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Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and nonvasodilating agents according to patients' characteristics: a meta-analysis of clinical trials |
Bonet S, Agusti A, Arnau J M, Vidal X, Diogene E, Galve E, Laporte J R |
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Authors' objectives To clarify the effect of beta-adrenergic blocking agents on sudden death, to ascertain the magnitude of their benefit according to the cause of heart failure, and to investigate whether there is any difference between vasodilating and non-vasodilating agents.
Searching MEDLINE (January 1966 to January 31 1998) and EMBASE (January 1 1974 to May 30 1997) were searched. Other publications were identified by browsing the citation lists of reviews on heart failure. The authors of all published trials and the manufacturers of beta-blockers were contacted in an attempt to discover any unpublished studies. No language restrictions were reported.
Study selection Study designs of evaluations included in the reviewStudies were included in the review if they were randomised controlled trials (RCTs) of parallel or crossover design (although from crossover studies only the results from the first phase of the study were used). All RCTs included in the review were of a minimum duration of eight weeks and were analysed on an intention-to-treat basis. Trials with and without run-in phases were included in the review.
Specific interventions included in the reviewBeta-adrenergic blocking agents devoid of intrinsic sympathomimetic activity, including: metoprolol, metoprolol tartrate, carvedilol, bucindolol hydrochloride, bisoprolol, bisoprolol fumarate, propranolol hydrochloride. These treatments were compared with placebo or standard treatment.
Participants included in the reviewPatients with heart failure (ischaemic (IHD) or non-ischaemic (non-IHD)). The review included mostly male patients (75% of the total). Of the total number of patients included in the review 48.6% had IHD and 49.6% had non-IHD and 88.7% of patients were NYHA class II or III. Most were being treated with angiotensin converting enzyme inhibitors, diuretics and digitalis.
Outcomes assessed in the reviewTotal mortality; cardiovascular mortality; mortality due to pump failure and mortality due to sudden death; all cause hospitalisation and hospitalisation for heart failure.
How were decisions on the relevance of primary studies made?Three investigators independently considered the inclusion of each trial without knowledge of the title, authors, and publishing journal. Differences were resolved by consensus.
Assessment of study quality The authors did not state that they assessed validity.
Data extraction Two reviewers independently extracted from the studies using a standard form. First authors were contacted about any missing data. The categories of data extracted were: sex, age, New York Heart Association (NYHA) functional classification, ejection fraction, standard treatments, duration of study, beta-adrenergic agent tested, number of withdrawals, and deaths during the run-in stage, and mortality during the double-blind phase of each study. Relative risks (RR) with their 95% confidence intervals (CIs) were calculated.
Methods of synthesis How were the studies combined?Pooled relative risks (RR) with their 95% confidence intervals (CIs) were calculated using the random-effects model (DerSimonian and Laird (see Other Publications of Related Interest no.1)). Sub-group analyses for vasodilating and non-vasodilating beta-blockers and IHD and non-IHD were performed. Comparisons between relative risk estimates were performed using the method described by Schesselman (see Other Publications of Related Interest no.2).
How were differences between studies investigated?Heterogeneity was tested using a ch-squared test for heterogeneity. The use of a random-effects model was chosen to be more generally applicable in the presence of some degree of heterogeneity.
Results of the review Twenty-one studies were included in the review (n=5849). Eleven of the studies involved a vasodilating beta-blocker and ten tested a non-vasodilating beta-blocker. In three studies, heart failure was due to IHD, in eight it was due to non-IHD and in nine it was due to either IHD or non-IHD and in one it was not stated.
The RR for total mortality was 0.71 (95% CI: 0.63, 0.80) giving a NNT for six months of 17. The RR for cardiovascular mortality was 0.71 (95% CI: 0.59, 0.86) giving a NNT for six months of 21. The RR for death due to pump failure was 0.66 (95% CI: 0.47, 0.92) and the RR for death due to sudden death was 0.70 (95% CI: 0.54, 0.89). The results were calculated with and without the data from the CIBIS-II trial and their inclusion increased the estimate of the benefit of beta-blocker treatment on the incidence of sudden death.
