EFFECT OF MINERALOCORTICOID RECEPTOR ANTAGONISTS ON CARDIOVASCULAR MORTALITY IN ADULTS WITH HEART FAILURE: AMETA-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
DOI:
https://doi.org/10.22159/ijcpr.2026v18i2.8086Keywords:
Heart failure, Mineralocorticoid Receptor Antagonists, Cardiovascular mortality, Randomized controlled trials, Meta-analysis, Spironolactone, EplerenoneAbstract
Objective: To evaluate the effect of mineralocorticoid receptor antagonists on cardiovascular mortality in adults with heart failure using evidence from randomized controlled trials.
Methods: A systematic review and meta-analysis of randomized controlled trials was conducted in accordance with PRISMA 2020 guidelines. Electronic databases, including PubMed, Scopus, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched for eligible studies. Trials enrolling adult patients with heart failure and comparing MRAs with placebo were included. Cardiovascular mortality was the primary outcome. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for individual studies and pooled using an inverse-variance fixed-effect model. Statistical heterogeneity was evaluated using Cochran’s Q test and the I² statistic. Risk of bias was assessed using the Cochrane Risk of Bias tool, and certainty of evidence was evaluated using the GRADE framework.
Results: Three large, double-blind randomized controlled trials comprising 11,032 patients met the inclusion criteria. Treatment with MRAs was associated with a significant reduction in cardiovascular mortality compared with placebo. The pooled analysis demonstrated a 20% relative reduction in cardiovascular mortality (pooled RR = 0.80; 95% CI: 0.73–0.86). No significant heterogeneity was observed among the included studies (I² = 0%). All trials were judged to have a low risk of bias, and the certainty of evidence for the primary outcome was rated as high.
Conclusion: Mineralocorticoid receptor antagonists significantly reduce cardiovascular mortality in patients with heart failure. These findings provide high-certainty evidence supporting their use as an essential component of guideline-directed medical therapy.
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References
1. Savarese G, Lund LH. Global public health burden of heart failure. Card Fail Rev. 2017;3(1):7-11. doi: 10.15420/cfr.2016:25:2, PMID 28785469.
2. Roger VL. Epidemiology of heart failure: a contemporary perspective. Circ Res. 2021;128(10):1421-34. doi: 10.1161/CIRCRESAHA.121.318172, PMID 33983838.
3. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345(23):1689-97. doi: 10.1056/NEJMra000050, PMID 11759649.
4. Pitt B. Aldosterone blockade in patients with chronic heart failure. Cardiol Clin. 2008;26(1):15-21, doi: 10.1016/j.ccl.2007.12.016, PMID 18312902.
5. Struthers AD. Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J. 1995;16(Suppl N):103-6. doi: 10.1093/eurheartj/16.suppl_N.103, PMID 8682054.
6. Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJ, Swedberg K. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J. 2012;33(22):2782-95. doi: 10.1093/eurheartj/ehs257, PMID 22942339.
7. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC) with the special contribution of the heart failure association (HFA) of the ESC. Eur J Heart Fail. 2022;24(1):4-131. doi: 10.1002/ejhf.2333, PMID 35083827.
8. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ. Cochrane handbook for systematic reviews of interventions. Version 6.4. London (UK): Cochrane; 2023. Available from: https://training.cochrane.org/handbook.
9. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71, PMID 33782057.
10. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. doi: 10.1136/bmj.d4002, PMID 21784880.
11. Das P. Meta-analysis in excel: a beginner’s guide: simplifying statistics for medical students and researchers. 1st ed. Chhattisgarh: Shashwat Publication; 2024.
12. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A. The effect of spironolactone on morbidity and mortality in patients with severe heart failure randomized aldactone evaluation study investigators. N Engl J Med. 1999;341(10):709-17. doi: 10.1056/NEJM199909023411001, PMID 10471456.
13. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B. Eplerenone a selective aldosterone blocker in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-21. doi: 10.1056/NEJMoa030207, PMID 12668699.
14. Zannad F, McMurray JJ, Krum H, Van Veldhuisen DJ, Swedberg K, Shi H. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21. doi: 10.1056/NEJMoa1009492, PMID 21073363.
15. Sterne JA, Higgins JP, Elbers RG, Reeves BC. Risk of bias 2: a tool to assess risk of bias in randomised trials. Version 22. In: Cochrane; 2019. Available from: https://www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2.
16. Brilla CG, Weber KT. Mineralocorticoid excess dietary sodium and myocardial fibrosis. J Lab Clin Med. 1992;120(6):893-901. PMID 1453111.
17. Pitt B, Pedro Ferreira J, Zannad F. Mineralocorticoid receptor antagonists in patients with heart failure: current experience and future perspectives. Eur Heart J Cardiovasc Pharmacother. 2017;3(1):48-57. doi: 10.1093/ehjcvp/pvw016, PMID 27530337.
18. McMurray JJ, Packer M. How should we sequence the treatments for heart failure and a reduced ejection fraction? a redefinition of evidence-based medicine. Circulation. 2021;143(9):875-7. doi: 10.1161/circulationaha.120.052926, PMID 33378214.
19. Matsumoto S, Kondo T, Jhund PS, Campbell RT, Swedberg K, Van Veldhuisen DJ. Underutilization of mineralocorticoid antagonists in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol. 2023;82(11):1080-91. doi: 10.1016/j.jacc.2023.06.021, PMID 37642608.
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Copyright (c) 2026 Dr. Pranab Das, Dr. Mahaprasad Pal, Dr. Wasim Akram, Dr. Bodhisatya Das
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