The Effect of Mineralocorticoid Receptor Antagonists on Heart Failure with Nonreduced Ejection Fraction: A Systematic Review and Meta-Analysis

Background: The recommendations for mineralocorticoid receptor antagonists (MRAs) in patients with heart failure with nonreduced ejection fraction (HFnrEF), defined as heart failure with left ventricular ejection fraction > 40%, are not clear. This systematic review and meta-analysis aims to evaluate the effect of MRAs on patient-important outcomes in HFnrEF. Methods: We searched MEDLINE, Embase, Cochrane Database/Register from inception to September 6, 2024, for all randomized controlled trials comparing MRAs to placebo/standard of care in HFnrEF. Fixed and random effects models pooled estimates for mortality (all-cause and cardiovascular), HF hospitalization (HFH), functional capacity, health-related quality of life, and adverse outcomes. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed certainty-of-evidence assessments. Results: Eight RCTs reported on 10,313 patients with HFnrEF. Compared to placebo or standard of care, MRAs result in a reduction in HFH (risk ratio [RR] 0.83, 95% confidence interval [CI] 0.76-0.91; risk difference [RD] 29 fewer per 1000, 95% CI 31 fewer to 15 fewer; high certainty). Moderate-certainty evidence suggests that MRAs probably result in a slight reduction in all-cause mortality (RR 0.93, 95% CI 0.85-1.02; RD 11 fewer per 1000, 95% CI 23 fewer to 3 more) and cardiovascular mortality (RR 0.92, 95% CI 0.81-1.05; RD 7 fewer per 1000, 95% CI 16 fewer to 5 more). MRA use is associated with more hyperkalemia and worsening renal function, with no difference in withdrawal of the drug due to adverse events. compared to placebo. Conclusions: Among patients with HFnrEF, MRAs reduce HFH. Although MRAs increase the risk of hyperkalemia and worsening renal function, this does not lead to higher rates of drug discontinuation.