Conditions: Heart Failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
Hyponatremia is a common finding in acute heart failure (HF) patients and is associated with worse prognosis. In addition to its prognostic value, hyponatremia may have importance during the acute management of HF. We've recently shown that acute or chronic hyponatremia, especially \<130 mEq/L, was associated with higher loop diuretic dose requirements and more frequent need for escalation of the diuretic regimen to achieve the same level of diuresis as normonatremic HF patients. Aquaresis with tolvaptan represents a potentially advantageous approach to the management of volume overload in HF, especially in patients presenting with concomitant hyponatremia. The purpose of the current study is to prospectively evaluate the comparative efficacy and safety of a tolvaptan-based diuretic regimen compared to conventional diuresis with a furosemide-based regimen on short-term clinical and treatment outcomes in hyponatremic acute HF patients.

This will be a prospective, open-label, parallel-group, randomized study comparing a tolvaptan-based aquaretic regimen to a conventional continuous infusion loop diuretic-based regimen of furosemide. Up to 55 (target sample size of 50) adult subjects admitted with acute HF and signs of volume overload, and serum sodium less than 135 mEq/L will be randomized to tolvaptan or furosemide treatment arms. The initial 24 hours of study treatment will compare tolvaptan monotherapy to furosemide monotherapy. After the initial 24 hours, treatment regimens may be altered to achieve desired clinical goals. Patients will be followed for up to 96 hours and at discharge for study purposes.

Detailed description:

Arms:
arm 1: Tolvaptan 30-60mg once daily (with rescue loop diuretic or metolazone) arm 2: Furosemide continuous infusion 5mg/h with option to titrate (with rescue metolazone)

Interventions: intervention 1: Tolvaptan intervention 2: Furosemide
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 1 
 
 
 
CLINICAL PROTOCOL 
 
 
AQUARESIS UTILITY FOR HYPONATREMIC ACUTE HEART FAILURE  
(AQUA-AHF) STUDY 
Protocol #: HS-13-00705 
Phase IV 
 
Principal Investigators: 
Tien M.H. Ng, Pharm.D. 
Uri Elkayam, M.D. 
 
Co-Investigators: 
Luanda Grazette, M.D. 
Michael Fong, M.D. 
Andrew Yoon, M.D. 
 
Study Site: 
Los Angeles County + University of Southern California Medical Center 
University of Southern California 
Los Angeles, California 
 
 
PI Contact Information: 
Tien M.H. Ng, Pharm.D., FCCP, BCPS (AQ-C) 
Associate Professor of Clinical Pharmacy and Medicine 
University of Southern California School of Pharmacy 
1985 Zonal Ave 
Los Angeles, California, USA 90033 
tienng@usc.edu 
323-442-184 office 
323-442-1681 fax 
 
 
 
Version:  March 8, 2013 
 
Amendment 1:  July 30, 2014 
 
Amendment 2: August 9, 2017 
 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 2 
 
Protocol Synopsis 
AQUARESIS UTILITY FOR HYPONATREMIC ACUTE HEART FAILURE (AQUA-AHF) STUDY 
Protocol # HS-13-00705 
Study Type 
Prospective, randomized, open-label, parallel-group 
 
Hypothesis 
Volume management of acute congestive heart failure complicated by 
hyponatremia with a vasopressin-receptor antagonist-based aquaretic regimen 
is more effective and with fewer adverse events than a loop diuretic-based 
regimen. 
 
Objectives 
1. Compare urine output and length of hospital stay between a vasopressin 
receptor antagonist-based regimen to a loop diuretic-based regimen for 
hyponatremic heart failure patients hospitalized with evidence of volume 
overload. 
2. Compare the safety (renal function, electrolyte abnormalities, and 
hemodynamics) of vasopressin receptor antagonist-based to a loop 
diuretic-based regimen for hyponatremic heart failure patients hospitalized 
with evidence of volume overload. 
 
Interventions 
1. Tolvaptan (with rescue loop diuretic or metolazone). 
2. Furosemide (with rescue metolazone) 
 
Eligible patients will be randomized within 48 hours of presentation to the 
hospital.  Tolvaptan will be dosed initially at 30mg daily, with the option to 
titrate up to a maximum of 60mg daily.  Furosemide will be initiated as a 
continuous infusion at 5mg/h, with the option to titrate higher.  Monotherapy 
with the study medication must be continued for at least the first 24 hours.   If 
after 24 hours the diuretic response is deemed inadequate, the dose of study 
medication may be increased and/or the use of additional diuretic agents may 
be initiated at the discretion of the treating physician.  Physicians will be 
encouraged to increase the primary study drug before the use of additional 
diuretic agents as clinically acceptable.   
 
Patient Population 
N=50 
Requiring hospitalization for acute heart failure with evidence of volume 
overload, and a serum sodium concentration of < 135 mEq/L documented 
within the first 48 hours of the admission.  Initial treatment with diuretics prior 
to randomization is allowable.  A maximum of 25 patients will be enrolled with 
serum sodium concentrations between 130 to 134 mEq/L as the inclusion. 
 
Inclusion Criteria 
Acute HF with signs or symptoms of volume overload (i.e. elevated JVP, rales, 
edema) 
Serum sodium < 135 mEq/L at time of or within first 48 hours of hospitalization 
Randomized within 48 hours of presentation to hospital 
≥ 18 years of age 
Informed consent 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 3 
 
Exclusion Criteria 
Severe symptomatic hyponatremia requiring acute treatment (Patients 
requiring intervention to raise serum sodium urgently to prevent or to treat 
serious 
neurological symptoms e.g. any seizure activity or any neurologic impairment 
deemed to require immediate treatment by the primary treating physician) 
Severe renal impairment upon admission (creatinine clearance < 20 mL/min) 
Renal replacement therapy dependent, or requiring upon admission 
Acute coronary syndrome on admission 
Evidence of cardiogenic shock or requiring intravenous vasopressors 
VAD 
Pregnancy 
Patient requiring concomitant use of strong CYP3A4 inhibitors (clarithromycin, 
ketoconazole, itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, 
nefazodone, and telithromycin) 
 
