[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.197.142.219. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Effect of β-blockers on overall mortality in the 21 trials. RR indicates relative risk; CI, confidence interval.

Effect of β-blockers on overall mortality in the 21 trials. RR indicates relative risk; CI, confidence interval.

Table 1. 
Main Characteristics of Trials of β-Blockers in Patients With Heart Failure*
Main Characteristics of Trials of β-Blockers in Patients With Heart Failure*
Table 2. 
Effect of β-Blockers on Mortality in Patients With Heart Failure*
Effect of β-Blockers on Mortality in Patients With Heart Failure*
Table 3. 
Effect of Vasodilating β-Blockers on Overall Mortality*
Effect of Vasodilating β-Blockers on Overall Mortality*
Table 4. 
Effect of Nonvasodilating β-Blockers on Overall Mortality*
Effect of Nonvasodilating β-Blockers on Overall Mortality*
Table 5. 
Summary Effects of Vasodilating and Nonvasodilating β-Adrenergic Blocking Agents on Mortality*
Summary Effects of Vasodilating and Nonvasodilating β-Adrenergic Blocking Agents on Mortality*
Table 6. 
Effect of β-Blockers on Overall Mortality in Patients With Ischemic Heart Failure*
Effect of β-Blockers on Overall Mortality in Patients With Ischemic Heart Failure*
Table 7. 
Effect of β-Blockers on Overall Mortality in Patients With Nonischemic Heart Failure*
Effect of β-Blockers on Overall Mortality in Patients With Nonischemic Heart Failure*
1.
Dargie  HJMcMurray  JJV Diagnosis and management of heart failure. BMJ. 1994;308321- 328Article
2.
McKee  PACastelli  WPMcNamara  PMKannel  WB The natural history of congestive heart failure: the Framingham Study. N Engl J Med. 1971;2851441- 1445Article
3.
Cowie  MRMosterd  AWood  DA  et al.  The epidemiology of heart failure. Eur Heart J. 1997;18208- 225Article
4.
The CONSENSUS Trial Study Group, Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;3161429- 1435Article
5.
The SOLVD Investigators, Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325293- 302Article
6.
The Digitalis Investigation Group, The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336525- 533Article
7.
Thomas  JAMarks  BH Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978;41233- 243Article
8.
Cohn  JNLevine  TBOlivari  MT  et al.  Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311819- 823Article
9.
Yates  JCBeamish  REDhalla  NS Ventricular dysfunction and necrosis produced by adrenochrome metabolite of epinephrine: relation to pathogenesis of catecholamine cardiomyopathy. Am Heart J. 1981;102210- 221Article
10.
Mann  DLKent  RLParsons  BCooper  IV Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992;85790- 804Article
11.
Packer  M Pathophysiology of chronic heart failure. Lancet. 1992;34088- 92Article
12.
Anderson  JLLutz  JRGilbert  EM  et al.  A randomized trial of low-dose β-blockade therapy for idiopathic dilated cardiomyopathy. Am J Cardiol. 1985;55471- 475Article
13.
Bristow  MRO'Connell  JBGilbert  EM  et al. Bucindolol Investigators, Dose-response of chronic β-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circulation. 1994;891632- 1642Article
14.
Eichhorn  EJHeesch  CMBarnett  JH  et al.  Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1994;241310- 1320Article
15.
Engelmeier  RSO'Connell  JBWalsh  RRad  NScanlon  PJGunnar  RM Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation. 1985;72536- 546Article
16.
Fisher  MLGottlieb  SSPlotnik  GD  et al.  Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol. 1994;23943- 950Article
17.
Krum  HSackner-Bernstein  JDGoldsmith  RLKukin  MLSchwartz  BPenn  J Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;921499- 1506Article
18.
Metra  MNardi  MRaccagni  DGiubbini  RDei  Cas L Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;241678- 1687Article
19.
Waagstein  FBristow  MRSwedberg  K  et al. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group, Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993;3421441- 1446Article
20.
CIBIS Investigators and Committees, A randomized trial of β-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;901765- 1773Article
21.
Australia/New Zealand Heart Failure Research Collaborative Group, Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997;349375- 380Article
22.
Packer  MBristow  MRCohn  JN  et al. US Carvedilol Heart Failure Study Group, The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;3341349- 1355Article
23.
Doughty  RNRodgers  ASharpe  NMacMahon  S Effects of beta-blocker therapy on mortality in patients with heart failure: a systematic overview of randomized controlled trials. Eur Heart J. 1997;18560- 565Article
24.
Heidenreich  PALee  TTMassie  BM Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 1997;3027- 34Article
25.
Lechat  PPacker  MChalon  SCucherat  MArab  TBoissel  JP Clinical effects of β-adrenergic blockade in chronic heart failure. Circulation. 1998;981184- 1191Article
26.
CIBIS-II Investigators and Committees, The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;3539- 13Article
27.
Breslow  NLDay  NE Statistical Methods in Cancer Research.  Lyon, France Inernational Agency for Research on Cancer1980;
28.
Petitii  DB Meta-analysis: Decision Analysis and Cost-effectiveness Analysis: Methods for Quantitative Synthesis in Medicine.  New York, NY Oxford University Press1994;
29.
Schlesselman  J Case-Control Studies: Design, Conduct, Analysis.  New York, NY Oxford University Press1982;
30.
