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European Journal of Heart Failure 2007 9(11):1136-1139; doi:10.1016/j.ejheart.2007.09.003
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© 2007 European Society of Cardiology

Comparison of the beneficial effect of beta-blockers on mortality in patients with ischaemic or non-ischaemic systolic heart failure: A meta-analysis of randomised controlled trials

Laurent Fauchier*, Bertrand Pierre, Axel de Labriolle and Dominique Babuty

Cardiologie, Centre Hospitalier Universitaire Trousseau 37044 Tours
Université François-Rabelais 37032 Tours, France

* Corresponding author. Service de Cardiologie B et Laboratoire d'Electrophysiologie Cardiaque, Pole Cœur Thorax Vasculaire Hémostase, Centre Hospitalier Universitaire Trousseau, 37044 Tours, France. Tel.: +33 2 47 47 46 50; fax: +33 2 47 47 59 19. E-mail address: lfau{at}med.univ-tours.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Mechanisms by which beta-blockers bring benefit may differ according to the aetiology of heart failure (HF). It is uncertain whether the magnitude of the benefit of beta-blockers is the same in ischaemic or non-ischaemic HF.

Methods: We performed a systematic review of all randomised, placebo-controlled, parallel-design trials of beta-blockers in HF that collected data on mortality during follow-up.

Results: Among 26 randomised trials comparing beta-blockers with placebo in HF, 4 studies with 7250 patients provided information on the number of patients who died during follow-up in subgroups of ischaemic and non-ischaemic aetiology of HF. Two studies were performed with bisoprolol, one with carvedilol and one with metoprolol. HF was associated with ischaemic aetiology in 4746/7250 patients (65%) and non-ischaemic aetiology in 2504/7250 patients (35%). Mortality occurred in 301 patients. The risk ratio (RR) for beta-blockers versus placebo was 0.62 (95% confidence interval [CI] 0.52–0.75, p<0.00001) in ischaemic HF, compared with a RR of 0.62 (95% CI 0.45–0.84, p=0.002) in the presence of non-ischaemic HF.

Conclusion: The magnitude of the prognostic benefit conferred by beta-blockers for overall mortality in non-ischaemic HF appears to be very similar to that in ischaemic HF.

Key Words: Heart failure • Beta-blockers • Coronary artery disease • Dilated cardiomyopathy

Received July 3, 2007; Revised August 18, 2007; Accepted September 11, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Beta-blockers (BBs) confer significant prognostic benefit in patients with chronic systolic heart failure (HF) [1]. However, the mechanisms by which beta-blockers confer benefit may differ according to the aetiology of HF. Among other features, different aetiologies of HF may be associated with different outcomes and most studies have suggested that the prognosis of patients with ischaemic heart disease is worse than for patients with idiopathic dilated cardiomyopathy [2]. Moreover, it has been suggested that the increase in ejection fraction during treatment with a beta-blocker is less marked in patients with coronary artery disease [3]. It is uncertain whether the magnitude of the benefit of BBs in patients with systolic HF associated with coronary artery disease is the same as in patients with non-ischaemic aetiology, as this has not been specifically evaluated to date. We thus performed a meta-analysis to compare the mortality benefit obtained with beta-blockers in patients with ischaemic and those with non-ischaemic heart failure aetiology.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
We searched through Medline for all randomised controlled trials which compared beta-blockers with placebo in heart failure. We looked for outcome trials which met all of the following specified criteria: (i) direct comparison between a beta-blocker and placebo regardless of the background therapy; (ii) publication before 1 June 2007 in a peer-reviewed journal indexed in Medline; (iii) incidence of death as a specified event (iv) follow-up of at least 6 months and (v) number of events in each subgroup of patients with ischaemic or non-ischaemic aetiology of heart failure. The final search identified 4 trials which fulfilled all inclusion criteria [4-8]. We reviewed the methodological quality of these trials (CIBIS, US Carvedilol, CIBIS 2 and MERIT HF) by using the Jadad scoring system [9]. We pooled events for patients with "non-ischaemic heart failure" (US carvedilol and MERIT HF) with those in patients with "idiopathic" or "primary dilated cardiomyopathy" (CIBIS 1 and CIBIS 2). We ignored events in the group of patients with undefined aetiology of HF in CIBIS 2. Since numbers of events were not fully available for patients with ischaemia in CIBIS 1, numbers of events were extracted for those with a history of myocardial infarction (87% of all patients with ischaemia) and pooled with those of patients with aetiology of heart failure defined as ischaemic in the other trials.

