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(Circulation. 1998;98:1184-1191.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Clinical Effects of ß-Adrenergic Blockade in Chronic Heart Failure

A Meta-Analysis of Double-Blind, Placebo-Controlled, Randomized Trials

Philippe Lechat, MD, PhD; Milton Packer, MD; Stephan Chalon, MD; Michel Cucherat, MD; Tarek Arab, MD; ; Jean-Pierre Boissel, MD, PhD

From the Service de Pharmacologie, Hôpital Pitié-Salpêtrière, Paris, France; the Division of Circulatory Physiology, Columbia University, College of Physicians and Surgeons, New York, NY; and the Unité de Pharmacologie Clinique, Hôpitaux de Lyon, Lyon, France.

	Abstract

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Background—ß-Blockers have improved symptoms and reduced the risk of cardiovascular events in studies of patients with heart failure, but it is unclear which end points are most sensitive to the therapeutic effects of these drugs.

Methods and Results—We combined the results of all 18 published double-blind, placebo-controlled, parallel-group trials of ß-blockers in heart failure. From this combined database of 3023 patients, we evaluated the strength of evidence supporting an effect of treatment on left ventricular ejection fraction, NYHA functional class, hospitalizations for heart failure, and death. ß-Blockers exerted their most persuasive effects on ejection fraction and on the combined risk of death and hospitalization for heart failure. ß-Blockade increased the ejection fraction by 29% (P<10^-9) and reduced the combined risk of death or hospitalization for heart failure by 37% (P<0.001). Both effects remained significant even if >90% of the trials were eliminated from the analysis or if a large number of trials with a neutral result were added to the analysis. In contrast, the effect of ß-blockade on NYHA functional class was of borderline significance (P=0.04) and disappeared with the addition or removal of only 1 moderate-size study. Although ß-blockade reduced all-cause mortality by 32% (P=0.003), this effect was only moderately robust and varied according to the type of ß-blocker tested, ie, the reduction of mortality risk was greater for nonselective ß-blockers than for ß₁-selective agents (49% versus 18%, P=0.049). However, selective and nonselective ß-blockers did not differ in their effects on other measures of clinical efficacy.

Conclusions—These analyses indicate that there is persuasive evidence supporting a favorable effect of ß-blockade on ejection fraction and the combined risk of death and hospitalization for heart failure. In contrast, the effect of these drugs on other end points requires additional study.

Key Words: heart failure • meta-analysis • receptors, adrenergic, ß • trials

	Introduction

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In recent years, there has been considerable interest in the use of ß-adrenergic blocking agents for the treatment of heart failure, because such agents may prevent the adverse effects of sympathetic stimulation on the failing heart.¹ ß-Blockade has produced favorable results in a large number of randomized, controlled trials.^{2 3} However, these studies varied considerably in size and duration, enrolled patients at different stages of the diseases, were designed with different objectives, and evaluated ß-blockers that differed in their selectivity for adrenergic receptors and their effects on the peripheral circulation.

We performed a meta-analysis of all available placebo-controlled, parallel-group trials with ß-blockers in heart failure to evaluate the overall results with this therapeutic approach. Two meta-analyses of the effects of ß-blockers in heart failure have been published,^{2 3} but these focused only on mortality and relied on published data from clinical trials, including some that were not double-blind or placebo-controlled. In contrast, in the present analysis, we obtained most of the data from original sources and examined the effect of ß-blockers on a range of clinically meaningful end points, including measures not reported in the original publications.

	Methods

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We performed an extensive MEDLINE search of all controlled trials with ß-blockers in heart failure. Additional information was obtained from references included in previously published articles, from a search of abstracts of international meetings, and from communications with colleagues, investigators, and sponsors in the pharmaceutical industry.

