International Journal of Cardiology and Cardiovascular Research IJCCR

II Vol. 5(2), pp. 111-115, August, 2019. © www.premierpublishers.org ISSN: 2326-7262

Research Article
Use of Tolvaptan 15 mg in Heart Failure Patients to Improve
Sodium Level (Serum & Urinary) and Urinary Osmolality
Tejas Shah MD, DNB Cardiology
Assistant Professor, Department of Cardiology, Sumandeep Vidyapeeth, Piparia, Waghodia, Vadodara, Gujarat, India
E-Mail: tejaschaitri@gmail.com; Tel: 8951274202

Decompensated Heart Failure (HF) due to volume overload often results in adverse clinical
outcomes. Hyponatremia has been reported to be a potent predictor of poor outcome in patients
hospitalized for heart failure (HF). The aim of the study was to observe improvement in serum and
urinary sodium along with urinary osmolality in HF patients due to any cause.25 patients with
Heart failure were recruited. Their body weight, serum sodium, urinary sodium and urinary
osmolality were measured at admission and at one week after starting of TOLVAPTAN 15 mg. Out
of 25 patients,20(80%) were males and 5(20%) females having mean age of 63.28 year.10 (40%)
patients were between 61-70 year of age, followed by 9(36%) patients were between 51-60
year.16(64%) patients had old ischemic heart disease,5(20%) had diabetes,2(8%) had valvular and
2 (8%) had idiopathic dilated cardiomyopathy as cause of heart failure.24(96%) patients had
reduced ejection fraction (mean value 30%),while 1(4%) had preserved ejection
fraction.14(56%)patients had acute decompensated heart failure, while 11(44%) had acute on
chronic decompensated heart failure. All 25 (100%) patients were on optimal medical management
for heart failure. It was found that mean weight of the patients was reduced significantly at 1 week
follow up (62.52±9.32 kg to 61.4±9.20 p value 0.001). It was also found that mean serum sodium
and urinary sodium level significantly improved at 1 week follow up (129.64±5.64 mmol/L to
136.28±4.48 mmol/L, p value 0.001 &46.20±34.30 meq/L to 28.12±10.98 meq/L, p value 0.004
respectively).Tolvaptan acts as aqauretics without affecting urinary osmolality with reduction of
body weight and increases serum sodium level. It also improves dyspnea in heart failure patients.

Keywords: Heart failure, Hyponatremia, Urinary sodium, Urinary osmolality, Body Weight, Tolvaptan

INTRODUCTION

Hyponatremia is a commonly found in Congestive Heart
Failure (CHF) and the most common electrolyte
abnormality found in hospitalized patients with HF
[Gerasimos Filippatos FD et al.,2009, Oren RM et al.,
2005]. In patients hospitalized with HF plasma sodium
concentration below 135 mmol/L is considered as
Hyponatremia [Ghali JK et al.,2010, Bettari L et al., 2010].It
is recommended that such patients are followed in
specialized HF clinics[Dickstein K et al., 2008].It has been
found U –shaped association with mortality risk in heart
failure patient, when serum sodium is 135-139 mmol/L,
patient had high mortality risk while with 140-145 mmol/L
had low risk [Deubner et al., 2012]. Those patients should
be managed with optimal management of diuretic therapy
and strict compliance with fluid restriction [Deubner et al.,
2012]. Pathophysiologically elevated levels of plasma
vasopressin is primarily responsible for free water
retention and hyponatremia in a heart failure patient
[Gerasimos Filippatos FD et al.,2009].
Elevated vasopressin level is associated with more severe
clinical manifestations, [Gustafsson F et al. 2005, Lee CR
et al., 2003, Goldsmith SR et al., 1983 , Szatalowicz VL et
al., 1981]where alternative signals, such as
haemodynamic and neurohormonal factors, override the
suppressive effect of hypo-osmolarity in driving
vasopressin secretion [Francis GS et al. ,1990].Study by
[Aronson et al. 2012], showed improved Serum sodium
levels in such patients, the majority of whom had heart
failure, with the V2-selective vasopressin receptor
antagonist, Satavptan. It has found effective in treating the
patients with heart failure. Though diuretics have been the