Primary Endpoints 
Primary efficacy endpoint: Mean urine output at 24 hours post randomization 
Primary safety endpoint:  Mean change in serum creatinine at 24 hours post 
randomization 
 
Secondary 
Endpoints 
Efficacy: 
Urine output at 8, 48, 96 hours post-randomization, total at discharge 
Mean hourly urine output at 24 hours 
Serum sodium change at 8, 24, 48, 96 hours, and at discharge 
Weight change at 24, 48, 96 hours, and at discharge 
Cumulative furosemide dose at 48, 96 hours, and at discharge 
Cumulative use of metolazone at 48, 96 hours, and at discharge 
Self-rated change in dyspnea (Likert Scale) at 24 and 96 hours 
Safety: 
GFR change at 24, 48, 96 hours, and at discharge (estimated from Scr) 
Acute worsening of kidney function (increase in Scr 0.3 mg/dL or 25% above 
baseline) 
Electrolyte abnormalities (hypokalemia, hypomagnesemia, 
hyper/hyponatremia)  
Hypotension 
Changes in plasma renin activity, copeptin, cystatin C concentrations, NT-
proBNP 
In-hospital mortality 
Hospital length of stay (ICU and total) 
 
Statistical Plan 
A total of 50 patients (25 in each group) would provide 93% power to detect a 
difference of 50% in urine output at 24 hours between treatments, alpha=0.05.  
The power was calculated based on the magnitude of difference in urine output 
seen in the ACTIV-CHF (24 hour mean urine output for tolvaptan was 
approximately 4100±2100mL vs 2300±1100mL compared to placebo when 
added to standard therapy) and in the Udelson et al study (24 hour mean 
increase in urine output with tolvaptan monotherapy 2600±1500mL vs 
900±850mL with furosemide).  Based on our previous data demonstrating poor 
response to loop diuretics in the hyponatremia acute HF population, we believe 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 4 
 
a 50% difference (standard deviation of 25%) is a reasonable and conservative 
estimate of what the difference will likely be.     
 
Descriptive statistics will be computed for each treatment group. For all 
comparative analyses between the two treatment groups, independent 
samples t-test and Chi-Square test (or Fisher’s exact test) will be performed for 
continuous variables or categorical variables, respectively.  If either the 
normality or equal-variance assumptions underlying the traditional t-tests are 
violated, a non-parametric test will be used. 
 
Amendment August 9, 2017: 
Due to slow enrollment, we anticipate not achieving our desired sample size of 
50 subjects.  Our revised power calculation reveals that if we achieve a mean 
difference with the same magnitude standard deviation between groups (e.g. 
mean difference is 1000±1000mL), our power will be between 80-90% with a 
sample size between 34-46 subjects.  Based on current rate of enrollment, it is 
likely that we will achieve a sample of at least 34 subjects, which should allow 
the results to be meaningful despite early termination of enrollment. 
 
   
Study Duration 
18 months 
 
 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 5 
 
Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
   
List of Abbreviations …………………………………………………………………………………………….  
1. Introduction …………………………………………………………………………………………………….  
2. Study Rationale and Objectives .……………………………………………………………………….  
3. Study Design 
 
3.1 Trial Design 
 
 
3.1.1 Design .……………………………………………………………………………….  
 
 
3.1.2 Study Procedures Overview .………………………………………………  
 
 
3.1.3 Study Duration …………………………………………………………………..  
 
3.2 Study Endpoints 
 
 
3.2.1 Efficacy Endpoints  …………………………………………………………….  
 
 
3.2.2 Safety Endpoints ……………………………………………………………….. 
3.3 Study Population 
 
 
3.3.1 Inclusion Criteria ………………………………………………………………..  
 
 
3.3.2 Exclusion Criteria ……………………………………………………………….  
 
 
3.3.3 Informed Consent ………………………………………………………………  
 
3.4 Randomization 
 
 
3.4.1 Randomization Procedure ………………………………………………….  
3.4.2 Study Drugs ………………………………………………………………………..  
 
3.5 Study Procedures 
 
 
3.5.1 Screening ……………………………………………………………………………  
 
 
3.5.2 Randomization ……………………………………………………………………  
 
 
3.5.3 12 hours ……………………………………………………………………………..  
3.5.4 24 hours ……………………………………………………………………………..  
3.5.5 48 hours ……………………………………………………………….. …………..  
3.5.6 72 hours ……………………………………………………………………………..  
3.5.7 96 hours ……………………………………………………………………………..  
3.5.8 Discharge from hospital ………………………………………………………  
 
3.6 Removal of Patient from Study ……………………………………………................  
4. Endpoint Assessment 
4.1 Data Points …………………………………………………………………………………………  
4.2 Study Laboratory Assessments 
 
 
4.2.1 Assessments of Investigational Laboratory Parameters ……….  
 
 
4.2.2 Performance of Investigational Laboratory Assays ………………  
5. Evaluation of Adverse Effects 
 
5.1 Definitions …………………………………………………………………………………………..  
 
5.2 Reporting …………………………………………………………………………………………….  
6. Statistical Analysis 
 
6.1 Sample Size Calculation and Power Analysis ………………………………………..  
 
6.2 Endpoint Analyses ……………………………………………………………………………….  
7. Risk Analysis 
7.1 Data Safety Monitoring ……………………………………………………………………….  
8. Drug Management 
 
8.1 Drug Storage ……………………………………………………………………………………….  
 
8.2 Drug Dispensing and Tracking ……………………………………………………………..  
9. Reports and Records Management 
Page 
6 
7 
9 
 
 
10 
10 
10 
 
11 
11 
 
11 
11 
11 
 
12 
12 
 
12 
12 
12 
13 
13 
13 
13 
13 
14 
 
14 
 
14 
14 
 
15 
15 
 
16 
16 
 
16 
 
16 
16 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 6 
 
 
9.1 Source Documents ……………………………………………………………………………..  
 
9.2 Data Collection …………………………………………………………………………………… 
 
9.3 File Management and Retention ………………………………………………………… 
10. Ethics and Regulatory Issues 
 
10.1 Institutional Review Board ……………………………………………………………….  
 
10.2 Informed Consent and HIPAA …………………………………………………………..  
 
10.3 Clinical Trials registration …………………………………………………………………  
10. Confidentiality ………………………………………………………………………………………………..  
11. Investigator Listing ………………………………………………………………………………………….  
12. References ……………………………………………………………………………………………………..  
 
