Equivalent Efficacy and Decreased Rate of Overcorrection in Patients With Syndrome of Inappropriate Secretion of Antidiuretic Hormone Given Very Low-Dose Tolvaptan

Abstract

Rationale & Objective: Euvolemic hyponatremia often occurs due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Vasopressin 2 receptor antagonists may be used to treat SIADH. Several of the major trials used 15 mg of tolvaptan as the lowest effective dose in euvolemic and hypervolemic hyponatremia. However, a recent observational study suggested an elevated risk for serum sodium level overcorrection with 15 mg of tolvaptan in patients with SIADH. Study Design: A retrospective chart review study comparing outcomes in patients with SIADH treated with 15 versus 7.5 mg of tolvaptan. Settings & Participants: Patients with SIADH who were treated with a very low dose of tolvaptan (7.5 mg) at a single center compared with patients using a 15-mg dose from patient-level data from the observational study described previously. Predictors: Tolvaptan dose of 7.5 versus 15 mg daily. Outcomes: Appropriate response to tolvaptan, defined as an initial increase in serum sodium level > 3 mEq/L, and overcorrection of serum sodium level (>8 mEq/L per day, and >10 mEq/L per day in sensitivity analyses). Analytical Approach: Descriptive study with additional outcomes compared using t tests and Ftests (Fischer's Exact χ2 Test). Results: Among 18 patients receiving 7.5 mg of tolvaptan, the mean rate of correction was 5.6 ± 3.1 mEq/L per day and 2 (11.1%) patients corrected their serum sodium levels by >8 mEq/L per day, with 1 of these increasing by >12 mEq/L per day. Of those receiving tolvaptan 7.5 mg, 14 had efficacy, with increases ≥ 3 mEq/L; similar results were seen with the 15-mg dose (21 of 28). There was a statistically significant higher chance of overcorrection with the use of 15 versus 7.5 mg of tolvaptan (11 of 28 vs 2 of 18; P = 0.05; and 10 of 28 vs 1 of 18; P = 0.03, for >8 mEq/L per day and >10 mEq/L per day, respectively). Limitations: Small sample size, retrospective, and nonrandomized. Conclusions: Tolvaptan, 7.5 mg, daily corrects hyponatremia with similar efficacy and less risk for overcorrection in patients with SIADH versus 15 mg of tolvaptan. Complete author and article information provided before references.

Diagnosis and Management of Hyponatremia

“…Rare cases of osmotic demyelination have been reported and approximately 10% of patients develop hypernatremia. A dose of 7.5 mg/d of tolvaptan, which is lower than the recommended dose, is effective and safe . The US Food and Drug Administration warns that tolvaptan should not be used longer than 30 days and should not be administered to patients with liver disease.…”

Hyponatremia in the cancer patient

“…A recent retrospective study in 2 cohorts of patients, 35% of them suffering from malignancy-associated SIAD, confirmed the efficacy and safety of this lower dose of tolvaptan (i.e., 7.5 mg daily). 136 We believe it is prudent to start tolvaptan at a reduced dose in cancer patients with SIAD (especially in SCLC) and titrate up as needed.…”

Tolvaptan for the treatment of the syndrome of inappropriate antidiuresis (SIAD)

“… 37 , 38 All real-world studies suggest that a starting 7.5 mg dose, half the approved initiation dose of tolvaptan, is effective in treating hyponatraemia. With respect to the risk of over-rapid sodium correction, some studies suggest that a low dose may reduce it, 35 , 39 – 41 whereas other studies still report high rates of too rapid correction. 25 , 28 , 36 , 37 , 42 Critical review of these data suggests that tolvaptan at a 7.5 mg dose seems to be still associated with a substantial risk for overly rapid sodium correction, especially in individuals with more severe hyponatraemia and a basal serum sodium level below 120 mmol/litre.…”