Clinical trial NCT05411991
Conditions: Acute Heart Failure Diuretics Drug Reactions
Keywords: Acute Heart Failure Natriuresis Diuretics Edema
Sponsor: Vrije Universiteit Brussel
Start date: 2022-06-12; Completion date: 2024-07-01
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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

Arms: arm 1: 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 arm 2: 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.
Interventions: intervention 1: UNa measurement after intravenous loop diuretic bolus intervention 2: Intravenous acetazolamide 500 mg OD intervention 3: Intravenous bumetanide TID intervention 4: Oral chlorthalidone OD intervention 5: Intravenous canrenoate 200 mg OD intervention 6: Maintenance infusion intervention 7: Oral potassium supplements intervention 8: Intravenous hypertonic saline intervention 9: Switch to oral diuretic therapy intervention 10: Usual AHF care
Intervention descriptions: intervention 1: Sodium concentration is measured on a urine spot sample, collected 30-120 min after administration of every protocol-specified intravenous bumetanide dose. intervention 2: 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. intervention 3: 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. intervention 4: 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. intervention 5: 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. intervention 6: 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%). intervention 7: 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 intervention 8: 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. intervention 9: 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 intervention 10: 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.

Protocol documents:
SAP_002.pdf: 
i 
 
Appendix B: Statistical Analysis Plan 
 
Diuretic Treatment in Acute Heart Failure 
with Volume Overload Guided by Serial 
Spot Urine Sodium Assessment 
(DECONGEST) Study 
 
Version 1.0 
June 23, 2024 
 
 
 
 
 
 
 
EudraCT: 2021-005426-18 
ClinicalTrials.gov ID: NCT05411991 
Sponsor Number: EC 2021/361 
Protocol version: 1.3 (April 15, 2024) 


ii 
 
Table of Contents 
 
1. 
Study Objectives and Endpoints ........................................................................ iii 
 
1.1. Primary objective and outcome measure ................................................... iii 
 
1.2. Secondary objectives and outcome measures .......................................... iii 
 
1.3. Exploratory outcome measures ................................................................... v 
 
2. 
Randomization & Allocation Concealment ....................................................... vii 
 
3. 
Sample size calculation ..................................................................................... vii 
 
4. 
Statistical analysis ............................................................................................ viii 
 
4.1. General principles ...................................................................................... viii 
 
4.2. Interim analysis ............................................................................................ ix 
 
4.3. Multiplicity adjustment ................................................................................. ix 
 
4.4. Independent statistician ............................................................................... ix 
 
4.5. Datasets to be analysed ................................................................................ x 
 
4.6. Subject disposition........................................................................................ x 
 
4.7. Protocol violations and deviations ............................................................... x 
 
4.8. Concomitant therapies .................................................................................. x 
 
4.9. Baseline characteristics ............................................................................... xi 
 
4.10. Analysis of the primary outcome .............................................................. xi 
 
4.11. Subgroup analysis..................................................................................... xii 
 
4.12. Handling of missing data ......................................................................... xiii 
 
4.13. Analysis of the secondary outcomes ...................................................... xiii 
 
 


iii 
 
1. Study Objectives and Endpoints 
1.1. 
Primary objective and outcome measure 
Primary objective 
Primary endpoint 
To determine whether an intensive 
diuretic regimen focused on early 
combination therapy, based on serial 
post-diuretic 
spot 
urine 
sodium 
concentration (UNa+) assessments, 
is safe and leads to faster and more 
effective decongestion 
Hierarchical composite endpoint of: 
1. survival at 30 days 
2. days alive out of hospital or care facility up 
to 30 days 
3. relative decrease in N-terminal of 
pro-hormone B-type natriuretic peptide 
(NTproBNP) levels from baseline to day 30 
 
Definition of the primary endpoint: 
Vital status is assessed at 30 days after randomization. Deceased subjects get the 
lowest rank for the analysis. Surviving subjects are subsequently compared for the 
total number of days from randomization to day 30 that they are alive without 
hospital admission or admission to a care facility to declare a winner. An admission 
day is defined by an overnight stay within the hospital (including the emergency 
department) or care facility. In surviving subjects, tied for the number of days 
without hospital or care facility admission, the relative decrease in NTproBNP from 
baseline levels to day 30 (rounded to the nearest percentage) is assessed and 
compared to declare a winner (the one with the greatest decrease, if the difference 
between them is at least 5%). 
 
1.2. 
Secondary objectives and outcome measures 
Secondary objective 
Secondary endpoints 
To further explore whether the 
studied intervention leads to more 
effective decongestion 
Relative NTproBNP decrease from baseline to 
day 30 [%] 
Relative carboxyhydrate antigen 125 (CA-125) 
decrease from baseline to day 30 [%] 
Successful decongestion, defined as no more 
than trace oedema, absence of jugular venous 
distension and no rales upon the moment of 
transition from intravenous diuretics to oral 
maintenance therapy [%] 
Length of intravenous diuretic therapy [days] 


iv 
 
To further explore whether the 
studied intervention leads to faster 
decongestion 
Length of the index hospital admission [days] 
To assess whether the studied 
intervention is associated with more 
symptomatic relief of congestion 
5-point Likert scale for overall well-being 
assessed upon the transition from intravenous 
diuretics to oral maintenance therapy 
compared to baseline (much improved/slightly 
improved/neutral/slightly worse/much worse) 
To assess whether the studied 
intervention is safe without significant 
renal adverse events 
Doubling of the serum creatinine or plasma 
cystatin C 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 at any time 
during the index hospital admission 
To assess whether the studied 
intervention is safe without significant 
hemodynamic adverse events 
Systolic blood pressure <90 mmHg or mean 
arterial pressure <65 mmHg or use of 
vasopressors and/or inotropes at any time 
during the index hospital admission 
To assess the impact of the studied 
intervention on clinical outcomes 
Death, non-elective readmission or 
non-elective medical contact after discharge 
within the 30-day follow-up period 
Death or non-elective readmission after 
discharge within the 30-day follow-up period 
 
Definitions of the secondary endpoints 
 
NTproBNP is measured with the Elecsys proBNP II test on the cobas® e801 
immunoassay analyser (Roche Diagnostics). 
 
CA-125 is measured with the Elecsys CA 125 II test on the cobas® e801 
immunoassay analyser (Roche Diagnostics). 
 
Length of intravenous diuretic therapy is defined as the date of transition 
from intravenous diuretics to oral maintenance therapy minus the date of 
randomization +1. 
 
