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Rekha Garg, MD, MS; Salim Yusuf, MBBS, FRCP, DPhil; the Collaborative Group on ACE Inhibitor Trials; W. D. Bussmann, MD; Peter Sleight, MD; Andrew Uprichard, MD; Barry Massie, MD; Barry McGrath, MD; Berit Nilsson, PhD; Bertram Pitt, MD; Bruno Magnani, MD; Carol Maskin, MD; Ettore Ambrosioni, MD; Ewa Rucinska, MD; Franz X. Kleber, MD; Gary Jennings, MD; Gianni Tognoni, MD; Helmut Drexler, MD; John G. F. Cleland, MD; Joseph A. Franciosa, MD; Jouko Remes, MD; Karl Swedberg, MD; Karl Swedberg, MD; Kenneth Dickstein, MD; Lothar Maass, MD; Marc Pfeffer, MD; Mark A. Creager, MD; Maryann Gordon, MD; Michael Joy, MD; Norman Sharpe, MD; Peter Sleight, MD; Pierre Desche, MD; Robin McGarry, MD; Rory Collins, MD; Steven G. Chrysant, MD; Vincenzo Cicchetti, MD; W. D. Bussmann, MD

JAMA. 1995;273(18):1450-1456.

Abstract
Objective.
—To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure.

Data Sources and Study Selection.
—Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat, regardless of sample size. Trials were identified based on literature review and correspondence with investigators and pharmaceutical firms.

Data Extraction.
—Using standard tables, data were extracted by one author and confirmed where necessary by the other author or the principal investigator of the trial. Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm.

Data Synthesis.
—The data for each outcome were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method. Overall, there was a statistically significant reduction in total mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.67 to 0.88; P<.001) and in the combined endpoint of mortality or hospitalization for congestive heart failure (OR, 0.65; 95% CI, 0.57 to 0.74; P<.001). Similar benefits were observed with several different ACE inhibitors, although the data were largely based on enalapril maleate, captopril, ramipril, quinapril hydrochloride, and lisinopril. Reductions for total mortality and the combined endpoint were similar for various subgroups examined (age, sex, etiology, and New York Heart Association class). However, patients with the lowest ejection fraction appeared to have the greatest benefit. The greatest effect was seen during the first 3 months, but additional benefit was observed during further treatment. The reduction in mortality was primarily due to fewer deaths from progressive heart failure (OR, 0.69; 95% CI, 0.58 to 0.83); point estimates for effects on sudden or presumed arrhythmic deaths (OR, 0.91; 95% CI, 0.73 to 1.12) and fatal myocardial infarction (OR, 0.82; 95% CI, 0.60 to 1.11) were less than 1 but were not significant.

Conclusions.
—Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients.

(JAMA. 1995;273:1450-1456)

Author Affiliations
Klinikum der Universitat, Frankfurt, Germany; Oklahoma Cardiovascular and Hypertension Center, Oklahoma City; University of Genoa (Italy); Hammersmith Hospital, London, England; Brigham and Women's Hospital, Boston, Mass; Institut de Recherches Internationales Servier, Courbevoie, France; Central Hospital, Rogaland, Norway; University of Freiburg (Germany); CIBA-GEIGY Corp, Summit, NJ; Hoechst-Roussel Pharmaceutical, Somerville, NJ; Alfred Hospital and Baker Medical Unit, Melbourne, Australia; St Peter's Hospital, Chertsey, England; Ludwig Maximilian Universitat, Munich, Germany; Hoechst AG, Frankfurt, Germany; University of Bologna (Italy); Bristol-Myers Squibb, Princeton, NJ; Veterans Administration Medical Center, San Francisco, Calif; CIBA-GEIGY Corp, Summit, NJ; Monash Medical Center, Melbourne, Australia; Astra Hassle AB, Molndal, Sweden; Kuopio (Finland) University Hospital; Merck Human Health Division, West Point, Pa; University of Auckland (New Zealand); Goteborg (Sweden) University; Parke-Davis, Ann Arbor, Mich. Facilitators; (chair), University of Michigan, Ann Arbor; Universita degli Studi di Bologna (Italy); Oxford (England) University; Brigham and Women's Hospital, Boston, Mass; Oxford (England) University; Goteborg (Sweden) University; Instituto M. Negri, Milan, Italy

Klinikum der Universitat, Frankfurt, Germany; Oxford (England) University

From the Clinical Trials Branch, National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Garg), and the Division of Cardiology, Hamilton General Hospital, McMaster University, Hamilton, Ontario (Dr Yusuf). Dr Yusuf is a Career Scientist of the Medical Research Council of Canada.

Footnotes
Dr Yusuf has received monetary compensation for speaking engagements from several pharmaceutical companies, including some that manufacture ACE inhibitors.

A complete list of the Collaborative Group on ACE Inhibitors is provided at the end of this article.

Reprint requests to the Clinical Trials Branch, National Heart, Lung, and Blood Institute, Federal Bldg, Room 5C10, Bethesda, MD 20892 (Dr Garg).

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