Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR)

Study Overview
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Brief Summary
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This clinical research study is being conducted in multiple hospitals in Belgium and approximately 519 patients with acute decompensated heart failure are expected to participate. Large-scale research shows that 90% of the physicians treat volume overload with high doses of loop diuretics. However, there is not a lot of scientific data available regarding the optimal doses of these diuretic medications. In addition, it is observed that a lot of people, treated with these drugs, are being readmitted to the hospital due to a new episode of heart failure. The hypothesis of this study is that the volume overload could be better treated when patients receive a combination of different types of diuretics. Additionally, the total dose of the administrated diuretics might be lower this way.

Detailed Description
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This is a randomized, double blind study with 2 treatment groups. This means that the patients will be randomized to one of the two treatment groups by chance. Patients randomized to the first group will receive standard treatment with high doses of intravenous loop diuretics and a placebo. Patients randomized to the other treatment group will receive a combination of the same doses of loop diuretics and an additional diuretic, acetazolamide (Diamox®). All diuretics will be administered intravenously. It is expected that the patients of the treatment group with the combination therapy will have a faster reduction of their fluid overload. In consequence the treatment duration and total dose of diuretics administered will be shorter. Acetazolamide (Diamox®) is a diuretic that acts at a different location in the kidney compared to the loop diuretics. This mutual reinforcement will probably reduce the total dose and duration of the diuretics. The study will start during the hospitalization and will last around 3 months.

Official Title
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A Multi-center, Randomized, Double-blind, Phase IV Clinical Trial on the Diuretic Effects of Acetazolamide in Patients With Decompensated Heart Failure and Volume OveRload

Conditions
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Acute Decompensated Heart Failure, Volume Overload

Intervention / Treatment
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* Drug: Acetazolamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent must be obtained before any study assessment is performed Male or female patients 18 years of age or older An elective or emergency hospital admission with clinical diagnosis of decompensated HF with at least one clinical sign of volume overload (e.g. oedema (score 2 or more), ascites confirmed by echography or pleural effusion confirmed by chest X-ray or echography) Maintenance therapy with oral loop diuretics at a dose of at least 1 mg bumetanide or an equivalent dose for at least 1 month before hospital admission (Conversion: 1 mg bumetanide = 40 mg furosemide = 20 mg torsemide) Plasma NT-proBNP levels >1000 ng/mL or BNP levels >250 ng/mL at the time of screening. Assessed LVEF by any imaging technique; i.e. echocardiography, catheterization, nuclear scan or magnetic resonance imaging within 12 months of inclusion Exclusion Criteria: Concurrent diagnosis of an acute coronary syndrome defined as typical chest pain in addition to a troponin rise above the 99th percentile and/or electrocardiographic changes suggestive of cardiac ischemia History of congenital heart disease requiring surgical correction History of a cardiac transplantation and/or ventricular assist device Systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg at the moment of admission Expected use of intravenous inotropes, vasopressors or nitroprusside during the study. Use of nitrates is allowed only if the patient's systolic blood pressure is >140 mmHg Estimated glomerular filtration rate <20 mL/min/1.73m² at screening Use of renal replacement therapy or ultrafiltration at any time before study inclusion Treatment with acetazolamide during the index hospitalization and prior to randomization Exposure to nephrotoxic agents (i.e. contrast dye) anticipated within the next 3 days Use of any non-protocol defined diuretic agent with the exception of mineralocorticoid receptor antagonists. Thiazides, metolazone, indapamide and amiloride should be stopped upon study inclusion. If patient is taking a combination drug including a thiazide-type diuretic, the thiazide-type diuretic should be stopped Current use of sodium-glucose transporter-2 inhibitors Subjects who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: high-dose loop diuretics+placebo<br>At the moment of randomization (day 1), oral loop diuretics are stopped and the patient receives IV loop diuretics at a dose equal to the double of his oral daily maintenance dose + 500 mg IV bolus of placebo. If the patient still have signs of volume overload the next mornings (day 2 and day 3), the patient will receive IV loop diuretics at a dose equal to the oral daily maintenance dose + 500 mg IV bolus of placebo. It the patient has no sign of volume overload at these time points, the study treatment will be stopped. | Drug: Placebo<br>* In the placebo group, the patient will receive the standard of care loop diuretics and the placebo<br>|
| Experimental: high-dose loop diuretics+acetazolamide<br>At the moment of randomization (day 1), oral loop diuretics are stopped and the patient receives IV loop diuretics at a dose equal to the double of his oral daily maintenance dose + 500 mg IV bolus of acetazolamide. If the patient still have signs of volume overload the next mornings (day 2 and day 3), the patient will receive IV loop diuretics at a dose equal to the oral daily maintenance dose + 500 mg IV bolus of acetazolamide. It the patient has no sign of volume overload at these time points, the study treatment will be stopped. | Drug: Acetazolamide<br>* In the experimental group, the patient will receive the standard of care loop diuretics and acetazolamide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment success | Treatment success (decongestion achieved) on the morning of day 4 without the need for escalating diuretic strategy on the morning of day 3. | 4 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | All-cause mortality during the first 3 months after start of the study | 3 months | 
| Hospital readmission | If a patient is readmitted to the hospital within 3 months, this data will be collected | 3 months | 
| Length of index hospital admission | The time frame between hospital admission and discharge will be calculated | 3 months | 
| EuroQoL five dimensions questionnaire (EQ-5D) | A questionnaire about the patients' quality of life will be performed at baseline, the morning of day 4, at any readmission, 3 months. The questionnaire is divided into 5 levels of severity with a score varying from 1 to 5. 1 indicates no problems and 5 indicates severe problems. | at day 1, day 4, at any hospital readmission within 3 months, at 3 months |