FINEARTS-HF Trial

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Table of contents for the The FINEARTS-HF Trial summary:

Visual abstract
Summary
References
Credits
Twitter Archive

October 3, 2024

Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

S.D. Solomon, J.J.V. McMurray, M. Vaduganathan, B. Claggett, P.S. Jhund, A.S. Desai, A.D. Henderson, C.S.P. Lam, B. Pitt, M. Senni, F. Amarante, P. Kolkhof, and P. Viswanathan et al

https://www.nejm.org/doi/full/10.1056/NEJMoa2407107

Relevant Literature

Trial	Study Population	Intervention	Outcome
RALES	Patients with severe heart failure (NYHA III-IV) and LVEF ≤35%	Spironolactone vs. placebo	Reduced all-cause mortality and hospitalizations for heart failure
EMPHASIS-HF	Patients with mild heart failure (NYHA II) and LVEF ≤30%	Eplerenone vs. placebo	Reduced risk of cardiovascular death or heart failure hospitalization
TOPCAT	Patients with HFpEF	Spironolactone vs. placebo	Reduced hospitalizations for heart failure, no significant difference in primary cardiovascular outcome
EPHESUS	Post-MI patients with LVEF ≤40% and HF symptoms	Eplerenone vs. placebo	Reduced all-cause and cardiovascular mortality
ARTS-HFf	HF patients with type 2 diabetes or chronic kidney disease	Finerenone vs. eplerenone	Reduced NT-proBNP levels and suggested reduction in clinical events
FIDELIO-DKD	Patients with CKD and type 2 diabetes	Finerenone vs. placebo	Reduced kidney failure and cardiovascular events
FIGARO-DKD	Patients with CKD and type 2 diabetes	Finerenone vs. placebo	Reduced cardiovascular events, including HF hospitalization

Relevant Guidelines

2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: Executive Summary

Recommendation for MRAs (Referenced studies that support the recommendation are summarized in the Online Data Supplements.)

COR LOE Recommendation 1 A

In patients with HFrEF and NYHA class IIIV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if estimated glomerular filtration rate is > 30 mL/min/1.73 and serum potassium is < 5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency.

Take-Home Message No. 2

Mildly reduced LVEF has new medication recommendations, including use of SGLT2i (Fig. 2). SGLT2i has a COR 2a in HF with mildly reduced EF (HFmrEF). Weaker recommendations (COR 2b) are made for ARNi, ACEi, ARB, MRA, and beta-blockers in this population.

Fig 2

ACC/AHA 2022 Guidelines:

For HFrEF, MRAs hold a Class I recommendation (strong evidence) for patients with NYHA class II-IV heart failure

For HFpEF, MRAs are assigned a Class IIb recommendation, indicating that they may be considered, especially in those with elevated filling pressures (e.g., BNP levels)

Rationale:

Heart failure (HF) with mildly reduced or preserved ejection fraction (EF ≥40%) presents a treatment challenge. While therapies such as SGLT2 inhibitors have shown benefits, there remains a gap in effective treatments specifically targeting this population. Steroidal mineralocorticoid receptor antagonists (like spironolactone) have shown benefits in HF with reduced EF, but their efficacy in preserved EF is unclear. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has shown promise in chronic kidney disease and HF with diabetes, prompting investigation in this broader HF population.

Objective:

The primary goal was to determine if finerenone could reduce the composite endpoint of worsening HF events (defined as unplanned HF-related hospitalizations or urgent visits) and cardiovascular death in patients with mildly reduced or preserved EF.

	Details
Trial Type	Double-blind, randomized, international, event-driven trial across 37 countries.
Randomization	Finerenone (3003 patients) vs. Placebo (2998 patients) in a 1:1 ratio.
Dosage	Finerenone administered at 20 mg or 40 mg daily, based on renal function.
Follow-up	Median duration of 32 months.
Interim Analyses	Two interim analyses for futility and efficacy, both continued the trial.

Enrollment Criteria

Patients ≥40 years of age, symptomatic HF (New York Heart Association [NYHA] class II-IV), left ventricular EF ≥40%, elevated levels of natriuretic peptides (such as NT-proBNP), on diuretic therapy (for 30 days prior to randomization) and structural heart disease.

Patients were required to be on standard HF therapy, and those with severe chronic kidney disease (GFR <25), serum potassium > 5 mmol/L at any visit or recent use of mineralocorticoid receptor antagonists were excluded.

Outcomes

Primary Outcome: A composite of worsening HF events (first and recurrent unplanned hospitalizations or urgent visits for HF) and death from cardiovascular causes.

Secondary Outcomes: Included total HF events, change in symptoms (measured by the Kansas City Cardiomyopathy Questionnaire [KCCQ]), improvement in NYHA class, kidney function decline, cardiovascular death, and death from any cause.

Statistical Analysis

The trial was designed with 90% power to detect a 19% reduction in the primary outcome event rate in the finerenone group vs. placebo.

The primary analysis was performed based on an intention-to-treat approach and utilized the semiparametric proportional rates method, which considers both first and recurrent HF events to capture the full burden of disease.

Subgroup analyses were predefined, and 17 were analyzed based on characteristics like baseline EF, use of other therapies (e.g., SGLT2 inhibitors), and geographic region.

Secondary outcomes were tested in a hierarchical order (As listed in the above section).

Notable Baseline Characteristics

Of 6016 patients who underwent randomization, 6001were included; those who were excluded did not had severe violations of Good Clinical Practice guidelines

Mean age 72; 54% were male

Most patients were white (79%), from Eastern Europe (44%), NYHA functional class II (69%), III (30%)

Most characteristics were well matched. The finerenone group had 87.9 % of patients with HTN and 38.8 % with atrial fibrillation whereas the placebo group had 89.% with HTN and 37.6% with afib.