Selection of Studies
We included all double-blind, randomized, placebo-controlled, parallel-group trials of ß-blockers in patients with chronic heart failure. Trials were excluded if they focused on patients with a recent myocardial infarction, and trials with xamoterol were not considered because this compound has considerable agonist activity. All qualifying trials were included regardless of sample size or duration, except those that evaluated only a single administration of the drug. In contrast to earlier meta-analyses, the results of most studies were obtained through direct communication with the investigators or sponsors. Consequently, the results presented in this article may not be identical to the results that appeared in the original publications of these studies.

Measures of Efficacy
This meta-analysis focused on 5 measures of efficacy: (1) all-cause mortality, (2) morbidity (defined as hospitalization for worsening heart failure), (3) the combined risk of all-cause mortality and hospitalizations for worsening heart failure (combined morbidity and mortality), (4) changes in functional status (as assessed by the NYHA classification), and (5) changes in left ventricular ejection fraction.

Information on deaths was obtained in all 18 trials. Data on hospitalizations for heart failure were collected in all except the MDC trial⁴ ; for this trial, we used the number of hospitalizations for heart failure and arrhythmias, because its database did not distinguish between the 2 types of hospitalization. Changes in NYHA class and ejection fraction were each reported in 16 trials. Information on the combined end point of death and hospitalizations for heart failure was not included in most of the published articles but was obtained through direct communication with the investigators or sponsors. This was successfully achieved for 9 trials, which enrolled 87% of the total number of patients in this meta-analysis.

Mortality was analyzed according to the intention-to-treat principle; events were included if they occurred during the intended duration of the study whether or not patients were receiving double-blind medication. Morbidity was assessed by determining the number of patients in each treatment group with at least 1 hospitalization for heart failure; repeat hospitalizations were not considered. Changes in functional status were evaluated by determining the number of patients who improved or deteriorated by at least 1 NYHA class as assessed during the last visit on double-blind therapy. The effect of treatment on ejection fraction was analyzed by comparing mean values in the 2 treatment groups at protocol-specified time points (3 to 12 months).

Primary Analysis
For each end point, we pooled the data by weighting the treatment effect of each trial by the reciprocal of its variance. The significance of the overall treatment effect was evaluated by a ² statistic (association test). For the analysis of all dichotomous variables (all variables except ejection fraction), a treatment effect model was selected (1) by testing for heterogeneity of the effect across the trials with a ² statistic (to select between a fixed or random effects model) and (2) by determining whether the intercept of the regression line (which plotted the event rate in the placebo groups versus the event rate in the ß-blocker groups) was different from zero with a t test (to select between a multiplicative or additive model).⁵ For the analysis of morbidity and mortality (alone and combined), there was no significant heterogeneity among the trials, and the regression line intersected zero. Thus, a fixed multiplicative effect model was used, and significance was evaluated by the methods of Peto,⁶ Mantel-Haenszel,⁷ Cochran,⁸ and the logarithm of the odds ratio.⁹ For the analysis of NYHA class, the regression line intersected zero, but there was significant heterogeneity among the trials. Thus, a random multiplicative effects model was used, and significance was evaluated with the random odds ratio.¹⁰ Finally, for the analysis of ejection fraction (a continuous variable), the ratio of the treatment difference to the standard deviation of the ejection fraction was calculated for each trial, and a z score was used to assess the overall effect size.¹¹ Although the ² test for heterogeneity was significant (P=0.025), this heterogeneity was suppressed after withdrawal of 2 small trials (representing only 2% of the data); both showed a substantial imbalance between treatment groups in the baseline values for ejection fraction.

Secondary Analyses
Subgroup Analysis
We divided the trials into 2 groups: (1) those using a ß₁-selective ß-blocker (eg, metoprolol, bisoprolol, and nebivolol) and (2) those using a nonselective ß-blocker (eg, carvedilol and bucindolol). Differences in the magnitude of the treatment effects between the 2 subgroups were evaluated for significance by 2 methods: (1) for dichotomous variables, heterogeneity of the odds ratios was assessed by the Mantel-Haenszel procedure,⁷ and (2) for ejection fraction, an ANOVA procedure was performed on the weighted effect size of each trial, followed by an interaction test.

