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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Hasselt University
Sponsor:
Collaborator:
Ziekenhuis Oost-Limburg
Information provided by (Responsible Party):
Wilfried Mullens, MD PhD, Ziekenhuis Oost-Limburg
ClinicalTrials.gov Identifier:
NCT01973335
First received: October 25, 2013
Last updated: August 3, 2014
Last verified: August 2014
  Purpose

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 Intervention 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 Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Diamox/Aldactone to Increase the URinary Excretion of Sodium: an Investigational Study in Congestive Heart Failure

Resource links provided by NLM:


Further study details as provided by Hasselt University:

Primary Outcome Measures:
  • Acetazolamide arm: natriuresis 24 h [ Time Frame: 24h ] [ Designated as safety issue: No ]
    Total natriuresis (mmol) after 24 h: After initiation of therapy, urine is collected for 3 consecutive 24 h intervals. For each interval, natriuresis is calculated as the total amount of diuresis (L) multiplied by the urinary sodium concentration (mmol/L).

  • Spironolactone arm: incidence of hypo- (serum potassium <3.5 mmol/L) or hyperkalemia (serum potassium >5.0 mmol/L) [ Time Frame: 72h ] [ Designated as safety issue: Yes ]
    At three consecutive mornings after study inclusion, blood samples will be taken to assess serum potassium levels.


Secondary Outcome Measures:
  • NT-proBNP change after 72 h [ Time Frame: 72h ] [ Designated as safety issue: No ]
    Relative NT-proBNP change (%) after 72 h compared to baseline.

  • Worsening renal function [ Time Frame: 72h ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 4 weeks after hospital discharge ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: 72h ] [ Designated as safety issue: No ]
    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 [ Time Frame: 72h ] [ Designated as safety issue: No ]
    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:
  • Natriuresis 48 h [ Time Frame: 48h ] [ Designated as safety issue: No ]
    Total natriuresis (mmol) after 48 h.

  • Natriuresis 72 h [ Time Frame: 72h ] [ Designated as safety issue: No ]
    Total natriuresis (mmol) after 72 h.

  • Diuresis 24 h [ Time Frame: 24h ] [ Designated as safety issue: No ]
    Total amount of urine output (L) after 24 h.

  • Diuresis 48 h [ Time Frame: 48h ] [ Designated as safety issue: No ]
    Total amount of urine output (L) after 48 h.

  • Diuresis 72 h [ Time Frame: 72h ] [ Designated as safety issue: No ]
    Total amount of urine output (L) after 72 h.

  • Weight change after 72 h [ Time Frame: 72h ] [ Designated as safety issue: No ]
    Body weight change after 72 h compared to admission.

  • Visual analogue scale score for dyspnea after 24 h [ Time Frame: 24h ] [ Designated as safety issue: No ]
  • Visual analogue scale score for dyspnea after 48 h [ Time Frame: 48h ] [ Designated as safety issue: No ]
  • Visual analogue scale score for dyspnea after 72 h [ Time Frame: 72h ] [ Designated as safety issue: No ]
  • 4-point Likert scale for edema after 24 h [ Time Frame: 24h ] [ Designated as safety issue: No ]
  • 4-point Likert scale for edema after 48 h [ Time Frame: 48h ] [ Designated as safety issue: No ]
  • 4-point Likert scale for edema after 72 h [ Time Frame: 72h ] [ Designated as safety issue: No ]
  • Incidence of therapy-refractory congestion [ Time Frame: 72h ] [ Designated as safety issue: Yes ]
    Need for combinational diuretic therapy with thiazide-type diuretics, bail-out ultrafiltration or renal replacement therapy

  • All-cause mortality [ Time Frame: After 1 year of follow-up ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: November 2013
Estimated Study Completion Date: January 2017
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01973335

Contacts
Contact: Frederik H. Verbrugge, M.D. +3289321516 frederik.verbrugge@zol.be
Contact: Petra Nijst, M.D. +3289321525 petra.nijst@zol.be

Locations
Belgium
Ziekenhuis Oost-Limburg Recruiting
Genk, Limburg, Belgium, 3600
Contact: Frederik H. Verbrugge, M.D.    +3289321516    frederik.verbrugge@zol.be   
Contact: Petra Nijst, M.D.    +3289321525    petra.nijst@zol.be   
Principal Investigator: Frederik H. Verbrugge, M.D.         
Principal Investigator: Wilfried Mullens, M.D. Ph.D.         
Sub-Investigator: Petra Nijst, M.D.         
Sub-Investigator: Philippe B. Bertrand, M.D. M.Sc.         
Sub-Investigator: Lars Grieten, Ph.D. M.Sc.         
Sub-Investigator: Matthias Dupont, M.D.         
Sub-Investigator: Joris Penders, M.D. Ph.D.         
Sponsors and Collaborators
Hasselt University
Ziekenhuis Oost-Limburg
Investigators
Principal Investigator: Wilfried Mullens, M.D. Ph.D. Ziekenhuis Oost-Limburg
Principal Investigator: Frederik H. Verbrugge, M.D. Ziekenhuis Oost-Limburg
  More Information

No publications provided

Responsible Party: Wilfried Mullens, MD PhD, Prof. Dr., Ziekenhuis Oost-Limburg
ClinicalTrials.gov Identifier: NCT01973335     History of Changes
Other Study ID Numbers: ZOL-DIURESIS-CHF
Study First Received: October 25, 2013
Last Updated: August 3, 2014
Health Authority: Belgium: Federal Agency for Medicines and Health Products, FAMHP

Keywords provided by Hasselt University:
acetazolamide
bumetanide
cardio-renal syndrome
diuretics
heart failure
natriuresis
spironolactone

Additional relevant MeSH terms:
Heart Failure
Cardiovascular Diseases
Heart Diseases
Acetazolamide
Diuretics
Sodium Potassium Chloride Symporter Inhibitors
Spironolactone
Anticonvulsants
Carbonic Anhydrase Inhibitors
Cardiovascular Agents
Central Nervous System Agents
Diuretics, Potassium Sparing
Enzyme Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Membrane Transport Modulators
Mineralocorticoid Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014