Length of the index hospital admission is defined as the date of discharge 
from the hospital minus the date of randomization +1. 
 
Cystatin C is measured with the Tina-quant Cystatin C Gen.2 test on the 
cobas® c 501 (Roche Diagnostics). 
 
Non-elective readmission is defined as any unforeseen hospital admission 
with at least 1 overnight stay (including the emergency department. Hospital 
admissions for planned procedures are not counted in this respect. 


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 
Non-elective medical contacts are any unforeseen contacts of a patient with 
a medical caregiver at the patient’s initiative for any health problem. 
 
1.3. 
Exploratory outcome measures 
Outcome Measure 
Measure Description 
Overall well-being at 
discharge 
5-point Likert scale for overall well-being upon the moment of 
hospital discharge from the index hospitalisation compared to 
baseline (5: much improved/4: slightly improved/3: neutral/2: 
slightly worse/1: much worse). 
Overall well-being 
after 30 days 
5-point Likert scale for overall well-being at 30 days after 
randomisation compared to baseline (5: much improved/4: 
slightly improved/3: neutral/2: slightly worse/1: much worse). 
Edema score after 
decongestion 
Oedema score (1+: trace; 2+: ankle; 3+: knee; 4+: above 
knee) upon the moment of transition from intravenous 
diuretics to oral diuretic therapy. 
Edema score at 
discharge 
Oedema score (1+: trace; 2+: ankle; 3+: knee; 4+: above 
knee) upon the moment of hospital discharge from the index 
hospitalisation. 
Edema score after 
30 days 
Oedema score (1+: trace; 2+: ankle; 3+: knee; 4+: above 
knee) at the 30-day follow-up visit. 
Weight change with 
decongestion 
Weight change [kg] from baseline to the moment of transition 
from intravenous diuretics to oral diuretic therapy. 
NTproBNP change 
after decongestion 
Relative NT-proBNP change [%] from baseline to the moment 
of transition from intravenous diuretics to oral diuretic therapy.
CA-125 change after 
decongestion 
Relative CA-125 [%] change from baseline to the moment of 
transition from intravenous diuretics to oral diuretic therapy. 
Change in estimated 
glomerular filtration 
rate (eGFR) after 30 
days (serum 
creatinine-based) 
Change in eGFR from baseline to the 30-day follow-up visit 
[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) 
Change in eGFR from baseline to the 30-day follow-up visit 
[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) 
Change in eGFR from baseline to the 30-day follow-up visit 
[mL/min/1.73m²] with eGFR calculated according to the 
Chronic Kidney Disease Epidemiology Collaboration formula 
with serum creatinine and plasma cystatin C. 
Hyperkalemia 
Hyperkalemia with serum potassium levels >5.5 mmol/L at 
any time during the study period. 
Severe hyperkalemia
Severe hyperkalemia with serum potassium levels >6.5 
mmol/L at any time during the study period. 
Hypokalemia 
Hypokalemia with serum potassium levels <3.5 mmol/L at 
any time during the study period. 
Hyponatremia 
Hyponatremia with serum sodium levels <135 mmol/L at any 
time during the study period. 
Severe 
hyponatremia 
Severe hyponatremia with serum sodium levels <125 mmol/L 
at any time during the study period. 


vi 
 
Hypernatremia 
Hypernatremia with serum sodium levels >145 mmol/L at any 
time during the study period. 
Severe metabolic 
acidosis 
Severe metabolic acidosis with serum bicarbonate levels <20 
mmol/L at any time during the study period. 
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. 
E/e' at discharge 
Averaged medial/lateral E/e' ratio on transthoracic 
echocardiography upon the moment of hospital discharge 
from the index hospitalisation. 
E/e' after 30 days 
Averaged medial/lateral E/e' ratio on transthoracic 
echocardiography at the 30-day follow-up visit. 
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. 
Peak left atrial 
longitudinal strain at 
discharge 
Peak left atrial longitudinal strain on transthoracic 
echocardiography upon the moment of hospital discharge 
from the index hospitalisation. 
Peak left atrial 
longitudinal strain 
after 30 days 
Peak left atrial longitudinal strain on transthoracic 
echocardiography at the 30-day follow-up visit. 
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. 
TAPSE/RVSP ratio at 
discharge 
TAPSE/RVSP ratio on transthoracic echocardiography upon 
the moment of hospital discharge from the index 
hospitalisation. 
TAPSE/RVSP ratio 
after 30 days 
TAPSE/RVSP ratio on transthoracic echocardiography at the 
30-day follow-up visit. 
B-lines after 
decongestion 
Number of B-lines on lung ultrasound (8 thoracic sites) upon 
the moment of transition from intravenous diuretics to oral 
diuretic therapy. 
B-lines at discharge 
Number of B-lines on lung ultrasound (8 thoracic sites) upon 
the moment of hospital discharge from the index 
hospitalisation. 
B-lines after 30 days 
Number of B-lines on lung ultrasound (8 thoracic sites) at the 
30-day follow-up visit. 
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. 
VExUS score at 
discharge 
VExUS score for venous Doppler measurements upon the 
moment of hospital discharge from the index hospitalisation. 
VExUS score after 
30 days 
VExUS score for venous Doppler measurements at the 
30-day follow-up visit. 


vii 
 
*The following Doppler patterns are considered severely abnormal: Vv. Hepaticae: systolic 
flow reversal; V. Portae: >50% pulsatility; Vv. Intrarenalis: monophasic diastolic flow 
 
2. Randomization & Allocation Concealment 
The DECONGEST study is a randomized clinical trial with 2 treatment arms. Patients are 
randomly assigned in a 1:1 ratio to standard of care or the care bundle that comprises the 
DECONGEST study intervention. Randomization is performed through an online, 
protected website, using the Castor Electronic Data Capture system (Castor, Amsterdam, 
the Netherlands) after confirming eligibility. Block randomization is performed, stratified by 
study centre and left ventricular ejection fraction (<50% versus ≥50%), with variable blocks 
of 2 or 4 subjects for allocation concealment. 
 
3. Sample size calculation 
According to a sample size simulation, 96 patients need to be enrolled and analysed in the 
DECONGEST study, given a 2-sided significance level (α) of 0.05, to yield a statistical 
power (1-β) equal to 90%. To account for a potential drop-out and the impact of correlation 
between outcomes, the targeted study sample size was set at 104 subjects. 
 
