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European Journal of Heart Failure 2000 2(3):333-340; doi:10.1016/S1388-9842(00)00100-8
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© 2000 European Society of Cardiology

Are beta-blockers effective in patients who develop heart failure soon after myocardial infarction? A meta-regression analysis of randomised trials

Timothy Houghtona, Nick Freemantleb and John G.F. Clelanda,*

a Department of Cardiology, Castle Hill Hospital, University of Hull Kingston-upon-Hull HU16 5JQ, UK
b Medicines Evaluation Group, Centre for Health Economics, University of York York, UK

* Corresponding author. Tel.: +44-1482-624084; fax: +44-1482-624085


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The great majority of post-infarction studies of beta-blockers were conducted in an era when these agents were widely held to be contra-indicated for the management of heart failure. We now know that beta-blockers are highly effective for the management of patients with chronic stable heart failure. However, there remains uncertainty about their role in the setting of post-infarction heart failure and ventricular dysfunction.

Aim: the primary objective in this paper, was to investigate the extent to which heart failure or evidence of major cardiac dysfunction influenced outcome in previous trials of beta-blockers in heart failure after myocardial infarction.

Methods: We assessed the extent to which the inclusion of patients with heart failure or major cardiac dysfunction influenced outcome in randomised trials of long-term use of beta-blockade after myocardial infarction. The primary analysis was to assess the extent to which the proportion of patients included in each trial with heart failure influenced the relative odds of all-cause mortality in the trials. All randomised trials without crossover with treatment lasting more than one month and with 50 or more patients were considered. All those that provided information on the proportion of patients with heart failure or major cardiac dysfunction in the original or subsequent articles were included in the analysis.

Results: Overall treatment with a beta-blocker was associated with a 22.6% reduction in the odds of death (95% C1 11-32.3%). There were very few data on the effects of beta-blockers after myocardial infarction in patients with documented left ventricular systolic dysfunction. In the analysis that included heart failure as a factor, treatment with a beta-blocker was associated with a non-significant interaction with the presence of heart failure. However, because the group including heart failure patients were at higher risk, the absolute benefit of treatment with beta-blockers appeared greater in this group.

Conclusions: This analysis suggests that the relative benefit of beta-blockers on mortality after a myocardial infarction is similar in the presence or absence of heart failure but that the absolute benefit may be greater in the former. However, as current clinical practice has changed radically from the time when the majority of these trials were conducted, further trial evidence would be desirable.

Received May 1, 2000; Revised June 9, 2000; Accepted June 12, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Clinical trials show that beta-blockers are safe and effective when administered to patients with chronic, stable mild or moderate heart failure [1–4]. Meta-analysis of published trials indicates a 35% (95% CI 25–45%) reduction in the odds of death. Beta-blockers have also reduced mortality after myocardial infarction in several large studies and meta-analysis has shown a 23% (95% CI 15–31%) reduction in the odds of death [5]. However, beta-blockers remain under-utilised in both settings. Indeed, the appearance of heart failure after a myocardial infarction is often cited as a reason for withholding or even withdrawing a beta-blocker.

Most of the randomised controlled trials of beta-blockers were conducted in the 1970s and 1980s at a time when beta-blockers were believed to be contra-indicated for heart failure. Consequently, many trials of beta-blockers in this setting deliberately excluded patients with heart failure. Only two small trials of conventional beta-blockers deliberately targeted patients with heart failure or major left ventricular dysfunction, one of which showed a trend to harm [4,6]. The one trial of post-infarction heart failure that did show benefit included only patients with ‘diastolic’ heart failure [6].

Currently, patients with evidence of major left ventricular systolic dysfunction in the aftermath of a myocardial infarction, who frequently have or are at high risk of developing heart failure, are often not treated with beta-blockers. Because of an absence of conclusive clinical trial evidence in this setting, a large randomised controlled trial (CAPRICORN: CArvedilol Post-infaRct survIval COntRol in LV dysfunctioN), with the two primary end-points of (a) all-cause mortality or cardiovascular hospitalisation and (b) all-cause mortality, has been designed conducted and reported elsewhere in this issue. Our objective, in this paper, is to investigate, using meta-regression analysis, the extent to which heart failure or evidence of major cardiac dysfunction influenced outcome in previous trials of beta-blockers in heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Objectives
We assessed the extent to which the inclusion of patients with heart failure or evidence of major cardiac dysfunction influenced the outcome in randomised trials of long-term use of β blockade in patients with a history of myocardial infarction. Our primary analysis was to examine the extent to which the proportion of patients included in each trial with heart failure influenced the relative odds of all cause mortality in the trials. Only four small trials measured left ventricular function objectively, one of which excluded systolic dysfunction. Only a few trials reported an alternative objective measure of cardiac dysfunction. Accordingly, this type of analysis was conducted using only heart failure criteria.

In addition, we undertook a systematic review of the above trials to identify those that reported outcome in subgroups of patients with evidence of major cardiac dysfunction or heart failure to identify whether outcome differed among patients with or without such problems.

