Acute Decompensated Heart Failure, Volume Overload
Conditions
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.
Interventions
DRUGAcetazolamide
In the experimental group, the patient will receive the standard of care loop diuretics and acetazolamide
DRUGPlacebo
In the placebo group, the patient will receive the standard of care loop diuretics and the placebo
Sponsors
Ziekenhuis Oost-Limburg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Successful Decongestion | 4 days | defined as the absence of signs of volume overload, within 3 days after randomization and with no indication for escalation of decongestive therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 3 months | All-cause mortality during the first 3 months after start of the study |
| Hospital Readmission | 3 months | If a patient is readmitted to the hospital within 3 months, this data will be collected |
| Length of Index Hospital Admission | 3 months | The time frame between hospital admission and discharge will be calculated |
| EuroQoL Five Dimensions Questionnaire (EQ-5D) | at baseline, day 4 (or discharge), at 3 months | 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. The EQ-5D-5L health status, defined by the EQ-5D-5L descriptive system, are converted into a single index value (utility data). Values are anchored at 1 (full health) and 0 (a state as bad as being dead) as required by their use in economic evaluation. Values less than 0 represent health states regarded as worse than a state that is as bad as being dead. |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo In the placebo group, the patient will receive the standard of care loop diuretics and the placebo. | 260 |
| Acetazolamide In the experimental group, the patient will receive the standard of care loop diuretics and acetazolamide. | 259 |
| Total | 519 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Acetazolamide | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 77.9 Years STANDARD_DEVIATION 9 | 78.2 Years STANDARD_DEVIATION 8.9 | 78.5 Years STANDARD_DEVIATION 8.8 |
| Beta-blocker | 207 Participants | 419 Participants | 212 Participants |
| Comorbidities - Diabetes | 112 Participants | 245 Participants | 133 Participants |
| Comorbidities - History of atrial fibrillation | 187 Participants | 376 Participants | 189 Participants |
| Comorbidities - Hypertension | 182 Participants | 389 Participants | 207 Participants |
| Composite of volume assessment score - Ascites | 21 Participants | 46 Participants | 25 Participants |
| Composite of volume assessment score - Edema | 237 Participants | 478 Participants | 241 Participants |
| Composite of volume assessment score - Pleural Effusion | 130 Participants | 273 Participants | 143 Participants |
| Congestion score | 4 units on a scale | 4 units on a scale | 4 units on a scale |
| CRT | 36 Participants | 61 Participants | 25 Participants |
| Diastolic blood pressure | 72 mmHg STANDARD_DEVIATION 13 | 72 mmHg STANDARD_DEVIATION 13 | 73 mmHg STANDARD_DEVIATION 13 |
| eGFR | 40 mL/min/1.73m^3 | 39 mL/min/1.73m^3 | 38 mL/min/1.73m^3 |
| eGFR < 60mL/min/1.73m^3 | 209 Participants | 424 Participants | 215 Participants |
| Heart rate | 79 bpm STANDARD_DEVIATION 19 | 78 bpm STANDARD_DEVIATION 18 | 77 bpm STANDARD_DEVIATION 18 |
| ICD | 38 Participants | 79 Participants | 41 Participants |
| Ischaemic aetiology | 119 Participants | 232 Participants | 113 Participants |
| LVEF | 43 % STANDARD_DEVIATION 15 | 43 % STANDARD_DEVIATION 15 | 43 % STANDARD_DEVIATION 15 |
| Maintenance dose - furosemide equivalent | 80 mg | 60 mg | 60 mg |
| MRA | 113 Participants | 216 Participants | 103 Participants |
| NT-proBNP | 5600 pg/mL | 6173 pg/mL | 6483 pg/mL |
| NYHA II | 31 Participants | 66 Participants | 35 Participants |
