Tolvaptan, hyponatremia, and heart failure

Figures & data

Table 1 Arginine vasopressin receptors^18–21

Receptor	Location	Function
V1A	Vascular smooth muscle cells, hepatocytes, platelets, uterus, renal, adrenal, and brain cells.	Vasoconstriction, glycogenolysis, platelet aggregation, and myocytes hypertrophy.
V1B	Anterior pituitary gland	Mediate the release of adrenocorticotropin hormone and endorphines.
V2	Collecting ducts of the kidney.	Mediate free water absorption by mobilizing intracellular vesicles of aquaporin-2 (AQP2) to the apical plasma membrane of the collecting duct cells, causing an increase in water permeability and antidiuretic effect.

Table 2 Tolvaptan studies in hyponatremic patients

Reference Design	Intervention	Patient population	Major measures	Major results
Multicenter, prospective, randomized, open-label, active-controlled, dose titration^Citation34	Patients were randomized to tolvaptan or fluid restriction with placebo	n = 28 Hyponatremic patients with serum Na^+ concentration <135 mEq/L	Normalization of serum Na^+ concentration	A total of 11 patients normalized their Na^+ levels by the last inpatient visit in the tolvaptan group compared to 3 patients in the placebo group (P = 0.049) 50% of the patients achieved normalization in their Na^+ level within 4 days in the tolvaptan group compared to 8 days in the fluid restriction group (P < 0.03) Tolvaptan patients had significantly larger increases in mean serum Na^+ from baseline
Two randomized, double-blind, placebo-controlled, Phase III trials^Citation35	Patients were randomized to receive 15 mg/day of oral tolvaptan or placebo for 30 days	n = 448 Euvolemic or hypervolemic hyponatremic patients	The change in the average daily area under the curve (AUC) for the serum Na^+ concentration from baseline to day 4 and day 30 The percentage of patients with normalized serum Na^+ concentration at day 4 and 30	Tolvaptan significantly increased the average daily AUC for the serum Na^+ concentration from baseline to study day 4 and during the entire 30-day study period as compared with placebo Significantly more patients in the tolvaptan group had normal serum Na^+ concentration and fewer patients had marked hyponatremia at day 4 and day 30, as compared with placebo
Open-label extension of the SALT-1 and SALT-2 trials^Citation36	4-year sequential, open-label extension of the SALT-1 and SALT-2 trials	n = 111 Euvolemic or hypervolemic hyponatremic patients	Evaluate the safety and efficacy of long-term tolvaptan use in hyponatremia	Multiple adverse events were judged to be related to tolvaptan
Post hoc analysis on the SALT trials^Citation37	7 patients were randomized to receive tolvaptan and 12 to placebo	n = 19 Schizophrenic patients with idiopathic hyponatremia	Evaluate the effects of tolvaptan on idiopathic hyponatremia in schizophrenia	Tolvaptan patients had significantly greater increase in the average daily AUC for Na^+ concentration from baseline to day 4, as compared with placebo Mean serum Na^+ concentrations were significantly higher at all measurement times after receiving the study medication except at 8 hours, where it was marginally different (P = 0.07)

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