17 
17 
17 
 
17 
17 
17 
17 
18 
19 
 
 
 
List of Abbreviations 
 
CRF – case report form 
CYP450 – cytochrome P-450 oxidative enzymes 
GFR – glomerular filtration rate 
HF – heart failure 
HIPAA – Health Insurance Portability and Accountability Act  
ICU – intensive care unit 
JVP – jugular venous pulsation 
LVSD – left ventricular systolic dysfunction 
NYHA FC – New York Heart Association Functional Classification 
PRA – plasma renin activity 
RAAS – Renin-Angiotensin-Aldosterone System 
Scr – serum creatinine concentration 
UO – urine output 
 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 7 
 
 
1. Introduction 
 
1.1 Hyponatremia in Hospitalized Patients 
Hyponatremia is one of the most commonly encountered electrolyte abnormalities in hospitalized 
patients.1-5 In clinical practice, hyponatremia is usually defined as serum sodium of ≤ 135 mmol/L 
(mEq/L). Although hyponatremia is commonplace in the hospitalized setting, the true incidence of this 
condition remains poorly characterized.  Zilberberg and colleagues in a retrospective cohort study of 
over 190,000 patients reported a 5.5% incidence of hyponatremia at the point of hospital admission.6 
However, other studies suggest that the incidence may be as high as 15%.1    
 
Extensive literature suggest that hyponatremia in the hospitalized setting is associated with an increase 
in mortality.  Uncontrolled trials have reported mortality in hyponatremic patients ranging from 5-51% 
depending on study design and serum sodium cut- offs. One prospective observational, case controlled 
study found that mortality of hospitalized patients with hyponatremia was 27% compared to 9% in 
normonatremic patients.7  This study also found that patients with hyponatremia had higher serum 
creatinine concentrations and longer length of hospital stays as compared to controls.  Zilberberg et. al. 
also found a higher in-hospital mortality rate in hyponatremic patients (5.9%) compared to 
normonatremic patients (3%).6  In addition, even mild hyponatremia (serum sodium concentration 
between 130-134 mEq/L) may be detrimental, increasing in-hospital mortality by 37% compared to 
those with normonatremia.2  It remains unclear why hyponatremia is associated with increased 
mortality.  It is hypothesized that hyponatremia may be a signal for important physiologic abnormalities 
in patients with cardiovascular diseases, or a predictor of other severe consequence associated with 
sodium irregularities such as cerebral edema.2 
 
1.2 Hyponatremia and Heart Failure Outcomes 
Heart failure (HF) patients are especially prone to developing hyponatremia. Several retrospective 
analyses have reported the prevalence of hyponatremia in the chronic HF population to be 19.7-27% 
based on admission serum sodium concentrations.8-12 Heart failure patients often develop hypervolemic 
hyponatremia due to water retention which is associated with excessive neurohormonal stimulation.13  
However, hyponatremia may also persist in HF patients who are euvolemic.   
 
Hyponatremia is frequently regarded as a marker for the severity of HF.  Several studies have suggested 
that hyponatremia in HF is associated with increased length of stay, morbidity, and mortality.8-12 In the 
OPTIMIZE-HF registry, lower admission sodium (<135 mmol/L) was associated with higher in-hospital 
mortality (6.0% vs. 3.2%), longer length of stay (6.4 days vs. 5.5 days), and 60-90 day mortality (12.4% vs. 
7.1%) compared to normal admission sodium.  For each 3 mmol/L decrease in admission sodium below 
140 mmol/L, the risk of in-hospital mortality was increased by 19.5% in patients with left ventricular 
systolic dysfunction (LVSD) and by 8.6% in patients with non-LVSD.9  Similarly, in the OPTIME-CHF trial, 
patients with the lowest baseline serum sodium (median < 134 mmol/L) experienced longer length of 
hospital stays, and higher in-hospital and 60-day mortality. Consistent with the results from OPTIMIZE-
HF, each 3 mmol/L decrease in admission sodium values was associated with an 18% relative increase in 
the probability of death within 60 days.8  In a study of HF patients with preserved left ventricular 
ejection fraction, Rusinaru et. al. demonstrated hyponatremia was a powerful predictor of 7-year 
mortality.12  One limitation of all the above studies was that the assessment of hyponatremia was made 
based solely on admission serum sodium concentrations.   Results from the ESCAPE trial suggest that a 
significant proportion of normonatremic patients on admission also developed hyponatremia during  
the hospitalization.  This study found a 15.9% incidence of acute hyponatremia, although the association 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 8 
 
to patient outcomes was not assessed.11  However, we recently demonstrated that acute hyponatremia 
has the same prognostic value as hyponatremia detected upon admission.14  There is now mounting 
evidence that hyponatremia is more than just a marker of disease severity. The ACTIV in CHF trial 
suggested that correction of hyponatremia was associated with a survival advantage. The 60-day 
mortality among patients with serum sodium levels that improved was 11.1% compared to 21.7% in 
those with persistent hyponatremia.10  
 
1.3 Hyponatremia and Treatment Response 
In addition to its prognostic value, hyponatremia may have importance during the acute management of 
HF i.e. influencing responses to treatment.  One concern related to the pharmacologic management of 
acute HF is the development of hypotension.  Data from ADHERE, a registry of acute HF patients, 
demonstrated that low systolic blood pressure is an independent predictor of in-hospital mortality.15  
Hyponatremia may predispose patients to hypotension.  In the OPTIME-CHF study, sustained 
hypotension defined as a low systolic blood pressure for > 30 minutes requiring intervention, was more 
common in patients within the lowest quartile of serum sodium (132-135 mEq/L).8  We also 
demonstrated that hyponatremia was associated with an increased risk of sustained hypotension in our 
acute HF patient population.14 
 
