The FINEARTS-HF Trial: Exploring Finerenone’s Efficacy and Safety in Heart Failure Management

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The FINEARTS-HF Trial: Exploring Finerenone’s Efficacy and Safety in Heart Failure Management

Written by: Tanmaya Phanda, PharmD,  InpharmD Team

This blog will provide an overview of heart failure, explore key insights from the FINEARTS-HF trial, and discuss the potential impact of finerenone in heart failure with mildly reduced or preserved ejection fraction patients.

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Introduction2-5

Affecting more than 6.7 million people in the United States, heart failure is a chronic condition where the heart cannot maintain its workload and supply blood to the rest of the body effectively. Its prevalence is expected to rise to 8.5 million by 2030. 

Heart failure rates are steadily increasing as about 1 in 4 people will be diagnosed in their lifetime. Poor lifestyle choices like smoking tobacco, physical inactivity, and a high-fat and sodium diet increase the risk of heart failure. Additional risk factors include diabetes (A1C ≥7%), hypertension (≥130/80 mmHg), obesity (BMI  ≥30 kg/m2), and cardiovascular conditions like coronary artery disease and valvular heart disease.

There are three types of heart failure, depending on the left ventricular ejection fraction (LVEF) which measures the percentage of blood pumped out of the left ventricle with each contraction. —Table 1. 

Type of Heart Failure	LVEF (%)
Reduced Ejection (HFrEF)	≤40
Mildly Reduced Ejection Fraction (HFmrEF)	41-49
Preserved Ejection Fraction (HFpEF)	≥ 50

 

The American College of Cardiology (ACC) and the American Heart Association (AHA) classify heart failure in four stages, and patients with a stage C and D (symptomatic stages) diagnosis are also given a New York Heart Association (NYHA) functional classification. —Table 2. 

Table 2a. ACC/AHA Heart Failure Classes

Stage A	At risk for heart failure but do not yet have symptoms or structural or functional heart disease
Stage B	No current or previous symptoms but with either structural heart disease, increased filling pressures in the heart, or other risk factors
Stage C	Current or previous symptoms
Stage D	Symptoms that interfere with daily activities or lead to repeated hospitalizations

 

Table 2b. NYHA Functional Classifications

I	No limitation on physical activity
II	Ordinary physical activity results in fatigue, palpitation, shortness of breath, or chest pain
III	Less than ordinary activity causes fatigue, palpitation, shortness of breath or chest pain
IV	Symptoms at rest

 

Symptoms may include shortness of breath from physical activity (in severe cases during ordinary activity or at rest), leg or stomach edema, fatigue, and weakness. Poorly managed heart failure can lead to further complications such as pulmonary embolism, strokes, and arrhythmias. According to the Centers for Disease Control and Prevention (CDC) reports 13.9% of all deaths in the U.S. were due to heart failure in 2022.

Although there is no cure for heart failure, there are various treatment options that provide symptomatic relief and reduce morbidity and mortality. According to the 2022 ACC/AHA heart failure guidelines, diuretics are recommended first-line to decrease fluid retention, relieve congestion, improve symptoms, and prevent worsening events. The guidelines provide stronger evidence-based recommendations for reducing mortality, morbidity, and cardiovascular events in HFrEF compared to HFpEF and HFmrEF.

In HFrEF, specific beta-blockers (bisoprolol, carvedilol, sustained-release metoprolol succinate), SGLT-2 (sodium-glucose cotransporter-2) inhibitors, MRAs (mineralocorticoid receptor antagonists) such as spironolactone and eplerenone, and ARNi, ARBs, or ACE inhibitors (angiotensin receptor-neprilysin inhibitors, angiotensin receptor blockers, or angiotensin-converting enzyme inhibitors)  provide cardiovascular and mortality/morbidity benefits. Hydrzaline and isosorbide dinitrate may improve symptoms and reduce morbidity and mortality in specific patient populations, such as African Americans with NYHA class II-IV HFrEF. 

In patients with HFmrEF and HFpEF,  only SGLT-2 inhibitors are recommended to decrease hospitalizations and cardiovascular mortality. ARNi or ARBs and MRAs may help reduce hospitalizations, although their effectiveness needs to be more established and studied.

Clinical trials like The Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF; NCT04435626) explore the benefits of finerenone (Kerendia™), the only nonsteroidal selective MRA, in heart failure management to evaluate its role in guideline-directed therapy. Unlike steroidal MRAs like spironolactone and eplerenone, finerenone blocks the mineralocorticoid receptor (MR)-mediated sodium reabsorption and MR overactivation in the kidney, heart, and blood vessel tissues. Currently, it is FDA-approved to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease associated with type 2 diabetes. 

 

Methods

FINEARTS-HF was an international, multicenter, parallel-group, event-driven, double-blind, randomized trial conducted between September 14, 2020 to June 14, 2024. The trial was done on patients who were ≥40 years old, had symptomatic HFmrEF and HFpEF, an LVEF of ≥40%, evidence of structural heart disease, and high levels of natriuretic peptides (≥300 pg/mL). Patients with a serum potassium level > 5mmol/L during screening or randomization and patients with myocardial infarction, stroke, or coronary artery bypass graft surgery within 90 days before randomization were excluded from the study.