Bristow  MRGilbert  EMAbraham  WT  et al. MOCHA Investigators, Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;942807- 2816Article
31.
Cohn  JNFowler  MBBristow  MA  et al.  Effect of carvedilol in severe chronic heart failure [abstract]. J Am Coll Cardiol. 1996;27(suppl A)169AArticle
32.
Olsen  SLGilbert  EMRenlund  DGTaylor  DOYanowitz  FDBristow  MR Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double blind randomized study. J Am Coll Cardiol. 1995;251225- 1231Article
33.
Packer  MColucci  WSSackner-Bernstein  JD  et al. PRECISE Study Group, Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE trial. Circulation. 1996;942793- 2799Article
34.
Paolisso  GGambardella  AMarrazzo  G  et al.  Metabolic and cardiovascular benefits deriving from β-adrenergic blockade in chronic congestive heart failure. Am Heart J. 1992;123103- 110Article
35.
Pollock  SGLystash  JTedesco  CCraddock  GSmucker  ML Usefulness of bucindolol in congestive heart failure. Am J Cardiol. 1990;66603- 607Article
36.
Sano  HKawabata  NYonezawa  KSakuma  IHirayama  HYasuda  H Metoprolol was more effective than captopril for dilated cardiomyopathy in Japanese patients [abstract]. Circulation. 1989;80(suppl 2)118
37.
Gilbert  EMAnderson  JLDeitchman  D  et al.  Long-term β-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990;88223- 229Article
38.
Colucci  WPacker  MBristow  MR  et al. US Carvedilol Heart Failure Study Group, Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996;942800- 2806Article
39.
Aronow  WSAhn  CKronzon  AI Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction >40% treated with diuretics plus angiotensin-converting–enzyme inhibitors. J Am Coll Cardiol. 1997;80207- 209Article
40.
Hall  JAFerro  ADickerson  JECBrown  MJ β-Adrenoceptor subtype cross regulation in the human heart. Br Heart J. 1993;69332- 337Article
41.
Ikram  HFitzpatrick  D Double blind trial of chronic oral β-blockade in congestive cardiomyopathy. Lancet. 1981;2490- 493Article
42.
Boutelant  SLechat  PKomajda  M  et al.  Evaluation non invasive des effets cardiovasculaires du nebivolol chez l'insuffisant cardiaque. Arch Mal Coeur. 1992;85863- 870
43.
Currie  PJKelly  MJMcKenzie  A  et al.  Oral beta-adrenergic blockade with metoprolol in chronic severe dilated cardiomyopathy. J Am Coll Cardiol. 1984;3203- 209Article
44.
Freudenberger  RSMannino  MMKalman  J  et al.  Does amlodipine provide benefit beyond beta blockade in heart failure? [abstract] Circulation. 1995;92(suppl 1)394
45.
Persson  HRythe'n-Alder  EMelcher  AErhardt  L Effects of β-receptor antagonists in patients with clinical evidence of heart failure after myocardial infarction: double blind comparison of metoprolol and xamoterol. Br Heart J. 1995;74140- 148Article
46.
Simarro  ERodríguez  MALastra  JA  et al.  Efecto del gallopamil y del propranolol en pacientes con cardiopatía isquémica y depresión moderada de la función ventricular. Rev Esp Cardiol. 1995;48741- 745
47.
Sanderson  JEChan  WWMHung  YT  et al.  Effect of low dose beta blockers on atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of metoprolol and a third generation vasodilating beta blocker. Br Heart J. 1995;74502- 507Article
48.
Yamada  SOhkura  TUchida  S  et al.  A sustained increase in beta-adrenoceptors during long-term therapy with metoprolol and bisoprolol in patients with heart failure from idiopathic dilated cardiomyopathy. Life Sci. 1996;581737- 1744Article
49.
Regitz  VLeuchs  BWellnhofer  EKrülls-Münch  JFleck  E Improvement in heart failure with long term ACE inhibitors and β-blockers therapy is comparable [abstract]. Circulation. 1992;86(suppl 1)119
50.
Chadda  KGoldstein  SByington  RCurb  JD Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation. 1986;73503- 510Article
51.
Leung  WHLau  CPWong  CKCheng  CHTai  YTLim  SP A double-blind crossover trial of labetalol in patients with idiopathic dilated cardiomyopathy [abstract]. Circulation. 1989;80(suppl II)118
52.
Yoshikawa  THanda  SAkaishi  MMitamura  HOgawa  S Beta1-selectivity is not essential to achieve therapeutic efficacy with beta-blockade therapy for idiopathic dilated cardiomyopathy. Cardiology. 1995;86217- 223Article
53.
The BEST Steering Committee, Design of the Beta-Blocker Evaluation Survival Trial (BEST). Am J Cardiol. 1995;751220- 1223Article
54.
Sachdev  VMoore  CKDas  SKStarling  MR Effects of beta-blocking therapy on left ventricular systolic function in heart failure [abstract]. Circulation. 1992;86(suppl I)119
55.
Wisenbaugh  TKatz  IDavis  J  et al.  Long term (3 month) effects of a new beta-blocker (nevibolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol. 1993;211094- 1100Article
56.
Sigmund  MJakob  HBecker  H  et al.  Effect of metoprolol on myocardial β-adrenoceptors and G1β-proteins in patients with congestive heart failure. Eur J Clin Pharmacol. 1996;51127- 132Article
57.
Cleland  JGSwedberg  K Carvedilol for heart failure, with care. Lancet. 1996;3471199- 1201Article
58.
Pfeffer  MAStevenson  LW β-Adrenergic blockers and survival in heart failure. N Engl J Med. 1996;3341396- 1397Article
59.
Krum  H β-Adrenoceptor blockers in chronic heart failure: a review. Br J Clin Pharmacol. 1997;44111- 118Article
60.
Kukin  MLKalman  JMannino  MFreudenberger  RBuchholz  COcampo  O Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta-blockade alone in chronic congestive heart failure. Am J Cardiol. 1996;77486- 491Article
61.
Not Available, Metoprolol ups survival in heart failure. Scrip. 1998;238827
Original Investigation
March 13, 2000

