2. Introduction
Hyponatremia is defined as a serum
sodium <135 meq/l
The most common disorder of body
fluid and electrolyte balance
encountered in clinical practice
Upadhyay A, Jaber BL, Madias NE. Seminars in Nephrology 2009;
29:227-238
3. Introduction
Hyponatremia is primarily a disorder of
water balance
Relative excess of body water compared
to total body sodium and potassium
content
H2O > Na
It is usually associated with a disturbance in
ADH
Goce Spasovski et al, Nephrol Dial Transplant (2014); 29 (suppli 2):ii2-ii39
4. Patient group Prevalence (%)
ICU patients 11.0–29.6
Elderly outpatients 7.2–11.0
Elderly inpatients 18.0–53.0
Patients with heart failure 10.2–27.0
Patients with cirrhosis 20.8–49.4
Patients with cancer 3.7–47.0
Patients with pneumonia 8.1–27.9
Predialysis patients with CKD 13.6
Patients on dialysis 29.3
Marathon runners 3.0–13.0
Elderly patients with falls 9.1–13.0
Epidemiology
Schrier, R. W. et al. Nat. Rev. Nephrol. 9, 37–50 (2013);
5.
6.
7.
8.
9. Treatment options
Intravenous fluids and water restriction
When faced with a patient with hyponatremia,
the first decision is what type of fluid, if any,
should be given
Pharmacologic treatment
Aquaretics
A new class of drugs, AVP receptor antagonists,
designed specifically to promote aquaresis (i.e.,
electrolyte-sparing excretion of free water)
10.
11.
12. Problems with the existing diuretics
Careful observation for development of a variety
of side effects is recommend in patients treated
with diuretics, especially when used at high
doses and in combination
We should care:
Renal dysfunction
Electrolyte abnormalities: K+, Ca2+
Symptomatic hypotension
Gout
HFSA 2010 Practice Guideline
14. Limitations of vaptans
other than Tolvaptan
Lixivaptan:
Stopped because of
adverse events in trials
(Sanofi)
Conivaptan:
• Given intravenously
• No patient compliance
• Can not used long term
• No receptor specific
inhibition (Block
V1a/V2)
Satavaptan:
Stopped because of
adverse events in trials
(Cardiokine)
22. SALTWATER Trial
Prolonged administration (Over 2yrs) of tolvaptan
maintains an increased serum sodium with an
acceptable margin of safety
J Am Soc Nephrol 21: 705–712, 2010
26. The EVEREST Outcome Trial demonstrate
that tolvaptan was superior to placebo in
terms of dyspnea, pedal edema, and
quality of life
27. ACTIV in CHF trial
(Acute and Chronic Therapeutic Impact of a Vasopressin
Antagonist in Chronic Heart Failure trial)
Evaluated the
relationship
between:
Baseline
serum sodium,
Change in
serum sodium,
and
60-day
mortality in HF
Post hoc analysis
N= 319
Receive tolvaptan at
30, 60, or 90 mg, or
placebo in addition to
standard therapy
First 10 days in
Hospital
For additional 7weeks
(49–51 days) treated
as outpatients
Two primary
endpoints for the
assessment of
effects of tolvaptan
(acute (inpatient)
and intermediate-
term (outpatient))
24hr bodyweight
change and
worsening HF at
60 days
Background Method Endpoint
Acute Cardiac Care. 2007; 9: 82–86
28. Patients with hyponatremia treated with tolvaptan demonstrated
normalization of serum sodium that was maintained during the 60-day
follow-up period Acute Cardiac Care. 2007; 9: 82–86
29. Outcomes of ACTIV trial
Significantly reduced body weight at 24 h
after the first administration
No changes in heart rate or blood pressure
Did not induce hypokalemia or worsen renal
function
Urine volumes were significantly higher
60-day mortality was lower in tolvaptan-
treated patients with renal dysfunctions
or severe systemic congestion than in
placebo-treated patients
Acute Cardiac Care. 2007; 9: 82–86
31. Effect of Tolvaptan on physical component in
SIADH patients with hyponatremia
A SALT study subgroup analysis
Demonstrated a greater improvement in the physical
component of the SF-12 Health Survey than in the full
mixed etiology SALT patient group
Eur J Endocrinol. 2011 May ; 164(5): 725–732
32. Dual impact of tolvaptan on intracellular and
extracellular water in chronic kidney disease
patients with fluid retention
Change in the absolute body water before (day 0) and after (day
5 or 6) tolvaptan treatment (A)
BIA (bioelectric impedance analysis) showed that tolvaptan
significantly decreased ICW, ECW and TBW
The ratio of ECW to TBW (ECW/TBW) was similar among the
treatments (B)
Intern Med 55: 2759-2764, 2016
33. Dual impact of tolvaptan on intracellular and
extracellular water in chronic kidney disease
patients with fluid retention
The eGFR
and serum Na
remained
unchanged
during
tolvaptan
treatment
Tolvaptan ameliorates body fluid retention, and induces
an equivalent reduction rate of ICW and ECW without a
worsening renal function Intern Med 55: 2759-2764, 2016
