Efficacy and Safety of corticoSTEROids Added to Standard Therapy in Patients With Acute Heart Failure (STERO-AHF)

Inclusion criteria:

1. Full age of consent at screening (at least ≥18 years old according to locallegislation).
2. Able to provide written informed consent or a legally authorized representative isable to provide written informed consent.
3. Hospitalized for AHF, either de novo or decompensated chronic HF, regardless of LVEF.
4. Treatment with a minimum single dose of 40 mg of intravenous furosemide or equivalentintravenous loop diuretic dose (defined as 20 mg of torsemide or 1 mg of bumetanide)at any time between presentation and the end of screening.
5. Insufficient diuretic response assessed at 2-6 hours after the first intravenous loopdiuretic dose administration, according to the latest 2021 ESC guidelines on themanagement of acute and chronic HF, defined as either urinary sodium <70 mEq/L at asingle spot urinary sodium analysis performed at 2 hours or an average urine output <150 mL/h in the first 6 hours after first intravenous diuretic administration. Incase of early insufficient diuretic response and persistence of congestion, the doseof intravenous loop diuretic will have to be doubled and the patient may be enrolled.
6. New York Heart Association functional class II, III or IV at screening.
7. Elevated NT-proBNP ≥1400 pg/mL or BNP ≥350 pg/mL according to the local laboratory forpatients without atrial fibrillation, or NT-proBNP ≥2200 pg/mL or BNP ≥550 pg/mL forpatients with atrial fibrillation at the time of admission and/or in the 72 hoursprior to hospital admission.
8. Elevated CRP ≥10 mg/L according to the local laboratory, measured during the currenthospitalization.
9. Eligible for randomization within the first 24 hours from presentation.

Exclusion criteria:

