Acute Heart Failure, Diuretics Drug Reactions
Conditions
Keywords
Acute Heart Failure, Natriuresis, Diuretics, Edema
Brief summary
This is a pragmatic, multicenter, interventional, parallel-arm, randomized, open-label trial to investigate whether a diuretic regimen, based on serial assessment of sodium concentration (UNa) on spot urine samples after diuretic administration and with low-threshold use of combination diuretic therapy, improves decongestion versus usual care in acute heart failure (AHF), potentially leading to better clinical outcomes.
Detailed description
Key interventions are: * Assessment of UNa in spot urine samples after every bolus administration of loop diuretics with continuation of intravenous diuretics until resolution of clinical signs of fluid overload AND UNa \<80 mmol/L * Dosing of loop diuretic bolus according to estimated glomerular filtration rate (eGFR) * Upfront use of intravenous acetazolamide 500 mg OD unless hypernatremia (\>145 mmol/L) or metabolic acidosis (bicarbonate \<22 mmol/L) * Upfront use of oral chlorthalidone 50 mg OD if eGFR \<30 mL/min/1.73m² OR hypernatremia (\>145 mmol/L) * Switch to full nephron blockade with intravenous acetazolamide 500 mg OD, intravenous bumetanide 4 mg TID, oral chlorthalidone 100 mg OD, and intravenous canrenoate 200 mg OD in case of diuretic resistance, defined as UNa \<80 mmol/L and persistent clinical signs of fluid overload * Provision of 500 mL intravenous Dextrose 5% with 3 g MgSO4 and 40 mmol KCl daily during diuretic therapy with intravenous diuretics
Interventions
DIAGNOSTIC_TESTUNa measurement after intravenous loop diuretic bolus
Sodium concentration is measured on a urine spot sample, collected 30-120 min after administration of every protocol-specified intravenous bumetanide dose.
DRUGIntravenous acetazolamide 500 mg OD
Upfront use of intravenous acetazolamide 500 mg OD as part of the diuretic treatment, unless hypernatremia (\>145 mmol/L) or metabolic acidosis (bicarbonate \<22 mmol/L) is present at the moment of the scheduled administration.
DRUGIntravenous bumetanide TID
An intravenous bolus of bumetanide is administered TID, with dosing according to eGFR: 2 mg for an eGFR \>45 mL/min/1.73m²; 3 mg for an eGFR 30-45 mL/min/1.73m²; and 4 mg for an eGFR \<30 mL/min/1.73m². At any time diuretic resistance is encountered (persistent clinical signs of fluid overload with UNa \<80 mmol/L), a dose of 4 mg TID is used.
DRUGOral chlorthalidone OD
In case of hypernatremia (\>145 mmol/L) or low eGFR (\<30 mL/min/1.73m²), oral chlorthalidone 50 mg OD is added to the diuretic treatment. At any time diuretic resistance is encountered (persistent clinical signs of fluid overload with UNa \<80 mmol/L), oral chlorthalidone is provided at a dose of 100 mg OD. Chlorthalidone is never administered in case of hypotonic hyponatremia with serum sodium concentration \<135 mmol/L.
DRUGIntravenous canrenoate 200 mg OD
At any time diuretic resistance is encountered (persistent clinical signs of fluid overload with UNa \<80 mmol/L), intravenous canrenoate 200 mg OD is provided. Canrenoate is never administered in case of hypotonic hyponatremia with serum sodium concentration \<135 mmol/L or if serum potassium levels are \>5.5 mmol/L. If canrenoate is administered, oral mineralocorticoid receptor drugs are temporarily withhold until switch to oral diuretic treatment.
OTHERMaintenance infusion
A maintenance infusion with 500 mL dextrose 5% and 3 g MgSO4 is started at an infusion rate of 20 mL/h upon the moment of first protocol-specified administration of intravenous diuretics and continued until switch to oral diuretic therapy. 40 mmol KCl is added if serum potassium levels are \<4 mmol/L. In case of hypotonic hyponatremia with serum sodium concentration \<130 mmol/L, dextrose 5% will not be provided and MgSO4 will be administered in 50 mL of normal saline (NaCl 0.9%).
DRUGOral potassium supplements
If serum potassium levels are \<3.5 mmol/L at any time during the administration of intravenous diuretics, oral potassium supplements are provided as needed to keep serum potassium levels \>4 mmol/L
In case of hypotonic hyponatremia with serum sodium concentration \<125 mmol/L, a bolus of 150 mL hypertonic saline 3% is administered and repeated OD if necessary, until sodium levels are ≥135 mmol/L.
