Trial Outcomes & Findings for Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (NCT NCT01973335)

Results Overview

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)

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

34 participants

Primary outcome timeframe

24h

Results posted on

2019-05-21

Participant Flow

* Dates of the recruitment period: 28/12/2013 till 14/03/2017 * location: emergency services and outpatient cardiology clinic of 2 tertiary care centers (Ziekenhuis Oost-Limburg, Genk, Belgium \& UZ Leuven, Leuven, Belgium)

None, every patient that was enrolled was immediately randomised and started with the protocol of the study.

Participant milestones

Participant milestones
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Overall Study STARTED	9	7	9	9
Overall Study COMPLETED	9	7	9	9
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge	Total n=34 Participants Total of all reporting groups
Age, Continuous	81 years STANDARD_DEVIATION 8 • n=5 Participants	75 years STANDARD_DEVIATION 7 • n=7 Participants	81 years STANDARD_DEVIATION 5 • n=5 Participants	81 years STANDARD_DEVIATION 7 • n=4 Participants	80 years STANDARD_DEVIATION 7 • n=21 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	3 Participants n=4 Participants	12 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	5 Participants n=7 Participants	4 Participants n=5 Participants	6 Participants n=4 Participants	22 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants	9 Participants n=4 Participants	34 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Region of Enrollment Belgium	9 Participants n=5 Participants	7 Participants n=7 Participants	9 Participants n=5 Participants	9 Participants n=4 Participants	34 Participants n=21 Participants
New York Heart Association functional class II	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
New York Heart Association functional class III	5 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants	4 Participants n=4 Participants	19 Participants n=21 Participants
New York Heart Association functional class IV	2 Participants n=5 Participants	4 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	12 Participants n=21 Participants
History of ischemic heart disease	5 Participants n=5 Participants	6 Participants n=7 Participants	3 Participants n=5 Participants	7 Participants n=4 Participants	21 Participants n=21 Participants
History of atrial fibrillation	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	6 Participants n=4 Participants	20 Participants n=21 Participants
History of diabetes	3 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	10 Participants n=21 Participants
Estimated glomerular filtration rate	36 mL/min/1.73m² STANDARD_DEVIATION 17 • n=5 Participants	32 mL/min/1.73m² STANDARD_DEVIATION 9 • n=7 Participants	35 mL/min/1.73m² STANDARD_DEVIATION 16 • n=5 Participants	40 mL/min/1.73m² STANDARD_DEVIATION 31 • n=4 Participants	36 mL/min/1.73m² STANDARD_DEVIATION 20 • n=21 Participants
Renin-angiotensin blocker therapy	2 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	3 Participants n=4 Participants	14 Participants n=21 Participants
Beta-blocker therapy	8 Participants n=5 Participants	7 Participants n=7 Participants	8 Participants n=5 Participants	8 Participants n=4 Participants	31 Participants n=21 Participants

PRIMARY outcome

Timeframe: 24h

Population: 2 patients not analysed because of errors with 24 h urinary collection

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)

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=8 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=6 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Acetazolamide Arm: Natriuresis 24 h	324 mmol Standard Deviation 133	300 mmol Standard Deviation 165	211 mmol Standard Deviation 96	190 mmol Standard Deviation 91

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Spironolactone Arm: Incidence of Hypo- (Serum Potassium <3.5 mmol/L) or Hyperkalemia (Serum Potassium >5.0 mmol/L)	1 Participants	2 Participants	5 Participants	2 Participants

SECONDARY outcome

Timeframe: 72h

Relative NT-proBNP change (%) after 72 h compared to baseline.

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
NT-proBNP Change After 72 h	-20 percentage change from baseline Standard Deviation 36	-11 percentage change from baseline Standard Deviation 19	-3 percentage change from baseline Standard Deviation 40	-6 percentage change from baseline Standard Deviation 51

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Number of Participants With Worsening Renal Function	2 Participants	0 Participants	3 Participants	0 Participants

SECONDARY outcome

Timeframe: 4 weeks after hospital discharge

Population: 9 patients died or were too sick for follow-up appointment; 9 refused a venous blood sample at the follow-up appointment (protocol violation)

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.

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=5 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=2 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=5 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=4 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Persistent Renal Impairment	3 Participants	1 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Peak Plasma Aldosterone Concentration After 72 h	196 ng/L Interval 127.0 to 338.0	234 ng/L Interval 149.0 to 334.0	302 ng/L Interval 165.0 to 909.0	204 ng/L Interval 153.0 to 756.0

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 Participants * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 Participants * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Peak Plasma Renin Activity After 72 h	3.8 µg/L/h Interval 0.9 to 6.5	5.0 µg/L/h Interval 3.8 to 10.2	12.0 µg/L/h Interval 0.8 to 34.3	2.5 µg/L/h Interval 0.8 to 28.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 72h

Need for combinational diuretic therapy with thiazide-type diuretics, bail-out ultrafiltration or renal replacement therapy

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: After 1 year of follow-up

Outcome measures

Outcome data not reported

Adverse Events

Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone

Serious events: 3 serious events

Other events: 6 other events

Deaths: 6 deaths

High-dose Loop Diuretics, Upfront Spironolactone

Serious events: 5 serious events

Other events: 4 other events

Deaths: 5 deaths

Acetazolamide/Low-dose Loop Diuretics, no Spironolactone

Serious events: 2 serious events

Other events: 7 other events

Deaths: 5 deaths

High-dose Loop Diuretics, no Spironolactone

Serious events: 3 serious events

Other events: 5 other events

Deaths: 5 deaths

Serious adverse events

Serious adverse events
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 participants at risk * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 participants at risk * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 participants at risk * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 participants at risk * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Cardiac disorders Hospital readmission due to heart failure	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	71.4% 5/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.
Renal and urinary disorders Serious hyperkalemia	0.00% 0/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	0.00% 0/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	0.00% 0/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	0.00% 0/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.

Other adverse events

Other adverse events
Measure	Acetazolamide/Low-dose Loop Diuretics, Upfront Spironolactone n=9 participants at risk * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	High-dose Loop Diuretics, Upfront Spironolactone n=7 participants at risk * 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. * Patients receive open-label oral spironolactone at a dose of 25 mg unless serum potassium levels are \>5 mmol/L.	Acetazolamide/Low-dose Loop Diuretics, no Spironolactone n=9 participants at risk * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.	High-dose Loop Diuretics, no Spironolactone n=9 participants at risk * 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. * Spironolactone use is prohibited during the first 72 h, but encouraged at discharge.
Renal and urinary disorders Metabolic acidosis	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	42.9% 3/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.
Renal and urinary disorders Moderate hyperkalemia	0.00% 0/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	14.3% 1/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	0.00% 0/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.
Renal and urinary disorders Hypokalemia	11.1% 1/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	14.3% 1/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.
Renal and urinary disorders Worsening renal function	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	0.00% 0/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	0.00% 0/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.
Cardiac disorders Hypotension	22.2% 2/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	14.3% 1/7 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.	33.3% 3/9 • 6 months Each patient was contacted by phone after 3 months, 6 months, and 12 months. A qualified study nurse assessed whether the patient died or was hospitalized during the previous 3 months. The electronic medical record was used to assess the reason for hospitalizations.

Additional Information

Dr. Frederik Verbrugge, researcher

Ziekenhuis Oost-Limburg

Phone: 0473924199

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place