Conditions: Heart Failure
Keywords: acetazolamide bumetanide cardio-renal syndrome diuretics heart failure natriuresis spironolactone
Allocation: RANDOMIZED | Intervention model: FACTORIAL
Enrollment: 34
Healthy volunteers: no

Brief summary:
This study has two primary objectives:

1. To compare combination therapy with acetazolamide and low-dose loop diuretics versus high-dose loop diuretics (standard of care) in patients with acute decompensated heart failure at high risk for diuretic resistance.
2. To demonstrate the safety and efficacy of upfront therapy with spironolactone in addition to loop diuretic therapy in patients with acute decompensated heart failure at high risk for diuretic resistance.

Detailed description:

Arms:
arm 1: 2x2 factorial design: This group is the experimental group for both study interventions (acetazolamide and upfront spironolactone).

See interventions for more details. arm 2: 2x2 factorial design: This group is the experimental group for the study intervention with upfront spironolactone. This group receives high-dose loop diuretics as an active comparator to the study intervention with acetazolamide.

See interventions for more details. arm 3: 2x2 factorial design: This group is the experimental group for the study intervention with acetazolamide. This group receives no intervention with regards to the spironolactone arm.

See interventions for more details. arm 4: 2x2 factorial design: This group receives high-dose loop diuretics as an active comparator to the study intervention with acetazolamide. This group receives no intervention with regards to the spironolactone arm.

See interventions for more details.

Interventions: intervention 1: Combination therapy with acetazolamide and low-dose loop diuretics intervention 2: High-dose loop diuretics intervention 3: Upfront therapy with oral spironolactone
Intervention descriptions: intervention 1: * Patients receive 500 mg of intravenous acetazolamide immediately after randomization, with 250 mg intravenous acetazolamide administered on each consecutive day in the morning for as long as the patient is considered volume overloaded by his/her treating cardiologist.
* Patients receive 2 mg of intravenous bumetanide immediately after randomization, with 1 mg intravenous bumetanide administered on each consecutive day in the morning for as long as the patient is considered volume overloaded by his/her treating cardiologist.
* If diuresis \<1,5 L while the patient is still considered volume overloaded by his/her treating cardiologist, the dose of acetazolamide is maintained at 500 mg and the dose of bumetanide is maintained at 2mg.

In case of therapy-refractory congestion, treatment is at the discretion of the treating physician, but addition of chlorthalidone 50 mg PO is recommended by the investigators as a first-line option. intervention 2: * Patients receive the double of their daily maintenance dose of oral loop diuretics converted to mg bumetanide as an intravenous bolus after randomization.
* Patients continue to receive this dose daily on the next 3 days divided between two administrations with at least a 6 h interval for as long as they are considered volume overloaded by the treating cardiologist.
* If diuresis \<1,5 L while the patient is still considered volume overloaded by the treating cardiologist, the dose of bumetanide is doubled.

In case of therapy-refractory congestion, treatment is at the discretion of the treating physician, but addition of chlorthalidone 50 mg PO is recommended by the investigators as a first-line option. intervention 3: Patients randomized to this group receive oral spironolactone (25mg) immediately after randomization and in the morning of each subsequent day unless the serum potassium level is \>5 mmol/L.

Note: Investigators and treating physicians are blinded to treatment allocation for this arm, but no matching placebo is provided, so patients are not.

Protocol document:
Prot_SAP_000.pdf: 
DIURESIS-CHF – Study protocol version August 27, 2015 
 
1
Official Title: Diamox/Aldactone to Increase the URinary Excretion of 
Sodium: an Investigational Study in Congestive Heart Failure 
NCT01973335 
Date: August 27, 2015 
 
 


