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

Acute Heart Failure Clinical Trial

— DECONGEST  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05411991
• Other study ID #: EC-2021-236
• Secondary ID: 2021-005426-18
• Status: Recruiting
• Phase: Phase 4
• Start date: June 12, 2022
• Est. completion date: April 30, 2024

Study information

• Verified date: September 2023
• Source: Vrije Universiteit Brussel
• Contact: Simon Vanhentenrijk, M.D.; Pharm.D.
• Phone: +32 2 474 9060
• Email: simon.vanhentenrijk[@]uzbrussel.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 104
• Est. completion date: April 30, 2024
• Est. primary completion date: March 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Heart Failure
• Diuretics Drug Reactions
• Drug-Related Side Effects and Adverse Reactions
• Heart Failure

Intervention

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.
• 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.
• 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.
• 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:
• 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:
• 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.
• 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
• 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.

Locations

Country	Name	City	State
Belgium	Jessa Hospital	Hasselt	Limburg
Belgium	University Hospital Brussels	Jette	Brussels

Sponsors (3)

Lead Sponsor	Collaborator
Vrije Universiteit Brussel	Jessa Hospital, Roche Diagnostics

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Overall well-being at discharge	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).	30 days
Other	Overall well-being after 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).	30 days
Other	Edema score after decongestion	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.	30 days
Other	Edema score at discharge	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.	30 days
Other	Edema score after 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.	30 days
Other	Weight change with decongestion	Weight change [kg] from baseline to the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.	30 days
Other	Natriuretic peptide change after decongestion	Relative NT-proBNP change from baseline to the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol [%].	30 days
Other	Cancer antigen 125 (CA125) change after decongestion	Relative cancer antigen 125 (CA125) change from baseline to the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol [%].	30 days
Other	Change in eGFR after 30 days (serum creatinine-based)	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.	30 days
Other	Change in eGFR after 30 days (plasma cystatin C-based)	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.	30 days
Other	Change in eGFR after 30 days (serum creatinine/plasma cystatin C-based)	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.	30 days
Other	Hyperkalemia	Hyperkalemia with serum potassium levels >5.5 mmol/L at any time during the study period.	30 days
Other	Severe hyperkalemia	Severe hyperkalemia with serum potassium levels >6.5 mmol/L at any time during the study period.	30 days
Other	Hypokalemia	Hypokalemia with serum potassium levels <3.5 mmol/L at any time during the study period.	30 days
Other	Hyponatremia	Hyponatremia with serum sodium levels <135 mmol/L at any time during the study period.	30 days
Other	Severe hyponatremia	Severe hyponatremia with serum sodium levels <125 mmol/L at any time during the study period.	30 days
Other	Hypernatremia	Hypernatremia with serum sodium levels >145 mmol/L at any time during the study period.	30 days
Other	Severe metabolic acidosis	Severe metabolic acidosis with serum bicarbonate levels <20 mmol/L at any time during the study period.	30 days
Other	E/e' after decongestion	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.	30 days
Other	E/e' at discharge	Averaged medial/lateral E/e' ratio on transthoracic echocardiography upon the moment of hospital discharge for the index hospitalisation.	30 days
Other	E/e' after 30 days	Averaged medial/lateral E/e' ratio on transthoracic echocardiography 30 days after randomisation.	30 days
Other	Peak left atrial longitudinal strain after decongestion	Peak left atrial longitudinal strain on transthoracic echocardiography upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.	30 days
Other	Peak left atrial longitudinal strain at discharge	Peak left atrial longitudinal strain on transthoracic echocardiography upon the moment of hospital discharge for the index hospitalisation.	30 days
Other	Peak left atrial longitudinal strain after 30 days	Peak left atrial longitudinal strain on transthoracic echocardiography 30 days after randomisation.	30 days
Other	Tricuspid plane annular excursion over right ventricular systolic pressure (TAPSE/RVSP) ratio after decongestion	TAPSE/RVSP ratio on transthoracic echocardiography upon the moment of transition from intravenous diuretics to oral diuretic therapy according to the protocol.	30 days
Other	TAPSE/RVSP ratio at discharge	TAPSE/RVSP ratio on transthoracic echocardiography upon the moment of hospital discharge for the index hospitalisation.	30 days
Other	TAPSE/RVSP ratio after 30 days	TAPSE/RVSP ratio on transthoracic echocardiography 30 days after randomisation.	30 days
Other	B-lines after decongestion	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.	30 days
Other	B-lines at discharge	Number of B-lines on lung ultrasound, scanning 8 thoracic sites upon the moment of hospital discharge for the index hospitalisation.	30 days
Other	B-lines after 30 days	Number of B-lines on lung ultrasound, scanning 8 thoracic sites 30 days after randomisation.	30 days
Other	VExUS score after decongestion	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	30 days
Other	VExUS score at discharge	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	30 days
Other	VExUS score after 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	30 days
Primary	Mortality, days in hospital & decongestion	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.	30 days
Secondary	Renal safety endpoint	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.	30 days
Secondary	Hemodynamic safety endpoint	Systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg or need for vasopressors and/or inotropes during the index hospital admission.	30 days
Secondary	Natriuretic peptide change after 30 days	Relative NT-proBNP change from baseline to 30 days after randomisation [%].	30 days
Secondary	Cancer antigen 125 (CA125) change after 30 days	Relative cancer antigen 125 (CA125) change from baseline to 30 days after randomisation [%].	30 days
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.	30 days
Secondary	Length of intravenous diuretic therapy	Number of consecutive days from randomization during the index admission on which intravenous diuretic therapy was administered.	30 days
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).	30 days
Secondary	Length of the index hospital admission	Length of the index hospital admission [days].	30 days
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	30 days
Secondary	Number of participants who are death or have a non-elective hospital admission	Number of participants who are death or have a non-elective hospital admission	30 days