OTHERSwitch to oral diuretic therapy
Upon complete resolution of clinical signs of fluid overload with UNa \<80 mmol/L, intravenous diuretics are switched to an oral schedule including: * Loop diuretics with dose \& frequency at the discretion of the treating physician * Chlorthalidone 50 mg if added for diuretic resistance at any time during the intravenous diuretic phase * Spironolactone 25 mg or another equivalent mineralocorticoid receptor antagonist
OTHERUsual AHF care
It is recommended to administer an intravenous loop diuretic dose at least BID (or through continuous infusion), with the aim of achieving a urine output 3-5 L per day until the patient is considered in an optimal volume status as is recommended by current guidelines.
Sponsors
Vrije Universiteit Brussel
Roche Diagnostics GmbH
Jessa Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* At least 18 y/o and able to provide informed consent * Hospital admission (anticipated stay \>24 h after randomisation) with diagnosis of acute heart failure according to the treating physician * At least one of the following three signs of volume overload: 1. bilateral oedema 2+, indicating clear pitting 2. ascites that is amenable for drainage, confirmed by echography (no obligation to perform abdominal echocardiography, but necessary when presence of ascites is used as an entry criterion for the study) 3. uni- or bilateral pleural effusions that are amenable for drainage, confirmed by chest X-ray or lung ultrasound (no obligation to perform chest X-ray, but necessary when presence of pleural effusions is used as an entry criterion for the study) * Plasma NTproBNP level \>1,000 ng/L
Exclusion criteria
* No possibility to collect reliable urine spot samples after diuretic administration * Administration of any diuretic within 6 h before randomisation, except for a mineralocorticoid receptor antagonist or sodium glucose co-transporter-2 inhibitor as part of the patient's maintenance treatment for heart failure. Patients can still be included after withholding these diuretics for 6 h, after which randomisation can be performed if they qualify all other criteria. * Severe kidney dysfunction, defined as an eGFR \<15 mL/min/1.73m² calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and/or previous, current, or planned future renal replacement therapy * Systolic blood pressure \<90 mmHg, mean arterial pressure \<65 mmHg, or need for inotropes/vasopressor therapy at randomisation * Any acute coronary syndrome within 30 days prior to enrolment, defined as typical chest pain with a troponin rise above the 99th percentile of normal and/or electrocardiographic changes suggestive of cardiac ischemia * History of heart or kidney transplantation * History of mechanical circulatory support * Known obstructive hypertrophic cardiomyopathy, congenital heart disease, acute mechanical cause of acute heart failure (e.g., papillary muscular rupture), acute myocarditis, or constrictive pericarditis according to the treating physician * Pregnant or breastfeeding woman * Concomitant participation in another interventional study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mortality, Days in Hospital & Decongestion | 30 days | The net treatment benefit is calculated for the hierarchical composite primary endpoint. Every patient from the intervention group is pair-wise compared with each patient from the control group to declare a winner or tie. The following criteria are sequentially assessed to declare a winner or a tie: 1. Any subject surviving until 30 days after randomization wins from a subject who died. If both subjects did not survive until day 30, there is a tie. 2. In a pair of subjects, both surviving up till day 30, the subject with the highest number of days alive and out of hospital or care facility during the 30-day follow-up window is declared the winner. 3. In a pair of subjects, both surviving up till day 30 with the same number of days alive and out of hospital/care facility, the subject with the greatest relative reduction in NTproBNP from baseline is the winner (rounded to the closest percentage with a minimal difference of 5%). If the difference is \<5%, there is a tie. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Safety Endpoint | 30 days | Number of patients with doubling of the serum creatinine or plasma cystatin C value compared to baseline with an absolute value \>2 mg/dL or \>2 mg/L, respectively, or the need for ultrafiltration and/or renal replacement therapy during the index hospital admission. |
| Hemodynamic Safety Endpoint | 30 days | Number of patients with a ystolic blood pressure \<90 mmHg or mean arterial pressure \<65 mmHg or need for vasopressors and/or inotropes during the index hospital admission. |
| Natriuretic Peptide Change After 30 Days | 30 days | Relative NT-proBNP change from baseline to 30 days after randomisation \[%\]. |
| Cancer Antigen 125 (CA125) Change After 30 Days | 30 days | Relative cancer antigen 125 (CA125) change from baseline to 30 days after randomisation \[%\]. |
| Number of Participants With Successful Clinical Decongestion | 30 days | Number of participants with no more than trace edema, absence of jugular venous distension and no rales upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol. |
| Length of Intravenous Diuretic Therapy | 30 days | Number of consecutive days from randomization during the index admission on which intravenous diuretic therapy was administered. |
| Overall Well-being After Decongestion | 30 days | Five-point Likert scale for overall well-being upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol and compared with the moment of randomisation (5: much improved/4: slightly improved/3: neutral/2: slightly worse/1: much worse). |
| Length of the Index Hospital Admission | 30 days | Length of the index hospital admission \[days\]. |
| Number of Participants Who Are Death, or Have a Non-elective Hospital Admission or Non-elective Medical Contact | 30 days | Number of participants who are death, or have a non-elective hospital admission or non-elective medical contact |
Countries
Belgium
Contacts
PRINCIPAL_INVESTIGATORFrederik H Verbrugge, M.D.; Ph.D.; M.Sc.
