Tolvaptan versus fluid restriction in moderate-profound hyponatremia: An open-label randomized clinical trial.

Context: 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 uptake.

Objective: To compare the efficacy of tolvaptan and fluid restriction, with a pre-specified protocol for dextrose 5% intervention if sodium correction targets were exceeded.

Design: Open-label randomized trial.

Setting: Single centre tertiary hospital Austin Health in Melbourne, Australia.

Participants: 54 hospitalized patients with pNa 115-130mmol/L (mean 124mmol/L) meeting criteria for syndrome of inappropriate antidiuresis (SIAD).

Interventions: Tolvaptan 7.5mg oral daily or FR <1000ml/day (1:1) for 3 days, with daily titration according to pNa response.

Main Outcome Measures: Plasma sodium change from Day 1 to 4; requirement for IV 5% dextrose to prevent or treat overcorrection; symptom measures; length of hospital stay.

Results: Plasma sodium concentrations increased more in the tolvaptan group, compared to FR, over 3 days (p.overall<0.001). 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 2.5mmol/L (95%CI 0.8-4.2), respectively. Five tolvaptan recipients (19%) required dextrose 5% to treat rapid sodium rise. With this intervention, no patient had sodium rise >10mmol/L at 24 hours. There was no difference in length of stay or symptoms.

Conclusion: 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.