Another major concern in the management of acute HF is diuretic resistance.  Patients on chronic loop 
diuretic therapy may fail to respond to escalating doses of diuretics.  One proposed mechanism is the 
routine use of diuretics, which promotes the excretion of sodium, leads to the development or 
exacerbation of hyponatremia.13,16 Decreased sodium delivery to the kidney as a result of the decreased 
plasma sodium concentration would stimulate the macula densa to release renin, thereby activating the 
renin-angiotensin-aldosterone system (RAAS). This increase in RAAS activation may lead to further 
vasoconstriction and water retention, essentially counteracting the desired diuretic effect.  In support of 
this contention, we’ve recently shown that acute or chronic hyponatremia, especially <130 mEq/L, was 
associated with higher loop diuretic dose requirements and more frequent need for escalation of the 
diuretic regimen to achieve the same level of diuresis as normornatremic HF patients.14  Severity of 
hyponatremia was also associated with a greater than two-fold increase in the incidence of diuretic 
resistance, acute worsening renal function, sustained hypotension, increased length of stay, and in-
hospital mortality.  Our study results raised two important questions: 1) whether correction of 
hyponatremia can prevent or lower the risk of complications with conventional diuretics and 2) whether 
alternative treatments such as aquaretics (i.e. vasopressin receptor antagonists) represent a superior 
treatment modality for these patients.   
 
1.4 Tolvaptan and Volume Management in Heart Failure  
Aquaresis with tolvaptan represents a potentially advantageous approach to the management of 
volume overload in HF, especially in patients presenting with concomitant hyponatremia.  Several 
prospective, randomized, controlled trials have clearly demonstrated the efficacy of tolvaptan for 
augmenting diuresis when administered in combination with furosemide for the management of 
congestive HF symptoms.17-22  In addition, tolvaptan was also associated with a favorable safety profile, 
devoid of significant effects on serum electrolytes and incidence of acutely worsening renal function.  
The potential for tolvaptan to be used as an alternative to furosemide was recently considered in a 
study by Udelson et al.23  Eighty-three patients with stable NYHA FC II-III systolic HF and evidence of 
congestive symptoms were randomized to tolvaptan 30mg, furosemide 80mg, or the combination for 7 
days.  Tolvaptan was associated with a significantly greater daily urine output (approximately 
1700mL/24h greater than furosemide monotherapy) and decrease in body weight compared to 
furosemide or the combination.  Importantly, this study did not evaluate patients in an acute 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 9 
 
decompensated state, included only systolic HF patients, did not allow titration of diuretic doses, and 
was limited to comparison with furosemide administered orally.  Our data indicating poor outcomes 
with loop diuretics in hyponatremic acute HF patients, along with the Udelson study, suggest that 
tolvaptan may be a superior treatment modality for patients presenting in acute HF complicated by 
hyponatremia.  These are clinically challenging patients to manage due to their poor response to loop 
diuretics and their propensity for adverse effects.  Hence they represent an important niche for 
alternative diuretic strategies.  Therefore, there is a critical need to evaluate the role of tolvaptan 
monotherapy as a first-line option for the treatment of these clinically complex patients.  The purpose 
of the current study is to prospectively evaluate the comparative efficacy and safety of a tolvaptan-
based diuretic regimen compared to conventional diuresis with a furosemide-based regimen on short-
term clinical and treatment outcomes in hyponatremic acute HF patients.   
 
2. Study Rationale and Objectives 
 
Hyponatremia is the most common electrolyte abnormality in the hospital setting.1,3  Hyponatremia, 
based on admission values, has been associated with higher in-hospital mortality, 60-day mortality, 
longer length of hospital stay, and requirement for hospital readmissions.2,4,5  Similar findings are 
applicable to hospitalized HF patients as well.8-11  However despite these associations, the importance of 
hyponatremia to influence acute treatment decisions in acute HF remains equivocal due to a lack of 
data.  Importantly, we've recently shown that moderate to severe hyponatremia, especially <130 mEq/L, 
was associated with higher loop diuretic dose requirements and more frequent need for escalation of 
the diuretic regimen to achieve the same level of diuresis as normornatremic patients.14  Severity of 
hyponatremia was also associated with a greater than two-fold increase in the incidence of diuretic 
resistance, acute worsening renal function, sustained hypotension, increased length of stay, and in-
hospital mortality.  Our study results raised two important questions: 1) whether correction of 
hyponatremia can prevent or lower the risk of complications with conventional diuretics and 2) whether 
alternative treatments such as aquaretics (i.e. vasopressin receptor antagonists) represent a superior 
treatment modality for these patients?  Data from small subgroups of hyponatremic patients in the 
EVEREST and ACTIV-CHF studies indicated that tolvaptan is effective at raising serum sodium and urine 
output in these patients.20,21  In addition, tolvaptan monotherapy was shown to exert a greater effect on 
urine volume and weight loss than a fixed dose of furosemide in stable NYHA FC II-III systolic HF 
patients.23  However, these were not acutely decompensated patients, and a fixed dose of tolvaptan was 
being compared to fixed dose oral furosemide.  Therefore, there is a critical need to evaluate the role of 
aquaresis with tolvaptan as an acute treatment modality for acute HF complicated by hyponatremia.  
These patients pose a particularly difficult challenge when attempting to gain effective diuresis with 
loop diuretics.  The purpose of the current study is to prospectively evaluate the comparative efficacy 
and safety of a tolvaptan-based diuretic regimen compared to conventional diuresis with a furosemide-
based regimen on short-term clinical and treatment outcomes in hyponatremic acute HF patients.  Both 
reduced and preserved left ventricular systolic function patients will be studied. 
 
