Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

NCT01973335 | Completed Phase 4 Results DMC

• 1 other identifier: ZOL-DIURESIS-CHF
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 2

Brief Summary

This study has two primary objectives:

1. 1.To compare combination therapy with acetazolamide and low-dose loop diuretics versus high-dose loop diuretics (standard of care) in patients with acute decompensated heart failure at high risk for diuretic resistance.
2. 2.To demonstrate the safety and efficacy of upfront therapy with spironolactone in addition to loop diuretic therapy in patients with acute decompensated heart failure at high risk for diuretic resistance.

Conditions

Heart Failure

Keywords

acetazolamide; bumetanide; cardio-renal syndrome; diuretics; heart failure; natriuresis; spironolactone

Outcome Measures

Primary Outcomes (2)

• Acetazolamide Arm: Natriuresis 24 h

  For the acetazolamide arm of the study, the primary end-point is total natriuresis after 24 h (mmol). To assess this, urine is collected for 24 h after the first administration of diuretics according to the study protocol and natriuresis is calculated as the total amount of diuresis (L) multiplied by the urinary sodium concentration (mmol/L). Subsequently, patients receiving acetazolamide and low-dose loop diuretics (both the groups with and without upfront spironolactone together) are compared to patients not receiving acetazolamide but high-dose loop diuretics instead (both the groups with or without upfront spironolactone together)

  24h

• Spironolactone Arm: Incidence of Hypo- (Serum Potassium <3.5 mmol/L) or Hyperkalemia (Serum Potassium >5.0 mmol/L)

  For the spironolactone arm of the study, the primary end-point is the incidence of either hypo- (serum potassium \<3.5 mmol/L) or hyperkalemia (serum potassium \>5.0 mmol/L) at any of 3 morning blood samples at consecutive days after randomization. Patients receiving upfront spironolactone (both the group receiving acetazolamide+low dose loop diuretics and the group receiving high-dose loop diuretic therapy) are compared with them receiving no spironolactone (both the group receiving acetazolamide+low dose loop diuretics and the group receiving high-dose loop diuretic therapy).

  72h

Secondary Outcomes (5)

• NT-proBNP Change After 72 h

  72h

• Number of Participants With Worsening Renal Function

  72h

• Persistent Renal Impairment

  4 weeks after hospital discharge

• Peak Plasma Aldosterone Concentration After 72 h

  72h

• Peak Plasma Renin Activity After 72 h

  72h

Other Outcomes (14)

• Natriuresis 48 h

  48h

• Natriuresis 72 h

  72h

• Diuresis 24 h

  24h

Study Arms (4)

Acetazolamide/low-dose loop diuretics, upfront spironolactone

EXPERIMENTAL

2x2 factorial design: This group is the experimental group for both study interventions (acetazolamide and upfront spironolactone). See interventions for more details.

Drug: Combination therapy with acetazolamide and low-dose loop diuretics; Drug: Upfront therapy with oral spironolactone

High-dose loop diuretics, upfront spironolactone

EXPERIMENTAL

2x2 factorial design: This group is the experimental group for the study intervention with upfront spironolactone. This group receives high-dose loop diuretics as an active comparator to the study intervention with acetazolamide. See interventions for more details.

Drug: High-dose loop diuretics; Drug: Upfront therapy with oral spironolactone

Acetazolamide/low-dose loop diuretics, no spironolactone

EXPERIMENTAL

2x2 factorial design: This group is the experimental group for the study intervention with acetazolamide. This group receives no intervention with regards to the spironolactone arm. See interventions for more details.

Drug: Combination therapy with acetazolamide and low-dose loop diuretics

High-dose loop diuretics, no spironolactone

ACTIVE COMPARATOR

2x2 factorial design: This group receives high-dose loop diuretics as an active comparator to the study intervention with acetazolamide. This group receives no intervention with regards to the spironolactone arm. See interventions for more details.

Drug: High-dose loop diuretics

Interventions

Combination therapy with acetazolamide and low-dose loop diuretics DRUG

* Patients receive 500 mg of intravenous acetazolamide immediately after randomization, with 250 mg intravenous acetazolamide administered on each consecutive day in the morning for as long as the patient is considered volume overloaded by his/her treating cardiologist. * Patients receive 2 mg of intravenous bumetanide immediately after randomization, with 1 mg intravenous bumetanide administered on each consecutive day in the morning for as long as the patient is considered volume overloaded by his/her treating cardiologist. * If diuresis \<1,5 L while the patient is still considered volume overloaded by his/her treating cardiologist, the dose of acetazolamide is maintained at 500 mg and the dose of bumetanide is maintained at 2mg. In case of therapy-refractory congestion, treatment is at the discretion of the treating physician, but addition of chlorthalidone 50 mg PO is recommended by the investigators as a first-line option.

