# Should Exogenous Ketone Body Supplementation Be Considered in Patients Hospitalized for Acute Heart Failure? Rationale and Design of the KETO-AHF Trial

Kristoffer Berg-Hansen, Andreas Bugge Tinggaard, Roni Nielsen, Thomas Hvid Jensen, Nigopan Gopalasingam, Anders Hostrup Larsen, Niels Møller, Morten Böttcher, Malene Hollingdal, Mikael Kjær Poulsen, et al.

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## To cite this version:

Kristoffer Berg-Hansen, Andreas Bugge Tinggaard, Roni Nielsen, Thomas Hvid Jensen, Nigopan Gopalasingam, et al. "Should Exogenous Ketone Body Supplementation Be Considered in Patients Hospitalized for Acute Heart Failure? Rationale and Design of the KETO-AHF Trial." Journal of Cardiac Failure, 2025, pp.S1071-9164(25)00333-1. 10.1016/j.cardfail.2025.07.013. inserm-05379617

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JCF
Journal of Cardiac Failure

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Methodology and Design

Should Exogenous Ketone Body Supplementation Be Considered in Patients
Hospitalized for Acute Heart Failure? Rationale and Design of the KETO-AHF Trial

KRISTOFFER BERG-HANSEN, MD, PhD<sup>1,14</sup> ANDREAS BUGGE TINGGAARD, MD, PhD<sup>1</sup>

RONI NIELSEN, MD, PhD<sup>1</sup> THOMAS HVID JENSEN, MD<sup>1</sup>

NIGOPAN GOPALASINGAM, MD, PhD<sup>1,2</sup> ANDERS HOSTRUP LARSEN, MD, PhD<sup>1</sup>

NIELS MØLLER, MD, PhD<sup>3</sup> MORTEN BÖTTCHER, MD, PhD<sup>2</sup> MALENE HOLLINGDAL, MD, PhD<sup>4</sup>

MIKAEL KJÆR POULSEN, MD, PhD<sup>5</sup> LISBETH ANTONSEN, MD, PhD<sup>5</sup> TORU KONDO, MD, PhD<sup>6</sup>

PARDEEP S. JHUND, MD, PhD<sup>7</sup> BARRY A. BORLAUG, MD, PhD<sup>8</sup>

ALEXANDRE MEBAZAA, MD, PhD<sup>9</sup> JACOB EIFER MØLLER, MD, PhD<sup>10</sup> SØREN VRAA, MD, PhD<sup>11</sup>

JOHANNES GRAND, MD, PhD<sup>10,12</sup> JENS DAHLGAARD HOVE, MD, PhD<sup>12</sup>

EMIL WOLSK, MD, PhD<sup>13</sup> MORTEN SCHOU, MD, PhD<sup>13</sup> and HENRIK WIGGERS, MD, PhD<sup>1</sup>

Aarhus, Herning, Viborg, Odense, Copenhagen, Aalborg, and Hvidovre, Denmark; Nagoya, Japan; Glasgow, United Kingdom; Rochester, Minnesota, USA; and Paris, France

A B S T R A C T

**Background:** Acute heart failure (AHF) is associated with high mortality rates, and contemporary medical treatments provide limited benefits in survival. Emerging evidence suggests that exogenous ketone bodies may have beneficial cardiovascular effects in patients with heart failure. The KETO-AHF (KETOne Supplements in Patients Hospitalized for Acute Heart Failure) trial is designed to assess the clinical benefits of initiating ketone supplementation with 1,3-butanediol compared with placebo in patients hospitalized for AHF with reduced ejection fraction.

**Methods:** KETO-AHF is a multicenter, randomized, double-blind, placebo-controlled trial investigating the effects of 1,3-butanediol (33 g 3 times daily) in patients hospitalized for AHF. Patients with symptoms and signs of AHF requiring intravenous loop diuretics and/or vasoactive treatment, elevated natriuretic peptides, and a left ventricular ejection fraction ≤ 35%, whether de novo or known heart failure, will be enrolled within 5 days of hospital admission. Participants will be randomized 1:1 to receive either 1,3-butanediol or placebo for a 30-day treatment period. The study aims to enroll 125 patients in each group. The primary endpoint is a hierarchical composite of all-cause mortality, heart failure rehospitalization, 6-minute walk test improvement, and reduction in NT-proBNP levels at 30 days.

From the ¹Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; ²Department of Cardiology, Gødstrup Hospital, Herning, Denmark; ³Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark; ⁴Department of Cardiology, Viborg Hospital, Viborg, Denmark; ⁵Department of Cardiology, Odense University Hospital, Odense, Denmark; ⁶Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; ⁷BHF Glasgow Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom; ⁸Department of Cardiology, Mayo Clinic Hospital, Rochester, Minnesota, USA; ⁹Department of Anesthesia and Critical Care, Université Paris Cité, Paris, France; ¹⁰Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; ¹¹Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; ¹²Department of Cardiology, Copenhagen University Hospital-Amager and Hvidovre Hospital, Hvidovre, Denmark;

¹³Department of Cardiology, Herlev-Gentofte Hospital, Copenhagen, Denmark. and ¹⁴Department of Anaesthesiology and Intensive Care, Horsens Regional Hospital, Horsens, Denmark.

Manuscript received February 11, 2025; revised manuscript received July 3, 2025; revised manuscript accepted July 6, 2025.

Reprint requests: Kristoffer Berg-Hansen, MD, PhD, Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark. E-mail: krisbe@rm.dk

See page 7 for disclosure information.

