Pragmatic Urinary Sodium-based Treatment algoritHm in Acute Heart Failure
Phase: NA
Conditions: Heart Failure Acute
Sponsor: University Medical Center Groningen

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Protocol Investigator Initiated Study 
 
PUSH AHF 
Pragmatic Urinary Sodium-based treatment algoritHm in Acute Heart Failure 
 
 

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PROTOCOL TITLE ‘Pragmatic urinary sodium-based treatment algorithm in acute heart 
failure’ 
 
Protocol ID 
PUSH AHF 
Short title 
Urinary sodium based treatment in AHF 
EudraCT number  
NA 
Version 
4.0 
Date 
17 October 2021 
Coordinating investigator/project 
leader 
 
J.M. ter Maaten, MD, PhD 
University Medical Center Groningen 
Department of Cardiology 
P.O. Box 30 001, 9700 RB Groningen 
R. +31 (0) 50 361 2355 
Email: j.m.ter.maaten@umcg.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
J.M. ter Maaten, MD, PhD 
University Medical Center Groningen 
Department of Cardiology 
P.O. Box 30 001, 9700 RB Groningen 
R. +31 (0) 50 361 2355 
Email: j.m.ter.maaten@umcg.nl 
 
K. Damman, MD, PhD 
University Medical Center Groningen 
Department of Cardiology 
P.O. Box 30 001, 9700 RB Groningen 
R. +31 (0) 50 361 2355 
Email: k.damman@umcg.nl 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Investigator initiated study 

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Subsidising party 
Hartstichting 
Independent expert (s) 
Dr. P.P. van Geel 
 
 
 
 
Laboratory sites  
NA 
 
 
Pharmacy  
NA 
 
 

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PROTOCOL SIGNATURE SHEET
Name
Signature
Date
Sponsor or legal representative:
Head of Department of Cardiology:
Prof. dr. DJ. van Veldhuisen
IS-IO-'m
Coordinatlng Investigator:
Dr. J.M. ter Maaten
---------------------------------------------
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Version number: 05,17 October 2021

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE 
9 
2. 
OBJECTIVES 
10 
3. 
STUDY DESIGN 
11 
3.1 
Study visits 
11 
3.2 
Screening 
15 
3.3 
Assessment 1 (Baseline) 
15 
3.4 
Assessment 2 (2 hours) 
15 
3.5 
Assessment 3.0 (6 hours) 
16 
3.6 
Assessment 3.1 (12 hours) 
16 
3.7 
Assessment 3.2 (18 hours) 
16 
3.8 
Assessment 4.0 (24 hours) 
17 
3.9 
Assessment 4.1 (36 hours) 
17 
3.10 
Assessment 5 (48 hours) 
17 
3.11 
Assessment 6 (72 hours) 
18 
3.12 
Assessment 7 (discharge) 
18 
3.13 
Assessment 8 (180 days +/- 10 days) 
19 
3.14 
Treatment algorithm 
19 
3.14.1 
Loop diuretic dose at baseline 
20 
3.14.2 
Standard of care group 
21 
3.14.3 
Natriuresis determined treatment algorithm 
22 
3.15 
Renal ultrasound substudy 
24 
3.16 
Pharmacodynamic substudy 
26 
4. 
STUDY POPULATION 
27 
4.1 
Population (base) 
27 
The study population consist of male and female patients (≥18 years old) admitted to the 
hospital for acute heart failure and requiring intravenous diuretic therapy at the University 
Medical Centre Groningen. 
27 
4.2 
Inclusion criteria 
27 
4.3 
Exclusion criteria 
27 
4.4 
Sample size calculation 
27 
5. 
TREATMENT OF SUBJECTS 
29 
5.1 
Investigational product/treatment 
29 
5.2 
Use of co-intervention (if applicable) 
29 
5.3 
Escape medication (if applicable) 
29 
6. 
METHODS 
30 
6.1 
Study parameters/endpoints 
30 
6.1.1 
Main study parameter/endpoint 
30 
6.1.2 
Secondary study parameters/endpoints (if applicable) 
30 
6.1.3 
Other study parameters (if applicable) 
30 
6.2 
Randomization, blinding and treatment allocation 
30 
6.3 
Study procedures 
31 

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6.4 
Withdrawal of individual subjects 
32 
6.4.1 
Specific criteria for withdrawal (if applicable) 
32 
6.5 
Replacement of individual subjects after withdrawal 
32 
6.6 
Follow-up of subjects withdrawn from treatment 
32 
6.7 
Premature termination of the study 
32 
7. 
SAFETY REPORTING 
33 
7.1 
Temporary halt for reasons of subject safety 
33 
7.2 
AEs, SAEs and SUSARs 
33 
7.2.1 
Adverse events (AEs) 
33 
7.2.2 
Serious adverse events (SAEs) 
33 
7.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
34 
7.3 
Annual safety report 
34 
7.4 
Follow-up of adverse events 
34 
7.5 
Endpoint adjudication committee 
34 
STATISTICAL ANALYSIS 
36 
7.6 
Primary study parameter(s) 
36 
7.7 
Secondary study parameter(s) 
36 
7.8 
Other study parameters 
36 
7.9 
Interim analysis (if applicable) 
36 
Not applicable 
36 
8. 
ETHICAL CONSIDERATIONS 
37 
8.1 
Regulation statement 
37 
8.2 
Recruitment and consent 
37 
8.3 
Objection by minors or incapacitated subjects (if applicable) 
37 
8.4 
Benefits and risks assessment, group relatedness 
37 
8.5 
Compensation for injury 
38 
8.6 
Incentives 
38 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
39 
9.1 
Handling and storage of data and documents 
39 
9.2 
Monitoring and Quality Assurance 
39 
9.3 
Amendments 
39 
9.4 
Annual progress report 
39 
9.5 
Temporary halt and (prematurely) end of study report 
39 
9.6 
Public disclosure and publication policy 
40 
unreservedly. 
40 
10. 
STRUCTURED RISK ANALYSIS 
41 
10.1 
Potential issues of concern 
41 
10.2 
Synthesis 
41 
11. 
REFERENCES 
42 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
AHF 
Adverse Event 
Acute Heart Failure 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EHR 
Electronic Health Record 
ESC 
European Society of Cardiology 
EudraCT 
European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
HCT 
Hydrochlorothiazide 
HF 
Heart Failure 
IC 
Informed Consent 
JVP 
Jugular Venous Pressure 
LD 
Loop Diuretic 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
NT-
proBNP 
N-terminal pro blood natriuretic peptide 
NYHA 
New York Heart Association 
(S)AE 
(Serious) Adverse Event  
SGLT2i 
Sodium Glucose Transporter 2 inhibitor 
SOC 
Standard Of Care 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UMCG 
University Medical Centre Groningen 
VAS 
Visual Analog Scale 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Administration of loop diuretics to achieve decongestion is the current 
cornerstone of therapy for acute heart failure. Unfortunately, there is a lack of evidence of 
how to guide diuretic treatment. Recently, urinary sodium, as a response measure of diuretic 
response, has been proposed as a target for therapy.  
The hypothesis of this study is that natriuresis guided therapy in patients with acute heart 
failure will improve diuretic response, decongestion, and reduce length of hospital stay, as 
well as heart failure rehospitalisations.  
Objective: To assess the effect of natriuresis guided therapy in acute heart failure to improve 
diuretic response, decongestion, and clinical outcomes 
Study design: Randomised, controlled, open label study 
Study population: 310 patients admitted with the primary diagnosis of acute heart failure 
requiring intravenous loop diuretics. 
Intervention (if applicable): natriuresis guided treatment versus standard of care 
Main study parameters/endpoints:  
Co-primary outcome: total natriuresis after 24 hours and first occurrence of all-cause 
mortality or heart failure rehospitalisation at 6 months 
Secondary outcomes: 48- and 72-hours natriuresis, length of hospital stay, percentage 
change in NT-proBNP at 48 and 72 hours.  
Safety endpoints: doubling of serum creatinine at 24 or 48 hours, occurrence of worsening 
heart failure 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Since this is a pragmatic trial, the study will be embedded within the 
normal care of patients with acute heart failure, which already includes timed urinary 
collections and laboratory assessment at set time points. The patients in the natriuresis 
guided therapy will undergo additional urinary assessments, and undergo more stringent 
monitoring of response, and therefore might receive more intravenous diuretics. For study 
parameters, blood and urine will be collected at set time points. Survival and rehospitalisation 
will be assessed after 6 months by telephone call.  
 

