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 d

2、ensity (fmol/mg protein)*b1:b2 80%:20%b1:b2 65%:35%Adrenergic Receptors in Normal vs Failing Left VentriclesEffects of Initiation of BB TherapyFirst Generation BB (Propranolol): No Beta adrenergic support, Profound reduction in CO (Reduced LV contractility & increased PVR)Second Generation BB (Metop

3、rolol, Bisoprolol): Selective Beta-1 blockade, Beta-2 support intact + less vasoconstriction. Better tolerated & better perfusionThird Generation BB (Carvedilol): Additional Alpha blocking action, Afterload reduction, Frequent orthostatic symptomsAfterload reduction with carvedilol is not long term1

4、981 GMT NORVEGIAN timolol multicenter 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-CHF

5、P1994CIBIS200. BEST COPERNICUS 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 te

6、st p = 0.01Placebo: n = 42 deaths/187 (22.5%)CIBIS Investigators and Committees. Lechat Ph et al. Circulation 1994; 90: 1765177347% reduction47% reduction34% Time after inclusion (days)1.00.80.600200400600800SurvivalBisoprolol: 156 deaths (n = 1327)Placebo: 228 deaths (n = 1320)log rank test, p .25S

7、OLVD2IIIII8.28.8.25SAVE3I57.291CONSENSUS 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-up03691215182120155010MERIT-HF: Total MortalityM

8、ERIT-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

9、Time to 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(n1500) Metoprolol 50 mg bid(n1500) Carvedilol 25 mg bidPoole-Wilson PA et al. Eur J

10、 Heart Fail 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 pressureMetoprol

11、olCarvedilolSystolicDiastolicDifference 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

12、 from strokeTime (years)Mortality (%)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

13、IR 50 mg BID is not an effective treatment.2. Metoprolol 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=.00

14、14)Number of DeathsThe BenefitsImprovement in LVEF in 3 monthsReverse Remodeling (normalization of LV mass & shape): 4-12 monthsSurvival BenefitDecrease in SCDDecreased HospitalizationsEndpoint Data from the SENIORS StudyCleland et al., Eur J Heart Fail 2004;6:787Primary endpoint375 (35.3%)332 (31.1

15、%)0.86 (0.74-0.99)0.039Mortality192 (18.1%)169 (15.8%)0.88 (0.71-1.08)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

16、(n=627)17%18%BEST: All-Cause Mortality by RaceThe Beta-Blocker Evaluation 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 C

17、HF with the 1-selective -blocker bisoprolol (to which an ACE inhibitor is 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 endpointCombined endpoint of mortality (all cause) an

18、d all cause hospitalization at study end (time to event analysis)Secondary endpoints (selected)Individual components of the primary endpoint at study end + at end of monotherapy phaseCombined primary endpoint at end of monotherapy phaseEnalapril first (b.i.d.)Bisoprolol o.d.Enalapril b.i.d1.252.53.7

19、55.07.52.55.010.0 mg10.0 mgStudy designBisoprolol-firstBisoprolol o.d.Enalapril b.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 periodSe

20、cond up-titrationSecond maintenance period All Cause Hospitalizations over the entire study period (ITT)50607080901000612182777638728985386B/E vs E/BHR 0.95 (95% CI 0.76-1.19)P=0.66 (difference)% withouthospitalizations505505mesiPatientsat riskBisoprolol-firstEnalapril-firstDOI: 10.1161/CIRCULATIONA

21、HA.105.582320Primary EndpointDOI: 10.1161/CIRCULATIONAHA. 105.582320Per-protocol (PP)5060708090100061218B/E vs E/BHR 0.97 (95% CI 0.78-1.21)non-inferiority P=0.0465034983563532652598073Bisoprolol-firstEnalapril-firstIntention-to-treat (ITT)5060708090100061218B/E vs E/BHR 0.94 (95% CI 0.77-1.16)non-i

22、nferiority P=0.0195055053893882912778776Bisoprolol-first was consideredsignificantly non-inferior to enalapril-firstif the upper limit of 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 populatio

23、n, bisoprolol-first was significantly non-inferior toenalapril-first% withoutendpoint% withoutendpointNumbers at riskNumbers at riskmonthsmonthsAll 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)% survivalmonthsNumbers