Acetazolamide or Metolazone in Acute Heart Failure

NCT06273397 | Not Yet Recruiting DMC

• 1 other identifier: ACME-AHF
• Study Type: interventional
• Target: 1,050
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Heart Failure Acute; Decompensated Heart Failure

Keywords

Acetazolamide; Metolazone; Heart Failure Acute

Outcome Measures

Primary Outcomes (1)

• Treatment success

  Complete decongestion by the third morning without requiring escalation in diuretic therapy (by the second morning).

  4 days

Secondary Outcomes (8)

• Mortality

  3 months

• Worsening Heart Failure

  3 months

• Cumulative 24-hour Natriuresis

  Day 2

• Cumulative weight loss

  4 days

• Subclinical congestion

  4 days

Other Outcomes (3)

• Any adverse event

  3 months

• Changes in pH value

  4 days

• Change in plasma electrolyte values

  4 days

Study Arms (3)

Furosemide alone

ACTIVE COMPARATOR

Active comparator arm with intravenous furosemide dosing based on glomerular filtration rate (protocol).

Drug: Furosemide Injection

Acetazolamide plus Furosemide

EXPERIMENTAL

Experimental arm number 1 corresponds to oral acetazolamide 250mg (once daily) in combination with furosemide according to the protocol.

Drug: Acetazolamide 250 MG; Drug: Furosemide Injection

Metolazone plus Furosemide

EXPERIMENTAL

Experimental arm number 2 corresponds to oral metolazone 2.5mg (once daily) in combination with furosemide according to the protocol.

Drug: Metolazone 2.5 MG; Drug: Furosemide Injection

Interventions

Acetazolamide 250 MG DRUG

Acetazolamide 250mg orally per day plus furosemide as per protocol. The intervention is administered on the day of hospital admission and for two consecutive mornings. The total intervention consists of 3 doses. The intervention is discontinued on the third morning. The calculation of the congestion score is performed every morning until the third morning. If complete decongestion is achieved, the primary outcome will be considered fulfilled.

Acetazolamide plus Furosemide

Metolazone 2.5 MG DRUG

Metolazone 2.5mg orally per day plus furosemide as per protocol. The intervention is administered on the day of hospital admission and for two consecutive mornings. The total intervention consists of 3 doses. The intervention is discontinued on the third morning. The calculation of the congestion score is performed every morning until the third morning. If complete decongestion is achieved, the primary outcome will be considered fulfilled.

Metolazone plus Furosemide

Furosemide Injection DRUG

Intravenous furosemide in a double daily dose. The dosage is determined by a predefined table based on the admission renal function and the outpatient dose prior to admission. In general terms, for patients with an estimated glomerular filtration rate above 60 ml/min/1.73m² or those experiencing heart failure debut, the dose will be 1x the outpatient dose. For those with a glomerular filtration rate below 60 ml/min/1.73m², the dose will be 2x the outpatient dose. The dosing protocol for this arm also serves as guidance for furosemide in the intervention arms.

Acetazolamide plus Furosemide; Furosemide alone; Metolazone plus Furosemide

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Clinica Alemana de Santiago: lead

Related Publications (7)

• Rivas-Lasarte M, Maestro A, Fernandez-Martinez J, Lopez-Lopez L, Sole-Gonzalez E, Vives-Borras M, Montero S, Mesado N, Pirla MJ, Mirabet S, Fluvia P, Brossa V, Sionis A, Roig E, Cinca J, Alvarez-Garcia J. Prevalence and prognostic impact of subclinical pulmonary congestion at discharge in patients with acute heart failure. ESC Heart Fail. 2020 Oct;7(5):2621-2628. doi: 10.1002/ehf2.12842. Epub 2020 Jul 7.

  PMID: 32633473 BACKGROUND

• Urbich M, Globe G, Pantiri K, Heisen M, Bennison C, Wirtz HS, Di Tanna GL. A Systematic Review of Medical Costs Associated with Heart Failure in the USA (2014-2020). Pharmacoeconomics. 2020 Nov;38(11):1219-1236. doi: 10.1007/s40273-020-00952-0.

  PMID: 32812149 BACKGROUND

• Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Mar 17;75(10):1178-1195. doi: 10.1016/j.jacc.2019.12.059.

  PMID: 32164892 BACKGROUND

• Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez AF, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O'Connor CM; NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011 Mar 3;364(9):797-805. doi: 10.1056/NEJMoa1005419.

  PMID: 21366472 BACKGROUND

• Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, Tartaglia K, Chenot F, Moubayed S, Dierckx R, Blouard P, Troisfontaines P, Derthoo D, Smolders W, Bruckers L, Droogne W, Ter Maaten JM, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M; ADVOR Study Group. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022 Sep 29;387(13):1185-1195. doi: 10.1056/NEJMoa2203094. Epub 2022 Aug 27.

  PMID: 36027559 BACKGROUND

• Trullas JC, Morales-Rull JL, Casado J, Carrera-Izquierdo M, Sanchez-Marteles M, Conde-Martel A, Davila-Ramos MF, Llacer P, Salamanca-Bautista P, Perez-Silvestre J, Plasin MA, Cerqueiro JM, Gil P, Formiga F, Manzano L; CLOROTIC trial investigators. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J. 2023 Feb 1;44(5):411-421. doi: 10.1093/eurheartj/ehac689.

  PMID: 36423214 BACKGROUND

• Appiani F. [Monitoring decongestion in acute heart failure]. Rev Med Chil. 2022 Apr;150(4):493-504. doi: 10.4067/S0034-98872022000400493. Spanish.

  PMID: 36155759 BACKGROUND

MeSH Terms

Interventions

Acetazolamide; Metolazone; Furosemide

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; Sulfanilamides; Aniline Compounds; Amines

Central Study Contacts

Franco Appiani, MD

CONTACT

222101111; fappiani@alemana.cl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an Open, Multicenter, Prospective, and Randomized study with three treatment arms. The outcomes to be assessed in the initial phase will be at 4 days post-randomization, followed by evaluation at 90 days after hospital discharge.

Study Record Dates

• First Submitted: January 31, 2024
• First Posted: February 22, 2024
• Study Start: May 1, 2024
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): May 1, 2027
• Last Updated: March 18, 2024

Record last verified: 2024-03