Sensitivity Analyses
To determine whether the results were unduly influenced by a single trial or a small number of trials, we repeated the meta-analyses of all variables after successively withdrawing trials in decreasing order of statistical weight (as determined by the reciprocal of the variance of the treatment effect for each trial); thereby, trials with the largest number of events were eliminated first. A second sensitivity analysis was performed by repeating the meta-analyses after successively withdrawing trials in decreasing order of their odds ratios; thereby, trials with largest treatment effects were eliminated first.

Robustness Analysis
The robustness was estimated by computing the number of trials with a neutral treatment effect that, if added to the present database, would produce a nonsignificant result (P>0.05). To perform this analysis, the size of each hypothetical trial was assumed to be equal to the mean of the size of the trials included in the meta-analysis and to have an event rate equal to the overall event rate in the placebo groups. A robustness ratio was calculated by dividing the number of hypothetical trials by the number of real trials in the meta-analysis.

	Results

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Eighteen clinical trials with ß-blockers in heart failure met the criteria for inclusion in the present analysis.^{4 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29} The study by Gilbert et al³⁰ was excluded because it focused on a subset of patients included in the report by Woodley et al.¹⁵ The article summarizing the mortality results of the US carvedilol program³¹ was replaced by the individual reports of the 4 component trials,^{26 27 28 29} because these provided information on nonfatal (as well as fatal) end points. The 2 reports^{23 24} presenting the short- and long-term results of the carvedilol trial carried out by the Australia New Zealand Heart Failure Research Collaborative Group were considered as 1 trial.

Patient Characteristics
The 18 trials enrolled a total of 3023 patients with heart failure, of whom 1305 were randomized to treatment with placebo and 1718 to treatment with a ß-blocker (Table 1). The cause of heart failure was an idiopathic dilated cardiopathy in 1513 patients and ischemic heart disease in 1445 patients. Most patients had NYHA class II or III symptoms, despite the use of diuretics and usually digitalis and an ACE inhibitor. Few patients (0% to 5%) had class IV symptoms, and only 2 trials enrolled class I patients.^{4 24}

View this table: [in this window] [in a new window]   Table 1. Characteristics of Controlled Clinical Trials of ß-Blockers in Heart Failure

Effect of ß-Blockade on Clinical Measures
For all end points, there was a significant effect (P<0.05) in favor of treatment with a ß-blocker. The magnitude and significance of the treatment effect were similar regardless of the statistical model used (Tables 2 and 3, Figures 1 to 3).

View this table: [in this window] [in a new window]   Table 2. Effect on Key Hemodynamic and Clinical Measures in Individual Trials

View this table: [in this window] [in a new window]   Table 3. Comparative Effects of Selective and Nonselective ß-Blockers on Major Clinical End Points

View larger version (61K): [in this window] [in a new window]   Figure 1. Effect of ß-blockade on risk of death in chronic heart failure. Effect of ß-blockade in each trial (by first author and year of publication) is represented by horizontal bar whose central vertical tick represents point estimate of odds ratio and whose width displays 95% CIs of estimate (logarithmic scale). Solid vertical line represents odds ratio of 1 (neutral treatment effect); dotted vertical line represents odds ratio for treatment effect across all trials. Odds ratio <1 indicates lower risk of death with ß-blockade, whereas odds ratio >1 indicates higher risk of death with active treatment. Overall, ß-blockers reduced risk of death by 31% (P=0.0029).

View larger version (57K): [in this window] [in a new window]   Figure 2. Effect of ß-blockade on risk of being hospitalized at least once for heart failure. Format is similar to Figure 1. Overall, ß-blockers reduced risk of being hospitalized for heart failure by 41% (P<0.001).

