Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure - FINEARTS-HF

Oct 24, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
Bayer
Date Presented:
09/01/2024
Date Published:
10/24/2024
Date Updated:
10/24/2024
Original Posted Date:
09/01/2024
References

Contribution To Literature:

Highlighted text has been updated as of October 24, 2024.

The FINEARTS-HF trial showed that in patients with symptomatic HF with preserved or mildly reduced LVEF, finerenone resulted in a lower composite rate of worsening HF events and CV death compared with placebo.

Description:

The goal of the trial was to determine the efficacy and safety of the nonsteroidal mineralocorticoid antagonist finerenone in patients with heart failure (HF) with preserved or mildly reduced left ventricular ejection fraction (LVEF).

Study Design

  • International
  • Randomized
  • Double-blind

Patients with symptomatic HF and LVEF ≥40% were randomized in a 1:1 fashion to receive finerenone at a maximum dose of 40 mg daily (20 mg if estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2, n = 3,003) or matching placebo (n = 2,998). Finerenone was started at 20 mg daily (10 mg if eGFR <60 mL/min/1.73 m2) and up-titrated after 4 weeks based on potassium levels and if eGFR did not decline ≥30%.

  • Total number of enrollees: 6,001
  • Median follow-up: 32 months
  • Mean patient age: 72 years
  • Percentage female: 46%

Inclusion criteria:

  • Age ≥40 years
  • New York Heart Association (NYHA) class II-IV symptoms
  • LVEF ≥40% within 12 months
  • Left atrial dilation or LV hypertrophy within 12 months
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥300 pg/mL or BNP ≥100 pg/mL if in sinus rhythm (≥900 pg/mL or ≥300 pg/mL, respectively, if in atrial fibrillation)

Exclusion criteria:

  • eGFR <25 mL/min/1.73 m2
  • Serum/plasma potassium >5.0 mmol/L
  • Myocardial infarction, coronary artery bypass grafting, or stroke ≤90 days prior
  • Percutaneous coronary intervention ≤30 days prior
  • Comorbid conditions that may contribute to dyspnea (e.g., chronic hypoxic respiratory failure from pulmonary disease, hemoglobin <10 g/dL, body mass index ≥50 kg/m2)

Other salient features/characteristics:

  • Mean LVEF: 53% (EF 40-50%: 36%)
  • eGFR <60 mL/min/1.73 m2: 48%
  • Mean serum potassium: 4.4 mmol/L
  • NYHA class III-IV symptoms: 31%
  • Prior HF hospitalization: 60%
  • <3 months since last HF event: 84%
  • Sodium-glucose cotransporter-2 inhibitor (SGLT2i) use: 14%
  • Glucagon-like peptide-1 receptor antagonists (GLP1ra): 3%
  • Type 2 diabetes mellitus: 41%

Principal Findings:

The primary outcome, composite of worsening HF events (first or recurrent unplanned HF hospitalization or urgent visit) and cardiovascular (CV) death, for finerenone vs. placebo, was: 14.9 vs. 17.7 events per 100 patient-years (rate ratio [RR] 0.84, 95% confidence interval [CI] 0.74-0.95, p = 0.007).

  • Worsening HF events: 842 vs. 1,024 events (RR 0.82, 95% CI 0.71-0.94, p = 0.007)
  • CV death: 8.1% vs. 8.7% (hazard ratio [HR] 0.93, 95% CI 0.78-1.11)

The primary outcome across LVEF ranges for finerenone vs. placebo (p for interaction = 0.75):

  • <50%: 15.7 vs. 19.2 events per 100 patient-years (RR 0.83, 95% CI 0.68-1.03)
  • >60%: 14.8 vs. 17.9 events per 100 patient-years (RR 0.79, 95% CI 0.62-0.92)
  • >60%: 13.8 vs. 14.8 events per 100 patient-years (RR 0.82, 95% CI 0.61-1.10)

The primary outcome across baseline SGLT2i use for finerenone vs. placebo (p for interaction = 0.76):

  • Baseline SGLT2i: 21.8 vs. 26.5 events per 100 patient-years (RR 0.83, 95% CI 0.60-1.16)
  • No baseline SGLT2i: 14.0 vs. 16.5 events per 100 patient-years (RR 0.85, 95% CI 0.74-0.98)

Estimated primary event-free survival by age at randomization for finerenone vs. placebo:

  • Age 55: 13.6 vs. 10.5 years, difference 3.1 years (95% CI 0.8 to 5.4, p = 0.007)
  • Age 65: 11.0 vs. 8.9 years, difference 2.0 years (95% CI 0.8 to 3.3, p = 0.001)
  • Age 75: 8.2 vs. 7.6 years, difference 0.6 years (95% CI -0.2 to 1.5, p = 0.14)

