Abstract 2730: Results from the SALT 1 and 2 Trials: Multicenter, Randomized, Placebo-controlled Trials in Patients with Euvolemic and Hypervolemic Hyponatremia
Background: Hyponatremia (Na+≤134 mEq/L) predicts higher mortality in CHF, cirrhosis and SIADH. Current treatments are ineffective. Earlier CHF studies indicate tolvaptan, an oral vasopressin V2 receptor blocker, may improve serum sodium levels by removal of free water (aquaresis).
Methods: Two pivotal, multicenter, randomized, double-blind, placebo-controlled trials (SALT-1 [US] and SALT-2 [international]) evaluated efficacy and safety of tolvaptan in patients with hyponatremia arising from CHF, cirrhosis and SIADH. The studies enrolled 205 and 243 patients, respectively. Patients received daily oral doses of either placebo or tolvaptan 15 mg with titration to 30 and 60 mg qd as needed to correct sodium over 30 days, with a follow-up visit 7 days after study end. Primary endpoints were average change in serum sodium from baseline to day 4 and day 30 of treatment.
Results: In SALT-1, patients receiving tolvaptan had an average daily AUC change in serum sodium to day 4 of 3.62 ± 2.68 (mean ± SD) as compared with 0.25 ± 2.08 mEq/L in the placebo group (p<0.0001). At 30 days this averaged 6.22 ± 4.10 for tolvaptan vs. 1.66 ± 3.59 mEq/L for placebo (p<0.0001). SALT-2 results were similar (4.33 ± 2.87 vs. 0.42 ± 2.56 mEq/L at day 4 and 6.20 ± 3.92 vs. 1.84 ± 3.83 mEq/L in the placebo group [both p<0.0001]). In both studies serum sodium improved more in tolvaptan-treated patients whether they had mild (130–134 mEq/L) or severe (<130 mEq/L) hyponatremia(p<0.0001). Combined data proved efficacy in hyponatremia arising from all etiologies (CHF, cirrhosis, SIADH all p<0.0001). More tolvaptan-treated patients reached normal serum sodium levels (p<0.0001 for all comparisons). In hypervolemic subjects, net fluid loss exceeded that of placebo by >1 L over the first 24 hours therapy (15 mg) (p<0.005). Within seven days after stopping tolvaptan, serum sodium returned to the placebo levels. The most frequent adverse events reported for tolvaptan vs. placebo overall were thirst 14.3 vs. 4.5% and dry mouth 12.6 vs. 5.1%, consistent with the intended mechanism of action.
Conclusions: The results of the SALT 1 and 2 trials showed that serum sodium can be safely improved in patients with hyponatremia through removal of excess free water, producing additional clinical benefits.