The aim was to review the evidence for the clinical and cost-effectiveness of MRAs in people with HFREF. 6.2.4.2 Review question: What is the clinical and cost effectiveness of adding a mineralocorticoid receptor antagonist to existing standard first line treatment in people with heart failure with reduced ejection fraction? For full details see review protocol in Appendix L. Table 46: PICO characteristics of review question Population People diagnosed with heart failure with reduced ejection fraction (HFREF). Interventions Mineralocorticoid receptor antagonist: Spironolactone (up to 50mg/day) Eplerenone (up to 50mg/day) Comparison Placebo Outcomes CRITICAL All-cause mortality Quality of life Unplanned hospitalisation IMPORTANT Improvement of NYHA class Adverse events - Renal function Adverse events Gynaecomastia Adverse events Hypotension Adverse events - Hyperkalaemia Study design Systematic Review RCT Chronic Heart Failure Treating Heart Failure NICE 2018. All rights reserved. Subject to Notice of rights. ISBN: 978-1-4731-3093-7 6.2.4.3 Clinical evidence A search was conducted for randomised controlled trials comparing the effectiveness of mineralocorticoid receptor antagonists with placebo in in people with heart failure with reduced ejection fraction (HFREF) on current standard first line treatment. Four studies (reported in 13 papers) were included in the review: Eplerenone in Mild Patients Hospitalization and Survival Study , EMPHASIS-HF in Japanese patients (J- , Randomized Aldactone Evaluation Study (RALES)268, 350, 351 and Udelson 2010345 . These are summarised in Table 47 below. Three of the included studies compared eplerenone with placebo and one study compared spironolactone with placebo. Evidence from these studies is summarised in the clinical evidence summary below (Table 48). See also the study selection flow chart in Appendix C, forest plots in Appendix E, study evidence tables in Appendix F, GRADE tables in Appendix H and excluded studies list in Appendix I. 