The RRs for total mortality in the vasodilating and non-vasodilating beta-blockers were 0.55 (95% CI: 0.38, 0.78) and 0.73 (95% CI:0.64, 0.83) respectively (p=0.007). The RR for cardiovascular mortality were similar but with wider confidence intervals and the difference between them was not statistically significant (p=0.14). The inclusion of the CIBIS-II data rendered the difference between vasodilating and non-vasodilating beta-blockers on sudden death non-significant.
The RRs for total mortality for IHD and non-IHD were 0.70 (95% CI: 0.60, 0.81) and 0.74 (95% CI: 0.60, 0.91) (p=0.08).
In patients with non-IHD the RR with vasodilating beta-blockers was lower than with non-vasodilating beta-blockers (0.38 (95% CI: 0.18, 0.83) and 0.78 (95% CI: 0.63, 0.96) respectively (p=0.03).
The RR for all-cause hospitalisation due to heart failure was 0.85 (95% CI: 0.77, 0.92) (four trials) and the RR for all-cause hospitalisation due to heart failure was 0.67 (95% CI: 0.43, 0.94). The RRs for vasodilating beta-blockers and non-vasodilating beta-blockers were similar (0.64 (95% CI: 0.43, 0.94) and 0.67 (95% CI: 0.57, 0.78) respectively.
Authors' conclusions "In patients with heart failure beta-blockers reduce total and cardiovascular mortality by decreasing mortality at the expense of a decrease in mortality due to pump failure and sudden death. The magnitude of the benefit is similar in patients with IHD and in those with non-IHD. Vasodilating beta-blockers have a greater effect on overall mortality than non-vasodilating agents, particularly in non-IHD patients".
CRD commentary This review addressed an appropriate question with well-defined inclusion criteria applied independently by more than one reviewer. The search of the literature was reasonably comprehensive, with suitable databases selected and appropriate efforts made to uncover other trials, including unpublished ones. The studies included in the review were not assessed for validity, however the inclusion criteria did address criteria pertinent to validity such as randomisation and intention-to treat analysis, thus the minimum quality of studies included in the review appears to have been acceptable. Details of the individual studies are presented in tables within the review. The majority of studies did not take mortality as their primary end point: most assessed left ventricular function. The meta-analysis conducted in the review appears to have been appropriate, however, the authors do not present any results for the tests of heterogeneity, despite including details in the description of methods. One study at least (CIBIS-II) did have a significant effect on the results of the analysis. Overall the authors' conclusions appear to be supported by the results as presented in the review, however, the short term nature of many of the studies (eight were only three or four months duration) should be borne in mind, particularly as the outcome was mortality. In addition, the findings were based on a predominantly male population and thus should be generalised to female patients with some degree of caution.
Implications of the review for practice and research Practice: In non-IHD patients vasodilating beta-blockers are particularly effective in reducing mortality.
Research : The authors do not state any implications for further research.
Funding Catalan Agency for Health Technology Assessment, grant number 042996.
Bibliographic details Bonet S, Agusti A, Arnau J M, Vidal X, Diogene E, Galve E, Laporte J R. Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and nonvasodilating agents according to patients' characteristics: a meta-analysis of clinical trials. Archives of Internal Medicine 2000; 160(5): 621-627 Other publications of related interest 1. Petiti DB. Meta-analysis: Decision analysis and cost-effectiveness analysis. New York (NY): Oxford University Press; 1994. 2. Schlesselman J. Case-control studies: design, conduct, analysis. New York (NY): Oxford University Press; 1982.
This additional published commentary may also be of interest. Dickerson LM, Carek PJ. Are there differences between vasodilating and nonvasodilating beta-blockers in patients with heart failure? Do patients with ischemic heart disease benefit to the same degree? J Fam Pract 2000;49:496,571.
Indexing Status Subject indexing assigned by NLM MeSH Adrenergic beta-Antagonists /therapeutic use; Cross-Over Studies; Death, Sudden, Cardiac /etiology /prevention & Heart Failure /drug therapy /etiology /mortality; Hospitalization; Humans; Randomized Controlled Trials as Topic; Survival Rate; Vasodilator Agents /therapeutic use; control AccessionNumber 12000008196 Date bibliographic record published 31/03/2001 Date abstract record published 31/03/2001 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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