Use of Tolvaptan 15 mg in Heart Failure Patients to Improve Sodium Level (Serum & Urinary) and Urinary Osmolality
Shah T. 112

mainstay in the treatment of fluid retention, but their use WHO technical report series 854, 1995]. Serum sodium
has been associated with adverse neurohormonal and urinary sodium were analysed using auto analyzer
activation, [Uretsky BF et al., 1985, Francis GS et al.,1985] Hitachi P800/ISE 900.Urinary osmolality was analysed
worsening renal function, electrolyte abnormalities, using osmometer. Normal values for serum sodium,
increased parathyroid hormone levels, and urinary calcium urinary sodium and osmolality were 138-145 mmol/L,15-
and magnesium excretion [Bayliss J et al., 1987, Butler J 200 meq/L and 50-650 mosm/kg of water as laboratory
et al., 2004, Greenberg A et al., 2000].Use of it is also reference values.
associated with proinflammatory vascular response,
[Weber KT et al 2004] which has adverse effect on Statistical Analysis
remodeling, and higher doses of diuretics have been
associated with higher mortality.[Weber KT et al., 2004, In this study discrete data are presented as frequencies
McCurley JM et al., 2004, Cooper HA et al., 1999, Ahmed and percentages. Continuous variables as mean and
A et al., 2006, Hasselblad V et al. ,2007] standard deviation. Independent t test was used to find
significant mean difference of parameters. Non parametric
Tolvaptan is selective vasopressin receptor 2 antagonist. test wilcoxon signed rank test was applied to find statistical
It acts as aquaretic. It is used for hyponatremia associated significance. P value<0.05 was consider statistically
with congestive heart failure, cirrhosis and syndrome of significant. Data were analysed using SPSS version 16.
inappropriate antidiuretic hormone. [G. Michael et al.,
2017]
RESULTS
The aim of the study was to observe the effectiveness of
Tolvaptan 15 mg in patients of Heart Failure in terms of Table 1: Baseline characteristics of the patients.
body weight reduction, improvement of serum & urinary Baseline Characteristics N %
sodium levels, urinary osmolality and dyspnea Gender
improvement. Male 20 80%
. Female 5 20%
Cardiomyopathy
METHODS IHD 16 64%
Study design and assessments Valvular 2 08%
Diabetes Mellitus 5 20%
This was an interventional study, carried out at tertiary care DCMP (Idiopathic) 2 08%
center in which patients of either gender of age more than NYHA Class
18 years with signs and symptoms of acute, chronic, acute II 2 08%
on chronic HF, defined as requiring standard HF treatment III 2 08%
were included in the study if they had both documented left IV 21 84%
ventricular ejection fraction (LVEF) determination (by Ejection Fraction
Simpson volumetric method),reduced or preserved, on < 50 24 96%
admission. whereas patients with Acute ST elevation ≥ 50 01 04%
myocardial infarction or stroke; major surgery within 3
months, hypothyroidism, tuberculosis, active myocarditis Table 1 shows that in present study 4/5thof enrolled
and chronic kidney disease were excluded. patients were male whereas remaining were female and
majority of them were in 6th decade of their age with the
Total 25 consecutive patients who were admitted in tertiary mean age of 63.28±11.57 years. Among all the patients,
care centre with history and clinical findings of heart failure Ischemic Heart Disease (64%) was found as most
with hyponatremia (euvolemic or hypervolemic) and on common cause of Heart Failure followed by Diabetes
optimal congestive cardiac failure medications were given Mellitus (20%), Valvular Heart Disease and Idiopathic
Tolvaptan 15 mg. Before starting drug patient parameters, Dilated Cardiomyopathy respectively. Majority (84%) of
body weight, serum sodium, spot urinary sodium, spot our study patients had NYHA Class IV symptoms with
urinary osmolality was measured. After one week of significantly reduced ejection fraction (96%). More than
starting Tolvaptan 15 mg, same parameters were half of the patients (56%) were admitted with acute cardiac
measured. failure symptoms whereas 44% of the patients had acute
on chronic heart failure symptoms. 100% patients were on
Venous sample was taken for serum sodium optimal cardiac failure drugs starting from Angiotensin
measurement. Urinary sodium and osmolality were Converting Enzyme Inhibitors (ACEI)/ Angiotensin
measured with spot urine sample. Body weight was Receptor Blockers (ARBs), Beta Blockers (BB),
measured as per WHO norm [Mielniczuk LM et al., 2008, Aldosterone antagonist, Diuretics, etc.