The following are the study objectives: 
1. Compare urine output and length of hospital stay between a vasopressin receptor antagonist-based 
regimen to a loop diuretic-based regimen for hyponatremic heart failure patients hospitalized with 
evidence of volume overload. 
2. Compare the safety (renal function, electrolyte abnormalities, hemodynamics, neurohormonal 
activation) of vasopressin receptor antagonist-based to a loop diuretic-based regimen for 
hyponatremic heart failure patients hospitalized with evidence of volume overload.   


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 10 
 
 
3. Study Design 
 
3.1 Trial Design 
 
3.1.1 Design 
This will be a prospective, open-label, parallel-group, randomized study comparing a tolvaptan-based 
aquaretic regimen to a conventional continuous infusion loop diuretic-based regimen of furosemide.  
The initial 24 hours of study treatment will compare tolvaptan monotherapy to furosemide 
monotherapy.  After the initial 24 hours, treatment regimens may be altered to achieve desired clinical 
goals. 
 
3.1.2 Study Procedures Overview 
 
3.1.3 Study Duration 
Study subject enrollment to occur over a 12-18 month period.  Data analysis will occur simultaneously 
once the final subject has been discharged from the hospital since no long term follow-up is planned. 
 
 
 
 
 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 11 
 
3.2 Study Endpoints 
 
3.2.1 Efficacy Endpoints 
 
Primary efficacy endpoint:  
Mean urine output at 24 hours post randomization 
 
Secondary efficacy endpoints: 
Urine output at 8, 48, 96 hours post-randomization, total at discharge 
Mean hourly urine output at 24 hours 
Serum sodium change at 8, 24, 48, 96 hours, and at discharge 
Weight change at 24, 48, 96 hours, and at discharge 
Cumulative furosemide dose at 48, 96 hours, and at discharge 
Cumulative use of metolazone at 48, 96 hours, and at discharge 
Change in self-rated dyspnea (Likert Scale) at 24 and 96 hours 
 
3.2.2 Safety Endpoints 
 
Primary safety endpoint:   
Mean change in serum creatinine at 24 hours post randomization 
 
Secondary safety endpoints: 
GFR change at 24, 48, 96 hours, and at discharge (estimated from Scr) 
Acute worsening of kidney function (increase in Scr 0.3 mg/dL or 25% above baseline) 
Electrolyte abnormalities (hypokalemia, hypomagnesemia, hyper/hyponatremia)  
Hypotension 
Changes in plasma renin activity, copeptin, NT-proBNP, and cystatin C concentrations 
In-hospital mortality 
Hospital length of stay (ICU and total) 
 
3.3 Study Population 
 
3.3.1 Inclusion Criteria 
• 
Requiring hospitalization for acute HF with signs or symptoms of volume overload (i.e. elevated 
JVP, rales, edema) 
• 
Serum sodium <135 mEq/L at time of or within first 48 hours of hospitalization (A maximum of 
25 patients will be enrolled with serum sodium concentrations between 130 to 134 mEq/L as 
the inclusion). 
• 
Randomized within 48 hours of presentation to hospital 
• 
≥ 18 years of age 
• 
Informed consent 
 
3.3.2 Exclusion Criteria 
• 
Severe symptomatic hyponatremia requiring acute treatment (Patients requiring intervention to 
raise serum sodium urgently to prevent or to treat serious neurological symptoms e.g. any 
seizure activity or any neurologic impairment deemed to require immediate treatment by the 
primary treating physician) 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 12 
 
• 
Severe renal impairment upon admission (creatinine clearance < 20 mL/min) 
• 
Renal replacement therapy dependent, or requiring upon admission 
• 
Acute coronary syndrome on admission 
• 
Evidence of cardiogenic shock or requiring intravenous vasopressors 
• 
Pregnancy 
• 
Patient requiring concomitant use of strong CYP3A4 inhibitors (clarithromycin, ketoconazole, 
itraconazole, ritonavir, indinavir, nelfinavir, saquinavir, nefazodone, and telithromycin) 
 
3.3.3 Informed Consent 
Signed written informed consent will be obtained prior to initiating any study procedure for each 
patient.   A signed copy of the Right of Research Participants and the Informed Consent, will be provided 
to each study subject, one copy in the patient medical records, and one copy retained by the 
investigators. 
 
3.4 Randomization 
 
3.4.1 Randomization Procedure 
If a patient is suitable to participate in the study and has given signed informed consent, the patient will 
be assigned a study number and randomized to one of the treatment arms.  Randomization will occur 
using a computer generated randomization list prepared by the principal investigator using a 10-block 
scheme prior to enrollment of the first study subject.  Randomization will also be stratified based on 
serum sodium at inclusion to 130-134 mEq/L and <130 mEq/L. 
 
3.4.2 Study Drugs 
Study drugs (and scheduled in-patient medications) will be administered in an open-label fashion. 
 
Patients randomized to tolvaptan will receive the study medication orally once daily.  Tolvaptan tablets 
will be administered at 24 hour intervals, scheduled based on when the initial dose is received.   
 
Patients randomized to furosemide will receive the medication as a continuous infusion.  The loop 
diuretic furosemide will be prepared as per standard procedures of the hospital pharmacy for 
administration via continuous intravenous infusion.   
 
After the initial 24 hour monotherapy period, escalation of the treatment regimen for either study arm 
will be either based on a minimum urine output < 100 mL/h or otherwise at the discretion of the 
primary treating physician to achieve clinical goals (e.g. relief of dyspnea, improvement in peripheral 
edema, resolution of jugular venous distention, improvement in pulmonary congestion based on chest 
radiograph, etc.).  Patients randomized to furosemide will not be eligible to receive tolvaptan as a mode 
to treatment escalation.  Tolvaptan dose will not be increased if serum sodium rises > 8 mEq/8 hours or 
>12 mEq/24h.   
 