| NYHA III | 148 Participants | 296 Participants | 148 Participants |
| NYHA IV | 80 Participants | 157 Participants | 77 Participants |
| Proportion LVEF ≤ 40% | 113 Participants | 224 Participants | 111 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) White | 258 Participants | 514 Participants | 256 Participants |
| Serum creatinine | 1.5 mg/dL | 1.5 mg/dL | 1.5 mg/dL |
| Serum hemoglobin | 11.9 g/dL STANDARD_DEVIATION 2 | 11.9 g/dL STANDARD_DEVIATION 2 | 11.9 g/dL STANDARD_DEVIATION 2 |
| Sex: Female, Male Female | 89 Participants | 194 Participants | 105 Participants |
| Sex: Female, Male Male | 170 Participants | 325 Participants | 155 Participants |
| Sodium | 139 mmol/L STANDARD_DEVIATION 4 | 139 mmol/L STANDARD_DEVIATION 4 | 140 mmol/L STANDARD_DEVIATION 4 |
| Systolic blood pressure | 126 mmHg STANDARD_DEVIATION 20 | 127 mmHg STANDARD_DEVIATION 21 | 127 mmHg STANDARD_DEVIATION 22 |
| Use of ACEi/ARB/ARNi | 130 Participants | 270 Participants | 140 Participants |
| Weight | 85.3 kg STANDARD_DEVIATION 23 | 84.8 kg STANDARD_DEVIATION 21.4 | 84.4 kg STANDARD_DEVIATION 19.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 31 / 259 | 39 / 256 |
| other Total, other adverse events | 184 / 259 | 192 / 256 |
| serious Total, serious adverse events | 124 / 259 | 123 / 256 |
Outcome results
Primary
Successful Decongestion
defined as the absence of signs of volume overload, within 3 days after randomization and with no indication for escalation of decongestive therapy.
Time frame: 4 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Successful Decongestion | 79 Participants |
| Acetazolamide | Successful Decongestion | 108 Participants |
Secondary
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. The EQ-5D-5L health status, defined by the EQ-5D-5L descriptive system, are converted into a single index value (utility data). Values are anchored at 1 (full health) and 0 (a state as bad as being dead) as required by their use in economic evaluation. Values less than 0 represent health states regarded as worse than a state that is as bad as being dead.
Time frame: at baseline, day 4 (or discharge), at 3 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | EuroQoL Five Dimensions Questionnaire (EQ-5D) | Baseline | 0.571 score on a scale | Standard Deviation 0.027 |
| Placebo | EuroQoL Five Dimensions Questionnaire (EQ-5D) | Day 4 (or discharge) | 0.688 score on a scale | Standard Deviation 0.028 |
| Placebo | EuroQoL Five Dimensions Questionnaire (EQ-5D) | 3 months FU | 0.592 score on a scale | Standard Deviation 0.028 |
| Acetazolamide | EuroQoL Five Dimensions Questionnaire (EQ-5D) | Day 4 (or discharge) | 0.656 score on a scale | Standard Deviation 0.028 |
| Acetazolamide | EuroQoL Five Dimensions Questionnaire (EQ-5D) | Baseline | 0.546 score on a scale | Standard Deviation 0.027 |
| Acetazolamide | EuroQoL Five Dimensions Questionnaire (EQ-5D) | 3 months FU | 0.546 score on a scale | Standard Deviation 0.028 |
Secondary
Hospital Readmission
If a patient is readmitted to the hospital within 3 months, this data will be collected
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Hospital Readmission | 45 Participants |
| Acetazolamide | Hospital Readmission | 47 Participants |
Secondary
Length of Index Hospital Admission
The time frame between hospital admission and discharge will be calculated
Time frame: 3 months
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Length of Index Hospital Admission | 9.9 days |
| Acetazolamide | Length of Index Hospital Admission | 8.8 days |
Secondary
Mortality
All-cause mortality during the first 3 months after start of the study
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality | 31 Participants |
| Acetazolamide | Mortality | 39 Participants |