Tolvaptan vs Fluid Restriction in Moderate-Profound Hyponatremia: An Open-Label Randomized Clinical Trial

Current first-line therapy for hyponatremia, fluid restriction (FR), is often unsuccessful. Tolvaptan, an arginine vasopressin V2-receptor antagonist, is effective; however, concerns about plasma sodium (pNa) overcorrection risk have limited its uptake.

This work aimed to compare the efficacy of tolvaptan and FR, with a prespecified protocol for dextrose 5% intervention if sodium correction targets were exceeded.

An open-label, randomized trial was conducted at a single-center tertiary hospital, Austin Health, in Melbourne, Australia. Fifty-four hospitalized patients with pNa 115 to 130 mmol/L (mean 124 mmol/L) were enrolled and randomized to tolvaptan 7.5 mg oral daily or FR less than 1000 mL/day (1:1) for 3 days, with daily titration according to pNa response. Main outcome measures included plasma sodium change from day 1 to 4, requirement for intravenous 5% dextrose to prevent or treat overcorrection, symptom measures, and length of hospital stay.

Plasma sodium concentrations increased more in the tolvaptan group, compared to FR, over 3 days (Poverall < .001). The mean adjusted difference in pNa between groups at days 2, 3, and 4 was 3.2 (95% CI, 1.6-4.7), 3.5 (95% CI, 1.9-5.2), and 2.5 mmol/L (95% CI, 0.8-4.2), respectively. Five tolvaptan recipients (19%) required dextrose 5% to treat rapid sodium increase. With this intervention, no patient had an Na increase more than10 mmol/L at 24 hours. There was no difference in length of stay or symptoms.

Tolvaptan was superior to FR at raising pNa over 3 days. However, intervention was required to prevent overcorrection in some, with no benefit in secondary outcomes. This is the first prospectively validated protocol to detect and prevent tolvaptan-related overcorrection.