Targeted Hyponatremia Intervention Does Not Reduce Mortality

SAN DIEGO — The use of a targeted plasma sodium correction did not reduce 30-day mortality and rehospitalization rates in hospitalized patients with hyponatremia despite often achieving normonatremia, results of a large, prospective, randomized study showed.
The findings suggest that “hyponatremia in hospitalized patients is more a marker of a worse outcome than the cause of it,” first study author Julie Refardt, MD, PhD, University Hospital Basel, Basel, Switzerland, told Medscape Medical News.
With a wide range of potential causes of hyponatremia, sometimes overlapping, the diagnosis as well as appropriate treatment can be a challenge. Findings from a hyponatremia registry showed that up to 25% of hospitalized patients with mild to moderate hyponatremia never received treatment, and the majority of patients who had hyponatremia in the hospital were discharged while still being hyponatremic.
The implications can be serious, with chronic hyponatremia associated with issues such as neurocognitive disorders, gait instability, and falls, as well as an increased rate of rehospitalization and adverse outcomes, including death.
However, data are lacking on how — or even if — proper treatment of hyponatremia can prevent those disorders, said Refardt, who presented the results here at the Kidney Week 2024: American Society of Nephrology Annual Meeting.
To investigate, she and her colleagues conducted the randomized, international, multicenter Hyponatremia Intervention Trial (HIT), enrolling 2174 hospitalized patients at nine centers across Europe with hyponatremia, defined for the study as serum sodium concentrations < 130 mmol/L. Patients were recruited between August 2018 and April 2024.
Study participants were randomized to either undergo targeted correction of plasma sodium levels based on European hyponatremia and cardiology and hepatology guidelines (n = 1079) or to a control group receiving hyponatremia correction based on standard practice (n = 1095). Standard practice often involved either no treatment or fluid restriction only, Refardt explained.
The median age of all the participants was about 72.5 years, and about 48% were men. Approximately 53.8% had euvolemia, 30.8% had hypovolemia, and 15.4% had hypervolemia, with about equal proportions in both groups.
Patients were excluded if they had severe symptomatic hyponatremia in need of hypertonic saline or if they had end-stage kidney disease or active liver failure or were receiving end-of-life care.
Overall, 641 (60.4%) patients in the intervention group achieved normonatremia compared with 493 (46.2%) patients in the control group.
For the coprimary endpoints, death occurred within 30 days among nearly identical proportions of patients in the intervention and control groups (8.6% and 8.5%, respectively), while rehospitalization within 30 days also occurred in nearly the same percentages (13.0% vs 14.0%, respectively).
Combined, the overall event rate was not significantly different, occurring in 21.0% of patients in the intervention group and 22.2% of patients in the control group (P = .50).
At discharge, 55.9% in the intervention group and 36.9% in the control group had normonatremia, while 41.5% and 41.3% in the intervention and control groups, respectively, developed hyponatremia within 30 days.
Those who reached normonatremia at discharge had 25% lower odds of experiencing the primary outcome; however, the association was independent of whether or not patients received the intervention, Refardt noted.
The results were consistent in a subgroup analysis that included hyponatremia severity, etiology, treatment, sex, and age.
The rates of sodium overcorrection were low, occurring in 2.4% of the intervention group and 1.5% of the control group (P = .143), and there were also no significant differences in adverse events due to sodium overcorrection (1.2% vs 0.8%, respectively; P = .372) or cases of severely symptomatic hyponatremia (0.5% and 0.1%; P = .0983).
Refardt noted that key caveats include that the results only reflect outcomes involving hospitalized patients. In addition, most patients had mild to moderate hyponatremia.
Nevertheless, she said, the results came as a surprise to the authors.
“Doing research in the hyponatremia field for some time and knowing all the adverse outcomes associated with it, we expected a positive outcome,” she told Medscape Medical News.
“However, the results are convincing and also robust in the subgroup analyses.”
Refardt further noted that the rate of only 60% of patients in the intervention group achieving normonatremia was disappointingly low. We concluded that “in some patients with hyponatremia, you simply cannot [improve] with the guideline treatment we have at the moment because they are just too ill,” she told the presentation audience.
That being said, she emphasized that “one important message is that our results do not suggest that we should not treat hyponatremia, as the control group received the standard of care.” 
Further Allays Concerns of Over-Correction
Commenting on the study, discussant Carol Pollock, a clinical professor of medicine at The University of Sydney, Sydney, Australia, said caveats include questions such as how chronic vs acute hyponatremia was determined in the study, which could modify the treatment, and what proportion of patients had comorbidities such as malnourishment or alcoholism, which dictates how rapidly sodium should be corrected.
She noted concerns that clinicians have had surrounding the potential of over-correction of hyponatremia leading to the rare but potentially devastating osmotic demyelination syndrome (ODS).
Recent studies, however, including a 2023 study that analyzed more than 22,000 hospitalizations, have shown only a very small fraction of patients (0.05%) developing ODS in the context of rapid hyponatremia correction.
Pollock said the results of the new study make her “feel more comfortable about attempts to improve hyponatremia more rapidly in patients with moderate levels of hyponatremia, with the aim of early discharge.”
“How that is to be done isn’t yet clear and depends on the cause,” she said, with “options including fluid restriction or rehydration, depending on volume status; K replenishment; loop diuretics; oral urea; AVP antagonists; sodium-glucose cotransporter-2 inhibitors; and 3% sodium chloride.”
The HIT was funded by a clinical trial grant from the Swiss National Science Foundation. Refardt had no disclosures to report. Pollock disclosed that she is an advisor to Otsuka.
 
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