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1. INTRODUCTION AND RATIONALE 
Heart failure is one of the leading causes of hospitalization in the world, is associated with 
significant morbidity and mortality, and as such responsible for a large proportion of health 
care expenses.(1) It is estimated that the total number of heart failure patients will continue to 
increase. An increase of 88% in 2040 is predicted, resulting in a further increase of health 
care expenditures attributable to heart failure.(1) While treatment for chronic heart failure has 
improved greatly over the last decades, this is not true for acute heart failure (AHF) where 
therapies with a proven positive effect on outcome are non-existent. Additionally, a large 
number of AHF patients show impaired response to the only available therapy, i.e. loop 
diuretics.(2) Over the last years several studies consistently showed that impaired diuretic 
response is associated with residual congestion and an increased risk of mortality and heart 
failure rehospitalisations.(3-7) Given the working mechanisms of loop diuretics, natriuresis 
might be a more sensitive, objective, quantifiable, and reliable marker to assess response. 
We recently showed that insufficient natriuretic response in AHF patients was indeed 
associated with an increased risk of poor outcome.(8) Additionally, even early assessment of 
natriuresis (one to two hours after initiation of loop diuretics) in AHF patients has been shown 
to be an accurate marker of insufficient diuretic response during hospitalization.(9) Therefore, 
natriuresis might have a role in actively assessing response to loop diuretics and to 
subsequently guide diuretic treatment in AHF patients. Natriuresis possesses all the 
characteristics required for a marker that can be used to actively guide decongestive 
treatment and move towards a personalized treatment approach in AHF. Interventions aimed 
at improving diuretic response, using natriuresis guided therapy have the potential to 
significantly improve effectiveness of decongestion, speed up inhospital treatment, prevent 
readmissions for heart failure, and decrease health care expenses (figure 1). We therefore 
hypothesize that natriuresis guided therapy in patients with AHF will improve diuretic 
response, decongestion, and reduce length of hospital stay, as well as heart failure 
rehospitalisations.  
 
 
Figure 1. 
Legend: in patients with AHF, loop diuretics are the first and only recommended choice of treatment aimed at 
relieving congestion by increasing diuresis and natriuresis. Actively assessing natriuresis and using this to 
optimize diuretic treatment could improve decongestion and clinical outcomes.  

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2. OBJECTIVES 
 
Primary Objective:  
To assess the effect of natriuresis guided therapy versus standard of care (SOC) on 24-hour 
urinary sodium excretion after the start of intravenous loop diuretic and the effect on first 
occurrence of all-cause mortality or heart failure rehospitalisation at 6 months in patients with 
acute heart failure 
 
Secondary Objective(s):  
To assess the effect of natriuresis guided therapy on: 
- 
48- and 72 hours urinary sodium excretion 
- 
Length of hospital stay 
- 
Percentage change in NT-proBNP at 48 and 72 hours 
 
Safety endpoints: 
- 
Doubling of serum creatinine at 24 or 48 hours 
- 
Occurrence of worsening heart failure 

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3. STUDY DESIGN 
This is a pragmatic, randomized, controlled, open label study in patients presenting with 
acute heart failure requiring intravenous loop diuretics. In total 310 patients will be 
randomized at the start of intravenous treatment (inhospital) to standard of care or natriuresis 
guided treatment. Due to the severe illness of acute heart failure patients, and the necessity 
to perform the first study assessment early (i.e. within the first hours of hospitalization) 
patients will be enrolled at the emergency department using deferred consent. Written 
informed will be obtained during the first four days of hospitalization. Patients will be followed 
for the duration of the hospitalization. Adverse clinical events, including all-cause mortality 
and heart failure rehospitalisation will be assessed by a telephone call after 6 months.  
 
3.1 Study visits 
Table 1 lists all of the assessments and indicates with an “X” when the required assessments 
and/or procedures are performed at a scheduled visit day. All laboratory assessments, 
including blood and urine assessment for the treatment algorithm and for the primary 
outcome will be integrated in clinical practice. The results of the urinary assessments will be 
blinded in the standard of care group during the study duration.  
 
Study candidates will be identified upon arrival at the emergency department. When a patient 
is diagnosed with AHF and intravenous diuretic therapy is started, randomization will occur 
using Epic (Epic Systems Corporation). The study procedures will then start according to this 
protocol. Patients will receive a urinary catheter if this is deemed necessary by the treating 
physician.  
 