1071-9164/$ - see front matter

© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

https://doi.org/10.1016/j.cardfail.2025.07.013
**Conclusion:** The KETO-AHF trial will provide insights into the effects of supplementation with the ketone body 1,3-butanediol in patients hospitalized for AHF. (J Cardiac Fail 2025;00:1–9)

**Key Words:** Acute heart failure, 1,3-butanediol, ketone bodies, metabolism.

© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

## Introduction

Acute heart failure (AHF) is a life-threatening condition, responsible for 5% of all hospital admissions, with 30-day mortality rates ranging from 10%–50%.¹ The current medical treatment for AHF consists of diuretics, inotropes and mechanical circulatory support.² Trials of neurohormonal therapies and sodium glucose cotransporter inhibitors (SGLT2is) have shown positive results in the predischarge and/or early postdischarge phases, but to date, no randomized trial has documented survival benefits of early initiation of medical treatment in this group of patients, highlighting the need for novel therapies in this high-risk population.

Ketone bodies, particularly 3-hydroxybutyrates (3-OHBs), are essential energy sources during fasting, exercise and severe illness.³ The heart efficiently absorbs and uses ketone bodies in direct correlation with their plasma concentrations.⁴ Due to the high energy yield and low oxygen cost of 3-OHBs, elevating systemic 3-OHB levels may confer cardiovascular advantages.⁵ Patients with heart failure with reduced ejection fraction (HFrEF) have increased myocardial use of 3-OHBs, and it has been hypothesized that ketone bodies may aid the failing heart.⁵,⁶ Studies in patients with stable HFrEF demonstrate that 3-OHB increases cardiac output and left ventricular ejection fraction (LVEF) without compromising cardiac efficiency,⁷ suggesting that it is a viable alternative energy source for the failing heart. Short-term ketone ester supplementation for 14 days in patients with HFrEF has demonstrated improvements in cardiac function and decongestion, with reductions in NT-proBNP levels.⁸ Additionally, ketone therapy in AHF patients with cardiogenic shock has shown promising hemodynamic benefits without adverse effects.⁹ The ketone precursor 1,3-butanediol supports sustained ketone availability.¹⁰ Notably, it induces significant and sustained ketosis, leading to prolonged improvements in cardiac performance compared to the ketone ester used in previous trials, and it allows for reduced dosing frequency. Thus, 1,3-butanediol supplementation could be a practical therapeutic approach for AHF by boosting circulating 3-OHB levels, providing a viable alternative to other exogenous ketones due to its extended duration and favorable tolerance.¹¹ Given the beneficial cardiovascular effects of ketone treatment in patients with HF, treatment with 1,3-butanediol could provide a promising bridge to chronic therapy in patients with AHF.

The KETO-AHF (KETOne Supplements in Patients Hospitalized for Acute Heart Failure) trial is designed to assess the efficacy of 1,3-butanediol as a novel treatment for patients with AHF with reduced LVEF. The aim of this article is to describe the rationale and design of the trial.

## Methods

### Trial Structure

KETO-AHF is an investigator-initiated multicenter, randomized, double-blind study designed to assess the impact of 3 x times daily oral administration of a ketone supplement drink containing 1,3-butanediol (33 g [117 mL]; Ketone-IQ Health Via Modern Nutrition, USA) vs a taste-matched placebo drink (isovolumic [117 mL], isoviscous water with stevia and bitterness additive, Health Via Modern Nutrition, USA). The study aims to determine the treatment efficacy in patients admitted for AHF with reduced LVEF. Each intervention will be administered along with clinically indicated medical therapy and fluid restriction. This trial has been registered at ClinicalTrials.gov (NCT06653725), adheres to the ethical standards of the Declaration of Helsinki, and aligns with Danish national guidelines for Good Clinical Practice. The trial has been approved by the Danish Research Ethics Committee. All participants must provide informed written consent. To ensure unbiased and fair oversight, an independent adjudication committee is tasked with reviewing and adjudicating clinical trial endpoints (ie, deaths and HF events) and all serious adverse events.

### Study Participants

The study will enroll adult patients (≥ 18 years) admitted with AHF as the primary diagnosis, as detailed in Table 1. The enrollment window extends to the first 5 days of a hospital stay (Fig. 1). Participants must exhibit symptoms of AHF along with at least 2 objective signs of HF compensation requiring treatment with at least 40 mg of intravenous furosemide or its equivalent and/or vasoactive drugs. An LVEF of ≤ 35% is required, measured during the current hospitalization. Furthermore, participants must present with elevated levels of natriuretic peptides, specifically NT-proBNP levels ≥ 600 pg/mL or BNP levels ≥ 150 pg/mL. For those in atrial fibrillation at the time of inclusion, NT-proBNP levels must be ≥ 900 pg/mL or BNP levels ≥225 pg/mL. The trial will enroll patients with de novo or acute decompensated chronic HFrEF (ADHF).
<table><caption>**Table 1 Eligibility criteria**</caption><thead><tr><th>Key Inclusion Criteria</th><th>Key Exclusion Criteria</th></tr></thead><tbody><tr><td>1. Adult (≥18 years) patients hospitalized with acute heart failure (AHF)*<br>with reduced ejection fraction as the primary diagnosis with<br>– ≥1 documented new or worsening symptom due to HF (dyspnea,<br>decreased exercise tolerance, fatigue)<br>– Objective evidence of AHF, consisting of at least 2 physical exami-<br>nation findings¹ or 1 physical examination finding and at least 1<br>laboratory evidence†</td><td>1. Current hospitalization for AHF triggered by significant arrhythmia<br>(atrial fibrillation flutter with sustained ventricular response &gt;130<br>beats per minute, clinically significant bradycardia or sustained ven-<br>tricular tachycardia)</td></tr><tr><td>2. Treatment with ≥40 mg IV furosemide or equivalent dose loop<br>diuretic and/or IV vasoactive drugs and/or IV inotropic drugs because<br>of AHF</td><td>2. Cardiogenic shock in INTERMACS level 1 or 2 (ie, unstable hemody-<br>namics despite inotropic/vasopressor therapy)</td></tr><tr><td>3. LVEF ≤35% during index hospitalization</td><td>3. Likelihood or current use of mechanical circulatory support</td></tr><tr><td>4. Elevated natriuretic peptides during index admission:<br>– No atrial fibrillation flutter: NT-proBNP ≥600 pg/mL or BNP<br>≥150 pg/mL<br>– Atrial fibrillation flutter: NT-proBNP ≥900 pg/mL or BNP ≥225 pg/mL</td><td>4. Recent cardiac surgery within 3 days</td></tr><tr><td>5. Enrollment within 5 days of hospital admission</td><td>5. Ongoing severe infection or sepsis, severe anemia, acute exacerba-<br>tion of chronic obstructive pulmonary disease, pulmonary embolism,<br>or cerebrovascular accident</td></tr><tr><td></td><td>6. Significant primary valvular disease (hemodynamically severe uncor-<br>rected primary cardiac valvular disease)</td></tr><tr><td></td><td>7. eGFR &lt;15 mL/min/1.73 m² during current hospitalization (except in<br>patients receiving continuous renal-replacement therapy)</td></tr><tr><td></td><td>8. Type 1 diabetes</td></tr><tr><td></td><td>9. Advanced liver disease (Child-Pugh class C)</td></tr></tbody></table>