β-Adrenergic Blocking Agents in Heart FailureBenefits of Vasodilating and Nonvasodilating Agents According to Patients' Characteristics: A Meta-analysis of Clinical Trials

Author Affiliations

From the Fundació Institut Català de Farmacologia, Service of Clinical Pharmacology, Department of Pharmacology and Therapeutics (Drs Bonet, Agustí, Arnau, Vidal, Diogène, and Laporte), and the Service of Cardiology (Dr Galve), Hospitals Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Arch Intern Med. 2000;160(5):621-627. doi:10.1001/archinte.160.5.621
Abstract

Background  In patients with heart failure, β-adrenergic blocking agents reduce overall and cardiovascular mortality. This meta-analysis aimed at clarifying their effect on sudden death, the magnitude of their benefit according to the cause of heart failure, and whether there is any difference between vasodilating and nonvasodilating agents.

Methods  Randomized, clinical trials were included if they evaluated a β-adrenergic blocking agent without intrinsic sympathomimetic activity, included a control group receiving placebo or standard treatment, evaluated mortality on an intention-to-treat basis, and lasted at least 8 weeks.

Results  Twenty-one trials with 5849 patients (3130 receiving β-blockers) were included. Median length of treatment was 6 months. Most patients had mild or moderate heart failure and were treated with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. The β-blockers significantly reduced overall mortality, cardiovascular mortality, and mortality due to pump failure and sudden death by 34% to 39%. The decrease in overall mortality in patients with ischemic heart disease (IHD) (30%) was no different from that among patients with non-IHD (26%) (P=.08). The reduction in overall mortality was greater with vasodilating than with nonvasodilating agents (45% vs 27%; P=.007), particularly in patients without IHD (62%), compared with those with IHD (22%; P=.03).

Conclusions  In patients with heart failure, β-blockers reduce total and cardiovascular mortality at the expense of a decrease in mortality due to pump failure and sudden death. The magnitude of the benefit is similar in patients with IHD and in those with non-IHD. Vasodilating β-blockers have a greater effect on overall mortality than nonvasodilating agents, particularly in patients with non-IHD.

DESPITE MAJOR advances in knowledge about heart failure, it remains a serious public health problem, with a growing prevalence of 0.2% to 4% in the general population and about 10% in patients older than 80 years.1 Case-fatality rate is 10% to 20% within 1 year of diagnosis and 50% or more within 5 years.1,2 Although death rates due to other cardiovascular diseases are falling, advanced heart failure progresses to rapid deterioration and is a cause of rising mortality rates.36 This has stimulated research into a more intensive treatment of less advanced stages of the disease and treatments based on new pathophysiological targets.

