1NHMRC Centre of Clinical Research Excellence in Therapeutics. Departments of Epidemiology and Preventive Medicine and Medicine, Monash University Central and Eastern Clinical School, Alfred Hospital, Melbourne 3004, Australia
2Cardiology Division, Department of Internal Medicine, University of Texas Southwestern and Dallas VA Medical Centers, Dallas, TX, USA
3Cardiac Centers of Louisiana, Shreveport, LA, USA
4Division of Cardiology, School of Medicine, University of Utah, Salt Lake City, UT, USA
5Pharmacology Department, Pitie-Salpetriere Hospital, Paris, France
6Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York, NY, USA
7University of Wisconsin, Madison, WI, USA
8Global Head Established ProductsClinical Research, Merck KGaA, Darmstradt, Germany
9Nordic School of Public Health, Göteborg, Sweden
10Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden
11AstraZeneca, Mölndal, Sweden
Received 25 November 2004; revised 6 June 2005; accepted 16 June 2005; online publish-ahead-of-print 13 July 2005.
* Corresponding author. Tel: +61 3 9903 0042; fax: +61 3 9903 0556. E-mail address: henry.krum{at}med.monash.edu.au
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Abstract |
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Methods and results We performed a meta-analysis of all placebo-controlled BB studies in patients with CHF (n>200). Trials were identified via Medline literature searches, meeting abstracts, and contact with study organizations. Results for all-cause mortality and death or heart failure hospitalization were pooled using the MantelHaenszel (fixed effects) method. The impact of BB therapy on all-cause mortality in CHF, in the absence (4.8%) and presence (95.2%) of ACE-I (or ARB), was determined from six trials of 13 370 patients. The risk ratio (RR) for BBs vs. placebo was 0.73 [95% confidence interval (CI) 0.531.02] in the absence of ACE-I or ARB at baseline, compared with a RR of 0.76 (95% CI 0.710.83) in the presence of these agents. When ACE-Inhibitors were analysed in the same way (pre-BB), a RR of 0.89 (0.800.99) vs. placebo was observed in studies of >90 days. The impact of BB therapy on death or HF hospitalization in systolic CHF, in the absence and presence of ACE-I, was determined from three trials of 8988 patients. The RR for BBs vs. placebo was 0.81 (95% CI 0.611.08) in the absence of ACE-I or ARB at baseline, compared with a RR of 0.78 (95% CI 0.740.83) in the presence of these agents. When ACE-Is were analysed in the same way (pre-BB), a RR of 0.85 (95% CI 0.780.93) vs. placebo was observed in studies of >90 days.
Conclusion The magnitude of the prognostic benefit conferred by BBs in the absence of ACE-I appears to be similar to those of ACE-Is in systolic CHF. These data therefore suggest that either ACE-Is or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective studies directly comparing these agents are required to definitively address this issue.
Key Words: Chronic heart failure Beta-blocker ACE-Inhibitor Mortality Hospitalization
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Introduction |
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Thus, the aim of the present study was to perform a meta-analysis regarding the clinical effects of BB therapy (for all-cause mortality and death or heart failure hospitalization) in systolic CHF patients not receiving background ACE-Inhibitor (or ARB) at baseline, within the major placebo-controlled BB trials.
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Methods |
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Results of individual trials for all-cause mortality and death or heart failure hospitalization were pooled using the MantelHaenszel (fixed effects) method of meta-analysis using the STATA version 7.0 program. STATA calculates relative risks and 95% confidence intervals (CIs) for each study involved in the meta-analysis and assigns relative weights according to the contribution of each study to each analysis. Tests of heterogeneity were performed. Statistical significance was set at the 0.05 level on the basis of two-way z-tests and 2 tests.
Historical comparison of ACE-Inhibitor efficacy in the pre-BB era of systolic CHF management was performed using the same methodology, on the basis of data derived from the systematic review of Garg and Yusuf.2 Raw event data was re-analysed utilizing the same analytical technique as in the BB meta-analysis. ACE-Inhibitor studies were divided into those of 90 and >90 days duration. Studies of >90 days are compared as these are closest in duration to the long-term BB mortality studies analysed.
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Results |
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In the COPERNICUS6 study, patients were well matched within the two groups (i.e. ACE-Inhibitor/ARB yes or no) for age, gender, left-ventricular ejection fraction, etiology of heart failure, systolic blood pressure, heart rate, serum sodium, and per cent hospitalized for heart failure within the previous 12 months.
However, within COPERNICUS, patients not on ACE-Inhibitor (or ARB) at baseline had a higher serum creatinine (150±47 µmol/l) compared with those who were receiving these agents (133±36 µmol/l), P=0.021 for difference. In addition, there was greater use of spironolactone in patients not receiving ACE-Inhibitor (or ARB) at baseline (31%) compared with those who were receiving these agents (19%), P<0.02 for difference.
In the MERIT-HF7 study, patients in the two groups were well matched at baseline for race, gender, systolic and diastolic blood pressure, heart rate, and NYHA class. However, patients not receiving ACE-Inhibitors or ARBs at baseline were significantly older (P<0.05), had lower body mass index, higher serum creatinine, and lower use of calcium channel blockers and nitrates than the majority who were receiving background ACE-Inhibitors or ARBs.
