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European Journal of Heart Failure 2003 5(3):281-289; doi:10.1016/S1388-9842(03)00042-4
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© 2003 European Society of Cardiology

Beta-blocker benefit according to severity of heart failure

Anissa Bouzamondo*, Jean-Sébastien Hulot, Paola Sanchez and Philippe Lechat

Pharmacology Department, Pitié – Salpêtrière Hospital 47 Boulevard de l'Hôpital, 75013 Paris, France

* Corresponding author. Tel.: '33-1-42-16-16-73; fax: +33-1-42-16-16-88. E-mail address: anissa.bouzamondo{at}psl.ap-hop-paris.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background and aims: Beta-blockers are an established treatment for chronic heart failure. However, the relationship between their benefit and the severity of the disease remains to be determined.

Methods and results: We studied the relationship between amplitude of benefit of beta-blockers and severity of chronic heart failure, based on data for mortality and hospitalizations for worsening heart failure, using a meta-analysis of randomized controlled trials, complementary subgroup analyses and analysis of individual data from the CIBIS II trial. In the meta-analysis, mortality was reduced by 22% (95%CI: 16 to 28) and hospitalizations for worsening heart failure by 24% (95%CI: 20 to 29). Benefit was similar with metoprolol, bisoprolol and carvedilol. After exclusion of bucindolol trials, due to the heterogeneity of results for mortality, the reduction in mortality was similar according to the severity of heart failure, assessed either by left ventricular ejection fraction or by New York Heart Association classification. In CIBIS II, beta-blockers induced a significant reduction in mortality of 45% (95%CI: 9 to 66), 41% (95%CI: 17 to 59) and 23% (95%CI: 1 to 40) in the low, intermediate and high risk groups, respectively. Hospitalizations were reduced by 35% (95%CI: 2 to 57), 41% (95%CI: 18 to 58) and 23% (95%CI: 0 to 41), there was no significant difference between the three score groups.

Conclusion: We conclude that the amplitude of benefit of the beta-blockers carvedilol, metoprolol and bisoprolol on mortality and morbidity is similar, regardless of the severity of chronic heart failure.

Key Words: Heart failure • Meta-analysis • Prognosis • Mortality

Received June 11, 2002; Revised October 28, 2002; Accepted February 17, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Beta-blocker treatment has become an established therapy for heart failure in combination with diuretics and angiotensin converting enzyme inhibitors. It provides a marked reduction in mortality and morbidity, as demonstrated in large scale clinical trials such as CIBIS II [1] with bisoprolol, MERIT-HF [2] with metoprolol and COPERNICUS [3] with carvedilol, with a similar risk reduction of 34% for all cause death in all three trials. Whether the amplitude of benefit depends on patient characteristics including the severity of the disease or on the different properties of the tested compounds is still unclear, especially in view of the absence of significant benefit on mortality observed with bucindolol in the BEST study [4].

We therefore studied the determinants of amplitude of benefit of beta-blockers in chronic heart failure, by analysis of sources of heterogeneity of effects, using a meta-analysis of randomized clinical trials (overall data and subgroups) and by analysis of individual data from CIBIS II.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Analysis of overall effect: meta-analysis of randomized controlled trials
Previous meta-analyses of the placebo-controlled clinical trials of beta-blockers in heart failure have provided results of their benefit in heart failure [5–9]. In order to evaluate the amplitude and heterogeneity of the beta-blocker effect in heart failure, we performed a meta-analysis of all trials including those recently published. We used a computerized bibliographic search of the Medline database. Trials that fulfilled the following criteria were included: (a) randomized and controlled trials testing oral beta-blocker treatment compared to placebo, (b) parallel group design, (c) trials providing data on all cause mortality and hospitalization for worsening heart failure (d) presenting at least one death in each treatment group since relative risk (RR) cannot accurately be estimated in the absence of an event in one group. We therefore included 16 studies testing metoprolol, bisoprolol, carvedilol and bucindolol. The outcomes of interest were all cause mortality and hospitalizations for worsening heart failure.

We used published data and also some complementary data provided by investigators from MERIT, BEST and COPERNICUS especially for subgroups with left ventricular ejection fraction (LVEF) <or ≥ to 25% and according to New York Heart Association (NYHA) class at baseline.

