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Cited by 9,214Heart Failure Treatment and ManagementHormonal Regulation and HypertensionPotassium and Related Disorders

The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure

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Pitt, Bertram, Zannad, Faiez, Remme, Willem J., Cody, Robert, Castaigne, Alain, Perez, Alfonso, Palensky, Jolie, Wittes, Janet·1999·New England Journal of Medicine
DOI 10.1056/nejm199909023411001
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Abstract

BACKGROUND AND METHODS: Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. RESULTS: The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. CONCLUSIONS: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

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Crossref · 10.1056/nejm199909023411001

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  • Steroidal MRA, such as spironolactone and eplerenone, have established cardiovascular benefits in those with heart failure and are useful for treating primary hyperaldosteronism and refractory hypertension.

    “Steroidal MRA, such as spironolactone and eplerenone, have established cardiovascular bene fi ts in those with heart failure and are useful for treating primary hyperaldosteronism and refractory hypertension.”

    From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [157]

    The Conclusions (page unavailable) report that spironolactone reduced morbidity and death in patients with severe heart failure. The discussion (page unavailable) mentions eplerenone as a possible way to reduce gynecomastia, but does not establish its cardiovascular benefit. The paper also does not establish usefulness for primary hyperaldosteronism or refractory hypertension; it only suggests implications for hypertension generally. (LLM, conf=0.90)

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  • Steroidal MRA are standard of care for treatment of heart failure (particularly with reduced ejection fraction) and primary hyperaldosteronism.

    “Steroidal MRA are standard of care for treatment of heart failure (particularly with reduced ejection fraction) and primary hyperaldosteronism.”

    From KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease (2022) · cites this paper as [157]

    The Conclusions report that adding spironolactone to standard therapy reduced morbidity and death in severe heart failure, and Background and Methods specifies patients with ejection fraction of 35% or less. The paper does not establish steroidal MRAs as standard of care for primary hyperaldosteronism; it mentions that condition only in a reference. It also says aldosterone-receptor blockers were used infrequently for heart failure at the time, rather than describing them as existing standard care (Conclusions; page not specified in our copy). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Steroidal MRA are useful for management of heart failure as well as primary hyperaldosteronism and resistant hypertension.

    “Steroidal MRA are useful for management of heart failure as well as primary hyperaldosteronism and resistant hypertension.32,33”

    From Executive summary of the KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease: an update based on rapidly emerging new evidence (2022) · cites this paper as [33]

  • Beta-blockers are effective at reducing all-cause death and hospitalization for heart failure in patients with HFrEF, with or without diabetes.

    “Beta-blockers are effective at reducing all-cause death and hospitalization for HF in patients with HFrEF, with or without diabetes.[509][510][511][512]”

    From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [509]

  • Mineralocorticoid receptor antagonists can lower blood pressure, especially with borderline or low potassium, and reduce morbidity and mortality in left ventricular dysfunction.

    “Mineralocorticoid receptor antagonists (spironolactone, eplerenone) can also be effective antihypertensive agents (particularly for those with borderline or low potassium levels)89 and are important for morbidity and mortality reduction in patients with left ventricular dysfunction.90,91”

    From Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association (2020) · cites this paper as [91]

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Cites

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1 of the 48 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulat- ing cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation 1990;82:1730-6.

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Authors
Pitt, B., Zannad, F., Remme, W. J., Cody, R., Castaigne, A., Perez, A., Palensky, J., & Wittes, J.
Affiliations
  • University of Michigan (US)
  • Cardiovascular Research Foundation (US)
  • Centre Hospitalier Universitaire Henri-Mondor (FR)
  • Statistics Collaborative (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
1999-09-02
Volume
341
Issue
10
Pages
709-717
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm199909023411001
OpenAlex
W2323458614
Cited by
9,214
References
48
Citations by year
2026: 264 · 2025: 279 · 2024: 273 · 2023: 298 · 2022: 335 · 2021: 309 · 2020: 326 · 2019: 295 · 2018: 298 · 2017: 304 · 2016: 344 · 2015: 351 · 2014: 366 · 2013: 383 · 2012: 398
FWCI
198.11
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Potassium and Related Disorders
Keywords
spironolactone, severe heart failure, aldosterone receptor blockade, mortality, hospitalization for worsening heart failure, sudden cardiac death, gynecomastia, hyperkalemia, NYHA functional class, ACE inhibitors, loop diuretics, digoxin
MeSH terms
Aged, Mineralocorticoid Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Cause of Death, Diuretics, Double-Blind Method, Drug Therapy, Combination, Female, Gynecomastia, Heart Diseases, Heart Failure, Hospitalization, Humans, Hyperkalemia, Male, Middle Aged, Risk, Spironolactone, Survival Analysis

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