3.5 Study Procedures 
 
3.5.1 Screening 
Patients eligible for enrollment will be screened for inclusion and exclusion criteria by one of the 
approved study investigators.  This includes assessment and documentation of patient’s past and 
current medical history, current admitting diagnosis, medications on admission, physical exam, and 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 13 
 
laboratory tests.  If the patient meets inclusion and exclusion criteria, signed written informed consent 
will be obtained.  Pregnancy test will be obtained in women of childbearing age. 
 
3.5.2 Randomization 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Blood drawn for cystatin C, plasma renin activity, NT-proBNP, and copeptin A 
Urine sample (for future analyses) 
Fluid balance and urine output  
Body weight 
Study drug dispensed and initiation time recorded 
Administer dyspnea survey (Likert Scale) 
 
3.5.3 8 hours 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Fluid balance and urine output  
Recording of any patient or physician reported adverse events 
 
3.5.4 24 hours 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Blood drawn for cystatin C, plasma renin activity, NT-proBNP, and copeptin A 
Urine sample (for future analyses) 
Fluid balance and urine output  
Body weight 
Recording of any patient or physician reported adverse events 
Study drug continued and/or adjustments to treatment regimen 
Administer change in dyspnea survey (Likert Scale) 
 
3.5.5 48 hours 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Urine sample (for future analyses) 
Fluid balance and urine output  
Body weight 
Recording of any patient or physician reported adverse events 
Study drug continued and/or adjustments to treatment regimen 
 
3.5.6 72 hours 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Blood drawn for cystatin C, plasma renin activity, NT-proBNP, and copeptin A 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 14 
 
Urine sample (for future analyses) 
Fluid balance and urine output  
Body weight 
Recording of any patient or physician reported adverse events 
Study drug continued and/or adjustments to treatment regimen 
 
3.5.7 96 hours 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Blood drawn for cystatin C, plasma renin activity, NT-proBNP, and copeptin A 
Urine sample (for future analyses) 
Fluid balance and urine output  
Body weight 
Recording of any patient or physician reported adverse events 
Study drug continued and/or adjustments to treatment regimen 
Administer change in dyspnea survey (Likert Scale) 
 
3.5.8 Discharge from hospital 
Implementation and documentation of the following procedures: 
Vital statistics 
Laboratory tests obtained 
Fluid balance and urine output  
Body weight 
Recording of any patient or physician reported adverse events 
 
3.6 Removal of Patient from Study 
If at any time the primary treating physician or the principal investigators feel it would be unsafe for the 
patient to continue on the study protocol, the patient will be discontinued from any further study 
procedures.  The patient will continue to be followed for non-investigational related endpoints (vital 
statistics, daily weights, fluid balance, standard laboratory tests, and disposition) until discharge from 
the hospital.   
 
4. Study Laboratory Assessments 
 
4.1 Data Points 
 
 
Randomization 
8 hours 
24 
hours 
48 
hours 
72 
hours 
96 
hours 
Discharge 
Vital Statistics 
X 
X 
X 
X 
X 
X 
X 
UO 
(Fluid Balance) 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
X 
X 
X 
X 
X 
Serum 
Chemistries 
X 
X 
X 
X 
X 
X 
X 
Cystatin C 
X 
 
X 
 
 
X 
 
PRA 
X 
 
X 
 
 
X 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 15 
 
Copeptin  
X 
 
X 
 
 
X 
 
NT-proBNP 
X 
 
X 
 
 
X 
 
 
4.2 Study Laboratory Assessments 
 
Neurohormonal activation has been implicated as a pathophysiologic mediator of acute worsening renal 
function and diuretic resistance in HF when conventional diuretics are utilized.  However, vasopressin 
receptor antagonists do not appear to increase plasma renin activity, which provides a potential 
mechanism to support the safety of these agents over conventional diuretics.   Copeptin is a marker for 
vasopressin activation and has been shown to have prognostic value in HF patients.  In addition, it may 
be a useful marker to identify patients who may exhibit a greater response to vasopressin receptor 
antagonists.  Cystatin C has been shown to have prognostic importance in acute HF and is a more stable 
marker of glomerular filtration rate compared to serum creatinine.  These additional laboratory 
assessments will be obtained to provide a more complete pathophysiologic model for the safety 
comparison between the two treatment groups. 
 
4.2.1 Assessments of Investigational Laboratory Parameters 
Blood samples will be obtained for analysis of cystatin C, plasma renin activity, and copeptin A at 
baseline, 24 hours and 96 hours.  Urine samples will be collected and stored for potential future analysis 
of renal injury markers. 
 
4.2.2 Performance of Investigational Laboratory Parameter Assays 
The investigational laboratory assessments (cystatin C and plasma renin activity) will be outsourced to 
Quest Diagnostics.  Copeptin A will be determined using a commercially available immunoassay (Brahms 
Copeptin Immunoassay, Thermofisher Scientific, Middleton, VA). 
 
5. Evaluation of Adverse Events 
 
5.1 Definitions 
Acute worsening of kidney function will be defined as an increase in Scr of 0.3 mg/dL or 25% above 
baseline (Scr at time of randomization). 
 
Electrolyte abnormalities will be defined as an occurrence of a laboratory value beyond the upper or 
lower limit of normal as defined by the institution’s laboratory standards (hypokalemia K+<3.5 mEq/L, 
hypomagnesemia Mg2+<1.7 mEq/L, hypernatremia Na+>145 mEq/L) 
 
Serum sodium overcorrection will be defined as the occurrence of an increase in serum Na+ > 8 mEq/L in 
8 hours or > 12 mEq/L in 24 hours.  For each event, any new neurologic sequelae (dysarthria, mutism, 
dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death) of 
overcorrection will also be recorded, otherwise the subject will be noted to be asymptomatic. 
 
Hypotension will be defined as a systolic blood pressure reading < 80 mmHg (confirmed by immediate 
repeat assessment) or a systolic blood pressure < 90 mmHg with symptoms.    
 
In-hospital mortality will be defined as any study subject death during the hospitalization regardless of 
cause. 
 
Safety Information will be collected in accordance with the current Code of Federal Regulations.   