DIURESIS-CHF – Study protocol version August 27, 2015 
 
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1. Background 
Aging of the population and prolongation of the lives of cardiac patients by modern 
therapeutic innovations have led to an increased incidence of congestive heart failure 
(CHF).1 During the last two decades, important progress has been made in the treatment of 
ambulatory CHF patients with reduced ejection fraction. Renin-angiotensin system blockers, 
β-blockers, mineralocorticoid receptor antagonists (MRA), ivabradine and cardiac 
resynchronization therapy have all demonstrated to reduce morbidity and/or mortality in 
ambulatory CHF patients.2-17 Despite these important advances, many patients are still 
hospitalized frequently with signs and symptoms of systemic congestion, which is associated 
with worse outcome.18 Treatment in these cases mainly focuses on symptomatic relief 
through administration of diuretics, although clear evidence on the optimal agent, dosing 
schedule, and administration route is lacking. 
Coexisting renal dysfunction often complicates decongestive treatment and 
worsening renal function (WRF), often defined as a 0.3 mg/dL rise in serum creatinine (Cr), is 
a common finding in this context.19 However, the prognostic impact of WRF, defined as Cr 
change is unsure as it might be associated with worse, neutral or even better outcome.20-22 In 
contrast, persistent congestion, as a reflection of the inability of the kidneys to preserve 
sodium homeostasis, has been more consistently associated with higher mortality and more 
frequent readmissions in CHF.23 This suggests that achieving a negative sodium balance 
might be an attractive treatment target in heart failure. 
Loop diuretics are by far the most commonly used diuretic agents to achieve a 
negative sodium balance in acute decompensated heart failure (ADHF). Especially in 
diuretic-naïve patients, they are often very effective to relief dyspnea and congestive 
symptoms. However, in the recent Diuretic Optimization Strategies Evaluation (DOSE) trial, 
no differences in patients’ global assessment of symptoms or change in renal function were 
observed when loop diuretics were administered by bolus as compared with continuous 


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infusion or at high versus low dose during a hospitalization for ADHF, with high dose therapy 
currently considered as usual care by most clinicians.24 Importantly, there are several 
reasons why loop diuretics might be less effective or even harmful in CHF. First, loop 
diuretics directly stimulate renin production by inhibiting the Na+/K+/2Cl--cotransporter on the 
luminal side of the macula densa, which depletes intracellular chloride levels in the macula 
densa. The consequence is an increased COX-2 and NOS I activity in macula densa cells, 
leading to paracrine PGE2 and NO secretion.25 Both PGE2 and NO work in concert to 
stimulate renin release by granulosa cells of the afferent arteriole and further detrimental 
activation of the renin-angiotensin-aldosterone axis. Second, impaired secretion of loop 
diuretics in the proximal tubules of CHF patients, especially when there is concomitant renal 
dysfunction, results in lower concentrations at the place where these agents act – the luminal 
side of the thick ascending limb of Henle’s loop (TAL). Third, increased sodium reabsorption 
in the proximal tubules might result in less sodium offered to the TAL, especially if glomerular 
filtration is concomitantly impaired, hampering the efficacy of loop diuretics. As a result, 
physicians often use combination therapies of different acting diuretic agents in order to 
increase the overall diuretic effect.  
From a pathophysiological point of view, targeting sodium reabsorption in the 
proximal tubules has several potential benefits in CHF. First, it is the place where most 
sodium is reabsorbed, especially in ADHF. Second, greater delivery of chloride to macula 
densa cells will decrease renin production, ceasing neurohumoral activation. Third, 
endogenous natriuretic peptides (acting in the distal nephron) will possibly regain their 
effects. The carbonic anhydrase inhibitor acetazolamide (Diamox®), which is approved for 
the treatment of mountain sickness and is used to increase the diuretic efficacy of loop 
diuretics in patients with therapy-refractory congestion, inhibits sodium reabsorption in the 
proximal tubules. Remarkably, in a small study of 9 patients with advanced CHF and diuretic 
resistance, therapy with acetazolamide was able to elicit potent diuresis.26 Despite this 