Based on the results of the Acetazolamide in Decompensated Heart Failure with Volume 
Overload (ADVOR) trial, which recruited a similar population in a comparable setting, the 
anticipated 30-day mortality for DECONGEST was estimated at 5%, with no differences 
among the treatment arms. 
 
To anticipate the true effect size, different components of the DECONGEST intervention 
were considered. First, the upfront use of acetazolamide in the ADVOR trial was associated 
with a 1-day reduction in the length of the index hospitalization. Second, a similar effect 
was seen with systematic urine sodium concentration assessment in the Pragmatic Urinary 


viii 
 
Sodium-based Treatment Algorithm in Acute Heart Failure (PUSH-AHF) trial. As the use 
of acetazolamide was unneglectable in the PUSH-AHF trial, we anticipated an additive 
effect of 2 days (IQR: 4 days) decrease in length of the index hospitalization, combining 
both treatment. Several other parts of the DECONGEST intervention bundle justify a further 
additive effect: (1) the low-threshold use of chlorthalidone and canreonate would be 
expected to have an independent effect to reduce index hospitalization length; (2) the loop 
diuretic dosing according to eGFR could reduce the number of patients with loop diuretic 
resistance due to underdosing and might speed up the decongestion process. Additionally, 
the more intensive diuretic schedule would result in lower NTproBNP levels in the 
intervention group, reducing the number of ties compared to ADVOR and turning them into 
wins for the intervention group. Based on the ADVOR trial a difference of 25% (with 
standard deviation of 22%) is anticipated in the relative decrease in NTproBNP. A 
difference of at least 5% between two subjects is set as a threshold to declare a winner. If 
the difference in NTproBNP decrease is less than 5% between two subjects, they’re 
considered a tie. 
 
4. Statistical analysis 
4.1. 
General principles 
This statistical analysis plan dated May 15, 2024, is based on the statistical information 
documented in the finally approved study protocol version 1.3 dated April 15, 2024. The 
scope of this statistical analysis plan is to outline the statistical tools used for the primary 
and secondary objectives of the DECONGEST study following the procedures 
documented in the study protocol version 1.3 in both participating centres. Prior to the 
statistical analysis, the collected study data will be cleaned by the data manager of the 
University Hospital Brussels (Dr. Bram Roosens). All statistical hypotheses are 2-sided 
and a 5% significance level will be used. If the primary endpoint is statistically significant, 
secondary endpoints are subsequently tested in a predefined hierarchical order to 


ix 
 
preserve alfa spending without further correction for multiple testing. If the primary 
endpoint or any of the secondary study endpoints is non-significant, all following endpoints 
are considered explorative and no formal statistical testing will be reported in the main 
paper for these endpoints. Trial results will be reported according to the CONSORT 
statement on reporting randomized controlled trials. For the analysis of the primary 
outcome and each non-exploratory secondary outcome the following information will be 
presented: 
 
the number of patients included in each analysis, by treatment arm  
 
a summary statistic of the outcome by treatment arm 
 
the estimated treatment effect 
 
a 95% confidence interval for the estimated treatment effect  
 
A two-sided p-value for all analyses, a significance level of 5% will be used. 
All statistical analysis will be done with SAS (SAS institute, Cary, NC, United States) and 
R. 
 
4.2. 
Interim analysis 
No interim analysis is planned regarding the DECONGEST study. 
 
4.3. 
Multiplicity adjustment 
There will be no correction for multiplicity of testing as there is only one primary endpoint. 
Secondary endpoint are tested in a hierarchical fashion to avoid type I error inflation. 
 
4.4. 
Independent statistician 
Once the database is cleaned, the dataset will be locked and transferred to an 
independent academic statistician (Johan Verbeeck –Hasselt University) for analysis 
according to this statistical analysis plan. 
 
 


x 
 
4.5. 
Datasets to be analysed 
For all endpoints, the statistical analysis will be based on a modified intention-to-treat 
analysis set, including all randomized patients that received at least one dose of diuretics 
according to the study protocol. Patients will be analysed according to the treatment group 
they were allocated to according to the electronic randomization system (irrespective of 
the actual treatment received). 
 
4.6. 
Subject disposition 
After closing of the database, a CONSORT diagram will be produced for transparent status 
of the subject reporting. 
 
4.7. 
Protocol violations and deviations 
The important protocol deviations listed below will be summarised by randomized 
treatment group: 
 
Patients who were randomized but did not meet inclusion and exclusion criteria 
 
Patients in the standard of care arm in whom UNa+ assessment was performed 
and patients with missing UNa+ assessments in the intervention arm 
 
Patients in the intervention arm who received the wrong diuretic treatment 
according to the protocol at any time during the study 
As the primary analysis is a modified intention-to-treat analysis, protocol deviation will not 
imply exclusion from the primary analysis. 
 
4.8. 
Concomitant therapies 
The frequency of baseline medications will be shown for the modified intention-to-treat 
analysis set per treatment group. Counts and percentages will be presented, grouping the 
baseline medication per drug classes. 
 
 


xi 
 
4.9. 
Baseline characteristics 
To describe the study population, characteristics of all the patients in the modified 
intention-to-treat analysis set per treatment group will be presented. Numbers (%), 
means ± standard deviation (SD) and medians (interquartile range) will be given for each 
treatment group, as appropriate. 
 
4.10. Analysis of the primary outcome 
The primary statistical analysis in the DECONGEST study will be a modified 
intention-to-treat (see section 4.5). The generalized pairwise comparison method is used 
to calculate a net treatment benefit for the hierarchical composite primary endpoint (see 
section 1.1). Every patient from the standard-of-care group will be pair-wise compared 
with each patient from the DECONGEST intervention 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 will win from a subject who 
died during the same timeframe. If both subjects did not survive until the 30-day 
follow-up, there is a tie. 
 
2. In a pair of subjects, both surviving up till the 30-day follow-up moment, the number 
of days in-hospital or in a care facility are counted (as in section 1.1.). The subject 
with the highest number of days alive and out of hospital or care facility during the 
30-day follow-up window will be declared the winner. 
 