*Patients with both de novo and acute decompensated chronic heart failure with reduced ejection fraction will be enrolled.

†Physical examination findings considered to be due to heart failure, including new or worsened: (1) peripheral edema; (2) increasing abdominal distention or ascites (in the absence of primary hepatic disease); (3) pulmonary rales/crackles/crepitations; (4) increased jugular venous pressure and/or hepatojugular reflux; (5) S3 gallop; (6) clinically significant or rapid weight gain thought to be related to fluid retention.

‡Laboratory evidence of acute heart failure³⁰ if obtained within 24 hours of presentation, including: (1) increased B-type natriuretic peptide (BNP)/N-terminal pro-BNP (NT-proBNP) concentrations consistent with decompensation of heart failure; in patients with chronically elevated natriuretic peptides, an increase of >30% above baseline should be noted; radiological evidence of pulmonary congestion; and (2) echocardiographic criteria, including: dilated inferior vena cava with minimal collapse on inspiration; decreased left ventricular outflow tract (LVOT) minute stroke distance (velocity time integral [VTI]); septal or lateral E/e' >15 or >12, respectively; (3) D-dominant pulmonary venous inflow pattern; (4) invasive diagnostic evidence with right-heart catheterization showing pulmonary capillary wedge pressure ≥18 mmHg, central venous pressure ≥12 mmHg, or a cardiac index <2.2 L/min/m². INTERMACS, Interagency Registry of Mechanically Assisted Circulatory Support.

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Trial design of KETO-AHF (KETOne Supplements in Patients Hospitalized for Acute Heart Failure).</figcaption></figure>
Key exclusion criteria include uncontrolled atrial fibrillation with a high ventricular rate > 130 beats per minute, cardiogenic shock with unstable hemodynamics despite inotropic/vasopressor therapy, likelihood or current use of mechanical circulatory support, and recent cardiac surgery within 3 days. Exclusion also applies to severe infections or sepsis (Supplementary material) and severely reduced estimated glomerular filtration rate (eGFR < 15 mL/min/1.73 m²; although patients receiving continuous renal replacement therapy may still be eligible for inclusion), type 1 diabetes, significant valvular cardiac conditions, advanced liver disease (Child-Pugh class C), dementia, pregnancy, challenges with oral intake of medication, severe gastrointestinal issues, or gastroparesis. Additional exclusion criteria are detailed in the Supplementary Material. Screen failures will be registered.

## Study Program

Patients admitted for AHF will be screened on hospital admission (Fig. 1). Eligible patients who provide informed consent will be randomized in a 1:1 ratio to receive either 1,3-butanediol or a placebo during a 30-day period, with 125 patients assigned to each group. Randomization will be stratified by HF status (de novo and ADHF presentation). Before treatment begins, a thorough baseline assessment will be conducted, including measurements of body weight, symptoms (via a visual analogue score [VAS] for dyspnea), vital signs, urine output, and blood samples for renal function (eGFR), and natriuretic peptides. Additional evaluations will include health status (using the 12-item version of the Kansas City Cardiomyopathy Questionnaire [KCCQ-12]), resting echocardiography, and a 6-minute walk test (6MWT).

A run-in phase will be implemented to strengthen the trial's efficacy¹²; participants who drop out after receiving the first dose in the allocated treatment arm (ie, after randomization) but before the second dose will be excluded from the final modified intention-to-treat (mITT) analysis. This approach ensures that the mITT population consists only of patients who received at least 2 doses. Dropout rates during the run-in phase will be monitored, and any participant who withdraws during this phase will not be included in the mITT analysis. To preserve sample size and maintain group balance, the study will follow a structured replacement strategy, continuously enrolling new participants to replace run-in dropouts until the full target of participants completing the run-in phase is reached (see Supplementary Material for details).

Further in-hospital assessments will be conducted according to Fig. 1. A comprehensive assessment schedule is detailed in the Supplementary material. Study procedures will take place daily during the first 3 days of hospitalization or until discharge, whichever comes first. During the hospitalization phase, safety parameters will be closely monitored, with regular measurements of body

weight, dyspnea symptoms, vital signs, urine output, and blood samples for eGFR. On the day of discharge, these assessments will be repeated, along with resting echocardiography and a 6MWT. Additionally, daily physical activity will be monitored by using wrist-worn accelerometers from discharge until the 30-day follow-up. Changes in background medical therapy will be meticulously recorded at each study visit.

