Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (FINEARTS-HF)

Authors, Journal, Affiliations, Type, DOI

• Solomon SD, McMurray JJV, Vaduganathan M, Claggett B, Jhund PS, Desai AS, Henderson AD, Lam CSP, Pitt B, Senni M, Shah SJ, Voors AA, Zannad F, et al. (FINEARTS-HF Committees and Investigators)
• N Engl J Med 2024;391(16):1475–1485
• Multi-institutional (654 sites, 37 countries); co-corresponding authors at Brigham and Women's Hospital/Harvard and University of Glasgow
• Phase 3, international, multicenter, double-blind, randomized, placebo-controlled, event-driven trial
• DOI: https://doi.org/10.1056/NEJMoa2407107
• Funded by Bayer

Overview

FINEARTS-HF is a large phase 3 double-blind RCT (n=6,001; 654 sites; 37 countries; median 32 months) evaluating finerenone — a nonsteroidal mineralocorticoid receptor antagonist (MRA) — vs placebo in patients with heart failure and LVEF ≥40% (HFmrEF and HFpEF). Finerenone significantly reduced the composite primary endpoint of total worsening HF events and CV death (rate ratio 0.84; 95% CI 0.74–0.95; P=0.007), becoming the first MRA to achieve a positive primary endpoint in this population. The benefit was driven by HF hospitalizations (rate ratio 0.82; P=0.006) rather than CV mortality (HR 0.93; NS) or all-cause mortality (HR 0.93; NS). Finerenone was associated with hyperkalemia but no hyperkalemia deaths; it reduced hypokalemia. Crucially, benefits were consistent in patients on and off SGLT2 inhibitors at baseline.

Keywords

Finerenone, mineralocorticoid receptor antagonist (MRA), nonsteroidal MRA, HFpEF, HFmrEF, heart failure with preserved ejection fraction, FINEARTS-HF, TOPCAT, SGLT2 inhibitors, hyperkalemia, worsening heart failure, Kansas City Cardiomyopathy Questionnaire

Key Takeaways

Background and Rationale

• Steroidal MRAs (spironolactone, eplerenone) reduce morbidity and mortality in HFrEF (RALES, EMPHASIS-HF, EPHESUS) but efficacy in HFmrEF/HFpEF had not been established; TOPCAT (spironolactone in HFpEF) failed its primary composite endpoint (HR 0.89; P=0.14), though HF hospitalizations were reduced and data integrity issues in Russia/Georgia confounded interpretation.
• Finerenone is a nonsteroidal MRA with distinct physicochemical properties from spironolactone: greater MR selectivity, no off-target steroid receptor binding (reduced androgenic side effects), and different pharmacokinetics (shorter half-life, no active metabolites). Previously shown to reduce CV events and kidney disease progression in CKD+T2DM (FIDELIO-DKD, FIGARO-DKD).
• Finerenone was designed to test whether a more selective MRA could succeed in HFmrEF/HFpEF where spironolactone had failed.

Study Design

• Phase 3, international, multicenter, double-blind, parallel-group, event-driven RCT; 1:1 randomization; finerenone vs placebo in addition to usual therapy.
• Finerenone dosing: Maximum 20 mg OD (eGFR ≥60) or maximum 40 mg OD (eGFR ≥25 and <60) — dose individualized based on eGFR and potassium.
• Stratification: Geographic region; baseline LVEF (<60% or ≥60%).
• Key inclusion criteria: Age ≥40; symptomatic HF; LVEF ≥40%; structural heart disease (echo); elevated natriuretic peptides.
• Background therapy at baseline (overall): Beta-blockers 84.9%; ACE-I 35.9%; ARB 35.0%; ARNI 8.5%; SGLT2i 13.6%.
• Mean LVEF 53±8%; 69.1% NYHA class II; 20.3% enrolled during or within 7 days of a HF event.
• Enrollment: September 2020 – January 2023; trial end June 2024; median follow-up 32 months.

Primary Endpoint: Total Worsening HF Events + CV Death

• Rate ratio 0.84 (95% CI 0.74–0.95; P=0.007) — finerenone significantly better than placebo.
• 1,083 primary-outcome events in 624 (20.8%) finerenone patients vs 1,283 events in 719 (24.0%) placebo patients.
• Total events analysis used (LWYY model — same as HELIOS-B) — captures recurrent clinically meaningful events.
• Sensitivity analysis (time-to-first HF event or CV death): HR 0.84 (95% CI 0.76–0.94) — consistent.
• Results consistent across all 17 prespecified subgroups including: LVEF <60% vs ≥60%; SGLT2i use at baseline (yes vs no).

Secondary Endpoints: Worsening HF Events (Total)

• Total worsening HF events (alone): 842 vs 1,024; rate ratio 0.82 (95% CI 0.71–0.94; P=0.006) — significant.

