1、Beta Blockers in CHFAJIT BHAGWATMD,DM,FACC,FISE,FCSI,FSCAIDiplomate,American Board of CardiologyKamalnayan Bajaj HospitalAurangabad,INDIA01020304050607080Mean+SD.Adapted from Bristow.J Am Coll Cardiol.1993.Normal function(n=12)Cardiomyopathy(n=54)b1b2a1*P.05 vs normal functionReceptor density(fmol/m
2、g protein)*b1:b2 80%:20%b1:b2 65%:35%Adrenergic Receptors in Normal vs Failing Left VentriclesEffects of Initiation of BB Therapy First Generation BB(Propranolol):No Beta adrenergic support,Profound reduction in CO(Reduced LV contractility&increased PVR)Second Generation BB(Metoprolol,Bisoprolol):Se
3、lective Beta-1 blockade,Beta-2 support intact+less vasoconstriction.Better tolerated&better perfusion Third Generation BB(Carvedilol):Additional Alpha blocking action,Afterload reduction,Frequent orthostatic symptoms Afterload reduction with carvedilol is not long term1981 GMT NORVEGIAN timolol mult
4、icenter study1982/1983 SOTALOL trial BHAT The effect of pindolol.1999 CIBIS II MERIT-HF1985 BELFAST metoprolol trial MIAMI1987LIT1990APSI1993 ESVEM CASH MDC1984PREMIS1986ISIS-11975Effect of chronic betaClinical Trials with Beta-BlockersPOST-MI TRIALS HF TRIALS1996US-CHFP1994CIBIS200.BEST COPERNICUS
5、CAPRICORN CARMEN COMET1992Simpaticetomia cardiaca sx e oxprenololo in pz.con IMACIBIS I:Survival in CHF patientswithout a history of MI1008060400200400600800100012001400survival(%)survival time(days)Bisoprolol PlaceboBisoprolol:n=18 deaths/151(11.9%)log-rank test p=0.01Placebo:n=42 deaths/187(22.5%)
6、CIBIS Investigators and Committees.Lechat Ph et al.Circulation 1994;90:1765177347%reduction47%reductionInitial Carvedilol Trials in the US MOCHA PRECISE Mild Carvedilol Severe CarvedilolAll trials were prematurely stopped due to marked reduction in mortality Double-blind,placebo-controlled,randomise
7、d trial 2,647 patients included(NYHA III+IV)Bisoprolol on top of standard therapy(diuretic+ACE inhibitor)FU for 1.3 yearsCIBIS IICardiac Insufficiency Bisoprolol Study199934%Time after inclusion(days)1.00.80.600200400600800SurvivalBisoprolol:156 deaths(n=1327)Placebo:228 deaths(n=1320)log rank test,
8、p.25SOLVD2IIIII8.28.8.25SAVE3I57.291CONSENSUS Trial Study Group.N Engl J Med.1987;316:14291435.2The SOLVD Investigators.N Engl J Med.1991;325:293302.3Rutherford JD et al.Circulation.1994;90:17311738.RiskReduction34%Percent of PatientsMonths of follow-up036912 15182120155010MERIT-HF:Total MortalityME
9、RIT-HF Study Group.Lancet.1999;253:20012007.P=.0062(adjusted)Metoprolol CR/XL(n=1990)Placebo(n=2001)MERIT-HFCIBIS-IIRandomized(No run-in phase)COMET Study Design3029 patients with stable heart failure,New York Heart Association Class II-IV,receiving standard treatment including ACE inhibitors Time t
10、o 1020 deathsEstimated to be 4 to 6 yearsScreeningTitration to maximum toleratedor target dose(Start:carvedilol 3.125 mg bid,metoprolol tartrate 5 mg bid)Assessments every four months during maintenance phase(n 1500)Metoprolol 50 mg bid(n 1500)Carvedilol 25 mg bidPoole-Wilson PA et al.Eur J Heart Fa
11、il 2002;4:321-329.Heart rate(beats.min-1)MetoprololCarvedilolTime(years)7075800123456585*COMET:Change of heart rate*p0.05,*p0.01Error bars represent 1 standard error Time(years)Blood pressure(mm Hg)708090100110120130012345*p=0.05*p=0.01*p=0.001 COMET:Blood pressureMetoprololCarvedilolSystolicDiastol
12、icDifference at 4 months-1.8 mm Hg,(%CI 3.2 to 0.4Time(years)Percentage Mortality(%)010203040012345Relativerisk95%CIp valueCarvedilol vs Metoprolol0.8280.736,0.9310.0017*CarvedilolMetoprolol17%COMET:Primary endpoint of mortality Sudden DeathCirculatory FailureDeath from strokeTime(years)Mortality(%)
13、COMET:Mode of deathHazard ratio:0.81 95%CI:0.677,0.97p=0.0216Hazard ratio:0.827 95%CI:0.673,1.016p=0.0702Hazard ratio:0.332 95%CI:0.177,0.624p=0.0006051015200123450510152001234501234012345MetoprololCarvedilolCOMET Trial:Questions Raised1.Metoprolol IR 50 mg BID is not an effective treatment.2.Metopr
14、olol IR 50 mg BID does not provide the same degree of b1 blockade as carvedilol 25 mg BID.3.Metoprolol IR 50 mg BID is a less effective b-blocker than metoprolol XL.COPERNICUSCopernicus:Mortality Carvediloln=1156Placebon=113335%reduction(p=.0014)Number of DeathsThe Benefits Improvement in LVEF in 3