Also known as: Diamox (acetazolamide), Burinex/Bumex (loop diuretics)

Acetazolamide/low-dose loop diuretics, no spironolactone; Acetazolamide/low-dose loop diuretics, upfront spironolactone

High-dose loop diuretics DRUG

* Patients receive the double of their daily maintenance dose of oral loop diuretics converted to mg bumetanide as an intravenous bolus after randomization. * Patients continue to receive this dose daily on the next 3 days divided between two administrations with at least a 6 h interval for as long as they are considered volume overloaded by the treating cardiologist. * If diuresis \<1,5 L while the patient is still considered volume overloaded by the treating cardiologist, the dose of bumetanide is doubled. In case of therapy-refractory congestion, treatment is at the discretion of the treating physician, but addition of chlorthalidone 50 mg PO is recommended by the investigators as a first-line option.

Also known as: Burinex/Bumex

High-dose loop diuretics, no spironolactone; High-dose loop diuretics, upfront spironolactone

Upfront therapy with oral spironolactone DRUG

Patients randomized to this group receive oral spironolactone (25mg) immediately after randomization and in the morning of each subsequent day unless the serum potassium level is \>5 mmol/L. Note: Investigators and treating physicians are blinded to treatment allocation for this arm, but no matching placebo is provided, so patients are not.

Also known as: Aldactone

Acetazolamide/low-dose loop diuretics, upfront spironolactone; High-dose loop diuretics, upfront spironolactone

Eligibility Criteria

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

You may qualify if:

• Older than 18 years and able to give informed consent
• Clinical diagnosis of acute decompensated heart failure within the previous 8 h
• At least two clinical signs of congestion (edema, ascites, jugular venous distension, or pulmonary vascular congestion on chest radiography)
• Maintenance therapy with oral loop diuretics at a dose of at least 1 mg bumetanide (1 mg bumetanide = 40 mg furosemide = 20 mg torsemide) for at least 1 month before hospital admission
• NT-proBNP \>1000 ng/L
• Left ventricular ejection fraction \<50%
• At least one out of three of the following criteria:
• Serum sodium \<136 mmol/L
• Serum urea/creatinine ratio \>50 (comparable to a BUN/creatinine ratio \>25)
• Admission serum creatinine increased with \>0.3 mg/dL compared to previous value within 3 months before admission

You may not qualify if:

• History of cardiac transplantation and/or ventricular assist device
• Concurrent diagnosis of an acute coronary syndrome defined as typical chest pain and/or electrocardiographic changes in addition to a troponin rise \>99th percentile
• Mean arterial blood pressure \<65 mmHg, or systolic blood pressure \<90 mmHg at the moment of admission
• Use of intravenous inotropes, vasopressors or nitroprusside at any time point during the study
• Treatment with acetazolamide within the previous month
• Treatment with ≥2 mg bumetanide or an equivalent dose during the index hospitalization before randomization
• Use of diuretics, vasopressin antagonists or mineralocorticoid receptor antagonist not specified by the protocol
• Exposure to nephrotoxic agents (i.e. contrast dye) anticipated within 3 days

Sponsors & Collaborators

• Hasselt University: lead
• Ziekenhuis Oost-Limburg: collaborator
• Universitaire Ziekenhuizen KU Leuven: collaborator

Study Sites (2)

Ziekenhuis Oost-Limburg

Genk, Limburg, 3600, Belgium

Location

University Hospital Leuven

Leuven, Vlaams-Brabant, 3000, Belgium

Location

Related Publications (2)

• Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogne W, Mullens W. Spironolactone to increase natriuresis in congestive heart failure with cardiorenal syndrome. Acta Cardiol. 2019 Apr;74(2):100-107. doi: 10.1080/00015385.2018.1455947. Epub 2018 Mar 27.

  PMID: 29587582 RESULT

• Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogne W, Mullens W. Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance. Eur J Heart Fail. 2019 Nov;21(11):1415-1422. doi: 10.1002/ejhf.1478. Epub 2019 May 9.

  PMID: 31074184 RESULT

MeSH Terms

Conditions

Heart Failure; Cardio-Renal Syndrome

Interventions

Combined Modality Therapy; Acetazolamide; Sodium Potassium Chloride Symporter Inhibitors; Bumetanide; Spironolactone

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Diuretics; Natriuretic Agents; Physiological Effects of Drugs; Sulfonamides; Amides; meta-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Lactones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and Caveats

Slow recruitment: switch from monocentric to 2-center study; longer than anticipated duration of the study; eventually termination of the study after only 34 of the originally intended 80 patients had been included resulting in an underpowered study.

Results Point of Contact

• Title: Dr. Frederik Verbrugge, researcher
• Organization: Ziekenhuis Oost-Limburg

frederik.verbrugge@zol.be

0473924199

Study Officials

• Wilfried Mullens, M.D. Ph.D.

  Ziekenhuis Oost-Limburg

  PRINCIPAL INVESTIGATOR

• Frederik H. Verbrugge, M.D. Ph.D.

  Ziekenhuis Oost-Limburg

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: October 25, 2013
• First Posted: October 31, 2013
• Study Start: November 1, 2013
• Primary Completion: April 1, 2017
• Study Completion: October 1, 2017
• Last Updated: May 21, 2019
• Results First Posted: March 21, 2019

Record last verified: 2019-05

Locations

BE (2)