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 16 
 
 
Safety information is defined as “Any information from any source containing information” such as: 
• Adverse event or suspicion thereof 
• Lack of efficacy 
• Overdose, abuse, misuse (even without resulting adverse reaction) 
• Medication error 
• Exposure during pregnancy or lactation (including uneventful) and reports where the embryo or 
fetus may have been exposed to medicinal products (either through maternal exposure or 
transmission of a medicinal product via semen following paternal exposure) 
• Counterfeit product 
• Transfer of infectious disease by the medicinal product concerned 
• Product complaint report which includes medically important information 
• Pediatric use 
• Occupational exposure  
• 
Off-label use 
 
5.2 Reporting 
Study subjects will be continuously monitored during the trial for the development of all serious and 
non-serious adverse events which were not present at the time of randomization in accordance with the 
current Code of Federal Regulations.  This information will be obtained through examination of the 
patient, laboratory work-up, and discussion with the patient and/or nursing staff.  All adverse events will 
be recorded and assessed for severity.  Serious adverse events will be reported within 24 hours to 
Otsuka (IRAE.Receipt@otsuka-us.com), and the Food and Drug Administration AERS via the Medwatch 
website (Form 3500). 
 
Otsuka will be notified of any adverse events or other safety information arising out of or relating to 
your study in accordance with the following timeline: 
(a) Twenty-four (24) hours from Date of First Receipt for Serious AE’s. (defined below);  
A serious adverse event includes any event that results in any of the following outcomes:  death, is life-
threatening (opinion of the investigator that the subject was at immediate risk of death), persistent or 
significant disability/incapacity, requires in-patient hospitalization or prolongs hospitalization, congenital 
anomaly/birth defect, other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above; or 
(b) Three (3) working days for pregnancy cases; or 
(c) End of study for non-serious adverse events or during the study upon Otsuka’s request. 
(d) At least two (2) weeks prior to submission of an aggregate safety report. 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 17 
 
A line-by-line listing of all serious adverse events will be sent once fifty percent (50%) enrollment is 
reached and at the end-of-study in order for Otsuka Safety & Pharmacovigilance to perform a 
reconciliation.   
 
The estimated start date for this study is August 15th, 2013.  Data collection will be considered complete 
once the final study subject has been discharged from the hospital.  This event is estimated to occur 
January 15th, 2015.  A study report will be finalized within one year of the end of data collection. 
 
6. Statistical Analysis 
 
6.1 Sample Size Calculation and Power Analysis 
A total of 50 patients (25 in each group) would provide 93% power to detect a difference of 50% in urine 
output at 24 hours between treatments, alpha=0.05.  The power was calculated based on the magnitude 
of difference in urine output seen in the ACTIV-CHF20 (24 hour mean urine output for tolvaptan was 
approximately 4100±2100mL vs 2300±1100mL compared to placebo when added to standard therapy) 
and in the Udelson et al23 study (24 hour mean increase in urine output with tolvaptan monotherapy 
2600±1500mL vs 900±850mL with furosemide).  Based on our previous data demonstrating poor 
response to loop diuretics in the hyponatremia acute HF population, we believe a 50% difference 
(standard deviation of 25%) is a reasonable and conservative estimate of what the difference will likely 
be.     
 
Amendment August 9, 2017: 
Due to slow enrollment, we anticipate not achieving our desired sample size of 50 subjects.  Our revised 
power calculation reveals that if we achieve a mean difference with the same magnitude standard 
deviation between groups (e.g. mean difference is 1000±1000mL), our power will be between 80-90% 
with a sample size between 34-46 subjects.  Based on current rate of enrollment, it is likely that we will 
achieve a sample of at least 34 subjects, which should allow the results to be meaningful despite early 
termination of enrollment. 
 
6.2 Endpoint Analyses 
Descriptive statistics will be computed for each treatment group. For all comparative analyses between 
the two treatment groups, independent samples t-test and Chi-Square test (or Fisher’s exact test) will be 
performed for continuous variables or categorical variables, respectively.  If either the normality or 
equal-variance assumptions underlying the traditional t-tests are violated, a non-parametric test will be 
used. 
  
7. Risk Analysis 
 
 
7.1 Data Safety Monitoring 
The principal investigators will be responsible for monitoring adverse events which may occur during the 
course of the study, and determine if the benefit to risk of amending study procedures or continuing the 
study is appropriate in order to mitigate any unforeseen risks. 
 
8. Drug Management 
 
 
8.1 Drug Storage  
All study medications will be stored by the Investigational Drug Service pharmacy.   


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 18 
 
 
 
8.2 Drug Dispensing and Tracking  
The Investigational Drug Service pharmacy will maintain all records related to receipt, inventory, 
dispensing of the study medications.   
 
9. Reports and Records Management 
 
9.1 Source Documents 
All source documents pertaining to the study will be maintained by the principal investigators.  These 
include the screening log, case report forms (CRFs), informed consent forms, laboratory results, and 
other supporting documentation where appropriate or needed.   
 
9.2 Data Collection 
All data will be collected manually on standardized CRFs.  Data from completed CRFs will be entered into 
a computer database.   
 
9.3 File Management and Retention 
All study documents will be retained by the principal investigators in a secured location for a minimum 
of 2 years after the study results have been published.   
 
10. Ethics and Regulatory Issues 
 
10.1 Institutional Review Board 
The study will be conducted in compliance all applicable laws and regulatory requirements.  The study 
will be submitted and approved through the Los Angeles County + University of Southern California 
Institutional Review Board.   
 
10.2 Informed Consent and HIPAA 
Signed written informed consent will be obtained prior to initiating any study procedure for each 
patient.   A signed copy of the Right of Research Participants and the Informed Consent, will be provided 
to each study subject, one copy in the patient medical records, and one copy retained by the 
investigators.  All study documents and procedures will be HIPAA compliant and use of protected health 
information will be minimized by encoding of the data. 
 
10.3 Clinical Trials Registration 
The study will be registered with www.clinicaltrials.gov through the Protocol Registration System. 
 
