Focus on finerenone: the FINEARTS-HF study

Abstract

Mineralcorticoid receptor (MR) blockade is a mainstay of treatment for heart failure with reduced ejection fraction (HFrEF); however, the benefit is less well established in heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF). The TOPCAT study failed to demonstrate a reduction in cardiovascular mortality and heart failure (HF) hospitalizations in this population but suggested potential benefits of mineralocorticoid receptor antagonists (MRAs) in specific patients subgroups. The FINEARTS-HF study, which evaluated the non-steroidal MRA finerenone in patients with HFmrEF or HFpEF, demonstrated a significant reduction in the primary composite endpoint of cardiovascular death and events related to worsening of heart failure (WHF), primarily driven by a decrease in total WHF events. Moreover, the FINEARTS-HF study demonstrated consistent efficacy across the entire left ventricular ejection fraction (LVEF) spectrum, regardless of sodium–glucose cotransporter 2 inhibitors use, sex, or age, with an early onset of benefit and a favourable safety and tolerability profile. Finerenone is currently indicated in class I in diabetic patients with chronic kidney disease to reduce the risk of HF; in light of the FINEARTS-HF results, it could become a new pillar of therapy for patients with HFpEF and HFmrEF.

Introduction

For decades, the treatment of heart failure with preserved ejection fraction (HFpEF) primarily focused on managing comorbidities and symptoms, mainly with diuretics. Only recently, sodium–glucose cotransporter 2 inhibitors (SGLT2i), originally developed as antidiabetic agents, have been approved to reduce mortality and hospitalizations in patients with heart failure (HF); SGLT2is have demonstrated significant efficacy across a broad spectrum of conditions, including chronic kidney disease (CKD) and HFpEF.^1,2

A key pathological process in HF is the heightened activation of mineralocorticoid receptors (MR), linked to an imbalance in the renin–angiotensin–aldosterone system. Guidelines recommend MR blockade in patients with reduced ejection fraction heart failure (HFrEF); however, in patients with HFpEF and in heart failure with mildly reduced ejection fraction (HFmrEF), the clinical benefit appears less evident.

A first attempt to test the efficacy of a mineralocorticoid receptor antagonist (MRA) in HFpEF and HFmrEF was conducted with spironolactone in 2014 with the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist).³ However, this study did not reach the primary endpoint of reducing cardiovascular mortality and hospitalizations for HF, mainly due to issues related to the study conduct itself, patient selection, and protocol adherence. Nonetheless, it provided important indications about the potential use of this class of drugs in certain patient subgroups.

Recently, finerenone, a new selective non-steroidal mineralocorticoid receptor antagonist characterized by high diuretic and antifibrotic efficacy and a reduced risk of side effects, has demonstrated in the parallel studies FIGARO-DKD (in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease)⁴ and FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease)⁵—the former focused on renal outcomes while the latter focused on cardiovascular outcomes in patients with diabetic nephropathy—the ability to reduce multiple outcomes, including the decline in glomerular filtration rate, end-stage renal disease, cardiovascular mortality, and hospitalizations for HF.

‘FIDELITY’, the aggregated analysis of data from the FIDELIO-DKD and FIGARO-DKD studies considered a composite cardiovascular endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalizations for HF, and a composite renal outcome (end-stage renal disease, renal death, dialysis, or kidney transplant).⁶ In a median follow-up of 3 years, among the 13 026 enrolled patients, the treatment arm, compared to placebo, showed a significant 14% reduction in the composite cardiovascular endpoint and a 23% reduction in the composite renal endpoint. In terms of safety, finerenone determined a higher incidence of hyperkalaemia (1.7% vs. 0.6%) with treatment discontinuation.⁶

