受体阻滞剂在慢性心衰中的作用（英文）课件幻灯

Beta Blockers in CHF,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.,Normal function (n=12),Cardiomyopathy (n=54),b1,b2,a1,*P.05 vs normal function,Receptor density (fmol/mg protein),*,b1:b2 80%:20%,b1:b2 65%:35%,Adrenergic Receptors in Normal vs Failing Left Ventricles,Effects 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): Selective 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 term,British Heart Journal, 1975,37:1022-1036 Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy 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,Clinical Trials with Beta-Blockers,POST-MI TRIALS HF TRIALS,CIBIS I: Survival in CHF patients without a history of MI,100,80,60,40,0,200,400,600,800,1000,1200,1400,survival (%),survival time (days),Bisoprolol,Placebo,Bisoprolol: n = 18 deaths/151 (11.9%),log-rank test,p = 0.01,Placebo: n = 42 deaths/187 (22.5%),CIBIS Investigators and Committees. Lechat Ph et al. Circulation 1994; 90: 17651773,47% reduction,47% reduction,Initial Carvedilol Trials in the US,MOCHA PRECISE Mild Carvedilol Severe Carvedilol,All trials were prematurely stopped due to marked reduction in mortality,Double-blind, placebo-controlled, randomised trial 2,647 patients included (NYHA III + IV) Bisoprolol on top of standard therapy (diuretic + ACE inhibitor) FU for 1.3 years,CIBIS II Cardiac Insufficiency Bisoprolol Study,1999,34%,Time after inclusion (days),CIBIS II: Survival,CIBIS II Investigators and Committees. Lancet 1999; 353: 913,All-cause mortality reduction,Also reduced hospitalizations and CV deaths,Bisoprolol was associated with a reduction in: All-cause mortality: - 34% Sudden death: - 44% All-cause hospital admissions: - 20% Hospital admissions due to WHF: - 36%,CIBIS II,CIBIS II Investigators and Committees. Lancet 1999; 353: 913,SCD: ACE Inhibitors,1CONSENSUS 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.,Risk Reduction 34%,Percent of Patients,Months of follow-up,0,3,6,9,12,15,18,21,20,15,5,0,10,MERIT-HF: Total Mortality,MERIT-HF Study Group. Lancet. 1999;253:20012007.,P=.0062 (adjusted),Metoprolol CR/XL (n=1990),Placebo (n=2001),MERIT-HF,CIBIS-II,Randomized (No run-in phase),COMET Study Design,3029 patients with stable heart failure, New York Heart Association Class II-IV, receiving standard treatment including ACE inhibitors,Time to 1020 deaths Estimated to be 4 to 6 years,Screening,Titration to maximum tolerated or 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 bid,Poole-Wilson PA et al. Eur J Heart Fail 2002;4:321-329.,Heart rate (beats.min-1),Metoprolol,Carvedilol,Time (years),70,75,80,0,1,2,3,4,5,65,85,*,*,*,COMET: Change of heart rate,* p0.05, * p0.01,Error bars represent 1 standard error,Time (years),Blood pressure (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: Blood pressure,Metoprolol,Carvedilol,Systolic,Diastolic,Difference at 4 months -1.8 mm Hg, (% CI 3.2 to 0.4,Time (years),Percentage Mortality (%),0,10,20,30,40,0,1,2,3,4,5,Relative,risk,95% CI,p value,Carvedilol vs,Metoprolol,0.828,0.736, 0.931,0.0017 *,Carvedilol,Metoprolol,17%,COMET: Primary endpoint of mortality,Sudden Death,Circulatory Failure,Death from stroke,Time (years),Mortality (%),COMET: Mode of death,COMET Trial: Questions Raised,1. Metoprolol 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.,COPERNICUS,Copernicus: Mortality,Carvedilol n=1156,Placebo n=1133,35% reduction (p=.0014),Number of Deaths,The Benefits,Improvement in LVEF in 3 months Reverse Remodeling (normalization of LV mass & shape): 4-12 months Survival Benefit Decrease in SCD Decreased Hospitalizations,Endpoint Data from the SENIORS Study,Cleland et al., Eur J Heart Fail 2004;6:787,Probability of Survival,P=.01 Total Events = 652,0,6,12,18,24,30,36,42,0.4,0.6,0.8,1.0,Bucindolol,Placebo,P=.27 Total Events = 208,0,6,12,18,24,30,36,42,0.4,0.6,0.8,1.0,Bucindolol,Placebo,Nonblacks (n=2081),Blacks (n=627),17%,18%,BEST: All-Cause Mortality by Race,The Beta-Blocker Evaluation of Survival Trial Investigators. N Engl J Med. 2001;344:16591667.,Months Post-randomization,Months Post-randomization,CIBIS III Cardiac Insufficiency BIsoprolol Study,CIBIS III: Hypothesis,Initiation of treatment of patients with CHF 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 points,Primary endpoint Combined endpoint of mortality (all cause) and 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 phase Combined primary endpoint at end of monotherapy phase,Enalapril first (b.i.d.),Bisoprolol o.d.,Enalapril b.i.d,1.25,2.5,3.75,5.0,7.5,2.5,5.0,10.0 mg,10.0 mg,Study design,Enalapril b.i.d,All Cause Hospitalizations over the entire study period (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),% without hospitalizations,505,505,mesi,Patients at risk,Bisoprolol-first,Enalapril-first,DOI: 10.1161/CIRCULATIONAHA.105.582320,Primary Endpoint,DOI: 10.1161/CIRCULATIONAHA. 105.582320,Per-protocol (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,Bisoprolol-first,Enalapril-first,Intention-to-treat (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,Bisoprolol-first was considered significantly non-inferior to enalapril-first if the upper limit of the 95% CI was below hazard ratio (HR) 1.17 (P0.025) In the PP population, bisoprolol- first was not significantly non-inferior to enalapril-first In the ITT population, bisoprolol- first was significantly non-inferior to enalapril-first,% without endpoint,% without endpoint,Numbers at risk,Numbers at risk,months,months,All cause mortality (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,months,505,505,Bisoprolol-first,Enalapril-first,Numbers at risk,80,85,90,95,100,0,1,2,3,4,5,6,492,473,458,4