In patients with heart failure, the renin-angiotensin and sympathetic nervous systems are activated and contribute to progressive deterioration of the patient's condition.7,8 Long-term sympathetic activation has detrimental effects on the myocardium, through direct myocardial toxic effects and arrhythmogenesis caused by excess of catecholamines, and through indirect stimulation of the renin-angiotensin system.911 The results of several clinical trials suggest that β-adrenergic blocking agents improve symptoms, left ventricular function, and the rate of hospital admission.1221 For carvedilol, a beneficial effect on mortality has also been reported.22 Three meta-analyses2325 have indicated that β-blockers reduce overall and cardiovascular mortality. However, it is not known whether they reduce sudden death, whether their efficacy is influenced by the cause of heart failure, or whether there is any difference in the effect of vasodilating and nonvasodilating agents. Our study addressed these questions, including additional information from the recently published Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) trial.26

MATERIALS AND METHODS

Clinical trials were identified through a computerized bibliographic search of the MEDLINE (from January 1, 1966, to January 31, 1998) and EMBASE (from January 1, 1974, to May 30, 1997) databases and by browsing the bibliography from review articles on heart failure. A letter, asking about any unpublished or unknown trial on β-blockers in heart failure, was also sent to the first author of identified clinical trials, to experts in heart failure, and to the pharmaceutical companies manufacturing β-blocking agents. Furthermore, since January 1998, we have been following the progress and possible termination of a number of ongoing clinical trials.

Clinical trials were included if they (1) were randomized and tested a β-adrenergic blocking agent devoid of intrinsic sympathomimetic activity in patients with heart failure; (2) had a control group treated with placebo or standard treatment; (3) had a parallel or crossover design (from the latter, only the results of the first part of the study before the crossover were included); (4) evaluated mortality on an intention-to-treat basis; and (5) had a minimum duration of 8 weeks. Trials with and without run-in phase were included.

Three investigators (A.A., J.M.A., X.V.) independently considered the inclusion of each trial without knowledge of the title, authors, and publishing journal. Differences were resolved by consensus. The information on each trial included in the meta-analysis usually was obtained from the corresponding publication. For each trial, the following information was independently collected by two of us (S.B., A.A.), using a standard form: sex, age, New York Heart Association (NYHA) functional classification, ejection fraction, standard treatments, duration of the study, β-adrenergic agent tested, number of withdrawals and deaths during the run-in phase, and mortality during the double-blind phase of each trial. When some of these items were missing in the article, the first investigator of the study was asked for them. When information on a particular variable ultimately was not obtained, the trial was excluded from the analysis of that particular variable.

Heterogeneity of treatment effects between studies was tested by using a χ2 test for heterogeneity.27 Relative risks (RR) and their 95% confidence intervals (CIs) were calculated using the DerSimonian and Laird random-effects methods28 with the Rev-man program developed by the Cochrane Collaboration.28 The random effects model was chosen because, in absence of heterogeneity, the results are the same as those obtained with the fixed effects model, and they can be more confidently generalized, as they are also more conservative. Comparisons between relative risk estimates were performed using the method described by Schlesselman.29

RESULTS
CLINICAL TRIALS INCLUDED IN THE META-ANALYSIS

Thirty-nine studies1222,26,3056 were evaluated, but only 211221,26,3039 met the preestablished criteria and were included in the study (Table 1). Four studies were excluded because they lasted less than 8 weeks4043; 6 studies because they did not include a control group receiving placebo or standard treatment4449; 1 study because it was a subanalysis of patients with heart failure in the β-Blocker Heart Attack Trial50; 1 study because labetalol hydrochloride, the agent used, has some intrinsic sympathomimetic activity51; 1 study because the assignment procedure was suboptimal52; 1 study because it only described the design of a study53; 1 study because it did not report on mortality54; and 2 studies because of discrepancies in the numerical data.55,56 Finally, 1 was the summary report22 of 4 randomized trials with carvedilol,30,31,33,38 and its results were used only when data were not available from the individual trials.

BASELINE CHARACTERISTICS OF PATIENTS

A total of 5849 patients were studied (75% male; 3130 randomized to β-blocking agents and 2719 to the control group). The median duration of treatment was 6 months (range, 3-32 months). In 8 trials, the drug under study was carvedilol17,18,21,3033,38; in 7 studies, metoprolol (metoprolol tartrate in three studies15,16,19; nonspecified salt in the others)12,1416,19,34,36; in 3 studies, bucindolol hydrochloride13,35,37; in 2 studies, bisoprolol fumarate20,26; and in 1 study, propranolol hydrochloride39(Table 1). Eleven trials (1839 patients, of whom 1658 were included in trials with carvedilol) tested a β-blocker with vasodilating properties, and 10 (4010 patients) tested a nonvasodilating agent (3288 patients in trials with bisoprolol).

