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1、正确评价-受体阻滞剂在高血压治疗中一线药物的地位,SNS 在心血管疾病的重要性 高血压早期已有SNS激活,Medalie JH,et al.J Chronic Dis,以色列公务员研究：心率与心肌梗死危险,Framingham：心率与死亡率,Gillman MW,et al.Am Heart J 1993;125:1148-1154,Adjusted survival curves for overall mortality by RHR quintiles,Cumulative survival,RHR in quintilies,-83 bpm,1.0,0.9,0.8,0.7,0.6,0.
2、5,0.00,5.00,10.00,15.00,20.00,Years after enrolment,Figure 1 adjusted for age,gender,hypertension,diabetes mellitus,cigarette smoking,clinically significant coronary vessel,EF,recreational activity,treatment with antiplatelets,diuretics,b-blockers,and lipid-lowering drugs.RHR,resting heart rate.,n=2
3、4,913FU 14.7 years,Ariel Diaz et al.EHJ 2005,Cumulative survival,RHR in quintilies,-83 bpm,1.0,0.9,0.8,0.7,0.6,0.5,0.00,5.00,10.00,15.00,20.00,Years after enrolment,Adjusted survival curves for CV mortality by RHR,Figure 2 Asterisk indicates adjusted as Figure 1 plus BMI.CV,cardiovas-cular;RHR,resti
4、ng heart rate.,n=24,913FU 14.7 years,Ariel Diaz et al.EHJ 2005,心理社会应激为触发因素,猝死,January 1994,Leor et al,NEJM 1996,0,10,20,30,Number of Sudden Deaths,11,14,17,20,23,The Northridge EarthquakeJanuary 17,1994,at 4.31 am,Relative Risk 5.2(p0.001),Psychosocial Stress and the Triggering of Sudden Death,-受体阻滞
5、剂的作用机制-受体阻滞剂具有无与伦比的 心脏保护作用 国际高血压指南-受体阻滞剂始终是 首选或一线药物-受体阻滞剂的临床实践,-阻滞剂的作用机制,降低交感神经张力 防止儿茶酚胺的心脏毒性作用 抑制异常、过度、持续的神经激素活性增高 和 RAS 间的相互作用:降低血压 缓解心肌缺血(减少心肌耗氧、冠脉血流有利的重分配）改善心肌重构 减慢心率 减少心律失常（包括复杂室性心律失常）提高心室颤动阈值 降低猝死,ESC Expert Consensus Document on-blockers 2004,Schlaish MP Hypertension 2004;43:169,去甲肾上腺素释放增加,肌肉
6、交感兴奋,高血压时交感活性增加,BP 107/58,BP 148/102,ECG,MSNA,BP(mmHg),B,A,48 y.o.femaleBP:107/58 mmHgMSNA:32 bursts per min 45 bursts per 100 hb,49 y.o.femaleBP:148/102 mmHgMSNA:42 bursts per min 77 bursts per 100 hb,150,100,50,p 0.01,MSNA(bursts/100 heartbeats),100,80,60,40,20,0,NT,EH,A,800,600,400,200,0,Total bo
7、dy NE spillover(ng/min),Cardiac NE spillover(ng/min),Ronal NE spillover(ng/min),B,80,60,C,40,20,0,250,200,150,100,50,0,NT,EH,NT,EH,NT,EH,Schlaich MP Circulation 2003;108:560,高血压交感活性增加和左心室肥厚的关系,去甲肾上腺素释放增加,左室重量/交感活性,A,70,60,50,40,30,20,10,0,HEART,Cardiac NE spillover(ng/min),NT,EH-,EH+,100,80,60,40,20
