Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

34 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-11-30

Study Completion Date

2017-10-31

Brief Summary

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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.

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Detailed Description

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Conditions

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Heart Failure

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Caregivers Investigators Outcome Assessors

Study Groups

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Acetazolamide/low-dose loop diuretics, upfront spironolactone

2x2 factorial design: This group is the experimental group for both study interventions (acetazolamide and upfront spironolactone).

See interventions for more details.

Group Type EXPERIMENTAL

Combination therapy with acetazolamide and low-dose loop diuretics

Intervention Type DRUG

* 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.

Upfront therapy with oral spironolactone

Intervention Type DRUG

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.

High-dose loop diuretics, upfront spironolactone

2x2 factorial design: This group is the experimental group for the study intervention with upfront spironolactone. This group receives high-dose loop diuretics as an active comparator to the study intervention with acetazolamide.

See interventions for more details.

Group Type EXPERIMENTAL

High-dose loop diuretics

Intervention Type DRUG

* 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

Intervention Type DRUG

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.

Acetazolamide/low-dose loop diuretics, no spironolactone

2x2 factorial design: This group is the experimental group for the study intervention with acetazolamide. This group receives no intervention with regards to the spironolactone arm.

See interventions for more details.

Group Type EXPERIMENTAL

Combination therapy with acetazolamide and low-dose loop diuretics

Intervention Type DRUG

* 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, no spironolactone

2x2 factorial design: This group receives high-dose loop diuretics as an active comparator to the study intervention with acetazolamide. This group receives no intervention with regards to the spironolactone arm.

See interventions for more details.

Group Type ACTIVE_COMPARATOR

High-dose loop diuretics

Intervention Type DRUG

* 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.

Interventions

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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.

Intervention Type DRUG

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.

Intervention Type DRUG

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.

Intervention Type DRUG

Other Intervention Names

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Diamox (acetazolamide) Burinex/Bumex (loop diuretics) Burinex/Bumex Aldactone

Eligibility Criteria

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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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No