A total of 6016 patients were randomized 1:1 with 3003 patients receiving finerenone and 2998 patients receiving a placebo. In the finerenone group, patients with a baseline estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 had a starting dose of 20 mg and a maximum dose of 40 mg, and patients with an eGFR  ≤60 ml/min/1.73 m2 had a starting dose of 10 mg and a maximum dose of 20 mg.

The demographics and baseline characteristics were similar in both treatment groups —Table 3.

Table 3. Patient Baseline Characteristics.

Baseline Characteristics	Finerenone	Placebo
Mean Age  — years	71.9±9.6	72.0±9.7
Female  — no. (%)	1355 (45.1)	1377 (45.9)
Left ventricular ejection fraction — no. (%)	52.6±7.8	52.5±7.8
Any previous hospitalization for heart failure  — no. (%)	1797 (59.8)	1822 (60.8)
New York Heart Association  (NYHA) functional class II  — no. (%)	2081 (69.3)	2065 (68.9)

 

Along with their respective treatment arms, patients continued their usual heart failure therapy—Table 4.

Table 4. Most Common Heart Failure Medications Continued with Treatment Arm

Medication Class	Finerenone— no. (%)	Placebo — no. (%)
ACEi	1083 (36.1)	1072 (35.8)
ARB	1047 (34.9)	1055 (35.2)
ARNi	256 (8.5)	257 (8.6)
Beta-blockers	2541 (84.6)	2554 (85.2)
Calcium-channel blocker	958 (31.9)	1010 (33.7)
SGLT-2 inhibitors	393 (13.1)	424 (14.1)

 

Outcomes

The primary outcome was the total of worsening heart failure events (defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The primary outcome was evaluated across 17 prespecified subgroups, including patients with or without concurrent SGLT-2 inhibitor use and those with a left ventricular ejection fraction of ≤60% or ≥60%.

Secondary outcomes included: total worsening heart failure events, the change from baseline in the total symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) at the 6, 9, and 12-month mark, improvement in the NYHA functional class at 12 months; and a kidney composite outcome (defined as a composite of a sustained decrease in the eGFR of ≥50%, a sustained decline in the eGFR to <15 ml/min/1.73m2, or the initiation of long-term dialysis, or kidney transplantation). 

Safety was assessed by serious adverse events and hyperkalemia occurrences in those who received at least one dose of finerenone or placebo and occurred during treatment or up to 3 days after permanent discontinuation of finerenone or placebo was reported. 

Results

Over a median follow-up of 32 months, 1083 primary-outcome events (842 worsening heart failure events and 242 deaths from cardiovascular causes) occurred in 624 of 3003 patients in the finerenone treatment arm. A total of 1283 primary-outcome events (1024 worsening heart failure events and 260 deaths from cardiovascular causes) occurred in 719 of 2998 patients in the placebo treatment arm (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P=0.007). —Figure 1.  The results for the primary outcome were consistent across all subgroups (rate ratio <1, favoring finerenone). —Table 5.

 

Figure 1. Total of Worsening Heart Failure Events and Death From Cardiovascular Causes*

*One patient in each group had a worsening heart failure event and died from cardiovascular causes on the same day; for the primary outcome, only the fatal event was counted.

Table 5. Select Primary Outcome Subgroups

Subgroup	Finerenone  — no. events	Placebo — no. events	Rate Ratio (95% CI)
SGLT-2 Inhibitor Use at Baseline	176	234	0.83 (0.60 to 1.16)
No SGLT-2 Inhibitor Use at Baseline	907	1049	0.85 (0.74 to 0.98)
LVEF <60%	877	1061	0.82 (0.71 to 0.94)
LVEF ≥60%	206	222	0.94 (0.70 to 1.26)

 

The secondary outcomes measured how finerenone affects quality of life, heart failure classification, and kidney outcomes

The KCCQ total symptom score increased by 8.0±0.3 in the finerenone group, compared to the placebo group 6.4±0.3 (treatment difference, 1.6; 95% CI, 0.8 to 2.3; P<0.001). At the 12-month mark, both groups had similar improvements in  NYHA functional class with 557 finerenone-treated patients (18.6%) and 553 placebo-treated (18.4%) achieving a better class. The odds ratio was 1.01 (95% CI, 0.88 to 1.15), indicating no significant difference. A kidney composite was seen in 75 (2.5%) patients in the finerenone group and 55 patients (1.8%) in the placebo group (hazard ratio, 1.33; 95% CI, 0.94 to 1.89)—Table 6. 

