Michael J. Koren, MD, Jacksonville Center for Clinical Research, Jacksonville, Florida, USA, reported a prospective clinical trial that evaluated the effect of the selective, competitive vasopressin 2 antagonist tolvaptan in the treatment of hyponatremia [Koren MJ et al. ICE ENDO 2014 (poster LBSA-0737)].

Hyponatremia is the most common clinically encountered serum electrolyte abnormality, occurring in 7% to 8% of elderly, ambulatory patients and 15% to 20% of hospitalized patients [Huda MS et al. Postgrad Med J 2006]. If left untreated, a subnormal (< 130 mEq/L) serum sodium concentration can led to seizure, reduced alertness, diminished pain sensitivity, and death, especially if the decline occurs rapidly.

The present study evaluated the influence of tolvaptan on medically necessary hospital length of stay (LOS) and time to improvement of neurocognitive (NC) symptoms of hyponatremia caused by water retention. The study was terminated early when only 124 of a planned 400 patients had been randomized into the study at 2 years.

Patients hospitalized with symptoms of mild to moderate dilutional hyponatremia were randomized to tolvaptan (15 to 60 mg) with fluid replacement as needed (n = 66) or placebo with < 1.5 L fluid daily (fluid restriction; n = 58). Patients were stratified by Clinical Global Impression– Severity (CGI-S) scores of 3 to 4 and 5 to 6 (of a maximum score of 7), a measure of NC symptoms.

Fifty-three (80.3%) and 48 (82.8%) of the tolvaptan and fluid-restricted patients, respectively, completed the trial. The rate of study discontinuation was similar in the tolvaptan and fluid-restricted arms (19.7% and 17.2%, respectively), mostly due to adverse events (AEs; 6.1% and 5.2%, respectively) or investigator decision (9.1% and 10.3%, respectively). The baseline demographics of both groups were similar (Table 1).

The primary end point of LOS was not significantly different between patients receiving tolvaptan (estimated mean, 3.5 days; range, 3.0 to 4.5 days) and fluid-restricted patients (estimated mean, 4.0 days; range, 3.5 to 5.0 days; p = .95). The baseline CGI-S was 3.88 and 3.64 in the tolvaptan and fluid-restricted arms, and at 48 hours it was reduced to 2.65 and 2.73, respectively. The secondary end point of improvement in NC symptoms measured by CGI-S showed a nominal improvement with tolvaptan compared with fluid restriction (between-group difference, −0.30; 95% CI, 0.70 to 0.11; p = .1460).

The mean serum sodium levels at baseline and before discharge were similar in both arms (Table 2).

At discharge, serum sodium had normalized in 25 of 60 (41.7%) and 8 of 54 (14.8%) of patients in the tolvaptan and fluid restriction arms, respectively. The majority (71.1%) of patients were discharged with hyponatremia despite clinical intervention to correct sodium levels. Of these, 32.5% of the total patients were moderately hyponatremic and 11.4% were severely hyponatremic (Table 3).

The incidence of treatment-emergent AEs was higher in the tolvaptan arm (87.9%) than in the fluid restriction group (80.0%), as was the incidence of serious AEs (27.3% and 16.4%, respectively).

The findings that a majority of patients were discharged with moderate or severe hyponatremia suggests that hyponatremia influences, but does not prevent, hospital discharge. Study limitations included difficulty in accurately defining the LOS because the discharge decision was typically not made by the physician treating the hyponatremia and the relatively small sample size.