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Randomized Controlled Trial
. 2025 Jan 1;10(1):42-48.
doi: 10.1001/jamacardio.2024.4539.

Finerenone, Serum Potassium, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Orly Vardeny  1 , Muthiah Vaduganathan  2 , Brian L Claggett  2 , Akshay S Desai  2 , Pardeep S Jhund  3 , Carolyn S P Lam  4 , Michele Senni  5   6 , Sanjiv J Shah  7 , Adriaan A Voors  8 , Faiez Zannad  9 , Bertram Pitt  10 , Shingo Matsumoto  3 , Béla Merkely  11 , Shelley Zieroth  12 , Mehmet Birhan Yilmaz  13 , James Lay-Flurrie  14 , Prabhakar Viswanathan  15 , Andrea Horvat-Broecker  16 , Andrea Scalise  17 , John J V McMurray  3 , Scott D Solomon  2
Affiliations
Randomized Controlled Trial

Finerenone, Serum Potassium, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Orly Vardeny et al. JAMA Cardiol. .

Abstract

Importance: Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up.

Objective: To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels.

Design, setting, and participants: Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included.

Intervention: Participants received finerenone or placebo.

Main outcomes and measures: The primary outcome was a composite of total worsening heart failure events or cardiovascular death.

Results: A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L.

Conclusions and relevance: In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L.