These findings led to a study designed to test the efficacy of finerenone in patients with HFmrEF and HFpEF, the FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure).⁷ Inclusion criteria included NYHA classes II–IV, serum potassium <5.0 mmol/L, estimated glomerular filtration rate (eGFR) > 25 mL/min/1.73 m2, and NT-proBNP ≥ 300 pg/mL or brain natriuretic peptide ≥ 100 pg/mL. Patients with a history of myocardial infarction within 90 days of randomization or with systolic blood pressure values >160 mmHg were excluded. Patients were randomized to placebo or finerenone based on eGFR (up to 20 mg of finerenone if eGFR ≤ 60 mL/min/1.73 m², up to 40 mg of finerenone if eGFR ≥60 mL/min/1.73 m²) and followed for a median of 42 months. The primary endpoint was a composite of cardiovascular death and HF events (first or recurrent event, hospitalization or urgent visit for HF), a choice that took into account repeated events, which have a significant clinical impact. Secondary endpoints were total HF events, improvement in NYHA class from baseline to 12 months, changes in NYHA class, increase in the Kansas City Cardiomyopathy questionnaire (KCCQ-TSS) score from baseline and at 6, 9, and 12 months, renal outcome (a composite of persistent reduction in eGFR ≥50% from baseline for a period ≥ 4 weeks, persistent decline in eGFR < 15 mL/min/1.73 m², dialysis or kidney transplant) and all-cause mortality.

In the first 28 months, 6014 patients were enrolled with a mean age of 72 ± 10 years, 45% women, and 69% in NYHA class II. The mean baseline LVEF was 53 ± 8% and 271 (4.5%) patients had a history of previous LVEF <40%. The median baseline eGFR was 61 (47–77) mL/min/1.73 m², and 2785 patients (48%) had eGFR < 60 mL/min/1.73 m². The median baseline albumin/creatinine ratio (UACR) was 18 (7–67) mg/g, and 2256 patients (39%) had UACR >30 mg/g.

While the inclusion criteria for FINEARTS-HF were similar to those of other recent studies in this patient population, participants in FINEARTS-HF had a higher overall risk of HF-related events.

A substantial proportion of FINEARTS-HF participants had experienced an HF-related event within 3 months of enrollment (54%), and 20% were enrolled shortly after hospitalization (within 7 days). Furthermore, FINEARTS-HF participants were more commonly treated with currently available HF drugs, particularly SGLT2is: among concomitant therapies, 85% of patients were on beta-blockers, 36% on angiotensin-converting enzyme inhibitors, 44% on angiotensin receptor blockers, 9% on angiotensin receptor-neprilysin inhibitors (ARNIs), 33% on calcium antagonists, 14% on SGLT2is. Although modest, the implementation of SGLT2is and ARNIs in the trial was the highest among those reported in contemporary trials. Finerenone reduced the primary composite endpoint by 16% compared to placebo (RR, 0.84; 95% CI, 0.74–0.95; P = 0.007), primarily driven by a significant reduction in total worsening heart failure (WHF) events (RR, 0.82; 95% CI, 0.71–0.94; P = 0.006). Cardiovascular mortality rates were similar between the finerenone and placebo groups (8.1% vs. 8.7%, respectively; RR, 0.93; 95% CI, 0.78–1.11).

Results from the more traditional analysis of a composite endpoint of the first event of HF worsening or cardiovascular death also demonstrated a significant benefit with finerenone, with a 16% relative risk reduction compared to placebo (RR, 0.84; 95% CI, 0.76–0.94).

The mean change in KCCQ-TSS score at 6, 9, and 12 months was 8.0 ± 0.3 points in the finerenone group and 6.4 ± 0.3 points in the placebo group (difference 1.6 points; 95% CI 0.8–2.3; P < 0.001). However, no significant improvement in NYHA functional class was observed at 12 months (18.6% in the finerenone group and 18.4% in the placebo group, RR 1.01; 95% CI, 0.88–1.15). Additionally, no significant differences were found in all-cause mortality (16.4% vs. 17.4%, RR 0.93; 95% CI, 0.83–1.069) or in the composite renal endpoint of eGFR decline exceeding 50%, end-stage renal disease, dialysis, or renal transplantation (HR 1.33; 95% CI 0.94–1.89). The authors attributed these findings to the characteristics of the study population, which had a low risk of renal disease progression, low prevalence of albuminuria, and a reduced absolute number of renal events. Despite an initial greater reduction in eGFR in the treatment group compared with placebo (−2.9 mL/min/1.73 m²; 95% CI −3.4–2.4), this effect was not sustained long term. Notably, finerenone significantly reduced the risk of new-onset microalbuminuria (− 24%, HR 0.76; 95% CI 0.68–0.83) and macroalbuminuria (−38%, HR 0.62; 95% CI 0.53–0.73).⁸

Regarding safety, increases in serum creatinine and potassium were more common with finerenone than with placebo Hyperkalaemia, defined as potassium levels >6.0 mmol/L occurred in 3.0% of patients in the finerenone group compared with 1.4% of patients in the placebo group; however, no episodes were fatal.