A follow-up phone call will be conducted 15 days post-randomization. On day 30 post-randomization, participants will attend a study visit after an overnight fast, where endpoints will be assessed, mirroring the baseline and discharge assessments. On day 60, a similar study visit will be conducted, and the endpoints will be assessed as exploratory. A participant is considered to have completed the trial upon attending the end-of-treatment visit on day 30, at which time the primary endpoint is to be assessed. Compliance with the intervention will be evaluated by a questionnaire and a bottle count.

## Endpoints

The primary endpoint is clinical benefit from 30-day oral treatment with a 3-times-daily regimen of 1,3-butanediol as compared with placebo (Table 2). Clinical benefit is defined through a hierarchical composite endpoint, analyzed using a win ratio, incorporating (1) all-cause death within 30 days; (2) HF events within 30 days (ie, unplanned hospitalization or outpatient visit due to worsening HF (see Supplementary material); (3) between-group difference in 6MWD change from baseline to 30 days (threshold is set as ≥ 30 meters); (4) between-group difference in NT-proBNP-level change from baseline to 30 days (threshold is set as ≥ 30%); and (5) difference in NT-proBNP

<caption>**Table 2** Trial endpoints</caption>

### Primary Endpoint:

* Clinical benefit: a hierarchical composite assessed by the win ratio after 30 days of treatment, including: all-cause mortality, number of heart failure events,ª a ≥30-meter between-group increase in 6-minute walk test distance from baseline to follow-up, 30% between-group reduction in NT-proBNP levels from baseline to follow-up, and percentage reduction in NT-proBNP (continuous variable).

### Key Secondary Endpoints:

* Time to all-cause death and first heart failure event*

* Each individual component of the primary endpoint

* Change in VAS dyspnea score from baseline to discharge and end of treatment

* Change in KCCQ-12 total summary score from baseline to end of treatment

* Change in systolic blood pressure from baseline to discharge and end of treatment

* Initiation or reinitiation inotropes from baseline to end of treatment†

* Transfer or retransfer to the intensive care unit from baseline to end of treatment†

* Need for dialysis from baseline to end of treatment

<footnote>*Includes hospitalization for heart failure and urgent outpatient heart failure visit requiring intravenous loop diuretics, metolazone or inotropic therapy.</footnote>

<footnote>†Among patients not on inotropes at baseline and those in whom inotropes were stopped and later restarted</footnote>

<footnote>‡Among patients not in the intensive care unit at baseline or those discharged from the intensive care unit and later readmitted during the treatment periodKCCQ-12, 12-item version of the Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-B-type natriuretic peptide; VAS, visual analogue scale.</footnote>
<table><caption>**Table 3** Assumptions for power calculation</caption><thead><tr><th>Tiers</th><th>Primary Endpoint Composition</th><th>Assumptions</th></tr></thead><tbody><tr><td>Tier 1</td><td>Proportion of patients who die within 30 days</td><td>30-day mortality: 5.0% in the placebo group and 3.75% in the ketone-supplementation group<br>Intervention wins in this tier: 4.8% vs 3.6%</td></tr><tr><td>Tier 2</td><td>Proportion of heart failure events* within 30 days</td><td>Incidence of heart failure event within 30 days: 8.0% in the placebo group and 6.0% in the ketone-supplementation group<br>Intervention wins in this tier: 6.9% vs 5.1%</td></tr><tr><td>Tier 3</td><td>Difference in the 6MWD change baseline to 30 days between the treatment groups:<ul><li>The threshold for the difference is ≥30 meters for a win</li><li>Tied if the difference is &lt;30 meters</li><li>Pairs involving missing values count as ties</li></ul></td><td>6MWT mean change from baseline to 30-day follow-up in the placebo group: 100±80 meters<br>6MWT mean change from baseline to 30-day follow-up in the ketone-supplementation group: 130±80 meters, assuming 10% is missing.<br>Intervention wins in this tier 32.4% vs 19.3%</td></tr><tr><td>Tier 4</td><td>Difference in NT-proBNP change from baseline to 30 days between the treatment groups:<ul><li>The threshold for the difference is ≥30% for a win.</li><li>Tied if the difference is &lt;30%</li><li>Pairs involving missing values count as ties.</li></ul></td><td>NT-proBNP % change from baseline to 30-day follow-up: 36% for placebo and 50% for NT-proBNP<br>Intervention wins in this tier 11.0% vs 7.7%</td></tr><tr><td>Tier 5</td><td>Difference in NT-proBNP change between the 2 groups<ul><li>Greater from baseline is better</li><li>Pairs involving missing values count as ties.</li></ul></td><td>Treatment effect on NT-proBNP placebo % change from baseline as continuous variable<br>Intervention wins in this tier 5.2% vs 4.0%</td></tr></tbody></table>

Overview of hierarchical composite endpoint components. Additional references for the presented assumptions are provided in the Supplementary material.