Heart failure due to ischemic heart disease (IHD) resulted in 3 trials,16,21,39 to non-IHD (idiopathic) in 8,12,14,15,18,19,34,36,37 and to mixed in 913,17,20,26,30,32,33,35,38; cause was not stated in 1 study.31 In total, heart failure was judged to be ischemic in 2841 patients (48.6%) and nonischemic in 2903 (49.6%). Patients with NYHA class II or III disease constituted 88.7%. In trials that included information on concomitant treatment, 70% to 100% of patients received an angiotensin-converting enzyme (ACE) inhibitor (15 trials); 75% to 100%, a diuretic (14 trials); and 34% to 100%, digitalis (16 trials).

TOTAL AND CARDIOVASCULAR MORTALITY

Seven hundred eighty-three patients died, 333 (10.6%) of 3130 treated with β-blockers, and 450 (16.6%) of 2719 in the control group (RR, 0.71; 95% CI, 0.63-0.80) (Table 2). Thus, 1 death can be prevented by treating 17 patients for 6 months. In 14 trials, a trend toward reduced mortality was seen, but only in 3 was this statistically significant (Figure 1). Including deaths during the run-in phase of trials (n=15) in the analysis did not materially change the estimate of mortality reduction (OR, 0.71; 95% CI, 0.63-0.80).

Information on cardiovascular mortality was obtained from 18 studies.1221,26,30,32,3436,38,39 There were 262 (9.0%) of 2913 cardiovascular deaths among patients treated with β-blockers, compared with 347 (13.7%) of 2530 in the control group (RR, 0.71; 95% CI, 0.59-0.86). This corresponds to 1 cardiac death prevented for every 21 patients treated. Reduced cardiovascular mortality was the result of a decrease in the number of deaths due to heart failure (RR, 0.66 [95% CI, 0.47-0.92]) and sudden death (RR, 0.70 [95% CI, 0.54-0.89]). There were few deaths due to myocardial infarction (12 vs 14; RR, 0.81 [95% CI, 0.38-1.72]) and other cardiovascular causes (41 vs 45; RR, 0.87 [95% CI, 0.48-1.57]).

The inclusion of the CIBIS-II trial did not change the estimates of overall, cardiovascular, or heart failure mortality (Table 2), but it did increase the estimate of the benefit on sudden death.

VASODILATING VS NONVASODILATING β-ADRENERGIC BLOCKING AGENTS

Both groups of drugs reduced overall mortality, and this effect was greater with vasodilating agents (RR, 0.55 [95% CI, 0.38-0.78] vs RR, 0.73 [95% CI, 0.64-0.83]; P=.007) (Table 3 and Table 4). The point estimate of the reduction in cardiovascular mortality was also greater with vasodilating agents (RR, 0.50 [95% CI, 0.22-1.17]) than with nonvasodilating agents (RR, 0.74 [95% CI, 0.64-0.86]), but the CIs were wide, and the difference was not statistically significant (P=.14). A similar nonsignificant trend was seen when the effect of vasodilating (RR, 0.33 [95% CI, 0.08-1.35]) and nonvasodilating agents (RR, 0.72 [95% CI, 0.51-1.01]) (P=.24) on mortality due to pump failure was considered. Both groups of drugs similarly reduced mortality due to sudden death (RR, 0.63 [95% CI, 0.35-1.12] vs RR, 0.76 [95% CI, 0.53-1.10]).

Before the publication of the CIBIS-II trial, a trend toward a greater protective effect of vasodilating agents on sudden death was seen (Table 5), but this disappeared when the CIBIS-II was included.

CAUSES OF HEART FAILURE

Information on the causes of heart failure was available from 15 trials.12,1416,1821,26,32,3437,39 Reduction in overall mortality with β-blockers was slightly greater in patients with IHD (RR, 0.70 [95% CI, 0.60-0.81]) (Table 6) than in those with non-IHD (RR, 0.74 [95% CI, 0.60-0.91]) (Table 7), but this difference was not statistically significant (P=.08). In patients with IHD, overall mortality was similarly reduced by vasodilating (RR, 0.61 [95% CI, 0.35-1.06]) and nonvasodilating agents (RR, 0.71 [95% CI, 0.60-0.83]) (Table 5). In patients with non-IHD, the decrease in overall mortality was greater with vasodilating (RR, 0.38 [95% CI, 0.18-0.83]) than with nonvasodilating β-blockers (RR, 0.78 [95% CI, 0.63-0.96]; P=.03) (Table 5).

HOSPITALIZATION

Four trials gave information on all-cause hospital admissions,21,26,34,36 and 9 gave information on hospitalization for heart failure.15,18,20,21,26,30,34,36,38 The β-blockers reduced the rate of all-cause hospital admissions by 15% (RR, 0.85 [95% CI, 0.77-0.92]), and the rate of hospital admissions for heart failure by 33% (RR, 0.67 [95% CI, 0.58-0.77]). Vasodilating (RR, 0.64 [95% CI, 0.43-0.94]) and nonvasodilating agents (RR, 0.67 [95% CI, 0.57-0.78]) similarly reduced hospitalization for heart failure (Table 5).

