Authors' objectives

To assess the effects of angiotensin-converting enzyme (ACE) inhibitors in patients with left ventricular dysfunction or heart failure using data from individual patients.

Searching

MEDLINE was searched for relevant trials of ACE inhibitors in acute MI (the search terms and dates were not reported). Researchers and colleagues in the pharmaceutical industry were consulted, and the reference lists from review articles were examined for other published or unpublished trials. The SOLVD trials were not part of the search strategy.

Study selection

Assessment of study quality

IPD sets from the included trials of ACE inhibitors in acute MI and the SOLVD trials were rigorously checked for completeness and consistency, and to check for agreement with the original publications. Queries concerning the validity of the included studies were resolved through communication with the principal investigators. The authors did not report any judgements relating to the excluded studies on the basis of validity.

Data extraction

The collaborative review group agreed on a common data set of 88 variables and specified these in a prospective protocol. IPD sets from each trial were sent to a coordinating centre. After checking, the data sets were incorporated into a master database. The variables presented in the review included age, gender, history (previous MI, diabetes, hypertension, smoker), clinical parameters, and the use of aspirin, diuretics and beta-blockers.

Methods of synthesis

Results of the review

Three RCTs (5,966 patients) in acute MI were included. These were compared with the two SOLVD trials (6,797 patients).

In the three post-MI trials, mortality was significantly lower with ACE inhibitors than with placebo (OR 0.74, 95% CI: 0.66, 0.83, p<0.0001). The results in the SOLVD trials were similar, with no apparent heterogeneity between the two categories of trials when the data were examined at the same time point. Pooling the post-MI trials and the SOLVD trials together showed fewer deaths with ACE inhibitors compared to placebo (OR 0.80, 95% CI: 0.74, 0.87, p<0.0001, n=12,763).

In the three post-MI trials, the rates of readmission for heart failure were lower with ACE inhibitors (OR 0.73, 95% CI: 0.63, 0.85, p<0.0001). The findings also favoured ACE inhibitors for the combined outcome of death or readmission for heart failure (OR 0.74, 95% CI: 0.67, 0.83, p<0.0001). The result was similar in all five trials combined (OR 0.74, 95% CI: 0.69, 0.80, p<0.0001).

Reinfarction in the three post-MI trials was lower with ACE inhibitors (OR 0.80, 95% CI: 0.69, 0.94, p<0.006). The SOLVD results were similar. Pooling all five trials gave an OR of 0.79 (95% CI: 0.70, 0.89, p=0.0001).

For the end point of death, infarction and readmission for heart failure, the overall OR was 0.72 (95% CI: 0.67, 0.78, p<0.0001). Thus, the treatment of 100 patients could prevent seven major events.

The benefits on all outcomes were independent of age, gender, and the baseline use of diuretics, aspirin and beta-blockers.

Stroke rates in the ACE inhibitor group and control groups were similar. A further analysis among patients with a history of hypertension or baseline systolic blood-pressure of 140 mmHg or higher did not reach statistical significance. Adverse event data were available from two post-MI trials and SOLVD. Hypotension and renal dysfunction were less common with ACE inhibitors (p<0.0001).

Authors' conclusions

ACE inhibitors lower rates of mortality, MI and hospital admission for heart failure in patients with left ventricular dysfunction or heart failure with or without a recent myocardial infarct.

CRD commentary

The inclusion criteria were stated for the intervention, participants and study design. It should be noted that only two particular trials in left ventricular dysfunction (the SOLVD trials) were included, i.e. the authors did not conduct a comprehensive search for other possibly relevant trials. The literature search to identify myocardial infarction trials was limited to one database, and the dates and search terms were not reported. An attempt was made to locate unpublished studies using appropriate sources. A prospective protocol was written before the data were collected, and the principal investigators of the included trials were invited to join a collaborative group to facilitate collection of IPD. The data were checked for validity using appropriate methods for IPD. The potential impact of the authors' decision to exclude trials with less than 1,000 patients was not discussed, nor was there any mention of an attempt to identify how much data might exist in smaller trials and be missing from this analysis. In the analyses of events from which the reported ORs were derived, it was unclear what time points were used. Hazard ratios that take account of the whole follow-up period and censoring within each trial should have been reported. The survival analyses should not have treated the data as if they came from one trial.

The authors' conclusions follow from the results presented. However, some aspects of the methodology are questionable, particularly the comprehensiveness of the search to identify relevant trials and the appropriateness of the analysis.

Implications of the review for practice and research

Practice: The authors state that the use of ACE inhibitors should be part of routine practice in patients with left ventricular dysfunction or heart failure with or without a recent myocardial infarct. Also, that they should be routinely used long-term in all eligible high-risk patients.

Research: The authors did not state any implications for further research.

Funding

Medical Research Council of Canada.

Bibliographic details

Flather M D, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet 2000; 355: 1575-1581. [PubMed: 10821360]

Other publications of related interest

1. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Eng J Med 1991;325:293-302. 2. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48. 3. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-71.

Indexing Status

Subject indexing assigned by NLM

MeSH

Aged; Angiotensin-Converting Enzyme Inhibitors /therapeutic use; Female; Heart Failure /drug therapy /mortality; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Ventricular Dysfunction, Left /drug therapy /mortality

AccessionNumber

12000008280

Database entry date

31/05/2003

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.