8、,0,MSNA(burals/105 heartbeaths),MSNA,NT,EH-,EH+,250,200,150,100,50,0,B,C,KIDNEY,NT,EH-,EH+,Renal NE spillover(ng/min),200,A,160,140,120,100,80,60,40,20,0,Left Vontilcular Miss inder(g/m2),200,C,160,140,120,100,80,60,40,20,0,Left Vontilcular Miss inder(g/m2),200,D,160,140,120,100,80,60,40,20,0,Left V
9、ontilcular Miss inder(g/m2),180,180,180,0,10,20,30,40,50,60,70,Cardiac NE Spillover(ng/min),0,200,400,600,800,1000,1200,1400,Whole Body NE Spillover(ng/min),180,160,140,120,100,80,60,40,20,0,Left Vontilcular Miss inder(g/m2),B,0,50,100,150,200,250,Reral NE Spillover(ng/min),0,20,40,60,80,MSNA(bursts
10、/100 hoartboats),r=0.50;p 0.01,r=0.41;p=0.054,r=0.52;p 0.001,r=0.50;p 0.01,100,Schlaish MP Hypertension 2004;43:169,高血压心脏NE和AII释放之间缺乏关系,动脉,冠脉窦,EH=原发性高血压,NT=正常血压,20,A,15,10,5,0,Anglotonsin II(fmol/ml),NT,EH,C,NT,EH,1.4,1.2,1.0,0.8,0.6,0.4,0.2,0.0,Anglotensln II/I ratlo(fmol/fmol,NT,EH,Anglotonsin I(f
11、mol/ml),B,D,20,15,10,5,0,50,40,30,20,10,0,0,2,4,6,8,10,12,14,Cardiac NESpillover(ng/min),CS Angiotensin II(fmol/ml),r=-0.009p=0.961,原发性高血压交感活性增加,中枢交感活性输出增加总体、心脏及肾脏去甲肾上腺素释放增加肌肉交感张力增加神经元去甲肾上腺素重新摄取降低左心室肥厚程度与心脏交感活性相关血管紧张素-II 浓度不增加,研究结果提示高血压时交感神经系统激活先于肾素血管紧张素系统激活,Slaich MP Hypertension 2004;43:169,因此治疗高血
12、压时在阻断RAS之前阻断NE活性可能更为合理,治疗无并发症的高血压患者 阻滞剂可在ACEI或ARB之前应用,-受体阻滞剂的作用机制-受体阻滞剂具有无与伦比的 心脏保护作用 国际高血压指南-受体阻滞剂始终是 首选或一线药物-受体阻滞剂的临床实践,高血压病的一级预防,MAJOR CARDIOVASCULAR EVENTS Comparisons of different active treatments,RR(95%CI),Favours first listed,Favours second listed,BP difference(mm Hg),0.5,1.0,2.0,Relative Ri
13、sk,ACEI vs.CA,CA vs.D/BB,ACEI vs.D/BB,0.97(0.92,1.03),1.04(0.99,1.08),1.02(0.98,1.07),2/0,1/0,1/1,BPLT 2003,CARDIOVASCULAR DEATHComparisons of different active treatments,RR(95%CI),Favours first listed,Favours second listed,BP difference(mm Hg),0.5,1.0,2.0,Relative Risk,ACEI vs.CA,CA vs.D/BB,ACEI vs
14、.D/BB,1.03(0.94,1.13),1.05(0.97,1.13),1.03(0.95,1.11),2/0,1/0,1/1,BPLT 2003,TOTAL MORTALITYComparisons of different active treatments,RR(95%CI),Favours first listed,Favours second listed,0.5,1.0,2.0,Relative Risk,BP difference(mm Hg),ACEI vs.CA,CA vs.D/BB,ACEI vs.D/BB,1.04(0.98,1.10),0.99(0.95,1.04)