2.2. Inclusion criteria
We included randomised controlled trials, without cross-over, with treatment lasting more than 1 month, and with follow up that examined the clinical effectiveness of β blockers vs. placebo or control in patients who had experienced a myocardial infarction. Only trials which randomised 50 or more patients per group were included. This disqualified only three small trials, two of which excluded patients with heart failure at baseline. Treatment may have begun at any stage after myocardial infarction, and may have been commenced intravenously. Trials were only included if the proportion of patients in the trials that had signs of heart failure or evidence of major cardiac dysfunction was reported either in the original or subsequent articles.

2.3. Search strategy
We conducted sensitive electronic searches of Medline, Embase, Biosis, Healthstar, Sigle, IHTA, Conference Papers Index, Derwent Drug File, Dissertation Abstracts, Pascal, International Pharmaceutical Abstracts and Science Citation Index. We reviewed the reference list of each identified study. We also examined existing bibliographies and reviews for relevant studies, including data from the Beta-Blocker Pooling Project [7].

2.4. Data abstraction and appraisal of study quality
The following data from each study were abstracted; number of patients randomised to active treatment or control, the β blocker used and the route and dose, duration of treatment, loss to follow up, level of blinding, concealment of allocation, specific study inclusion and exclusion criteria, duration of follow up and deaths from all causes.

2.5. Statistical analysis
Standard statistical methods for meta analysis are not appropriate for meta regression analysis. Thus, we used a full random effects approach, based upon Markov chain Monte Carlo simulation, with appropriate uninformative priors using the BUGS software described by Smith et al. [8]. This provides a robust treatment estimate that avoids the large sample assumptions of standard methods, can account for the inclusion of trials in which one or more groups experience no events without crude fixes, and is highly suited to meta regression analysis.

In the analysis the logit of the probability of death (pt) in the intervention group was attributed to a constant ({alpha}), the effects of treatment ({delta}), the inclusion of heart failure patients (I) and its effect on outcome (β).


Formula


Formula


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Included trials
In total, 17 trials met the inclusion criteria (see Table 1 for references). These trials included 20 333 subjects, 1882 (9.3%) of whom died over a mean follow-up of 22 months. The proportion of patients included with heart failure varied substantially between trials. For example, three trials contained no patients with heart failure [9,10,19]. By contrast, two trials contained only patients with heart failure or major ventricular dysfunction [4,6] although one of these included only ‘diastolic’ heart failure [6]. The characteristics of included trials are described in Table 1.


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  		Table 1 Characteristics of trials of beta-blockers where rate of heart failure is reporteda

 
3.2. Overall effect of β blockade upon all cause mortality
Overall, treatment with a β blocker was associated with a 22.6% reduction in the odds of death (95% CI 11.0–32.3%). This effect is very similar to the effect observed in a meta-analysis that included all post-infarction trials of beta-blockers regardless of whether or not they excluded patients with heart failure [5]. The odds ratios for individual trials, exact 95% confidence intervals and full random effects estimates of the effect of β blockade on all cause mortality, plotted in order of increasing proportion of heart failure patients included, are described in Fig. 1.


Figure 1
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  		Fig. 1 Effect of β blockade in trials reporting rates of heart failure. Odds ratios, pooled odds ratios and 95% confidence intervals. Trials plotted in order of increasing proportion of heart failure patients included. See Tables 1 and 2 for references.

 
3.3. Meta regression analysis: the influence of the proportion of patients with heart failure included
In the analysis that used the proportion of patients included with heart failure as a factor, treatment with a β blocker was associated with a non-significant interaction with the presence of heart failure [odds ratio for the interaction 0.60 (95% CI 0.32–1.13%)]. In other words, the proportion of patients included with heart failure had no clear effect on the benefits of beta-blockers and the results may be interpreted as a lack of sufficient evidence to show that the benefits of beta-blockers after myocardial infarction are different in patients with and without heart failure.

3.4. Subgroup analysis of patients with heart failure or ventricular dysfunction after myocardial infarction
A small number of trials described all cause mortality for sub-groups of patients with evidence of heart failure or major left ventricular dysfunction. These trials are shown in Table 2. These studies suggested similar relative benefits with beta-blockers compared to placebo in patients with and without heart failure or ventricular dysfunction. However, patients with heart failure were at a greater absolute risk, therefore, the absolute benefits of treatment appears greater in this group.


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  		Table 2 Characteristics of trials of beta-blockade where data from subgroups of patients with heart failure or other evidence of major ventricular dysfunction were reported. Note that patients with severe uncontrolled heart failure were excluded from these studies

 
Similarly, Table 3, which is derived from the Beta Blocker Pooling Project [7], describes the comparative benefits in patients with and without heart failure or major ventricular dysfunction, using a variety of descriptors, in the trials included in that analysis. Overall, this analysis also suggests similar relative benefits with beta-blockers in patients with and without heart failure and, therefore, that the absolute benefits of treatment may be greater in this group of patients.


