Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload (DRAIN-AHF)

Optimal Diuretic Therapies for Acute Heart Failure With Volume Overload - A Randomized Clinical Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Heart Failure
• Intervention / Treatment: Drug: Acetazolamide; Drug: Metolazone 2.5 MG; Other: Double-placebo

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 Type: Interventional
• Enrollment (Estimated): 939
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Johannes Grand, MD, PhD, MPH; Phone Number: +4522817126; Email: johannes.grand@regionh.dk
• Study Contact Backup: Name: Sandra Tonning, MD

Study Locations

• Denmark
  • Capital Region Of Denmark
    • Hvidovre, Capital Region Of Denmark, Denmark, 2650
      • Amager-Hvidovre Hospital
      • Contact: Johannes Grand, MD, PhD, MPH; Phone Number: +4522817126; Email: johannes.grand@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: Standard of care including loop-diuretics
Active Comparator: Metolazone; 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; 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.; Other Names: Standard of care including loop-diuretics
Placebo Comparator: 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).	Other: Double-placebo; 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive out-of-hospital to day 30	Days alive out-of-hospital to day 30	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Number of 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.	30 days
Kansas City Cardiomyopathy Questionnaire	Kansas City Cardiomyopathy Questionnaire (KCCQ). Minimum and Maximum Values: The KCCQ is scored on a scale from 0 to 100. Interpretation of Scores: Higher Scores: Indicate better heart failure-related quality of life, fewer symptoms, and fewer physical and social limitations. Lower Scores: Suggest more severe heart failure symptoms, greater physical limitations, and a poorer quality of life.	30 days
Decongestion score 72 hours after inclusion	scale from 0 to 10 on the basis of the sum of scores for the degree of edema (0 to 4), pleural effusion (0 to 3), and ascites (0 to 3), with higher scores indicating a worse condition on all scales	72 hours

Collaborators and Investigators

• Sponsor: Johannes Grand
• Investigators: Principal Investigator: Johannes Grand, MD, Phd, MPH, Amager-Hvidovre Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: December 3, 2023
• First Submitted That Met QC Criteria: December 3, 2023
• First Posted (Actual): December 12, 2023

Study Record Updates

• Last Update Posted (Estimated): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: acute heart failure; diuretic; decongestion
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Anticonvulsants; Sodium Chloride Symporter Inhibitors; Acetazolamide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Metolazone
• Other Study ID Numbers: DRAIN_AHF

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No