 

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Table 3.1 Assessment schedule 
 
Screening 
Participation  
 
 
 
 
 
 
 
 
Follow-
up 
Time points 
Hour -6 
Hour 0 (day 
1) 
Hour 2 
(day 1) d 
Hour 6 
(day 1) 
Hour 12 
(day 1) d 
Hour 18 
(day 1) d 
Hour 24 
(day 1) 
Hour 36 
(day 2) d 
Hour 48 
(day 2) 
Hour 72 
(day 3) 
Discharge Day 180 
(+/- 10 
days) a 
Visits 
0 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
5 
6 
7 
8 
Written informed 
consent 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Heart failure 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Physical 
examination 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 

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Screening 
Participation  
 
 
 
 
 
 
 
 
Follow-
up 
Time points 
Hour -6 
Hour 0 (day 
1) 
Hour 2 
(day 1) d 
Hour 6 
(day 1) 
Hour 12 
(day 1) d 
Hour 18 
(day 1) d 
Hour 24 
(day 1) 
Hour 36 
(day 2) d 
Hour 48 
(day 2) 
Hour 72 
(day 3) 
Discharge Day 180 
(+/- 10 
days) a 
Visits 
0 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
5 
6 
7 
8 
Blood pressure 
and heart rate 
measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NYHA class 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Physician 
assessment of HF 
signs and 
symptoms  
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Echocardiogram b 
 
 
 
 
 
 
 
 
 
 
 
 
X-ray c 
X 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Loop diuretics 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Standard local 
laboratory analysis 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Timed urine 
collection (24h) 
 
 
 
 
 
 
X 
 
X 
X 
 
 

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Screening 
Participation  
 
 
 
 
 
 
 
 
Follow-
up 
Time points 
Hour -6 
Hour 0 (day 
1) 
Hour 2 
(day 1) d 
Hour 6 
(day 1) 
Hour 12 
(day 1) d 
Hour 18 
(day 1) d 
Hour 24 
(day 1) 
Hour 36 
(day 2) d 
Hour 48 
(day 2) 
Hour 72 
(day 3) 
Discharge Day 180 
(+/- 10 
days) a 
Visits 
0 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
5 
6 
7 
8 
Spot natriuresis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine sample 
 
X 
X 
X 
 
 
X 
 
X 
X 
X 
 
Plasma sample 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Fluid intake 
assessment 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Diuresis 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital status and 
outcome 
assessments 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Events and serious 
adverse events 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
a the day 180 visit will be a telephone visit 
b if performed as part of standard of care at any time during hospitalization 
c if performed as part of standard of care at admission 
d in the natriuresis guided group

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3.2 Screening 
At screening the following assessments will be executed (all part of standard of care):  
- 
Deferred informed consent 
- 
Demographic data, including cardiovascular risk factors 
- 
Medical history by chart review  
- 
Vital signs 
- 
Physical examination, including weight, height (only at screening), oedema, rales, 
jugular venous pressure (JVP), orthopnoea assessment, New York Heart Association 
(NYHA) class 
- 
12-lead electrocardiogram (ECG) 
- 
NYHA class assessment 
- 
Laboratory assessments, including haematology, renal function, NT-proBNP 
- 
Concomitant medication 
- 
In- and exclusion criteria 
 
3.3 Assessment 1 (Baseline) 
After having confirmed eligibility by confirming all inclusion criteria and by ruling out 
either one of the exclusion criteria, the following assessments will be executed: 
- 
Randomization 
- 
Vital signs 
- 
Physical examination, including weight, oedema, rales, JVP, orthopnoea assessment, 
NYHA class 
- 
Concomitant medication 
- 
Initial loop diuretic dose in both groups will be determined based on several patients 
characteristics described in more detail in section 3.14.1 and figure 3 
- 
Collection of EDTA blood sample for biomarker analysis and collection of spot urine 
sample for biomarker analysis 
- 
Start fluid balance by noting ingested and excreted fluid volumes 
 
3.4 Assessment 2 (2 hours) 
At two hours, in patients randomized to the natriuresis guided group, the following 
assessments will be executed: 
- 
Vital signs 
- 
Evaluate Diuretic Response: 
o Spot urine sodium  

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▪ 
If applicable adjust loop diuretic therapy based on this result (please 
see also section 3.14.2, and figure 4) 
- 
Loop diuretic dose 
- 
Collection of spot urine sample for biomarker analysis (in both groups) 
- 
Diuresis assessment 
 
3.5 Assessment 3.0 (6 hours) 
At six hours the following assessments will be executed: 
- 
Vital signs 
- 
Physical examination, including oedema, rales, JVP, orthopnoea assessment, NYHA 
class 
- 
Spot urinary sodium (result will be blinded in the SOC group) 
- 
6 hours urine collection  
- 
In the Natriuresis Guided Group:  
o Evaluate Diuretic Response based on spot urinary sodium and diuresis and 
adjust loop diuretic therapy based on these results (please see also section 
3.14.2, and figure 4)  
- 
Loop diuretic dose 
- 
Laboratory assessments, including haematology, and kidney function 
- 
Collection of EDTA blood sample for biomarker analysis and collection of spot urine 
sample for biomarker analysis 
- 
Diuresis assessment  
 
3.6 Assessment 3.1 (12 hours) 
In the natriuresis guided group the following assessments will be executed: 
- 
Vital signs 
- 
Evaluate Diuretic Response based on spot urinary sodium and diuresis and adjust 
loop diuretic therapy based on these results (please see also section 3.14.2, and 
figure 4)  
- 
Loop diuretic dose 
 
3.7 Assessment 3.2 (18 hours) 
In the natriuresis guided group the following assessments will be executed: 
- 
Vital signs 

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- 
Evaluate Diuretic Response based on spot urinary sodium and diuresis and adjust 
loop diuretic therapy based on these results (please see also section 3.14.2, and 
figure 4)  
- 
Loop diuretic dose 
 
3.8 Assessment 4.0 (24 hours) 
At twenty-four hours the following assessments will be executed: 
- 
Written informed consent (if not yet provided) 
- 
Concomitant medication 
- 
Vital signs 
- 
Physical examination, including weight, oedema, rales, JVP, orthopnoea assessment, 
NYHA class 
- 
Spot urinary sodium (result will be blinded in the SOC group) 
- 
24 hours urine collection  
- 
In the Natriuresis Guided Group:  
o Evaluate Diuretic Response based on spot urinary sodium and diuresis and 
adjust loop diuretic therapy based on these results (please see also section 
3.14.2, and figure 5)  
- 
Loop diuretic dose 
- 
Laboratory assessments, including haematology, and kidney function 
- 
End of first timed twenty-four hour urine collection 
- 
Collection of EDTA blood sample for biomarker analysis and collection of spot urine 
sample for biomarker analysis 
- 
Diuresis and first 24 hour fluid intake assessment  
- 
(Serious) adverse events 
 
3.9 Assessment 4.1 (36 hours) 
In the natriuresis guided group the following assessments will be executed: 
- 
Vital signs 
- 
Evaluate Diuretic Response based on spot urinary sodium and diuresis and adjust 
loop diuretic therapy based on these results (please see also section 3.14.2, and 
figure 5)  
- 
Loop diuretic dose 
 
