DECONGEST: Diuretic Treatment in Acute Heart Failure With Volume Overload Guided by Serial Spot Urine Sodium Assessment

Sponsor

Vrije Universiteit Brussel (Other)

Overall Status

Recruiting

CT.gov ID

NCT05411991

Collaborator

Roche Diagnostics (Industry), Jessa Hospital (Other)

104

Enrollment

Locations

Arms

13.6

Anticipated Duration (Months)

Patients Per Site

3.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Heart Failure Diuretics Drug Reactions	Diagnostic Test: UNa measurement after intravenous loop diuretic bolus Drug: Intravenous acetazolamide 500 mg OD Drug: Intravenous bumetanide TID Drug: Oral chlorthalidone OD Drug: Intravenous canrenoate 200 mg OD Other: Maintenance infusion Drug: Oral potassium supplements Other: Intravenous hypertonic saline Other: Switch to oral diuretic therapy Other: Usual AHF care	Phase 4

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

104 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Diuretic Treatment in Acute Heart Failure With Volume Overload Guided by Serial Spot Urine Sodium Assessment

Actual Study Start Date :

Jun 12, 2022

Anticipated Primary Completion Date :

Jul 31, 2023

Anticipated Study Completion Date :

Jul 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention arm Application of a standardized diuretic schedule with following key components: UNa assessment in spot urine sample after every bolus of loop diuretics with continuation of intravenous diuretics until absence of clinical signs of fluid overload AND UNa <80 mmol/L Loop diuretic dosing according to estimated glomerular filtration rate (eGFR) with higher dose for lower eGFR Upfront use of intravenous acetazolamide 500 mg OD unless hypernatremia or metabolic acidosis Upfront use of oral chlorthalidone 50 mg OD if eGFR <30 mL/min/1.73m² OR hypernatremia 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 intravenous diuretics	Diagnostic Test: UNa 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. Drug: Intravenous 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. Other Names: Diamox (brand name for acetazolamide) Drug: Intravenous 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. Other Names: Burinex (brand name for bumetanide) Drug: Oral 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. Other Names: Hygroton (brand name for chlorthalidone) Drug: Intravenous 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. Other Names: Soldactone (brand name for canrenoate) Other: Maintenance 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%). Drug: Oral 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 Other Names: KCl Other: Intravenous hypertonic saline 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. Other: Switch 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
Active Comparator: 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.	Other: 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.

Arm

Intervention/Treatment

Experimental: Intervention arm

Application of a standardized diuretic schedule with following key components: UNa assessment in spot urine sample after every bolus of loop diuretics with continuation of intravenous diuretics until absence of clinical signs of fluid overload AND UNa <80 mmol/L Loop diuretic dosing according to estimated glomerular filtration rate (eGFR) with higher dose for lower eGFR Upfront use of intravenous acetazolamide 500 mg OD unless hypernatremia or metabolic acidosis Upfront use of oral chlorthalidone 50 mg OD if eGFR <30 mL/min/1.73m² OR hypernatremia 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 intravenous diuretics

Diagnostic Test: UNa 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.

Drug: Intravenous 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.

Other Names:

Diamox (brand name for acetazolamide)

Drug: Intravenous 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.

Other Names:

Burinex (brand name for bumetanide)

Drug: Oral 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.

Other Names:

Hygroton (brand name for chlorthalidone)

Drug: Intravenous 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.

Other Names:

Soldactone (brand name for canrenoate)

Other: Maintenance 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%).

Drug: Oral 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

Other Names:

KCl

Other: Intravenous hypertonic saline

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.

Other: Switch 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

Active Comparator: 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.

Other: 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.

Outcome Measures

Primary Outcome Measures

Mortality, days in hospital & decongestion [30 days]
Win ratio for a hierarchically composed endpoint of mortality, days in hospital and relative decrease in N-terminal pro-hormone of B-type natriuretic peptide (NT-proBNP) levels after 30 days.

Secondary Outcome Measures

Renal safety endpoint [30 days]
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]
Systolic 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
Number of participants who are death or have a non-elective hospital admission [30 days]
Number of participants who are death or have a non-elective hospital admission