DIURESIS-CHF – Study protocol version August 27, 2015 
 
4
promising case series and the pathophysiological rationale for inhibition of proximal sodium 
reabsorption in ADHF, acetazolamide is now a largely forgotten diuretic. 
MRA have an established role in the treatment of chronic CHF.11, 12 However there 
are remarkable few data on their use in patients who present with ADHF. Nevertheless, in 
this context with frequent use of potassium wasting diuretics, they might be of particular 
interest to prevent occurrence of hypokalemia, which has been associated with a worse 
prognosis.27 Moreover, by inhibiting distal tubular sodium reabsorption and counteracting 
aldosterone breakthrough, MRA might improve the natriuretic efficiency of loop diuretics. 
2. Study Hypotheses 
1. Combination therapy with acetazolamide improves loop diuretic efficacy to induce 
natriuresis in ADHF patients, allowing for a lower dose of the latter medication and 
potentially less adverse events such as worsening renal function. 
2. Combination therapy with acetazolamide and low-dose loop diuretics leads to less 
pronounced neurohumoral activation compared to treatment with high-dose loop 
diuretics in ADHF patients. 
3. Upfront therapy with MRA is safe in patients presenting with ADHF and lowers the 
incidence of hypokalemia and the need for potassium supplementation, without 
causing a higher incidence of hyperkalemia. 
4. Combination diuretic therapy with acetazolamide and/or upfront spironolactone will 
lead to improved clinical outcome (less heart failure rehospitalizations and lower 
all-cause mortality). 
3. Study Protocol 
3.1. 
Study design 
Randomized clinical trial with factorial 2x2 design, 2 treatment arms, and 4 groups (n=20 
each): 


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 
Arm 1: Acetazolamide + low-dose loop diuretics versus high-dose loop diuretics 
(=standard of care) 
 Triple blinded to treatment allocation (patient, treating physician and investigator 
blinded) 
 
Arm 2: Upfront versus discharge spironolactone 
 Treating physician and investigator blinded to treatment allocation. Patient not 
blinded to treatment allocation because no matching placebo will be provided due to 
logistic constraints. 
Consecutive patients, presenting with ADHF at different Belgian hospitals will be screened by 
staff members, cardiology fellows, a study nurse and the cardiology Ph.D. fellows. All those 
people will be able to login via the website www.hartcentrumlimburg.be, where they can print 
the case report form and informed consent of the study and will receive the randomization 
number by a computer algorithm with blocks of 4. 
3.2. 
Study population 
3.2.1. Inclusion criteria 
 
Older than 18 years of age and able to give informed consent 
 
Clinical diagnosis of ADHF within the previous 8 h 
 
At least two clinical signs of congestion (e.g. edema, ascites, jugular venous 
distension or pulmonary vascular congestion on chest radiography) 
 
Maintenance therapy with oral loop diuretics at a dose of at least 1 mg bumetanide or 
an equivalent dose for at least 1 month before hospital admission 
Conversion: 1 mg bumetanide = 40 mg furosemide = 20 mg torsemide 
 
Plasma NT-proBNP >1,000 pg/mL 
 
Left ventricular ejection fraction <50% (on examination ≤3 months) 
 
One out of three of the following criteria: 
o Serum sodium <136 meq/L 


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6
o Urea/creatinine ratio >50 
o WRF defined as a >0.3 mg/dL increase in Cr compared to a previous value 
within 3 months before admission 
3.2.2. Exclusion criteria 
 
History of a cardiac transplantation and/or ventricular assist device 
 
Concurrent diagnosis of an acute coronary syndrome defined as typical chest pain 
and/or electrocardiographic changes in addition to a troponine rise >99th percentile 
 
Systolic blood pressure <90 mmHg or mean arterial pressure <65 mmHg at the 
moment of admission 
 
Use of intravenous inotropes, vasopressors or nitroprusside at any time point during 
the study 
 
A baseline estimated glomerular filtration rate <15 mL/min/1.73m² according to the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 
 
Use of renal replacement therapy or ultrafiltration before study inclusion 
 
Treatment with acetazolamide during the previous month 
 
Treatment with ≥2 mg bumetanide or an equivalent dose of loop diuretics during the 
index hospitalization before randomization 
 
Use of diuretics or MRA not specified by the protocol 
 
Exposure to nephrotoxic agents (i.e. contrast dye) anticipated within 3 days 
 
 