15、,1.00(0.95,1.05),2/0,1/0,1/1,BPLT 2003,Similar net effects on total cardio-vascular events of:ACE inhibitorsCalcium antagonistsDiuretics/beta-blockers,Conclusions I,高血压的一级预防 阿替洛尔随机研究(22150 病人年),HAPPHY,MRC 老年病人,两个研究荟萃分析,利尿剂组(n=1604),阿替洛尔组(n=1599),利尿剂组(n=1081),阿替洛尔组(n=1102),利尿剂组(n=2685),阿替洛尔组(n=2701),
16、死亡例数,Wikstrand J et al,In Clinical trials in Hypertension,2001,pp 141-58;The Steering Com.of the HAPPHY Trial,JAMA 1989;262:3273-74;MRC Working Party,Br Med J 1992;304:405-12.,26,33,134,160,160,200,0,50,100,150,200,250,美托洛尔预防高血压患者动脉粥样硬化研究（MAPHY）,3234例男性高血压患者，40-64y，平均随访 5.0年总病死率 22%（P=0.028）美托洛尔组4.0
17、%（65/1609例）利尿剂组5.1%（83/1625例）与利尿剂组相比，美托洛尔组心血管猝死 30%（P=0.017）冠心病事件(致死+非致死)24%（P=0.0010）,Wikstrand J et al JAMA 1988,一级预防-MAPHY,利尿剂,美托洛尔,p=0.028,随访时间，年,5,10,0,累计死亡数,90,50,0,累计死亡数,50,40,0,20,70,30,20,10,总死亡率,心血管猝死,利尿剂,美托洛尔,p=0.017,随访时间，年,5,10,0,Olsson G et alAm J Hypertens 1991,Wikstrand J et alJAMA 19
18、88,一级预防 MAPHY致死性非致死性事件(至首次事件发生时间),冠脉事件,累计事件数,160,40,0,20,60,100,80,120,140,5,10,0,卒中事件,危险性降低 24%,利尿剂,美托洛尔,p=0.0010,利尿剂,美托洛尔,随访时间，年,Wikstrand et al,Hypertension 1991;17;579-88,MRC,IPPPSH 和 MAPHY研究结果荟萃分析10,951 例病人随机分组,随访51,100 病人年,总死亡率24720220%0.023猝死1016438%0.003冠心病(致死32526321%0.006+非致死性),随机分组非阻滞剂1 阻
19、滞剂 危险性(n=5452)(n=5499)降低p值 事件发生数(%),研究终点,Wikstrand et al,In Clinical trials in Hypertension,ed Henry Black,New York,2001,pp 141-158,1主要为利尿剂,卡托普利与阿替洛尔：型糖尿病患者终点事件发生率比较（UKPDS）,UK Prospective Diabetes Study Group.BMJ 1998;317(7160):713-20,LIFE研究：主要结果,9193例高血压左室肥厚患者，平均随访54个月主要终点（中风/心肌梗死/心血管病死亡）氯沙坦组11%vs
20、阿替洛尔组13%（降低13.0%，p=0.021）二级终点（10项，包括总死亡率）致死或非致死中风降低24.9%（5%vs 7%p=0.001）致死或非致死心肌梗死增高7.3%（p=0.49）心血管病死亡率降低11.4%（p=0.21）,Lancet 2002,所有终点总结,The area of the blue square is proportional to the amount of statistical information,阿替洛尔 苄氟噻嗪更好,0.50,0.70,1.00,1.45,主要终点Non-fatal MI(incl silent)+fatal CHD次要终点No
21、n-fatal MI(exc.Silent)+fatal CHDTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure3级终点 Silent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onse
22、t diabetes mellitusNew-onset renal impairment事后分析 Primary end point+coronary revasc procsCV death+MI+stroke,2.00,Unadjusted Hazard ratio(95%CI)0.90(0.79-1.02)0.87(0.76-1.00)0.87(0.79-0.96)0.84(0.78-0.90)0.89(0.81-0.99)0.76(0.65-0.90)0.77(0.66-0.89)0.84(0.66-1.05)1.27(0.80-2.00)0.68(0.51-0.92)0.98(0.
