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European Journal of Heart Failure 2001 3(3):351-357; doi:10.1016/S1388-9842(01)00144-1
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© 2001 European Society of Cardiology

Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure

Marcelo C. Shibataa,*, Marcus D. Flathera,b and Duolao Wangc

a Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Trust Sydney Street, SW3 6NP, London, UK
b Imperial College of Science Technology and Medicine London, UK
c London School of Hygiene and Tropical Medicine London, UK

* Corresponding author. Tel.: +44-20-7351 8827; fax: +44-20-7351 8829 E-mail address: m.shibata{at}rbh.nthames.nhs.uk (M.C. Shibata).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Heart failure is a common condition that carries a high burden of mortality and morbidity. Several randomised trials have evaluated the effects of beta blockers in heart failure. This paper gives a systematic overview of published randomised trials of beta blockers in heart failure using standard methods. In all, 22 randomised controlled trials were identified with a total of 10480 patients, and an average of 11 months of treatment. The average age was 61 years and 4% were female. Most studies excluded patients with severe heart failure. Death rates in patients randomised to receive beta blockers compared to controls were 458/5657 (8.0%) and 635/4951 (12.8%) respectively, odds ratio 0.63, 95% CI 0.55–0.72, P < 0.00001. Similar reductions were observed for hospital admissions for worsening heart failure (11.3 vs. 17.1%, respectively, odds ratio 0.63) and for the composite outcome of death or heart-failure hospital admission (19.4 vs. 26.9%, respectively, odds ratio 0.66). These results show that beta blockers reduce the risk of mortality or the need for heart-failure hospital admission by approximately one third. Absolute reductions of 5–6% in event rates were observed over approximately 1 year of treatment period. These important benefits should be implemented as a priority, since treatment with beta blockers is inexpensive and heart failure carries a high risk of death and disability. Further information on the effect of beta blockers in elderly patients and women would be helpful.

Key Words: Beta blocker • Heart failure • Meta-analysis • Randomised controlled trial • Systematic review

Received August 4, 2000; Revised February 2, 2001; Accepted February 12, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Heart failure (HF) is associated with high rates of mortality and morbidity and is a growing public health problem. It is estimated that 2–3% of the population in developed countries have heart failure and the majority of these are people >65 years [1,2]. Heart failure is also associated with high rates of hospital admission. In the UK, it is estimated that there are approximately 120 000 hospital admissions per year, and approximately six times this number in the whole of Europe [3]. As a consequence, the management of HF accounts for between 1 and 2% of the healthcare budgets in Western Europe and the United States [4,5].

Established treatments for HF include ACE inhibitors and diuretics. The use of beta blockers in HF has been demonstrated to prevent deterioration of myocardial function, reverse the remodelling process, improve beta adrenergic response and reverse adverse effects of neurohormonal activation [6–8]. Systematic reviews of the randomised trials of beta blockers in heart failure have shown a beneficial effects on mortality and hospital admissions, but this evidence did not lead to a widespread use of these agents [9–13]. Two large clinical trials, ‘Cardiac Insufficiency Bisoprolol Study’ (CIBIS-II) and ‘Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure’ (MERIT-HF), have been published subsequent to these systematic reviews [14–16]. We have included CIBIS-II and MERIT-HF in an updated systematic review to provide more reliable estimates of the effects of beta blockers on mortality and hospital admissions in patients with HF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Data identification
There have been five previously published meta-analyses of beta blockers in heart failure that have broadly included the same trials [9–13]. To identify any more recent trials, we used a computerised bibliographic search of the Medline database (National Library of Medicine, Bethesda, Maryland) from January 1998 to January 2000, using the key words ‘beta blocker’, ‘clinical trials’ and ‘congestive heart failure’. We also hand-searched abstract reports from the main cardiology and heart failure meetings for the period 1996–2000. We included trials that fulfilled the following criteria: oral beta blocker compared to inactive control, randomised allocation and parallel group design. The primary outcome of interest was mortality, but we have also included information about hospitalisation where available. This systematic review was restricted to data published in manuscript or abstract form. We also checked that the previous meta-analyses had covered all randomised trials published from 1975 up to 1997 by repeating the search from January 1970 to December 1999. Trials were excluded if they had a cross-over design or if mortality data were not available.