3. In a pair of subjects, both surviving up till the 30-day follow-up moment and with 
the same number of days alive and out of hospital or care facility, the subject with 
the greatest relative reduction in NTproBNP from baseline, rounded to the closest 
percentage will be declared the winner, if the difference between 2 subjects is at 
least 5%. In case of relative NTproBNP reduction smaller than 5%, there is a tie. 


xii 
 
To calculate the net treatment benefit in the DECONGEST study, essentially, each 
individual in the intervention group is compared against each individual in the control group 
and the resulting pair is assigned a score of +1, -1, or 0, depending on whether the pair is 
a win, a loss, or a tie, respectively. The net treatment benefit is subsequently calculated 
as the average of scores for all possible pairs and reported with a 95% confidence interval 
and the associated p-value. To aid the interpretation of the results, the proportions of wins 
and losses for each outcome are reported to understand the contribution of each 
component to the overall treatment effect. 
 
4.11. Subgroup analysis 
For exploratory purposes, subgroup analyses for the primary endpoint will be conducted, 
to assess whether the treatment effect differs according subgroups. The following 
subgroups will be created: 
 
Effect according to study center 
 
Left ventricular ejection fraction<50% versus ≥50% 
 
Baseline estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² versus 
≥45 mL/min/1.73m² 
 
Loop diuretic home maintenance dose ≤1 mg bumetanide, ≤10 mg torsemide, or 
≤40 mg furosemide versus >1 mg bumetanide, >10 mg torsemide, or >40 mg 
furosemide 
 
Net treatment benefits with 95% confidence intervals will be presented for each subgroup 
and tested against the null hypothesis of no effect in each subgroup with a significance 
level of 5%. A forest plot will be used to summarize the results visually. 
 
 


xiii 
 
4.12. Handling of missing data 
The proposed statistical model assumes the missing data mechanism to be missing at 
random. If the level of missing data for the primary outcome in the modified 
intention-to-treat population exceeds 5%, a sensitivity analysis to assess the robustness 
of the analysis of the primary outcome by means of multiple imputation technique will be 
performed for the primary endpoint. 
 
4.13. Analysis of the secondary outcomes 
To avoid inflation of the type I error, secondary outcomes will be tested in a hierarchical 
order. If the primary endpoint or any of the secondary endpoints is not statistically 
significant, effect sizes with 95% confidence intervals will be reported for the subsequent 
secondary outcomes, yet no formal statistical testing will be performed and no p-values 
will be reported. All statistical models implemented for the analysis of the secondary 
outcomes are mixed-effects models, including a fixed treatment effect and a random 
centre effect. For outcomes measured at multiple time-points, random patient effects 
(intercept and slope) are also included. 
 
Secondary outcome 1: Relative NTproBNP decrease from baseline to 30 days after 
randomization [%] 
For descriptive purposes, the geometric mean difference is reported with a 95% 
confidence interval with a fixed treatment effect, a random centre effect and random 
patient effects for intercept and slope. 
 
Secondary outcome 2: Relative CA-125 decrease from baseline to 30 days after 
randomization [%] 
For descriptive purposes, the geometric mean difference is reported with a 95% 
confidence interval with a fixed treatment effect, a random centre effect and random 
patient effects for intercept and slope. 


xiv 
 
Secondary outcome 3: Length of intravenous diuretic therapy [days] 
For each treatment arm mean, median and interquartile range for the length of intravenous 
diuretic therapy will be presented for patients who survived to hospital discharge. The 
effect of treatment on length of intravenous diuretic therapy, for patients who survived to 
hospital discharge, is compared among treatment arms with a linear mixed model (fixed 
treatment effect and random centre effect). A log transformation will be employed as the 
model assumptions (i.e., normality) will likely be violated. Model assumptions will be 
investigated by means of diagnostic plots. The results of this model will be presented as 
(geometric) mean length of intravenous diuretic therapy (and 95% confidence interval) per 
treatment group, the rate ratio, 95% confidence interval and associated p-value. 
 
Secondary outcome 4: Length of the index hospital admission [days] 
For each treatment arm mean, median and interquartile range for the length of the index 
hospital admission will be presented for patients who survived to hospital discharge. The 
effect of treatment on length of the index hospital admission, for patients who survived to 
hospital discharge, is compared among treatment arms with a linear mixed model (fixed 
treatment effect and random centre effect). A log transformation will be employed as the 
model assumptions (normality) will likely be violated. Model assumptions will be 
investigated by means of diagnostic plots. The results of this model will be presented as 
(geometric) mean length of index hospitalization (and 95% confidence interval) per 
treatment group, the rate ratio, 95% confidence interval and associated p-value. 
 
Secondary outcome 5: Successful decongestion defined as no more than trace oedema, 
absence of jugular venous distension and no rales upon the moment of transition from 
intravenous diuretics to oral maintenance therapy 
For descriptive purposes, the number of patients in each treatment arm (percentages) who 
have successful decongestion are reported. To investigate the treatment effect on the 
occurrence of the combined endpoint, a generalized linear mixed model for a binary 


xv 
 
outcome will be employed. The model will incorporate a fixed treatment effect and random 
centre effect. The results of this model will be presented as an odds ratio with 95% 
confidence interval and the associated p value. 
 
Secondary outcome 6: 5-point Likert scale for overall well-being assessed upon the 
transition from intravenous diuretics to oral maintenance therapy compared to the moment 
of randomization (much improved/slightly improved/neutral/slightly worse/much worse) 
For descriptive purposes, the number of patients in each treatment arm (percentages) per 
category of overall well-being are reported. To investigate the treatment effect on the 
overall well-being, a generalized linear mixed model for an ordinal outcome will be 
employed. The model will incorporate a fixed treatment effect and random centre effect. 
The results of this model will be presented as odds ratios with 95% confidence interval 
and the associated p value. 
 
Secondary outcome 7: Doubling of the serum creatinine or plasma cystatin C 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 (renal 
safety endpoint) 
For descriptive purposes, the number of patients in each treatment arm (percentages) who 
meet the criteria for the renal safety endpoint are reported. To investigate the treatment 
effect on the occurrence of the combined endpoint, a generalized linear mixed model for 
a binary outcome will be employed. The model will incorporate a fixed treatment effect and 
random centre effect. The results of this model will be presented as an odds ratio with 
95% confidence interval and the associated p value. 
 
 


xvi 
 
Secondary outcome 8: Systolic blood pressure <90 mmHg or mean arterial pressure <65 
mmHg or need for vasopressors and/or inotropes during the index hospital admission 
(hemodynamic safety endpoint) 
For descriptive purposes, the number of patients in each treatment arm (percentages) who 
meet the criteria for the hemodynamic safety endpoint are reported. To investigate the 
treatment effect on the occurrence of the combined endpoint, a generalized linear mixed 
model for a binary outcome will be employed. The model will incorporate a fixed treatment 
effect and random centre effect. The results of this model will be presented as an odds 
ratio with 95% confidence interval and the associated p value. 
 