Vrije Universiteit Brussel
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intervention Arm Application of a standardized diuretic schedule with following key components:
* Serial post-diuretic spot urine sodium (UNa) assessment
* Loop diuretic dosing according to estimated glomerular filtration rate (eGFR)
* Upfront use of intravenous acetazolamide 500 mg OD
* Upfront use of oral chlorthalidone 50 mg OD if eGFR \<30 mL/min/1.73m² OR hypernatremia
* Full nephron blockade for diuretic resistance
* Provision of 500 mL intravenous Dextrose 5% with 3 g MgSO4 and 40 mmol KCl daily during intravenous diuretics | 52 |
| Control Arm Usual care for AHF. It is recommended to administer an intravenous loop diuretic dose at least BID (or through continuous infusion), with the aim of achieving a urine output 3-5 L per day until the patient is considered in an optimal volume status as is recommended by current guidelines. Urine electrolyte assessment in the control arm is not allowed as it is a key component of the studied intervention.
Usual AHF care: It is recommended to administer an intravenous loop diuretic dose at least BID (or through continuous infusion), with the aim of achieving a urine output 3-5 L per day until the patient is considered in an optimal volume status as is recommended by current guidelines. | 51 |
| Total | 103 |
Baseline characteristics
| Characteristic | Intervention Arm | Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 81 years STANDARD_DEVIATION 10 | 79 years STANDARD_DEVIATION 10 | 80 years STANDARD_DEVIATION 10 |
| NTproBNP (ng/L) | 4134 ng/L | 4989 ng/L | 4622 ng/L |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 49 Participants | 49 Participants | 98 Participants |
| Sex: Female, Male Female | 21 Participants | 24 Participants | 45 Participants |
| Sex: Female, Male Male | 31 Participants | 27 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 52 | 4 / 51 |
| other Total, other adverse events | 13 / 52 | 21 / 51 |
| serious Total, serious adverse events | 6 / 52 | 14 / 51 |
Outcome results
Primary
Mortality, Days in Hospital & Decongestion
The net treatment benefit is calculated for the hierarchical composite primary endpoint. Every patient from the intervention group is pair-wise compared with each patient from the control group to declare a winner or tie. The following criteria are sequentially assessed to declare a winner or a tie: 1. Any subject surviving until 30 days after randomization wins from a subject who died. If both subjects did not survive until day 30, there is a tie. 2. In a pair of subjects, both surviving up till day 30, the subject with the highest number of days alive and out of hospital or care facility during the 30-day follow-up window is declared the winner. 3. In a pair of subjects, both surviving up till day 30 with the same number of days alive and out of hospital/care facility, the subject with the greatest relative reduction in NTproBNP from baseline is the winner (rounded to the closest percentage with a minimal difference of 5%). If the difference is \<5%, there is a tie.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intervention Arm | Mortality, Days in Hospital & Decongestion | 54.68 % wins |
| Control Arm | Mortality, Days in Hospital & Decongestion | 44.16 % wins |
p-value: 0.35795% CI: [-11.9, 31.9]General pairwaise comparison
Secondary
Cancer Antigen 125 (CA125) Change After 30 Days
Relative cancer antigen 125 (CA125) change from baseline to 30 days after randomisation \[%\].
Time frame: 30 days
Population: This endpoint could not be assessed in patients who died (n=3 in the intervention arm and n=4 in the control arm). In addition, 1 patient in the intervention arm withdrew consent during follow-up. Vital status could be assessed, but no blood sample was available for this patient. Finally, 5 blood samples were missing in the control group because patients were unable to physically attend the final follow-up visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention Arm | Cancer Antigen 125 (CA125) Change After 30 Days | -69 % of change from baseline | Standard Deviation 40 |
| Control Arm | Cancer Antigen 125 (CA125) Change After 30 Days | -21 % of change from baseline | Standard Deviation 68 |
Secondary
Hemodynamic Safety Endpoint
Number of patients with a ystolic blood pressure \<90 mmHg or mean arterial pressure \<65 mmHg or need for vasopressors and/or inotropes during the index hospital admission.