*Includes hospitalization for heart failure and urgent outpatient heart failure visit requiring intravenous loop diuretics, metolazone or inotropic therapy. NT-proBNP, N-terminal pro-B-type natriuretic peptide; 6MWT, 6-minute walk test.

change as a continuous variable. The thresholds for tiers 3 and 4 serve as clinically meaningful cutoffs to define a favorable treatment response.¹³,¹⁴ For the win ratio analysis, each participant in the treatment group is compared pairwise with each participant in the placebo group; a win is assigned to the participant with the better outcome at the first tier of the hierarchy in which the 2 differ. For example, if 2 participants survive and have no HF events, the comparison moves to the 6MWD change, and a win is assigned if 1 participant improves ≥ 30 meters more than the other. The primary endpoint will be evaluated using this win ratio approach in a mITT analysis with unmatched pairs; participants will be analyzed according to their randomized treatment group. Secondary and exploratory endpoints will also be assessed using the mITT population. These endpoints include each individual component of the primary endpoint. Additional key secondary endpoints and statistical considerations are listed in Table 2 and the Supplementary material. Exploratory endpoints include components of metabolic, hemodynamic, and renal substudies to investigate mechanistic insights resulting from ketone therapy (Supplementary material). The trial concludes with a visit on day 60, during which changes in secondary endpoints from the end-of-treatment visit (day 30) are assessed as exploratory to evaluate whether any treatment effects persist beyond the intervention period. A centralized electronic case report form will be used for data capture, and all data will be stored in a coded, pseudonymized form, in accordance with local regulations.

## Sample Size and Statistics

In determining the sample size and win ratio estimate, with a 2-sided significance level of 0.05 and a power of 80%, assuming a 4% dropout rate, we estimated the necessary sample size as 250 patients with 1:1 randomization to detect a win ratio of 1.52 (Supplementary material). Thus, a minimum of 125 participants will be included in each treatment arm. A set of assumptions was applied based on experience and findings from previous trials (Table 3). Missing values of the components of the win ratio will be counted as ties in the win ratio. Exploratory subgroup analyses will be performed of the primary endpoint to determine whether treatment effects vary across differing patient subgroups. The subgroups for analysis will include: (1) HF status, categorized as de novo HF and ADHD; (2) patients treated with or without vasoactive treatment; (3) Baseline characteristics categorized (based on median values if continuous variable) based on sex, age, body mass index, HF etiology (ischemic vs nonischemic), use of SGLT2is, LVEF and NT-proBNP levels.

## Discussion

AHF is a condition characterized by high morbidity and mortality rates, accompanied by an elevated risk of readmission shortly after discharge.¹ Current treatment options remain limited, emphasizing the critical need for innovative and effective therapeutic strategies. The KETO-AHF trial is designed to provide valuable insights
into the potential of exogenous ketone body therapy as a bridge to long-term management in patients with AHF with reduced LVEF. Notably, the study emphasizes early initiation of therapy, beginning within 5 days of admission and extending to treatment through the high-risk first 30 days following hospitalization. The trial also encompasses patients with ADHF already treated with established guideline-directed medical HFrEF therapy and those with de novo HFrEF and a broader range of AHF severities, including patients with advanced disease requiring vasoactive support.

## Rationale for Treatment With 1,3-Butanediol in Patients Hospitalized for AHF

HFrEF is increasingly understood as a state of profound metabolic dysfunction, driven by impaired mitochondrial energy production, with adenosine triphosphate depletion closely linked to worsening cardiac performance.¹⁵ Addressing this cardiometabolic imbalance represents a promising avenue for innovative HF therapies. The myocardium demonstrates a remarkable ability to use ketone bodies efficiently, supported by high levels of ketolytic enzymes.¹⁶ Importantly, myocardial ketone uptake is proportional to circulating levels,⁴ suggesting that increasing ketone availability could positively influence cardiac metabolism. Thus, treatment with exogenous ketone supplements may benefit patients with HFrEF by improving myocardial energy production. The therapeutic potential of exogenous ketone supplementation has been demonstrated in multiple studies. Intravenous 3-OHB infusion enhances cardiac function in patients with HFrEF and with pulmonary hypertension.¹⁷ In chronic HFrEF, a 14-day qid regimen of ketone ester improved cardiac function and induced decongestive effects, including reductions in filling pressures and NT-proBNP levels.⁸ Similar findings have been reported in patients with HF with preserved ejection fraction.¹⁸ This intervention may enhance myocardial energy production and cardiac function, reduce cardiac load, and ultimately improve clinical outcomes in patients with AHF, particularly during the vulnerable immediate postadmission phase.¹⁹

1,3-butanediol, a ketone precursor, presents a novel therapeutic strategy for AHF by sustaining ketone availability.¹⁰ Notably, it induces significant and sustained ketosis, leading to prolonged improvements in cardiac performance compared to the ketone ester used in previous trials, and it allows for reduced dosing frequency. Participants will be randomized to receive a 30-day oral treatment with either nutritional supplements with ketone bodies through 1,3-butanediol 3 times daily or an isovolumic, isoviscous, taste-matched placebo drink 3 times daily. A noncaloric placebo was deliberately chosen to avoid confounding from nutrient-induced cardiac effects.²⁰ This 3-times-daily regimen is expected to produce sustained and safe hyperketonemia, maintaining 3-OHB levels between 1 and 2 mmol/L for at least 20 hours

daily.¹⁰ Hyperketonemia within this range has been shown to be safe and is associated with improved cardiac function in prior clinical trials.⁷⁻⁹,¹⁷,¹⁸,²¹

## Patient Selection

KETO-AHF includes patients with both ADHF and de novo HFrEF, aligning with the broad inclusion criteria. This approach is grounded in the presumed mechanisms of exogenous ketone therapy,²²⁻²⁴ which may target the underlying pathophysiology of AHF, regardless of prior HF status. KETO-AHF also includes patients across the severity spectrum of AHF, including those requiring vasoactive therapy, thus extending beyond most AHF trials. While the inclusion criteria allow for a broad AHF population, including those requiring vasoactive support, patients with overt cardiogenic shock requiring mechanical circulatory support are excluded. Although rare, patients may occasionally receive vasoactive therapy without concurrent loop diuretics, for example, in low-output states with borderline filling pressures, reflecting the nuanced real-world management of advanced HFrEF. The trial design enables subgroup analyses to explore differential treatment effects across the spectrum of AHF severity, ensuring meaningful interpretation despite heterogeneity. Given the ability of ketone treatment to enhance forward flow, the trial specifically includes AHF patients with reduced LVEF ≤35%, who may derive particular benefit from this intervention.

