Acetazolamide or Metolazone in Acute Heart Failure

After inclusion in the study and signing the informed consent, the patient will be randomized into one of the following three intervention groups:

• Group A: Intravenous furosemide alone.
• Group B: Intravenous furosemide with oral metolazone 2.5mg.
• Group C: Intravenous furosemide with oral acetazolamide 250mg.

Metolazone or acetazolamide will be administered in fixed doses for a total of 3 doses (D0, D1, and D2) - at admission (D0), on the morning of the second day (D1), and on the morning of the third day (D2).

The use of intravenous furosemide will follow a protocol for dose and frequency of administration. Its dose should not be modified before D2. On D2, modification is allowed according to the protocol (details later).

In cases of major adverse events only, the local practitioner may suspend these therapies (as indicated later).

The study is driven by a clinical outcome based on a congestion score. The primary outcome will assess the ability to achieve effective decongestion (score 0 - 1) for each of the three interventions over 3 days. The primary outcome will be considered achieved if a score of 0 - 1 is reached on D1, D2, or D3, without requiring escalation of diuretic therapy on D2. The congestion score consists of 3 clinical parameters (edema, jugular venous distension, lung crepitations), one radiological parameter (pleural effusion on X-ray), and one ultrasonographic parameter (LUS: B-line count in 4 zones). A score is assigned based on the intensity of each parameter, with 0 and 1 considered as a score indicative of complete decongestion.

The key determinant on D0, D1, and D2, guiding whether the intervention continues or stops, is the persistence of congestion. The intervention should continue for those with a congestion score of 2 or more during the first assessment of the day. If the congestion score is 0 or 1, the intervention is suspended, and the patient should transition to oral furosemide (in preparation for hospital discharge).

Here is the detailed procedure for each day of intervention (total 3 days, closing on the third morning of hospitalization or D3):

• D0 or admission day: Eligibility criteria are reviewed for study inclusion, informed consent is obtained, and randomization to the intervention arm is conducted. Admission data is collected.
• D1 or first morning after admission: Congestion score is calculated. In case the primary outcome is not achieved, the intervention continues without modifications. Clinical and biochemical data are collected according to the protocol.
• D2 or second morning of hospitalization: Congestion score is calculated, and the intervention continues in case the primary outcome is not achieved. On this day, decongestive therapy is titrated based on the total diuresis and weight loss achieved in the previous 24 hours (according to the protocol).
• D3 or third morning: Congestion score is calculated. The intervention is discontinued regardless of the achieved score. Further management is at the discretion of the treating physician. Clinical and biochemical data for the last day are collected.
• 90-day Follow-up: The patient will be contacted, and the medical records will be reviewed to assess clinical and biochemical data 90 days after discharge. Information on worsening heart failure and mortality during this period will be extracted.

Additional recommendations for the intervention include:

• Optimal Medical Treatment: Maintain chronic heart failure therapy (ACEI/ARNI/ARB, Beta-blockers, Mineralocorticoid receptor antagonists, and SGLT2 inhibitors) unless contraindicated. Initiate these treatments before discharge, if not already instituted. Encourage early medical follow-up for discharged patients. Decisions on ferric carboxymaltose administration and entry into cardiac rehabilitation are at the physician's discretion.
• Potassium Control: Suggested to keep plasma levels above 4.0 mEQ/L (oral or intravenous correction).
• Patient Diet and Mobilization: Recommend restricting sodium and volume to less than 1.5g and 2000cc daily, respectively. Encourage early mobilization and kinesiotherapy, if no contraindications. Provide thromboembolic prevention based on local guidelines.
• Situations for Intervention Cessation: (protocol termination and AE reporting)

• Hypokalemia < 2.5 mEQ/L
• Hyponatremia < 125 mEQ/L
• Acidosis with pH < 7.20 or Bicarbonate < 15 mEQ/L
• Asymptomatic hypotension (SBP < 90mmHg) or symptomatic hypotension (SBP < 100mmHg).
• Significant deterioration in renal function (creatinine rise above 0.8mg and 1.5x baseline) NOTE: If early intervention suspension occurs with complete decongestion, consider the primary outcome achieved.

Inclusion criteria

• Acute heart failure: Hospitalization due to symptoms of heart failure, congestion signs documented with a congestion score greater than 1, NT-proBNP above 1000 pg/ml.
• Randomization within 24 hours of admission.

Exclusion criteria

• Under 18 years of age.
• Received more than one dose of intravenous furosemide before randomization.
• Cause of heart failure: hypertrophic or restrictive cardiomyopathy, or constrictive pericarditis.
• Acute coronary syndrome or severe acute valvulopathy as the cause of decompensation.
• Systolic blood pressure < 90mmHg before randomization.
• Requirement for vasopressors, inotropes, or invasive mechanical ventilation. Use of intravenous vasodilators or non-invasive mechanical ventilation is allowed.
• Glomerular filtration rate < 20ml/min/1.73m2.
• Potassium < 2.5 mEQ/L or Sodium < 125 mEQ/L before randomization.
• pH < 7.2 or Bicarbonate < 15mEQ/L before randomization.
• Use of another diuretic in addition to furosemide before randomization. Dapagliflozin or Empagliflozin can be maintained upon admission or initiated early during hospitalization if desired by the treating physician (variable to be recorded).
• Patients who cannot achieve adequate recording of variables (e.g., inability to quantify diuresis or weight).
• Pregnant or lactating individuals. If of childbearing age and there is inconsistency with contraceptive use or reasonable doubts about current pregnancy, a pregnancy test must be conducted before study entry.