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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
34
* 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.
Ziekenhuis Oost-Limburg
Genk, Limburg, Belgium
University Hospital Leuven
Leuven, Vlaams-Brabant, Belgium
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)
Time frame: 24h
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).
Time frame: 72h
NT-proBNP Change After 72 h
Relative NT-proBNP change (%) after 72 h compared to baseline.
Time frame: 72h
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.
Time frame: 72h
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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.
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.
Time frame: 4 weeks after hospital discharge
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).
Time frame: 72h
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).
Time frame: 72h