Primary Outcome

Finerenone significantly reduced the composite primary outcome (rate ratio 0.84; 95% CI 0.74-0.95; p=0.007).

HF events: 842 (finerenone) vs. 1024 (placebo); rate ratio 0.82; 95% CI 0.71-0.94; p=0.006.

Cardiovascular deaths: 242 (8.1%) vs. 260 (8.7%); hazard ratio 0.93 (95% CI 0.78-1.11).

Secondary Outcomes

Improved symptom score (KCCQ): +1.6 points (p<0.001).

No significant difference in NYHA class improvement, kidney outcomes, or death from any cause.

Here is a table summarizing the different endpoints of the study:

Endpoint	Finerenone Group (n = 3003)	Placebo Group (n = 2998)	Effect Estimate	P-value
PRIMARY OUTCOMES
Total Worsening HF events + CV death	1083 events	1283 events	Rate ratio 0.84 (95% CI 0.74-0.95)	0.007
Worsening HF Events	842 events	1024 events	Rate ratio 0.82 (95% CI 0.71-0.94)	0.006
CV Death	242 patients (8.1%)	260 patients (8.7%)	Hazard ratio 0.93 (95% CI 0.78-1.11)	0.42
SECONDARY OUTCOMES
Change in KCCQ Total Symptom Score	+8.0 points	+6.4 points	Difference: 1.6 (95% CI 0.8-2.3)	<0.001
Improvement in NYHA Class	18.6%	18.4%	Odds ratio 1.01 (95% CI 0.88-1.15)	0.89
Kidney Composite Outcome	75 patients (2.5%)	55 patients (1.8%)	Hazard ratio 1.33 (95% CI 0.94-1.89)	0.11
All-Cause Death	491 patients (16.4%)	522 patients (17.4%)	Hazard ratio 0.93 (95% CI 0.83-1.06)	0.30

Adverse Events

Hyperkalemia: hyperkalemia was higher in the finerenone group

>this is consistent with findings from other studies involving finerenone, such as the FIDELIO-DKD and FIGARO-DKD trials

Hypokalemia: Interestingly, finerenone was associated with a reduced risk of hypokalemia compared to placebo.

Other Adverse Events: The trial also reported adverse events such as hypotension and hyponatremia, which occurred more frequently in the finerenone group than in the placebo group.

Reduction in Heart Failure Events and Cardiovascular Death: Finerenone significantly reduced the composite rate of heart failure (HF) events (first or recurrent hospitalizations) and cardiovascular (CV) death compared to placebo. The event rate was 14.9 per 100 patient-years in the finerenone group versus 17.7 in the placebo group, demonstrating a 16% relative risk reduction in this primary outcome (Rate Ratio 0.84, p=0.007).

All-Cause Mortality: Though there was a numerical reduction in all-cause mortality in the finerenone group (16.4% vs. 17.4%), this difference was not statistically significant

Improvement in Patient-Reported Outcomes: Finerenone showed modest improvement in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), with a greater increase in scores compared to placebo

Renal Outcomes: While finerenone did not demonstrate a significant reduction in renal outcomes (e.g., progression of chronic kidney disease), the trial highlighted potential benefits in subgroups with comorbid kidney disease.
- In patients with low risk of kidney disease progression, finerenone did not result in a lower risk of secondary kidney outcome. However, it did reduce the risk of secondary kidney outcome in patients with kidney disease and diabetes.

Limitations

Lack of Mortality Benefit: did not demonstrate a significant reduction in cardiovascular mortality. This aligns with challenges faced by previous studies in this population

Low Use of SGLT2 Inhibitors: Only a small percentage of patients were on SGLT2 inhibitors, a therapy already known to benefit HFmrEF/HFpEF. Further studies are needed to explore the potential synergistic effects of combining finerenone with SGLT2 inhibitors.

Finerenone was associated with a higher rate of hyperkalemia (14.3% vs. 6.9%) and hypotension, which are important considerations in clinical practice, particularly in patients with chronic kidney disease.

Few black patients

NHYA Class is a physician-reported measure of functional status, so could be a less sensitive.

Underpowered subgroup analysis, interpret with caution.

Considerations

Exploration of Combination Therapy: Future studies should assess the benefits of finerenone when used in combination with other therapies, particularly SGLT2 inhibitors, which were underutilized in this trial.

Kidney Disease Progression: Given the overlap between heart failure and chronic kidney disease, further research is needed to evaluate finerenone’s role in modifying renal outcomes in HFmrEF/HFpEF. Additionally,

Further Trials in Subpopulations: Additional trials are needed to explore whether finerenone’s benefits extend to other heart failure subgroups, including those with different comorbidities (diabetes or advanced kidney disease)

Summary by:

Dr. Georgia Vasilakis Tsatiris, Internal Medicine Resident, University of Pittsburgh Medical Center, @gmvasilakis

Dr. Swagata Patnaik, Internal Medicine Resident, Mount Sinai Hospital, @Swagata_P

Visual abstract by:

Dr. Mariam Riad, Cardiology Fellow, University of South Alabama, @MariamfrAdel

Trial Tweets, Promotion, & Archive by:

Dr. Saihariharan Nedunchezhian, Internal Medicine Resident, George Washington, @SaiNedu

Moderator of Twitter during CardsJC by:

Dr. Swagata Patnaik, Internal Medicine Resident, Mount Sinai Hospital, @Swagata_P

Interns:

Pacey Wetstein, Medical Student, Lake Erie College of Osteopathic Medicine

Under the guidance of House Chief:

Dr. Cali Clark, Cardiology Fellow, Allegheny Health Network, @CaliRClark

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