3.10 Assessment 5 (48 hours) 
At forty-eight hours the following assessments will be executed: 

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- 
Written informed consent (if not yet provided) 
- 
Concomitant medication 
- 
Vital signs 
- 
Physical examination, including weight, oedema, rales, JVP, orthopnoea assessment, 
NYHA class 
- 
Loop diuretic dose 
- 
Laboratory assessments, including haematology, NT-proBNP, and kidney function 
- 
End of second timed 24 hour urine collection 
- 
Collection of EDTA blood sample for biomarker analysis and collection of spot urine 
sample for biomarker analysis 
- 
Diuresis and second 24 hour fluid intake assessment  
- 
(Serious) adverse events 
 
3.11 Assessment 6 (72 hours) 
At seventy-two hours the following assessments will be executed: 
- 
Written informed consent (if not yet provided) – last opportunity 
- 
Concomitant medication 
- 
Vital signs 
- 
Physical examination, including weight, oedema, rales, JVP, orthopnoea assessment, 
NYHA class 
- 
Loop diuretic dose 
- 
Laboratory assessments, including haematology, NT-proBNP, and kidney function 
- 
End of third and final timed 24 hour urine collection 
- 
Collection of EDTA blood sample for biomarker analysis and collection of spot urine 
sample for biomarker analysis 
- 
Diuresis and third 24 hour fluid intake assessment  
- 
(Serious) adverse events 
 
3.12 Assessment 7 (discharge) 
At discharge the following assessments will be executed: 
- 
Concomitant medication 
- 
Vital signs 
- 
Physical examination, including weight, oedema, rales, JVP, orthopnoea assessment, 
NYHA class 
- 
Loop diuretic dose 
- 
Laboratory assessments, including haematology, NT-proBNP, and kidney function 

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- 
Collection of EDTA blood sample for biomarker analysis and collection of spot urine 
sample for biomarker analysis 
- 
Diuresis and first 24 hour fluid intake assessment  
- 
(Serious) adverse events 
 
3.13 Assessment 8 (180 days +/- 10 days) 
On day 180 the following assessments will be executed by phone call. 
- 
Concomitant medication 
- 
Weight (patient reported) and NYHA class 
- 
Loop diuretic dose 
- 
Heart failure admissions and/or mortality 
- 
(Serious) adverse events 
 
3.14 Treatment algorithm 
Patients presenting with acute heart failure will be randomized to natriuresis guided therapy 
or standard of care (figure 2). When patients are randomized to the natriuresis guided 
treatment arm, decongestive treatment will be adjusted based on the spot urine sodium 
values assessed at set time points. The first natiuresis assessment takes place two hours 
after randomization. Patients will be required to empty the bladder at randomization (if 
deemed feasible), and a baseline urine sample will be obtained. In patients with a catheter 
the first sample (after placement of the urinary catheter) will be discarded. At two hours, a 
spot urinary sample will be obtained in patients with a urinary catheter after voiding the 
collected urine output in a container and obtaining the first produced urine after this. Patients 
without a catheter will be encouraged to urinate at this time point. This method will be 
repeated at the consecutive time points.   
 

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Figure 2: Overview of the treatment algorithm 
 
Abbreviations: HF: heart failure, iv: intravenously, LD: loop diuretic, NTproBNP: N-terminal pro blood 
natriuretic peptide 
 
3.14.1 
Loop diuretic dose at baseline 
Baseline loop diuretic dose will be determined based on the renal function of the patient and 
his/her outpatient loop diuretic dose (figure 3). If available, bumetanide will be used, as this 
has better bioavailability than furosemide. Conversion from furosemide to bumetanide doses 
will be done by dividing the furosemide dose by 40. If bumetanide is not in stock at the 
UMCG, furosemide will be used.  
 
If patients use loop diuretics in the outpatients setting and have a preserved renal function 
(estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2), starting intravenous loop 
diuretic dose will be the total daily outpatient dose as a bolus and consequently continued in 
twice daily dosing.  
If patients use loop diuretics in the outpatient setting and have an impaired renal function 
(eGFR < 60 ml/min/1.73m2), starting intravenous loop diuretic dose will be twice the total 
daily outpatient dose as a bolus and this consequently continued in twice daily dosing.  

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If patients do not use loop diuretics in the outpatient setting (naïve), the loop diuretic dose will 
only be determined based on the renal function. In case of a preserved renal function a 
starting dose of 1 mg bumetanide will be administered which will be continued in twice daily 
dosing. When renal function is impaired a starting loop diuretic dose of 2 mg bumetanide will 
be used, which will consequently be continued in twice daily dosing. 
In all groups, the maximum bolus dose will be 5 mg of bumetanide (200 mg of furosemide) 
as an additional effect above this initial bolus dose is not expected. 
 
The determination of the loop diuretic dose at baseline is further illustrated in the following 
figure:  
 
Figure 3: Determination of the starting loop diuretic dose in all patients 
 
Abbreviations: eGFR: estimated glomerular filtration rate, iv: intravenously, LD: loop diuretic 
 
Patients will be randomized using Epic in a 1:1 ratio to natriuresis guided therapy or standard 
of care.  
 
3.14.2 
Standard of care group 
In the standard of care group decongestive treatment will be performed as it is currently done 
in clinical practice at the UMCG. After randomization patients will receive twice daily loop 

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diuretic doses intravenously, as previously described (figure 2 and 3). The maximum starting 
dose will be 5 mg of bumetanide (200 mg of furosemide) twice daily.  
 
3.14.3 
Natriuresis determined treatment algorithm 
Based on the urinary sodium value obtained from 2 hours onwards in the natriuresis guided 
group, decongestive therapy will be adjusted using the following treatment algorithm.  
 
Figure 4: Treatment algorithm for the natriuresis guided group during the first 24 hours after 
randomization 
 
Abbreviations: HCT: hydrochlorothiazide, LD: loop diuretic, SGLT2-I (sodium glucose transporter 2 
inhibitor) 
 

