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Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (DIURESIS-CHF)

Primary Purpose

Heart Failure

Status

Completed

Phase

Phase 4

Locations

Belgium

Study Type

Interventional

Intervention

Combination therapy with acetazolamide and low-dose loop diuretics

High-dose loop diuretics

Upfront therapy with oral spironolactone

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring acetazolamide, bumetanide, cardio-renal syndrome, diuretics, heart failure, natriuresis, spironolactone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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

Exclusion Criteria:

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
A baseline estimated glomerular filtration rate <15 mL/min/1.73m² according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at the moment of inclusion
Use of renal replacement therapy or ultrafiltration before study inclusion
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

Sites / Locations

Ziekenhuis Oost-Limburg
University Hospital Leuven

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Arm Label

Acetazolamide/low-dose loop diuretics, upfront spironolactone

High-dose loop diuretics, upfront spironolactone

Acetazolamide/low-dose loop diuretics, no spironolactone

High-dose loop diuretics, no spironolactone

Arm Description

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

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.

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.

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.

Outcomes

Primary Outcome Measures

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)

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).

Secondary Outcome Measures

NT-proBNP Change After 72 h

Relative NT-proBNP change (%) after 72 h compared to baseline.

Number of Participants With Worsening Renal Function

Worsening renal function is defined as a rise in serum creatine >0.3 mg/dL or a >20% decrease in estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula compared to baseline at any time point before 72 h. Serum creatinine values are assessed at three consecutive mornings after study inclusion.

Persistent Renal Impairment

Persistent renal impairment is defined as a persistently elevated serum creatine >0.3mg/dL or >20% decrease in estimated glomerular filtration rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, above the baseline value of the patient and will be assessed on a scheduled follow-up appointment 4 weeks after hospital discharge.

Peak Plasma Aldosterone Concentration After 72 h

At three consecutive mornings after study inclusion, blood samples will be taken to assess plasma aldosterone levels. The highest value will constitute the peak plasma aldosterone concentration (ng/L).

Peak Plasma Renin Activity After 72 h

At three consecutive mornings after study inclusion, blood samples will be taken to assess plasma renin activity. The highest value will constitute the peak plasma renin activity (ng/mL/h).

Full Information

NCT ID

NCT01973335

First Posted

October 25, 2013

Last Updated

May 11, 2019

Sponsor

Hasselt University

Collaborators

Ziekenhuis Oost-Limburg, Universitaire Ziekenhuizen KU Leuven

1. Study Identification

Unique Protocol Identification Number

NCT01973335

Brief Title

Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

Acronym

DIURESIS-CHF

Official Title

Diamox/Aldactone to Increase the URinary Excretion of Sodium: an Investigational Study in Congestive Heart Failure

Study Type

Interventional

2. Study Status

Record Verification Date

May 2019

Overall Recruitment Status

Completed

Study Start Date

November 2013 (Actual)

Primary Completion Date

April 2017 (Actual)

Study Completion Date

October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Hasselt University

Collaborators

Ziekenhuis Oost-Limburg, Universitaire Ziekenhuizen KU Leuven

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study has two primary objectives: 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Factorial Assignment

Masking

Care ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Acetazolamide/low-dose loop diuretics, upfront spironolactone

Arm Type

Experimental

Arm Description

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

Arm Title

High-dose loop diuretics, upfront spironolactone

Arm Type

Experimental

Arm Description

Arm Title

Acetazolamide/low-dose loop diuretics, no spironolactone

Arm Type

Experimental

Arm Description

Arm Title

High-dose loop diuretics, no spironolactone

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Combination therapy with acetazolamide and low-dose loop diuretics

Other Intervention Name(s)

Diamox (acetazolamide), Burinex/Bumex (loop diuretics)

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

High-dose loop diuretics

Other Intervention Name(s)

Burinex/Bumex

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Upfront therapy with oral spironolactone

Other Intervention Name(s)

Aldactone

Intervention Description

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.

Primary Outcome Measure Information:

Title

Acetazolamide Arm: Natriuresis 24 h

Description

Time Frame

24h

Title

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

Description

Time Frame

72h

Secondary Outcome Measure Information:

Title

NT-proBNP Change After 72 h

Description

Relative NT-proBNP change (%) after 72 h compared to baseline.

Time Frame

72h

Title

Number of Participants With Worsening Renal Function

Description

Time Frame

72h

Title

Persistent Renal Impairment

Description

Time Frame

4 weeks after hospital discharge

Title

Peak Plasma Aldosterone Concentration After 72 h

Description

Time Frame

72h

Title

Peak Plasma Renin Activity After 72 h

Description

At three consecutive mornings after study inclusion, blood samples will be taken to assess plasma renin activity. The highest value will constitute the peak plasma renin activity (ng/mL/h).

Time Frame

72h

Other Pre-specified Outcome Measures:

Title

Natriuresis 48 h

Description

Total natriuresis (mmol) after 48 h.

Time Frame

48h

Title

Natriuresis 72 h

Description

Total natriuresis (mmol) after 72 h.

Time Frame

72h

Title

Diuresis 24 h

Description

Total amount of urine output (L) after 24 h.

Time Frame

24h

Title

Diuresis 48 h

Description

Total amount of urine output (L) after 48 h.

Time Frame

48h

Title

Diuresis 72 h

Description

Total amount of urine output (L) after 72 h.

Time Frame

72h

Title

Weight Change After 72 h

Description

Body weight change after 72 h compared to admission.

Time Frame

72h

Title

Visual Analogue Scale Score for Dyspnea After 24 h

Description

Scale name and construct: Visual analogue scale presented as a line with a movable indicator. Far left of the line indicates no dyspnea at all and far right of the line indicates the worst imaginable dyspnea. The participant can move the indicator to one certain point among the line and the investigator can read at the back a number going from 0 to 100 with 0 indicating no dyspnea and 100 the worst imaginable dyspnea.

Time Frame

24h

Title

Visual Analogue Scale Score for Dyspnea After 48 h

Time Frame

48h

Title

Visual Analogue Scale Score for Dyspnea After 72 h

Time Frame

72h

Title

4-point Likert Scale for Edema After 24 h

Time Frame

24h

Title

4-point Likert Scale for Edema After 48 h

Time Frame

48h

Title

4-point Likert Scale for Edema After 72 h

Time Frame

72h

Title

Incidence of Therapy-refractory Congestion

Description

Need for combinational diuretic therapy with thiazide-type diuretics, bail-out ultrafiltration or renal replacement therapy

Time Frame

72h

Title

All-cause Mortality

Time Frame

After 1 year of follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Exclusion Criteria: 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 A baseline estimated glomerular filtration rate <15 mL/min/1.73m² according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula at the moment of inclusion Use of renal replacement therapy or ultrafiltration before study inclusion 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Wilfried Mullens, M.D. Ph.D.

Organizational Affiliation

Ziekenhuis Oost-Limburg

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Frederik H. Verbrugge, M.D. Ph.D.

Organizational Affiliation

Ziekenhuis Oost-Limburg

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ziekenhuis Oost-Limburg

City

Genk

State/Province

Limburg

ZIP/Postal Code

3600

Country

Belgium

Facility Name

University Hospital Leuven

City

Leuven

State/Province

Vlaams-Brabant

ZIP/Postal Code

3000

Country

Belgium

12. IPD Sharing Statement

Citations:

PubMed Identifier

29587582

Citation

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.

Results Reference

result

PubMed Identifier

31074184

Citation

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.

Results Reference

result

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Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

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