Use of Tolvaptan 15 mg in Heart Failure Patients to Improve Sodium Level (Serum & Urinary) and Urinary Osmolality
 Int. J. Cardiol. Cardiovasc. Res. 113

Table 2: Pre and Post Treatment Laboratory Parameter Acute and Chronic Therapeutic Impact of a Vasopressin
comparison Antagonist in Congestive Heart Failure) Tolvaptan was
Parameter Mean SD p-value associated with body weight reduction at 24 hours and
Urinary Sodium (Baseline) 46.20 34.30 often-normalized serum sodium levels among patients
Urinary Sodium (Post 0.004 with hyponatremia. However there was no long-term
28.12 10.98 mortality improvement but lower mortality was found in
Treatment)
Serum Sodium (Baseline) 129.64 5.64 patient with clinical congestion ,hyponatremia or abnormal
Serum Sodium (Post 0.001 renal function.
136.28 4.48
Treatment)
In the Efficacy of Vasopressin Antagonism in Heart Failure
Urine Osmolality (Baseline) 333.88 87.35
Outcome Study with Tolvaptan (EVEREST) trial showed
Urinary Osmolality (Post 0.073
297.00 84.45 no effect of tolvaptan initiated for acute treatment of
Treatment) patients hospitalized with HF on long-term mortality or HF-
Body Weight (Baseline) 62.52 9.32 related morbidity nor was there any interaction between
Body Weight (Post 0.001 plasma sodium (hyponatremia) and treatment effect on
61.40 9.26
Treatment) outcome in this trial. This study demonstrated a beneficial
volume unloading by the selective V2 receptor blocker
As shown in table 2 all patients were underwent laboratory Tolvaptan in participants with HF and volume overload.
assessment at the time of admission and at 1 week follow Tolvaptan significantly reduced body weight 1 day after
up of starting Tolvaptan 15 mg treatment. It was found that administration and maintained this effect with continued
at one week of follow up, Urinary Sodium Level and Body administration over the 1-week treatment period. Body
Weight was significantly reduced as compared to at the weight reduction occurred irrespective of baseline LVEF
time of admission (p value 0.004 and 0.001 respectively). (Preserved or Reduced). Improvements in orthopnea and
Serum Sodium Level significantly improved at one week of dyspnea were also observed in the Tolvaptan group during
follow up as compared to at the time of admission, p value the1-week course of therapy. The beneficial effects of
0.001. We have also done urine osmolality test of all Tolvaptan on body weight were noted due to possible
patients at pre and post treatment and found that it was aquaretic effect of Tolvaptan in patients with HF. The
reduced but we did not find any statistically significant sustained reductions in body weight seen in the current
mean difference between pre and post treatment. study are consistent with those reported with Tolvaptan in
patients with HF [Gheorghiade M et al 2003., Verbrugge
Table 3: Pre and Post Treatment Borg Dyspnea Scale FH et al 2015, Gheorghiade M et al., 2004].
Analysis
Borg Scale Mean SD p value Fluid retention is considered as common cause for
At the time of Admission 8.01 1.14 development of the Heart Failure. Diuretics are main stay
0.001 in its management; however, treatment with these agents
At one week of Follow up 2.42 1.21
may be associated with unfavourable effects like
In present study we have found that all the patients had electrolyte abnormalities, worsening renal function, and
symptomatic improvement in dyspnea. We have used activation of the neurohormonal system. In contrast, the
Borg Dyspnea Scale to grade the severity of dyspnea. At actions of vasopressin antagonists are mediated by
the time of admission mean of Borg Dyspnea Scale was blocking the activation of V2 receptors in the collecting
8.01±1.14 whereas same was reduced to 2.42±1.21 at the ducts, thus leading to decreased free water resorption
one week follow up with p value 0.001. [Konstam MA et al 2007]. This aquaretic effect—
electrolyte-free water excretion—combined with no
worsening renal function or activation of the
DISCUSSION neurohormonal systems place this class of drugs as a
useful complement to currently available agents for the
In our study of Heart failure patients on Tolvaptan had treatment of HF and potentially better alternative to
significant improvement in serum sodium, urinary sodium diuretics.
and body weight. There was symptomatic improvement in
dyspnea according to Borg scale. Recent research studies concluded that Tolvaptan add on
therapy neither improve worsening of renal function nor
Incidence of hyponatremia in Acute heart failure is 20% short term mortality in acute decompensated heart failure
[Gheorghiade M et al 2003]. Pathophysiology of patient [Guang Ma et al., 2019]. Main benefit found was an
hyponatraemia in HF is complex and sometimes difficult to add on therapy which reduced body weight and improved
overcome with treatment modality. There was elevated serum sodium of the patient and these results are
AVP levels in HF, hope was offered by the introduction of consistent with our study results.
vasopressin receptor antagonists. In the Acute and
Chronic Therapeutic Impact of a Vasopressin Antagonist Patient with renal impairment and diuretic resistance low
in Congestive Heart Failure Trial (ACTIV in CHF, The dose tolvaptan i.e. 15 mg as add on therapy increase urine

