β受体阻滞剂在CHF治疗中的作用.ppt

Fare clic per modificare lo stile del titolo dello schema,Fare clic per modificare gli stili del testo dello schema,Secondo livello,Terzo livello,Quarto livello,Quinto livello,*,B,受体阻滞剂在,CHF,治疗中的作用,AJIT BHAGWAT,MD,DM,FACC,FISE,FCSI,FSCAI,Diplomate,American Board of Cardiology,Kamalnayan Bajaj Hospital,Aurangabad,INDIA,0,10,20,30,40,50,60,70,80,Mean+SD.,Adapted from Bristow.J Am Coll Cardiol.1993.,功能正常,(n=12),心脏病,(n=54),b,1,b,2,a,1,*,P,.05 vs,功能正常,受体密度,(fmol/mg protein),*,b,1,:b,2,80%:20%,b,1,:b,2,65%:35%,心功能正常与左心功能下降两组肾上腺受体分布,B,受体阻滞剂治疗的启示作用,第一代,B,受体阻滞剂,(,普奈洛尔,):,无肾上腺受体选择性,第二代,B,受体阻滞剂,(,美托洛尔,比索洛尔,):,高,Beta-1,选择性,，较少,Beta-2,作用,+,较低的血管收缩作用,.,良好的耐受性,&,更好的灌注,第三代,B,受体阻滞剂,(,卡维地洛,):,阻断,a,受体,降低后负荷,减少体位性症状的发生,卡维地洛对,a,受体的阻滞并不是长期的,British Heart Journal,1975,37:1022-1036,在充血性心力衰竭治疗上,B,受体阻滞剂的作用,F.Waagstein,A.Hjalmarson,E.Varnauskas,and I.Wallentin,From the Department of Medicine I,Division of Cardiology and Department of Clinical Physiology,Sahlgrens,Hospital,University of Gteborg,Sweden,1981,GMT,NORVEGIAN,timolol,multicenter,study,1982/1983,SOTALOL trial,BHAT,The,effect,of,pindolol,.,1999,CIBIS II,MERIT-HF,1985,BELFAST,metoprolol,trial,MIAMI,1987,LIT,1990,APSI,1993,ESVEM,CASH,MDC,1984,PREMIS,1986,ISIS-1,1975,Effect of chronic beta,使用,B,受体阻滞剂的临床实验,POST-MI TRIALS,HF TRIALS,1996,US-CHFP,1994,CIBIS,200.,BEST,COPERNICUS,CAPRICORN,CARMEN,COMET,1992,Simpaticetomia cardiaca sx,e oxprenololo in pz.con IMA,CIBIS I:,CHF,患者的生存率,无心梗的发病史,100,80,60,40,0,200,400,600,800,1000,1200,1400,生存率,(%),生存时间,(days),比索洛尔,安慰剂,比索洛尔,:n=18 deaths/151(11.9%),log-rank test,p=0.01,安慰剂,:n=42 deaths/187(22.5%),CIBIS Investigators and Committees.Lechat Ph et al.Circulation 1994;90:17651773,47%reduction,降低,47%,在美国最早的卡维地洛实验,MOCHA,PRECISE,Mild Carvedilol,Severe Carvedilol,所有的实验提前终止是因为死亡率可以明显的降低,双盲,安慰剂对照,随机,2,647,名患者,心功能分级,(NYHA III+IV),在标准治疗的基础上使用比索洛尔,(,利尿剂,+ACE,I,),随访,1.3,年,CIBIS II,心功能不全比索洛尔研究,1999,34%,Time after inclusion(days),1.0,0.8,0.6,0,0,200,400,600,800,生存率,比索洛尔,:156 deaths(n=1327),安慰剂,:228 deaths(n=1320),log rank test,p.25,SOLVD,2,IIIII,8.2,8.8,.25,SAVE,3,I,5,7,.29,1,CONSENSUS Trial Study Group.,N Engl J Med,.1987;316:14291435.,2,The SOLVD Investigators.,N Engl J Med,.1991;325:293302.,3,Rutherford JD et al.,Circulation,.1994;90:17311738,.,下降,34%,患者的百分比,时间,0,3,6,9,12,15,18,21,20,15,5,0,10,MERIT-HF,:,总死亡率,MERIT-HF Study Group.,Lancet,.1999;253:20012007.,P,=.0062(adjusted),美托洛尔,(n=1990),安慰剂,(n=2001),MERIT-HF,CIBIS-II,心率,(beats.min,-1,),美托洛尔,卡维地洛,时间,(,年,),70,75,80,0,1,2,3,4,5,65,85,*,*,*,COMET:,心率变化,*p0.05,*p0.01,Error bars represent 1 standard error,时间,(,年,),血压,(mm Hg),70,80,90,100,110,120,130,0,1,2,3,4,5,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*,*p=0.05,*p=0.01,*p=0.001,COMET:,血压变化,美托洛尔,卡维地洛,收缩压,舒张压,四个月时的差异,-1.8 mm Hg,(%CI 3.2 to 0.4,Time(years),死亡率,(%),0,10,20,30,40,0,1,2,3,4,5,Relative,risk,95%CI,p