34. Tolvaptan in the treatment of hyponatremia in cirrhosis
Sub-analysis of the SALT trial cirrhotic patients with
hyponatremia
Serum sodium concentration
throughout the study treatment
period (days 1–30) and 7 days after
stopping (day 37) tolvaptan (I) or
placebo (P) in:
(A) All patients,
(B) Those with mild hyponatremia
and
(C) Those with marked
hyponatremia
One month of tolvaptan therapy
improved serum sodium levels in
cirrhotic patients with
hyponatremia
Journal of Hepatology 2012 vol. 56 j 571–578
35. Short-term effects of tolvaptan in patients
with acute heart failure and volume
overload
Objective:
It was hypothesized that the addition of tolvaptan to a
background diuretic improved dyspnea early
Method:
Double-blind, randomised
Tolvaptan 30 mg/day or placebo
Hospitalization within the previous 36 h, active dyspnea
The primary endpoint was a 7-point change in self-assessed
dyspnea at 8 and 16 h
J Am Coll Cardiol 2017;69:1409–19
36. Change in body weight as well as reduces the dose
of diuretics with the treatment of tolvaptan
J Am Coll Cardiol 2017;69:1409–19
37. Improvement
in dyspnea
over 3 days
Despite rapid and persistent weight loss with
tolvaptan compared with placebo was not associated
with greater early improvement in dyspnea (It need
further exploration)
J Am Coll Cardiol 2017;69:1409–19
38. Urine Osmolality, Response to Tolvaptan, and
Outcome in Autosomal Dominant Polycystic
Kidney Disease: Results from the TEMPO 3:4
Trial
Objective:
To investigate the determinants of baseline
urine osmolality (Uosm) and its value as a
severity marker of ADPKD, the factors
influencing the response to tolvaptan, and
whether change in Uosm associated with key
trial end points
J Am Soc Nephrol 28: 2016
39. Outcome of TEMPO 3:4 trial
Baseline Uosm in ADPKD reflects age, renal
function, and TKV, and baseline Uosm, eGFR, and
TKV (total kidney volume) influence the effect of
Tolvaptan on Uosm
The greatest renal benefit occurred in subjects
achieving greater suppression of Uosm, that is, those
with better eGFR at baseline
These results support the link between vasopressin
V2 receptor signaling and ADPKD progression
J Am Soc Nephrol 28: 2016
40. TEMPO 4:4 Trial
TEMPO 4:4 was designed to provide an
additional 2 years of data on the long-term
safety and efficacy of tolvaptan in subjects
completing TEMPO 3:4
The results of TEMPO 4:4 support a
sustained disease-modifying effect of
tolvaptan on eGFR
The safety profile was similar to that
observed in TEMPO 3:4
Nephrol Dial Transplant (2017) 1–13
41. Summary
US FDA approved vaptan
The efficacy of oral tolvaptan was demonstrated in
multicenter trials (SALT-1 and SALT-2)
Tolvaptan significantly increased serum sodium
concentration
In SALTWATER trial, the serum sodium concentration
normalized in approximately 60% of the patients
In cirrhosis patients the serum concentration shown
normalized in one month therapy
In both TEMPO trials shown efficacy and safety in
ADPKD patients
In concomitant use tolvaptan reduces the dose of
diuretics in acute heart failure patients
42. Conclusion
Hyponatremia is common and associated with
significant morbidity and mortality
Treatment depends upon the underline cause
Rate of correction must be tailored to duration and
severity of symptoms
Rapid correction for acute hyponatremia with
symptoms
Slow correction for chronic hyponatremia to avoid
ODS (Osmotic demyelination syndrome)
Tolvaptan is suitable, safe and effective for
euvolemic or hypervolemic hyponatremia
ABSTRACT
Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and
hypervolemia with hyponatremia in the short term (30 days), but their safety and efficacy with longer
term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of
Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with
hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days
of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued
to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to
tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse
effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per
h at initiation in five patients. Hypernatremia (145 mmol/L) led to discontinuation in one patient. Mean
serum sodium increased from 130.8 mmol/L at baseline to 135 mmol/L throughout the observation
period (P 0.001 versus baseline at most points). Responses were comparable between patients with
euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion,
prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin
of safety.
Physical Component Summary (PCS) and Mental Component
Summary (MCS) of the Medical Outcomes Study 12-item Short-Form (SF-12) General
Health Survey