We calculated values for agreement by using the methods described by Fleiss [10]. We calculated odds ratios and 95% confidence intervals for the incidence of all-cause mortality for each trial separately and for combinations of studies according to fixed-effect models in the presence of statistical homogeneity defined as a chi-square test p value more than 0.10 [11]. The p value threshold for statistical significance was set at 0.05 for effect sizes. Statistical calculations were performed using RevMan, version 4.2.6 (The Cochrane Collaboration, Oxford, United Kingdom).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Our initial search identified a total of 26 randomised, controlled, double-blind, human trials performed since 1985, which compared beta-blockers with placebo in the field of HF, representing a total of 19,170 patients. Of these, 4 studies (n=7250 patients) provided information on the number of patients who died during follow-up according to ischaemic and non-ischaemic aetiology of HF and were included in the meta-analysis. Two studies were performed with bisoprolol, one with carvedilol and one with metoprolol. Table 1 summarizes the characteristics of the 4 trials. All four trials were randomised, controlled and double blinded and received the maximum Jadad score of 5 points. Follow-up duration ranged from 6.5 to 21 months. For the considered endpoint, a Funnel plot of trials appeared to be symmetrical, suggesting the absence of publication bias (Fig. 1). HF was associated with ischaemic aetiology in 4746/7250 patients (65%) and non-ischaemic aetiology in 2504/7250 patients (35%). Mortality occurred in 301 patients. Mortality was significantly higher in patients with ischaemic heart failure (550/4746, 11.6%) than in patients with non-ischaemic aetiology of heart failure (183/2504, 7.3%, p<0.00001). Data of the comparison groups for all-cause mortality were homogeneous on the basis of the chi-square statistic. Therefore, we assumed fixed-effects models. The risk ratio (RR) for beta-blockers versus placebo was 0.62 (95% confidence interval 0.52-0.75, p<0.00001) in ischaemic HF, compared with a RR of 0.62 (95% confidence interval 0.45-0.84, p=0.002) in the presence of non-ischaemic HF (Fig. 2).


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  		Table 1 Characteristics of the beta-blocker heart failure mortality trials meeting criteria for meta-analysis

 


Figure 01
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  		Fig. 1 Funnel plot of trials of beta-blockers versus placebo for the endpoint of all-cause mortality in heart failure of ischaemic or non-ischaemic aetiology.

 


Figure 02
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  		Fig. 2 Effect of beta-blockers versus placebo on all-cause mortality, in heart failure of ischaemic (top) or non-ischaemic aetiology (lower).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
We found that the benefit conferred by beta-blockers for overall mortality in non-ischaemic HF was very similar to that in ischaemic HF, with a 38% reduction of the relative risk of death in both groups. The fact that we found a better prognosis in non-ischaemic heart failure; similar to many previous studies [2,12,13]; did not alter the magnitude of the benefit conferred by beta-blocker treatment on the endpoint of mortality. The mechanisms to explain the protective action of beta-blockers usually include the antiarrhythmic and myocardial oxygen demand-reducing effects of the drugs. Information on mode of death (sudden or non sudden) were not available in the subgroups of patients with or without coronary artery disease. Our result does not confirm a previous report suggesting that beta-blockers may have an enhanced action in patients without ischaemia, in the absence of a history of myocardial infarction or in patients with an idiopathic dilated cardiomyopathy [4]. In addition, the suggestion that beta-blockers may have specific cardioprotective action in survivors of myocardial infarction [14] (protection of vulnerable coronary artery plaque rupture, limited antithrombotic action) which may bring further benefit in these patients, did not result specifically in a better outcome in our analysis. Reverse left ventricular remodelling with beta-blockade is a potential mechanism of benefit common to both aetiologies of HF [15]. The fact that functional and haemodynamic improvement with beta-blockade may be greater in non-ischaemic patients than in ischaemic patients, has been reported previously [16,17]; however, it did not result in a difference in mortality in the patient groups in the present study. Of note, we were unable to conclude whether the similar response to beta-blockade in ischaemic and non-ischaemic HF also applies to elderly patients, since this population was poorly represented in the trials included in the present analysis.

Although we tried to conduct a thorough review of the existing literature, our study has limitations inherent to any meta-analysis. We were unable to obtain data on ischaemic or non-ischaemic aetiology of HF from all studies identified in our initial literature search. We speculate that data from smaller trials or unpublished reports not included in our study are unlikely to significantly influence our results. Potential limitations also include heterogeneity of study design, patient populations, treatment effect, and time period and duration of follow-up of the included trials. Other limitations include variation in the definition of ischaemic and non-ischaemic aetiology between studies, and the possibility of effects specific to beta-blockers that are dose dependent. The potential confounding influence of other treatments, and particularly the complementary and additive benefit from beta-blockade administered on top of angiotensin converting enzyme (ACE) inhibition has to be considered. The percentage of patients receiving ACE inhibitors in our analysis ranged from 89.7% in CIBIS 1 to 96.2% in CIBIS 2 study. The main benefit of ACE inhibition is in preventing progressive HF, whereas an important part of the benefit of beta-blockade is in preventing sudden death through a presumed antiarrhythmic effect.

Finally, on the basis of overall homogeneity found in the present analysis, we did not find differences in the actions of beta-blockers with respect to beta-receptor selectivity and alpha-1 receptor blockade in subgroups of patients with or without coronary artery disease.


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

  1. Swedberg K., Cleland J., Dargie H., et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J (2005) 26:1115–1140.[Free Full Text]
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