Impact of Acute Heart Failure:

According to the World Health Organization (WHO), approximately 26 million people suffer from Heart Failure (HF), with a mortality rate of up to 50% within five years of diagnosis. Acute Heart Failure (AHF) exacerbations, leading to hospitalization, are common and represent the primary cause of hospital admissions in those over 65. Effective decongestion during hospitalization is crucial, as failure to achieve it doubles the risk of rehospitalization and mortality, incurring significant healthcare costs.

Use of Diuretics in Acute Heart Failure:

Diuretics, particularly loop diuretics like furosemide, are a cornerstone in managing AHF by inducing natriuresis and achieving decongestion. Clinical experience supports their use, though limited clinical trials exist. Pharmacological concepts guide their administration, emphasizing intravenous delivery in high doses and adjusting subsequent doses based on decongestive efficacy. Additionally, sequential tubular blockade with other diuretics like metolazone and acetazolamide is explored to enhance decongestion.

Use of Metolazone and Acetazolamide:

Sequential tubular blockade, using metolazone and acetazolamide in conjunction with furosemide, aims to achieve rapid and effective decongestion. While metolazone targets the distal tubule, inhibiting sodium-chloride channels, acetazolamide affects proximal tubular function. Studies like ADVOR (acetazolamide) and CLOROTIC (thiazide-like diuretic) demonstrate the potential benefits of combining these diuretics for quicker decongestion but with potential risks (in the case of Hydrochlorothiazide).

Outcomes Measured by Major Studies:

Recent studies assessing decongestion in AHF reveal a lack of uniformity in outcome selection. The primary focus should be on reducing rehospitalizations and post-discharge mortality by achieving effective decongestion. The ADVOR study, using a simple congestion score based on clinical and imaging criteria, underscores the importance of reaching a congestion score of 0 or 1 promptly.

Congestion Monitoring:

Monitoring diuretic treatment solely based on clinical aspects may not capture subclinical congestion, necessitating biochemical and imaging parameters. The ACME-AHF trial proposes a diagnostic score integrating clinical and imaging aspects to evaluate congestion status. Secondary outcomes include cumulative diuresis, weight loss, diuretic efficiency, and natriuresis, with a focus on natriuresis as a reliable physiological parameter for decongestion.

Aim of the study:

The ACME-AHF trial is designed to compare the efficacy and safety of two diuretic combination strategies: acetazolamide with furosemide and metolazone with furosemide. The primary objective is to relieve congestion, assessed using a congestion score, within the first three days of treatment during an hospitalization for 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:

1. 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.

2. Potassium Control: Suggested to keep plasma levels above 4.0 mEQ/L (oral or intravenous correction).

3. 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.

4. 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.