Use of Tolvaptan 15 mg in Heart Failure Patients to Improve Sodium Level (Serum & Urinary) and Urinary Osmolality
Shah T. 114
volume without deteriorating renal function [Inomata T et
al., 2017]. Tolvaptan added to standard HF therapy
demonstrated a favorable safety profile in our study.
Further investigation is needed to identify the ideal
Tolvaptan dosing regimen to optimize fluid/electrolyte
balance in patients with HF, as the we used a fixed-dose
regimen.
LIMITATIONS
This study was designed to assess the effects of fixed
dose Tolvaptan 15 mg in HF with very limited numbers of
patients (i.e.25).Probably long term follow up study
required to evaluate morbidity and mortality benefit of
drug.
CONCLUSION
In our patients with HF and volume overload, the addition
of Tolvaptan 15 mg once daily to standard therapy reduced
body weight, improved dyspnea, decrease urinary sodium
excretion and was well tolerated. It also increases serum
sodium level. It has no effect on urinary osmolality.
CONFLICT OF INTEREST: None
REFERENCES
Ahmed A, Husain A, Love TE, Gambassi G, Dell’Italia LJ,
Francis GS, Gheorghiade M, Allman RM, Meleth S,
Bourge RC. Heart failure, chronic diuretic use, and
increase on mortality and hospitalization: an
observational study using propensity score methods.
Eur Heart J 2006;27:1431–1439.
Ali F, Guglin M, Vaitkevicius P, Ghali JK. Therapeutic
potential of vasopressin receptor antagonists. Drugs
2007;67:847–858.
Aronson D, Verbalis JG, Mueller M, Krum H. Short- and
long-term treatment of dilutional hyponatremia with
satavaptan, a selective arginine vasopressin V2
receptor antagonist: the DILIPO study. Eur J Heart Fail
2011;13:327–336.
Bayliss J, Norell M, Canepaanson R, Sutton G, Poole
Wilson P. Untreated heart failure: clinical and
neuroendocrine effects of introducing diuretics. Br
Heart J 1987;57:17–22.
Bettari L, Fiuzat M, Felker GM, O’Connor CM. Significance
of hyponatremia in heart failure. Heart Fail Rev
2010;doi:10.1007/s10741-010-9193-3.
Borg G.Borg's Perceived Exertion and Pan Scales.
Champaign, IL: Human Kinetics,1998
Butler J, Forman DE, Abraham WT, Gottlieb SS, Loh E,
Massie BM, O’Connor CM, Rich MW, Stevenson LW,
Wang Y, Young JB, Krumholz HM. Relationship
between heart failure treatment and development of
Use of Tolvaptan 15 mg in Heart Failure Patients to Improve Sodium Level (Serum & Urinary) and Urinary Osmolality
worsening renal function among hospitalized patients.
Am Heart J 2004;147:331–338.
Cooper HA, Dries DL, Davis CE, SHen YL, Domanski MJ.