Endpoint of all-cause mortality
Table 2 summarizes the no ACE-Inhibitor (or ARB) meta-analysis of BB trials in tabular form. Over 600 patients in the six trials were not receiving ACE-Inhibitor or ARB at baseline. This compares with almost 13 000 who were receiving these agents.
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When data for clinically utilized beta-blocking agents were analysed for mortality in a similar manner to the preceding meta-analysis, it was observed that a RR of 0.67 was obtained for both groups; 0.67 (95% CI 0.431.04, P=0.073) inpatients not receiving ACE-Inhibitor/ARB at baseline and 0.67 (95% CI 0.600.75, P<0.001) for those who were receiving these agents.
The effect of ACE-Inhibitor therapy on all-cause mortality in patients with systolic CHF in the pre-BB era of CHF management was assessed from re-analysis of the Garg dataset.2 In studies of >90 days duration, the RR was 0.89 (95% CI 0.800.99). Overall, the RR was 0.85 (95% CI 0.770.94).
Endpoint of death or heart failure hospitalization
Three studies contributed data to the endpoint of death or HF hospitalization. These studies were BEST,3 COPERNICUS,6 and MERIT-HF7.
Inpatients who were receiving ACE-Inhibitor or ARB at baseline, the overall RR was 0.78 (95% CI 0.740.83, P<0.001). Inpatients who were not receiving ACE-Inhibitor or ARB at baseline, the RR was 0.81 (95% CI 0.611.08, P=0.148). Direct head-to-head comparison of these CIs revealed no statistically significant difference (P=0.8136 via z-test).
There was an increase in death or CHF hospitalization events in patients not receiving ACE-Inhibitor or ARB at baseline vs. those who were. There was a beneficial impact of BB therapy in both groups (Figure 3).
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The RR for ACE-Inhibitor therapy vs. placebo on the endpoint of death or heart failure hospitalization in studies of >90 days duration was 0.85 (95% CI 0.780.93). Overall, there was a RR of 0.66 (95% CI 0.610.71), favouring ACE-Inhibitor therapy.
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Discussion |
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Therefore, the findings of the present study would suggest that BBs could be considered as an alternative first-line neurohormonal agent in a manner analogous to the way ACE-Inhibitor therapy is currently prescribed. The widespread utilization of neurohormonal blocking therapy and guidelines recommendations supporting ACE inhibition prior to the introduction of beta-blockade therefore appears to be primarily based on the historical sequence of study of these agents, i.e. ACE-Inhibitor therapies were studied before beta-blockade. The BB studies were thus performed in the era of background ACE-Inhibitor therapy in the majority of patients.
There are a number of theoretical reasons why BB therapy may be advantageous early in the course of CHF disease management. Firstly, sympathetic activation occurs before reninangiotensin system activation in CHF.9 Thus, the adverse consequences of activation of the sympathetic nervous system theoretically need to be intervened on as early as possible to maximize therapeutic benefit in this setting.
Next, BBs have been demonstrated to reduce sudden death,10 a beneficial effect not as readily observed with reninangiotensin blocking therapies. Given that sudden death is a more frequent mode of death early in the course of HF disease progression than in the end-stages this may be of substantial clinical benefit.
Finally, the anti-remodelling effects of beta-blockade appear to be greater in magnitude than that observed for ACE-Inhibitors.11
On the other hand, initiating therapy with an ACE-Inhibitor may provide a beneficial early unloading effect in the left ventricle.12
The previous observations are supported by the findings of a recent randomized trial comparing initiation of BB (carvedilol) to ACE-Inhibitor in systolic HF patients.13 In that study, left-ventricular function, brain natriuretic peptide, and achieved carvedilol dose were all improved with a BB first strategy.
The previous observations are no substitute for a prospective randomized major clinical outcome trial comparing the two strategies head-to-head over the period of initiation of therapy. Such a study is currently under way (CIBIS III).14
Caveats
There are a number of important caveats to consider in analyses such as that presented in the present manuscript. Firstly, patients able or unable to tolerate ACE-Inhibitor or ARB at baseline may differ. There is clear evidence from the baseline characteristics of the patients evaluated in the present study (at least from COPERNICUS and MERIT-HF) that this is indeed the case. In addition, differences between the two groups were observed in rates of clinically significant events, among placebo treated patients particularly combined death and heart failure hospitalization.
Crude RRs were evaluated in assessing the impact of these therapies. We were unable to use hazard ratios and Cox proportional hazards modelling to take into account time to these events occurring.
As with all meta-analyses, there is heterogeneity in study design, patient populations and outcomes within individual trials that may make these studies difficult to interpret. Indeed, heterogeneity was noted in a number of analyses performed when 2 testing was performed.
There was a relatively small number of events noted in the group of patients not receiving ACE-Inhibitor or ARB in comparison with the overall group of patients within the meta-analysis. These small numbers of events greatly increase the possibility of spurious results within individual trials and possibly in the overall analysis.
The 95% CIs for the benefit of beta-blockade in patients not on ACE-Inhibitors crosses the line of no effect, therefore it cannot be definitively concluded that BBs are beneficial in the absence of ACE-Inhibitors.
Finally, comparisons with the older ACE-Inhibitor trials were retrospective, historical and post hoc in nature.
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Conclusions |
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These data therefore suggest that either ACE-Inhibitors or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective trials, directly comparing these two strategies, are required to definitively address this issue.
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Acknowledgements |
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References |
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