Subsequent post-hoc analyses (Table 1) estimated that treatment with finerenone could extend the time to the first occurrence of HF-related events by up to three years.⁹ No statistically significant interactions were observed between any analysed variable and the study endpoints, including the concomitant use of SGLT2 inhibitors, the current standard of care for these patients, or LVEF. Previous studies in patients with HFmrEF or HFpEF have suggested that the benefits of neurohumoral modulation therapies may be attenuated or absent at higher LVEF values.¹⁷ However, in the FINEARTS-HF trial, finerenone consistently reduced the risk of cardiovascular death and worsening HF events across the entire LVEF range (LVEF <50% RR 0.84, 95% CI 0.68–1.03; LVEF ≥50– < 60% RR 0.80, 95% CI 0.66–0.97; LVEF ≥60% RR 0.94 95% CI 0.70–1.25; P for interaction = 0.70).¹⁰

Table 1.

Pre-specified analyses of FINEARTS-HF

Author	Type of analysis	Outcome	Analysed subgroup	Main results	Predictors of efficacy/risk-benefit modifiers	Conclusions
Vaduganathan M. et al. 20249	Pre-specified	Long-term effects of finerenone treatment in patients with HFmrEF and HFpEF if treated for the patient's lifetime	Entire FINEARTS-HF study cohort (n = 6001)	In patients aged 55, an increase of 3.1 event-free years (95% CI, 0.8–5.4 years; P = 0.007) In patients aged 65, an increase of 2 event-free years (95% CI, 0.8–3.3 years; P = 0.001)	Improvement in long-term event-free survival is particularly evident when treatment is initiated in younger and middle-aged patients	Prolongation of event-free survival by up to 3 years in patients with HFmrEF and HFpEF
Docherty K.F. et al. 202410	Pre-specified	Effect of finerenone treatment based on LVEF values (<50%, 50% to <60%, and ≥60%) and considering LVEF as a continuous variable	FINEARTS-HF patients with available baseline LVEF (n = 5993)	Reduced primary outcome risk in all LVEF categories: LVEF <50% rate ratio (RR) = 0.84 (95% CI 0.68, 1.03), LVEF 50%–<60% RR = 0.80 (0.66, 0.97), and LVEF ≥60% RR = 0.94 (0.70, 1.25); P for interaction = 0.70.	No modification of the finerenone benefit when LVEF was analysed as a continuous variable (P for interaction = 0.28).	Reduction in the risk of cardiovascular death and worsening heart failure events, regardless of LVEF.
Vaduganathan M. et al. 202411	Pre-specified	Efficacy and safety of finerenone in patients treated and not treated with SGLT2is at baseline	FINEARTS-HF patients treated and not treated with SGLT2is at baseline (n = 817)	Similar reduction in the primary outcome in participants treated with an SGLT2i (hazard ratio 0.83; 95% CI 0.60–1.16) and without an SGLT2i at baseline (hazard ratio 0.85; 95% CI 0.74–0.98); P for interaction = 0.76.	Use of SGLT2is at baseline or during follow-up did not significantly alter the treatment effects on the primary endpoint.	Combined use of SGLT2is and a non-steroidal MRA may provide additive protection against cardiovascular events in patients with HFmrEF and HFpEF
Chimura M. et al. 202412	Pre-specified	Efficacy and safety of finerenone stratified by age quartiles	Entire FINEARTS-HF study cohort (n = 6001)	Consistent reduction in the primary outcome across all age quartiles: hazard ratio in Q1, 0.70 (95% CI, 0.53–0.92); Q2, 0.83 (95% CI, 0.64–1.07); Q3, 0.98 (95% CI, 0.76–1.26); and Q4, 0.85 (95% CI, 0.67–1.07); P for interaction = 0.27.	Adverse events were similar across all age groups	Reduction in the primary event and its components across a broad age spectrum, resulting in a safe and well-tolerated outcome regardless of age.
Vaduganathan M. et al. 202413	Pre-specified	Time to first statistical significance of finerenone in reducing clinical events	Entire FINEARTS-HF study cohort (n = 6001)	FIrst nominal statistical significance for the primary endpoint observed on day 28 (HR: 0.62; 95% CI: 0.40–0.97; P = 0.037)0.037).	Finerenone achieved early and statistically significant benefits within 1 month of treatment initiation, suggesting a possible effect related to a rapid decongestant and haemodynamic response	The first statistical significance for the primary endpoint was observed within 1 month of treatment initiation and was maintained until the final follow-up