23、81-1.19)0.65(0.52-0.81)1.07(0.62-1.85)0.70(0.63-.078)0.85(0.75-0.97)0.86(0.77-0.96)0.84(0.76-0.92),氨氯地平 培哚普利更好,only 14.3%of patients in the amlodipine group and 8.6%in the beta-blocker group remained on monotherapy at the end of the study,making this a trial of combination regimens.Dahlf said.Devere
24、ux said.I think the differences should be interpreted as being between regimens rather than between classes of drugs.,ASCOT,为药物联合方案之间的比较,而非 二类药物之间的比较 一级终点:非致死性MI和致死性冠心病 二组无差异-受体阻滞剂应用的是氨酰心胺,The results observed are not necessarily applicable to all blockers.They could simply indicate particulardisadv
25、antages of the specific drugs usedeg.atenololas recently suggested.However,pending further information,we believe the combination of a blocker and a diuretic should not be recommended in preference to the comparator regimenused in ASCOT-BPLA for routine use,but only forspecific circumstances.Bjrn Da
26、hlf et al in ASCOT-BPLA,Lancet,Carlberg B Lancet 2004;364:1684,Atenol vs placebo in hypertension,Stroke,Mortality,AMI,CV Mortality,Atenolol in hypertension:is it a wise choice?Bo Carlberg,Ola Samuelsson,Lars Hjalmar Lindholm Lancet 2004,Hence,based on the results of our meta-analyses and on the effe
27、cts of atenolol in other cardiovascular disorders,we have doubts about the suitability ofatenolol as a first-line antihypertensive drug and as areference drug in outcome trials of hypertension.,Asked how these findings should affect how patients currently on treatment should be managed,Dr Bjrn Dahlf
28、(coprincipal investigator of the trial),said that patients currently controlled on existing treatment should probably not be switched away from these drugs,but that,given the diabetes result,the combination of a beta blocker and diuretic should probably be avoided.Maybe switch the beta blocker to so
29、mething that blocks the renin angiotensin system,or switch the diuretic to a calcium channel blocker,he said.,The results observed are not necessarily applicable to all blockers.They could simply indicate particulardisadvantages of the specific drugs usedeg.atenololas recently suggested.However,pend
30、ing further information,we believe the combination of a blocker and a diuretic should not be recommended in preference to the comparator regimenused in ASCOT-BPLA for routine use,but only forspecific circumstances.Bjrn Dahlf et al in ASCOT-BPLA,Lancet,Dr Peter S Sever(Imperial College London,UK)told
31、 a press conference here.We recognize that there are clearly subgroups of patients in whom beta blockers are indicated:”those with a prior myocardial infarction or symptomatic coronary heart disease”.but in uncomplicated hypertension,I think the ASCOT data seriously raise questions about the future
