Ketones have been suggested to have significant physiological effects in patients with heart failure. Potential mechanisms for these effects include energy provision for the failing heart and direct protective effects on other organs. Despite the strong physiological rationale, the acute effects of ketone therapy in patients with acute heart failure (AHF) is unclear. AHF is a major healthcare issue, with in-hospital mortality exceeding 10%. Therefore, we propose a vanguard randomized controlled trial to assess the effects of ketone esters in patients with AHF. Sixty patients hospitalized with AHF will be randomized to receive either 25 grams of ketone esters three times per day or a matching placebo for five days, or until death or hospital discharge. We hypothesize that ketone therapy will improve markers of systemic congestion and heart failure symptoms. Primary endpoint will be changes in NT-proBNP levels during therapy. Secondary endpoints will be KCCQ scores, and hemodynamic profile as assessed by echocardiogram. Exploratory endpoints will clinical outcomes including mortality, need for intensive care unit admission, among others.

KETO-AHF (Ketone Ester for Treatment of Acute Heart Failure) is a single-site, double-blind, randomized, placebo-controlled vanguard clinical trial evaluating the feasibility, safety, and preliminary efficacy of exogenous ketone ester therapy in adults hospitalized with acute heart failure (AHF). The trial is conducted as a domain within the Heart Failure Efficacy and Research Trial (HEART) Platform master protocol framework.

Adults (≥18 years) admitted with a primary diagnosis of acute heart failure will be screened and enrolled within 48 hours of hospital admission. Eligible participants must have dyspnea and clinical evidence of congestion and meet protocol-specified laboratory and clinical criteria, including elevated NT-proBNP and adequate kidney function (eGFR >15 mL/min/1.73m²). Key exclusions include type 1 diabetes mellitus, dialysis dependence, inability to tolerate enteral therapy, and need for advanced mechanical circulatory support or inopressor therapy.

Participants will be randomized 1:1 to receive ketone ester therapy or matching placebo for up to 5 consecutive days (or until hospital discharge or death), in addition to standard-of-care acute heart failure management. Randomization will occur through a centralized web-based system using stratified randomization by sex, and both participants and study staff will remain blinded to allocation.

The investigational intervention is KetoneAid MonoEster (D-β-hydroxybutyrate bonded to R-1,3-butanediol), administered orally or enterally at 25 g three times daily (total 75 g/day). The placebo arm receives a taste- and appearance-matched placebo administered on the same schedule. Study drug administration occurs after meals with flexibility to accommodate clinical care.

The primary endpoint is change in NT-proBNP over the treatment period. Secondary outcomes include change in heart failure symptoms using the Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score and change in echocardiographic measures of cardiac function. Exploratory outcomes include glycemic control and insulin requirements, renal function, daily fluid balance adjusted for diuretic dose, and clinical outcomes through 30 days including mortality and days alive and out of hospital. The vanguard design also evaluates feasibility outcomes to inform a subsequent full-scale trial, including consent rate, representation of women, intervention adherence, and follow-up completeness.

Safety monitoring includes daily clinical assessment and laboratory monitoring (including acid-base measures), with predefined adverse events of special interest and stopping rules. An independent Data Safety Monitoring Committee (DSMC) reviews safety data at prespecified enrollment intervals.

Domain-Specific Inclusion Criteria:

1. Primary diagnosis of AHF with dyspnea on exertion or at rest, and at least two of the following: congestion on chest radiograph, rales on chest auscultation, clinically relevant edema, or an elevated jugular venous pressure [21]
2. Admitted to the hospital for less than 48 hours
3. Estimated glomerular filtration rate above 15 mL/min/1.73m²
4. NT-proBNP ≥ 1000 pg/ml

Domain-Specific Exclusion Criteria:

1. Type 1 diabetes mellitus
2. Patients on mechanical circulatory support
3. Patients on more than one inotrope or on inopressors
4. Patients on dialysis
5. Patients with non-functioning enteral tracks

Blinding: Double-blind using placebo matching taste and appearance of ketone esters