KETO-AHF also includes patients with severely reduced kidney function, consistent with the inclusive approach of our prior trials, which even incorporated individuals undergoing renal-replacement therapy.⁹ Although 3-OHB is excreted primarily in the urine, circulating levels equilibrate with acetoacetate and acetone, the latter being eliminated through pulmonary excretion, ensuring systemic ketone excretion even in the context of renal impairment. Additionally, patients with postcardiotomy shock are excluded within the first 3 days postsurgery, as this period is characterized by hemodynamic instability and postoperative physiological changes that may confound the interpretation of treatment effects. Patients with type 2 diabetes, who represent a significant proportion of individuals with AHF,²⁵ are eligible for inclusion. This enhances the generalizability of the trial while leveraging recent evidence, demonstrating the safety of ketone therapy in this population.⁸,¹⁸ However, patients with type 1 diabetes are excluded due to the increased risk of diabetic ketoacidosis and the reduced cardiac ability to effectively use ketone bodies observed in this group.²⁶ Similarly, patients with AHF secondary to acute coronary syndrome are not eligible, because the trial is limited to patients in whom AHF is the primary diagnosis. These eligibility criteria ensure the safety of trial participants while maintaining a focus on populations most likely to benefit from ketone therapy.
## Study Design

The acute enhancement of cardiac function and peripheral tissue perfusion observed with exogenous ketone administration suggests its potential as an additional therapy during the stabilization phase of AHF.⁹,²⁷ Therefore, KETO-AHF enrolls patients hospitalized for AHF within 5 days of admission. This approach ensures early initiation of therapy during a critical time window,¹⁹ maximizing the opportunity to influence outcomes in this vulnerable population. Furthermore, treatment in KETO-AHF extends for 30 days from enrollment, thus also addressing the particularly vulnerable postdischarge phase.¹⁹ Evidence from prior studies suggests that focusing solely on in-hospital treatment may miss opportunities for sustained benefits.²⁸ Meanwhile, the improvement in cardiac function and decongestive effects seen after just 14 days of ketone ester treatment in stable patients with HFrEF suggest its usefulness in patients hospitalized for AHF as a bridge to chronic therapy.⁸ By maintaining exogenous ketone therapy throughout hospitalization and into the early postdischarge period, KETO-AHF aims to harness these benefits while complementing the optimization of guideline-recommended HF treatments.² This dual approach offers a promising strategy to mitigate the risks associated with the early recovery phase and improve long-term outcomes for patients with AHF. Additionally, extending follow-up to 30 days after cessation of therapy may reveal the durability or reversibility of treatment effects, highlighting the potential need for prolonged intervention beyond 30 days. To capture the potential of in-hospital clinical deterioration, key secondary endpoints include initiation of inotropes, transfer to the intensive care unit, need for dialysis, and cumulative loop diuretic dosages administered during hospitalization. These metrics provide insight into the early clinical courses and treatment responses prior to discharge.

The KETO-AHF trial employs a hierarchical composite endpoint, analyzed using the win ratio, to evaluate the clinical efficacy of exogenous ketone therapy in patients with AHF.²⁹ This composite was selected to capture a range of clinically relevant effects within a relatively short follow-up period, combining hard clinical events with objective and functional measures of disease severity. Clinically meaningful thresholds were applied for the 6MWT and NT-proBNP levels to enhance interpretability, while NT-proBNP levels also entered the hierarchy as a continuous variable to reduce ties. The win ratio offers a robust analytic framework for such a hierarchy, enabling comparison across all unmatched patient pairs by assessing the first outcome in the hierarchy where they differ.²⁹ It yields an estimate of the odds that a randomly selected patient from the intervention group will fare better than 1 from the control group. Measures such as the 6MWT and NT-proBNP levels may be influenced by regression to the mean, but the randomized design ensures baseline balance between groups, mitigating systematic bias resulting from such effects.

## Conclusion

Treatment with exogenous ketone body supplements has several potentially beneficial cardiovascular effects in patients with HF. Thus far, the efficacy of ketone therapy has been demonstrated during acute administration in patients across the HF spectrum, in both stable patients and patients with AHF, and for a 14-day period. However, the sustained efficacy and safety of ketone supplementation in patients hospitalized due to AHF remain unexplored. By exploring the therapeutic potential of sustained ketone supplementation, the KETO-AHF trial aims to explore innovative strategies for improving outcomes in patients admitted for AHF with reduced LVEF.

## Lay Summary

* Acute heart failure is life-threatening, and ketone therapy may improve outcomes in these patients.

* The KETO-AHF trial investigates whether ketone supplementation can improve survival, functional capacity, and heart failure markers in patients hospitalized due to acute heart failure.

* The trial is a randomized, double-blind, phase II trial that will explore the potential of ketone body supplements to improve outcomes in this patient group.

Patients hospitalized with acute heart failure face high risks and few proven treatments. The KETO-AHF trial will test whether a ketone supplement, 1,3-butanediol, can safely improve clinical outcomes in these patients. Ketones provide an efficient energy source for the failing heart, and boosting their levels could offer a new way to help patients recover during hospitalization and beyond.

