OPTIMAL DIURETIC THERAPIES FOR ACUTE HEART FAILURE WITH VOLUME OVERLOAD

Phase 3

Recruiting

• Conditions: acute heart failure
• Interventions: Other: Double-placebo; Drug: Metolazone 2.5 MG; Drug: Acetazolamide

• Registration Number: 2024-510633-17-00
• Lead Sponsor: Region Hovedstaden, Region Hovedstaden

Brief Summary

The main objective is to determine the most effective diuretic treatment strategy for patients with acute decompensated heart failure who have volume overload and are at risk of diuretic resistance.

Detailed Description

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)

Study Timeline

• Study First Posted: 2024-04-15
• Last Update Posted: 2025-06-24

Recruitment & Eligibility

• Status: Ongoing, recruiting
• Sex: Not specified
• Target Recruitment: 939

Inclusion Criteria

1. Aged 18 years or older. 2. Admitted acutely with a clinical diagnosis of acute heart failure. 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 defined as an INR > 1.5 (not due to anticoagulant therapy) and/or a Child-Pugh score ≥ B7 8. Known pregnancy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Double-placebo	Usual care with loop-diuretics as the sole diuretic (SGLT2-inhibitors allowed) including guideline-recommended increase in loop-diuretic dose and fluid and salt-restriction. This arm will also receive both a placebo-acetazolamide injection together with a placebo-metolazone-tablet at randomization and repeated the next 3 mornings (day 1, day 2 and day 3).
Metolazone	Metolazone 2.5 MG	2.5 mg oral Metolazone at randomization (day 0) and repeated the next 3 mornings (day 1, day 2 and day 3). This arm will also receive a placebo- acetazolamide injection together with each metolazone-tablet.
Acetazolamide	Acetazolamide	1. 500 mg IV bolus of acetazolamide at randomization (day 0) and repeated the next 3 mornings (day 1, day 2 and day 3). This arm will also receive a placebo- Metolazone tablet together with each acetazolamide-injection.

Primary Outcome Measures

Name	Time	Method
Days alive and outside hospital until day 30		Days alive and outside hospital until day 30

Secondary Outcome Measures

Name	Time	Method
1. Clinical benefit at 30 days, consisting of a composite of 1. all-cause death, 2. Readmission 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. Days alive and outside hospital until day 90 3. Days of admittance in the primary admission		1. Clinical benefit at 30 days, consisting of a composite of 1. all-cause death, 2. Readmission 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. Days alive and outside hospital until day 90 3. Days of admittance in the primary admission

Trial Locations

Locations (6)

Hvidovre Hospital; 🇩🇰 Hvidovre, Denmark

Aarhus Universitetshospital; 🇩🇰 Aarhus N, Denmark

Odense University Hospital; 🇩🇰 Odense C, Denmark

Herlev Hospital; 🇩🇰 Herlev, Denmark

Copenhagen University Hospital; 🇩🇰 Roskilde, Denmark

Bispebjerg Hospital; 🇩🇰 København, Denmark

Hvidovre Hospital

🇩🇰Hvidovre, Denmark

Morten Petersen

Site contact

+4550738586

morten.petersen@regionh.dk