Randomized, double blinded, placebo‐controlled trial to evaluate the efficacy and safety of tolvaptan in Chinese patients with hyponatremia caused by SIADH

Abstract

To study the effect of tolvaptan on non-acute, non-hypovolemic hyponatremia in inappropriate secretion of antidiuretic hormone (SIADH) syndrome in Chinese patients. Hyponatremic SIADH patients received placebo (N = 18) or tolvaptan (N = 19) at an initial dose of 15 mg/day with further titration to 30 mg/day and 60 mg/day based on serum sodium concentrations. Randomized, double-blind, placebo-controlled trial. Primary endpoint was the change of the serum sodium from baseline to days 4 and 7. Analysis of covariance (ANCOVA) was used for statistical analysis. At day 4, average daily changes in serum sodium levels from baseline was 1.9 ± 2.9 mmol/L (1.9 ± 2.9 mEq/L) in the placebo group and 8.1 ± 3.6 mmol/L (8.1 ± 3.6 mEq/L) in the tolvaptan group; at day 7, the values were 2.5 ± 3.9 mmol/L (2.5 ± 3.9 mEq/L) and 8.6 ± 3.9 mmol/L (8.6 ± 3.9 mmEq/L) for the placebo and tolvaptan groups (ANCOVA, P < 0.001). At days 4 and 7, daily urine output and proportions of patients with normalized serum sodium were significantly superior in the tolvaptan group. The most common adverse events occurring in the tolvaptan group were dry mouth and thirst. Tolvaptan demonstrated superiority to placebo in the treatment of Chinese SIADH patients with hyponatremia by elevating serum sodium concentration with acceptable safety profile.

A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta‐analysis of the vaptans

“…The trials at day 30 showed high levels of heterogeneity ( I 2 = 74%). Results were similar for tolvaptan compared to placebo when considering SIADH population/subgroups only at day 4 …”

“…Two trials assessed conivaptan, 13,14 four assessed lixivaptan, [15][16][17][18] three assessed satavaptan [19][20][21] and nine assessed tolvaptan. [22][23][24][25][26][27][28][29] There were no RCTs published assessing other known interventions such as urea, sodium tablets or mannitol. We contacted the authors of ten studies and Otsuka, to seek additional information about the trials' design and outcomes.…”

“…Response was defined in the protocol as an increase in serum sodium of ≥5 mmol/l and/or normalization of serum sodium concentration (≥135-145 mmol/l). A random-effects meta-analysis suggests that patients randomized to lixivaptan, [15][16][17] satavaptan [19][20][21] and tolvaptan 22,26,29 are significantly more likely to experience a response compared to placebo, with tolvaptan showing the largest treatment effect (RR 3Á30 [1Á97, 5Á54]). Tolvaptan data were available up to 30 days 24,29 and in all cases tolvaptan was significantly superior to placebo, with the exception of day 14.…”

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“…Two trials assessed conivaptan, 13,14 four assessed lixivaptan, [15][16][17][18] three assessed satavaptan [19][20][21] and nine assessed tolvaptan. [22][23][24][25][26][27][28][29] There were no RCTs published assessing other known interventions such as urea, sodium tablets or mannitol. We contacted the authors of ten studies and Otsuka, to seek additional information about the trials' design and outcomes.…”

“…Some trials reported data for a specific population and others included patients with various underlying causes. Three trials assessed hyponatraemia in patients with SIADH, 15,21,22 four assessed hyponatraemia in patients with congestive heart failure, [24][25][26][27] two assessed hyponatraemia in patients with cirrhosis, 17,20 and one assessed hyponatraemia in patients with cancer. 28 The other eight trials assessed hyponatraemia in patients with a range of underlying conditions.…”