<figure><img src="image_5.png" /><figcaption>Kristoffer Berg-Hansen</figcaption></figure>

## Disclosures

H.W. has been the principal investigator or a subinvestigator in studies involving the following pharmaceutical companies: MSD, Bayer, Daiichi-Sankyo, Novartis, Novo Nordisk, Sanofi-Aventis, and Pfizer. B.A.B. receives research support from the National Institutes of Health and the U.S. Department of Defense, as well as research grant funding from AstraZeneca, Axon, GlaxoSmith-Kline,
Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics and has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Jansen, Merck, Novo Nordisk, NGM, NXT, and VADovations and is also named inventor (U.S. patent No. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. P.S.J. reports speakers' fees from AstraZeneca, ProAdWise Communications, advisory board fees from AstraZeneca, and research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices, and Roche Diagnostics and is a director of Global Clinical Trial Partners. P.S.J.'s employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer, Novartis, and Novo Nordisk. All other authors report no conflicts.

CRediT authorship contribution statement

**KRISTOFFER BERG-HANSEN:** Writing – original draft, Visualization, Resources, Project administration, Methodology, Conceptualization.
**ANDREAS BUGGE TINGGAARD:** Writing – review & editing, Software, Resources, Methodology, Conceptualization.
**RONI NIELSEN:** Writing – review & editing, Supervision, Methodology, Conceptualization.
**THOMAS HVID JENSEN:** Writing – review & editing, Methodology, Conceptualization.
**NIGOPAN GOPALASINGAM:** Writing – review & editing, Validation, Resources, Methodology, Conceptualization.
**ANDERS HOSTRUP LARSEN:** Writing – review & editing, Resources, Methodology.
**NIELS MØLLER:** Writing – review & editing, Resources, Methodology.
**MORTEN BÖTTCHER:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
**MALENE HOLLINGDAL:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
**MIKAEL KJÆR POULSEN:** Writing – review & editing, Supervision, Resources, Methodology, Formal analysis, Conceptualization.
**LISBETH ANTONSEN:** Writing – review & editing, Resources, Methodology, Conceptualization.
**TORU KONDO:** Writing – review & editing, Software, Methodology, Formal analysis, Conceptualization.
**PARDEEP S. JHUND:** Writing – review & editing, Software, Methodology, Formal analysis, Conceptualization.
**BARRY A. BORLAUG:** Writing – review & editing, Methodology, Conceptualization.
**ALEXANDRE MEBAZAA:** Writing – review & editing, Methodology, Conceptualization.
**JACOB EIFER MØLLER:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
**SØREN VRAA:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
**JOHANNES GRAND:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
**JENS DAHLGAARD HOVE:** Writing – review & editing, Supervision, Resources,

**Methodology, Funding acquisition, Conceptualization.**
**EMIL WOLSK:** Writing – review & editing, Resources, Methodology.
**MORTEN SCHOU:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Conceptualization.
**HENRIK WIGGERS:** Writing – review & editing, Supervision, Resources, Methodology, Funding acquisition, Formal analysis, Conceptualization.

Acknowledgments

The Novo Nordic Foundation (NNF23OC0085612) has provided support to cover the running costs for this study.

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.card fail.2025.07.013.

References

1. Guha K, McDonagh T. Heart failure epidemiology: European perspective. Curr Cardiol Rev 2013;9:123–7. https://doi.org/10.2174/1573403x11309020005.

2. McDonagh TA, Metra M, Adamo M, Baumbach A, Böhm M, Burri H, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. https://doi.org/10.1093/eurheartj/ehab368.

3. Selvaraj S, Kelly DP, Margulies KB. Implications of altered ketone metabolism and therapeutic ketosis in heart failure. Circulation 2020;141:1800–12. https://doi.org/10.1161/CIRCULATIONAHA.119.045033.

4. Monzo L, Sedlacek K, Hromanikova K, Tomanova L, Borlaug BA, Jabor A, et al. Myocardial ketone body utilization in patients with heart failure: the impact of oral ketone ester. Metabolism 2021;115:154452. https://doi.org/10.1016/j.metabol.2020.154452.

5. Lopaschuk GD, Karwi QG, Tian R, Wende AR, Abel ED. Cardiac energy metabolism in heart failure. Circ Res 2021: 1487–513. https://doi.org/10.1161/CIRCRESA- HA.121.318241.

6. Bedi KC, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 2016;133:706–16. https://doi. org/10.1161/CIRCULATIONAHA.115.017545.

7. Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 2019;139:2129–41. https://doi.org/10.1161/CIRCULA- TIONAHA.118.036459.

8. Berg-Hansen K, Gopalasingam N, Christensen KH, Ladefoged B, Andersen MJ, Poul- sen SH, et al. Cardiovascular effects of oral ketone ester treatment in patients with heart failure with reduced ejection fraction: a randomized, controlled, double-blind trial. Circulation 2024;149:1474–89. https://doi.org/10.1161/CIRCULATIONA- HA.123.067971.

9. Berg-Hansen K, Christensen KH, Gopalasingam N, Nielsen R, Eiskjær H, Møller N, et al. Beneficial effects of ketone ester in patients with cardiogenic shock: a randomized, controlled, double-blind trial. JACC Hear Fail 2023;11:1337–47. https://doi. org/10.1016/j.jchf.2023.05.029.

10. Guldbrandsen H, Gopalasingam N, Christensen KH, Hørsdal OK, Nielsen R, Wiggers H, et al. Cardiovascular and metabolic effects of modulating circulating ketone bodies with 1,3-butanediol in patients with heart failure with reduced ejection fraction. J Am Heart Assoc 2025;14(1):e038461. https://doi.org/10.1161/JAHA.124.038461.

11. Lowder J, Fallah S, Venditti C, Musa-Veloso K, Kotlov V. An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela™). Front Physiol 2023;14:1–14. https://doi.org/10.3389/fphys.2023.1195702.

12. Schechtman KB. Run-in periods in randomized clinical trials. J Card Fail 2017;23:700–1. https://doi.org/10.1016/j.cardfail.2017.07.042.

