Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: ACE inhibitors reduce mortality and hospitalization in congestive heart failure

ACP J Club. 1995 Nov-Dec;123:62. doi:10.7326/ACPJC-1995-123-3-062


Source Citation

Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995 May 10;273:1450-6.


Abstract

Objective

To determine whether angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity in symptomatic congestive heart failure (CHF).

Data sources

Studies were identified using MEDLINE and other databases, bibliographies of relevant articles, and correspondence with investigators and pharmaceutical firms.

Study selection

Published and unpublished studies were selected if they were randomized controlled trials of ACE inhibitors ≥ 8 weeks, included intention-to-treat data on total mortality, and did not compare active agents.

Data extraction

Individual ACE inhibitor, mortality (all-cause and from CHF, sudden death, and myocardial infarction [MI]), length of hospitalization, and patient characteristics (numbers, age, sex, New York Heart Association [NYHA] functional class, ejection fraction, and cause of CHF [ischemic and nonischemic heart disease]).

Main results

32 trials (3870 patients receiving ACE inhibitors and 3235 receiving placebo) were included. Results are shown in the Table. Patients receiving ACE inhibitors had lower all-cause mortality than patients receiving placebo (P < 0.001) and a lower occurrence of mortality combined with hospitalization for CHF (P < 0.001). Subgroup analyses showed that both enalapril (P < 0.001) and ramipril (P = 0.003) compared with placebo reduced the combined end point of mortality and hospitalization for CHF. Fewer patients receiving ACE inhibitors died of progressive CHF (6.5% vs 10.5% , P < 0.05). The reductions in mortality from CHF were greater for men than for women, for age ≤ 60 years than for age > 60 years, for NYHA class IV, for ejection fraction ≤ 0.25, and for CHF caused by ischemic heart disease. The greatest effect was seen during the first 3 months of treatment. The groups did not differ for reductions in sudden death or fatal MI.

Conclusion

Total mortality and mortality combined with hospitalization from congestive heart failure are reduced in patients with congestive heart failure who receive angiotensin-converting enzyme inhibitors.

Source of funding: Not stated.

For article reprint: Dr. R. Garg, Lily Research Laboratories, Eli Lily and Company, Indianapolis, IN 46285, USA. FAX 317-276-9357.


Table. Various angiotensin-converting enzyme (ACE) inhibitors vs placebo*

Outcomes Intervention Weighted event rates RRR (95% CI) NNT (CI)
Intervention Placebo
All-cause mortality ACE inhibitors 16% 22% 15% (8 to 22) 73 (43 to 244)
Mortality or hospitalization for CHF ACE inhibitors 22% 33% 19% (14 to 25) 42 (29 to 75)
Mortality or hospitalization for CHF Enalapril 42% 50% 13% (3 to 22) 20 (12 to 66)
Mortality or hospitalization for CHF Ramipril 5% 9% 43% (11 to 64) 26 (15 to 94)

*CHF = congestive heart failure. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

A recent wealth of evidence on the importance of neurohormonal mechanisms as orchestrators of the pathogenesis and outcome of heart failure has forced us to discard the common "hemodynamic perturbation" dogma that has existed for decades. Central to this theme is the verification of the benefits of pharmacologic modulation of neuroendocrine activity by ACE inhibitors at all stages of symptomatic and asymptomatic left ventricular dysfunction (1). ACE inhibitors are currently essential for treating CHF. Important questions, however, remain unanswered: Are all ACE inhibitors of similar benefit? Do all patients with CHF benefit equally? What is the mode of mortality reduction? What is the appropriate dose range? Garg and Yusuf address these first 3 issues.

Besides the reinforcement of individual trial suggestions of a clear reduction in the number of hospitalizations and death in symptomatic CHF, this incisive meta-analysis provides the following clinically important information on ACE inhibitors: 1) The reduction in mortality may be caused by a reduction in progressive CHF; 2) the benefit appears consistent among various ACE inhibitors, suggesting a class effect; 3) the benefit occurs and is most marked in the first 3 months of treatment; and 4) the patients likely to receive the greatest benefit are those with the lowest ejection fraction.

This meta-analysis makes a compelling argument for the early and routine use of any ACE inhibitor in patients with symptomatic CHF. The high mortality in patients who are optimally treated for CHF, however, indicates that the problem is far from solved. The challenge is now to develop strategies that prevent ventricular dysfunction from progressing to symptomatic CHF.

Mandeep R. Mehra, MD
Hector O. Ventura, MDOchsner Medical InstitutionsNew Orleans, Louisiana, USA


Reference

1. Coats AJ, Adamopoulos S. Neurohormonal mechanisms and the role of angiotensin-converting enzyme (ACE) inhibitors in heart failure. Cardiovasc Drugs Ther. 1994;8:685-92.


Author's update

An individual patient data meta-analysis (1) showed similar results.

1. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355:1575-81.