Efficacy of Low-Dose Tolvaptan for Treatment of Profound Hyponatremia in Syndrome of Inappropriate Antidiuresis (SIAD): The EFFLUX-FLUID TRIAL

Rationale & Objective Although tolvaptan is effective for treating hyponatremia in the syndrome of inappropriate antidiuresis (SIAD), fluid restriction remains the first-line therapy because of safety concerns. This study evaluated whether low-dose tolvaptan is more effective than a combination of fluid restriction, furosemide, and sodium chloride tablets in patients with profound hyponatremia and clinical predictors of fluid restriction failure. Study Design Single-center, open-label, randomized controlled trial. Setting & Participants Hospitalized adults with chronic SIAD and serum sodium concentration [Na + ] ≤125 mmol/L, meeting ≥ 1 predictor of fluid restriction failure (urine osmolality >500 mOsm/kg H 2 O, sum of urine sodium and potassium > [Na + ], or urine volume <1,500 mL/day). Twenty-nine patients were randomized (13 to tolvaptan, 16 to control). Exposure(s) Tolvaptan 7.5 mg/day with liberal fluid intake versus fluid restriction (800 mL/day), furosemide (20-40 mg/day), and sodium chloride tablets (3 g/day) for 28 days. Outcome(s) The primary outcome was change in [Na + ] from baseline to day 4. Secondary outcomes include change in [Na + ] through day 28, achievement of [Na + ] ≥130 mmol/L at day 4, time to correction, and adverse events. Analytical Approach Intention-to-treat analysis using t tests, Fisher exact test, Kaplan–Meier estimates, and generalized estimating equation models. Results Mean baseline [Na + ] was 120 ± 3 mmol/L. By day 4, [Na + ] increased significantly more with tolvaptan (12.2 ± 3.4 vs 6.3 ± 6.0 mmol/L; P = 0.004), with continued benefit on days 7 and 14. More patients achieved [Na + ] ≥130 mmol/L at day 4 (77% vs 25%; P = 0.009), with shorter median time to correction (2 vs 14 days; P = 0.02). Hypokalemia was less frequent with tolvaptan (8% vs 44%; P = 0.04). Overcorrection occurred in 3 tolvaptan patients (23%) without clinical sequelae ( P = 0.08). Limitations Small sample size and single-center design. Conclusions Low-dose tolvaptan effectively and rapidly increases [Na + ] in SIAD patients with predictors of fluid restriction failure, with acceptable safety under close monitoring. Plain-Language Summary Hyponatremia, or low blood sodium levels, is a common and potentially serious condition in hospitalized patients. Fluid restriction is the standard first-line treatment, but it is often ineffective in patients with the syndrome of inappropriate antidiuresis (SIAD). This study evaluated whether low-dose tolvaptan could improve outcomes in patients at high risk of fluid restriction failure. Patients receiving tolvaptan had faster and greater improvements in sodium levels compared with those treated with fluid restriction combined with furosemide and sodium chloride tablets. Although some patients experienced rapid sodium correction, no serious neurologic complications occurred. These findings suggest that tolvaptan may be a beneficial second-line treatment in carefully selected patients with SIAD and profound hyponatremia.