TOLVAPTAN

Major Clinical Trials

Efficacy and Safety of Tolvaptan in Heart Failure
Patients with Volume Overload (QUEST Study)
 Background:
 Diuretics recommended to treat volume overload with heart failure (HF) may cause
serum electrolyte imbalance
 This study evaluated the efficacy and safety of Tolvaptan, as a new drug to treat volume
overload in HF patients
 Results:
 Compared with placebo, tolvaptan administered for 7 days significantly reduced body
weight and improved symptoms associated with volume overload

Matsuzaki M et al. Cardiovasc Drugs Ther. 2011; 25 Suppl 1:S33-45.

Efficacy and Safety of Tolvaptan in Heart Failure
Patients with Volume Overload (QUEST Study)
 Results (Contd.):
 The safety profile of tolvaptan was considered acceptable for clinical use with minimal
adverse effects
 Conclusion:
 Tolvaptan reduced volume overload and improved congestive symptoms associated with
HF by a potent water diuresis (aquaresis)

Matsuzaki M et al. Cardiovasc Drugs Ther. 2011; 25 Suppl 1:S33-45.

Tolvaptan, a selective oral vasopressin V2-receptor
antagonist, for hyponatremia (SALT 1 & 2)
 Background:
 Hyponatremia (serum Na conc. <135 mmol/liter) is a predictor of death among patients
with chronic heart failure and cirrhosis
 Tolvaptan was investigated for its effects in hyponatremia
 Results:
 Serum Na conc. increased more in the tolvaptan group than in the placebo group during
the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001)

Schrier RW et al. N Engl J Med. 2006; 355(20):2099-112.

Tolvaptan, a selective oral vasopressin V2-receptor
antagonist, for hyponatremia (SALT 1 & 2)
 Results (Contd.):
 Condition of patients with mild or marked hyponatremia improved (P<0.001)
 Side effects associated with tolvaptan included increased thirst, dry mouth, and
increased urination
 Conclusions:
 In patients with euvolemic or hypervolemic hyponatremia, tolvaptan was effective in
increasing serum Na conc. at day 4 and day 30

Schrier RW et al. N Engl J Med. 2006; 355(20):2099-112.

Oral Tolvaptan is Safe and Effective in Chronic
Hyponatremia (SALTWATER )
 Background:
 Vasopressin antagonists increase the serum Na conc. 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)

Berl T et al. J Am Soc Nephrol. 2010; 21(4):705-12.

Oral Tolvaptan is Safe and Effective in Chronic
Hyponatremia (SALTWATER )
 Results:
 Mean serum Na increased from 130.8 mmol/L at baseline to >135 mmol/L throughout
the observation period
 Most common adverse effects were pollakiuria, thirst, fatigue, dry mouth, polydipsia,
and polyuria
 Conclusion:
 Prolonged administration of tolvaptan maintains an increased serum sodium with an
acceptable margin of safety

Berl T et al. J Am Soc Nephrol. 2010; 21(4):705-12.

 Effects of Oral Tolvaptan in Patients
Hospitalized for Worsening Heart Failure:
the EVEREST Outcome Trial
 Background:
 Vasopressin mediates fluid retention in heart failure
 Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart
failure
 Results:
 During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group
and 543 (26.3%) in the placebo group died (P = .68)

Konstam MA et al. JAMA. 2007; 297(12):1319-31.

 Effects of Oral Tolvaptan in Patients
Hospitalized for Worsening Heart Failure:
the EVEREST Outcome Trial
 Results (Contd.):
 Tolvaptan significantly improved secondary end points of day 1 patient-assessed
dyspnea, day 1 body weight, and day 7 edema
 In patients with hyponatremia, serum sodium levels significantly increased
 Conclusion: Tolvaptan initiated for acute treatment of patients
hospitalized with heart failure had no effect on long-term mortality
or heart failure-related morbidity

Konstam MA et al. JAMA. 2007; 297(12):1319-31.

 Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in
patients hospitalized for heart failure: the EVEREST Clinical Status Trials

 Objective: To evaluate short-term effects of tolvaptan when added to

standard therapy in patients hospitalized with heart failure
 Results:
 Mean (SD) body weight reduction was greater with tolvaptan on day 1 and day 7 or
discharge
 More patients receiving tolvaptan reported improvement in dyspnea at day 1

Gheorghiade M et al. JAMA. 2007; 297(12):1332-43.

 Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in
patients hospitalized for heart failure: the EVEREST Clinical Status Trials

 Results:
 Serious adverse event frequencies were similar between groups, without excess
renal failure or hypotension
 Conclusion:
 In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy
including diuretics improved many, though not all, heart failure signs and symptoms,
without serious adverse events

Gheorghiade M et al. JAMA. 2007; 297(12):1332-43.

