Effectively Treating Euvolemic Hyponatremia in Hospitalized Patients

Study results published in Kidney International show that lixivaptan, “a selective vasopressin V₂-receptor antagonist that blocks arginine vasopressin-mediated aquaporin synthesis and membrane insertion,” effectively increases serum sodium concentration in patients with euvolemic hyponatremia.

Hyponatremia occurs in up to 30% of hospitalized patients. Chronic hyponatremia is associated with increased mortality and a wide range of comorbidities, including “cognitive impairment, gait disturbances, and an increased incidence of falls and fractures.” The condition can be caused by multiple factors, including “the presence of tumors, central nervous system disease, pulmonary disease, or the use of certain drugs that act directly or indirectly on the arginine vasopressin pathway.”

Effective treatment of hyponatremia can be challenging, with fluid restriction being the commonly used approach. Recently, the approval of vasopressin receptor antagonists such as tolvaptan has provided clinicians with expanded options for treatment.

In a recent study, 206 patients in a variety of treatment settings who were diagnosed with chronic euvolemic hyponatremia (serum sodium <135&thinsp;mmol/liter) were randomized to receive daily treatment with 25, 50, or 100&thinsp;mg lixivaptan, titrated based on serum sodium levels, or placebo for 24 weeks.

The study population included 44 patients (21%) from long-term care facilities or nursing homes, with the remaining 162 patients recruited from “outpatient clinics, doctors’ offices, and hospitals” (more than 80% of patients were treated in non-hospital settings). Nearly half of the patients were age 65 or older.

At baseline, 16.9% of patients treated with lixivaptan and 11.5% of patients who received placebo were on fluid restriction.

130 (84.4%) patients in the lixivaptan group and 42 (80.8%) in the placebo completed eight weeks of treatment. Thirty-four percent of patients in the lixivaptan group and 32.7% of patients in the placebo group completed the entire 24-week treatment.

The investigators reported that “significantly greater serum sodium increases from baseline were observed at day 7 in subjects receiving lixivaptan compared with those receiving placebo.” They also reported that the mean increase in serum sodium concentrations from baseline to day 7 was “significantly greater” in patients who received lixivaptan compared with patients who received placebo, “regardless of sex or age.”

Patients treated with lixivaptan also experienced faster relief than patients treated with placebo. The authors reported that within eight hours of treatment, “serum sodium concentrations were significantly higher in the lixivaptan group compared with the placebo group.”

Nearly 40% of patients in the lixivaptan group “achieved normalized serum sodium concentrations” after one week of treatment, compared with 12.2% of subjects in the placebo group. Two-thirds (66.7%) of patients in the lixivaptan group achieved normalized serum sodium concentrations at the conclusion of treatment, compared with just under half (48%) of patients in the placebo group.

Adverse event frequency was similar between groups, with urinary tract infection, polyuria, and upper respiratory tract infection being the most commonly reported. Serious treatment-emergent adverse events were reported in 18.3% of subjects receiving lixivaptan and 26.9% of subjects receiving placebo. In all, 11% of patients treated with lixivaptan and 17% treated with placebo dropped out of the study due to an adverse event.

In their discussion of these results, the authors wrote that “once-daily oral lixivaptan given in an outpatient setting increased serum sodium concentrations in subjects with euvolemic hyponatremia in a gradual, well-tolerated manner, separating significantly from placebo by day 3.”