View larger version (43K): [in this window] [in a new window]   Figure 3. Effect of ß-blockade on combined risk of all-cause mortality and hospitalizations for heart failure. Format is similar to Figure 1. Overall, ß-blockers reduced risk of death or hospitalization for heart failure by 37% (P<0.001).

There were 156 deaths among 1305 patients (11.9%) assigned to placebo, but only 130 deaths among 1718 patients (7.5%) assigned to a ß-blocker (Figure 1). This difference reflected a 32% reduction in the risk of death (95% CI, 12% to 47%), P=0.003 (Peto's method). There were 223 hospitalizations for heart failure among 1305 patients (17.1%) assigned to placebo, but only 166 such hospitalizations among 1718 patients (9.6%) assigned to a ß-blocker (Figure 2). This difference reflected a 41% reduction in risk (95% CI, 26% to 52%), P<0.001. When morbidity and mortality were combined, there were 293 deaths or hospitalizations for heart failure among 1155 patients (25.4%) assigned to placebo but only 239 such events among 1486 patients (16.0%) assigned to a ß-blocker (Figure 3). This difference reflected a 37% reduction in risk (95% CI, 24% to 49%), P<0.001. In addition, patients assigned to treatment with a ß-blocker were 32% more likely to experience an improvement in NYHA class (95% CI, 1% to 74%, P=0.04) and 30% less likely to experience worsening of NYHA class (95% CI, 4% to 50%, P=0.03). The mean unweighted value for left ventricular ejection fraction was 0.23±0.04 in the placebo groups and 0.31±0.04 in the ß-blocker groups, reflecting an unweighted 29% mean increase in ejection fraction in patients treated with a ß-blocker, P<10^-9.

Assuming a treatment period identical to the mean duration of follow-up (7 months), we determined that physicians would need to treat 38 patients to avoid 1 death, 24 patients to avoid 1 hospitalization for heart failure, and 15 patients to avoid 1 combined end point.

Analysis of Sensitivity, Robustness, and Subgroups
The numbers of trials that would need to be withdrawn to induce a nonsignificant result were 4 trials for mortality (84% of the total weight), 9 trials for hospitalizations for heart failure (93% of the total weight), 5 trials for the combined end point (72% of the total weight), and 12 trials for ejection fraction (91% of the total weight). In contrast, the withdrawal of only 15% of the total weight (1 trial) induced a nonsignificant result for NYHA class improvement, and the withdrawal of only 67% (5 trials) induced a nonsignificant result for NYHA class deterioration. When the sensitivity analysis was repeated by subtracting trials with the largest treatment effect first, the numbers of trials that would need to be withdrawn to induce a nonsignificant result were 10 for hospitalizations for heart failure and 6 for the combined end point but only 1 each for mortality, NYHA class improvement, and NYHA class deterioration.

The numbers of trials with a neutral result (assuming a sample size equal to the mean number of patients enrolled in the trials and an event rate equal to the event rate in the placebo groups) that would need to be added to induce a nonsignificant overall result were 23 for mortality (robustness ratio of 23/18=1.28), 80 for hospitalizations for heart failure (robustness ratio of 80/18=4.4), 40 for the combined end point (robustness ratio of 40/9=4.44), 1 for NYHA class improvement (robustness ratio of 1/16=0.06), and 4 for NYHA class deterioration (robustness ratio of 4/16=0.25). For ejection fraction, the number of neutral trials required to induce a nonsignificant overall result exceeded the range of the calculation. Thus, we could rank the variables in decreasing order of robustness: ejection fraction > combined morbidity and mortality > hospitalizations for heart failure > all-cause mortality > NYHA class deterioration > NYHA class improvement. However, if 1 large-scale trial with a neutral result were added (assuming the enrollment of 1225 patients in each treatment group and a 20% mortality rate in the placebo group), the results of the present analysis would not be significant for mortality.