Secondary outcome 9: Death, non-elective rehospitalization or non-elective medical 
contact 
For descriptive purposes, the number (%) of failure and success for the combined outcome 
of all-cause mortality, non-elective rehospitalizations, and non-elective medical contacts 
during the 30-day follow-up period will be given per treatment arm. To investigate the 
treatment effect on the occurrence of the combined endpoint, a generalized linear mixed 
model for a binary outcome will be employed. The model will incorporate a fixed treatment 
effect and random centre effect. The results of this model will be presented as an odds 
ratio, 95% confidence interval and the associated p value. If the treatment effect on this 
composite endpoint turns out to be statistically significant, the analysis will be performed 
for the composite endpoint of death and non-elective rehospitalization. 

Prot_003.pdf: 
 
 
 
 
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Study Protocol  
 
Study Title: 
Diuretic Treatment in Acute Heart Failure with Volume 
Overload Guided by Serial Spot Urine Sodium Assess-
ment 
Study Acronym: 
DECONGEST 
Phase of Development: 
IV 
Protocol Number: 
Study_Protocol_DECONGEST_v1.3 
Protocol Version and Date: 
Version 1.3, April 15, 2024 
EudraCT Registry Number:  
 
2021-005426-18 
ClinicTrials.gov Registry Number:  
NCT05411991 
Indication: 
 
 
 
 
Acute Heart Failure 
Investigational product: 
 
 
None 
Sponsor: 
 UZ Brussel 
Coordinating/Principal Investigator: 
 Prof. Dr. Frederik Verbrugge 
 
The information contained in this document is the property of the Sponsor/Coordinating Investiga-
tor and may not be reproduced, published or disclosed to others without written authorization of 
the Sponsor/Coordinating Investigator. 
PROTOCOL SIGNATURE PAGE 
Protocol Version and date:  
 
Version 1.3, April 15, 2024 
 
Protocol Title: 
Diuretic Treatment in Acute Heart Failure with Volume 
Overload Guided by Serial Spot Urine Sodium Assess-
ment 
 
Sponsor:  
 
 
 
UZ Brussel 
 
Principal Investigator:   
 
Prof. Dr. Frederik Verbrugge 
 
I agree: 
- 
to assume responsibility for the proper conduct of this study 
- 
to conduct the study in compliance with this protocol and any future amendments  
- 
not to implement any deviations from or changes to the protocol without prior review 
and written approval from the Ethics Committee, except where necessary to eliminate 
an immediate hazard to the subjects, or for administrative aspects of the study (where 
permitted by all applicable regulatory requirements) 
- 
that I am thoroughly familiar with the appropriate use of the investigational drug, as 
described in this protocol 
- 
to ensure that all persons assisting me with the study are adequately informed about 
the investigational drug and their study-related duties and functions as described in the 
protocol 
- 
that I am aware of and will comply with the current good clinical practice (GCP) guide-
lines and ethical principles outlined in the Declaration of Helsinki 
- 
to conduct the study in accordance with all applicable laws and regulations 
 
 
Printed name: Frederik Verbrugge 
 
Signature                                         Date: 22/04/2024 


 
 
 
 
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Study Protocol 
Diuretic Treatment in Acute Heart Failure with Volume Overload Guided 
by Serial Spot Urine Sodium Assessment (DECONGEST) study 
 
1. Primary investigator (PI) 
Dr. Frederik Verbrugge (Centrum voor Hart- en Vaatziekten, UZ Brussel) 
 
2. Study design 
 
Prospective 
 
Pragmatic 
 
Interventional 
 
Randomised 
 
Open label 
 
Multicentre (UZ Brussel & Jessa Hospital Hasselt) 
 
3. Purpose & rationale 
Signs and symptoms of volume overload are the most frequent reason for hospital admission 
in patients with heart failure.1 During such episodes of acute heart failure (AHF), diuretics are 
the mainstay treatment. Good diuretic efficiency with complete decongestion is associated 
with better outcomes.2 However, these targets remain challenging in clinical practice as diu-
retic resistance occurs frequently and a normal volume status cannot be readily assessed. 
This at least partly explains why clinical outcomes after an episode of AHF remain dismal, 
with recent European registry data demonstrating a 1-year rehospitalization rate of 44.4% 


 
 
 
 
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(25.9% for heart failure readmissions only) and all-cause mortality of 26.7%.3 Residual (sub-
)clinical congestion is likely an important mediator of this high risk.4 
Spot urine sodium assessment is a reliable indicator of diuretic response.5 Its use in AHF has 
been recommended by the new guidelines on heart failure of the European Society of Car-
diology, with the aim of detecting diuretic resistance early to allow appropriate treatment in-
tensification.6,7 A sodium concentration <50-70 mmol/L on a spot urine sample collected 
within the time window of diuretic activity (approximately 6 h after administration for intrave-
nous furosemide/bumetanide) indicates poor diuretic response. When confronted with poor 
diuretic response in the presence of persistent signs of volume overload, more intensive di-
uretic treatment (i.e., dose increase or combination therapy) and/or ultrafiltration are indi-
cated to ensure proper decongestion. 
In addition, observational data suggest that a high urine sodium concentration on spot urine 
sample after diuretic therapy indicates persistent congestion, even when clinical signs of vol-
ume overload are not obvious.5,8,9 Therefore, hypothetically, intensive diuretic therapy in AHF 
until complete disappearance of clinical signs of volume overload and a urine sodium con-
centration drop <80 mmol/L, with immediate step-up care in case of diuretic resistance (i.e., 
low urine sodium concentration with persistent signs of volume overload), may improve the 
quality of decongestion and potentially clinical outcomes. This study prospectively examines 
a systematic approach to diuretic therapy in AHF, based upon serial assessment of sodium 
concentration on spot urine samples after diuretic administration. 
 
 


 
 
 
 
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4. Objectives 
Primary objective: 
To investigate whether a diuretic regimen based on serial assessment of sodium concentration 
on spot urine samples after diuretic administration improves decongestion versus usual care in 
AHF, potentially leading to better clinical outcomes. 
 
Secondary objectives: 
 
To provide prospective longitudinal data on the incidence and determinants of diuretic re-
sistance in patients with AHF and low-threshold use of combinational diuretic treatment. 
 
