Skip to main content
OpenTrials
Completed

NCT Number: NCT01973335

Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

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.

Completed

Looking for future studies?

Notify Me

Key information

Conditions

Heart Failure Cardio-Renal Syndrome Cardiovascular Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Heart Diseases Kidney Diseases Male Urogenital Diseases Renal Insufficiency Urogenital Diseases Urologic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Ziekenhuis Oost-Limburg, Genk, Limburg, Belgium

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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.

Other names: Diamox (acetazolamide), Burinex/Bumex (loop diuretics)

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.

Other names: Burinex/Bumex

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.

Other names: Aldactone

Primary outcomes

  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 outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

Hasselt University

Other

Collaborators

  • Universitaire Ziekenhuizen KU Leuven
  • Ziekenhuis Oost-Limburg

Registry information

Official study title

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

Acronym: DIURESIS-CHF

Important dates

Study start
2013
Primary completion
2017
Study completion
2017
First posted
Oct 31, 2013
Registry last updated
May 21, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.