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In patients randomized to natriuresis guided therapy, the first urinary sodium will be 
determined at 2 hours. All urinary sodium assessments will be spot urinary samples. These 
will be obtained from the urinary catheter (if applicable) at set time points. If spot urinary 
sodium at 2 hours is < 70 mmol/L, patients will receive an additional bolus of loop diuretic, 
which will be double the previous bolus with a maximum bolus dose of 5 mg of bumetanide 
or equivalent (figure 4). If the bolus dose is doubled, the maintenance dose of loop diuretics 
will be adjusted to twice daily the doubled bolus dose (figure 4). If a patient already received 
5 mg of bumetanide as a first dose, this dose will be repeated when there is insufficient 
natriuresis at this time point.  
The next urinary sodium assessment is at 6 hours. At this time point physicians are required 
to assess both urinary sodium, and urine output. If urinary sodium is < 70 mmol/L, and/or 
diuresis is < 150 mL/hour, patients will be eligible (if still deemed congested) for an additional 
dose of loop diuretic of double the previous dose (figure 4) with a maximum bolus dose of 5 
mg of bumetanide or equivalent. The maintenance dose will consequently be adjusted to 
twice daily the doubled bolus dose. Again, if a patient already received 5 mg of bumetanide 
as a first dose, this dose will be repeated when there is insufficient natriuresis or diuresis at 
this time point. Furthermore, if a patient has had two doses of 5 mg of bumetanide and has 
insufficient natriuresis or diuresis at two consecutive time points, the initiation of combination 
diuretic therapy with the addition of hydrochlorothiazide 25 mg once daily is indicated. If 
patients at admission already use a thiazide diuretic, yet no loop diuretic, the thiazide diuretic 
will be stopped upon admission. These patients are still eligible for combination diuretic 
therapy with hydrochlorothiazide and a loop diuretic. If patients intentionally use combination 
diuretic therapy at admission this will be continued. These patients will qualify for second 
step combination therapy with either acetazolamide or a sodium-glucose-cotransporter 2 
inhibitor (SGLT2i). 
The above protocol will be repeated at 12, 18, and 24 hours. When a patients has insufficient 
natriuresis or diuresis at two consecutive time points after the addition of hydrochlorothiazide, 
acetazolamide 500 mg iv once daily will be added. If this is contra-indicated or acetazolamide 
has been added as a first step for combination diuretic therapy, the addition of a sodium-
glucose transporter 2 inhibitor should be considered.  
The treatment algorithm will be continued until 48 hours, however after 24 hours natriuresis 
and diuresis assessment will only take place every 12 hours (figure 5). At every time point it 
is essential for physicians to only administer additional doses of diuretics if a patients is still 
congested. Combination diuretic therapy will be stopped when the patient is euvolemic or 
when this is indicated based on significant electrolyte disturbances or renal function decline 
in the absence of decongestion.   

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Figure 5: Treatment algorithm during the second 24 hours after randomization 
 
Abbreviations: LD: loop diuretic 
 
3.15 Renal ultrasound substudy 
3.15.1 Introduction and rationale ultrasound substudy 
It is well known that assessment of congestion status remains difficult, as clinical symptoms 
and signs of HF are in part difficult to assess, have high inter-observer variability, and are 
mostly non-specific. Non-invasive technologies such as ultrasound imaging to assess 
congestion and fluid status could aid in the (early) clinical identification of these HF signs and 
symptoms, and detect change in congested state as response to diuretic treatment.  
 
Ultrasound measurements are easily accessible, interpretable, non-invasive, inexpensive, 
safe, and can be performed at the bedside rapidly providing additional information and 
therefore might improve diagnosis and treatment in HF patients. Moreover, it may help detect 
patients in need of treatment (de)intensification to prevent (re-)admission for HF.  
 
Therefore, patients enrolled during daytime hours on Monday till Wednesday will be eligible 
for participation in a substudy aimed at better assessment of congestion using ultrasound.   
 
3.15.2 Objectives ultrasound substudy 
Primary objective: 
To assess congestion status through bedside renal, cardiac, and lung ultrasound 
assessments in patients with acute heart failure at baseline, day 1, day 2, day 3 and 
discharge, and change over time. 
 
Secondary Objective(s):  

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To assess the effect of diuretic therapy, the effect of natriuresis guided therapy specifically, 
and the relationship between biomarkers of congestion and (change in) congestion status 
measured by serial ultrasound assessments (cardiac, renal, lung). 
 
3.15.3 Study design ultrasound substudy 
This will be a prospective, observational, exploratory study, in which we will evaluate renal, 
lung, and cardiac ultrasound measurements at baseline (day 1), day 2, day 3 and at day of 
discharge. Patients will be enrolled from the primary study, with corresponding inclusion and 
exclusion criteria. All patients will provide additional informed consent for enrollment in the 
substudy. Patients will be included on week days during day time hours on Monday, Tuesday 
or Wednesday. We aim to enroll a total of 50 patients and will strive for equal distribution 
between the natriuresis and the standard of care group of the primary study. Treating 
physicians will be blinded to the results of the ultrasound assessments. Ultrasounds will be 
performed by trained clinicians.  
 
Study population 
In a proof-of-concept study we performed in patients with acute heart failure, we observed 
that 54% of patients had a normalization of renal venous flow after 3 days of decongestive 
therapy. We expect this to increase to approximately 80% of patients in the natriuresis 
guided group. With an alpha of 0.05 and a power of 80%, we require 48 patients for this 
study, which we will increase to 50 patients to prevent being underpowered for instance due 
to insufficient image quality.  
 
Study visits 
Table 3.15. Assessment schedule ultrasound substudy 
Assessments 
Baseline (day 1) 
Day 2 
Day 3 
Discharge 
Renal ultrasound 
- 
Renal venous flow pattern 
- 
Venous impedance index 
- 
Venous discontinuity index 
- 
Intrarenal arterial resistance 
index 
X 
X 
X 
X 
Transthoracic echocardiogram 
- 
Inferior vena cave diameter 
- 
Right ventricular peak 
pressure 
X 
X 
X 
X 

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- 
Pulmonary vein flow 
Lung ultrasound 
- 
B-lines 
X 
X 
X 
X 
 
 
Statistical analysis 
Baseline data will be presented using mean +- standard deviation for normally distributed 
variables, mean (interquartile ranges) for skewed variables, and as frequencies 
(percentages) for categorical variables. Participants will be divided into groups according to 
occurrence of change in renal, cardiac or lung ultrasound measurements. Baseline 
characteristics will be analyzed using t-test, linear regression models or Cuzick’s 
nonparametric test for continuous variables, and chi-square test for categorical variables. 
Predictors at baseline for change in ultrasound measurements will be determined using 
regression models. 
 
3.16 Pharmacodynamic substudy  
In a subset of patients we will perform a pharmacodynamic study aimed at gaining a better 
understanding of the effect of a bolus of intravenous diuretics on sodium excretion trajectory 
in contemporary acute heart failure patients. At the moment the only data regarding this 
stems from the eighties and was obtained in patients with chronic heart failure. This 
pharmacodynamic substudy can be performed after an intravenous dose of loop diuretics 
during daytime hours before day 3. Only patients with a urinary catheter will be eligible for 
this substudy. In addition to the urine samples already obtained per protocol at baseline, after 
2 hours and after 6 hours, additional urinary spot samples will be obtained every 30 minutes 
during the first 6 hours (12 urine samples). One additional plasma samples will be obtained. 
All patients will provide additional informed consent for enrollment in the pharmacodynamic 
substudy.  
 
