Highlight
This comprehensive individual participant data meta-analysis assessed the effectiveness and safety of mineralocorticoid receptor antagonists (MRAs) in Black versus non-Black patients with heart failure (HF). No significant racial differences were found in treatment outcomes or adverse event profiles across HF phenotypes. Despite younger age, Black patients experienced higher rates of HF hospitalization and mortality, underscoring the critical need for equitable therapeutic application.
Study Background
Heart failure remains a major global public health burden characterized by significant morbidity and mortality. The heterogeneity in HF epidemiology and treatment response across racial groups has raised clinical concerns, notably regarding the efficacy of renin-angiotensin system inhibitors in Black patients. Mineralocorticoid receptor antagonists (MRAs), including spironolactone, eplerenone, and finerenone, are cornerstone therapies with proven mortality benefits in HF with reduced ejection fraction (HFrEF) and increasingly evaluated in HF with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Given persistent disparities and underrepresentation of Black patients in clinical trials, clarifying MRA efficacy and safety by race is critical for informed evidence-based treatment and health equity.
Study Design
This post hoc individual participant data meta-analysis pooled data from four pivotal, randomized, double-blind, placebo-controlled trials investigating MRAs in HF: RALES and EMPHASIS-HF for HFrEF, and TOPCAT and FINEARTS-HF for HFmrEF/HFpEF. Collectively, 13,846 patients were randomized, including 577 (4.2%) self-identified as Black. The primary composite endpoint was cardiovascular death or first HF hospitalization, with secondary outcomes including each component separately. Safety outcomes entailed adverse events associated with MRA use. The analysis stratified results by self-reported race (Black versus non-Black) and by HF phenotype, employing hazard ratios (HR) and interaction testing for treatment effect heterogeneity.
Key Findings
Baseline characteristics revealed that Black patients were younger (median age 64 vs. 70 years) but had higher crude rates of HF hospitalization and cardiovascular death, highlighting disparities in clinical outcomes. The primary composite endpoint demonstrated hazard ratios for MRA versus placebo of 0.87 (95% CI, 0.66-1.15) in Black patients and 0.77 (95% CI, 0.72-0.82) in non-Black patients (Pinteraction=0.34), translating to absolute risk reductions of approximately 3.9 and 2.7 fewer events per 100 patient-years respectively.
For individual endpoints, first HF hospitalization showed HRs of 0.86 (95% CI, 0.63-1.17) for Black and 0.73 (95% CI, 0.68-0.80) for non-Black patients (Pinteraction=0.36). Cardiovascular death hazard ratios were 0.75 (95% CI, 0.48-1.17) in Black patients and 0.81 (95% CI, 0.74-0.90) in non-Black patients (Pinteraction=0.80). No statistically significant interaction by race was evident for either efficacy endpoint.
Safety profiles were comparable between racial groups, with no significant modification of adverse events such as hyperkalemia or renal dysfunction by race. Moreover, race did not influence MRA efficacy when analyzed separately within HFrEF and HFmrEF/HFpEF subgroups.
Expert Commentary
This large-scale meta-analysis provides robust evidence that MRAs offer consistent relative and absolute benefits across racial groups in HF, challenging presumptions of diminished efficacy in Black patients. The inclusion of a broad HF population spanning ejection fraction phenotypes enhances the generalizability of findings. Nevertheless, the low representation of Black patients (4.2%) reflects ongoing enrollment challenges, warranting enhanced efforts for diversity in HF trials.
Mechanistically, MRAs target the mineralocorticoid receptor-mediated pathways which appear universally relevant across racial backgrounds in HF pathophysiology. The findings agree with current guideline recommendations endorsing MRAs irrespective of race. However, addressing the disproportionately higher HF-related morbidity and mortality in Black patients also requires multifaceted approaches including improved social determinants of health and access to care.
Conclusion
The present individual participant data meta-analysis substantiates that mineralocorticoid receptor antagonists confer clinically meaningful benefits in heart failure patients regardless of racial identity and HF subtype. Treatment decisions should focus on established indications without race-based adjustments. Future research should aim to bolster inclusion of underrepresented populations and explore the complex interplay between genetics, environment, and HF outcomes to optimize personalized care.
Funding and ClinicalTrials.gov
This research was supported by institutions and trial sponsors corresponding to the original RALES, EMPHASIS-HF, TOPCAT, and FINEARTS-HF studies. For detailed trial registration information and funding sources, please refer to the individual trial registries and publications.
References
1. Butt JH, et al. MRAs and Race in Heart Failure: An Individual Participant Data Meta-Analysis of Randomized Trials. Circulation: Heart failure. 2026 Aug 7;e014355. PMID: 42565235.
2. McMurray JJV et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014;371:993–1004.
3. Zannad F et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med. 2011;364:11-21.
4. Pitt B et al. The RALES Investigators. N Engl J Med. 1999;341:709-17.
5. Lam CSP, et al. Therapeutic Approaches to HFpEF. Nat Rev Cardiol. 2020;17:559-574.
6. Yancy CW et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022;145:e895-e1032.
