Back to resultsAcetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR) (Advor)
Primary Purpose
Acute Decompensated Heart Failure, Volume Overload
Status
Completed
Phase
Phase 4
Locations
Belgium
Study Type
Interventional
Intervention
Acetazolamide
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Acute Decompensated Heart Failure
Eligibility Criteria
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
Sites / Locations
- Ziekenhuis Oost-Limburg AV
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
high-dose loop diuretics+placebo
high-dose loop diuretics+acetazolamide
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Mortality
All-cause mortality during the first 3 months after start of the study
Hospital readmission
If a patient is readmitted to the hospital within 3 months, this data will be collected
Length of index hospital admission
The time frame between hospital admission and discharge will be calculated
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03505788
Brief Title
Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR)
Acronym
Advor
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
November 11, 2018 (Actual)
Primary Completion Date
January 20, 2022 (Actual)
Study Completion Date
May 16, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ziekenhuis Oost-Limburg
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Decompensated Heart Failure, Volume Overload
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
519 (Actual)
8. Arms, Groups, and Interventions
Arm Title
high-dose loop diuretics+placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
high-dose loop diuretics+acetazolamide
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Acetazolamide
Intervention Description
In the experimental group, the patient will receive the standard of care loop diuretics and acetazolamide
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
In the placebo group, the patient will receive the standard of care loop diuretics and the placebo
Primary Outcome Measure Information:
Title
Treatment success
Description
Treatment success (decongestion achieved) on the morning of day 4 without the need for escalating diuretic strategy on the morning of day 3.
Time Frame
4 days
Secondary Outcome Measure Information:
Title
Mortality
Description
All-cause mortality during the first 3 months after start of the study
Time Frame
3 months
Title
Hospital readmission
Description
If a patient is readmitted to the hospital within 3 months, this data will be collected
Time Frame
3 months
Title
Length of index hospital admission
Description
The time frame between hospital admission and discharge will be calculated
Time Frame
3 months
Title
EuroQoL five dimensions questionnaire (EQ-5D)
Description
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.
Time Frame
at day 1, day 4, at any hospital readmission within 3 months, at 3 months
Other Pre-specified Outcome Measures:
Title
Body weight
Description
Body weight change after day 1, 2, 3, 4 discharge compared to admission
Time Frame
day 1, day 2, day3, day 4
Title
Use of medication
Description
A list of specific medication will be collected
Time Frame
3 months
Title
Diureses and natriuresis
Description
The volume of urine will be measured until the morning of day 3. In the same urine, natriuresis will be assessed.
Time Frame
3 days
Title
Adverse events
Description
Any undesired clinical outcomes will be reported
Time Frame
3 months
Title
Abnormal blood parameters
Description
Any abnormal laboratory parameters in the blood (electrolytes, heart failure markers and anemia markers) during hospital admission will be reported
Time Frame
an average of 7 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wiflried Mullens, MD PhD
Organizational Affiliation
Ziekenhuis Oost-Limburg
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ziekenhuis Oost-Limburg AV
City
Genk
State/Province
Limburg
ZIP/Postal Code
3600
Country
Belgium
12. IPD Sharing Statement
Citations:
PubMed Identifier
36027559
Citation
Mullens W, Dauw J, Martens P, Verbrugge FH, Nijst P, Meekers E, Tartaglia K, Chenot F, Moubayed S, Dierckx R, Blouard P, Troisfontaines P, Derthoo D, Smolders W, Bruckers L, Droogne W, Ter Maaten JM, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M; ADVOR Study Group. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022 Sep 29;387(13):1185-1195. doi: 10.1056/NEJMoa2203094. Epub 2022 Aug 27.
Results Reference
derived
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Acetazolamide in Decompensated Heart Failure With Volume OveRload (ADVOR)
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