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3.3. 
Interventions (See Addendum 1 for therapy schedules) 
3.3.1. Arm 1, control group: High-dose loop diuretics 
- 
At the moment of randomization the patient receives an intravenous bolus of loop 
diuretics at a dose equal to the double of his normal daily oral dose (e.g. a patient 
who takes 1x1 mg bumetanide will receive 2x1x1 mg = 2mg; or a patient who takes 
2x1 mg bumetanide will receive 2x2x1 mg = 4mg). 
- 
The next three days, the patient will receive the same dose equally divided between 
two administrations at 10u00 and 16u00 provided that the treating physician has 
concluded during the morning rounds that the patient is still volume overloaded. 
- 
If diuresis since administration of the previous dose of loop diuretics is <1,500 mL and 
the patient is still volume overload, subsequent bolus doses are doubled. 
- 
If after doubling of the dose, the patient is considered therapy-refractory. The treating 
physician is recommended to add chlorthalidone 50mg once daily and consider 
ultrafiltration or renal replacement therapy after which results of the patient will be 
censored. 
- 
Switch to treatment at the discretion of the treating physician if any of the following 
criteria is fulfilled 
 
After 3 days 
 
The patient had no longer clinical signs or symptoms of congestion 
 
Doubling of the serum creatinine value 
3.3.2. Arm 1, treatment group: Acetazolamide + low-dose loop diuretics 
- 
At the moment of randomization, the patient receives 500 mg of intravenous 
acetazolamide and 2 mg of intravenous bumetanide in bolus. 
- 
The next three days, the patient will receive 250 mg of intravenous acetazolamide 
and 1 mg of intravenous bumetanide in bolus at 10u00 provided that the treating 
physician has concluded during the morning rounds that the patient is still volume 
overloaded. 


DIURESIS-CHF – Study protocol version August 27, 2015 
 
8
- 
If diuresis since administration of the previous dose of loop diuretics is <1,500 mL and 
the patient is still volume overloaded, the patient continues to receive 500 mg of 
acetazolamide and 2 mg of bumetanide. 
- 
If after doubling of the dose, the patient is considered therapy-refractory. The treating 
physician is recommended to add chlorthalidone 50mg once daily and consider 
ultrafiltration or renal replacement therapy after which results of the patient will be 
censored. 
- 
Switch to treatment at the discretion of the treating physician if any of the following 
criteria is fulfilled 
 
After 3 days 
 
The patient had no longer clinical signs or symptoms of congestion 
 
Doubling of the serum creatinine value 
3.3.3. Arm 2, control group: Discharge spironolactone 
This group will receive no active treatment. No placebo will be provided either due to logistic 
constraints. As instructed by the guidelines, addition of a MRA to maintenance therapy will 
be recommended upon discharge from the hospital. 
3.3.4. Arm 2, treatment group: Upfront spironolactone 
This group will receive oral spironolactone 25 mg immediately after randomization and 
subsequently each day in the morning (10u00) provided serum potassium levels are 
<5.0 mmol/L. If no contraindications emerge during hospitalization, spironolactone will be 
added to the maintenance therapy of the patient upon hospital discharge. 
3.3.5. All groups 
All groups will receive the same maintenance intravenous therapy with 500 mL Glucose 5% 
and 3g MgSO4 administered over a 24enin-angiotensin system blockers and β-blockers) will 
be continued at the discretion of the treating physician, but they are recommended to keep 
maintenance dosages unchanged. 


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9
3.4. 
Collected data 
 
Baseline at the moment of randomization 
o Demographics, medical history, current medical therapy, baseline body 
weight, 
blood 
pressure, 
heart 
rhythm 
(sinus 
or 
not), 
heart 
rate, 
Visual-analogue scale (VAS) score for dyspnea and 4-point Likert scale for 
edema will be assessed upon study inclusion 
o Blood sample: hematocrit, electrolytes, serum osmolality, serum urea, serum 
creatinine, serum Cystatin C, serum urate, plasma renin activity (PRA), 
plasma aldosterone, plasma adrenaline, plasma noradrenaline, total protein, 
plasma NT-proBNP 
 