Study population 
With an estimate of Urinary sodium content of 90 +/- 27 mmol/L after 2 hours, with 95% CI, 
and making sure that what we measure is within 12 mmol/L of the true population (margin of 
error), the formula will be as follows N = (1.96(27)/12)2. This results in approximately 20 
patients to ensure that the 95% CI of 2 hour Urinary sodium concentration is within 12 
mmol/L of the true mean. Therefore, we aim to enroll 20 patients in this substudy. 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
The study population consist of male and female patients (≥18 years old) admitted to the 
hospital for acute heart failure and requiring intravenous diuretic therapy at the University 
Medical Centre Groningen.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
 
1. Male or female ≥ 18 years of age 
2. Primary diagnosis of acute /decompensated heart failure as assessed by treating 
physician 
a. Acute Heart failure can be de novo or exacerbation of known heart failure and 
diagnosis is based on criteria in the ESC HF guidelines  
3. Requirement of intravenous diuretic use 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study: 
 
1. Dyspnoea primarily due to non-cardiac causes 
2. Patients with severe renal impairment receiving dialysis or requiring ultrafiltration 
3. Inability to follow instructions 
4. Previous participation in this study 
5. Any other medical conditions that may put the patient at risk or influence study results 
in the investigator’s opinion, or that the investigator deems unsuitable for the study 
 
4.4 Sample size calculation 
Based on our previous study in acute heart failure patients, the mean 24 hours sodium 
excretion was 398 ± 246 mmol.(8; METC 2019/437) In this population, not 2 hours but 6 
hours measurements were available, and in these patients, 36% of patients had an 
insufficient response, defined as urinary sodium <90 mmol or urine output <900 mL at 6 
hours. Assuming a 40% improvement in these 36% of patients, and a conservative 15% 
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closer monitoring, this will assume an overall 24% improvement in 24-hours urinary sodium 
excretion (0.36*1.40 + 0.64*1.15). Therefore, to obtain a power of at least 80% at a two-sided 
significance level of 0.025 (Bonferroni correction), we calculated a sample size of 125 
patients in each group would be sufficient for the primary endpoint of 24-hour natriuresis. To 
prevent being underpowered due to drop-out or missing data, which is expected to be higher 
than average in this patient population and given the delicate nature of urinary collections, 
we will increase enrolment by 10% therefore requiring 140 patients per group, and enrolling a 
total of 280 patients.  
Based on this sample size, we will have 81% power with a two-sided significance level of 
0.025 to detect a HR of 0.49 for the other co-primary endpoint of all-cause mortality and 
heart failure rehospitalisation at 6 months (a reduction in events from 38% to 21%). However 
also accounting for 10% missing follow-up data, we will increase the total number of patients 
to 310 (155 patients per group).  
 
 
 
 
 
 

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5. TREATMENT OF SUBJECTS 
The aim of this study is to establish the value of natriuresis guided therapy in acute heart 
failure, to improve diuretic response, decongestion, and clinical outcomes.  
Patients will be randomized to either standard of care or natriuresis guided therapy. In the 
natriuresis guided group treatment will be adjusted based on urinary sodium values 
determined at set time points. The optimization of decongestive treatment will be done using 
a prespecified treatment algorithm (figures 4 and 5). In the standard of care group physicians 
are encouraged to treat patients according to current best practice consensus (figure 2).  
 
5.1 Investigational product/treatment 
The treatment algorithm used in this study is described in detail in section 3.14.2 and figures 
4 and 5. 
 
5.2 Use of co-intervention (if applicable) 
Not applicable 
 
5.3 Escape medication (if applicable) 
Not applicable 
 
 

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6. METHODS 
6.1 Study parameters/endpoints 
6.1.1 Main study parameter/endpoint 
To establish the effect of natriuresis guided therapy in patients with acute heart failure on 24-
hours natriuresis and first occurrence of all-cause mortality or heart failure rehospitalisation 
at 6 months.  
 
6.1.2 Secondary study parameters/endpoints (if applicable) 
Secondary outcomes:  
- 
48- and 72-hours natriuresis 
- 
Length of hospital stay 
- 
Percentage change in NT-proBNP at 48 and 72 hours 
 
6.1.3 Other study parameters (if applicable) 
Safety endpoints: 
- 
Doubling of serum creatinine at 24 or 48 hours 
- 
Occurrence of worsening heart failure (for definition see section 7.2.1.) 
- 
Adverse and serious adverse events 
 
6.2 Randomization, blinding and treatment allocation 
Subjects will be randomized 1:1 to natriuresis guided therapy or standard of care. 
Randomization will be executed using Epic. Treatment assignment will take place by Epic. 
Patients will maintain this randomization number throughout the study.  
Randomization will be achieved within the EPIC electronic health record (EHR) system using 
an internal random number rule. Randomization starts the first time the patients chart is 
opened by a provider from the department of cardiology. The randomization group is 
maintained as fixed variable in the EPIC EHR. Then, when treatment with loop diuretic 
therapy (intravenous) is started, based on this randomization number, the EPIC EHR 
automatically chooses the correct treatment orders and diagnostic tests based on the 
randomization arm. After enrollment of 150 patients we will perform an interim analysis to 
check whether the distribution of patients to groups is indeed 1:1. If necessary the internal 
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6.3 Study procedures 
Study patients will not be required to come to the hospital for additional visits. Blood will be 
drawn at 6 different time points during hospitalization. These are assessments that are 
already part of standard of care and therefore will not lead to additional blood draws. At these 
time points an additional sample of 5 mL will be obtained for additional assessments after 
completion of the trial. 
A timed collection of urine will take place for the first 72 hours, from which urine samples will 
be obtained at a maximum of 7 different time points (and one additional urine sample at 
discharge) in the interventional arm. At these time points an additional sample of 5 mL will be 
obtained for additional assessments after completion of the trial.  
In these urine and plasma samples, we will determine biomarkers to further elucidate 
response to treatment by assessing congestion markers, and markers specific for certain 
segments of the kidney. This will not only provide more insight in possible mechanisms of 
diuretic response, but may also lead to identification of (new) targets for therapy.  
Finally, a telephone call 180 days after baseline will be performed to assess signs and 
symptoms, weight as well as current medications. Vital status will first be verified by 
contacting the general practitioner.  
See also table 3.1 for a schedule of assessments.  
 
Study assessments as part of clinical care:  
- 
 Physical examination 
o Height, weight 
o Blood pressure, heart rate (vital signs) 
o Jugular venous pressure, heart sounds and murmurs, pulmonary rales, edema 
and ascites 
- 
NYHA functional class heart failure 
o Class I: patients with no limitation of activities; they suffer no symptoms from 
ordinary activities 
o Class II: Patients with slight, mild limitation of activity; they are comfortable 
with rest or with mild exertion 
o Class III: Patients with marked limitation of activity; they are comfortable only 
at rest 
o Class IV: Patients who should be at complete rest, confined to bed or chair; 
any physical activity brings on discomfort and symptoms occur at rest 
- 
HF signs and symptoms 
o Anamnesis: dyspnea d’effort, orthopnea, paroxysmal nocturnal dyspnea, 
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o Physical examination (see above)  
- 
Echocardiogram 
o Only if performed as standard of care during hospitalization  
- 
X-ray 
o Only if performed as standard of care during hospitalization 
- 
ECG 
o Only if performed as standard of care during hospitalization 
- 
Standard laboratory analysis (standard of care) 
o At admission: hematology, renal function, electrolytes, NT-proBNP 
o After 6 hours: renal function, electrolytes, NT-proBNP 
o Daily: hematology, renal function 
- 
Fluid intake assessment 
 
6.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
6.4.1 Specific criteria for withdrawal (if applicable) 
Not applicable 
 
6.5 Replacement of individual subjects after withdrawal 
Withdrawn subjects will not be replaced.  
 
6.6 Follow-up of subjects withdrawn from treatment 
Subjects withdrawn from treatment will be asked whether the investigator will be allowed 
to contact the patient for the 180-days visit in order to collect information regarding 
vital status and eventual (serious) adverse events. Investigators will be urged to have 
subjects consent to them gathering follow-up information of each withdrawn subject. 
 