32、position of beta blockers in the management of hypertension.“We have reason to believe there may well be an adverse interaction between atenolol,thiazides,and statins and also a potential for beneficial interaction between amlodipine,perindopril,and statins,Effects of combined statin and beta-blocke
33、r treatment onone-year morbidity and mortality after acute myocardialinfarction associated with heart failure,30,25,20,15,10,5,0,0,6,12,18,24,30,36,Month,Neither(n=830)Beta-blocker only(n=2004)Statin only(n=496)Both(n=1971),Endpoint rate(%),A Hognestad et al.Am J Cardid 2004;93:603-6,How to define t
34、he“uncomplicated hypertension”?,Importance of Primary Prevention,Women,0,Patients(%),Men,20,40,60,Murabito et al Circ 1993 88:2548,Framingham Heart Study(n=5144)MI or SD as 1st Presentation,朝鲜战争死亡者 300人尸检平均年龄 22.1岁 77.3%CAD 39%阻塞斑块 ENOS JAMA,Tuzcu Circ 1999,32 Year Old Female,Prevalence of Atheroscl
35、erosis by Donor Age,Atherosclerosis:Change in Approach,Early intervention pays long term dividends,高血压病早期受体阻滞剂的应用？高血压病早期已有交感神经系统的过度激活 受体阻滞剂在高血压病一级预防 对心脏的保护作用从未被超越 如何识别高血压病早期 晚期？高血压病早期仍应及早应用受体阻滞剂,冠心病高危患者心梗后患者心衰患者室上性和室性心律失常心源性猝死糖尿病,高血压病的二级预防,ACC/AHA指南：慢性稳定性心绞痛药物治疗（2002年版，推荐水平“Class I”）,阿斯匹林（无禁忌证者）-阻滞剂
36、：作为首选抗心绞痛药（无禁忌证者）ACE抑制剂：用于合并糖尿病和（或）左室收缩功能异常的 确诊冠心病患者降胆固醇药：LDL-C 130mg/dl的冠心病患者（目标 100mg/dl）硝酸甘油舌下或喷雾：用于迅速缓解心绞痛发作钙拮抗剂或长效硝酸盐：-阻滞剂有禁忌证的患者,全部患者必需 长期应用-阻滞剂,ESC Expert Consensus Document on-blockers 2004,慢性、稳定性冠心病,-阻滞剂治疗慢性稳定性冠心病指南（ESC 2004-阻滞剂专家共识）,UA/NSTEMI 指南如何使用-阻滞剂（ACC/AHA 2002）,若无禁忌证，-阻滞剂应早期开始使用(I类推荐
37、)高危患者以及持续胸痛的患者，-阻滞剂先静脉注射再继以口服中、低危患者口服给予-阻滞剂休息时的目标心率为5060bpm，除非发生限制性副作用,NSTEMI ACS 应尽早开始应用-阻滞剂(I B)急性期后全部病人均应接受-阻滞剂(I A)目标心率：50-60次/分,ESC Expert Consensus Document on-blockers 2004,-阻滞剂早期治疗急性心肌梗死的疗效28 项临床试验汇总分析（n27000）,ISIS Collaborative Group.Lancet 1986,2(8498):57-66,AMI后长期使用-阻滞剂的效益,总死亡率绝对危险显著降低（p0
38、.0001）827/10452例（7.9%）：986/9860例（10.0%）总死亡率相对危险降低23%95%可信区间15%30%（p0.00001）非致死性心肌梗死绝对危险显著降低（p0.0001）549/9643例（5.7%）：693/9198例（7.5%）非致死性心肌梗死相对危险降低26%95%可信区间17%34%（p0.0001）猝死相对危险降低30%95%可信区间20%40%（p0.00001）,Yusuf S,et al.Prog Cardiovasc Dis 1985,27(5):335-371,-阻滞剂降低老年心肌梗死患者死亡率,STEMI-阻滞剂治疗（ACC/AHA Guid
39、elines 2004）,无禁忌证的患者应立即给予-阻滞剂口服治疗 不论是否同时接受溶栓治疗或直接 PCI 治疗（I类推荐、A级证据）除非有禁忌证或低危（心室功能正常或接近正常、再灌注成功、没有明显室性心律失常），所有 STEMI 后的患者都应该接受-阻滞剂治疗。这种治疗是无限期的。（I 类推荐、A级证据）,-阻滞剂与心肌梗死 AMI:口服-阻滞剂适用于全部病人无禁忌症者(I A）i.v.-阻滞剂亦可应用（I B）MI后长期预防：口服-阻滞剂适用于全部病人无禁忌症者(I A）无限期使用。可：改善生存率、防止再梗、猝死 效益可见于并用再灌注治疗、ACE-I者 高危病人受益更大：大的、前壁梗死；糖
40、尿病、心梗后缺血、迟发室律失常、Q波与非Q波心梗、老年人 下列情况效益大于危险：I 型糖尿病、COPD、严重外周血管病、PR间期达0.24秒,ESC Expert Consensus Document on-blockers 2004,STEMI：-阻滞剂的相对禁忌证（ACC/AHA Guidelines 2004）,现有证据提示：-阻滞剂降低再梗死和死亡率的效益实际上超过其危险，包括非活动期轻度哮喘、胰岛素依赖糖尿病、COPD、严重外周血管疾病、PR0.24s、中度心力衰竭的患者。上述患者使用-阻滞剂时需加强监测，避免发生不良反应。大多数哮喘患者能够耐受心脏选择性的 1-阻滞剂。,二级预防：
41、-阻滞剂的受益人群（ACC/AHA 2004 STEMI Guidelines）,接受或未接受再灌注治疗的患者病程早期或较迟开始接受-阻滞剂治疗的患者所有各种年龄组的患者高危患者得益最大（死亡率降低）：左室功能异常、室性心律失常、未接受再灌注治疗的患者已经接受冠状动脉重建治疗（介入或搭桥手术）的患者，仍然需要长期-阻滞剂治疗；因为-阻滞剂能够进一步降低死亡率。,心肌梗死后的二级预防：-阻滞剂治疗（ESC 2004-阻滞剂专家共识）,-受体阻滞剂在冠心病中的应用从治疗指南到临床实践(全部I类推荐),稳定性心绞痛不稳定性心绞痛急性心肌梗死患者心肌梗死后患者相对禁忌证患者也应积极考虑使用 因为得益超