COMMENT

Previously published meta-analyses, which had each included from 3023 to 3141 patients, had already suggested a protective effect of β-blocking agents on mortality due to heart failure.2325 Our study, which includes 5849 patients, confirms previous estimates2325 of the benefit of β-adrenergic blocking agents on total, cardiovascular, and pump failure mortality in patients with heart failure. In addition, our results indicate that reduced cardiovascular mortality was the result of reduced mortality due to heart failure and sudden death, that the benefits in terms of mortality were of the same order in patients with IHD and non-IHD, and that vasodilating agents are more effective than nonvasodilating agents.

The results of several clinical trials had suggested that patients with heart failure resulting from IHD did not benefit from β-blockers. In contrast, in 1 meta-analysis,24 overall mortality was similarly reduced in patients with IHD and non-IHD heart failure. Our results show that the magnitude of the benefit of β-blockers in patients with IHD does not differ from that in patients with non-IHD.

Although β-adrenergic blocking agents are a relatively heterogeneous group of drugs, pharmacological differences rarely translate into therapeutic differences. However, in patients with heart failure, the vasodilating effect of certain β-blockers would compensate for the initial negative inotropic effect,57,58 and it has been suggested that this, rather than β-adrenergic blockade, would account for their beneficial effect in heart failure.59,60 In our analysis, vasodilating and nonvasodilating β-blockers reduced overall mortality, but this effect was greater with vasodilating agents, and mainly in patients with non-IHD cardiomyopathy. Our results suggest that the effect of vasodilating β-blockers could be greater on cardiovascular mortality and on mortality due to progressive pump failure. On the other hand, although a relative advantage of vasodilating β-blockers on sudden death had been suggested,24 adding the results of the CIBIS-II trial suggests that the latter do not significantly differ from nonvasodilating β-blockers in this respect.

A previously published meta-analysis25 had suggested a greater effect of nonselective agents on overall mortality compared with the selective agents. These results are in accord with ours, because, of 1600 patients treated with nonselective β-blocking agents and included in that meta-analysis, 1564 had received carvedilol or bucindolol, which are nonselective and vasodilating. The results of a recently early stopped trial with metoprolol, where a 34% reduction in mortality was seen,61 are also in accord with our results regarding selective nonvasodilating β-blockers.

We suggest that in patients with non-IHD, vasodilating β-blockers are more effective, and that the benefits of vasodilating and nonvasodilating β-blockers may be the result of different mechanisms. Although the exact mechanisms by which these drugs benefit patients with heart failure are unknown, it seems that the vasodilator component would be more important in reducing mortality due to heart failure, whereas the β-blocker component (or the antiarrhythmic effect) would mainly contribute to reducing sudden death.

In conclusion, β-blockers reduce total and cardiovascular mortality, as a result of a decrease in pump failure mortality and sudden death. Our results also show that the effect of β-blockers in patients with IHD is at least equal to that in patients with non-IHD. Compared with nonvasodilating agents, vasodilating β-blockers have a greater effect on overall mortality, particularly in patients with non-IHD. This may be attributable to a greater effect of vasodilating β-blockers on cardiac and pump failure mortality, rather than on sudden death.

Back to top
Article Information

Accepted for publication July 1, 1999.

This study was supported by grant 042996 from the Catalan Agency for Health Technology Assessment, Barcelona, Spain.

We deeply acknowledge additional information on the trials provided by Wilbert S. Aronow, MD; Eric J. Eichhorn, MD; John G. F. Cleland, MD; Jay N. Cohn, MD; Henry J. Dargie, MD; Leif Erhardt, MD; Marc A. Pfeffer, MD; Willem J. Remme, MD; and Karl Swedberg, MD.

Reprints: Joan-Ramon Laporte, MD, Fundació Institut Català de Farmacologia, Hospitals Vall d'Hebron, 08035, Barcelona, Spain (e-mail: jrl@icf.uab.es).