Mc Causland F.R. et al. 20248	Pre-specified	Effects of finerenone on renal outcomes in patients with HFmrEF and HFpEF	Entire FINEARTS-HF study cohort (n = 6001)	Incidence of the composite renal outcome (≥50% decline in eGFR or kidney failure) was numerically, but not significantly, higher for finerenone compared with placebo (HR 1.33; 95% CI 0.94, 1.89). Similar results were observed for the composite of ≥57% eGFR decline or kidney failure (HR 1.28; 95% CI 0.80, 2.05)	Event rate was relatively low; during the first three months of therapy, finerenone did not modify the chronic decline in eGFR and reduced the risk of new-onset micro- and macroalbuminuria by 24% (HR 0.76; 95% CI 0.68, 0.83) and 38% (HR 0.62; 95% CI 0.53, 0.73)	The overall event In a population at low risk of renal events, finerenone did not significantly modify composite renal outcomes and led to an early and sustained reduction in albuminuria and reduced the risk of new-onset micro- and macroalbuminuria
Desai A.S. et al. 202414	Pre-specified	Efficacy and safety of finerenone in relation to a recent WHF event.	Entire FINEARTS-HF study cohort (n = 6001)	The rate of the primary composite endpoint varied inversely with the time elapsed since WHF, with a risk >2 times higher in subjects enrolled during or within 7 days of WHF compared with those enrolled >3 months after WHF or with no prior WHF (hazard ratio [HR]: 2.13; 95% CI: 1.82–2.55).	Finerenone appears to reduce the risk of the primary composite outcome to a greater extent in subjects enrolled within 7 days of WHF (HR: 0.74; 95% CI: 0.57–0.95) or between 7 days and 3 months after WHF (HR: 0.79; 95% CI: 0.64–0.97) compared with those >3 months after WHF or with no prior WHF (HR: 0.99; 95% CI: 0.81–1.21); however, no definitive interaction between treatment and time could be confirmed (P = 0.07)	Patients with HFmrEF and HFpEF who have had a recent WHF event are at higher risk of recurrent HF events and CV death
Yang M. et al. 202415	Pre-specifiied	Efficacy and safety of finerenone based on baseline KCCQ Total Symptom Score (TSS) and the effect of finerenone on KCCQ-TSS	FINEARTS-HF patients with available baseline KCCQ-TSS (n = 5986)	Finerenone reduced the risk of the primary endpoint across the entire KCCQ-TSS range: tertile 1 (score 0-<57): HR: 0.82 (95% CI: 0.68–1.00); tertile 2 (57-<81): 0.88 (95% CI: 0.70–1.11); tertile 3 (81–100): 0.88 (95% CI: 0.69–1.14) (P for interaction =0.89).	Finerenone significantly improved KCCQ-TSS from baseline with a mean difference at 12 months of 1.62 points (95% CI: 0.69–2.56 points) (P < 0.001).	Finerenone significantly reduced HF events and improved health status in patients with HFmrEF and HFpEF across the entire baseline KCCQ-TSS spectrum.
Chimura M. et al. 202416	Pre-specified	To estimate the efficacy and safety of finerenone in both women and men.	Entire FINEARTS-HF study cohort (n = 6001)	Finerenone similarly reduced the risk of the primary endpoint in women and men: hazard ratio 0.78 (95% CI, 0.65–0.95) in women and 0.88 (95% CI, 0.74–1.04) in men (P = 0.41 for interaction).	Finerenone had similar tolerability in women and men.	Finerenone similarly reduced the risk of the primary endpoint in women and men with HFmrEF and HFpEF

HFmrEF, Heart Failure with mildly reduced Ejection Fraction; HFpEF, Heart Failure with preserved Ejection Fraction; CI, Confidence Interval; HR, hazard ratio; LVEF, Left Ventricular Ejection Fraction; eGFR, estimated Glomerular Filtration Rate; WHS, Worsening Heart Failure; KCCQ, Kansas City Cardiomyopathy Questionnaire.

This distinct response compared with other neurohormonal antagonists may be partly explained by the higher proportion of patients (42%) enrolled shortly after an acute HF event and by the relatively high values ​​of natriuretic peptides observed in patients with higher LVEF, potentially reflecting increased neurohumoral activation. However, the lack of any interaction between the effect of finerenone and baseline NT-proBNP levels argues against this hypothesis.