1. Dyspnea due to non-cardiac causes.
2. Systolic blood pressure <90 mmHg or >180 mmHg at time of screening and randomization.
3. Current hospitalization for AHF primarily caused by pulmonary embolism,cerebrovascular event, or acute myocardial infarction.
4. Current hospitalization for AHF not caused primarily by volume overload; for example,triggered by significant arrhythmia (e.g., sustained ventricular tachycardia [VT], oratrial fibrillation/flutter with sustained ventricular response >120 beats per minute,or bradycardia with sustained ventricular rate <45 beats per minute),infection/sepsis, severe anemia, uncorrected thyroid disease, or acute exacerbation ofchronic obstructive pulmonary disease.
5. Temperature >38.0 °C (oral or equivalent), sepsis, septic shock, or evidence of activeinfection (either bacterial, fungal or viral) requiring new oral or intravenousanti-microbial treatment (either antibacterial, antifungal or antiviral therapy).
6. History of chronic infections, latent infections, chronic inflammatory orimmunosuppressive disorders, chronic immunosuppressive therapy, ongoing chemotherapyor immunotherapy, or chronic anti-microbial therapy (either prophylactic orsuppressive).
7. Current treatment with intravenous corticosteroids or chronic oral corticosteroidtherapy for any other condition and of any duration in the past 6 months prior torandomization.
8. Documented active or history of hypocortisolism or hypercortisolism caused byprimary/secondary adrenal gland disorders, pituitary disorders, iatrogenic conditions,or genetic forms (e.g., adrenal insufficiency, Cushing disease or Cushing syndrome,prior chronic long-standing corticosteroid therapy).
9. Decompensated diabetes mellitus, defined as the presence of diabetic ketoacidosis,hyperglycemic hyperosmolar state, or glycemia > 250 mg/dL as measured at the latestlocal laboratory exams performed during hospitalization.
10. Acute coronary syndrome / myocardial infarction, stroke, transient ischemic attack, orintracranial bleeding in the past 90 days prior to randomization.
11. Any of the following major interventions performed in the past 30 days prior torandomization or planned during the current admission: major cardiac surgery (e.g.,coronary artery bypass graft or valve replacement), percutaneous coronaryintervention, transcatheter aortic valve replacement, or percutaneous mitral valverepair (e.g., transcatheter edge-to-edge mitral valve repair); implantation of acardiac resynchronization therapy device; implantation of a mechanical circulatorysupport (MCS) device; carotid artery disease revascularization (percutaneousintervention or surgery); or any other surgical procedure that is considered "major"according to investigator judgement.
12. Heart transplant recipient, or listed for heart transplant with expectation to receivetransplant during the study period (according to investigator judgement), or currentlyusing or planned for implantation of left ventricular assist device or intra-aorticballoon pump or any other MCS device, or planned inotropic support in an outpatientsetting, or planned for palliative care for HF.
13. Hemodynamically significant (severe) uncorrected primary cardiac valvular diseaseplanned for intervention during the study period. Secondary mitral regurgitation ortricuspid regurgitation due to dilated cardiomyopathy is not excluded unless plannedfor surgical or percutaneous intervention during the study period.
14. AHF caused by peripartum cardiomyopathy or Tako-tsubo syndrome diagnosed within thepast 6 months, active myocarditis, or other acute structural heart disease (e.g.,acute mitral cord rupture).
15. Cardiomyopathy due to infiltrative diseases (e.g., amyloidosis), accumulation diseases (e.g., haemochromatosis, Fabry disease), hypertrophic obstructive cardiomyopathy,complex congenital heart diseases, or known pericardial constriction.
16. Invasive mechanical ventilation at time of screening (endotracheal intubation).Continuous or intermittent non-invasive mechanical ventilation is allowed.
17. Symptomatic VT in patients without an implantable cardioverter defibrillator in thepast 90 days prior to randomization.
18. Symptomatic bradycardia with a documented heart rate <50 beats per minute atelectrocardiogram performed before randomization or evidence of advancedatrio-ventricular block (third-degree or second-degree type 2) without a pacemaker.
19. Atrial fibrillation/flutter with a documented, persistent resting heart rate >120beats per minute at electrocardiogram performed before randomization.
20. Severe impairment of renal function, defined as eGFR <20 mL/min/1.73m2 (according tothe CKD-EPI equation) as measured at the latest local laboratory exams performedduring hospitalization (between presentation and the end of screening), or requiringchronic dialysis or temporary renal replacement therapy.
21. Acute contrast-induced nephropathy.
22. Severe anemia, defined as hemoglobin <8 g/dL as measured at the latest locallaboratory exams performed during hospitalization.
23. Any major solid organ transplant recipient or planned organ transplant during thestudy period.
24. Known history of glaucoma.
25. Prior gastrointestinal surgery or gastrointestinal disorder that could interfere withthe absorption of the study drug (according to investigator judgement).
26. Documented active or suspected malignancy or history of malignancy of any organ systemwithin 1 year prior to screening, except appropriately treated localized basal cellcarcinoma of the skin.
27. Presence of any disease other than HF with life expectancy less than 6 months.
28. Decision for palliative care in HF (informed patient decision to adhere to limited HFtreatments only).
29. Currently enrolled in another investigational device or drug trial, or less than 30days since ending another investigational device or drug trial, or less than fivehalf-lives of the study drug (whichever is longer) in case of drug trial. Patientsparticipating in a purely observational study will not be excluded.
30. Known allergy or hypersensitivity to any corticosteroid or any excipient of the studydrug product.
31. Chronic alcohol or drug abuse or any condition that makes the patient unreliable orunlikely to complete the trial (according to investigator judgement).
32. Inability to follow instructions or comply with follow-up procedures.
33. Pregnant or nursing (lactating) women. Women of child-bearing potential must have anegative urine or serum pregnancy test prior to enrollment.
34. Any other medical condition that may put the patient at risk or influence studyresults according to the investigator judgement, or that the investigator deemsunsuitable for the study.
35. Inability to comply with all study requirements, due to major comorbidities that mightcompromise the patient's ability to understand and/or comply with the protocolinstructions or follow-up procedures.