Efficacy and Safety of Oral Tolvaptan Therapy
in Patients with SIADH
 Background:
 Tolvaptan has been found to improve hyponatremia in patients with mixed etiologies
 This study analyzed the efficacy and safety of tolvaptan in SIADH patients
 Results:
 Improvement in serum Na+ was significantly greater (P<0.0001) with tolvaptan than
placebo over the first 4 days of therapy as well as the entire 30-day study, with minimal
side effects of increased thirst, dry mouth, and urination

Verbalis JG et al. Eur J Endocrinol. 2011; 164(5):725-32.

Efficacy and Safety of Oral Tolvaptan Therapy
in Patients with SIADH
 Results(contd.):
 After discontinuation of tolvaptan, serum [Na(+)] declined to values similar to placebo
 Tolvaptan was associated with a significantly reduced incidence of fluid restriction
 Conclusion:
 Results for the SIADH subgroup were analogous to those of the combined SALT
population regarding efficacy and safety but demonstrated a greater improvement in the
physical component of the SF-12 Health Survey than in the full mixed etiology SALT
patient group

Verbalis JG et al. Eur J Endocrinol. 2011; 164(5):725-32.

New Clinical Use
Tolvaptan in Patients with Autosomal Dominant
Polycystic Kidney Disease (TEMPO 3:4)
 Background: ADPKD is often associated with pain, hypertension, and
kidney failure. Preclinical studies indicated that vasopressin V(2)-
receptor antagonists inhibit cyst growth and slow the decline of
kidney function.
 Results:
• Over a 3-year period, the increase in total kidney volume in
the tolvaptan group was 2.8% per year compared to 5.5% per year in the
placebo group (95% CI, 5.1 to 6.0; P<0.001)

Torres VE et al. N Engl J Med. 2012; 367(25):2407-18.

Tolvaptan in Patients with Autosomal
Dominant Polycystic Kidney Disease
(TEMPO 3:4)
 Results (contd.):
• Tolvaptan – Slower decline in kidney function (reciprocal of
the serum creatinine level, -2.61 [mg/ml] per year vs. -3.81
[mg/ml]per year; P<0.001)
• Lower rates of kidney pain with tolvaptan (5 vs. 7 events
per 100 person-years of follow-up, P=0.007)
 Conclusions: Tolvaptan, as compared with placebo,
slowed the increase in total kidney volume and the
decline in kidney function over a 3-year period in
patients with ADPKD but was associated with a higher
discontinuation rate, owing to adverse events

Torres VE et al. N Engl J Med. 2012; 367(25):2407-18.

New Therapeutic Indications
• Tolvaptan was approved in UK in May 2015
 To slow the progression of cyst development and renal insufficiency of autosomal
dominant polycystic kidney disease (ADPKD) in adults with CKD stage 1 to 3 at initiation
of treatment with evidence of rapidly progressing disease
• Tolvaptan was approved in Europe in June 2015
• To slow the progression of cyst development and renal insufficiency of autosomal
dominant polycystic kidney disease (ADPKD) in adults with CKD stage 1 to 3 at initiation
of treatment with evidence of rapidly progressing disease
Comparison with Diuretics
Acute Heart Failure Volume Control Multicenter Randomized
(AVCMA) Trial: Comparison of Tolvaptan and Carperitide
 Background:
 Diuresis is a major therapy for the reduction of congestive
symptoms. However, most diuretics cause hyponatremia, which is
a worsening factor of ADHF patients prognosis
 This study examined the efficacy and safety of tolvaptan compared
with carperitide
 Results:
 Subjective symptoms and plasma BNP level were similarly
improved by treatment in both groups

Suzuki S et al. J Clin Pharmacol. 2013; 53(12):1277-85.

Acute Heart Failure Volume Control Multicenter Randomized
(AVCMA) Trial: Comparison of Tolvaptan and Carperitide
 Results (contd.):
 Urine volume was significantly higher in the tolvaptan group
(P < .05), but volume of water intake was also higher in
the tolvaptan group (P < .05)
 Less adverse events such as worsening heart failure and
hypotension requiring drug discontinuation were observed in
the tolvaptan group (P = .027)
 Conclusions:
 Tolvaptan might be a novel promising agent for ADHF in terms of
efficacy and safety compared to carperitide

Suzuki S et al. J Clin Pharmacol. 2013; 53(12):1277-85.

Adverse Effects
• Dry mouth
• Constipation
• Thirst
• Asthenia
• Pyrexia
• Hyperglycemia
• Anorexia
• Pollakiuria or polyuria
Dosage and administration:
• The usual starting dose is 15 mg administered once
daily without regard to meals, increase the dose to 30
mg once daily, after at least 24 hours, to a maximum
of 60 mg once daily as needed to achieve desired
serum sodium levels
• Avoid fluid restriction during the first 24 hours of
therapy
Contraindications
• Hypersensitivity to Tolvaptan or excipients of the formulation
• Urgent need to raise serum sodium acutely
• Inability of the patient to sense or appropriately respond to thirst
• Hypovolemic hyponatremia
• Concomitant use of strong CYP 3A inhibitors
• Anuric patients