References
1.
Dargie  HJMcMurray  JJV Diagnosis and management of heart failure. BMJ. 1994;308321- 328Article
2.
McKee  PACastelli  WPMcNamara  PMKannel  WB The natural history of congestive heart failure: the Framingham Study. N Engl J Med. 1971;2851441- 1445Article
3.
Cowie  MRMosterd  AWood  DA  et al.  The epidemiology of heart failure. Eur Heart J. 1997;18208- 225Article
4.
The CONSENSUS Trial Study Group, Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;3161429- 1435Article
5.
The SOLVD Investigators, Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325293- 302Article
6.
The Digitalis Investigation Group, The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336525- 533Article
7.
Thomas  JAMarks  BH Plasma norepinephrine in congestive heart failure. Am J Cardiol. 1978;41233- 243Article
8.
Cohn  JNLevine  TBOlivari  MT  et al.  Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311819- 823Article
9.
Yates  JCBeamish  REDhalla  NS Ventricular dysfunction and necrosis produced by adrenochrome metabolite of epinephrine: relation to pathogenesis of catecholamine cardiomyopathy. Am Heart J. 1981;102210- 221Article
10.
Mann  DLKent  RLParsons  BCooper  IV Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992;85790- 804Article
11.
Packer  M Pathophysiology of chronic heart failure. Lancet. 1992;34088- 92Article
12.
Anderson  JLLutz  JRGilbert  EM  et al.  A randomized trial of low-dose β-blockade therapy for idiopathic dilated cardiomyopathy. Am J Cardiol. 1985;55471- 475Article
13.
Bristow  MRO'Connell  JBGilbert  EM  et al. Bucindolol Investigators, Dose-response of chronic β-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy. Circulation. 1994;891632- 1642Article
14.
Eichhorn  EJHeesch  CMBarnett  JH  et al.  Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1994;241310- 1320Article
15.
Engelmeier  RSO'Connell  JBWalsh  RRad  NScanlon  PJGunnar  RM Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation. 1985;72536- 546Article
16.
Fisher  MLGottlieb  SSPlotnik  GD  et al.  Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol. 1994;23943- 950Article
17.
Krum  HSackner-Bernstein  JDGoldsmith  RLKukin  MLSchwartz  BPenn  J Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995;921499- 1506Article
18.
Metra  MNardi  MRaccagni  DGiubbini  RDei  Cas L Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;241678- 1687Article
19.
Waagstein  FBristow  MRSwedberg  K  et al. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group, Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993;3421441- 1446Article
20.
CIBIS Investigators and Committees, A randomized trial of β-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;901765- 1773Article
21.
Australia/New Zealand Heart Failure Research Collaborative Group, Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997;349375- 380Article
22.
Packer  MBristow  MRCohn  JN  et al. US Carvedilol Heart Failure Study Group, The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;3341349- 1355Article
23.
Doughty  RNRodgers  ASharpe  NMacMahon  S Effects of beta-blocker therapy on mortality in patients with heart failure: a systematic overview of randomized controlled trials. Eur Heart J. 1997;18560- 565Article
24.
Heidenreich  PALee  TTMassie  BM Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol. 1997;3027- 34Article
25.
Lechat  PPacker  MChalon  SCucherat  MArab  TBoissel  JP Clinical effects of β-adrenergic blockade in chronic heart failure. Circulation. 1998;981184- 1191Article
26.
CIBIS-II Investigators and Committees, The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;3539- 13Article
27.
Breslow  NLDay  NE Statistical Methods in Cancer Research.  Lyon, France Inernational Agency for Research on Cancer1980;
28.
Petitii  DB Meta-analysis: Decision Analysis and Cost-effectiveness Analysis: Methods for Quantitative Synthesis in Medicine.  New York, NY Oxford University Press1994;
29.
Schlesselman  J Case-Control Studies: Design, Conduct, Analysis.  New York, NY Oxford University Press1982;
30.
Bristow  MRGilbert  EMAbraham  WT  et al. MOCHA Investigators, Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;942807- 2816Article
31.
Cohn  JNFowler  MBBristow  MA  et al.  Effect of carvedilol in severe chronic heart failure [abstract]. J Am Coll Cardiol. 1996;27(suppl A)169AArticle
32.
Olsen  SLGilbert  EMRenlund  DGTaylor  DOYanowitz  FDBristow  MR Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double blind randomized study. J Am Coll Cardiol. 1995;251225- 1231Article
33.
Packer  MColucci  WSSackner-Bernstein  JD  et al. PRECISE Study Group, Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE trial. Circulation. 1996;942793- 2799Article
34.
