Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload

NCT06166654 | Recruiting Phase 4 DMC

• 1 other identifier: DRAIN_AHF
• Study Type: interventional
• Target: 939
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Acute Heart Failure

Keywords

acute heart failure; decongestion; diuretic

Outcome Measures

Primary Outcomes (1)

• Days alive out-of-hospital to day 30

  Days alive out-of-hospital to day 30

  30 days

Secondary Outcomes (3)

• Win ratio of 1. all-cause death, 2. Readmisison, 3. 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.

  30 days

• Kansas City Cardiomyopathy Questionnaire

  30 days

• Decongestion score 72 hours after inclusion

  72 hours

Study Arms (3)

Acetazolamide

ACTIVE COMPARATOR

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.

Drug: Acetazolamide

Metolazone

ACTIVE COMPARATOR

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.

Drug: Metolazone 2.5 MG

Placebo

PLACEBO COMPARATOR

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).

Other: Double-placebo

Interventions

Acetazolamide DRUG

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.

Also known as: Standard of care including loop-diuretics

Acetazolamide

Metolazone 2.5 MG DRUG

2\. 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.

Also known as: Standard of care including loop-diuretics

Metolazone

Double-placebo OTHER

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).

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Acute hospital admission with a clinical diagnosis of acute heart failure with volume overload.
• Display risk of diuretic resistance, characterized by:
• Daily loop-diuretics administration for a minimum of 7 days before admission, or
• 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).
• 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.

You may not qualify if:

• Acute coronary syndrome
• Systolic blood pressure \<85 mmHg
• Treatment with acetazolamide or metolazone during the index hospitalization prior to randomization
• Known allergy to any of the used drugs
• Severe hypokalemia (\<2.5 mmol/l) or severe hyponatremia (\<125 mmol/l)
• Severe hepatic impairment or liver cirrhosis
• Known pregnancy

Sponsors & Collaborators

• Johannes Grand: lead

Study Sites (3)

Amager-Hvidovre Hospital

Hvidovre, Capital Region of Denmark, 2650, Denmark

RECRUITING

Bispebjerg Hospital

Copenhagen, 2400, Denmark

NOT YET RECRUITING

Herlev-Gentofte hospital

Copenhagen, 2730, Denmark

RECRUITING

MeSH Terms

Interventions

Acetazolamide; Metolazone

Intervention Hierarchy (Ancestors)

Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sulfonamides; Amides; Sulfones; Quinazolinones; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Johannes Grand, MD, Phd, MPH

  Amager-Hvidovre Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Johannes Grand, MD, Phd, MPH

CONTACT

+4535452121; johannes.grand@regionh.dk

Sandra Tonning, MD

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will employ a triple-blind design (Participants and relatives, investigators and clinicians, and data analysts and outcome adjudicators)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 3-arm parallel group RCT

Study Record Dates

• First Submitted: December 3, 2023
• First Posted: December 12, 2023
• Study Start: September 5, 2024
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027
• Last Updated: February 20, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

DK (3)