Diuretics and risk of arrhythmic death in patients with
left ventricular dysfunction. Circulation 1999;100:1311–
15.
Deubner N, Berliner D, Frey A, Guder G, Brenner S,
Fenske W, Allolio B, Ertl G, Angermann CE, Stork S.
Dysnatraemia in heart failure. Eur J Heart Fail. 2012;
14:1147-1154.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJV,
Ponikowski P, Poole-Wilson PA, Stro¨mberg A, van
Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa
A, Nieminen M, Priori SP, Swedberg K, ESC
Committee for Practice Guidelines (CPG). ESC
guidelines for the diagnosis and treatment of acute and
chronic heart failure 2008: the Task Force for the
diagnosis and treatment of acute and chronic heart
failure 2008 of the European Society of Cardiology.
Developed in collaboration with the Heart Failure
Association of the ESC (HFA) and endorsed by the
European Society of Intensive Care Medicine (ESICM).
Eur J Heart Fail 2008;10:933–989.
Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas
J, Liang CS, Kubo SH, Rudin-Toretsky E, Yusuf S.
Comparison of neuroendocrine activation in patients
with left ventricular dysfunction with and without
congestive heart failure: a substudy of the Studies of
Left Ventricular Dysfunction (SOLVD). Circulation
1990;82: 1724–1729.
Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine
TB, Cohn JN. Acute vasoconstrictor response to
intravenous furosemide in patients with chronic
congestive heart failure. Activation of the neurohumoral
axis. Ann Intern Med 1985;103:1–6.
G. Michael Felker, Robert J. Mentz, Robert T. Cole,
Kirkwood F. Adams, Gregory F. Egnaczyk, Mona
Fiuzat, Chetan B. Patel et al, Efficacy and safety of
Tolvaptan in patients hospitalized with acute heart
failure. JACC vol.69,no.11,2017.
Gerasimos Filippatos FD, Parissis J, Kremastinos DTH,
Gheorghiade M. Hyponatremia in heart failure. Heart
Fail Rev 2009;14:59–63.
Ghali JK, Tam SW. The critical link of hypervolemia and
hyponatremia in heart failure and the potential role of
arginine vasopressin antagonists. J Card Fail
2010;16:419–431.
Gheorghiade M, Gattis WA, O’Connor CM, Adams KF Jr,
Elkayam U, Barbagelata A, Ghali JK, Benza RL,
McGrew FA, Klapholz M, Ouyang J, Orlandi C; on
behalf of the Acute and Chronic Therapeutic Impact of
a Vasopressin Antagonist in Congestive HF (ACTIVE in
CHF) Investigators. Effects of tolvaptan, a vasopressin
antagonist, in patients hospitalized with worsening HF:
a randomized controlled trial. JAMA 2004;291:1963–
1971.
Gheorghiade M, Niazi I, Ouyang J, Czerwiec F,
Kambayashi J, ZampinoM,Orlandi C; Tolvaptan