Paolisso  GGambardella  AMarrazzo  G  et al.  Metabolic and cardiovascular benefits deriving from β-adrenergic blockade in chronic congestive heart failure. Am Heart J. 1992;123103- 110Article
35.
Pollock  SGLystash  JTedesco  CCraddock  GSmucker  ML Usefulness of bucindolol in congestive heart failure. Am J Cardiol. 1990;66603- 607Article
36.
Sano  HKawabata  NYonezawa  KSakuma  IHirayama  HYasuda  H Metoprolol was more effective than captopril for dilated cardiomyopathy in Japanese patients [abstract]. Circulation. 1989;80(suppl 2)118
37.
Gilbert  EMAnderson  JLDeitchman  D  et al.  Long-term β-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med. 1990;88223- 229Article
38.
Colucci  WPacker  MBristow  MR  et al. US Carvedilol Heart Failure Study Group, Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996;942800- 2806Article
39.
Aronow  WSAhn  CKronzon  AI Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction >40% treated with diuretics plus angiotensin-converting–enzyme inhibitors. J Am Coll Cardiol. 1997;80207- 209Article
40.
Hall  JAFerro  ADickerson  JECBrown  MJ β-Adrenoceptor subtype cross regulation in the human heart. Br Heart J. 1993;69332- 337Article
41.
Ikram  HFitzpatrick  D Double blind trial of chronic oral β-blockade in congestive cardiomyopathy. Lancet. 1981;2490- 493Article
42.
Boutelant  SLechat  PKomajda  M  et al.  Evaluation non invasive des effets cardiovasculaires du nebivolol chez l'insuffisant cardiaque. Arch Mal Coeur. 1992;85863- 870
43.
Currie  PJKelly  MJMcKenzie  A  et al.  Oral beta-adrenergic blockade with metoprolol in chronic severe dilated cardiomyopathy. J Am Coll Cardiol. 1984;3203- 209Article
44.
Freudenberger  RSMannino  MMKalman  J  et al.  Does amlodipine provide benefit beyond beta blockade in heart failure? [abstract] Circulation. 1995;92(suppl 1)394
45.
Persson  HRythe'n-Alder  EMelcher  AErhardt  L Effects of β-receptor antagonists in patients with clinical evidence of heart failure after myocardial infarction: double blind comparison of metoprolol and xamoterol. Br Heart J. 1995;74140- 148Article
46.
Simarro  ERodríguez  MALastra  JA  et al.  Efecto del gallopamil y del propranolol en pacientes con cardiopatía isquémica y depresión moderada de la función ventricular. Rev Esp Cardiol. 1995;48741- 745
47.
Sanderson  JEChan  WWMHung  YT  et al.  Effect of low dose beta blockers on atrial and ventricular (B type) natriuretic factor in heart failure: a double blind, randomised comparison of metoprolol and a third generation vasodilating beta blocker. Br Heart J. 1995;74502- 507Article
48.
Yamada  SOhkura  TUchida  S  et al.  A sustained increase in beta-adrenoceptors during long-term therapy with metoprolol and bisoprolol in patients with heart failure from idiopathic dilated cardiomyopathy. Life Sci. 1996;581737- 1744Article
49.
Regitz  VLeuchs  BWellnhofer  EKrülls-Münch  JFleck  E Improvement in heart failure with long term ACE inhibitors and β-blockers therapy is comparable [abstract]. Circulation. 1992;86(suppl 1)119
50.
Chadda  KGoldstein  SByington  RCurb  JD Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation. 1986;73503- 510Article
51.
Leung  WHLau  CPWong  CKCheng  CHTai  YTLim  SP A double-blind crossover trial of labetalol in patients with idiopathic dilated cardiomyopathy [abstract]. Circulation. 1989;80(suppl II)118
52.
Yoshikawa  THanda  SAkaishi  MMitamura  HOgawa  S Beta1-selectivity is not essential to achieve therapeutic efficacy with beta-blockade therapy for idiopathic dilated cardiomyopathy. Cardiology. 1995;86217- 223Article
53.
The BEST Steering Committee, Design of the Beta-Blocker Evaluation Survival Trial (BEST). Am J Cardiol. 1995;751220- 1223Article
54.
Sachdev  VMoore  CKDas  SKStarling  MR Effects of beta-blocking therapy on left ventricular systolic function in heart failure [abstract]. Circulation. 1992;86(suppl I)119
55.
Wisenbaugh  TKatz  IDavis  J  et al.  Long term (3 month) effects of a new beta-blocker (nevibolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol. 1993;211094- 1100Article
56.
Sigmund  MJakob  HBecker  H  et al.  Effect of metoprolol on myocardial β-adrenoceptors and G1β-proteins in patients with congestive heart failure. Eur J Clin Pharmacol. 1996;51127- 132Article
57.
Cleland  JGSwedberg  K Carvedilol for heart failure, with care. Lancet. 1996;3471199- 1201Article
58.
Pfeffer  MAStevenson  LW β-Adrenergic blockers and survival in heart failure. N Engl J Med. 1996;3341396- 1397Article
59.
Krum  H β-Adrenoceptor blockers in chronic heart failure: a review. Br J Clin Pharmacol. 1997;44111- 118Article
60.
Kukin  MLKalman  JMannino  MFreudenberger  RBuchholz  COcampo  O Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta-blockade alone in chronic congestive heart failure. Am J Cardiol. 1996;77486- 491Article
61.
Not Available, Metoprolol ups survival in heart failure. Scrip. 1998;238827
×