We used the RR as a parameter of efficacy and a fixed effect model (as opposed to the random effect model) in order to specifically detect heterogeneity of treatment effect. The pooled estimate of the overall RR was calculated using the inversed variance weighted RR for each study. As usually performed in meta-analysis, a {chi}2-test for association on the pooled estimate of overall RR was performed. P value for significance was set at 0.05.

The statistical analysis for the meta-analysis was performed using EASYMA software.

2.2. Analysis of heterogeneity (variability) of beta-blocker effect
This analysis was performed in three steps.

2.2.1. Heterogeneity between trials
Heterogeneity between trials was first studied during the meta-analysis of the randomized controlled trials, using the standard {chi}2 test of heterogeneity. The p value for heterogeneity was set at 0.05.

2.2.2. Heterogeneity according to pharmacological profile of beta-blocker
Variability of the beta-blocker effect was further studied by comparing subgroups of trials, according to the type of compound and to the beta-1 selectivity of the beta-blockers.

Heterogeneity of RR among subgroups was tested using the Mantel-Haentzel test.

2.2.3. Heterogeneity according to the severity of heart failure
This analysis was only possible for data devoid of heterogeneity according to the type of beta-blocker used.

This analysis was performed with two different levels of information as described below.

(1) The first approach used subgroup analysis of the large scale trials of the meta-analysis using some determinants of the severity of heart failure such as NYHA classification and LVEF. Since heterogeneity of benefit on mortality was disclosed and related to the BEST study, only data from CIBIS I [10], CIBIS II [1], MERIT [2] and COPERNICUS [3] could be used for this analysis.

(2) The second approach used individual data from CIBIS II. Multivariate analysis of CIBIS II using the Cox model provided the variables that were significantly related with all cause mortality. Each variable was weighted by its beta coefficient obtained in the Cox multivariate analysis. A score could then be calculated for each patient from the sum of each of the weighted variables. Patients could then be divided in three tertiles of score. We then could compare the RRs between the different levels of score using a test of heterogeneity of RR (Mantel-Haentzel).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Analysis of efficacy
3.1.1. Mortality (Fig. 1)


Figure 1
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  		Fig. 1 Meta-analysis of placebo controlled trials of beta-blockers in heart failure: treatment effect on mortality. Heterogeneity between trials was significant (P=0.035). Trials are ordered with increasing RR (beta-blockers/placebo).

 
A total of 14 857 patients with chronic heart failure were included from 16 selected trials (Table 1). Beta-blocker treatment reduced all cause mortality by 22% (95%CI: 16 to 28), (P<0.001).


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  		Table 1 Mortality and hospitalizations for heart failure worsening

 
One thousand two hundred and fifty seven (17.4%) patients died in the placebo groups, and 978 (12.8%) in the beta-blocker groups.

In a complementary analysis by mode of death (data available from 10 trials), sudden death and heart failure worsening related death were similarly reduced by beta-blockers: RR =0.76 (95%CI: 67 to 87), P<0.001 and 0.74 (95%CI: 62 to 88), P<0.001, respectively.

3.1.2. Hospitalizations for worsening heart failure (Fig. 2)


Figure 2
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  		Fig. 2 Meta-analysis of placebo controlled trials of beta-blockers in heart failure: treatment effect on hospitalizations for worsening heart failure. No heterogeneity between trials (P=0.16) was found. Trials are ordered with increasing RR (beta-blockers/placebo).

 
Such hospitalizations were significantly reduced in the beta-blocker groups by 24% (95%CI: 20 to 29).

One thousand seven hundred and forty two (24.2%) patients were hospitalized in the placebo groups and 1326 (17.4%) in the beta-blocker groups.

3.2. Analysis of heterogeneity
3.2.1. Heterogeneity between trials
Heterogeneity between trials was significant for mortality (P=0.035) but not for hospitalizations (P=0.13). Such heterogeneity for mortality was suppressed when results of BEST were excluded from the meta-analysis.

Because of this heterogeneity, subgroup analysis comparing selective and non-selective compounds excluded the bucindolol data.

3.2.2. Heterogeneity according to the pharmacological profile of the drugs
3.2.2.1. Mortality
In this analysis, mortality was reduced by 31% (95%CI: 17 to 42) with metoprolol, 29%, (95%CI: 17 to 40) with bisoprolol, and 37% (95%CI: 24 to 47) with carvedilol.

