Aim to identify the best strategy for treating acute heart failure (AHF) with volume overload, particularly focusing on patients resistant to standard loop-diuretics. The trial is a double-blinded, randomized, controlled, multicenter study. Its primary objective is to compare the efficacy of loop-diuretics combined with either Metolazone or Acetazolamide, against loop-diuretics alone. The trial will also determine the optimal type of loop-diuretic to use.

Eligible participants include adults over 18 years hospitalized with AHF and volume overload, showing signs of congestion and at risk of diuretic resistance. Exclusions apply to those with acute coronary syndrome, low systolic blood pressure, prior renal therapy, or previous treatment with Acetazolamide or Metolazone.

The primary outcome is the number of days alive and out-of-hospital by day 30. Secondary outcomes include a composite clinical benefit at 30 days, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and successful decongestion 72 hours post-inclusion.

The trial aims to enroll about 1,041,939 patients across three treatment arms over three years. The minimal important difference is set as a reduction in out-of-hospital days by at least two days, with an anticipated low dropout rate. The study's power is calculated to be 80% with an adjusted alpha level for comparing the three diuretic groups.

Trial synopsis Title: OPTIMAL DIURETIC THERAPIES FOR ACUTE HEART FAILURE WITH VOLUME OVERLOAD - A RANDOMIZED CLINICAL TRIAL

Background:

Intravenous loop-diuretics have been the key component in treating acute heart failure (AHF) since the nineteen sixties and has a Class 1 recommendation in the 2021 ESC guidelines for heart failure. Hospitalization for AHF with volume overload is the most frequent cause of hospital admission among elderly patients and is associated with poor outcome. There is a high need for additional decongestant therapies beyond the recommended use of intravenous loop diuretics.

Primary objective:

To determine the superior strategy of loop-diuretics + Metolazone, loop-diuretics + Acetazolamide, or loop-diuretics without additional diuretics during in-hospital treatment for acute decompensated heart failure with volume overload and diuretic resistance. Furthermore, to determine optimal type of loop-diuretic.

Hypothesis:

One of the three diuretic strategies are superior to the others for decongesting acute heart failure with volume overload.

Design: Investigator-initiated, double-blinded, randomized, controlled, multicenter, interventional clinical trial of acute decompensated heart failure patients at risk for diuretic resistanseresistance.

Intervention:

• Acetazolamide as add-on to loop-diuretics
• Metolazone as add-on to loop diuretics
• Usual care including guideline-recommended increase in loop-diuretic dose and fluid and salt-restriction.

Inclusion criteria:

1. Age ≥ 18 years
2. Acute hospital admission with a clinical diagnosis of acute heart failure with volume overload.
3. At risk of diuretic resistance
4. Clinical signs of congestion

Exclusion criteria:

1. Acute coronary syndrome
2. Systolic blood pressure <85 mmHg
3. Use of renal replacement therapy or ultrafiltration in-hospital before study inclusion
4. Treatment with acetazolamide or metolazone during hospitalization prior to randomization

Primary outcome: Days alive out-of-hospital to day 30.

Secondary outcomes:

1. Clinical benefit at 30 days, consisting of a composite of 1. all-cause death, 2. Readmisison after discharge from initial hospitalization, 3. new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as a final inpatient creatinine value ≥200% of the baseline value), assessed using a Hierarchical win-ratio' approach.
2. Kansas City Cardiomyopathy Questionnaire (KCCQ) at 30 days
3. Successful decongestion 72 hours after inclusion (measured as the decongestion score ad modum Advor)

Inclusion Criteria:

1. Age ≥ 18 years

2. Acute hospital admission with a clinical diagnosis of acute heart failure with volume overload.

3. Display risk of diuretic resistance, characterized by:

   1. Daily loop-diuretics administration for a minimum of 7 days before admission, or
   2. Insufficient decongestion observed in the preceding 24 hours (weight reduction <500g or negative fluid balance <1L) despite being treated with high-dose IV loop diuretic (equivalent to ≥120 mg IV furosemide within 24 hours).

4. Clinical signs of congestion, indicated by one or more of the following: pitting peripheral edema, ascites, elevated jugular venous pressure, or radiological/ultrasonic evidence of pulmonary congestion.

Exclusion Criteria:

1. Acute coronary syndrome
2. Systolic blood pressure <85 mmHg
3. Use of renal replacement therapy or ultrafiltration in-hospital before study inclusion
4. Treatment with acetazolamide or metolazone during the index hospitalization prior to randomization
5. Known allergy to any of the used drugs
6. Severe hypokalemia (<2.5 mmol/l) or severe hyponatremia (<125 mmol/l)
7. Severe hepatic impairment or liver cirrhosis
8. Known pregnancy

The study will employ a triple-blind design (Participants and relatives, investigators and clinicians, and data analysts and outcome adjudicators)