Tolvaptan and Neurocognitive Function in Mild to Moderate Chronic Hyponatremia: A Randomized Trial (INSIGHT)

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• 作者：Joseph G. Verbalis ; MD¹ ; ^{verbalis@georgetown.edu" class="auth_mail" title="E-mail the corresponding author} ; Howard Ellison ; MD² ; Mary Hobart ; PhD³ ; Holly Krasa ; MS³ ; John Ouyang ; PhD³ ; Frank S. Czerwiec ; MD ; PhD³ ; on behalf of the Investigation of the Neurocognitive Impact of Sodium Improvement in Geriatric Hyponatremia ; Efficacy ; Safety of Tolvaptan (INSIGHT) Investigators^&lowast ; ; Otis Barnum ; Karthikeya Devireddy ; Howard Ellison ; Miguel Franco ; Francis Goldstein ; Terrence C. Hack ; Kianoosh Kaveh ; Ali Khojasteh ; John LaFata ; Michael J. Lillestol ; Sarah Olelewe ; David Rosenbaum ; Mitchell H. Rosner ; Miguel Trevino ; Joseph Verbalis ; Wayne Wells
• 关键词：Chronic hyponatremia ; serum sodium ; tolvaptan ; vasopressin receptor antagonist ; aquaresis ; gait ; postural stability ; cognition ; neurocognitive function ; bone resorption ; bone metabolism ; osteoporosis ; randomized controlled trial (RCT)
• 刊名：American Journal of Kidney Diseases
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：67
• 期：6
• 页码：893-901
• 全文大小：592 K

文摘

This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia.

Study Design

Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study.

Setting & Participants

57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration >120-<135 mEq/L) at 16 sites.

Intervention

Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15 mg/d, with titration to 30 or 60 mg/d based on change in serum sodium concentration and tolerance.

Outcomes

Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations.

Results

Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P < 0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P = 0.03).

Limitations

There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n = 57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating.

Conclusions

Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal.