 15 treated patients, there were no patients aggravated or progress to death.,Case 1,Patient characteristics at admission and treatment response,：,Male patient, 74 yrs old,History of OMI for 7 yrs（inferior and,anterior,wall),Present illness: in recent years, the patient has suffered from,excertional,chest pain and nocturnal,paraxysmal,dyspnea,with heavy sweating and white foam sputum several times. This time he is reenter the hospital for the reason again.,PE: BP 120/80 mmHg，,rales,can be heard at lower lungs of both side, HR 80,bpm,，no murmurs can be heard,；,UCG：LA 54 mm、LV 67 mm、LVEF 38%,Case 1,Initial Diagnosis,Ischemic,cardiomyopathy,，,OMI (anterior and inferior wall),，,Cardiac dilatation,Cardiac function: NYHA IV,Diabetes (2 type),After routine treatment of CHF and ischemia, the symptoms were relieved,significantely,.,Case 1,Acute onset of heart failure,In the morning at the fourth day after breakfast, the patient suffered severe,dyspnea,and,orthopnea,with sweating heavily again.,Rales,can be heard at all field of both lungs.,BP 145/65 mmHg，HR 96,bpm,；,ECG：ST segments significantly depressed in V,5,-V,6,，I、,aVL,leads,；,V,1,-V,3,，AVR elevated,Chest X-ray showed pulmonary edema.,Treatments,：,Routine treatment of acute heart failure with high doses of,frusemide, nitroglycerin,nitroprusside, morphine etc. However the patients symptoms did not improve in about half an hour.,Metoprolol,was given to patients by intravenous infusion at a total dose of 15mg within 15 minutes,；,Case 1,After 30 minutes, HR was lowered to 70,bpm, the symptom of,dyspnea,was significantly relieved.,Rales,in both lungs were also diminished.,ST segments was returned and become an LBBB.,Chest X-ray at the second day showed pulmonary edema of both lungs was significantly abatement .,Case 1,Case 1,Fig.1 AHF on set followed by ischemia attack,Case,1,Fig.1 AHF,relieved,after,introvenous,beta blocker combined with standard administration,Experiences of Treatment,Possible mechanism,：,Vacious,circle of myocardial ischemia to heart failure,Careful judgment and observation on the following criteria,：,BP, HR and ECG changes,Symptoms of,dyspnea, sweating, temperature of extremities,Cautiousness/contraindication,No evidence of myocardial ischemia,II-III,AVB,HR 60,bpm,，judge based on the changes between basic HR,SBP 90 mmHg， judge based on the changes between basic BP level,Cardiogenic,shock,Conclusion,When a,stable CHF patients is suffered from a acute heart failure attack followed by an ischemia on set. If the patient respond to the standard treatment not well, we can consider to deal with i,ntravenous beta blocker. Because,the key reason is an ischemia on set. The management will stop the heart failure/ischemia vicious circle. At same time, the medication is safely.,心衰时应用,-,受体阻滞剂的注意事项,在利尿剂,，ACE,抑制剂（洋地黄）的基础上使用,选择,具有脂溶性和,-,受体阻滞作用而无内源性拟,交感作用者,从小剂量开始，逐渐加至靶剂量,在病人能够耐受的基础上坚持治疗，要有长期打,算,。,用,-,阻滞剂后出现心动过缓的问题,谢谢大家！,