Table 6. Secondary Outcomes 

Secondary Outcome	Finerenone	Placebo	Finerenone vs. Placebo (95% CI)
Change from baseline in KCCQ total symptom score at 6, 9, and 12 months  — points	8.0±0.3	6.4±0.3	Treatment Difference: 1.6 (0.8 to 2.3)
Improvement in NYHA functional class at 12 months — no. (%)	557 (18.6)	553 (18.4)	Odds Ratio: 1.01 (0.88 to 1.15)
Kidney Composite Outcome — no. (%)	75 (2.5)	55 (1.8)	Hazard Ratio: 1.33 (0.94 to 1.89)

 

Serious adverse events occurred in 1157 patients (38.7%) in the finerenone group and 1213 patients (40.5%) in the placebo group. There were 16 patients (0.5%) in the finerenone group and six patients (0.2%) in the placebo group who were hospitalized due to hyperkalemia, but no deaths were caused by hyperkalemia. Hypokalemia (<3.5 mmol/L) was seen less with finerenone than with placebo.  A total of 611 patients (20.4%) in the finerenone group and 616 patients (20.6%) in the placebo group discontinued their assigned treatment.—Table 7.

Table 7. Safety Outcomes

Safety Outcome	Finerenone  — no. (%)	Placebo  — no. (%)
Discontinuations	611 (20.4)	616 (20.6)
Any serious adverse event	1157 (38.7)	1213 (40.5)
Serum creatinine level ≥3.0 mg/dl	57 (2.0)	34 (1.2)
Hospitalizations due to hyperkalemia	16 (0.5)	6 (0.2)
Death due to hyperkalemia	0	0

 

Study Conclusions

Finerenone led to a significantly lower incidence of total worsening heart failure events and cardiovascular death compared to placebo across all primary outcome subgroups. The trial results also indicated that finerenone improved patient-reported health status, as measured by the KCCQ total symptom score, but did not improve NYHA functional class or reduce the risk of the kidney composite outcome. In regards to adverse events, hyperkalemia occurred more frequently in the finerenone group but resulted in no patient deaths. Also, hypokalemia was less common in the finerenone group than in the placebo group.

The trial posed limitations due to underpowered results in the primary outcome subgroups. In addition, the study population had a limited representation of African American patients, who are at the highest risk for heart failure, with only 49 (1.6%) and 39 (1.3%) in the finerenone and placebo groups, respectively. Furthermore, the trial results cannot be generalized to other MRAs, such as spironolactone and eplerenone, because of finerenone’s distinct physiochemical properties. 

Clinical Impact

The 2022 AHA/ACC Heart Failure guidelines state that MRAs reduce morbidity and mortality in patients with HFrEF. However, there is a lack of strong evidence supporting its use in patients with HFmrEF and HFpEF. Before the FINEARTS-HF trial, steroidal MRAs like spironolactone have shown varied results in cardiovascular benefits and lower hospitalizations. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, a randomized, double-blind study, concluded that spironolactone did not significantly reduce the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization in patients with HFpEF.6 

In contrast, FINEARTS-HF is the first clinical trial to demonstrate that finerenone provides cardiovascular benefits in patients with HFmrEF and HFpEF, indicating that it may complement standard-of-care agents like SGLT-2 inhibitors and Entresto™ (sacubitril/valsartan).  Despite being the only non-steroidal MRA with proven benefits for this patient group, finerenone is available exclusively as a brand-name drug, raising costs for hospitals and patients. The expense of finerenone, alongside the limited efficacy of spironolactone in the TOPCAT trial, underscores the need for further studies to optimize HFmrEF and HFpEF management.

FINEARTS-HF is part of the ongoing MOONRAKER clinical trial program, the largest heart failure global study program with more than 15,000 patients.7 This program, also consisting of the REDEFINE-HF, CONFIRMATION-HF, and FINALITY-HF trials, aims to provide additional data on finerenone’s role in guideline-directed therapy for HFmrEF and HFpEF.

References: 

1. Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. New England Journal of Medicine. 2024;391(16):1475-1485. doi:10.1056/nejmoa2407107 
2. About Heart Failure. Centers for Disease Control and Prevention. May 15, 2024. Accessed November 12, 2024. https://www.cdc.gov/heart-disease/about/heart-failure.html.
3. Bozkurt B, Ahmad T, Alexander KM, et al. Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. J Card Fail. 2023;29(10):1412-1451. doi:10.1016/j.cardfail.2023.07.006
4. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18). doi:10.1161/cir.0000000000001063 
5. Prescribing information: Kerendia® (finerenone). Kerendia-US. Accessed November 12, 2024. https://www.kerendia-us.com/pi. 
6. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131:34-42. 
7. 1. Bayer. ESC 2024: Late-breaking KERENDIA® investigational data showed a statistically significant reduction in the composite outcome of cardiovascular death and total heart failure. ESC 2024: Late-Breaking KERENDIA® Investigational Data Showed a Statistically Significant Reduction in the Composite Outcome of Cardiovascular Death and Total Heart Failure | Bayer United States. September 5, 2024. Accessed November 12, 2024. https://www.bayer.com/en/us/news-stories/late-breaking-kerendiardata. 

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