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  		Table 3 Selected sub-groups reported in the Beta-Blocker Pooling Project of nine trials with 13 679 patients [7]

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This analysis suggests that, for patients selected for inclusion in post-infarction trials in the 1970s and 1980s, the relative benefit was similar for patients with or without heart failure or major cardiac dysfunction. As patients with heart failure are at greater absolute risk, a similar relative benefit will translate into a greater absolute benefit, in terms of the number of deaths avoided. For example, if patients without heart failure have a 5% annual mortality and patients with heart failure have 20% mortality post-myocardial infarction then, assuming a 22% relative reduction in risk with a beta-blocker, for every 1000 patients treated, 11 and 44 deaths, respectively, attributable to the β blocker could be prevented.

Superficially, it would now seem appropriate to recommend that most patients with post-infarction heart failure or major left ventricular dysfunction should be treated with a combination of ACE inhibitors and beta-blockers. However, care should be taken in extrapolating the above data to current practice for several reasons.

The trials of beta-blockers were conducted in an era before the widespread use of imaging to assess post-infarction left ventricular function. Although it is likely that many patients with post-infarction heart failure had severe left ventricular systolic dysfunction the possibility that the patients with heart failure who benefited in the trials reported so far had well preserved left ventricular systolic dysfunction cannot be discounted. Forty percent of patients without major left ventricular function developed heart failure in the TRACE study, whereas approximately 25% of those with major left ventricular systolic dysfunction did not [11]. Indeed, numerically, there were similar numbers of patients with heart failure with and without systolic dysfunction in the TRACE study. In the studies of beta-blockers post-infarction there were too few data to ascertain whether similar benefits would have been observed in patients with left ventricular systolic dysfunction although patients with increased heart size did appear to benefit in one study [13]. Of note, the most impressive results in this review were from a trial in which patients had heart failure due to diastolic dysfunction, many of whom also had cardiomegaly [7].

The trials of beta-blockers post-infarction were conducted prior to the widespread use of ACE inhibitors and, to some extent, thrombolysis [5]. It is not clear that beta-blockers remain effective after myocardial infarction when taken in combination with ACE inhibitors. Beta-blockers are effective when added to an ACE inhibitor in patients with chronic, stable heart failure and left ventricular systolic dysfunction [1]. However, the combined hypotensive effect of ACE inhibitors and beta-blockers in the setting of myocardial infarction may not be desirable.

Until recently, beta-blockers were commonly believed to be contra-indicated in patients with heart failure. Consequently, it is likely that those patients with heart failure that were recruited into the trials in this retrospective analysis had rather mild heart failure. It is likely that randomised medication was frequently withdrawn if heart failure developed. These trials employed intention to treat analyses and so treatment withdrawal could have led to an underestimate of the real benefits of beta-blockade in these patients. Treatment withdrawal might also have contributed to the safety of beta-blockers in this setting. However, overall, most long-term trials of beta-blockers post-infarction have reported little overall difference in withdrawals for worsening heart failure [13,22], an early excess of withdrawals for worsening heart failure being followed, in the longer-term, by a similar number of or fewer withdrawals. The CAPRICORN study also excluded patients with severe heart failure and could include asymptomatic patients. Therefore, on current evidence, patients with severe or progressively worsening heart failure should not receive a beta-blocker immediately after myocardial infarction. However, the results of the COPERNICUS trial, (CarvedilOl ProspEctive RaNdomIsed CUmulative Survival Trial) comparing carvedilol and placebo in patients with severe stable heart failure, suggests that delayed initiation after stabilisation is indicated even in this group of patients.

All the studies conducted so far with beta-blockers in heart failure have required relatively long periods of clinical stability and have excluded patients with a recent deterioration of their heart failure. Beta-blockers have been shown to be safe in patients with chronic stable heart failure but their safety in patients with recent onset or worsening of heart failure post-infarction has not been adequately tested. In the CAPRICORN study, carvedilol was initiated 3–7 days after myocardial infarction. The protocol required clinical and haemodynamic stability for only 24 h, which is a radical departure from previous recommendations and practice.

For all of the above reasons it would be desirable to confirm that beta-blockers are effective for patients with post-infarction left ventricular systolic dysfunction and/or heart failure in contemporary clinical practice.

A further question of key importance is whether all beta-blockers are similarly effective. An analysis of all post-infarction trials failed to show differences between beta-blockers although agents with increased intrinsic sympathomimetic activity (ISA) tended to be less effective [5]. It is notable that in the trials of oxprenolol and pindolol reported here, patients with heart failure tended to have a higher mortality on the beta-blocker than on placebo. In addition, the data-set for atenolol, one of the more widely used beta-blockers post-infarction, proved to be weak. Classification of beta-blockers into those with, or without, important cardio selectivity, lipophilicity or ISA is not clear cut, and there is some debate in the literature on the attributes of acebutolol in particular [1–16]. Increased ISA may also account for the lack of effect of bucindolol in the BEST study, a study of patients with relatively severe heart failure [17]. It is clear that beta-blockers are pharmacologically different and it is uncertain whether it is appropriate to assume that there is a class benefit on morbid and fatal events. However, few direct comparisons of beta-blockers post-infarction exist. A large multi-centre, international trial comparing carvedilol and metoprolol has completed recruitment [18] (COMET). The results of this study should be highly informative regarding the future choice of beta-blockers, not only for heart failure but also for patients after myocardial infarction.


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

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