Investigators. Vasopressin V2-receptor blockade with
tolvaptan in patients with chronic heart failure: results
from a double-blind, randomized trial. Circulation
2003;107:2690–2696.
Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB,
Cohn JN. Increased plasma arginine vasopressin levels
in patients with congestive heart failure. J Am Coll
Cardiol1983;1:1385–1390.
Greenberg A. Diuretic complications. Am J Med
2000;319:10–24.
Gustafsson F, Ulriksen H, Villadsen H, Nielsen H, Bach
Andersen B,Hildebrandt R. Treatment with beta-
blockers in nurse-led heart failure clinics: titration
efficacy and predictors of failure. Eur J Heart Fail
2005;7:283–284.
Hasselblad V, Stough WG, Shah MR, Lokhnygina Y,
O’Connor CM, Califf RM, Adams KF Jr. Relation
between dose of loop diuretics and outcomes in a heart
failure population: results of the ESCAPE Trial. Eur J
Heart Fail 2007;9:1064–1069.
Inomata T, Ikeda Y, Kida K, et al. Effects of Additive
Tolvaptan vs. Increased Furosemide on Heart Failure
With Diuretic Resistance and Renal
Impairment Results From the K-STAR Study. Circ J
2017;82:159–67.
Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L,
Maggioni AP, Swedberg K, Udelson JE, Zannad F,
Cook T, Ouyang J, Zimmer C, Orlandi C. Effects of oral
tolvaptan in patients hospitalized for worsening heart
failure. The EVEREST Outcome Trial. JAMA
2007;297:1319–1331.
Lee CR, Watkins ML, Patterson JH, Gattis W, O’Connor
CM, Gheorghiade M, Adams KF Jr. Vasopressin: a new
target for the treatment of heart failure. Am Heart J
2003;146:9–18
Ma G, Ma X, Wang G, et al. Effects of tolvaptan add-on
therapy in patients with acute heart failure: meta-
analysis on randomised controlled trials. BMJ Open
2019;9:e025537. doi:10.1136/ bmjopen-2018-025537
McCurley JM, Hanlon SU, Wei SK, Wedam EF, Michalski
M, Haigney MC. Furosemide and the progression of left
ventricular dysfunction in experimental heart failure. J
Am Coll Cardiol2004;44:1301–1307.
Use of Tolvaptan 15 mg in Heart Failure Patients to Improve Sodium Level (Serum & Urinary) and Urinary Osmolality
Int. J. Cardiol. Cardiovasc. Res. 115
Mielniczuk LM, Tsang SW, Desai AS, Nohria A, Lewis EF,
Fang JC, Baughman KL, Stevenson LW, Givertz MM.
The association between high-dose diuretics and
clinical stability in ambulatory chronic heart failure
patients. J Card Fail 2008;14: 388–393.
Oren RM. Hyponatremia in congestive heart failure. Am J
Cardiol 2005;95(suppl):2B–7B.
Physical status: The use and interpretation of
anthropometry, Geneva: Report of a WHO expert
Committee, WHO technical report series 854, 1995,
324pp.
Szatalowicz VL, Arnold PE, Chaimovitz C, Bichet D, Berl
T, Schrier RW. Radioimmunoassay of plasma arginine
vasopressin in hyponatremic patients with congestive
heart failure. N Engl J Med 1981;305:263–266.
Uretsky BF, Verbalis JG, Generalovich T, Valdes A, Reddy
PS. Plasma vasopressin response to osmotic and
hemodynamic stimuli in heart failure. Am J Physiol
1985; 248:H396–H402.
Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WH,
Mullens W. Hyponatremia in Acute Decompensated
Heart Failure: Depletion Versus Dilution. J Am Coll
Cardiol2015;65:480-492.
Weber KT. Furosemide in the long term management of
heart failure: the good the bad and the uncertain. J Am
Coll Cardiol 2004;44:1308–1310.
Accepted 18 July 2019
Citation: Shah T (2019). Use of Tolvaptan 15 mg in Heart
Failure Patients to Improve Sodium Level (Serum &
Urinary) and Urinary Osmolality. International Journal of
Cardiology and Cardiovascular Research: 5(2): 111-115.
Copyright: © 2019 Shah T. This is an open-access article
distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the
original author and source are cited.