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.