2.2. Statistical analysis
The estimated treatment effect, as the odds ratio of event between active treatment to placebo, was calculated for the meta-analysis. We excluded trials that had no events reported in either treatment group.

We calculated pooled odds ratios with both the Mantel–Haenszel fixed effects model [17] and the DerSimonian and Laird random effects model [18]. In addition to incorporating variability within studies, the random effects model also incorporates the variance of treatment effect among studies, which gives the magnitude of heterogeneity of treatment effect. Special attention was paid to test the homogeneity among different trials when performing the meta-analysis. If the homogeneity test is statistically significant, it suggests that the pooled effect does not represent all trials included equally well, and the sources of heterogeneity should therefore be appropriately investigated and possibly controlled to avoid potential bias [19]. However, when heterogeneity does not exist, the fixed effects model may be more appropriate [18]. The test for heterogeneity is carried out by calculating a {chi}2 statistic. As this statistic is not very sensitive, we considered the presence of significant heterogeneity at the 10% level of significance as evidence that the random effects model would be more appropriate than the fixed effects model. The results (shown later) demonstrate that there is no statistically significant heterogeneity among the trials included for our three meta-analyses; therefore, we only report the results from the fixed effects model.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
We identified 22 eligible studies [14,15,20–39] (Table 1). Two large, randomised clinical trials were published in 1999 [14,15]. A total of 10480 patients were randomised, 5507 to active treatment and 4973 to control. We excluded eight trials from the analysis because no deaths were recorded in any of them [22–26,30,31,33].


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  		Table 1 Overview of randomised, double blind, placebo-controlled clinical trials of beta blockade in heart failure patients

 
3.1. Patient characteristics
After pooling information from all trials, the average age and ejection fraction were 61.6 years and 26%, respectively. Approximately 4% of the patients were female. The aetiologies of heart failure in these patients were: coronary artery disease (52%); non-ischaemic dilated cardiomyopathy (33%); idiopathic dilated cardiomyopathy (14%); and hypertrophic cardiomyopathy (0.3%). The proportion of patients who presented with NYHA functional class I, II, III and IV were 1.4, 28.3, 63.3 and 7.2%, respectively. Diuretics, ACE inhibitors, digitalis, and vasodilators were prescribed to 91, 91, 62, and 26% of the patients, respectively. Average follow-up across the studies was approximately 11 months, and average compliance to treatment at the end of follow-up was 85%.

3.2. Trial treatment
Of the 22 trials, two used bisoprolol, three bucindolol, eight carvedilol, seven metoprolol and two nebivolol in a double-blind, randomised fashion and in a wide range of doses. The proportion of all patients treated with the aforementioned beta blockers were 31, 2, 23, 42 and 0.3%, respectively.

3.3. Effect of beta blockade on all-cause mortality
The total number of deaths in all 14 trials [14,15,20,21,27–29,32,34–39] was 1065. The CIBIS-II and MERIT-HF studies accounted for 746 deaths (70% of all deaths). Deaths/number of patients randomised to beta blockers compared to control were 440/5378 (8.2%) and 622/4642 (13.3%), respectively, odds ratio 0.65, 95% CI 0.57–0.74, P<0.0001(Fig. 1a). The test for heterogeneity among the 14 trials was not significant: variance among studies=0; test for heterogeneity, {chi}2(13)=8.44, P=0.81.


Figure 1
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  		Fig. 1 The figure shows odds ratios and 95% confidence limits for randomised trials of beta blockers compared to control on: (a) mortality; (b) hospital admission; and (c) the composite of mortality or hospital admission. The squares or small vertical lines represent the point estimates for each trial and the horizontal lines the 95% confidence intervals. Arrows indicate that the 95% confidence intervals lie outside the horizontal scale. The size of the square is approximately proportional to the statistical weight of the trial in the meta-analysis. Trials represented by a small vertical line have the lowest statistical weight. Diamonds represent the pooled estimate and 95% confidence intervals. Heterogeneity-test P values for mortality, hospital admissions and the composite of mortality or hospital admission were 0.81, 0.95 and 0.73, respectively.