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm | Hemodynamic Safety Endpoint | 10 Participants |
| Control Arm | Hemodynamic Safety Endpoint | 4 Participants |
Secondary
Length of Intravenous Diuretic Therapy
Number of consecutive days from randomization during the index admission on which intravenous diuretic therapy was administered.
Time frame: 30 days
Population: This endpoint was not be assessed in patients who died (n=3 in the intervention arm and n=4 in the control arm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intervention Arm | Length of Intravenous Diuretic Therapy | 4 days |
| Control Arm | Length of Intravenous Diuretic Therapy | 4 days |
Secondary
Length of the Index Hospital Admission
Length of the index hospital admission \[days\].
Time frame: 30 days
Population: This endpoint was not be assessed in patients who died (n=3 in the intervention arm and n=4 in the control arm).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intervention Arm | Length of the Index Hospital Admission | 7 days |
| Control Arm | Length of the Index Hospital Admission | 7 days |
Secondary
Natriuretic Peptide Change After 30 Days
Relative NT-proBNP change from baseline to 30 days after randomisation \[%\].
Time frame: 30 days
Population: This endpoint could not be assessed in patients who died (n=3 in the intervention arm and n=4 in the control arm). In addition, 1 patient in the intervention arm withdrew consent during follow-up. Vital status could be assessed, but no blood sample was available for this patient. Finally, 5 blood samples were missing in the control group because patients were unable to physically attend the final follow-up visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intervention Arm | Natriuretic Peptide Change After 30 Days | -37 % of change from baseline | Standard Deviation 64 |
| Control Arm | Natriuretic Peptide Change After 30 Days | -46 % of change from baseline | Standard Deviation 40 |
Secondary
Number of Participants Who Are Death, or Have a Non-elective Hospital Admission or Non-elective Medical Contact
Number of participants who are death, or have a non-elective hospital admission or non-elective medical contact
Time frame: 30 days
Population: One patient in the intervention arm withdrew consent during follow-up. Vital status could be assessed, but not data on hospitalizations or medical contacts. Therefore the overall number of participants analyzed is 1 lower than for the primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm | Number of Participants Who Are Death, or Have a Non-elective Hospital Admission or Non-elective Medical Contact | 9 Participants |
| Control Arm | Number of Participants Who Are Death, or Have a Non-elective Hospital Admission or Non-elective Medical Contact | 12 Participants |
Secondary
Number of Participants With Successful Clinical Decongestion
Number of participants with no more than trace edema, absence of jugular venous distension and no rales upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
Time frame: 30 days
Population: This endpoint was not be assessed in patients who died (n=3 in the intervention arm and n=4 in the control arm). One edema score was missing in the control group and could not be retrieved, precluding the assessment of decongestion success.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm | Number of Participants With Successful Clinical Decongestion | 33 Participants |
| Control Arm | Number of Participants With Successful Clinical Decongestion | 26 Participants |
Secondary
Overall Well-being After Decongestion
Five-point Likert scale for overall well-being upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol and compared with the moment of randomisation (5: much improved/4: slightly improved/3: neutral/2: slightly worse/1: much worse).
Time frame: 30 days
Population: This endpoint could not be assessed in patients who died before switching to oral diuretics (n=1 in the intervention group and n=3 in the control group).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Intervention Arm | Overall Well-being After Decongestion | Better | 28 Participants |
| Intervention Arm | Overall Well-being After Decongestion | Significantly worse | 0 Participants |
| Intervention Arm | Overall Well-being After Decongestion | Significantly better | 17 Participants |
| Intervention Arm | Overall Well-being After Decongestion | Worse | 3 Participants |
| Intervention Arm | Overall Well-being After Decongestion | Unchanged | 3 Participants |
| Control Arm | Overall Well-being After Decongestion | Worse | 0 Participants |
| Control Arm | Overall Well-being After Decongestion | Unchanged | 4 Participants |
| Control Arm | Overall Well-being After Decongestion | Better | 35 Participants |
| Control Arm | Overall Well-being After Decongestion | Significantly better | 9 Participants |
| Control Arm | Overall Well-being After Decongestion | Significantly worse | 0 Participants |
Secondary
Renal Safety Endpoint
Number of patients with doubling of the serum creatinine or plasma cystatin C value compared to baseline with an absolute value \>2 mg/dL or \>2 mg/L, respectively, or the need for ultrafiltration and/or renal replacement therapy during the index hospital admission.
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intervention Arm | Renal Safety Endpoint | 9 Participants |
| Control Arm | Renal Safety Endpoint | 3 Participants |