6.7 Premature termination of the study 
The study may be prematurely terminated if the following criterion applies:  
- 
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7. SAFETY REPORTING 
7.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or 
safety. The sponsor will notify the accredited METC without undue delay of a temporary halt 
including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects are 
kept informed.  
 
7.2 AEs, SAEs and SUSARs 
7.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the intensified treatment. All adverse events 
reported spontaneously by the subject or observed by the investigator or his staff will be 
recorded. All (serious) adverse events will be recorded from baseline to the final follow-up 
visit (phone call) at 180 days.  
 
Pre-specified adverse events are defined as follows:  
- 
Worsening heart failure defined as: 
o Addition or starting of inotropes or vasopressors 
o Mechanical ventilation 
o Palliative care due to progressive heart failure 
o Any intervention/treatment for heart failure that leads to prolonged 
hospitalization 
- 
True worsening renal function 
o Doubling of creatinine from baseline to 48 or 72 hours without evidence of 
decongestion, or urine production < 10 cc / hour despite adequate dosing of 
loop diuretics 
 
7.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
- 
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- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgment by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events.. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
 
7.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable 
 
7.3 Annual safety report 
Not applicable. 
 
7.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study.  
 
7.5 Endpoint adjudication committee 
This committee of experts will adjudicate all rehospitalizations to judge whether a 
hospitalization is due to heart failure. The committee will be blinded to the treatment 
allocation, and will independently review each case in order of appearance. Their 
independent opinions are reconciled at the endpoint adjudication committee meeting. If an 
endpoint is not unanimous, the case is reviewed further and discussed with the aim of 
developing a consensus. If the committee is unable to reach a consensus, the endpoint will 
be established by the committee chair. 

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A hospitalization for heart failure will be defined as follows:  
Hospitalization for more than one day (change in calendar day) with an exacerbation of heart 
failure requiring treatment meeting the following criteria:  
- 
Signs and symptoms of heart failure 
o One or more of the following symptoms consistent with heart failure: 
▪ 
Dyspnea 
▪ 
Orthopnea 
▪ 
Paroxysmal nocturnal dyspnea 
▪ 
Increasing fatigue/decreasing exercise tolerance 
▪ 
Edema/anasarca 
▪ 
Other symptoms of worsened end-organ perfusion such as 
dizziness, mental confusion 
o AND two or more of the following sign consistent with heart failure: 
▪ 
Weight gain 
▪ 
Pulmonary edema or rales 
▪ 
Elevated jugular venous pressure 
▪ 
Radiologic signs of heart failure 
▪ 
Peripheral edema 
▪ 
Abdominal distension or ascites 
▪ 
S3 gallop rhythm 
▪ 
Positive hepatojugular reflux 
▪ 
Elevated NT-proBNP 
▪ 
Congestive hepatomegaly 
▪ 
Invasive/non-invasive tests showing elevated cardiac filling 
pressures or low cardiac output 
- 
AND treatment 
o The patient receives initiation or intensification of treatment specifically for 
heart failure, 
 

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STATISTICAL ANALYSIS 
7.6 Primary study parameter(s) 
The primary endpoint will be assessed in the intention to treat (ITT) population. The co-
primary endpoint will be total 24-hour natriuresis and first occurrence of all-cause mortality or 
heart failure rehospitalisation at 6 months. Following the Bonferroni correction used for the 
sample size calculation, the study will be deemed positive if one or both of the components 
of the co-primary endpoint are positive (P-value<0.025).  
24-hour natriuresis will be calculated and presented as mean +/- SD if normally distributed, 
or median (25th and 75th percentile) in the case of non-normal distribution. The between 
group difference will be tested using t-test if normally distributed, or Wilcoxon rank sum test if 
non-normally distributed. The effect of natriuresis guided treatment on long-term outcomes 
will be assessed using Cox regression for the between treatment difference. 
For the presentation of baseline characteristics in both treatment arms, continuous variables 
will be presented as mean +/- SD, non-normally distributed variables as median (25th – 75th 
percentile), and categorical values as count (percentages).  
 
7.7 Secondary study parameter(s)  
Secondary response variables include 48- and 72-hour natriuresis, length of hospital stay 
and percentage change in NT-proBNP at 48- and 72-hours. Changes in biomarkers, 
natriuresis at subsequent time points, and length of hospital stay will be assessed using t-test 
for normal distributed variables, and Wilcoxon rank sum test if non-normally distributed.  
 
7.8 Other study parameters 
Adverse event rates, including doubling of serum creatinine at 24 or 48 hours, serious 
adverse events, as well as worsening heart failure will be analyzed using Fisher’s exact 
tests, and presented as counts (percentages). To study differences in repeated assessments 
between treatment groups, such as natriuresis during hospitalization, repeated measures 
linear mixed effect modeling will be used.  
 
7.9 Interim analysis (if applicable) 
Not applicable 

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8. ETHICAL CONSIDERATIONS 
8.1 Regulation statement 
This clinical study was designed and shall be implemented and reported in accordance with 
the guidelines for Good Clinical Practice, with applicable local regulations, and with the 
ethical principles held down in the Declaration of Helsinki (date 19-10-2013). This study will 
be conducted in accordance with the medical Research involving Human Subjects Act 
(WMO). The guidelines mentioned in WMO will be the principle guidelines.  
An institutional review board that complies with the requirements of applicable Law shall 
review and approve this protocol, including the informed consent form, in accordance with 
Applicable Law.  
 