13. Khan MS, Anker SD, Friede TIM, Jankowska EA, Metra M, Piña IL, et al. Minimal clinically important differences in 6-minute walk test in patients with HFrEF and iron deficiency: MCID for 6MWT in patients with HFrEF and iron deficiency. J Card Fail 2023;29:760–70. https://doi.org/10.1016/j.cardfail.2022.10.423.

14. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro brain natriuretic peptide predicts outcome after hospital discharge in heart failure
patients. Circulation 2004;110:2168-74. https://doi.org/10.1161/01.CIR.0000144310.04433.BE.

15. Hansen KB, Sørensen J, Hansson NH, Nielsen R, Larsen AH, Frøkiaer J, et al. Myocar-dial efficiency in patients with different aetiologies and stages of heart failure. Eur Heart J Cardiovasc Imag 2022;23:328-37. https://doi.org/10.1093/ehjci/jeab227.

16. Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980;60:143-87. https://doi.org/10.1152/physrev.1980.60.1.143.

17. Nielsen R, Christensen KH, Gopalasingam N, Berg-Hansen K, Seefeldt J, Homilius C, et al. Hemodynamic effects of ketone bodies in patients with pulmonary hyperten-sion. J Am Heart Assoc 2023:e028232. https://doi.org/10.1161/JAHA.122.028232.

18. Gopalasingam N, Berg-Hansen K, Christensen KH, Ladefoged BT, Poulsen SH, Ander-sen MJ, et al. Randomized crossover trial of 2-week ketone ester treatment in patients with type 2 diabetes and heart failure with preserved ejection fraction. Circulation 2024;150(20):1570-83. https://doi.org/10.1161/CIRCULATIONAHA.124.069732.

19. Greene SJ, Fonarow GC, Vaduganathan M, Khan SS, Butler J, Gheorghiade M. The vulnerable phase after hospitalization for heart failure. Nat Rev Cardiol 2015;12:220-9. https://doi.org/10.1038/nrcardio.2015.14.

20. Watson WD, Green PG, Lewis AJM, Arvidsson P, De Maria GL, Arheden H, et al. Retained Metabolic Flexibility of the Failing Human Heart. Circulation 2023;148:109-23. https://doi.org/10.1161/CIRCULATIONAHA.122.062166.

21. Gopalasingam N, Christensen KH, Berg Hansen K, Nielsen R, Johannsen M, Gormsen LC, et al. Stimulation of the hydroxycarboxylic acid receptor 2 with the ketone body 3-hydroxybutyrate and niacin in patients with chronic heart failure: hemodynamic and metabolic effects. J Am Heart Assoc 2023;12:1-13. https://doi.org/10.1161/jaha.123.029849.

22. Homilius C, Seefeldt JM, Axelsen JS, Pedersen TM, Sørensen TM, Nielsen R, et al. Ketone body 3-hydroxybutyrate elevates cardiac output through peripheral vasore-laxation and enhanced cardiac contractility. Basic Res Cardiol 2023;118:37. https://doi.org/10.1007/s00395-023-01008-y.

23. Berg-Hansen K, Gopalasingam N, Christensen KH, Svart M, Rittig N, Nielsen R, et al. Neurohormonal and renal effects of 14-day oral ketone ester treatment in patients with heart failure with reduced ejection fraction. Circ Heart Fail 2024:e012167. https://doi.org/10.1161/CIRCHEARTFAILURE.124.012167.

24. Gopalasingam N, Moeslund N, Christensen KH, Berg-Hansen K, Seefeldt J, Homilius C, et al. Enantiomer-specific cardiovascular effects of the ketone body 3-hydroxybutyrate. J Am Heart Assoc 2024;13(8):e033628. https://doi.org/10.1161/JAHA.123.033628.

25. McAllister DA, Read SH, Kerssens J, Livingstone S, McGurnaghan S, Jhund P, et al. Incidence of hospitalization for heart failure and case-fatality among 3.25 million peo-ple with and without diabetes mellitus. Circulation 2018;138:2774-86. https://doi.org/10.1161/CIRCULATIONAHA.118.034986.

26. Berg-Hansen K, Bangshaab M, Gopalasingam N, Nielsen R, Svart M, Rittig N, et al. The cardiac and hemodynamic effects of ketone bodies are abnormal in patients with type 1 diabetes: a randomized controlled trial. Diabetes 2025;74(9):1643-51. https://doi.org/10.2337/db25-0243.

27. Hørsdal OK, Larsen AM, Wethelund KL, Dalsgaard FF, Seefeldt JM, Helgestad OKL, et al. The ketone body 3-hydroxybutyrate increases cardiac output and cardiac con-tractility in a porcine model of cardiogenic shock: a randomized, blinded, crossover trial. Basic Res Cardiol 2025;120:579-96. https://doi.org/10.1007/s00395-025-01103-2.

28. Tromp J, Ponikowski P, Salsali A, Angermann CE, Biegus J, Blatchford J, et al. Sodium-glucose co-transporter 2 inhibition in patients hospitalized for acute decom-pensated heart failure: rationale for and design of the EMPULSE trial. Eur J Heart Fail 2021;23:826-34. https://doi.org/10.1002/ejhf.2137.

29. Pocock SJ, Gregson J, Collier TJ, Ferreira JP, Stone GW. The win ratio in cardiology trials: lessons learnt, new developments, and wise future use. Eur Heart J 2024;45:4684-99. https://doi.org/10.1093/eurheartj/ehae647.

30. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al. 2017 cardio-vascular and stroke endpoint definitions for clinical trials. Circulation 2018;137:961-72. https://doi.org/10.1161/CIRCULATIONAHA.117.033502.