The effects of treatment in trials of nonselective ß-blockers were compared with those seen in trials of ß₁-selective agents (Table 3). For mortality, the risk of death was reduced by 49% in trials of nonselective ß-blockers (P<0.001) but by only 18% in trials of ß₁-selective agents (P=0.26); the difference in the mortality effects between the 2 subgroups was significant (P=0.049). In contrast, for all other measures, the magnitude of the treatment effect was similar in trials of selective and nonselective ß-blockers. Although an improvement in NYHA class was observed in trials of selective ß-blockers and a decrease in risk of NYHA deterioration was noted in trials of nonselective ß-blockers, the differences between the 2 subgroups for these 2 measures were not significant (Table 3).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of the present meta-analysis indicate that long-term treatment with a ß-adrenergic blocking drug can produce important benefits in chronic heart failure. The addition of a ß-blocker to conventional therapy was associated with a significant impact on morbidity and mortality, as evidenced by a 32% reduction in the risk of death, a 41% reduction in the risk of being hospitalized for heart failure, and a 37% reduction in the combined risk of morbidity and mortality. In addition, treatment with a ß-blocker produced significant hemodynamic and symptomatic benefits, as reflected by a 29% increase in left ventricular ejection fraction, a 32% increase in the likelihood of functional improvement, and a 30% decrease in the likelihood of functional deterioration. These findings increase the confidence gained from individual studies that ß-blockers can produce a wide range of favorable effects in chronic heart failure.

In the present analysis, the measures that were most consistently improved by ß-blockade were ejection fraction, the frequency of hospitalization for heart failure, and the combined risk of morbidity and mortality. The effect on these 3 measures was not only highly significant but also so robust that we could negate the effect only by removing 80% to 90% of the database or by adding to the database an exceedingly large number of trials with a neutral result. The effect on these variables was particularly persuasive because many of the trials were specifically designed to evaluate changes in ejection fraction and the combined risk of morbidity and mortality, and the effect was not accompanied by any important heterogeneity among the trials. In contrast, the favorable effect of ß-blockade on NYHA functional class was not robust and could be negated by removing only 15% of the database or by adding only 1 moderate-size trial with a neutral effect. The lack of a persuasive effect of ß-blockade on NYHA class may have been related to the fact that most trials had a short duration of follow-up; failed to record changes in NYHA class in patients who were withdrawn from a study for clinical deterioration between scheduled visits; and enrolled patients with class II symptoms, in whom demonstration of clinical benefit may be difficult. Indeed, the observation that NYHA class improved in trials of selective agents but not in trials of nonselective agents was probably related to the fact that class II patients composed only 18% of the patients enrolled in trials of selective ß-blockers but 51% of the patients enrolled in trials of nonselective ß-blockers.