Secondary Endpoints: Mortality

• CV death: 242 (8.1%) vs 260 (8.7%); HR 0.93 (95% CI 0.78–1.11) — NOT significant.
• All-cause death: 491 (16.4%) vs 522 (17.4%); HR 0.93 (95% CI 0.83–1.06) — NOT significant.

Secondary Endpoints: Quality of Life and Function

• KCCQ total symptom score (common effect months 6, 9, 12): LS mean change +8.0±0.3 (finerenone) vs +6.4±0.3 (placebo); difference +1.6 points (95% CI 0.8–2.3; P<0.001) — statistically significant but below 5-point MCID threshold.
• NYHA functional class improvement at month 12: 18.6% vs 18.4%; OR 1.01 (95% CI 0.88–1.15) — NOT significant.

Secondary Endpoints: Kidney Composite

• Sustained eGFR decrease ≥50%, sustained eGFR <15, or long-term dialysis/transplant: 75 (2.5%) vs 55 (1.8%); HR 1.33 (95% CI 0.94–1.89) — NOT significant; numerically higher with finerenone.
• Population had low prevalence of albuminuria and few kidney events — low-risk for kidney disease progression.

Safety

• Serious adverse events: 38.7% (finerenone) vs 40.5% (placebo) — lower with finerenone.
• Discontinuation (not death): 20.4% vs 20.6% — similar.
• At end-of-trial, 68.4% (finerenone) vs 78.4% (placebo) at individualized target dose — ~10% differential in dose attainment.
• Hyperkalemia (K+ >6.0 mmol/L): 86 (3.0%) vs 41 (1.4%) — higher with finerenone. No hyperkalemia deaths; 0.5% vs 0.2% hyperkalemia-related hospitalizations.
• Hypokalemia (K+ <3.5 mmol/L): Less common with finerenone.
• Creatinine increases: More common with finerenone.
• Systolic BP: 3.4 mmHg lower at 6 months with finerenone — does not appear to mediate primary benefit.

Context: TOPCAT vs FINEARTS-HF

• TOPCAT (spironolactone): primary composite HR 0.89 (95% CI 0.77–1.04; P=0.14) — NOT significant; HF hospitalization component HR 0.83 (P=0.04) significant. Data integrity problems in Russia/Georgia substantially confound interpretation.
• FINEARTS-HF (finerenone): primary composite rate ratio 0.84 (P=0.007) — SIGNIFICANT. Trial integrity maintained across 37 countries; no integrity concerns.
• The two trials differ in: drug (steroidal vs nonsteroidal MRA), endpoint analysis (time-to-first vs total events), follow-up (3.3 years vs 2.7 years), background therapy (no SGLT2i in TOPCAT era vs 13.6% in FINEARTS-HF), and data integrity.
• Direct drug comparison between spironolactone and finerenone in HFpEF is not possible from these data.

Context: FINEARTS-HF and SGLT2 Inhibitors

• Benefit of finerenone consistent in patients on SGLT2i (13.6% at baseline) vs those not on SGLT2i — suggests complementary mechanism.
• Both SGLT2i and finerenone reduce HF hospitalizations but not mortality in HFmrEF/HFpEF; whether combination is additive vs synergistic is unknown (no dedicated combination trial in this EF range).

Limitations of the document

• Few Black patients enrolled — proportional to regional demographics but limits generalizability.
• Conducted during COVID-19 pandemic — results were consistent after censoring data after first COVID-19 episode.
• All prespecified subgroups underpowered — subgroup results should be interpreted cautiously.
• Cannot determine whether similar benefits would be seen with other MRAs (e.g., spironolactone, eplerenone).
• Kidney composite numerically worse (HR 1.33) — though not statistically significant, this signals that nephroprotection from finerenone in HFpEF cannot be assumed; this population had low albuminuria burden unlike CKD-T2DM trials.
• KCCQ improvement (+1.6 points) statistically significant but clinically marginal (below 5-point MCID).
• Industry-funded (Bayer); academic investigators had data access and manuscript input.

Key Concepts Mentioned

• concepts/Diuretic-Resistance — background diuretic therapy in HFpEF management
• concepts/Cardiorenal-Syndrome — kidney composite outcome context; divergent nephroprotective signals in CKD vs HFpEF

Key Entities Mentioned

• entities/HFpEF — primary disease studied
• entities/Finerenone — the therapeutic agent studied
• entities/Heart-Failure — overarching framework
• entities/HFrEF — context for prior MRA evidence (RALES, EMPHASIS-HF)
• entities/Sacubitril-Valsartan — referenced via PARAGON-HF KCCQ comparison

Wiki Pages Updated

• wiki/sources/finerenone-hfpef-fineartshf-nejm-2024.md — created
• wiki/entities/HFpEF.md — added FINEARTS-HF results under MRA section; new contradictions added; source_count updated
• wiki/entities/Finerenone.md — created
• wiki/sourceindex.md — updated
• wiki/wikiindex.md — updated