8.2 Recruitment and consent 
Recruitment of patients will take place at the Emergency Department, Coronary Care Unit or 
Ward of the department of Cardiology of the University Medical Center Groningen. Once a 
potentially eligible patient is diagnosed with acute heart failure, the Principal Investigator or a 
sub-investigator (physician) will verify eligibility based on the in- and exclusion criteria. Once 
eligibility has been established, the patient will be enrolled. Because of the acute situation 
and the nature of the study treatment, there is limited time (at that moment) for the patient to 
consider participation, therefore deferred consent will be used. At this time treatment will 
start, as well as collection of urine. The patient will receive the patient information letter about 
the study during the first four days of hospitalization and will have a maximum of 24 hours to 
consider his/her participation. During this time written informed consent will be obtained by 
the researcher.  
.  
10.3 Objection by minors 
8.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
 
8.4 Benefits and risks assessment, group relatedness 
Loop diuretics are the cornerstone of treatment in patients with acute heart failure. Loop 
diuretics are relatively safe and well tolerated by patients in acute heart failure. There is a 
wealth of data describing its use in this patient group, as well as in patients with a decreased 
kidney function. Combination of loop diuretics with other diuretic agents, such as 
acetazolamide has been shown to be able to improved decongestion. Risks of combination 
diuretic therapy are electrolyte disorders and decrease in kidney function. We will therefore 

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only initiate combination diuretic therapy in patients with insufficient decongestion already on 
maximal loop diuretic doses. We will additionally closely monitor renal function and 
electrolytes throughout the study. Furthermore, assessment of natriuresis is at low risk and 
minimal hassle to the patient as it does not involve additional invasive procedures. Based on 
the previous, the relative risk is estimated to be relatively low, while potential benefit may be 
expected.  
 
8.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
8.6 Incentives  
Patients will not receive any incentives, compensations or treatment through participation in 
the study.  

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9. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
9.1 Handling and storage of data and documents 
A subject identification code list will be made to link the data to the subject in order to be able 
to trace data to an individual subject. This code will not be based on the patients initials and 
birth date. The key to the code will be safeguarded by the investigator since the data will be 
kept for a period of 15 years. The handling of personal data will comply with privacy laws, 
legislation, codes and/or guidelines that apply in the applicable jurisdictions the study is 
conducted.  
 
9.2 Monitoring and Quality Assurance  
Independent monitors will monitor the study according to a pre-specified monitoring plan. 
The monitors are trained in GCP and will be trained on study specific tasks and processes. 
As part of the UMCG Quality Management Strategy monitor oversight will be implemented 
through regular documentation reviews and co-monitoring activities.  
 
9.3 Amendments  
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will not be notified to the accredited METC and the competent 
authority, but will be recorded and filed by the sponsor.  
 
9.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
9.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the 
study within a period of 90 days. The end of the study is defined as the last patient’s last visit.  
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 

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accredited METC and the Competent Authority.  
 
9.6 Public disclosure and publication policy 
The trial will be registered in a public trial registry. The results will be disclosed 
unreservedly. 

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10. STRUCTURED RISK ANALYSIS  
10.1 Potential issues of concern 
Not applicable as the drugs in this study are used for their registered indication.  
 
10.2 Synthesis 
Loop diuretics are the cornerstone of treatment of acute heart failure by attempting to 
establish a negative sodium and consequently fluid balance. Loop diuretics inhibit the 
sodium-chloride-potassium co-transporter in the thick ascending loop of Henle and as such 
lead to decreased sodium and chloride reabsorption from the urine. There is ample data on 
loop diuretic use in acute heart failure patients as these are administered to >90% of patients 
hospitalization for acute heart failure. Loop diuretics currently have a class 1C indication in 
the heart failure guidelines to improve symptoms. All of the drugs used in the study have 
been used extensively in clinical trials of patients with (acute) heart failure and have been 
granted approval for their use in heart failure patients.  
In this study adverse events of special interest are collected. These include worsening heart 
failure and true worsening renal function. These side effects are rare but will be 
monitored closely by regular monitoring of clinical status and renal function. The potential 
benefits of natriuresis guided therapy to improve the treatment of acute heart failure clearly 
outweigh the risk of developing these adverse events. 

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11. REFERENCES 
1. www.volksgezondheidzorg.info/onderwerp/hartfalen.  
www.volksgezondheidzorg.info/onderwerp/hartfalen  
2. Ter Maaten JM, Valente MA, Damman K, Hillege HL, Navis G, Voors AA. Diuretic 
response in acute heart failure-pathophysiology, evaluation, and therapy. Nat Rev Cardiol 
2015;12:184-192. 
3. Testani JM, Brisco MA, Turner JM, Spatz ES, Bellumkonda L, Parikh CR, Tang WH. Loop 
Diuretic Efficiency: A Metric of Diuretic Responsiveness with Prognostic Importance in Acute 
Decompensated Heart Failure. Circ Heart Fail 2013; 
4. Valente MA, Voors AA, Damman K, Van Veldhuisen DJ, Massie BM, O'Connor CM, Metra 
M, Ponikowski P, Teerlink JR, Cotter G, Davison B, Cleland JG, Givertz MM, Bloomfield DM, 
Fiuzat M, Dittrich HC, Hillege HL. Diuretic response in acute heart failure: clinical 
characteristics and prognostic significance. Eur Heart J 2014; 
5. Voors AA, Davison BA, Teerlink JR, Felker GM, Cotter G, Filippatos G, Greenberg BH, 
Pang PS, Levin B, Hua TA, Severin T, Ponikowski P, Metra M, for the RELAX-AHF 
Investigators. Diuretic response in patients with acute decompensated heart failure: 
characteristics and clinical outcome-an analysis from RELAX-AHF. Eur J Heart Fail 2014; 
6. ter Maaten JM, Dunning AM, Valente MAE, Damman K, Ezekowitz JA, Califf RM, Starling 
RC, van der Meer P, O'Connor CM, Schulte PJ, Testani JM, Hernandez AF, Tang WHW, 
Voors AA. Diuretic response in acute heart failure - an analysis from ASCEND-HF. American 
Heart Journal 2015; 
7. Ter Maaten JM, Valente MA, Damman K, Cleland JG, Givertz MM, Metra M, O'Connor 
CM, Teerlink JR, Ponikowski P, Bloomfield DM, Cotter G, Davison B, Subacius H, van 
Veldhuisen DJ, van der Meer P, Hillege HL, Gheorghiade M, Voors AA. Combining Diuretic 
Response and Hemoconcentration to Predict Rehospitalization After Admission for Acute 
Heart Failure. Circ Heart Fail 2016;9:10.1161/CIRCHEARTFAILURE.115.002845. 
8. Damman K, Ter Maaten JM, Coster JE, Krikken JA, van Deursen VM, Krijnen HK, Hofman 
M, Nieuwland W, van Veldhuisen DJ, Voors AA, van der Meer P. Clinical importance of 
urinary sodium excretion in acute heart failure. Eur J Heart Fail 2020; 

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9. Testani JM, Hanberg JS, Cheng S, Rao V, Onyebeke C, Laur O, Kula A, Chen M, Wilson 
FP, Darlington A, Bellumkonda L, Jacoby D, Tang WH, Parikh CR. Rapid and Highly 
Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart 
Failure. Circ Heart Fail 2016;9:e002370.