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Heart Failure | Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure

Heart Failure research study

What is the primary objective of this study?

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.

Who is eligible to participate?

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

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Heart Failure

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:Combination therapy with acetazolamide and low-dose loop diureticsPatients 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.

Drug:High-dose loop diureticsPatients 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.

Drug:Upfront therapy with oral spironolactonePatients 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.

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

Acetazolamide/low-dose loop diuretics, upfront spironolactone2x2 factorial design: This group is the experimental group for both study interventions (acetazolamide and upfront spironolactone). See interventions for more details.

High-dose loop diuretics, upfront spironolactone2x2 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.

Acetazolamide/low-dose loop diuretics, no spironolactone2x2 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.

High-dose loop diuretics, no spironolactone2x2 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.

Study Status

Completed

Start Date: November 2013

Completed Date: October 2017

Phase: Phase 4

Type: Interventional

Design:

Primary Outcome: Acetazolamide arm: natriuresis 24 h

Secondary Outcome: NT-proBNP change after 72 h

Study sponsors, principal investigator, and references

Principal Investigator: Wilfried Mullens, M.D. Ph.D.

Lead Sponsor: Hasselt University

Collaborator: Ziekenhuis Oost-Limburg

More information:https://clinicaltrials.gov/show/NCT01973335

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