Day 1-3: 
o VAS score for dyspnea 
o 4-point Likert scale for edema 
o Body weight and fluid balance 
o Blood pressure, heart rate, heart rhythm 
o Blood sample: hematocrit, electrolytes, serum osmolality, serum urea, serum 
creatinine, serum Cystatin C, serum urate, PRA,  plasma aldosterone, plasma 
adrenaline, plasma noradrenaline, total protein, plasma NT-proBNP 
 
Three consecutive 24h urinary collections will be performed; the first one started with 
the first bolus administration of loop diuretics; urinary assessment of creatinine, 
protein, sodium, potassium, chloride, ureum, urate, microalbuminura 
 
At an outpatient follow-up appointment 2-6 weeks after hospital discharge, a final 
blood sample with hematocrit, electrolytes, serum osmolality serum urea, serum 
creatinine, serum Cystatin C, serum urate and plasma NT-proBNP will be collected. 
 
All-cause mortality and hospital readmissions will be collected prospectively for the 
study cohort. The patient will receive a telephone call from a study nurse after 3, 6, 9 
and 12 months 


DIURESIS-CHF – Study protocol version August 27, 2015 
 
10
3.5. 
Study end-points 
3.5.1. Primary study end-point acetazolamide arm 
Total urinary sodium excretion (mmol) after 24 h 
3.5.2. Pimary study end-point for spironolactone arm 
Incidence of hypo- (serum potassium <3.5mmol/L or need for oral/intravenous potassium 
supplements) or hyperkalemia (serum potassium >5.0mmol/L) during the entire 72 h 
interval after randomization. 
3.5.3. Secondary end-points 
 
Relative plasma NT-proBNP change (%) after 72 h compared to admission 
 
Worsening renal function defined as a >0.3 mg/dL increase in serum creatinine or a 
>20% decrease in estimated glomerular filtration rate by the CKD-EPI formula 
compared to baseline at any time point before 72 h 
 
Persistent renal impairment, defined as persistently elevated serum creatinine levels 
>0.3 mg/dL or a >20% decrease in estimated glomerular filtration rate by the CKD-
EPI formula compared to baseline at the moment of outpatient follow-up 2-6 weeks 
after hospital discharge. 
 
Peak plasma aldosterone concentration (ng/L) after 72 h 
 
Peak plasma renin activity (ng/mL/h) after 72 h 
3.5.4. Other pre-specified outcome measures 
 
Total urinary sodium excretion (mmol) after 48 h and 72 h 
 
Total urine output after 24 h, 48 h and 72 h 
 
Change in VAS score for dyspnea at 24 h, 48 h and 72 h 
 
Change in 4-point Likert scale for edema at 24 h, 48 h and 72 h 
 
Body weight change upon hospital discharge compared to admission 
 
Incidence of therapy-refractory congestion defined as the need for combinational 
diuretic therapy with chlorthalidone, bail-out ultrafiltration or renal replacement 
therapy 


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11
 
Incidence of all-cause mortality and readmissions after 1 year 
3.6. 
Statistical analysis 
Continuous variables will be expressed as mean ± standard deviation when normally 
distributed and as median (interquartile range) in case of a non-normal distribution. 
Normality 
will 
be 
assessed 
by 
the 
Shapiro-Wilk 
statistic. 
The 
independent-samples Student’s t-test and Mann-Whitney U test will be used as indicated 
to compare between groups. Categorical variables will be expressed as percentages 
and compared using Fisher’s exact test or Pearson’s χ2-test in case of a non-binary 
response. Statistical significance will always be set at a 2-tailed probability level of 
<0.05. All statistics will be performed using IBM SPSS® (Chicago, Illinois, USA) (version 
22.0 for Mac). 
4. Potential adverse events 
 
Metabolic acidosis is the only agent-specific adverse event that might be expected 
from treatment with acetazolamide. Serum bicarbonate is monitored daily. If serum 
bicarbonate <22 meq/L, substitution with oral NaHCO3 will be provided. 
 
Hyperkalemia might be expected as a potential adverse event of spironolactone, but 
this medication will be withheld when serum potassium levels are >5.0 mmol/L and 
serum potassium levels are monitored daily throughout the study. 
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