Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: Combination therapy with acetazolamide and low-dose loop diuretics; High-dose loop diuretics; Upfront therapy with oral spironolactone
Intervention description: 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.; 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.; 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.
Intervention MeSH terms: Spironolactone; Acetazolamide; Bumetanide; Diuretics; Sodium Potassium Chloride Symporter Inhibitors
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: acetazolamide; bumetanide; cardio-renal syndrome; diuretics; heart failure; natriuresis; spironolactone

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