To investigate the relationship between hemodynamic congestion (i.e., cardiac filling pres-
sures & diastolic function on transthoracic echocardiography) and urine sodium concentra-
tion under appropriately dosed diuretics according to a standardised regimen. 
 
To investigate the relationship between lung congestion (B-lines on lung ultrasound), as well 
as abdominal organ congestion (venous Doppler echography), and urine sodium concentra-
tion under appropriately dosed diuretics according to a standardised regimen. 
 
To compare diagnostic modalities for decongestion: urine sodium profiling, clinical examina-
tion, laboratory biomarkers, transthoracic echocardiography, lung ultrasound, and venous 
Doppler echocardiography. 
 
To investigate the relationship between right ventricular function, assessed by transthoracic 
echocardiography, and abdominal organ congestion, assessed by Doppler echography, as 
well as its evolution under decongestive treatment. 
 
To investigate the relationship between left atrial function, assessed by transthoracic echo-
cardiography, and urine sodium balance. 
 
 


 
 
 
 
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5. Study population 
Inclusion criteria: 
 
At least 18 y/o and able to provide informed consent 
 
Hospital admission (anticipated stay >24 h after randomisation) with diagnosis of 
AHF according to the treating physician 
 
At least one of the following three signs of volume overload: 
o bilateral oedema 2+, indicating clear pitting 
o 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) 
o 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 N-terminal of the pro-hormone of B-type natriuretic peptide (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 mineralo-
corticoid receptor antagonist (MRA) or sodium-glucose co-transporter 2 (SGLT2) in-
hibitor as part of the patient’s maintenance treatment for heart failure. Patients can 
still be included in the DECONGEST study after withholding these diuretics for 6 h, 
after which randomisation can be performed if they qualify all other criteria. 


 
 
 
 
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 
Severe kidney dysfunction, defined as an estimated glomerular filtration rate (eGFR) 
<15 mL/min/1.73m² calculated by the Chronic Kidney Disease Epidemiology Collab-
oration (CKD-EPI) formula10 at randomisation, 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 electrocar-
diographic changes suggestive of cardiac ischemia 
 
History of heart or kidney transplantation 
 
History of mechanical circulatory support 
 
Known obstructive hypertrophic cardiomyopathy, congenital heart disease, acute me-
chanical cause of AHF (e.g., papillary muscular rupture), acute myocarditis, or con-
strictive pericarditis according to the treating physician 
 
Pregnant or breastfeeding woman 
 
Concomitant participation in another interventional study 
 
6. Randomisation and allocation concealment 
Patients will be randomised through an online website using the Castor Electronic Data Cap-
ture system. Block randomisation will be performed, stratified for study centre and left ven-
tricular ejection fraction (<50% versus ≥50%) with variable blocks of 2 or 4 subjects for allo-
cation concealment. 
 
7. Control arm 
Usual care according to the treating physician. It is recommended to treating physicians to 
administer an intravenous loop diuretic dose at least twice a day (or through continuous in-
fusion), with the aim of achieving a urine output 3-5 L per day until the patient is considered 


 
 
 
 
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in an optimal volume status as is recommended by current guidelines.7 It is actively discour-
aged to switch from intravenous to oral diuretic therapy in the presence of persistent clinical 
signs of volume overload. Diuretic agents with their dose and administration method (bolus 
versus continuous infusion) are determined by the treating physician. It is recommended to 
keep disease-modifying treatments with angiotensin-converting enzyme inhibitors, angioten-
sin receptor blockers, angiotensin-neprilysin inhibitors, MRAs, and SGLT2 inhibitors un-
changed during the period of intravenous diuretic administration, although withdrawal or dose 
reduction in case of (relative) contraindications is allowed. Urine electrolyte assessment in 
the control arm is not allowed and qualifies as a major protocol violation as it is a key com-
ponent of the studied intervention. 
 
8. Intervention 
Diuretic administration after randomisation 
Immediately after randomisation, patients in the intervention arm receive an intravenous bo-
lus of bumetanide, with the dose depending on the eGFR: 2 mg for >45 mL/min/1.73m²; 3 mg 
for 45-30 mL/min/1.73m²; or 4 mg for <30 mL/min/1.73m². In addition, an intravenous bolus 
of 500 mg acetazolamide is administered unless hypernatremia (serum sodium concentra-
tion >145 mmol/L) or metabolic acidosis (serum bicarbonate <22 mmol/L) is present. Oral 
chlorthalidone 50 mg is added in case of hypernatremia (serum sodium concentration 
>145 mmol/L) or an eGFR <30 mL/min/1.73m². The patient is asked to void empty or, in case 
of a bladder catheter, any urine present at the time of initial diuretic administration is dis-
carded. A background maintenance infusion with 500 mL dextrose 5% and 3 g MgSO4 is 
started at an infusion rate of 20 mL/h and continued until switch to oral maintenance treat-
ment (see below). If serum potassium levels are <4 mmol/L at any time during administration 
of intravenous diuretics, 40 mmol KCl is added to this maintenance infusion. In case of sig-
nificant hyponatremia <130 mmol/L, the maintenance infusion is replaced by a daily bolus of 
3 g MgSO4. 


 
 
 
 
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Serial spot urine sodium assessment 
After every protocol-specified bolus administration of bumetanide, a spot urine sample is 
collected for assessment of sodium concentration and a subsequent treatment decision. The 
first urine within the period of 30 min to 3 h after bumetanide administration is used for anal-
ysis. 
 
Subsequent diuretic therapy guided by serial spot urine sodium assessment 
After the initial diuretic administration upon randomisation (Day 0), an intravenous bolus of 
bumetanide is provided twice daily on the next consecutive days. The dose for each bolus is 
as described above, based on the most recent eGFR value available. A minimal 6 h interval 
is respected between consecutive bumetanide administrations. Intravenous acetazolamide 
500 mg OD is provided together with the first bumetanide dose on any given day unless 
hypernatremia (serum sodium concentration >145 mmol/L) or metabolic acidosis (serum bi-
carbonate <22 mmol/L) is present. Oral chlorthalidone is continued at a dose of 50 mg OD 
in case that it was indicated upon randomisation (see above). 
If the spot urine sodium concentration following bumetanide administration is ≥80 mmol/L, 
the protocol continues with the next bumetanide bolus that is scheduled as described (com-
bined with acetazolamide and/or chlorthalidone as indicated). If the spot urine sodium con-
centration is <80 mmol/L, there are 2 possibilities: (1) the treating physician finds no clinical 
arguments for residual volume overload and there is no more than trace oedema, in which 
case the patient is switched from intravenous diuretics to oral maintenance therapy (see be-
low); or (2) there is residual volume overload and/or more than trace oedema, indicating 
diuretic resistance. In case of a missing urine sodium concentration because urine spot sam-
pling could not be performed, the previous bumetanide dose that has been administered is 
repeated. 
 