All cause mortality was reduced by 30% (95%CI: 21 to 38) with selective compounds (metoprolol and bisoprolol), and by 37% (95%CI: 24 to 47) with carvedilol.

3.2.2.2. Hospitalizations for heart failure worsening
Hospitalizations were reduced by 28% (95%CI: 19 to 36) with metoprolol, 32% (95%CI: 21 to 42) with bisoprolol and 29% (95%CI: 18 to 39) with carvedilol, without heterogeneity between subgroups of treatment.

Hospitalizations were reduced by 30% (95%CI: 23 to 36) and 29% (95%CI: 18 to 39) with the selective compounds (metoprolol and bisoprolol) and carvedilol, respectively.

3.2.3. Heterogeneity according to the severity of heart failure
Since heterogeneity of benefit on mortality was disclosed and related to the BEST study, only data from CIBIS I, CIBIS II, MERIT and COPERNICUS could be used for this analysis.

3.2.3.1. According to NYHA classification
From CIBIS I and II, MERIT and COPERNICUS data, 5020 patients in NYHA class III and 2911 in NYHA class IV could be included.

Six hundred and twenty seven patients died in NYHA class III: 255 in beta-blocker groups (10%) and 372 in placebo groups (14%). Beta-blockers reduced mortality by 32% in class III patients (95%CI: 21 to 41).

Available data for patients in NYHA class IV showed 456 deaths: 185 deaths (12.6%) in beta-blocker groups vs. 271 (18.6%) in placebo groups. Mortality was reduced by 32% in NYHA class IV patients (95%CI: 19 to 43%).

These numbers were obtained from the incidence of death provided in each trial. However mean annual mortality rates in the placebo groups were higher in class IV (24.1%) compared to class III (15.9%).

No significant heterogeneity of beta-blocker effect was observed between class III and IV subgroups (P=0.98).

Available data from NYHA II patients included in the MERIT study suggests a similar amplitude of mortality reduction (RR =0.76 (0.52 to 1.10)), this was, however, non-significant because it was under powered.

3.2.3.2. According to LVEF
From available subgroups (CIBIS I, CIBIS II, MERIT and COPERNICUS patients), 4501 patients with LVEF <25% and 5062 with LVEF ≥25% were included. Seven hundred and fifty nine patients with LVEF <25% died, 311 in beta-blocker groups (14%) and 448 in placebo groups (19.7%). In this subgroup, beta-blockers significantly reduced mortality by 29% (CI: 19 to 38), P<0.001.

For patients with LVEF ≥25%, 426 patients died, 172 in beta-blocker groups (6.7%), and 254 in placebo groups (10%). Mortality was significantly reduced by 34% (95%CI: 20 to 45%) with beta-blockers (P<0.001).

Heterogeneity between subgroups was not significant (P=0.57).

3.2.3.3. Analysis of individual data in CIBIS II patients (Figs. 3 and 4)


Figure 3
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  		Fig. 3 Subgroup analysis of CIBIS II patients: treatment effect on mortality in low, intermediate and high risk patients.

 


Figure 4
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  		Fig. 4 Survival curves for each treatment group (bisoprolol and placebo) for low, intermediate and high risk score groups in CIBIS II patients.

 
The multivariate Cox model analysis selected six demographic and clinical baseline variables as independent prognosis factors in CIBIS II (Table 2). An overall prognostic score could then be derived for each patient from these variables. Scores ranged between –1.29 (low risk patients) and +2.95 (high risk patients). Patients could then be divided into three tertile groups of increasing severity according to this prognosis score: n=880 in each score group. In the low risk subgroup, 5% of patients died in the beta-blocker group, vs. 9% in the placebo group. In the intermediate risk subgroup, 10 and 17% of patients died in the beta-blocker and placebo groups, respectively. In the high-risk subgroup, 19 and 25% of patients died in the beta-blocker and placebo groups, respectively. Mortality was significantly reduced by 45% (95%CI: 9 to 66), 41% (95%CI: 17 to 59) and 23% (95%CI: 1 to 40) from low to high risk groups, respectively. No significant heterogeneity of RR was observed between these three groups (P=0.32).