Another notable observation, considering the high prevalence of SGLT2i use in the trial population, was the consistent efficacy of finerenone in reducing cardiovascular mortality and HF-related events regardless of concomitant SGLT2is treatment. The relative risk reduction with finerenone was similar in patients receiving SGLT2is (RR 0.83; 95% CI 0.60–1.16) and those not receiving SGLT2is at baseline (RR 0.85; 95% CI 0.74–0.98; P for interaction = 0.76).¹¹ Moreover, the combination of SGLT2is and finerenone was not associated with an increased incidence of adverse events, including hyperkalaemia, suggesting that these two classes of medications may have a potentially additive beneficial effect in patients with HFpEF or HFmrEF.

Similar to the early benefit observed with SGLT2is treatment, the first statistically significant reduction in the primary endpoint with finerenone occurred within one month of treatment initiation, and this benefit was sustained throughout the follow-up period (Day 28, RR 0.62; 95% CI: 0.40–0.97; P = 0.037).¹³

In contrast to the TOPCAT trial, where patients hospitalized for heart failure within the year prior to randomization appeared to derive less benefit from spironolactone compared with those enrolled based solely on elevated natriuretic peptides, the FINEARTS-HF trial suggested a potential greater benefit with finerenone in patients enrolled during or shortly after a WHF event. However, no definitive interaction between treatment efficacy and recent WHF was confirmed at randomization (maximum reduction in the primary endpoint observed within 7 days of WHF, RR 0.74; 95% CI: 0.57–0.95; P for interaction = 0.07).¹⁴

Pre-specified analyses by sex did not reveal any significant interactions. Although women in the study population were older, had higher body mass index, and lower baseline LVEF, with worse New York Heart Association (NYHA) functional class and lower KCCQ- TSS, they experienced fewer absolute events. However, sex did not significantly interact with the effect of finerenone on the primary endpoint. This finding remained consistent even after adjusting for individual patient characteristics. Moreover, similar treatment benefits were observed for the individual components of the primary outcome, and the safety profile was comparable between men and women.¹⁶

Finerenone also demonstrated a consistent reduction in the risk of the primary endpoint (cardiovascular death and overall WHF events) across the entire spectrum of KCCQ-TSS scores.¹⁵ Furthermore, no significant interactions were observed between the primary endpoint, its components, and age at enrollment.¹²

The FINEARTS-HF trial provides the first evidence that a non-steroidal MRA can reduce cardiovascular mortality and HF-related events in patients with HFpEF and HFmrEF, an effect previously demonstrated only with SGLT2is.

Currently, the 2023 update of the European Society of Cardiology Guidelines recommends finerenone in Class I for diabetic patients with CKD to reduce the risk of HF.² The findings of the FINEARTS-HF trial may warrant an expansion of these guidelines, positioning finerenone, alongside SGLT2is, as a cornerstone of therapy for patients with HFpEF and HFmrEF.

Conclusions

MRAs are a cornerstone of treatment for HFrEF and may have a similar role in patients HFmrEF and HFpEF. While the TOPCAT study demonstrated a modest reduction in cardiovascular events with spironolactone, finerenone, a novel non-steroidal and selective MRA with potent diuretic and antifibrotic effects and a favorable safety profile, has been shown to reduce renal and cardiovascular endpoints in patients with diabetes mellitus and CKD.

Currently, SGLT2is are the only drug class approved to reduce mortality and hospitalizations in patients with HFpEF and HFmrEF. The positive findings of the FINEARTS-HF trial, which demonstrated the efficacy of finerenone in reducing cardiovascular mortality and HF-related events in patients with HF and LVEF ≥ 40%, may expand the therapeutic options for patients with HFpEF and HFmrEF, offering a promising new treatment approach.

Funding

No funding provided.

Data availability

No new data were generated or analysed in support of this research.

Disclaimer

This paper was originally published in the Italian language as ‘Focus sul Finerenone. Lo studio FINEARTS-HF’, in the Volume degli Atti del Congresso “Conoscere e Cuare il Cuore 2025”, published by Centro per la Lotta contro l'Infarto for distribution at the CCC Conference. This paper was translated by Dr. Mario Albertucci, representative of the CLI Foundation, and republished with permission.