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

• ClinicalTrials.gov Identifier: NCT01973335
• Recruitment Status: Completed
• First Posted: October 31, 2013
• Results First Posted: March 21, 2019
• Last Update Posted: May 21, 2019
• Sponsor: Hasselt University
• Collaborators: Ziekenhuis Oost-Limburg; Universitaire Ziekenhuizen Leuven
• Information provided by (Responsible Party): Wilfried Mullens, MD PhD, Ziekenhuis Oost-Limburg

Study Description

Brief Summary:

This study has two primary objectives:

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. 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.

Condition or disease	Intervention/treatment	Phase
Heart Failure	Drug: Combination therapy with acetazolamide and low-dose loop diuretics; Drug: High-dose loop diuretics; Drug: Upfront therapy with oral spironolactone	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Diamox/Aldactone to Increase the URinary Excretion of Sodium: an Investigational Study in Congestive Heart Failure
• Actual Study Start Date: November 2013
• Actual Primary Completion Date: April 2017
• Actual Study Completion Date: October 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Acetazolamide/low-dose loop diuretics, upfront spironolactone; 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; 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.; Other Names: Diamox (acetazolamide); Burinex/Bumex (loop diuretics); Drug: Upfront therapy with oral spironolactone; 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.; Other Name: Aldactone
Experimental: High-dose loop diuretics, upfront spironolactone; 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; 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.; Other Name: Burinex/Bumex; Drug: Upfront therapy with oral spironolactone; 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.; Other Name: Aldactone
Experimental: Acetazolamide/low-dose loop diuretics, no spironolactone; 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; 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.; Other Names: Diamox (acetazolamide); Burinex/Bumex (loop diuretics)
Active Comparator: High-dose loop diuretics, no spironolactone; 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; 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.; Other Name: Burinex/Bumex

Outcome Measures

Primary Outcome Measures :

1. Acetazolamide Arm: Natriuresis 24 h [ Time Frame: 24h ]
   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)
2. Spironolactone Arm: Incidence of Hypo- (Serum Potassium <3.5 mmol/L) or Hyperkalemia (Serum Potassium >5.0 mmol/L) [ Time Frame: 72h ]
   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 :

1. NT-proBNP Change After 72 h [ Time Frame: 72h ]
   Relative NT-proBNP change (%) after 72 h compared to baseline.
2. Number of Participants With Worsening Renal Function [ Time Frame: 72h ]
   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.
3. Persistent Renal Impairment [ Time Frame: 4 weeks after hospital discharge ]
   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.
4. Peak Plasma Aldosterone Concentration After 72 h [ Time Frame: 72h ]
   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).
5. Peak Plasma Renin Activity After 72 h [ Time Frame: 72h ]
   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).

Other Outcome Measures:

1. Natriuresis 48 h [ Time Frame: 48h ]
   Total natriuresis (mmol) after 48 h.
2. Natriuresis 72 h [ Time Frame: 72h ]
   Total natriuresis (mmol) after 72 h.
3. Diuresis 24 h [ Time Frame: 24h ]
   Total amount of urine output (L) after 24 h.
4. Diuresis 48 h [ Time Frame: 48h ]
   Total amount of urine output (L) after 48 h.
5. Diuresis 72 h [ Time Frame: 72h ]
   Total amount of urine output (L) after 72 h.
6. Weight Change After 72 h [ Time Frame: 72h ]
   Body weight change after 72 h compared to admission.
7. Visual Analogue Scale Score for Dyspnea After 24 h [ Time Frame: 24h ]
   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.
8. Visual Analogue Scale Score for Dyspnea After 48 h [ Time Frame: 48h ]
9. Visual Analogue Scale Score for Dyspnea After 72 h [ Time Frame: 72h ]
10. 4-point Likert Scale for Edema After 24 h [ Time Frame: 24h ]
11. 4-point Likert Scale for Edema After 48 h [ Time Frame: 48h ]
12. 4-point Likert Scale for Edema After 72 h [ Time Frame: 72h ]
13. Incidence of Therapy-refractory Congestion [ Time Frame: 72h ]
    Need for combinational diuretic therapy with thiazide-type diuretics, bail-out ultrafiltration or renal replacement therapy
14. All-cause Mortality [ Time Frame: After 1 year of follow-up ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Belgium

Ziekenhuis Oost-Limburg

Genk, Limburg, Belgium, 3600

University Hospital Leuven

Leuven, Vlaams-Brabant, Belgium, 3000

Sponsors and Collaborators

Hasselt University

Ziekenhuis Oost-Limburg

Universitaire Ziekenhuizen Leuven

Investigators

• Principal Investigator: Wilfried Mullens, M.D. Ph.D.; Ziekenhuis Oost-Limburg
• Principal Investigator: Frederik H. Verbrugge, M.D. Ph.D.; Ziekenhuis Oost-Limburg

  Study Documents (Full-Text)

Documents provided by Wilfried Mullens, MD PhD, Ziekenhuis Oost-Limburg:

Study Protocol and Statistical Analysis Plan  [PDF] August 27, 2015

More Information

Publications of Results:

Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogné 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.

Verbrugge FH, Martens P, Ameloot K, Haemels V, Penders J, Dupont M, Tang WHW, Droogné 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.

• Responsible Party: Wilfried Mullens, MD PhD, Prof. Dr., Ziekenhuis Oost-Limburg
• ClinicalTrials.gov Identifier: NCT01973335
• Other Study ID Numbers: ZOL-DIURESIS-CHF
• First Posted: October 31, 2013
• Results First Posted: March 21, 2019
• Last Update Posted: May 21, 2019
• Last Verified: May 2019

• 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

Keywords provided by Wilfried Mullens, MD PhD, Ziekenhuis Oost-Limburg:

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

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Spironolactone; Acetazolamide; Bumetanide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors; Mineralocorticoid Receptor Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Diuretics, Potassium Sparing; Natriuretic Agents; Anticonvulsants; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators