Tolvaptan for Volume Management in Heart Failure

Erik G. Gunderson,1 Matthew P. Lillyblad,2 Michelle Fine,3 Orly Vardeny,4 and Theodore J. Berei5,*
1
University of Iowa College of Pharmacy, Iowa City, Iowa; 2Department of Pharmacy, Abbott Northwestern
Hospital, Minneapolis, Minnesota; 3Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois;
4
University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota; 5Department of Pharmacy,
University of Wisconsin Hospitals and Clinics, Madison, Wisconsin

Volume management in acute decompensated and chronic heart failure (HF) remains a significant
challenge. Although progress has been made in the development of mortality-reducing neurohormonal
regimens in the reduced ejection fraction population, no clinical trial has yet demonstrated anything
more than symptomatic relief or biomarker reduction with pharmacotherapeutic volume-based inter-
ventions made in the acutely decompensated individual or those with evolving outpatient congestion.
As the number of patients with HF continues to grow, in addition to HF-related hospitalizations, iden-
tifying therapies that have the potential to aid in diuresis more safely and efficaciously is paramount to
decreasing inpatient length of stay and preventing unnecessary admissions. More recently, a significant
amount of research has been dedicated to the use of vasopressin antagonists, specifically tolvaptan, as
adjunctive therapy to loop and thiazide diuretics. Although these agents do not seem to have a perva-
sive role in fluid management in the acute decompensated and chronic HF populations, they are effec-
tive tools to have available for specific clinical situations. This review summarizes the literature
surrounding the use of tolvaptan for volume management in congestive HF, as well as offering practi-
cal guidance for use of this agent.
KEY WORDS heart failure, diuretics, cardiology, pharmacology, vasopressin receptor antagonists, vasopressin,
tolvaptan.
(Pharmacotherapy 2019;39(4):473–485) doi: 10.1002/phar.2239

Heart failure (HF), characterized by volume
overload in both extravascular and intravascular
spaces with reduced cardiac output, is a com-
mon clinical syndrome.1 Approximately 5.7 mil-
lion adults in the United States are currently
living with HF, and nearly half of those who
develop HF die within 5 years of diagnosis. The
global footprint of HF is also wide reaching,
with nearly 26 million diagnosed individuals,
placing the disease at pandemic level.2, 3 This
number is expected to grow, despite advances in
pharmacotherapy and prevention, given an aging
Conflict of interest: The authors have declared no
conflicts of interest for this article.
*Address for correspondence: Theodore J. Berei, Department
of Pharmacy, University of Wisconsin Hospitals and Clinics,
600 Highland Avenue, F6/133-1530, Madison, WI 53792-3284;
e-mail: Tedberei@gmail.com.
Ó 2019 Pharmacotherapy Publications, Inc.
population and life expectancy rates rising sec-
ondary to improved care of cancer, acute coro-
nary syndrome, and other comorbid conditions.
Total health care expenditures related to HF in
2012 were nearly $31 billion, with an expected
increase of 130% by 2030.4 As we continue
exploring the role of novel therapies in combat-
ing the morbidity and mortality of HF, there has
been a renewed focus on identifying better ways
to achieve more efficient diuresis. Given that the
number of HF hospitalizations for volume over-
load continues to rise annually and the progres-
sive nature of the disease, there is a need to
identify optimal pharmacotherapeutic options
for patients presenting initially and those on the
spectrum of refractoriness to conventional thera-
pies.5–7 Doing so can potentially decrease inpa-
tient length of stay and reduce readmissions,
particularly given that many patients are not
adequately diuresed at the time of discharge.8
474 PHARMACOTHERAPY Volume 39, Number 4, 2019
The introduction of the neprilysin-inhibitor/
angiotensin receptor blocker sacubitril/valsartan
and the funny channel inhibitor ivabradine
within the past 10 years has marked the next
wave of neurohormonal agents to combat the
progression of HF.9, 10 Although mortality has
been markedly reduced with the successive
introduction of renin-angiotensin-aldosterone
system (RAAS) inhibitors, b-blockers, and aldos-
terone antagonists, the literature has been
devoid of introducing any pharmacotherapy ini-
tiated at hospitalization for acute decompensated
HF or in the outpatient setting for patients with
congestive symptoms that improves clinical out-
comes. Although guidelines continue to support
the initial use of loop diuretics for volume man-
agement in chronic and acutely decompensated
patients, significant escalation in loop dosing is
often needed as the disease progresses. Further-
more, ceiling doses can be reached quickly, lim-
iting the ability to continue maximizing diuresis.
Given the variety of additional resistance mecha-
nisms that develop with continued exposure to
loop diuretics, physiologic adaptation in the dis-
tal renal tubule that allows for fluid reabsorp-
tion, and interplay between organic anion
transporters and loop diuretic nephron penetra-
tion, synergistic therapy is often needed with
thiazide (e.g., chlorothiazide, hydrochloroth-
iazide) or thiazide-like (e.g., metolazone) diuret-
ics as adjuncts.11 Not including ultrafiltration
and renal replacement therapy, no evidence-
based novel therapies have been added into the
diuretic armamentarium. With clinical research
demonstrating the neurohormone arginine vaso-
pressin (AVP), also known as antidiuretic hor-
mone, potentially playing a role in HF
progression, it was identified as a potential tar-
get to reduce morbidity and mortality.12
Vasopressin Physiology
Neurohormonal activation lies at the center of
HF, with activation of RAAS leading to a host of
compensatory downstream effects positively aug-
menting cardiac output. As such, the AVP path-
way is incited in this cascade causing systemic
release of AVP into the circulation. Once
secreted, AVP binds to the G-protein coupled
V1a (cardiac and smooth muscle vasculature),
V1b (pituitary), and V2 (cardiac and renal vascu-
lature) receptors. Binding of AVP to V1a recep-
tors increases intracellular calcium leading to
vasoconstriction and myocardial hypertrophy,
whereas stimulation of V2 receptors in the renal
collecting ducts leads to fluid retention through
aquaporin relocation to the luminal membrane.
Like RAAS stimulation, this process contributes
to clinical worsening of HF through fluid reten-
tion, increases in systemic vascular resistance,
and myocardial fibrosis.13 This is a cycle that
continues to progress rapidly unless treated with
neurohormonal modifying agents. Presumably,
blockade of the V1 receptors would lead to
vasodilation and reversal of cardiac remodeling.
V2 receptor blockade would then lead to
enhanced diuresis and sodium retention, both of
which are useful in hyponatremic HF patients.
Available Vasopressin Receptor Antagonists
Currently two vasopressin receptor antago-
nists (VRAs) are approved: tolvaptan and coni-
vaptan. Both have commonly been used for
treating hypervolemic and euvolemic hypona-
tremia. Major differences between the agents
include route of administration and vasopressin
receptor selectivity. Conivaptan, which primarily
targets the V1 receptors, is only available in an
intravenous formulation, limiting its use to the
inpatient setting. Tolvaptan more specifically
binds to V2 receptors, with nearly 5 times
greater affinity than conivaptan, and it is a more
versatile agent given oral availability. Both result
in a clinically significant increase in sodium
levels of 3–7 mmol/L on average with use, mak-
ing them useful agents for hyponatremia.9 More
recent research recognized the possible role of
AVP in congestive HF.13 As such, an abundance
of clinical trials has assessed the role of VRAs in
managing this disease. Given the more frequent
use of tolvaptan, this review focuses solely on
summarizing literature pertaining to its utilization.
Literature Search
Using PubMed and Embase databases, relevant
literature published between 1950 and 2018 was
identified using these keywords: vaptan, tolvap-
tan, acute decompensated heart failure, volume,
diuresis, heart failure, exacerbation, vasopressin,
vasopressin-2, and arginine vasopressin. A manual
search of reference lists was also conducted.
Articles not published in the English language
were excluded from this review, as well as case
reports and animal trials. Trials in progress were
identified by using the keywords just listed to
search the ClinicalTrials.gov database. Data in
the adult population (older than 18 yrs) were
the primary focus of this review.
 TOLVAPTAN USE IN HEART FAILURE Gunderson et al
Past Trials of Tolvaptan in Heart Failure
Vasopressin receptor antagonists represent a
novel therapeutic class for the treatment of acute
decompensated and chronic HF through
addressing the inappropriate antidiuretic hor-
mone secretion syndrome associated with
myocardial dysfunction. Over the past 2 dec-
ades, several large randomized controlled clini-
cal trials have explored the benefits and risks of
VRAs added to acute or acute then chronic HF
treatment. Much of the published literature used
tolvaptan for in-hospital HF treatment with the
primary objectives focused on tolvaptan’s effect
on diuresis, serum sodium, resolution of HF
signs and symptoms, and overall impact on
short- and long-term clinical outcomes
(Table 1). However, a growing body of literature
has assessed tolvaptan in the ambulatory setting.
Tolvaptan and Diuresis
The cardinal manifestations of HF include
dyspnea, fatigue, and fluid retention that can
lead to pulmonary, splanchnic, and peripheral
edema.22 Loop diuretics are considered the
mainstay of pharmacotherapy for volume man-
agement in the acutely decompensated and
chronic HF despite their association with
hypotension, electrolyte abnormalities, and
worsening renal function, all of which are pre-
dictors of poor prognosis.23 There remains a
critical need for more effective and safe conges-
tion management strategies in HF.
Elevations in AVP are proportional to the
severity of HF.24 V2 receptor binding leads to
fluid retention through solute-free water reab-
sorption in the collecting duct of the kidney.25
Antagonism of the V2 receptor with tolvaptan
has consistently enhanced diuresis when added
to standard of care across all studies in the acute
setting. The additional urine output gained in
the first 24 hours with tolvaptan when added to
standard care ranged from 641 ml to 1750 ml or
more in clinical trials14, 20 (Table 2). The
increase in urine output was associated with sig-
nificantly greater weight loss in the first
24 hours. In TACTICS-HF, a trial demonstrating
modest efficacy relative to other tolvaptan trials,
the diuretic response achieved was markedly
greater than other pharmacologic adjuncts to
traditional loop diuretic therapy previously
started in patients with HF.20, 26 The increased
urine output and weight loss provided by tolvap-
tan were in the setting of lower loop diuretic
475
dose compared with placebo.15, 18, 21 It is not
clear whether the reduction of 30–50 mg furose-
mide-equivalents daily was related to greater
titration of loop diuretics in the standard of care
arm or if tolvaptan provided a dose-sparing
effect. ACTIV, the only trial to compare different
doses of tolvaptan in HF, did not demonstrate a
substantial difference in urine output or weight
reduction between doses of 30, 60, and 90 mg/
day.14 The lack of dose response led subsequent
clinical trials to focus on the effect of tolvaptan
30 mg/day, with the exception of 15 mg used in
a patient population with diminished renal func-
tion.18 All dosing was daily and fixed with no
trial titrating tolvaptan doses to achieve a pre-
specified goal urine output or weight loss.
Increased urine output and weight loss was gen-
erally maintained throughout the duration of
treatment in the hospital, although the absolute
difference compared with standard of care
tapered off over time. In trials that continued
tolvaptan beyond hospitalization, the weight dif-
ferences were no longer significant at the first
follow-up assessment at 1 and 28 weeks, pre-
sumably related to loop diuretic titration in the
standard of care arms.14, 16 Overall, tolvaptan
added to standard therapy, including loop
diuretics, resulted in a greater net volume and
weight loss compared with placebo and standard
therapy.
Renal dysfunction is unfortunately prevalent
in HF patients and confers a poor prognosis.27
Decongestion in this population is particularly
problematic given that renal dysfunction con-
tributes to diuretic resistance and that the
cornerstone treatment for congestion, loop
diuretics, reduces renal blood flow leading to
prerenal azotemia and worsening renal func-
tion.28 Tolvaptan, however, was shown to
increase renal blood flow, decrease renal vascu-
lar resistance, and improve glomerular filtration
rate in patients with HF.29 Tolvaptan maintained
its effectiveness as a diuretic in trials that
enrolled a majority of patients with an estimated
glomerular filtration rate (eGFR) less than
60 ml/minute/1.73 m2.18, 21 Of note, the average
baseline serum creatinine was elevated in all tri-
als, but patients with serum creatinine greater
than 3.5 mg/dl or requiring renal replacement
therapy were excluded. Of the four trials evalu-
ating worsening renal function, defined as an
increase in serum creatinine of 0.3 mg/dl or
greater from baseline, only TACTICS described
a potential harm to the kidney with tolvaptan
(Table 2).20 This effect was transient with
476 PHARMACOTHERAPY Volume 39, Number 4, 2019
Table 1. Past Tolvaptan Trials in Heart Failure Patients
Design Population N Intervention Results of primary end point(s)
Multicenter Hospitalized adult patients 319 Tolvaptan 30 mg/ Change in body weight over 24 hrs:
prospective
randomized
with worsening systolic
heart failure and
day
Tolvaptan 60 mg/
• Day 1
double-blind systemic congestion day sT30 mg: 1.8 kg (p=0.002)
placebo- Tolvaptan 90 mg/ sT60 mg: 2.1 kg (p=0.002)
controlled day s T90 mg: 2.05 kg (p=0.009)
parallel group14 For up to 10 days s Placebo: 0.6 kg
inpatient followed Worsening heart failure (hospitalization
by a 7-wk (49– for heart failure, unscheduled visit
51 day) outpatient for heart failure to an emergency
treatment period department or clinic associated with
need for either increased therapy or
new therapy for heart failure, or
death):
• 26.7% vs 27.5% (p = NS)
Multicenter Hospitalized adult patients Trial A 2048 Tolvaptan 30 mg/ Change from baseline in patient-
prospective with worsening systolic Trial B 2085 day during assessed global clinical status (100-
randomized heart failure and hospitalization point visual analog scale) on the
double-blind systemic congestion inpatient day 7 or discharge, if
placebo- earlier:
controlled15
• Trial A: 1.06 vs 0.99 (p<0.001)
• Trial B: 1.07 vs 0.97 (p<0.001)
Multicenter Hospitalized adult patients 4133 Tolvaptan 30 mg/ All-cause mortality:
prospective
randomized
with worsening systolic
heart failure and
day for at least
60 days
• 25.9% vs 26.3% (p = NS)
Cardiovascular death or hospitalization
double blind systemic congestion for HF:
placebo
controlled15 • 42.0% vs 40.2% (p = NS)
Multicenter Adult patients with NYHA 240 Tolvaptan 30 mg/ Left ventricular end-diastolic volume
prospective functional class II to III day for 1 yr and function at 1 yr:
randomized
double blind
HF and EF ≤ 30%
• LVEDVI (ml/m2): 1.78 vs 0.04
(p = NS)
placebo
controlled16
• LVESVI (ml/m2): 3.28 vs
0.41 (p = NS)
• LVEF at 1 yr: 1.32 vs 0.52
(p = NS)
Multicenter Adult patients with 110 Tolvaptan 15 mg/ Change in weight from baseline:
randomized
double-blinded
evidence of fluid
overload on at least
day for 7 days
• 1.54  1.61 kg vs
0.45  0.93 kg, p<0.0001
placebo 40 mg/day of
controlled17 furosemide  thiazide
Multicenter Hospitalized adult patients 220 Tolvaptan 15 mg/ Urine output at 48 hrs:
prospective
randomized open
with ADHF and eGFR of
15–60 ml/min/1.73 m2
day for 48 hrs
• 6464.4 ml vs 4997.2 ml
(p<0.001)
label parallel
group 18
Prospective open Adult patients with 81 Tolvaptan 7.5– Daily urine output increase:
label
randomized19
residual congestion
despite furosemide dose
15 mg or up to
40 mg additional
• 459  514 vs 79  341 ml
(p<0.0003)
equivalent of at least furosemide
40 mg
Multicenter Hospitalized adult patients 257 Tolvaptan 30 mg/ Proportion of patient responders (at
prospective with ADHF and dyspnea day for 72 hrs least moderate improvement in
randomized at rest or with minimal dyspnea by 7-point Likert scale at
double blind exertion, elevated both 8 and 24 hrs, without death or
placebo natriuretic peptide level, need for rescue therapy within
controlled20 and at least one 24 hrs):
additional sign or
symptoms of congestion
• 16% vs 20% (p=0.32)

(continued)
 TOLVAPTAN USE IN HEART FAILURE Gunderson et al 477
Table 1 (continued)

Design Population N Intervention Results of primary end point(s)

Multicenter Hospitalized adult patients 250 Tolvaptan 30 mg/ Self-assessed dyspnea score (7-point
prospective with NYHA functional day during Likert scale) at 8 and 16 hrs
randomized class III or IV symptoms, hospitalization (for
• 8 hrs: 2.9 vs 3.0 (p = NS)
double blind
placebo
at least two signs of
extracellular volume
up to 7 days)
• 16 hrs: 2.7 vs 2.7 (p = NS)
controlled21 expansion plus dyspnea,
and at least one of the
following:
eGFR < 60 ml/min/
1.73 m2, serum
Na ≤ 134 mEq/L; or
UOP ≤ 125 ml/hr during
any 2-hr or longer
period during the initial
8 hrs after
administration of IV
furosemide of at least
40 mg (or equivalent)
ADHF = acute decompensated heart failure; EF = ejection fraction; eGFR = estimated glomerular filtration rate; HF = heart failure;
NA = sodium; NS = nonsignificant; NYHA = New York Heart Association; UOP = urine output.

Table 2. Heart Failure Improvement with Tolvaptan in Clinical Trials

Additional Additional weight Worsening Dyspnea Other
Daily UOP over loss over placebo renal symptoms signs/symptoms
Ejection fraction dose placebo at day 1 at day 1 function vs placebo of HF
14
< 40%: 100% 30 mg ↑ 1760 ml ↓ 1.2 kg No ↔ on day 1 ↔ JVD
60 mg ↑ 1879 ml ↓ 1.5 kg ↓ at DCa ↔ Edema
90 mg ↑ 1831 ml ↓ 1.5 kg
15
< 40%: 100% 30 mg NR ↓ 0.8 kg NR ↓ on day 1–4 ↓ Rales
↓ Orthopnea
↓ Fatigue
↓ JVD
↓ Edema
18
< 40%: 62% 15 mg ↑ 733 mlb ↓ 0.6 kgb No ↓ at 12 hrs ↔ Edema
↓ at 24 hrs ↔ Orthopnea
↓ at 48 hrs ↔ Pulmonary
Congestion
20
< 45%: 75% 30 mg ↑ 641 ml ↓ 1.5 kg Yes ↔ at 8 hrs NR
↔ at 24 hrs
↓ at 48 hrs
21
< 45%: 68% 30 mg NR ↓ 1.4 kg No ↔ at 24 hrs NR
↔ at 48 hrs
↓ at 72 hrs
DC = discharge, HF = heart failure, JVD = jugular vein distention, NR = not reported, UOP = urine output.
a
Median time to DC 4 days.
b
Total difference at 48 hrs divided by 2.

resolution after 72 hours of continued treatment.
The lack of renal effect with tolvaptan contrasts
with the DOSE trial in which higher doses of
loop diuretics produced more diuresis but also
worsened renal function more often.30 Despite
greater net fluid loss with tolvaptan, renal func-
tion does not appear to worsen. Treatment regi-
mens extended beyond hospitalization found no
clinically significant differences in renal function
parameters for up to 1 year.16, 31
Tolvaptan and Serum Sodium
Hyponatremia is prevalent in HF.32 Serum
sodium concentrations fall due to solute-free
fluid retention secondary to the antidiuretic
478 PHARMACOTHERAPY Volume 39, Number 4, 2019
properties of AVP, as well as the use of sodium-
depleting diuretic agents for management of
congestion.24, 33 Even when diuresis is the pri-
mary treatment target for tolvaptan, it is essen-
tial to understand tolvaptan’s effect on serum
sodium to avoid electrolyte derangements and
other adverse drug events.
Correction of sodium in euvolemic and
hypervolemic hyponatremia is the sole indica-
tion approved by the Food and Drug Adminis-
tration for tolvaptan, albeit not specific to the
HF population.34 This indication was a result
of the SALT-1 and SALT-2 clinical trials.35
SALT-1 and SALT-2 were identical concurrent
studies composed of roughly a third HF
patients with euvolemic or hypervolemic
hyponatremia conducted primarily in the outpa-
tient setting. The trials used a dose titration
strategy of 15–60 mg of tolvaptan based on
achieved serum sodium (less than 136 mEq/L)
and rate of rise (less than 5 mEq/24 hrs) to
achieve slow correction of serum sodium to a
target greater than 135 mEq/L. Serum sodium
levels were significantly higher at all study
assessments during the treatment period and
approached the normal range more rapidly than
placebo. Normonatremia (135–145 mEq/L) was
attained in 48% of patients on day 4 of treat-
ment and 56% on day 30 in patients with
tolvaptan. Marked hyponatremia (sodium less
than 130 mEq/L) was reduced to 11% of
patients on day 4 of treatment and 12% of
patients on day 30. Of note, the placebo arm
demonstrated an initial reduction in serum
sodium over the first 24–48 hours despite treat-
ment with standard of care. This is contrary to
the immediate rise in sodium achieved with the
addition of tolvaptan. The correction in serum
sodium did not consistently improve the mental
component of the Short Form-12 Health Survey
between the two trials. It is not clear whether
the beneficial effect on sodium end points with
tolvaptan was achieved in the HF cohort to the
same degree as the study population in either
trial. Although it was not studied specifically in
the HF population alone, the pathophysiology
of hyponatremia in HF and the mechanism of
action of tolvaptan suggest a response consis-
tent to the clinical trials. Tolvaptan can there-
fore be considered an effective treatment option
for patients with euvolemic and hypervolemic
hyponatremia.
Several clinical trials have evaluated tolvaptan
for the treatment of congestion in HF and also
reported its effect on serum sodium. All studies
used a fixed-dose approach to tolvaptan with
varying dosing from 15–90 mg/day as an adjunct
to standard diuresis. The average increase in
serum sodium with tolvaptan in the first
24 hours ranged from 2.8 mEq/L–3.5 mEq/L
(Table 3). ACTIV in CHF was the only study to
compare fixed doses of tolvaptan with each
other and placebo.14 The study reported less
than 1 mEq difference between fixed doses of
30, 60, and 90 mg at 24 hours and less than
1.5 mEq difference at discharge (average 4 days
of treatment) suggesting minimal dose-related
responses in patient populations that included a
normal baseline sodium. AQUAMARINE evalu-
ated tolvaptan 15 mg/day in patients with an
eGFR less than 60 ml/minute/1.73 m2 and found
comparable changes in sodium at 24 hours
(+2.8 mEq/L) to 30 mg/day studied in other tri-
als.18 Even in the setting of normonatremia, the
overall rates of hypernatremia with tolvaptan
were relatively low and tended to be more
prevalent in studies with less strict serum
sodium exclusion criteria. Investigators reported
the serum sodium in hypernatremic patients
were responsive to holding tolvaptan, and there
were no reports of critical hypernatremia with
clinical consequences. Osmotic demyelination
syndrome was not reported in any trial. Tolvap-
tan effect on serum sodium may not prohibit its
use to exploit its decongestive benefits regardless
of baseline serum sodium.
The pharmacodynamic response to tolvaptan
and subsequent serum sodium change varies
over the duration of treatment. In trials monitor-
ing serum sodium before 24 hours after the ini-
tial dose, the onset of sodium rise occurred at
6–8 hours and was consistent across stud-
ies.18, 35 After a peak response at 24 hours, the
effect of tolvaptan was maintained throughout
the study duration with slight increases in
sodium on subsequent treatment days in trials
using a fixed-dose strategy despite continued
diuresis and weight loss. This remained evident
in trials up to 1 year in duration and may be
explained, in part, by an increase in urine
sodium seen over time despite its primary aqua-
retic mechanism of action or a counterregulatory
response by the kidney.36 Sodium stabilization
took longer to occur in the SALT trials (5–
10 days), but these were the only studies with
dose titration targeting normonatremia.35 Serum
sodium remained stable for the remainder of the
30-day treatment period. After tolvaptan discon-
tinuation, there does not appear to be a honey-
moon period of sustained serum sodium levels
 TOLVAPTAN USE IN HEART FAILURE Gunderson et al 479
Table 3. Tolvaptan Trial Characteristics and Changes in Sodium
Exclusion % of population Change in sodium Rate of
Drug and dose Na level hyponatremia Mean baseline Na over time hypernatremia
35
Tolvaptan > 134 mEq/L 100% 128.7 mEq/L Day 1: +1.7 1.8%
15–60 mga < 120 mEq/L Day 4: +5.4
Day 30: +7.2
35
Tolvaptan > 134 mEq/L 100% 129.5 mEq/L Day 1: +2.1 1.8%
15–60 mga < 120 mEq/L Day 4: +6.3
Day 30: +6.9
14
Tolvaptan Day 1: +2.8
30 mg Dischargeb: +1.8
60 mg None 21.3% 138 mEq/L Day 1: +3.38 NR
Dischargeb: +3.1
90 mg Day 1: +3.50
Dischargeb: +3.2
15
Tolvaptan None 21% NR Day 1: +3.3 0.9%
30 mg Day 7 or discharge: +2.0
18
Tolvaptan > 147 mEq/L NR 140.5 mEq/L Day 1: +2.8 4.6%
15 mg Day 2: +2.4
20
Tolvaptan > 140 mEq/L NR 136 mEq/L Day 1: +3.2 0.8%
30 mg Day 2: +3.3
Day 3: +2.8
21
Tolvaptan > 144 mEq/L 19% NR NR 4.2%
30 mg
Na = sodium; NR = not reported.
a
Titrated to Na response.
b
Median time to discharge 4 days.

because serum sodium regressed to that of the
placebo arm at 7 days.35
Tolvaptan, Heart Failure Symptoms, and Clinical
Outcomes
Most patients hospitalized for decompensated
HF are highly symptomatic due, in part, to vol-
ume overload, making decongestion through
diuresis a primary treatment goal.22 Although
urine output and patient weight are objective
monitoring parameters for a patient’s volume
status, the congestive symptoms of HF are
equally important for the patient’s functional sta-
tus and overall well-being. Dyspnea is a com-
mon presenting symptom for patients in
decompensated HF, often secondary to pul-
monary edema, and it was a required presenting
symptom in the clinical trials of tolvaptan. All
trials of tolvaptan in acute HF evaluated dyspnea
at various time points in the treatment course
(Table 2). EVEREST and AQUAMARINE
reported dyspnea relief within 24 hours along-
side the demonstrated volume lost with
enhanced diuresis over the same time
frame.15, 18 Other tolvaptan trials did not
demonstrate early resolution of dyspneic symp-
toms but signaled improvements in dyspnea
compared with placebo after 72–96 hours of
treatment. The results of these trials suggest a
disconnect between early decongestion with
tolvaptan and the resolution of dyspnea. This
phenomenon was demonstrated previously.37
The disconnect may be related to the time
needed to redistribute fluid from the lung into
the vascular space. There are also challenges
associated with the patient-reported nature of
dyspnea including imperfect tools to quantify
improvements and psychological aspects of the
sensation unrelated to volume status. There is
nothing to suggest that VRAs can cause dyspnea,
so it is unclear why their decongestive efficacy
has not consistently improved this important
outcome. Other signs and symptoms of HF
including rales, orthopnea, fatigue, jugular
venous distention, and peripheral edema were
improved in some studies but not
others.15, 18, 20 Finally, global assessment scales
have not shown significant improvements with
tolvaptan over placebo potentially related to the
nonspecific nature of the measurement.14, 15
To date, chronic neurohormonal modulation
with guideline-directed medical therapy
improves important morbidity and mortality out-
comes in HF. Pharmacotherapeutic adjuncts to
traditional decongestion with loop diuretics in
hospitalized patients have yet to improve short-
and long-term clinical outcomes beyond volume
status and acute HF sign and symptom resolu-
tion. Arginine vasopressin represents another
480 PHARMACOTHERAPY Volume 39, Number 4, 2019
neurohormonal target for the treatment with
unique opportunity for use both acutely and
chronically in HF. Across all clinical trials,
enhanced decongestion and improvement in
serum sodium with tolvaptan did not lead to
clinically important improvements in outcome
such as length of stay or in-hospital mortality;
nor did they reduce the incidence of worsening
HF, readmissions, mortality, or other postdis-
charge outcomes. The results were the same
regardless of short-term treatment during hospi-
talization or extended treatment courses out to
1 year. Two post hoc analyses of clinical trials
found subpopulations of patient who may derive
greater benefit for VRAs than others. In EVER-
EST, patients with a serum sodium less than
130 mEq/L treated with tolvaptan had less car-
diovascular morbidity and mortality after dis-
charge.38 In ACTIV, extending treatment to
60 days was associated with significant reduc-
tions in mortality in high-risk subgroups includ-
ing hyponatremia, increased blood urea
nitrogen, and multiple signs of congestion.14 In
METEOR, tolvaptan was associated with a signif-
icant reduction in the combined end point of
mortality or HF hospitalization at 1 year for the
study population as a whole, but this was not a
prespecified end point, and the outcomes were
not adjudicated by a blinded central events com-
mittee.16 V2 receptor antagonism with tolvaptan
did not affect left ventricular remodeling, put-
ting into question its disease-modifying capabili-
ties. Vasopressin levels increased with V2
receptor blockade compared with placebo intro-
ducing the possibility that unopposed stimula-
tion of the V1a receptor could offset the
beneficial effects achieved with sole V2 antago-
nism. More research is needed to understand if
certain patient populations in HF confer a long-
term benefit from V2 antagonism or the potential
benefits of long-term dual V1a/V2 blockade.
Tolvaptan as Monotherapy
Based on the premise that a V2 receptor antag-
onist favorably affects volume-based weight loss
in patients with HF and the potential to reduce
loop diuretic dose requirements, investigators
undertook a randomized placebo-controlled trial
comparing tolvaptan, furosemide, or tolvaptan
and furosemide with placebo in patients with
chronic HF. Following a 2-day washout period
from their previous diuretic regimen, partici-
pants with New York Heart Association (NYHA)
functional class II or III with evidence of
persistent volume overload were randomized to
receive tolvaptan 30 mg, furosemide 80 mg,
tolvaptan 30 mg and furosemide 80 mg, or pla-
cebo daily, for 1 week. Participants were also
instructed to follow a low-+sodium diet during
the study (less than 2 g/day). The primary end
point was change in body weight from baseline
to day 8 or to the last day the participant was
on study for subjects who withdrew early. Inves-
tigators also assessed changes in urine volume,
electrolytes, neurohormones, and safety mea-
sures. Of 83 participants randomized, 79 com-
pleted the study. Significant differences in
baseline characteristics were not detected
between groups. On day 8, tolvaptan 30 mg/day
significantly reduced weight compared with pla-
cebo ( 1.27  1.60 kg vs +1.19  2.27 kg,
p<0.01). Differences between tolvaptan and furo-
semide, and tolvaptan compared with tolvaptan
plus furosemide, were in favor of tolvaptan at
day 2 but were not significantly different on day
8. Higher urine volumes were noted early in
tolvaptan groups compared with placebo and
furosemide monotherapy groups. Participants
taking tolvaptan exhibited early rises in serum
sodium compared with furosemide monotherapy
and placebo groups, which returned toward
baseline by day 8. Aldosterone levels were signif-
icantly reduced with tolvaptan compared with
placebo (p=0.025) and furosemide (p=0.015),
and with tolvaptan plus furosemide versus furo-
semide monotherapy (p=0.012). Adverse event
rates were similar between tolvaptan (59%) and
non-tolvaptan groups (62%); the most common
adverse effects were thirst and increased urinary
frequency. Notably, inclusion of a placebo, or
“no diuretic” group in this trial allowed for
assessment of monotherapy with tolvaptan.
Because p values were not adjusted for multiple
comparisons, and given the number of groups
and outcomes studied, findings should be inter-
preted cautiously.36
Tolvaptan and Renal Function
Although effects of tolvaptan on weight reduc-
tion have been demonstrated, impact on renal
function and neurohormone levels during acute
HF is less well defined. In a single-site study of
60 individuals with NYHA functional class IV
HF hospitalized with acute decompensated HF
(~30% with left ventricular ejection fraction less
than 40%), investigators randomized participants
to receive intravenous furosemide 20 mg twice/
day or oral tolvaptan 7.5 mg once/day for
 TOLVAPTAN USE IN HEART FAILURE Gunderson et al
5 days. All participants also received continu-
ously infused carperitide (a vasodilator) and
intravenous canrenoate potassium (a mineralo-
corticoid receptor antagonist). Furosemide
increased urine volume and resulted in larger
fluid balance compared with tolvaptan during
the first day of treatment. Over 5 days, both
treatments similarly increased urine volume and
fluid balance. Worsening renal function (defined
as a 0.3 mg/dl rise in serum creatinine) occurred
more frequently with furosemide compared with
tolvaptan (33% vs 6.7%; p<0.001), an effect that
was more pronounced in participants with HF
with preserved ejection fraction. Tolvaptan and
furosemide similarly reduced adrenaline, nora-
drenaline, and dopamine over the course of
treatment while furosemide increased plasma
renin more significantly compared with tolvap-
tan (p=0.014). Hyponatremia (defined as sodium
less than 135 mEq/L) was less common among
those taking tolvaptan (3.35% vs 30%, p<0.01).
Hospitalization duration did not differ signifi-
cantly between groups; nor did 6-month mortal-
ity between groups following hospital
discharge.39 Use of tolvaptan resulted in less
renal dysfunction and hyponatremia compared
with furosemide, with less potent early effects
on urine volume and fluid balance. The effect of
tolvaptan on fluid balance in the acute setting
without background intravenous vasodilator
therapy cannot be determined from this study.
As such, the prognostic importance differences
in renal effects between furosemide and tolvap-
tan are not known.
The Qualification of Efficacy and Safety in the
Study of Tolvaptan in cardiac edema (QUEST)
study explored the addition of tolvaptan in
patients with HF and fluid overload not ade-
quately controlled with conventional diuretics.
In this multicenter randomized double-blind pla-
cebo-controlled trial, 110 patients (inpatient or
outpatients who agreed to be hospitalized for
the study) with evidence of fluid retention and
using either at least 40 mg/day of furosemide, or
the combination of furosemide and thiazide or
mineralocorticoid receptor antagonist, were ran-
domized to receive tolvaptan 15 mg/day or
placebo for 7 days. The primary end point
was the change in weight from baseline between
treatment arms. Tolvaptan resulted in more
weight reduction compared with placebo (1.54 
1.61 kg vs 0.45  0.93 kg, p<0.0001) at the
end of the treatment phase. Improvements were
also noted with tolvaptan relative to placebo
in jugular venous distention (p=0.03) and
481
hepatomegaly (p=0.03). Daily urine volume was
significantly increased with tolvaptan (p<0.01
compared with placebo). Results appeared simi-
lar when examined by age (younger patients or
those 65 yrs of age and older), sex, NYHA func-
tional class, HF etiology, or background diuretic
therapy, although formal interaction testing was
not performed and would be underpowered to
capture potential differences. Participants ran-
domized to tolvaptan exhibited more significant
increases in serum sodium compared with pla-
cebo. Adverse event rates were similar between
treatment arms.17
The Kanagawa Aquaresis Investigators Trial of
Tolvaptan on Heart Failure Patients with Renal
Impairment (K-STAR) trial investigated the addi-
tion of tolvaptan versus increasing loop diuretic
dose on changes in urine output in patients with
residual congestion despite use of a loop diure-
tic. In this prospective open-label randomized
trial, 81 participants with evidence of congestion
(defined by at least one symptom and physical
sign of fluid overload) with a baseline eGFR less
than 45 ml/minute/1.73 m2, and taking at least
40 mg furosemide equivalents daily, were ran-
domized to receive tolvaptan 15 mg/day or less
or an added furosemide dose of 40 mg/day or
less (with dosing within threshold determined
by the treating provider) for 7 days in the hospi-
tal. The primary end point was the average urine
output change from baseline during the treat-
ment period between groups, and secondary end
points consisted of changes in body weight,
signs and symptoms of congestion, and renal
function. Treatment could be discontinued
before 7 days in the setting of improved conges-
tive symptoms or adverse effects. Of those
remaining on treatment at day 7, mean doses for
tolvaptan and furosemide were 10  4 mg/day
and 28  12 mg/day, respectively. In the tolvap-
tan arm, 17 subjects (43%) discontinued treat-
ment early (7 due to adverse effects, 10 due to
improved congestion); in the furosemide arm,
12 (29%) discontinued treatment early (8 due to
adverse effects, 4 due to improved congestion).
Changes in urine volume were significantly
more pronounced with tolvaptan relative to fur-
osemide at 7 days (or earlier for participants
who discontinued treatment). Body weight and
symptoms of congestion were similarly reduced
in both groups. Worsening renal function
occurred more frequently among those assigned
to take furosemide compared with tolvaptan,
and changes in creatinine between groups were
significant after 5 days of therapy.19
482 PHARMACOTHERAPY Volume 39, Number 4, 2019

Adverse Effects with Tolvaptan Treatment Ongoing Clinical Trials

The adverse event profile between VRAs and
placebo was similar in clinical trials. The most
common adverse events occurring during the
study in the tolvaptan groups were thirst, dry
mouth, and polyuria, which are consistent with
its therapeutic effect. Tolvaptan did not appear
to cause hypotension, tachycardia, or abnormali-
ties in serum potassium or magnesium levels.
This contrasts with what is often seen with
intensification of loop diuretic therapy or the
addition of a thiazide diuretic for diuretic syn-
ergy. There was no signal for harm related to
rapid sodium correction and/or osmotic demyeli-
nation with tolvaptan use.
The use of tolvaptan in HF continues to be
studied to further define its role as a diuretic.
Four ongoing studies (one awaiting publication
of results) are comparing tolvaptan with a vari-
ety of diuretic regimens in patients with loop
diuretic resistance (Table 4). Aiding Diuresis
with Tolvaptan (ADD-IT)40 is in recruitment
with the purpose of comparing the addition of
tolvaptan to intravenous diuretics versus alterna-
tive diuretic regimens including metolazone.
Patients admitted with an acute episode of HF
will be randomized to either tolvaptan 30 mg
orally with furosemide intravenously dosed
equivalent to their home dose of diuretic,

Table 4. Ongoing Clinical Trials Evaluating Tolvaptan in Heart Failure

Expected
Design Population Intervention Primary objective completion
40
Prospective Hospitalized patients Experimental: tolvaptan Length of December 2018
randomized with acutely 30 mg (PO) and hospitalization
interventional parallel decompensated heart furosemide (IV)
open label failure Active comparator:
Estimated enrollment: metolazone 5 mg (PO)
30 and furosemide (IV)
Active comparator:
furosemide IV alone
(2.5 9 participants
standard dose of diuretic)
41
Prospective Hospitalized patients Experimental: Weight change May 2019
randomized with decompensated chlorothiazide 500 mg IV after 48 hrs of
interventional parallel heart failure with twice/day 9 48 hrs treatment
blinded phase 4 hypervolemia Experimental: tolvaptan
Estimated enrollment: 30 mg/day (PO) 9 48 hrs
60 Active comparator:
metolazone 5 mg twice/
day (PO) 9 48 hrs
42
Prospective Hospitalized patients Experimental: tolvaptan 30 Mean urine output December 2017,
randomized with acute heart to 60 mg/day (PO), with at 24 hrs post awaiting
interventional parallel failure and signs of rescue loop diuretic or randomization publication of
open label phase IV volume overload, metolazone results
Estimated enrollment: with serum sodium Active comparator:
50 less than 135 mEq/L furosemide continuous
infusion 5 mg/hr with
option to titrate, with
rescue metolazone
44
Prospective Patients who present in Experimental: tolvaptan Change in body July 2018
randomized the outpatient setting 30 mg oral weight at 48 hrs
interventional parallel with signs and daily + augmentation of
blinded phase IV symptoms of current dose of loop
Estimated enrollment: worsening congestive diuretic
40 heart failure Placebo comparator:
augmentation of current
dose of loop diuretic
IV = intravenous; PO = oral.
 TOLVAPTAN USE IN HEART FAILURE Gunderson et al
metolazone 5 mg orally with furosemide intra-
venously dosed equivalent to their home dose of
diuretic, or furosemide intravenously dosed 2.5
times their home diuretic dose equivalent. ADD-
IT will evaluate the length of hospitalization
between the three groups as the primary out-
come, as well as other secondary outcomes
related to efficacy, safety, and rehospitalization
to determine benefit of a tolvaptan first approach
versus standard adjunctive thiazide use.
A second ongoing study, The Comparison of
Oral or Intravenous Thiazides versus Tolvaptan
in Diuretic Resistant Decompensated Heart Fail-
ure, will compare tolvaptan with thiazide-based
regimens. In this study, patients hospitalized
with decompensated HF with hypervolemia and
diuretic resistance will be randomized to
chlorothiazide 500 mg intravenously twice/day,
tolvaptan 30 mg orally daily, or standard of care
metolazone 5 mg orally twice/day. All therapies
will be added to loop diuretics and given for
48 hours. The primary outcome will measure
weight change after 48 hours of therapy using
the metolazone group as the comparator. Sec-
ondary outcomes aim was to compare adverse
effects of electrolyte abnormalities and renal
function, as well as a pharmacoeconomic analy-
sis. A barrier for use of both the intravenous for-
mulation of chlorothiazide and oral tolvaptan is
cost compared with oral metolazone; therefore,
this study will evaluate the direct costs related
to these therapies.41
A third study, Aquaresis Utility for Hypona-
tremic Acute Heart Failure Study (AQUA-AHF),
asks a novel and provocative question related to
tolvaptan’s role in diuretic therapy: Can tolvap-
tan replace loop diuretics in hyponatremic
patients requiring diuresis?42 In a previous study
done by the researchers, hyponatremic patients
with acute HF required higher doses of loop
diuretics and had a higher incidence of diuretic
escalation compared with normonatremic
patients.43 Therefore, AQUA-AHF aims to
explore an alternative diuretic regimen to con-
ventional diuresis with furosemide. Patients
admitted to the hospital with an acute HF exac-
erbation, signs of volume overload, and sodium
less than 135 mEq/L will be randomized to
either tolvaptan monotherapy or intravenous
furosemide monotherapy for the first 24 hours.
The primary end point will assess urine output
over the first 24 hours of therapy. Secondary
end points include mean change in serum crea-
tinine at 24 hours, as well as other safety and
efficacy outcomes.
483
The ongoing Tolvaptan for Worsening Outpa-
tient Heart Failure: Role of Copeptin in Identify-
ing Responders (TROUPER) study will evaluate
the role of copeptin levels on the rate of
response to tolvaptan. Copeptin is the c-terminal
section of the precursor of AVP.44 Therefore,
copeptin acts a surrogate marker of circulating
AVP, a hormone challenging to directly measure
due to its short half-life and instability during
sampling.45, 46 Copeptin, however, remains
stable after a blood draw with a longer half-
life.45, 47 TROUPER will randomize patients pre-
senting with worsening HF in the outpatient set-
ting to either tolvaptan 30 mg/day or placebo in
addition to augmentation of loop diuretics.
Patients will begin therapy inpatient with moni-
toring of sodium and efficacy for ~8 hours
depending on response. At which point the
patient will transition to the outpatient setting
for the remainder of the study. The primary end
point will assess change in body weight at
48 hours stratified with and without baseline
copeptin levels. Secondary outcomes include
longitudinal changes in copeptin levels, sodium
and renal function, as well as efficacy outcomes
of symptoms of congestion, weight change at
day 8, and a composite morbidity assessment.
Use of Tolvaptan in Clinical Practice
Based on available clinical data, tolvaptan is
unlikely to be routinely used for volume man-
agement in acute decompensated and chronic
HF patients. Cost is likely a large issue. Com-
pared with 250 mg intravenous chlorothiazide
(less than $50) or 5 mg oral metolazone (less
than $5), a single dose of tolvaptan, at the aver-
age wholesale price, is over $500. Given data
suggesting no distinguishing benefit with its use
to this point, although there continue to be
ongoing trials, cost alone in both inpatient and
ambulatory settings is prohibitive. With that
said, clinical trials have reinforced that tolvaptan
is both safe and efficacious. Its most likely place
in therapy, barring the patient is not clinically
euvolemic and hyponatremic, is as an adjunctive
diuretic to loop therapy in patients with hyperv-
olemic hyponatremia. In this subset of the HF
population, thiazide diuretics, through further
fluid loss, generally elevate serum sodium levels.
However, some patients may not see a subse-
quent shift in sodium, with it remaining low due
to the deleterious effects of thiazides on sodium
excretion. In these patients, tolvaptan therapy
for 24–72 hours may be advisable to aid in
484 PHARMACOTHERAPY Volume 39, Number 4, 2019
diuresis and correction of sodium. Tolvaptan
may also be useful in an as-needed fashion in
the ambulatory setting given the brisk diuresis
noted within 24 hours during clinical tri-
als.14, 15, 18, 20 Close clinical monitoring of elec-
trolytes should occur with any use of tolvaptan.
Use is not recommended in patients with a crea-
tinine clearance less than 10 ml/minute, end-
stage renal disease, or alanine/aspartate amino-
transferase more than 3 times the upper limit of
normal.
Conclusion
Volume management in acutely decompen-
sated and chronic HF patients with congestion
remains a challenge for a variety of reasons.
Although the theory surrounding the use of
vasopressin antagonism in this population
seemed logical and offered hope for a powerful
new tool in the fight against unnecessary hospi-
talization and disease progression, research to
this point suggests a limited role for tolvaptan.
Given its high cost along with judicious use
required in patients with renal and/or hepatic
dysfunction, vasopressin antagonism is likely
best used in acutely decompensated patients
with clinical hyponatremia who are refractory to
escalating doses of loop diuretics and adjunctive
thiazide therapy. They may also have a role as
initial adjunctive therapy in patients who have
been hospitalized and are refractory to conven-
tional therapy or requiring large doses of
adjunctive thiazide. Use in the outpatient setting
seems limited given cost and no true benefit that
is not already offered by conventional therapy
besides improving clinical hyponatremia. Future
studies will continue attempting to identify situ-
ations where tolvaptan may be most beneficial
in the HF population.
References
1. Wang C, Xiong B, Cai L. Effects of tolvaptan in patients with
acute heart failure: a systematic review and meta-analysis.
BMC Cardiovasc Disord 2017;17:164.
2. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease
and stroke statistics—2018 update: a report from the American
Heart Association. Circulation 2018;137:e67–492.
3. Savarese G, Lund LH. Global public health burden of heart
failure. Card Fail Rev 2017;03(01):7.
4. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and
stroke statistics—2016 update: a report from the American
Heart Association. Circulation 2016;133:e38–360.
5. Adams KF, Fonarow GC, Emerman CL, et al. Characteristics
and outcomes of patients hospitalized for heart failure in the
United States: rationale, design, and preliminary observations
from the first 100,000 cases in the Acute Decompensated Heart
Failure National Registry (ADHERE). Am Heart J 2005;149
(2):209–16.
6. Tavazzi L, Maggioni AP, Lucci D, et al. Nationwide survey on
acute heart failure in cardiology ward services in Italy. Eur
Heart J 2006;27(10):1207–15.
7. Gheorghiade M, Filippatos G, De luca L, Burnett J. Conges-
tion in acute heart failure syndromes: an essential target of
evaluation and treatment. Am J Med 2006;12(Suppl 1):S3–
10.
8. Pellicori P, Kaur K, Clark AL. Fluid management in patients
with chronic heart failure. Card Fail Rev 2015;1(2):90–5.
9. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprily-
sin inhibition versus enalapril in heart failure. N Engl J Med
2014;371(11):993–1004.
10. Swedberg K, Komajda M, B€ ohm M, et al. Ivabradine and out-
comes in chronic heart failure (SHIFT): a randomised placebo-
controlled study. Lancet 2010;376(9744):875–85.
11. Cox ZL, Lenihan DJ. Loop diuretic resistance in heart failure:
resistance etiology-based strategies to restoring diuretic effi-
cacy. J Card Fail 2014;20(8):611–22.
12. Wasilewski MA, Myers VD, Recchia FA, Feldman AM, Tilley
DG. Arginine vasopressin receptor signaling and functional
outcomes in heart failure. Cell Signal 2016;28:224–33.
13. Vinod P, Krishnappa V, Chauvin AM, Khare A, Raina R. Car-
diorenal syndrome: role of arginine vasopressin and vaptans in
heart failure. Cardiol Res 2017;8(3):87–95.
14. Feler GM, Mentz RJ, Cole RT, et al. Efficacy and safety of
tolvaptan in patients hospitalized with acute heart failure. J
Am Coll Cardiol 2017;69(11):1399–406.
15. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopa-
mine or low-dose nesiritide in acute heart failure with renal
dysfunction: the ROSE acute heart failure randomized trial.
JAMA 2013;310(23):2533–43.
16. Matsue Y, Suzuki M, Torii S, et al. Clinical effectiveness of
tolvaptan in patients with acute heart failure and renal dys-
function. J Card Fail 2016;22(6):423–32.
17. Jujo K, Saito K, Ishida I, et al. Randomized pilot trial compar-
ing tolvaptan with furosemide on renal and neurohumoral
effects in acute heart failure. ESC Heart Fail 2016;3(3):177–
88.
18. Konstam MA, Kiernan M, Chandler A, et al. Short-term
effects of tolvaptan in patients with acute heart failure and vol-
ume overload. J Am Coll Cardiol 2017;69(11):1409–19.
19. Matsuzaki M, Hori M, Izumi T, Fukunami M; Tolvaptan
Investigators. Efficacy and safety of tolvaptan in heart failure
patients with volume overload despite the standard treatment
with conventional diuretics: a phase III, randomized, double-
blind, placebo-controlled study (QUEST study). Cardiovasc
Drugs Ther 2011;25(Suppl 1):S33–45.
20. Gosmith SR, Gheorghiade M. Vasopressin antagonism in heart
failure. J Am Coll Cardiol 2005;46(10):1785–91.
21. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term
clinical effects of tolvaptan, an oral vasopressin antagonist, in
patients hospitalized for heart failure: the EVEREST Clinical
Status Trials. JAMA 2007;297(12):1332–43.
22. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA
guideline for the management of heart failure: a report of the
American College of Cardiology Foundation/American Heart
Association Task Force on practice guidelines. Circulation
2013;128(16):e240–327.
23. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV.
Predicting mortality among patients hospitalized for heart fail-
ure: derivation and validation of a clinical model. JAMA
2003;290(19):2581–7.
24. Konishi M, Haraguchi G, Ohigashi H, et al. Progression of
hyponatremia is associated with increased cardiac mortality in
patients hospitalized for acute decompensated heart failure. J
Card Fail 2012;18(8):620–5.
25. Bedict CR, Johnstone DE, Weiner DH, et al. Relation of neu-
rohumoral activation to clinical variables and degree of ven-
tricular dysfunction: a report from the Registry of Studies of
Left Ventricular Dysfunction. SOLVD Investigators. J Am Coll
Cardiol 1994;23(6):1410–20.
 TOLVAPTAN USE IN HEART FAILURE Gunderson et al
26. Ghorghiade 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 2004;291(16):1963–71.
27. Udelson JE, McGrew FA, Flores E, et al. Multicenter, ran-
domized, double-blind, placebo-controlled study on the effect
of oral tolvaptan on left ventricular dilation and function in
patients with heart failure and systolic dysfunction. J Am Coll
Cardiol 2007;49(22):2151–9.
28. Damman K, Navis G, Voors AA, et al. Worsening renal func-
tion and prognosis in heart failure: systematic review and
meta-analysis. J Card Fail 2007;13(8):599–608.
29. Licata G, Di Pasquale P, Parrinello G, et al. Effects of high-
dose furosemide and small-volume hypertonic saline solution
infusion in comparison with a high dose of furosemide as
bolus in refractory congestive heart failure: long-term effects.
Am Heart J 2003;145(3):459–66.
30. Costello-Boerrigter LC, Smith WB, Boerrigter G, et al. Vaso-
pressin-2-receptor antagonism augments water excretion with-
out changes in renal hemodynamics or sodium and potassium
excretion in human heart failure. Am J Physiol Renal Physiol
2006;290(2):F273–8.
31. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in
patients with acute decompensated heart failure. N Engl J Med
2011;364(9):797–805.
32. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of
oral tolvaptan in patients hospitalized for worsening heart fail-
ure: the EVEREST Outcome Trial. JAMA 2007;297(12):1319–
31.
33. 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. Eur Heart J 2007;28(8):980–
8.
34. Shchekochikhin DY, Schrier RW, Lindenfeld J, Price LL,
Jaber BL, Madias NE. Outcome differences in community-
versus hospital-acquired hyponatremia in patients with a diag-
nosis of heart failure. Circ Heart Fail 2013;6(3):379–86.
35. Otsuka Pharmaceutical Co., Ltd. SAMSCA (tolvaptan) [pack-
age insert]. Tokyo, Japan; 2018.
36. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a
selective oral vasopressin V2-receptor antagonist, for hypona-
tremia. N Engl J Med 2006;355(20):2099–112.
37. Udelson JE, Bilsker M, Hauptman PJ, et al. A multicenter,
randomized, double-blind, placebo-controlled study of
485
tolvaptan monotherapy compared to furosemide and the
combination of tolvaptan and furosemide in patients with
heart failure and systolic dysfunction. J Card Fail 2011;17
(12):973–81.
38. Kociol RD, McNulty SE, Hernandez AF, et al. Markers of
decongestion, dyspnea relief, and clinical outcomes among
patients hospitalized with acute heart failure. Circ Heart Fail
2013;6(2):240–5.
39. Hauptman PJ, Burnett J, Gheorghiade M, et al. Clinical course
of patients with hyponatremia and decompensated systolic
heart failure and the effect of vasopressin receptor antagonism
with tolvaptan. J Card Fail 2013;19(6):390–7.
40. Inomata T, Ikeda Y, Kida K, et al. Effects of additive tolvaptan
vs. increased furosemide on heart failure with diuretic resis-
tance and renal impairment—results from the K-STAR Study.
Circ J 2017;82(1):159–67.
41. Gupta D. Aiding diuresis with tolvaptan (ADD-IT). Clinical
Trials.gov. Bethesda, MD: National Library of Medicine. Avail-
able from https://clinicaltrials.gov/ct2/show/NCT02646540.
Accessed May 23, 2018.
42. Cox Z. Comparison of oral thiazides vs intravenous thiazides
vs tolvaptan in combination with loop diuretics for diuretic
resistant decompensated heart failure. ClinicalTrials.gov.
Bethesda, MD: National Library of Medicine. Available from
https://clinicaltrials.gov/ct2/show/NCT02606253. Accessed May
23, 2018.
43. Ng T, Elkayam U. Aquaresis utility for hyponatremic acute
heart failure study (AQUA-AHF). ClinicalTrials.gov. Bethesda,
MD: National Library of Medicine. Available from https://clini
caltrials.gov/ct2/show/NCT02183792. Accessed May 23, 2018.
44. Ng T, Cao DX, Wong YM, et al. Association of hyponatremia
to diuretic response and incidence of increased serum crea-
tinine levels in hospitalized patients with acute decompensated
heart failure. Cardiology 2014;128(4):333–42.
45. Adams KF. Tolvaptan treatment to reverse worsening outpa-
tient heart failure: possible role of copeptin in identifying
responders (TROUPER). ClinicalTrials.gov. Bethesda, MD:
National Library of Medicine. Available from https://clinicaltria
ls.gov/ct2/show/NCT02476409. Accessed May 23, 2018.
46. Tentzeris I, Jarai R, Farhan S, et al. Complementary role of
copeptin and high-sensitivity troponin in predicting outcome
in patients with stable chronic heart failure. Eur J Heart Fail
2011;13:726–33.
47. Robertson GL, Mahr EA, Athar S, et al. J Clin Invest 1973;52
(9):2340–52.