Trial registration: ClinicalTrials.gov Identifier: NCT04435626.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vardeny reported receiving grants from AstraZeneca and Cardior and institutional research support from Bayer and Cardurion outside the submitted work. Dr Vaduganathan reported receiving research grant support from, serving on advisory boards for, or having speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health and serving on clinical trial committees for AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics outside the submitted work. Dr Claggett reported receiving personal fees for statistical consulting from Alnylam, Cardior, Cardurion, Cytokinetics, CVRx, Intellia, Rocket, and Eli Lilly consulting outside the submitted work. Dr Desai reported receiving institutional research grants and personal fees from Bayer during the conduct of the study and institutional research grants from Abbott, Alnylam, AstraZeneca, DevPro Biopharma, Novartis, Pfizer and personal fees for consulting from Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, Icon Clinical Research, Novartis, Parexel, Porter Health, Regeneron, Roche, River2Renal, scPharmaceuticals, Veristat, Verily, and Zydus outside the submitted work. Dr Jhund reported receiving grants from Boehringer Ingelheim, Roche Diagnostics, Analog Devices, and AstraZeneca and personal fees from ProAdwise outside the submitted work and serving as director of Global Clinical Trial Partners. Dr Lam reported serving on a steering committee for FINEARTS-HF for Bayer during the conduct of the study and receiving research support from Novo Nordisk and Roche Diagnostics; serving as a consultant or on an advisory board or steering or executive committee for Alnylam Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Corteria, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Quidel Corporation, Radcliffe Group Ltd., Roche, and Us2.AI , serving as co-founder and nonexecutive director of Us2.AI outside the submitted work and having a patent for PCT/SG2016/050217 pending for a method for diagnosis and prognosis of chronic heart failure and a patent for 10,702, 247 issued for automated clinical workflow that recognizes and analyses 2-dimensional and Doppler echo images for cardiac measurements and the diagnosis, prediction, and prognosis of heart disease. Dr Senni reported receiving personal fees from Novartis, Merck, MSD, Abbott, Vifor, Novo Nordisk, Boehringer, AstraZeneca, Cardurion, and Bayer outside the submitted work. Dr Shah reported receiving personal fees from Bayer for consulting during the conduct of the study. Dr Voors reported receiving consultancy reimbursement to institution from Bayer outside the submitted work. Dr Zannad reported receiving personal fees from Bayer during the conduct of the study and personal fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer, CVRx, Cardior, Cambrian, Cereno pharmaceutical, Cellprothera, CVCT, Lupin, Merck, Northsea, Otsuka, Owkin, Salubris, and Viatris outside the submitted work. Dr Pitt reported receiving personal fees from Bayer outside the submitted work; having a patent for US 9931412 issued for site-specific delivery of eplerenone to the myocardium; and consulting for and/or having stock options in AstraZeneca, Boehringer Ingelheim, Lexicon, scPharmacuticals, SQinnovations, G3 Pharmaceuticals, KBP BioSciences, Sarfez Pharmaceuticals, Cereno Scientific, Sea Star Medical, Anacardio, Prointel, Brainstorm Medical, and Vifor; and a US patent pending 63/045,783 for histone-modulating agents for the prevention and protection of organ damage. Dr Merkely reported receiving personal fees from Astra Zeneca, Abbott, Boehringer Ingelheim, Novartis, Biotronik, CSL Behring, Daiichi Sankyo, and Medtronic and grants from Boston Scientific outside the submitted work. Dr Zieroth reported receiving personal fees from Bayer during the conduct of the study and personal fees from Abbott, AstraZeneca, BMS, Boehringer Ingelheim, Cytokinetics, Edwards, Eli Lilly, GSK, Medtronic, Merck, Novartis, Novo Nordisk, Pfizer, Salubris Bio, and Vifor outside the submitted work. Dr Yilmaz reported receiving institutional fees from Bayer, Amgen, Novartis, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Albert Health outside the submitted work. Dr McMurray reported receiving personal lecture fees from Abbott, Alkem, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharmaceuticals Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals Ltd., Lupin Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, The Corpus, Translation Research Group, and Translational Medicine Academy; receiving personal consultancy fees from Alynylam Pharmaceuticals, Amgen, AnaCardio, AstraZeneca, Bayer, Berlin Cures, BMS, Cardurion, Cytokinetics, Ionis Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, and River2Renal; receiving payment to Glasgow University from Novartis, Cytokinetics, Amgen, GSK, Cardurion, AstraZeneca, British Heart Foundation, National Institute for Health- National Heart Lung, and Blood Institute (NIH-NHLBI), Boehringer Ingelheim, SQ Innovations, and Catalyze Group; receiving personal fees as director from Global Clinical Trial Partners Ltd.; and receiving personal fees from WIRB-Copernicus Group Clinical Inc for serving on a data and safety monitoring board outside the submitted work. Dr Solomon reported receiving grants from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly, NIH/NHLBI, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, TheracosBio, and Us2.AI and grants and personal fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Lilly, Novartis, Roche, TheracosBio, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Potassium Levels During the Study by Treatment
The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up.
Figure 2.
Figure 2.. Incidence of Potassium Greater Than 5.5 mmol/L
Dosing was based on estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 (target dose: 40 mg daily) or ≤ 60 mL/min/1.73 m2 (target dose: 20 mg daily) at study baseline.
Figure 3.
Figure 3.. Incidence of Investigator-Reported Potassium-Related Events
Figure 4.
Figure 4.. Rates of Cardiovascular Death or Worsening Heart Failure
See this image and copyright information in PMC

Comment on

References

    1. 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):e895-e1032. doi:10.1161/CIR.0000000000001063 - DOI - PubMed
    1. Vardeny O, Claggett B, Anand I, et al. ; Randomized Aldactone Evaluation Study (RALES) Investigators . Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail. 2014;7(4):573-579. doi:10.1161/CIRCHEARTFAILURE.114.001104 - DOI - PubMed
    1. Rossignol P, Dobre D, McMurray JJ, et al. . Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7(1):51-58. - PubMed
    1. Aldahl M, Jensen AC, Davidsen L, et al. . Associations of serum potassium levels with mortality in chronic heart failure patients. Eur Heart J. 2017;38(38):2890-2896. doi:10.1093/eurheartj/ehx460 - DOI - PubMed
    1. Ferreira JP, Claggett BL, Liu J, et al. . Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial. Eur J Heart Fail. 2021;23(5):776-784. doi:10.1002/ejhf.2134 - DOI - PMC - PubMed

Associated data