Cardiology · Medical Literature
Systematic Review: Mineralocorticoid Receptor Antagonists in Heart Failure with Preserved and Mildly Reduced Ejection Fraction.
Abstract
Heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF) is a prevalent condition associated with significant morbidity and mortality, and the benefits of mineralocorticoid receptor antagonists (MRAs) remain unclear. To develop a systematic review on the use of MRAs in patients with HFpEF or HFmrEF, a systematic review and meta-analysis were conducted using a broad search strategy in the following databases: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Randomized controlled trials that evaluated the use of MRAs in patients with HFpEF compared to control groups were included. The quality of evidence and the strength of the recommendation were assessed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Eight studies were included. No statistically significant differences were observed for the outcomes of overall mortality and cardiovascular mortality compared to the control group for any of the MRAs. A benefit was observed with a reduced risk of hospitalization for heart failure (relative risk: 0.87; 95% confidence interval: 0.79 to 0.96; moderate certainty of evidence) and of worsening heart failure events (relative risk: 0.83; 95% confidence interval: 0.77 to 0.89; high certainty of evidence). The results of the meta-analysis indicate a significant benefit from MRAs, spironolactone or finerenone, to reduce hospitalizations and worsening heart failure events in patients with HFpEF or HFmrEF. Mineralocorticoid Receptor Antagonists; Diastolic Heart Failure; Systolic Heart Failure; Systematic Review; Meta-Analysis.
Clinical relevance
In patients with heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF), do mineralocorticoid receptor antagonists (MRAs) reduce overall mortality, cardiovascular mortality, or hospitalization for heart failure compared to control? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis of randomized controlled trials (RCTs), evidence quality assessed using GRADE methodology","setting":"International; databases searched: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL); not restricted to a single institution or country","sampleSize":"8 RCTs included; aggregate patient-level n not reported in the available abstract","population":"Adults with HFpEF or HFmrEF enrolled in RCTs evaluating MRA therapy versus control; specific EF thresholds, NYHA class distribution, and comorbidity profiles across included trials not detailed in the available abstract","intervention":"Mineralocorticoid receptor antagonists (MRAs); specific agents (e.g., spironolactone, eplerenone, finerenone) and doses not individually enumerated in the available abstract","comparator":"Control group (placebo or standard care; specific comparator per trial not detailed in the available abstract)","primaryOutcome":"Overall (all-cause) mortality, cardiovascular mortality, and hospitalization for heart failure","followUp":"Not reported in the available abstract","fundingSource":"Not reported in the available abstract"}
Key findings
Eight RCTs were included in this systematic review and meta-analysis. For the outcomes of all-cause mortality and cardiovascular mortality, no statistically significant differences were observed between MRA-treated patients and control groups across any of the MRAs evaluated. A statistically significant reduction in hospitalization for heart failure was identified with MRA therapy (relative risk [RR]: 0.87; 95% CI: 0.79–0.96; moderate certainty of evidence per GRADE). The absolute risk reduction, NNT, and p-value for this hospitalization outcome were not reported in the available abstract. Clinically important adverse events — notably hyperkalemia and renal impairment, which are recognized class effects of MRAs — were not quantitatively reported in the available abstract and therefore cannot be characterized from this summary alone. No agent-specific subgroup results or heterogeneity statistics (I²) were reported in the available abstract.
Practice implications
This systematic review establishes that MRA therapy is associated with a statistically significant, moderate-certainty reduction in heart failure hospitalization (RR 0.87; 95% CI 0.79–0.96) in patients with HFpEF or HFmrEF, while failing to demonstrate a significant mortality benefit (all-cause or cardiovascular). The hospitalization risk reduction of approximately 13% in relative terms is directionally consistent with findings from other recent meta-analyses and the landmark FINEARTS-HF trial, but the magnitude of absolute benefit is indeterminate from this abstract alone. Critically, this review did NOT establish a survival benefit for any MRA in this population, which is an important distinction for clinical decision-making. The findings apply to the HFpEF/HFmrEF spectrum collectively; whether benefits differ by EF subgroup, MRA agent (steroidal vs. non-steroidal), sex, or comorbidity profile cannot be determined from the abstract. Patients with significant renal impairment or baseline hyperkalemia — who are at highest risk for MRA-related harm — may not have been adequately represented in included trials. The moderate GRADE certainty rating reflects meaningful residual uncertainty. Practice should not change based on this abstract alone; however, the hospitalization signal is hypothesis-strengthening and consistent with an emerging evidence base supporting selective MRA use (particularly finerenone) in this population. Clinicians should also note this summary is based solely on the published abstract; full-text review is required before firm conclusions are drawn. __LIMITATIONS__ Only the abstract is available for review; critical methodological details (total N, individual trial follow-up duration, heterogeneity statistics, agent-specific subgroup results, adverse event quantification) cannot be verified or fully assessed.,Small number of included trials (n=8) limits statistical power and subgroup analyses; aggregate sample size not reported.,HFpEF and HFmrEF are pooled as a combined population; differential effects by EF category, age, sex, or comorbidities cannot be assessed from the available data.,No mortality benefit detected; the hospitalization reduction (RR 0.87), while statistically significant, may not reflect clinically meaningful benefit without absolute risk reduction and NNT data.,Surrogate and intermediate outcomes (e.g., echocardiographic parameters) not assessed in this review; hospitalization may itself be a proximate rather than ultimate patient-centered outcome.,Heterogeneity in HFpEF diagnostic criteria across included trials (EF thresholds, natriuretic peptide requirements) limits generalizability.,Known methodological concerns in landmark component trials (e.g., TOPCAT adherence and geographic enrollment issues) may introduce bias into pooled estimates if included.,Adverse event profile (hyperkalemia, renal impairment) not quantitatively reported in the available abstract, limiting benefit-risk characterization.,Funding source not reported; potential for publication bias or industry influence in primary RCTs cannot be excluded.,GRADE moderate certainty rating indicates some residual uncertainty that could change the estimate of effect with additional evidence. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This GRADE-assessed meta-analysis of 8 RCTs finds that MRA therapy in HFpEF/HFmrEF significantly reduces hospitalization for heart failure (RR 0.87; 95% CI 0.79–0.96; moderate certainty), but does not demonstrate a statistically significant benefit on all-cause or cardiovascular mortality. The hospitalization signal is clinically meaningful but should be contextualized with individual patient risk of hyperkalemia and renal impairment before initiating MRA therapy in this population, and full-text review is necessary before applying these findings to practice.