 
 
 
 
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Approach to diuretic resistance 
If the clinical exam and spot urine sodium assessment indicate diuretic resistance (i.e., so-
dium concentration <80 mmol/L with persistent volume overload), full nephron blockade is 
applied at the moment of the next scheduled bumetanide dose. The following combination 
therapy is administered: 
- 
Intravenous acetazolamide 500 mg as bolus, unless hypernatremia (serum sodium 
concentration >145 mmol/L) or metabolic acidosis (serum bicarbonate <22 mmol/L) 
- 
Intravenous bumetanide 4 mg as bolus 
- 
Oral chlorthalidone 100 mg 
- 
Intravenous potassium canrenoate 200 mg IV as bolus unless hyperkalaemia (serum 
potassium concentration >5 mmol/L). If the patient is already treated with an oral 
MRA as part of his/her maintenance therapy, this medication is paused until switch 
to oral maintenance treatment. 
The bumetanide dose is subsequently repeated after 6 h and 12 h (TID) in case of good 
diuretic response (i.e., spot urine sodium concentration ≥80 mmol/L). The entire combination 
is repeated after 24 h in case of good diuretic response. This schedule is continued until 
successful decongestion (spot urine sodium concentration <80 mmol/L and absence of vol-
ume overload with no more than trace oedema) or refractory volume overload with spot urine 
sodium concentration <80 mmol/L despite full nephron blockade. In the latter scenario, all 
diuretics are withdrawn and ultrafiltration with or without renal replacement therapy is started 
and continued according to the treating physician. 
 
Switch to oral maintenance therapy 
If urine sodium concentration is <80 mmol/L and the treating physician has no clinical argu-
ments for residual volume overload, with no more than trace oedema present, this is consid-
ered successful decongestion. Acetazolamide (and potassium canrenoate if it was indicated 


 
 
 
 
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according to the study protocol) are stopped. Chlorthalidone is continued at a dose of 50 mg 
OD only when it was previously added as part of full nephron blockade because of diuretic 
resistance. If chlorthalidone was started because of hypernatremia and/or low eGFR at ran-
domisation, it is withdrawn. Spironolactone 25 mg OD or an equivalent MRA is started (or 
continued) 
unless 
serum 
potassium 
levels 
are 
>5 mmol/L 
and/or 
eGFR 
is 
<20 mL/min/1.71m². Intravenous bumetanide is replaced by an oral loop diuretic with dose 
and administration frequency at the discretion of the treating physician. The maintenance 
dextrose 5% infusion is halted. 
 
Neurohumoral blocker treatment 
In the intervention group, it is obligatory to keep disease-modifying treatments with angioten-
sin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin-neprilysin inhib-
itors, MRAs, and SGLT2 inhibitors unchanged during the period of intravenous diuretic ad-
ministration, although withdrawal or dose reduction in case of (relative) contraindications is 
allowed. Dose up-titration or start of these treatments is allowed after transition from intrave-
nous to oral diuretic therapy and recommended in patients with reduced ejection fraction. 
 
 


 
 
 
 
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Intervention flowchart 
 
 
9. Safety precautions 
Anticipated adverse events, potentially related to the study intervention, include arterial hy-
potension, acute kidney injury (AKI) and electrolyte disorders. Arterial blood pressure is eval-
uated throughout the study protocol with continuous invasive measurements or frequent 
non-invasive assessment by cuff manometry. Serum creatinine, eGFR, and serum electrolyte 


 
 
 
 
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levels are followed on a daily base during the administration of intravenous diuretics accord-
ing to the study protocol and afterwards at the discretion of the treating physician. 
 
Arterial hypotension 
In case of significant arterial hypotension, defined as a systolic blood pressure <90 mmHg 
and/or mean arterial pressure <65 mmHg at any time during the period of intravenous diuretic 
therapy, all non-diuretic hypotensive medications are withdrawn and the next diuretic admin-
istration is postponed until blood pressure recovery. If use of vasopressors or inotropes is 
clinically indicated according to the treating physician as rescue therapy, the protocolised 
administration of diuretics is halted and further treatment is at the discretion of the treating 
physician. 
 
Acute kidney injury 
If the serum creatinine doubles (compared to its baseline value at randomisation) at any time 
during the period of intravenous diuretic therapy and has an absolute value >2 mg/dL, the 
protocolised administration of diuretics is halted and further treatment is at the discretion of 
the treating physician. 
 
Electrolyte disorders 
 
In case of clinically significant hyperkalaemia >5.5 mmol/L, any treatment with 
renin-angiotensin system blockers and/or MRAs is temporarily interrupted. If serum 
potassium levels rise further >6.5 mmol/L despite these precautions, the protocolised 
administration of diuretics is halted and further treatment is at the discretion of the 
treating physician. 
 
In case of hypokalaemia <3.5 mmol/L (despite administration of 40 mmol of daily KCl 
as specified above), oral supplementation is provided as necessary for correction, 
with target levels of serum potassium >4 mmol/L. 


 
 
 
 
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 
In case of hypotonic hyponatremia <135 mmol/L, chlorthalidone or potassium canren-
oate that is specified according to the study protocol is withheld and treatment with 
MRA is temporarily interrupted until restauration of a serum sodium level 
≥135 mmol/L. In patients with serum sodium levels <130 mmol/L, the hypotonic 
maintenance infusion will not be administered. In case of severe hyponatremia 
<125 mmol/L, a bolus of 150 mL hypertonic saline 3% is administered and repeated 
once daily if necessary, until sodium levels are ≥135 mmol/L. 
 
In case of hypernatremia >145 mmol/L, additional free water is administered as dex-
trose 5% to keep serum sodium levels ≤145 mmol/L and the patient will be allowed 
to have more liberal fluid intake if possible. 
 
In case of severe metabolic acidosis with serum bicarbonate levels <20 mmol/L, 
100 mL of intravenous NaHCO3 8.4% is administered. No further administration of 
acetazolamide is allowed during the entire study protocol in such cases. 
 
