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Cited by 1,215Electrolyte and hormonal disordersIon Transport and Channel RegulationHeart Failure Treatment and Management

Tolvaptan, a Selective Oral Vasopressin V 2 -Receptor Antagonist, for Hyponatremia

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Schrier, Robert W., Gross, Peter, Gheorghiade, Mihai, Berl, Tomas, Verbalis, Joseph G., Czerwiec, Frank S., Orlandi, Cesare·2006·New England Journal of Medicine
DOI 10.1056/nejmoa065181
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Abstract

BACKGROUND: Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis--excretion of electrolyte-free water--might be of benefit in hyponatremia. METHODS: In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. RESULTS: Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. CONCLUSIONS: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [ClinicalTrials.gov] [SALT-1] and NCT00201994 [ClinicalTrials.gov] [SALT-2].).

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  • Pharmacological blockade of V2R was associated with a 5% incidence of hyperglycemic events during 30 days of tolvaptan treatment in patients with hyponatremia compared to 1% in controls (12/223 vs 2/220).

    “pharmacological blockade of the V2R, a potent stimulus of increased AVP secretion,35 was associated with a 5% incidence in hyperglycemic events during 30 days of tolvaptan treatment in patients with hyponatremia compared to 1% in controls, although numbers were small (12/223 vs 2/220).8”

    From Plasma Copeptin and the Risk of Diabetes Mellitus (2010) · cites this paper as [8]

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Research works printed but not linked: 7

  1. [2]2. Schrier RW, ed. Diseases of the kidney and urinary tract. 8th ed. Philadelphia: Lippincott Williams & Wilkins (in press).
  2. [3]3. Schrier RW. Body water homeostasis: 1. 2. clinical disorders of urinary dilution and concentration. J Am Soc Nephrol 2006; 17:1820-32.
  3. [6]6. Wu CC, Yeung LK, Tsai WS, et al. In- cidence and factors predictive of acute 4. 5. 6. renal failure in patients with advanced liver cirrhosis. Clin Nephrol 2006;65:28-33.
  4. [10]10. Doggrell SA. Tolvaptan (Otsuka). Curr Opin Investig Drugs 2004;5:977-83.
  5. [15]15. in the treatment of hyponatremia. Am J Cardiol 2006;97:1064-7.
  6. [17]17. Fleiss JL. Design and analysis of clini- cal experiments. New York: Wiley-Inter- science, 1999:150-61.
  7. [28]28. Miller PD, Linas SL, Schrier RW. Plas- ma demeclocycline concentrations and nephrotoxicity: correlation in hypona- tremic cirrhotic patients. JAMA 1980;243: 2513-5.

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Authors
Schrier, R. W., Gross, P., Gheorghiade, M., Berl, T., Verbalis, J. G., Czerwiec, F. S., & Orlandi, C.
Affiliations
  • University of Colorado Denver (US)
  • University Hospital Carl Gustav Carus (DE)
  • Northwestern University (US)
  • Georgetown University (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2006-11-16
Volume
355
Issue
20
Pages
2099-2112
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa065181
OpenAlex
W2120040647
Semantic Scholar
03c7bf3ae4b2e38925cc612da5fc71d1372a76ec
Cited by
1,215
References
30
Citations by year
2026: 28 · 2025: 40 · 2024: 24 · 2023: 38 · 2022: 46 · 2021: 39 · 2020: 43 · 2019: 46 · 2018: 58 · 2017: 77 · 2016: 57 · 2015: 82 · 2014: 89 · 2013: 81 · 2012: 102
FWCI
55.84
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
Funders
National Center for Research Resources
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Electrolyte and hormonal disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
tolvaptan, hyponatremia, vasopressin V2 receptor antagonist, aquaresis, euvolemic hyponatremia, hypervolemic hyponatremia, serum sodium, chronic heart failure, liver cirrhosis, xerostomia, micturition, quality of life, tolerability
MeSH terms
Tolvaptan, Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Benzazepines, Double-Blind Method, Female, Heart Failure, Humans, Hyponatremia, Inappropriate ADH Syndrome, Liver Cirrhosis, Male, Middle Aged, Sodium, Area Under Curve, Antidiuretic Hormone Receptor Antagonists

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