BACKGROUND: Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V2-receptor antagonist that promotes aquaresis - excretion of electrolyte-free water - might be of benefit in hyponatremia. METHODS: In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. RESULTS: Serum sodium concentrations 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). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. CONCLUSIONS: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [SALT-1] and NCT00201994 [SALT-2]).
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