Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

Heart Failure Clinical Trial

— DIURESIS-CHF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01973335
• Other study ID #: ZOL-DIURESIS-CHF
• Status: Completed
• Phase: Phase 4
• Start date: November 2013
• Est. completion date: October 2017

Study information

• Verified date: May 2019
• Source: Hasselt University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: October 2017
• Est. primary completion date: April 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
Belgium	Ziekenhuis Oost-Limburg	Genk	Limburg
Belgium	University Hospital Leuven	Leuven	Vlaams-Brabant

Sponsors (3)

Lead Sponsor	Collaborator
Hasselt University	Universitaire Ziekenhuizen Leuven, Ziekenhuis Oost-Limburg

Country where clinical trial is conducted

Belgium, 

References & Publications (2)

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 May 9. doi: 10.1002/ejhf.147 — View Citation

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: 10.1080/00015385.2 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Natriuresis 48 h	Total natriuresis (mmol) after 48 h.	48h
Other	Natriuresis 72 h	Total natriuresis (mmol) after 72 h.	72h
Other	Diuresis 24 h	Total amount of urine output (L) after 24 h.	24h
Other	Diuresis 48 h	Total amount of urine output (L) after 48 h.	48h
Other	Diuresis 72 h	Total amount of urine output (L) after 72 h.	72h
Other	Weight Change After 72 h	Body weight change after 72 h compared to admission.	72h
Other	Visual Analogue Scale Score for Dyspnea After 24 h	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.	24h
Other	Visual Analogue Scale Score for Dyspnea After 48 h		48h
Other	Visual Analogue Scale Score for Dyspnea After 72 h		72h
Other	4-point Likert Scale for Edema After 24 h		24h
Other	4-point Likert Scale for Edema After 48 h		48h
Other	4-point Likert Scale for Edema After 72 h		72h
Other	Incidence of Therapy-refractory Congestion	Need for combinational diuretic therapy with thiazide-type diuretics, bail-out ultrafiltration or renal replacement therapy	72h
Other	All-cause Mortality		After 1 year of follow-up
Primary	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
Primary	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	NT-proBNP Change After 72 h	Relative NT-proBNP change (%) after 72 h compared to baseline.	72h
Secondary	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.	72h
Secondary	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.	4 weeks after hospital discharge
Secondary	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).	72h
Secondary	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).	72h