The present report confirms the conclusions of 2 recent meta-analyses^{2 3} that the use of ß-blockers is associated with a reduction in mortality of 30%. However, as in the previous reports, such an effect was only intermediate in robustness. On the one hand, we could negate the effect only with some difficulty: by either removing 84% of the database or adding to the database a large number of moderate-size trials with a neutral result. On the other hand, a neutral result in a single, large-scale, long-term study would make the mortality effect disappear entirely. Uncertainty about the effect of ß-blockers on survival is heightened further by our finding that the magnitude of the mortality reduction may depend on the pharmacological properties of the drug. Whereas both selective and nonselective ß-blockers were associated with similar increases in ejection fraction and decreases in the risk of hospitalization, nonselective ß-blockers were associated with a larger survival benefit than ß₁-selective agents. All-cause mortality was reduced in trials of nonselective agents by 49% (P<0.001) but was reduced by only 18% (P=0.26) in trials of ß₁-selective agents; the probability value for the difference between the 2 groups was significant (P=0.049). This observation is noteworthy because experience in postinfarction trials has suggested that agents that block both ß₁- and ß₂-receptors may provide more complete protection against catecholamine toxicity than agents that act only on the ß₁-receptor.³² Blockade of ß₂-receptors may be particularly important in heart failure, because ß₂-receptors are not downregulated in the failing heart.³³ Furthermore, blockade of ß₂-receptors (but not ß₁-receptors) reduces sympathetic drive to the heart³⁴ and may prevent ventricular arrhythmias, either directly³⁵ or by minimizing the risk of catecholamine-induced hypokalemia.³⁶ The latter mechanisms are of interest because earlier studies have ascribed the superior mortality effects of nonselective agents to their ability to prevent sudden death.^{3 32} However, it should be noted that nearly 90% of the experience with nonselective ß-blockers in clinical trials is with carvedilol, which blocks -adrenergic receptors in addition to ß₁- and ß₂-receptors. Because combined - and ß-blockade prevents the toxic effects of catecholamines more effectively than ß-blockade alone in experimental studies,^{37 38 39} it is possible that blockade of -receptors (rather than of ß₂-receptors) might account for the larger mortality reduction observed with nonselective agents in the present report. The hypothesis that ß-blockers differ in their survival effects is being prospectively evaluated in the Carvedilol or Metoprolol European Trial (COMET), which is comparing the effects of carvedilol and metoprolol on all-cause mortality in chronic heart failure.

The results of this meta-analysis should be interpreted cautiously. Because meta-analyses are based on the published literature, publication biases (ie, the tendency to selectively publish favorable results) could invalidate our findings.¹¹ For most end points, however, a large number of trials with a neutral result would be necessary to negate the finding of benefit, and we can reasonably assume that all large-scale randomized trials evaluating ß-blockers in heart failure are known to us. We recognize the possibility that a meta-analysis can be biased if the overall result is highly dependent on 1 or 2 trials or if the trials observed a high rate of withdrawals from active therapy. However, none of the 18 randomized trials included in the present meta-analysis had a weight >50%, and the number of patients lost to follow-up in each study was small (composing only 1% to 3% of the total randomized). Finally, for some end points (eg, mortality), the number of events may be too small to allow definitive conclusions, even though the reduction in risk was highly significant. Unlike other meta-analyses, however, this present analysis did not confine itself to mortality but rather analyzed nonfatal measures of outcome (eg, hospitalizations). For these other variables, the number of events was large and the treatment effects were robust.

In conclusion, a meta-analysis of more than 3000 patients enrolled in 18 randomized trials indicates that the addition of a ß-blocker to conventional therapy is associated with hemodynamic and symptomatic improvement as well as favorable effects on morbidity and mortality. Our results are particularly persuasive for the effect of treatment on the combined risk of all-cause mortality and hospitalizations for heart failure, a measure of efficacy that is receiving increasing attention as a primary end point in clinical trials and as the basis for approval of new drugs by regulatory agencies. In the present analysis, 3 trials^{4 24 28} were designed to evaluate a combined end point, and 2 (both with carvedilol^{24 28} ) showed a significant effect of treatment. Although the present analysis also indicates that ß-blockers probably prolong survival, the relatively small number of fatal events and the possibility of a difference in the effects of selective and nonselective ß-blockers on mortality indicate that further studies are needed before we can conclude that prolongation of life is a general property of ß-blockers in heart failure. Further insights on this issue will be provided by the results of several ongoing mortality trials of both selective (CIBIS II and MERIT) and nonselective (BEST and COPERNICUS) agents. However, given the persuasive evidence for a favorable effect of ß-blockade on the combined risk of morbidity and mortality, physicians would appear to have sufficient evidence to support the use of ß-blockers in heart failure, even before the completion of these large-scale studies.

	Footnotes

 
Reprint requests to Philippe Lechat, MD, PhD, Service de Pharmacologie, Hôpital Pitié-Salpêtrière, 47 Blvd de L'Hôpital, 75013 Paris, France.

Received November 25, 1997; revision received May 6, 1998; accepted May 30, 1998.

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