10. Study endpoints 
Primary study endpoint: 
The primary study endpoint is the win ratio for a hierarchically composed endpoint. The indi-
vidual components of this endpoint in order of importance are: 
1) Death within 30 days after discharge 
2) Number of days in hospital from the first 30 days after randomisation 
3) Relative NTproBNP decrease from baseline to 30 days after randomisation 
 
Secondary study endpoints: 
 
Relative NTproBNP decrease from baseline to 30 days after randomisation [%] 
 
Relative cancer antigen 125 (CA 125) from baseline to 30 days after randomisation 
[%] 
 
Length of intravenous diuretic therapy [days] 


 
 
 
 
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 
Successful decongestion defined as no more than trace oedema, absence of jugular 
venous distension and no rales upon the moment of transition from intravenous diu-
retics to oral maintenance therapy 
 
Five-point Likert scale for overall well-being assessed upon the transition from intra-
venous diuretics to oral maintenance therapy compared to the moment of randomi-
zation (much improved/slightly improved/neutral/slightly worse/much worse) 
 
Doubling of the serum creatinine or plasma cystatin C 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 (renal safety 
end-point) 
 
Systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg or need for 
vasopressors and/or inotropes during the index hospital admission (hemodynamic 
safety endpoint) 
 
Length of the index hospital admission [days] 
 
Death, non-elective rehospitalization or non-elective medical contact 
 
Death or non-elective hospital readmission rate 
 
Prespecified exploratory endpoints: 
 
Five-point Likert scale for overall well-being assessed at discharge and at 30 days 
after randomisation, compared to the moment of randomization (much im-
proved/slightly improved/neutral/slightly worse/much worse) 
 
Oedema score (1+: trace to 4+: above the knee) upon transition from intravenous 
diuretic towards oral maintenance therapy, at discharge, and at 30 days after ran-
domisation 
 
Weight change from baseline to switch towards oral maintenance therapy [kg] 
 
Cumulative intravenous loop diuretic dose administered according to the study proto-
col before transition towards oral maintenance therapy [mg bumetanide equivalents] 


 
 
 
 
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 
Weight change from baseline to switch towards oral maintenance therapy, adjusted 
for loop diuretic dose administered [kg per mg bumetanide equivalents] 
 
Relative NTproBNP change from baseline to switch towards oral maintenance ther-
apy [%] 
 
Relative CA 125 change from baseline to switch towards oral maintenance therapy 
[%] 
 
Change in eGFR (calculated according to the Chronic Kidney Diseases Collaboration 
formula with creatinine, cystatin C, and both) from baseline to switch towards oral 
maintenance therapy and to 30 days after randomisation 
 
Incidence of electrolyte disorders as described in the paragraph “Safety Precautions” 
(see above) during the phase of intravenous diuretic treatment 
 
Averaged medial/lateral E/e’ ratio on transthoracic echocardiography upon switch to-
wards oral maintenance therapy, at discharge, and at 30 days after randomisation 
 
Peak left atrial longitudinal strain on transthoracic echocardiography upon switch to-
wards oral maintenance therapy, at discharge, and at 30 days after randomisation 
[%] 
 
Tricuspid annular plane systolic excursion over right ventricular systolic pressure ratio 
on transthoracic echocardiography upon switch towards oral maintenance therapy, at 
discharge, and at 30 days after randomisation [mm/mmHg] 
 
Number of B-lines on lung ultrasound, scanning 8 thoracic sites upon switch towards 
oral diuretic regimen, at discharge, and at 30 days after randomisation11 
 
VExUS score for venous Doppler measurements as a marker for abdominal venous 
congestion upon switch towards oral diuretic regimen, at discharge, and at 30 days 
after randomisation12 
 
 


 
 
 
 
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11. Statistical analysis 
Power calculation: 
As the primary study end-point is anticipated to be driven mainly by the change in NTproBNP 
levels, the study is powered for that specific component of the primary end-point, which also 
constitutes the first secondary end-point. Assuming an average 75% relative decrease in 
NTproBNP levels at 30 days after discharge compared to baseline in the control group versus 
an 85% decrease in the intervention group, with a standard deviation of 15%, 94 patients 
need to be included given a significance level (alpha) of 0.05 to yield a statistical power 
(1-beta) of 90%. To account for potential drop-out up to 10%, the targeted study sample size 
is set at 104 subjects. 
 
Main statistical analysis: 
The primary analysis of the study assesses the win-ratio of the hierarchically composed pri-
mary end-point using the Finkelstein-Schoenfeld method.13 This method is based on the prin-
ciple that each subject in the study is compared to every other subject within each stratum in 
a pair-wise manner. This method gives the highest importance to all-cause mortality at 
30 days after discharge, subsequently to the number of days hospitalised during the 30 days 
after randomisation and finally to the relative change in NTproBNP levels at 30 days after 
randomisation compared to baseline. 
If the primary study endpoint is positive, secondary endpoints will be assessed in a hierar-
chical sequence without adjusting for multiple testing. If the primary endpoint or any of the 
secondary study endpoints is negative, all following endpoints will be considered explorative. 
Fisher’s Exact test, the independent-samples t-test and Mann-Whitney U test are used as 
indicated to assess the secondary endpoints. All primary study analyses will be performed 
according to the intention to treat principle. 
 
 


 
 
 
 
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12. Data collection 
A screening log with the relevant inclusion and exclusion criteria and the randomisation key 
will be obtained via the Castor Electronic Data Capture system. All other relevant study data 
will be collected and put in an online accessible Redcap database that is continuously up-
dated by the study researchers. All patients will get an appointment for an in-hospital study 
visit 30 days after randomisation (or are visited by a study person when they have a pro-
longed in-hospital stay >30 days during their index hospitalisation) to ensure complete data 
capturing. Patients who miss their appointment will be contacted by phone and e-mail to 
identify the reasons of not showing up and minimise loss of data. 
 
13. Timeline 
 
October
2021
• Obtain EudraCT number & FAGG approval
• Submission ethics committee UZ Brussel
March
2022
• Register study at clinicaltrials.gov
• Approval and start study at UZ Brussel
• Submission ethics committee at Jessa Hospital Hasselt
April
2022
• Activate study at Jessa Hospital Hasselt
JUNE
2024
• Estimated complete recruitment
August
2024
• Estimated study completion


 
 
 
 
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