value,卡维地洛,vs,美托洛尔,0.828,0.736,0.931,0.0017*,卡维地洛,美托洛尔,17%,COMET:,首要研究终点 死亡率,COMET,Trial:,引起的问题,1.,美托洛尔,IR,50 mg BID,不是有效的治疗手段,美托洛尔,IR 50 mg BID,不如,b,1,受体阻滞剂卡维地洛,25mg BID,同样有效,美托洛尔,IR 50 mg BID,不如美托洛尔,XL,有效,.,COPERNICUS,卡维地洛对于严重心衰存活率的影响,临床获益,三个月内改善,LVEF,逆转,LV,重塑（质量,&,形状）：,4-12,月,生存率获益,降低,SCD,降低住院率,SENIORS,研究终点,Cleland et al.,Eur J Heart Fail 2004;6:787,首要终点,375(35.3%),332(31.1%),0.86(0.74-0.99),0.039,死亡率,192(18.1%),169(15.8%),0.88(0.71-1.08),0.214,安慰剂,(N=1061),奈必洛尔,(N=1067),风险比,HR,P,存活率,P,=.01,Total Events=652,0,6,12,18,24,30,36,42,0.4,0.6,0.8,1.0,布新洛尔,安慰剂,P,=.27,Total Events=208,0,6,12,18,24,30,36,42,0.4,0.6,0.8,1.0,布新洛尔,安慰剂,非黑人,(n=2081),黑人,(n=627),17%,18%,BEST,:,不同种族,全因死亡率,The,Beta,-Blocker Evaluation of Survival Trial Investigators.N Engl J Med.2001;344:16591667.,随机分组后时间,随机分组后时间,CIBIS III,比索洛尔,心功能不全研究,CIBIS III:,设想？,对于慢性心衰患者（,CHF,），采用,1,选择性,受体阻滞剂,比索洛尔,进行初始治疗（后加用,ACEI,）与先采用,ACEI,依那普利（后加用,比索洛尔,）是同样有效和安全的。,CIBIS III,研究终点,首要终点,研究期末的全因死亡率和全因住院率的联合终点,次要终点,(,选择性的,),研究期末单药阶段期末首要终点的独立因素,单药治疗期末的联合首要终点,初始依那普利,(b.i.d.),比索洛尔,o.d.,依那普利,b.i.d,1.25,2.5,3.75,5.0,7.5,2.5,5.0,10.0 mg,10.0 mg,研究设计,初始比索洛尔,比索洛尔,o.d,.,依那普利,b.i.d.,1.25,2.5,3.75,5.0,7.5,2.5,5.0,10.0 mg,10.0 mg,比索洛尔,o.d,.,依那普利,b.i.d,周,Study end,1-2.5,年,16-94 weeks,0 2 4 6 8 10,26 28 30 32 34 36,*.*,初始加量阶段,维持期,第二期加量阶段,第二期维持阶段,整体研究阶段的全因住院率,(ITT),50,60,70,80,90,100,0,6,12,18,277,76,387,289,85,386,B/E vs E/B,HR 0.95(95%CI 0.76-1.19),P=0.66(difference),%,未住院百分比,505,505,mesi,风险例数,初始比索洛尔,初始依那普利,DOI:10.1161/CIRCULATIONAHA.105.582320,首要终点,DOI:10.1161/CIRCULATIONAHA.105.582320,方案治疗分析,(PP),50,60,70,80,90,100,0,6,12,18,B/E vs E/B,HR 0.97(95%CI 0.78-1.21),non-inferiority P=0.046,503,498,356,353,265,259,80,73,初始比索洛尔,初始依那普利,意向治疗分析,(ITT),50,60,70,80,90,100,0,6,12,18,B/E vs E/B,HR 0.94(95%CI 0.77-1.16),non-inferiority P=0.019,505,505,389,388,291,277,87,76,如果,95,可信区间（,CI,）的上限低于风险比,(HR)1.17,(P0.025),那么,认为初始比索洛尔治疗不显著的劣于初始依那普利治疗,ITT,定群分析中,初始比索洛尔治疗不显著的劣于初始依那普利治疗,PP,定群分析中，初始比索洛尔治疗不显著的劣于初始依那普利治疗,%without,endpoint,%without,endpoint,风险例数,风险例数,月,月,全因死亡率,(ITT),75,80,85,90,95,100,0,6,12,18,368,125,470,379,117,475,B/E vs E/B,HR 0.88(95%CI 0.63-1.22),P=0.44(difference),%survival,月,505,505,初始比索洛尔,初始依那普利,风险例数,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 vs E/B,HR 0.72(95%CI 0.42-1.24),P=0.24(difference),%survival,月,风险例数,研究全过程,单药治疗阶段末,ITT,分析，初始,比索洛尔,治疗不劣于初始依那普利治疗,(p=0.019).,PP,分析,95,可信区间的上限接近于非显著性,劣势,(p=0.046).,两种治疗策略的安全性方面没有差异,比索洛尔,初始治疗策略不导致担心,初始采用比索洛尔治疗的策略与初始采用依那普利治疗的策略同样有效,CIBIS III:,总结,Stevenson L.N Engl J Med 2002;346:1346-1347,B-,受体阻滞剂用于具有心梗、无症状的左心室功能不全或稳定性心衰患者流程图,Dispensed ACE Inhibitors or ARB Prescriptions,Dispensed,-Adrenoreceptor Antagonists,Low-Risk,Average-Risk,High-Risk,心衰风险治疗的不匹配性,Lee DS et al JAMA.2005;294:1240-1247,总结,在任何可行的情况下，,B,受体阻滞剂必须被用于慢性,CHF,的治疗,比索洛尔，卡维地洛,&,缓释美托洛尔,所有,BB,死亡率获益相当（,34,）,“Start low&Go slow”,（低剂量起始，逐渐缓慢加量）,Thanks!,