Tolvaptan in hospitalized cancer patients with hyponatremia: A double‐blind, randomized, placebo‐controlled clinical trial on efficacy and safety

Abstract

BACKGROUND:The rate of hyponatremia is higher in hospitalized cancer patients than in hospitalized patients without cancer and is associated with poor clinical outcomes. The availability of V 2 receptor antagonists has been a major breakthrough in the management of hyponatremia, but its efficacy and safety in treating hyponatremia in patients with cancer is not known. METHODS: Adult patients with cancer who were admitted to The University of Texas MD Anderson Cancer Center with nonhypovolemic hyponatremia (125-130 mmol/L) were randomized to receive either tolvaptan or placebo in a double-blind, placebo-controlled, adaptive, randomized trial. Both groups received the standard of care for hyponatremia, except that patients were allowed to drink to thirst. RESULTS: A preplanned Data Safety Monitoring Board analysis of 30 of 48 randomized patients who completed the study revealed that the primary endpoint of hyponatremia correction was met by 16 of 17 patients who received tolvaptan and by 1 of 13 patients who received placebo (94% vs 8%; P <.001), which met the study stopping rule for superiority. The secondary endpoints between the tolvaptan and placebo groups (mean 6 standard deviation) for length of stay (21 6 15 days vs 26 6 15 days, respectively) and change in the MiniMental State Examination score (20.35 6 1.66 vs 0.31 6 2.42, respectively) were not significantly different. No overcorrection of serum sodium (>12 mmol/L per day) was noted in the tolvaptan group, and the main adverse events noted were dry mouth, polydipsia, and polyuria, leading to 13% study withdrawal. CONCLUSIONS: Although tolvaptan was effective for correcting hyponatremia in patients with cancer, studies with a larger sample size will be required to confirm the current findings, including the outcomes of secondary endpoints. Cancer 2014;120:744-51. V C 2013 American Cancer Society.KEYWORDS: hyponatremia, cancer, onconephrology, randomized controlled trial, V 2 -receptor antagonists, tolvaptan. INTRODUCTIONHyponatremia is a common electrolyte abnormality in hospitalized patients, and its incidence is higher in those hospitalized patients who have cancer (nearly 1 in 2).1-3 Hyponatremia, compared with eunatremia, in hospitalized cancer patients is associated with higher mortality rates, longer hospital stays, and higher hospital bills. 3 In patients with cancer, the arginine vasopressin (AVP) hormone, especially the ectopic type, plays an important role in the pathogenesis of hyponatremia. 4,5 The binding of AVP to its V 2 receptors on the basolateral side of the collecting tubules leads to the insertion of aquaporin-2 on the apical side, promoting water reabsorption. The results from trials to determine whether V 2 -receptor antagonism can correct hyponatremia support the role of the AVP-V 2 receptor interaction in clinical settings of hyponatremia. 6,7 However, very few patients with cancer were included in those trials. 6,7 This is of concern, because the standard of care of severe fluid restriction is impractical in cancer patients who ar...

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“…Two trials assessed conivaptan, 13,14 four assessed lixivaptan, [15][16][17][18] three assessed satavaptan [19][20][21] and nine assessed tolvaptan. [22][23][24][25][26][27][28][29] There were no RCTs published assessing other known interventions such as urea, sodium tablets or mannitol. We contacted the authors of ten studies and Otsuka, to seek additional information about the trials' design and outcomes.…”

“…Three trials assessed hyponatraemia in patients with SIADH, 15,21,22 four assessed hyponatraemia in patients with congestive heart failure, [24][25][26][27] two assessed hyponatraemia in patients with cirrhosis, 17,20 and one assessed hyponatraemia in patients with cancer. 28 The other eight trials assessed hyponatraemia in patients with a range of underlying conditions. In these trials, results were reported for subgroups of patients in the Study of Ascending Levels of Tolvaptan in hyponatraemia (SALT 1 and SALT 2) trials with SIADH, 30 cirrhosis, 31 SIADH and cancer, 32 and schizophrenia 33 ; one trial reported some results for a subgroup of patients with cirrhosis and SIADH 18 and one trial reported some results for a subgroup of patients with congestive heart failure (CHF).…”

Electrolyte Disorders in Cancer Patients

“…In a small study of cancer patients, tolvaptan was shown to be safe and to have superior efficacy in controlling hyponatremia when compared with standard therapy using fluid restriction, diuretics, and salt tablets. No patients overcorrected [58]. Any combination of fluid restriction, NaCl tablets, furosemide, and/or a V2 receptor antagonist can be used to achieve a normal serum sodium value in this group of patients.…”

Hyponatrémies : de la physiopathologie aux traitements. Revue de la littérature pour le clinicien

“…Mieux, une é tude prospective randomisé e contrôlé e contre placebo en double insu, chez des patients hyponatré miques (secondairement à un cancer), a dû être arrêté e dè s la premiè re analyse intermé diaire en raison d'un net bé né fice chez les patients du groupe vaptans [74].…”