Clinical trial NCT01973335: Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure
Official title: Diamox/Aldactone to Increase the URinary Excretion of Sodium: an Investigational Study in Congestive Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure
Keywords: acetazolamide
bumetanide
cardio-renal syndrome
diuretics
heart failure
natriuresis
spironolactone
Lead sponsor: Hasselt University
Sponsor class: OTHER
Collaborators: name: Ziekenhuis Oost-Limburg
name: Universitaire Ziekenhuizen KU Leuven
First posted: 2013-10-31
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Acetazolamide Arm: Natriuresis 24 h
timeFrame: 24h
measure: Spironolactone Arm: Incidence of Hypo- (Serum Potassium <3.5 mmol/L) or Hyperkalemia (Serum Potassium >5.0 mmol/L)
timeFrame: 72h
Secondary outcomes:
measure: NT-proBNP Change After 72 h
timeFrame: 72h
measure: Number of Participants With Worsening Renal Function
timeFrame: 72h
measure: Persistent Renal Impairment
timeFrame: 4 weeks after hospital discharge
measure: Peak Plasma Aldosterone Concentration After 72 h
timeFrame: 72h
measure: Peak Plasma Renin Activity After 72 h
timeFrame: 72h
Other outcomes:
measure: Natriuresis 48 h
timeFrame: 48h
measure: Natriuresis 72 h
timeFrame: 72h
measure: Diuresis 24 h
timeFrame: 24h
measure: Diuresis 48 h
timeFrame: 48h
measure: Diuresis 72 h
timeFrame: 72h
measure: Weight Change After 72 h
timeFrame: 72h
measure: Visual Analogue Scale Score for Dyspnea After 24 h
timeFrame: 24h
measure: Visual Analogue Scale Score for Dyspnea After 48 h
timeFrame: 48h
measure: Visual Analogue Scale Score for Dyspnea After 72 h
timeFrame: 72h
measure: 4-point Likert Scale for Edema After 24 h
timeFrame: 24h
measure: 4-point Likert Scale for Edema After 48 h
timeFrame: 48h
measure: 4-point Likert Scale for Edema After 72 h
timeFrame: 72h
measure: Incidence of Therapy-refractory Congestion
timeFrame: 72h
measure: All-cause Mortality
timeFrame: After 1 year of follow-up
Locations:
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg
state: Limburg
city: Leuven
country: Belgium
facility: University Hospital Leuven
state: Vlaams-Brabant
Study officials:
affiliation: Ziekenhuis Oost-Limburg
name: Wilfried Mullens, M.D. Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ziekenhuis Oost-Limburg
name: Frederik H. Verbrugge, M.D. Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.