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  		Table 2 Survival analysis for prognosis factors (Cox's model)

 
Hospitalization for worsening heart failure occurred in 8 and 12% of patients in the bisoprolol and placebo groups, respectively, in the low risk subgroup, 11 and 18.7% in intermediate risk and 17 and 22% in high risk patients. Hospitalizations were significantly reduced with bisoprolol by 35% (95%CI: 2 to 57), 41% (95%CI: 18 to 58) and 23% (95%CI: 0 to 41) from low to high risk subgroups, without significant heterogeneity between the three subgroups (P=0.44).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The major finding of our study is that the benefit with metoprolol, bisoprolol and carvedilol appears similar, regardless of the severity of heart failure evaluated in terms of either NYHA class, LVEF or global severity score. In addition, reduction of mortality was similar for both sudden death and death related to worsening heart failure.

NYHA classification has several limitations since it is a rather basic classification, is a subjective assessment and fluctuates with time for a given patient. However, NYHA classification is one of the most potent predictors of prognosis in heart failure [11] and is commonly used for characterization of functional status at inclusion in clinical trials. In COPERNICUS, the inclusion criteria was not strictly NYHA class IV but ‘severe stable heart failure’. This could explain why the observed annual mortality rate (19.7%) was lower than normally expected for NYHA class IV patients (28–30%), as in the CONSENSUS trial [12]. In our NYHA subgroup analysis we included COPERNICUS patients in the NYHA class IV group as we believe this was the most appropriate way to classify these patients. Results of the meta-analysis were very similar if we either excluded COPERNICUS patients from the meta-analysis or if such patients were classified as NYHA class III.

Such results cannot yet be extrapolated to the potential benefit of beta-blocker treatment initiation in patients with higher levels of severity than those observed in these trials. Indeed, the benefit of beta-blocker initiation in very severe, end stage, class IV patients remains unknown. Subgroup analysis of the COPERNICUS trial, according to the investigators, suggests however that the amplitude of benefit is similar in the highest risk group of included patients.

The question of extrapolation of benefit of beta-blockers when initiated in more severe patients has now very limited interest, since beta-blocker treatment has to be initiated in the early stages of heart failure.

The interpretation of the results obtained with bucindolol is not straight-forward. Indeed the results induce in the meta-analysis an overall heterogeneity of beta-blocker treatment effect on mortality, but not on hospitalization.

At least three explanations maybe provided. Either the results of BEST are due to bad luck and fluctuations of effect from trial to trial, or they are the result of a specific property of bucindolol related to its pharmacological profile or they are due to a difference related to the patients included in the study.

In favor of the second hypothesis, some specific pharmacological properties of bucindolol could be responsible for the differences observed in the BEST trial. From several previous studies, bucindolol clearly showed its ability to reduce heart rate, improve left ventricular function [13], reduce myocardial oxygen consumption and decrease sympathetic activity [14], all properties that should a priori be beneficial in heart failure and have been advocated to explain the beta-blocker induced benefit in heart failure. However, the partial agonist properties of bucindolol could explain the reduced benefit in heart failure as previously observed with xamoterol [15]. Such partial agonist activity of bucindolol has been found in some animal models [16,17] and in preparations of human heart [18,19]. In addition a recent publication [20] confirmed that bucindolol exhibits approximately 60% of the beta-adrenergic agonist activity of xamoterol in normal human myocardium.

The decrease in sympathetic activity by bucindolol has also been used to explain the different result of BEST by Bristow et al. [21].

The precise mechanism by which a reduction in sympathetic tone (in addition to beta-blockade) could induce deleterious consequences in patients with heart failure remains to be established. Patients in NYHA class IV, in whom no benefit from bucindolol is observed [4], appear to require a minimum level of sympathetic drive especially to maintain blood pressure, myocardial perfusion and contractile state. However, carvedilol but not metoprolol, has been shown to decrease cardiac norepinephrine spill-over [22] yet a similar benefit is observed with these two compounds.

Could some other patient differences explain the results of BEST, namely the heterogeneity of bucindolol benefit according to the white, non-white subgroups. Indeed differences in the renin angiotensin system [23,24] and the sympathetic system [25] have previously been described in the black population. This may contribute to a reduced beta-blocker efficacy in heart failure in the black population.

In conclusion, no clear explanation can be found to explain the lesser benefit on mortality observed in the BEST trial with bucindolol.

In contrast, no heterogeneity of beta-blocker benefit according to the observed severity of heart failure can be detected from data from large scale trials performed with metoprolol, bisoprolol or carvedilol.


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

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