15、months Reverse Remodeling(normalization of LV mass&shape):4-12 months Survival Benefit Decrease in SCD Decreased HospitalizationsEndpoint Data from the SENIORS StudyCleland et al.,Eur J Heart Fail 2004;6:787Primary endpoint375(35.3%)332(31.1%)0.86(0.74-0.99)0.039Mortality192(18.1%)169(15.8%)0.88(0.7
16、1-1.08)0.214Placebo(N=1061)Nebivolol(N=1067)Hazard ratioPProbability of SurvivalP=.01Total Events=652061218243036420.40.60.81.0BucindololPlaceboP=.27Total Events=208061218243036420.40.60.81.0BucindololPlaceboNonblacks(n=2081)Blacks(n=627)17%18%BEST:All-Cause Mortality by RaceThe Beta-Blocker Evaluat
17、ion of Survival Trial Investigators.N Engl J Med.2001;344:16591667.Months Post-randomizationMonths Post-randomizationCIBIS IIICardiac Insufficiency BIsoprolol StudyCIBIS III:Hypothesis Initiation of treatment of patients with CHF with the 1-selective-blocker bisoprolol (to which an ACE inhibitor is
18、subsequently added)is as effective and safe as a regimen beginning with the ACE inhibitor enalapril(to which bisoprolol is subsequently added).CIBIS III End pointsPrimary endpoint Combined endpoint of mortality(all cause)and all cause hospitalization at study end(time to event analysis)Secondary end
19、points(selected)Individual components of the primary endpoint at study end+at end of monotherapy phase Combined primary endpoint at end of monotherapy phaseEnalapril first(b.i.d.)Bisoprolol o.d.Enalapril b.i.d1.252.53.755.07.52.55.010.0 mg10.0 mgStudy designBisoprolol-firstBisoprolol o.d.Enalapril b
20、.i.d.1.252.53.755.07.52.55.010.0 mg10.0 mgBisoprolol o.d.Enalapril b.i.d weekStudy end 1-2.5 yr16-94 weeks0 2 4 6 8 10 26 28 30 32 34 36*.*First up-titrationMaintenance periodSecond up-titrationSecond maintenance period All Cause Hospitalizations over the entire study period(ITT)50607080901000612182
21、777638728985386B/E vs E/BHR 0.95(95%CI 0.76-1.19)P=0.66(difference)%withouthospitalizations505505mesiPatientsat riskBisoprolol-firstEnalapril-firstDOI:10.1161/CIRCULATIONAHA.105.582320Primary EndpointDOI:10.1161/CIRCULATIONAHA.105.582320Per-protocol(PP)5060708090100061218B/E vs E/BHR 0.97(95%CI 0.78
22、-1.21)non-inferiority P=0.0465034983563532652598073Bisoprolol-firstEnalapril-firstIntention-to-treat(ITT)5060708090100061218B/E vs E/BHR 0.94(95%CI 0.77-1.16)non-inferiority P=0.0195055053893882912778776Bisoprolol-first was consideredsignificantly non-inferior to enalapril-firstif the upper limit of
23、 the 95%CI wasbelow hazard ratio(HR)1.17(P0.025)In the PP population,bisoprolol-first was not significantly non-inferior toenalapril-firstIn the ITT population,bisoprolol-first was significantly non-inferior toenalapril-first%withoutendpoint%withoutendpointNumbers at riskNumbers at riskmonthsmonthsA
24、ll cause mortality(ITT)7580859095100061218368125470379117475B/E vs E/BHR 0.88(95%CI 0.63-1.22)P=0.44(difference)%survivalmonths505505Bisoprolol-firstEnalapril-firstNumbersat risk 808590951000123456492473458448434254495481463453446234505505B/E vs E/BHR 0.72(95%CI 0.42-1.24)P=0.24(difference)%survival
25、monthsNumbersat riskThroughoutstudy periodAt end of mono-therapy phase The bisoprolol-first strategy is as efficacious as the enalapril-first strategy.CIBIS III:ConclusionsStevenson L.N Engl J Med 2002;346:1346-1347A Funnel Diagram Showing Use of Beta-Blocker Therapy in Patients with a History of My
26、ocardial Infarction,Asymptomatic Left Ventricular Dysfunction,or Stable Heart FailureDispensed ACE Inhibitors or ARB PrescriptionsDispensed b b-Adrenoreceptor AntagonistsLow-RiskAverage-RiskHigh-RiskRisk-Treatment Mismatch in the Heart FailureLee DS et al JAMA.2005;294:1240-1247Conclusions Beta Bloc
27、kers MUST be used in treatment of chronic CHF whenever feasible Bisoprolol,Carvedilol&Sustained Release Metoprolol Moratlity benefit is about the same(34%)with all BB“Start low&Go slow”结束语当你尽了自己的最大努力时，失败也是伟大的，所以不要放弃，坚持就是正确的。When You Do Your Best,Failure Is Great,So DonT Give Up,Stick To The End感谢聆听不足之处请大家批评指导Please Criticize And Guide The Shortcomings演讲人：XXXXXX 时 间：XX年XX月XX日