 
3.4. Effect of beta blockade on hospitalisation
A total of 1447 hospitalisations due to worsening heart failure were obtained from 13 trials [14,15,21,24,27–29,32,34–36,38,39]. CIBIS II and MERIT-HF contributed with 391 and 494 events respectively, (together representing 61% of the hospitalisations). Hospitalisations occurred in 613/5301 (11.5%) and 833/4827 (17.2%) in active and placebo groups, respectively, OR 0.63, 95% CI 0.56–0.71, P<0.0001, (Fig. 1b). Of the trials, 13 did not show heterogeneity in terms of odds ratio for hospitalisation [variance among studies=0; test for heterogeneity, {chi}2(12)=5.00, P=0.95].

The combined endpoint of all-cause mortality or hospital admission for heart failure was available from nine trials [14,15,27,29,33,34,36,38,39]. Events/patients randomised in treated and control groups were 1071/5035 (21.2%) and 1327/4610 (28.7%), respectively, OR 0.68, 95% CI 0.61–0.75, P<0.0001 (Fig. 1c). There is no significant heterogeneity among these nine trials in odds ratio at the level of 10% [variance among studies=0; test for heterogeneity, {chi}2(8)=5.22, P=0.73].


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
Our analysis shows a clear relative risk reduction in mortality among patients randomised to beta blocker compared to control of approximately 35%. The absolute difference in mortality rates was 5.1%, indicating that treatment of 20 patients for approximately 12 months would avoid one death. The absolute difference in hospital admissions for heart failure was 5.7%, indicating that approximately 16 patients should be treated over approximately 1 year to avoid one admission.

Together, MERIT-HF and CIBIS II provide data on approximately 65% of the total patients randomised in the 14 trials. In MERIT-HF, as well as in CIBIS II, the risk reduction was approximately one third, and absolute risk reductions were 3.9 and 5.5%, respectively. MERIT-HF and CIBIS II have provided substantial extra information to strengthen and extend the findings of the previous meta-analyses.

The ‘Bucindolol Evaluation Survival Trial’ (BEST) (presented at the American Heart Association meeting, Atlanta 1999) evaluated the effects of bucindolol in 2708 patients with heart failure NYHA class III or IV (ejection fraction ≤35%) [40]. The trial stopped early after a mean follow-up of 24 months with 33% deaths in the placebo group compared to 30% deaths in the bucindolol group. There was no apparent beneficial effect of bucindolol on mortality. The ‘Carvedilol Prospective Randomized Cumulative Survival Trial’ (COPERNICUS) study evaluated the effects of carvedilol in 2289 patients with heart failure and a mean ejection fraction of 29%. The trial (presented at the European Society of Cardiology meeting, Amsterdam, August 2000) was stopped early due to a reduction in the risk of death of 35% in patients randomised to carvedilol compared to placebo (130 deaths among 1156 patients randomised to carvedilol and 190 deaths among 1133 in placebo, OR 65, 95% CI 0.52–0.81, P=0.00014). If these results are incorporated into the systematic review, the odds ratio for the effect of beta blockers on mortality would be 0.71, 95% CI 0.64–0.78, P<0.0001. Thus, the inclusion of these recent trials results only has a modest impact on the magnitude of the treatment effect observed in the systematic overview of the published trials.

In 1995, $3 400 000 000 billion ($5153 per discharge) was paid to Medicare beneficiaries in the United States for congestive heart failure, which is the single most frequent cause of hospitalisation for people age 65 and older [41]. The demonstration of a reduction in hospital admissions for patients with heart failure, using a simple intervention such as beta blocker administration, is likely to have an important impact in quality of life and health economics, since heart failure accounts for a large proportion of hospital admissions due to cardiovascular disease.