11. Confidentiality 
All data collected in the conduct of the study will be treated as confidential and will not be disclosed to 
any personnel not directly related to the study or authorized regulatory officials.  All investigators will 
have completed HIPAA training.  Each study subject will be assigned a study number, and this number 
will be the only identifier linking study data to the protected health information.   
 
12. Investigator Listing 
 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 19 
 
Tien M.H. Ng, Pharm.D., FCCP, BCPS (AQ-
C) 
 
Associate Professor of Clinical Pharmacy 
Director, PGY2 Residency in Cardiology 
University of Southern California 
Los Angeles, CA 
Uri Elkayam, M.D., FACC 
Professor 
Division of Cardiovascular Medicine 
USC Keck School of Medicine 
 
 
Michael Fong, M.D., FACC 
Associate Professor of Clinical Medicine 
Co-Director, Advanced Heart Failure and 
Cardiomyopathy 
Division of Cardiovascular Medicine 
USC Keck School of Medicine 
Andrew Yoon, M.D. 
 
 
 
 
 
 
Assistant Professor of Clinical Medicine 
Division of Cardiovascular Medicine 
USC Keck School of Medicine 
 
 
13. References 
 
1. 
Asadollahi K, Beeching N, Gill G. Hyponatraemia as a risk factor for hospital mortality. QJM : 
monthly journal of the Association of Physicians 2006;99:877-80. 
2. 
Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and 
severe hyponatremia. The American journal of medicine 2009;122:857-65. 
3. 
Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE. Impact of hospital-associated hyponatremia 
on selected outcomes. Archives of internal medicine 2010;170:294-302. 
4. 
Patel GP, Balk RA. Recognition and treatment of hyponatremia in acutely ill hospitalized 
patients. Clinical therapeutics 2007;29:211-29. 
5. 
Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. The American 
journal of medicine 2006;119:S30-5. 
6. 
Zilberberg MD, Exuzides A, Spalding J, et al. Epidemiology, clinical and economic outcomes of 
admission hyponatremia among hospitalized patients. Current medical research and opinion 
2008;24:1601-8. 
7. 
Gill G, Huda B, Boyd A, et al. Characteristics and mortality of severe hyponatraemia--a hospital-
based study. Clinical endocrinology 2006;65:246-9. 
8. 
Klein L, O'Connor CM, Leimberger JD, et al. Lower serum sodium is associated with increased 
short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of 
a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) 
study. Circulation 2005;111:2454-60. 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 20 
 
9. 
Gheorghiade M, Abraham WT, Albert NM, et al. Relationship between admission serum sodium 
concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the 
OPTIMIZE-HF registry. European heart journal 2007;28:980-8. 
10. 
Rossi J, Bayram M, Udelson JE, et al. Improvement in hyponatremia during hospitalization for 
worsening heart failure is associated with improved outcomes: insights from the Acute and Chronic 
Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial. Acute 
cardiac care 2007;9:82-6. 
11. 
Gheorghiade M, Rossi JS, Cotts W, et al. Characterization and prognostic value of persistent 
hyponatremia in patients with severe heart failure in the ESCAPE Trial. Archives of internal medicine 
2007;167:1998-2005. 
12. 
Rusinaru D, Buiciuc O, Leborgne L, Slama M, Massy Z, Tribouilloy C. Relation of serum sodium 
level to long-term outcome after a first hospitalization for heart failure with preserved ejection fraction. 
The American journal of cardiology 2009;103:405-10. 
13. 
Goldsmith SR. Current treatments and novel pharmacologic treatments for hyponatremia in 
congestive heart failure. The American journal of cardiology 2005;95:14B-23B. 
14. 
Ng TMH, Cao DX, Patel KA, Wong YM, Prasad M, Elkayam U. Hyponatremia is associated with 
diuretic resistance and a higher incidence of worsening renal function in patients with acute 
decompensated heart failure. Journal of the American College of Cardiology 2011;59:E105. 
15. 
Fonarow GC, Adams KF, Jr., Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-
hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. 
JAMA : the journal of the American Medical Association 2005;293:572-80. 
16. 
Rosner MH. Hyponatremia in heart failure: the role of arginine vasopressin and diuretics. 
Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular 
Pharmacotherapy 2009;23:307-15. 
17. 
Gheorghiade M, Niazi I, Ouyang J, et al. Vasopressin V2-receptor blockade with tolvaptan in 
patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 
2003;107:2690-6. 
18. 
Udelson JE, Orlandi C, Ouyang J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 
receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: an international, 
multicenter, randomized, placebo-controlled trial. Journal of the American College of Cardiology 
2008;52:1540-5. 
19. 
Costello-Boerrigter LC, Smith WB, Boerrigter G, et al. Vasopressin-2-receptor antagonism 
augments water excretion without changes in renal hemodynamics or sodium and potassium excretion 
in human heart failure. American journal of physiology Renal physiology 2006;290:F273-8. 
20. 
Gheorghiade M, Gattis WA, O'Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in 
patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA : the journal of 
the American Medical Association 2004;291:1963-71. 
21. 
Konstam MA, Gheorghiade M, Burnett JC, Jr., et al. Effects of oral tolvaptan in patients 
hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA : the journal of the American 
Medical Association 2007;297:1319-31. 
22. 
Matsuzaki M, Hori M, Izumi T, Asanoi H, Tsutamoto T. Effects of tolvaptan on volume overload 
in Japanese patients with heart failure: results of a phase II, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study. Cardiovascular drugs and therapy / sponsored by the 
International Society of Cardiovascular Pharmacotherapy 2011;25 Suppl 1:S19-31. 
23. 
Udelson JE, Bilsker M, Hauptman PJ, et al. A multicenter, randomized, double-blind, placebo-
controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan 
and furosemide in patients with heart failure and systolic dysfunction. Journal of cardiac failure 
2011;17:973-81. 


AQUA-AHF Study Protocol 
PIs: Ng T and Elkayam U 
 
Page 21