42、过危险冠心病二级预防,PEACE ResultsCumulative Event Rates,Pfeffer M.NEJM 2004;351:2058,Cumulative Event Rate(%),EUROPA and PEACE Comparison CV death,MI,or Cardiac Arrest,合并治疗药物的患者数比较(安慰剂组),年份 Asprin 阻滞剂 他汀类HOPE 2000 76%40%29%EUROPA 2003 92%62%58%PEACE 2004 91%60%70%,心血管死亡率和心肌梗死发生率比较(安慰剂组),CVD死亡率 心肌梗死HOPE(4652例
43、)8.1%12.2%EUROPA(6108例)4.1%6.2%(非致死)PEACE(4132例)3.7%5.3%(非致死),心力衰竭,阻滞剂开拓了心力衰竭 生物学治疗的新纪元,美托洛尔提高扩张型心肌病的左心室射血分数,*P0.05*P0.0001#P=0.013，与标准治疗比较,Hall SA,et al.J Am Coll Cardiol 1995;35:1154-1161,4035302520,左心室射血分数(),标准治疗美托洛尔,基线第一天第一月第三月,*,*,#,b受体阻滞剂之所以能从“心衰的禁忌症”转而成为常规治疗的一部分，就是因为走出了“短期”“药理学”治疗的误区，认识到了长期治疗
44、的“生物学效应”，这也就是近年来心衰治疗概念发生根本性转变的依据，即：修复性策略-改变衰竭心脏的生物学性质。,n=10135，22个随机对照试验(不包括COPERNICUS和BEST)总死亡率的危险比：0.65(95%Cl 0.530.80)一致降低心衰病人的猝死率 MERIT-HF41%(P=0.002)CIBIS II44%(P=0.001),b 阻滞剂治疗心力衰竭荟萃分析(Brophy JM et al.Ann Intern Med 2001),Placebo-controlled trials withbeta-blockers in heart failure,Packer et a
45、l.NE JM 1996;CIBIS II Invest.Lancet 1999;MERIT-HF Study Group.Lancet 1999BEST Investigators.Lancet 1999;Packer et al.NE JM 2001,CIBIS II,MERIT-HF,COPERNICUS,BEST,CAPRICORN,Trial,n,Hazard Ratio(95%Cl),2.647,3.991,2.289,2.708,1.259,0.66(0.54-0.81),0.66(0.53-0.81),0.65(0.52-0.81),0.90(0.78-1.02),0.77(0
46、.60-0.98),Mild-moderate-Severe CHF,Severe CHF,Post-MlCHF,0,0.2,0.4,0.6,0.8,1,Pre-planned Subgroup Analysis of Post-MI Patients,MERIT-HF,n=192648%of all randomized,Jnosi A,et al.Am Heart J 2003,MERIT-HF Subgroup Analysis of Post-MI Patients,Outcome in PMI Patients with Heart Failure,CAPRICORN(n=1959)
47、and MERIT-HF(n=1926)1,1Subgroup analysis history of AMI 2Time to first event,CAPRICORN,All-cause mortality,All-cause mortality/CV hosp.2,MERIT-HF,23%,8%,Risk reduction,p-value,p=0.03,Plac/Beta,151/116122/74,40%,p=0.0004,CAPRICORN,MERIT-HF,367/340326/258,ns,22%,p=0.002,The CAPRICORN Investigators.Lan
48、cet 2001;357:1385-1390.Janosi A et al.In preparation.,Relative risk and 95%CI,0.0,1.0,Metoprolol CR/XL 1,Metoprolol CR/XL 1,Carvedilol 1 2(1),Carvedilol 1 2(1),已列为标准治疗 或常规治疗的药物 1.利尿剂 2.ACE抑制剂 3.受体阻滞剂 13联合应用 地高辛(IIa)改善症状,COMET试验中，未选用MERIT-HF中的制剂 美托洛尔琥珀酸缓释片，而且酒石酸美托洛尔平片应用的剂量亦偏小.提示阻滞剂制剂的选择和剂量的大小可对心衰患者的转
49、归有显著的影响.据此，2005年AHA/ACC和ESC心衰指南,只推荐应用比索洛尔、MERIT-HF中美托洛尔的制剂(琥珀酸美托洛尔)和剂量，以及卡维地洛.,Beta-Blockers class effect or drug effect?NE high affinity agonist binding:1/1/2=20/2/1 Class effect-1 blockade 2,1 AR blockade-unsettled:no vs small importance Drug specific effect-AR polymorphism,Michael R Bristow AHA C
50、linical Practice:2004 HF Management,ACE Dose at Baseline,No ACELow/mediumHighAll randomized,Total Mortality,FavorsMeto CR/XL,Total Mortality/Any Hosp.,Total Mortality/CHF Hosp.,Relative risk and 95%confidence interval,FavorsMeto CR/XL,FavorsMeto CR/XL,17/2473/11354/78145/217,73/93315/381252/290641/7