Other Outcome Measures

Overall well-being at discharge [30 days]
Five point Likert scale for overall well-being upon the moment of hospital discharge for the index hospitalisation and compared with the moment of randomisation (5: much improved/4: slightly improved/3: neutral/2: slightly worse/1: much worse).
Overall well-being after 30 days [30 days]
Five point Likert scale for overall well-being 30 days after randomisation and compared with the moment of randomisation (5: much improved/4: slightly improved/3: neutral/2: slightly worse/1: much worse).
Edema score after decongestion [30 days]
Edema score (1+: trace; 2+ clear pitting; 3+ clear pitting with visual deformation below the knee; 4+: clear pitting with visual deformation above the knee) upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
Edema score at discharge [30 days]
Edema score (1+: trace; 2+ clear pitting; 3+ clear pitting with visual deformation below the knee; 4+: clear pitting with visual deformation above the knee) upon the moment of hospital discharge for the index hospitalisation.
Edema score after 30 days [30 days]
Edema score (1+: trace; 2+ clear pitting; 3+ clear pitting with visual deformation below the knee; 4+: clear pitting with visual deformation above the knee) 30 days after randomisation.
Weight change with decongestion [30 days]
Weight change [kg] from baseline to the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
Natriuretic peptide change after decongestion [30 days]
Relative NT-proBNP change from baseline to the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol [%].
Cancer antigen 125 (CA125) change after decongestion [30 days]
Relative cancer antigen 125 (CA125) change from baseline to the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol [%].
Change in eGFR after 30 days (serum creatinine-based) [30 days]
Change in eGFR from randomisation towards 30 days [mL/min/1.73m²] with eGFR calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula with serum creatinine.
Change in eGFR after 30 days (plasma cystatin C-based) [30 days]
Change in eGFR from randomisation towards 30 days [mL/min/1.73m²] with eGFR calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula with plasma cystatin C.
Change in eGFR after 30 days (serum creatinine/plasma cystatin C-based) [30 days]
Change in eGFR from randomisation towards 30 days [mL/min/1.73m²] with eGFR calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula with serum creatinine and plasma cystatin C.
Hyperkalemia [30 days]
Hyperkalemia with serum potassium levels >5.5 mmol/L at any time during the study period.
Severe hyperkalemia [30 days]
Severe hyperkalemia with serum potassium levels >6.5 mmol/L at any time during the study period.
Hypokalemia [30 days]
Hypokalemia with serum potassium levels <3.5 mmol/L at any time during the study period.
Hyponatremia [30 days]
Hyponatremia with serum sodium levels <135 mmol/L at any time during the study period.
Severe hyponatremia [30 days]
Severe hyponatremia with serum sodium levels <125 mmol/L at any time during the study period.
Hypernatremia [30 days]
Hypernatremia with serum sodium levels >145 mmol/L at any time during the study period.
Severe metabolic acidosis [30 days]
Severe metabolic acidosis with serum bicarbonate levels <20 mmol/L at any time during the study period.
E/e' after decongestion [30 days]
Averaged medial/lateral E/e' ratio on transthoracic echocardiography upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
E/e' at discharge [30 days]
Averaged medial/lateral E/e' ratio on transthoracic echocardiography upon the moment of hospital discharge for the index hospitalisation.
E/e' after 30 days [30 days]
Averaged medial/lateral E/e' ratio on transthoracic echocardiography 30 days after randomisation.
Peak left atrial longitudinal strain after decongestion [30 days]
Peak left atrial longitudinal strain on transthoracic echocardiography upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
Peak left atrial longitudinal strain at discharge [30 days]
Peak left atrial longitudinal strain on transthoracic echocardiography upon the moment of hospital discharge for the index hospitalisation.
Peak left atrial longitudinal strain after 30 days [30 days]
Peak left atrial longitudinal strain on transthoracic echocardiography 30 days after randomisation.
Tricuspid plane annular excursion over right ventricular systolic pressure (TAPSE/RVSP) ratio after decongestion [30 days]
TAPSE/RVSP ratio on transthoracic echocardiography upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
TAPSE/RVSP ratio at discharge [30 days]
TAPSE/RVSP ratio on transthoracic echocardiography upon the moment of hospital discharge for the index hospitalisation.
TAPSE/RVSP ratio after 30 days [30 days]
TAPSE/RVSP ratio on transthoracic echocardiography 30 days after randomisation.
B-lines after decongestion [30 days]
Number of B-lines on lung ultrasound, scanning 8 thoracic sites upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.
B-lines at discharge [30 days]
Number of B-lines on lung ultrasound, scanning 8 thoracic sites upon the moment of hospital discharge for the index hospitalisation.
B-lines after 30 days [30 days]
Number of B-lines on lung ultrasound, scanning 8 thoracic sites 30 days after randomisation.
VExUS score after decongestion [30 days]
VExUS score for venous Doppler measurements (0: inferior vena cava diameter <2 cm; 1: inferior vena cava diameter ≥2 cm and normal Doppler measurements; 2: inferior vena cava diameter ≥2 cm and at least 1 severely abnormal* Doppler pattern in the Vv. hepaticae, V. portae or Vv. intrarenalis; 3: inferior vena cava diameter ≥2 cm and at least 2 severely abnormal* Doppler patterns in the Vv. hepaticae, V. portae or Vv. intrarenalis) upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol. *The following Doppler patterns are considered severely abnormal: Vv. Hepaticae: systolic flow reversal V. Portae: >50% pulsatility Vv. Intrarenalis: monophasic diastolic flow
VExUS score at discharge [30 days]
VExUS score for venous Doppler measurements (0: inferior vena cava diameter <2 cm; 1: inferior vena cava diameter ≥2 cm and normal Doppler measurements; 2: inferior vena cava diameter ≥2 cm and at least 1 severely abnormal Doppler pattern in the Vv. hepaticae, V. portae or Vv. intrarenalis; 3: inferior vena cava diameter ≥2 cm and at least 2 severely abnormal Doppler patterns in the Vv. hepaticae, V. portae or Vv. intrarenalis) upon the moment of hospital discharge for the index hospitalisation. *The following Doppler patterns are considered severely abnormal: Vv. Hepaticae: systolic flow reversal V. Portae: >50% pulsatility Vv. Intrarenalis: monophasic diastolic flow
VExUS score after 30 days [30 days]
VExUS score for venous Doppler measurements (0: inferior vena cava diameter <2 cm; 1: inferior vena cava diameter ≥2 cm and normal Doppler measurements; 2: inferior vena cava diameter ≥2 cm and at least 1 severely abnormal Doppler pattern in the Vv. hepaticae, V. portae or Vv. intrarenalis; 3: inferior vena cava diameter ≥2 cm and at least 2 severely abnormal Doppler patterns in the Vv. hepaticae, V. portae or Vv. intrarenalis) 30 days after randomisation. *The following Doppler patterns are considered severely abnormal: Vv. Hepaticae: systolic flow reversal V. Portae: >50% pulsatility Vv. Intrarenalis: monophasic diastolic flow

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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:

bilateral oedema 2+, indicating clear pitting
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)
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