Five previous meta-analyses published between 1996 and 2000 were identified [9–13]. These reports did not incorporate the results from MERIT-HF and CIBIS II. Aggregate proportional reductions in mortality observed in the previous meta-analyses were 31, 31, 28, 31 and 29%, respectively. These reductions are entirely consistent with the results of CIBIS-II and MERIT-HF. This consistency supports the reliability of the reductions in the risk of mortality and hospital admissions of approximately one third observed in our analysis. Risk reductions observed with beta blockers in heart failure are among the largest therapeutic benefits observed in important clinical outcomes.

Limitations of the current study include those common to any systematic review, such as publication bias, missing data, retrospective analyses, heterogeneity between studies, and inaccurate estimation of risk. The other important limitation is the use of tabular data (i.e. data obtained from published reports). This approach does not allow analysis of effects of beta blockers in important clinical subgroups, such as the elderly, or those with more advanced heart failure.

A recent systematic overview of individual patient data from more than 12 000 patients of the effect of ACE-inhibitors in patients with left ventricular dysfunction and heart failure showed an absolute reduction of 3.8% on death or hospital admissions in those randomised to ACE-inhibitors [42]. The effect of beta blockers on mortality in heart failure patients is comparable and is additional to the effect of ACE-inhibitors.

Further randomised trials of beta blockers in heart failure are being carried out, including ‘Carvedilol or Metoprolol European Trial’ (COMET), ‘Carvedilol Post-Infarct Survival Control in LV Dysfunction’ (CAPRICORN) [43] and ‘Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisations in Seniors with Heart Failure’ (SENIORS). The results of these studies will enhance our knowledge of the effect of beta blockers in different types of patients with heart failure.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The effects of beta blockers in reducing mortality and the need for hospital admission due to HF in a broad range of patients are dramatic. These important benefits should be implemented as a priority, since beta blocker treatment is inexpensive and HF carries a high risk of death and disability. Further information on the effect of beta blockers in elderly patients and women would be helpful.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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D. S. Lee, J. V. Tu, D. N. Juurlink, D. A. Alter, D. T. Ko, P. C. Austin, A. Chong, T. A. Stukel, D. Levy, and A. Laupacis
Risk-Treatment Mismatch in the Pharmacotherapy of Heart Failure
JAMA, September 14, 2005; 294(10): 1240 - 1247.
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M. D. Flather, M. C. Shibata, A. J.S. Coats, D. J. Van Veldhuisen, A. Parkhomenko, J. Borbola, A. Cohen-Solal, D. Dumitrascu, R. Ferrari, P. Lechat, et al.
Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)
Eur. Heart J., February 1, 2005; 26(3): 215 - 225.
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P. Roman-Sanchez, P. Conthe, J. Garcia-Alegria, J. Forteza-Rey, M. Montero, C. Montoto, and for the Heart Failure Working Group of the Spanish
Factors influencing medical treatment of heart failure patients in Spanish internal medicine departments: a national survey
QJM, February 1, 2005; 98(2): 127 - 138.
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D. Johnson, Y. Jin, H. Quan, and B. Cujec
Beta-blockers and angiotensin-converting enzyme inhibitors/receptor blockers prescriptions after hospital discharge for heart failure are associated with decreased mortality in Alberta, Canada
J. Am. Coll. Cardiol., October 15, 2003; 42(8): 1438 - 1445.
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D. D. Sin, S. F. P. Man, J. V. Tu, N. B. Pride, J. Vestbo, J. B. Soriano, and V. A. Kiri
Inhaled glucocorticoids in COPD: Immortal time bias
Am. J. Respir. Crit. Care Med., July 1, 2003; 168(1): 126 - 127.
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PROGRESS Collaborative Group
Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease
Eur. Heart J., March 1, 2003; 24(5): 475 - 484.
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J. Soler-Soler and D. Garcia-Dorado
How to best to counteract the enemies? By blocking neurohormonal activation
Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G45 - G50.
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C. Metcalfe
Comment on "Hospital admission following a diagnosis of heart failure: is time to first admission telling us what we want to know?"
Eur J Heart Fail, January 1, 2002; 4(1): 117 - 118.
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