Secondary outcomes for finerenone vs. placebo:

  • All-cause mortality: 16.4% vs. 17.4% (HR 0.93, 95% CI 0.83-1.06)
  • Change from baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) score at 12 months: +8.0 vs. +6.4, difference 1.6 (95% CI 0.8-2.3, p < 0.001)
  • Change in KCCQ across LVEF: +1.39 (LVEF <50%) vs. +1.37 (LVEF ≥50 to <60%) vs. +3.02 (LVEF ≥60%, p for interaction = 0.44)
  • Change in KCCQ across baseline SGLT2i use: +2.0 (SGLT2i) vs. +1.5 (no SGLT2i, p for interaction = 0.66)
  • Sustained eGFR decrease ≥50% or to <15 mL/min/1.73 m2, new dialysis requirement, or kidney transplantation: 2.5% vs. 1.8% (HR 1.33, 95% CI 0.94-1.89)
  • SGLT2i initiation after randomization: 17.7% vs. 20.1% (HR 0.86, 95% CI 0.76-0.97), p = 0.02

Safety outcomes for finerenone vs. placebo:

  • Serum potassium >5.5 mmol/L: 14.3% vs. 6.9%
  • Hyperkalemia resulting in hospitalization: 0.5% vs. 0.2%
  • Serum potassium <3.5 mmol/L: 4.4% vs. 9.7%
  • Systolic blood pressure <100 mm Hg: 18.5% vs. 12.4%

Interpretation:

In patients with HF with preserved or mildly reduced LVEF (EF ≥40%), finerenone reduced the composite CV endpoint compared with placebo; the clinical efficacy was driven largely by a reduction in first or recurrent worsening HF events. Prespecified secondary analyses demonstrated similar treatment efficacy with finerenone across both categories of LVEF as well as the continuum of LVEF approaching 70%, above which point estimates were limited by the available data. The primary findings are similar in magnitude to those observed in the EMPEROR-PRESERVED and DELIVER trials with SGLT2i, which carry a Class 2a indication in the 2022 ACC/AHA HF guideline for the treatment of HF with preserved EF. Baseline and drop-in SGLT2i use did not affect finerenone’s efficacy or safety endpoints, although patients receiving SGLT2i therapy had higher event rates overall. Moreover, in a prespecified secondary analysis, long-term actuarial estimates suggested greater event-free survival with finerenone regardless of SGLT2i use. This treatment effect was similarly driven by a reduction in HF events and was inversely proportional to age at finerenone initiation.

That said, concomitant SGLT2i and GLP1ra use was low; dedicated studies are underway to assess whether concomitant use with finerenone has clear additional benefit and safety in HF. It is not clear that finerenone’s efficacy extends to steroidal mineralocorticoid antagonists such as spironolactone, which did not reduce HF events in TOPCAT but may have been affected by regional variability in study protocol implementation (Class IIb recommendation in 2022 ACC/AHA HF guidelines for HF with preserved EF). Finally, although FIDELIO-DKD demonstrated reduced progression of diabetic chronic kidney disease with finerenone, the rate of composite kidney events was much lower and therefore perhaps less modifiable in the current study.

References:

Docherty KF, Henderson AD, Jhund PS, et al. Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: A Prespecified Analysis of The FINEARTS-HF Trial. Circulation 2024;Sep 29:[Epub ahead of print].

Vaduganathan M, Claggett BJ, Kulac IJ, et al. Effects of the Non-Steroidal MRA Finerenone With and Without Concomitant SGLT2 Inhibitor Use in Heart Failure. Circulation 2024;Sep 28:[Epub ahead of print].

Vaduganathan M, Claggett BL, Desai AS, et al. Estimated Long-Term Benefits of Finerenone in Heart Failure: A Prespecified Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol 2024;Sep 27:[Epublished].

Solomon SD, McMurray JJ, Vaduganathan M, et al., for the FINEARTS-HF Committees and Investigators. Finerenone in Heart Failure With Mildly Reduced or Preserved Ejection Fraction. N Engl J Med 2024;391:1475-85.

Editorial: McDonagh TA. FINEARTS-HF — The Latest Masterpiece for MRAs in Heart Failure. N Engl J Med 2024;391:1540-1.

Presented by Dr. Scott Solomon at the European Society of Cardiology Congress, London, UK, September 1, 2024.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Diuretics, Heart Failure, Mineralocorticoid Receptor Antagonists, ESC Congress, ESC24


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