Oral tolvaptan was superior to fluid restriction at raising plasma sodium concentration (pNa) in adults with hyponatremia, and those treated with tolvaptan who needed intravenous (IV) dextrose for overcorrection maintained their target pNa, according to data from an open-label study of 54 hospitalized patients. However, there were no significant differences in outcome measures including hospital stay, changes in symptom scores, and renal function.

The lack of difference in outcome measures may not justify the added costs, Annabelle M. Warren, MBBS, of Austin Health Department of Endocrinology, Heidelberg, Australia, and colleagues wrote in the study, which was published in The Journal of Clinical Endocrinology & Metabolism.

Tolvaptan, an arginine vasopressin V2-receptor antagonist, has demonstrated effectiveness in managing hyponatremia and was approved in 2009 for “clinically significant hyponatremia,” defined as serum sodium levels < 125 mmol/L. However, persistent concerns about the risk for an excessively rapid rise in pNa in patients with moderate-profound hyponatremia that would necessitate correction has limited its uptake in clinical practice, the researchers said.

In an open-label study at a single tertiary hospital, the researchers randomized 54 hospitalized patients with a mean pNa of 124 mmol/L to 7.5 mg oral tolvaptan daily or fluid restriction of < 1000 mL/d for 3 days, with daily titration based on changes in pNa. Any patients who exceeded their targeted sodium correction were treated with IV 5% dextrose.

The main outcomes included changes in pNa between 1 and 4 days of treatment, the need for IV dextrose to prevent overcorrection, symptom measures, and hospital stay.

Overall, pNa increases were significantly higher in the tolvaptan group compared to the fluid restriction group from day 1 to day 4 of treatment (P < .001), with mean adjusted differences between the groups at 2, 3, and 4 days of 3.16 mmol/L, 3.60 mmol/L, and 2.54 mmol/L, respectively, favoring tolvaptan. Five patients in the tolvaptan group (19%) needed 5% dextrose to correct rapid sodium increases; none of these patients experienced a sodium increase of more than 10 mmol/L at 24 hours.

No differences occurred between the tolvaptan group (including those who needed dextrose) and the fluid restriction group in terms of hospital stay, changes in symptom scores, or measures of renal function, serum glucose, or liver function during the study period. No serious adverse events occurred in either group, although five deaths were reported among tolvaptan patients (either in-hospital or within 30 days of discharge) compared to no deaths in the fluid restriction group. The deaths were deemed unrelated to the study.

The findings were limited by several factors, including the open-label design and the inclusion of patients at low risk for osmotic demyelination syndrome, the researchers noted.

Despite tolvaptan’s superiority at raising pNa, the lack of difference in hospital stay may fail to justify the higher cost of tolvaptan and the need for additional monitoring for overcorrection, they said. Therefore, fluid retention should remain first-line treatment for most moderate-profound hyponatremia cases, although tolvaptan may be justified, with appropriate safeguards, for patients with persistently low sodium despite fluid retention who would otherwise be fit for hospital discharge, the authors concluded.

Complicated Clinical Takeaways

Considerable controversy persists as to how and when to best manage hyponatremia, said David S. Goldfarb, MD, clinical chief of the Nephrology Division at NYU Langone Health and professor of medicine and physiology at NYU Grossman School of Medicine, New York City.

“Tolvaptan, a vasopressin antagonist, is clearly effective but has a risk of overcorrecting the plasma Na concentration,” said Goldfarb, who was not involved in the study. “The usual alternative, restriction of solute-free water intake, is not considered as effective,” and has poor acceptance by patients, he noted.

The findings of the current study were not surprising, he added. Tolvaptan was slightly more effective than fluid restriction in the first 24 hours, but it was handicapped by the decision to administer water IV to avoid overcorrection. “Without the reflexive administration of water, the tolvaptan group would have demonstrated a more marked clinical benefit,” he explained.

“Exactly how important this administration of water in response to an effective therapy is, and when it should be administered, is currently debated,” said Goldfarb.

“The importance, efficacy, and safety of administration of water and desmopressin acetate (DDAVP, not used in this trial) to prevent overcorrection, could be more thoroughly studied,” he told Medscape Medical News.

Patient selection was an important limitation in the study, Goldfarb pointed out. The population of the current study was a mixed group; all were hospitalized, but the duration of hyponatremia varied, and all were considered at low risk for osmotic demyelination syndrome or central pontine myelinolysis, the feared complication of overcorrection, he noted. However, he acknowledged that conducting a randomized, controlled trial of patients who are more clearly at risk would be difficult.

“This study does not address the many patients with chronic hyponatremia in the community and those in nursing homes for whom appropriate therapy is not defined,” he added.

The study was supported by grants to Warren and two coauthors from Otsuka Pharmaceutical Australia, a National Health and Medical Research Council Grant, and an Endocrine Society of Australia travel grant.

Goldfarb had no financial conflicts to disclose.