Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment

Hirai, Keita; Shimomura, Tokio; Moriwaki, Hisataka; Ishii, Hidetoshi; Shimoshikiryo, Takayuki; Tsuji, Daiki; Inoue, Ken‐ichiro; Kadoiri, Toshihiko; Itoh, Ken

doi:10.1007/s00228-016-2091-4

Cited by 29 publications

(31 citation statements)

References 26 publications

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“…In recent years, they, in particular tolvaptan, have assumed major importance compared with conventional therapeutic approaches (water restriction or 3% hypertonic saline solution) for the treatment of hyponatremia [21,22,23,24,25,26,27] (see also Table 2). In Table 3, Table 4, Table 5 and Table 6, some characteristics of VRAs are outlined.…”

Section: The Vasopressin Receptor Antagonists (Vras): Promoting Frmentioning

confidence: 99%

RETRACTED: Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current Clinical Practice?

Vecchis

Cantatrione

Mazzei

et al. 2016

JCM

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In the congestive heart failure (CHF) setting, chronic hyponatremia is very common. The present review aims at addressing topics relevant to the pathophysiology of hyponatremia in the course of CHF as well as its optimal treatment, including the main advantages and the limitations resulting from the use of the available dietary and pharmacological measures approved for the treatment of this electrolytic trouble. A narrative review is carried out in order to represent the main modalities of therapy for chronic hyponatremia that frequently complicates CHF. The limits of usual therapies implemented for CHF-related chronic hyponatremia are outlined, while an original analysis of the main advancements achieved with the use of vasopressin receptor antagonists (VRAs) is also executed. The European regulatory restrictions that currently limit the use of VRAs in the management of CHF are substantially caused by financial concerns, i.e., the high costs of VRA therapy. A thoughtful reworking of current restrictions would be warranted in order to enable VRAs to be usefully associated to loop diuretics for decongestive treatment of CHF patients with hyponatremia.

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Section: The Vasopressin Receptor Antagonists (Vras): Promoting Frmentioning

confidence: 99%

RETRACTED: Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current Clinical Practice?

Vecchis

Cantatrione

Mazzei

et al. 2016

JCM

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“…Serum potassium concentration was not found to be a risk factor in the study of Hirai et al 14 This difference could be attributed to the patient mix, because Hirai et al 14 included patients with liver cirrhosis in their study. The…”

Section: Discussionmentioning

confidence: 89%

Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart Failure

Kinugawa

Sato

Inomata

et al. 2018

Circ J

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tions were reported to occur following tolvaptan treatment in a dose-dependent manner, with rates of 6%, 11%, and 13% for 30, 45, and 60 mg tolvaptan, respectively. 7 Although the risk of hypernatremia was not clear in the pivotal Phase 3 QUEST study, 8 we reported 3 risk factors for hypernatremic events using the interim results of the Samsca Post-Marketing Surveillance In the Heart faiLurE (SMILE) study conducted in 2014. 9 These factors were higher baseline sodium concentration, lower baseline potassium concentration, and a 15-mg starting dose of tolvaptan. Moreover, based on subanalysis of the SMILE study in 2015, 10 we recommended a lower dose of tolvaptan for older patients (i.e., those >80 years of age) to prevent hypernatremic events. Herein, we report on the development of a risk score to predict the prevalence of hypernatremia using the final dataset of the SMILE study. MethodsThe present prospective multicenter observational study was conducted in compliance with Good Post-Marketing Study Practice, an ordinance issued by the Ministry of Health, Labor and Welfare for the implementation of post-marketing surveillance of new drugs approved in Japan. The study period was from 2011 to 2016, and the D iuretic resistance was common in the Acute Decompensated Heart Failure Registry (ADHERE), 1 being observed in 30% of patients with heart failure. Until the approval of tolvaptan, a vasopressin V2 receptor antagonist, there were limited therapeutic options for patients with heart failure and fluid retention who did not respond sufficiently to conventional diuretics.Tolvaptan has been approved in the US since 2009, with current indications for tolvaptan being the treatment of clinically significant hypervolemic and euvolemic hyponatremia, as well as Syndrome of Inappropriate Antidiuretic Hormone (SIADH). 2 However, in Japan, tolvaptan was approved in 2010 for the following expanded indication, which is quite different from indications in the US: "volume overload in heart failure patients when adequate response was not obtained with other diuretics (e.g., loop diuretics)". 3,4 Tolvaptan significantly increases urine volume with water excretion into the urine 5 and sometimes results in marked increases in serum sodium concentrations. Therefore, tolvaptan treatment must be started in an inpatient setting to avoid the adverse event of hypernatremia caused by its pharmacological action of aquaresis. In the EVEREST study, in which patients were treated with 30 mg tolvaptan, the incidence of hypernatremia was 1.7%. 6 In another study, abnormally high serum sodium concentra- Sugitani, Toyama 930-0914, Japan. E-mail: kinugawa0422@gmail.com ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart FailureKoichiro Kinugawa, MD, PhD; Naoki Sato, MD, PhD; Takayuki Inomata, MD, PhD; Moriyoshi Yasuda, PhD; Yoshiyuki Shibasaki, BSc; Toshiyuki Shimakawa, BScBackgrou...

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“…Tolvaptan potentially causes severe hypernatraemia at therapeutic doses. 5 Our data revealed that the CYP3A5*3 allele raised the plasma tolvaptan concentration. The effect of tolvaptan on serum sodium usually appeared within 5 days after starting the medication.…”

Section: Discussionmentioning

confidence: 50%

“…3 Adverse effects such as severe hypernatraemia and potentially fatal liver injury were reported in clinical settings. 4,5 However, tolvaptan plasma exposure itself has not fully explained the efficacy and safety. 6 Tolvaptan is mainly converted to three monohydroxylates (DM-4110, DM-4111 and DM-4119) and a ring-opened carboxylate (DM-4103) in the human liver ( Figure S1).…”

Section: Introductionmentioning

confidence: 99%

Impact of CYP3A5 genotype on tolvaptan pharmacokinetics and their relationships with endogenous markers of CYP3A activity and serum sodium level in heart failure patients

Hoshikawa

Naito

Akutsu

et al. 2019

Basic Clin Pharma Tox

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Tolvaptan efficacy for heart failure has a large interindividual variation. This study aimed to evaluate the influence of CYP3A5 and ABCB1 genotypes on tolvaptan pharmacokinetics and their relationships with plasma markers of CYP3A activity and laboratory test values in heart failure patients. Fifty‐eight heart failure patients receiving oral tolvaptan for volume overload were enrolled. Blood samples for determination of pre‐dose plasma concentrations of tolvaptan and its metabolites were collected. CYP3A5 and ABCB1 genotypes, plasma 4β‐hydroxycholesterol/total cholesterol ratio (4β‐OHC/TC) and 25‐hydroxyvitamin D (25‐OHD), and serum laboratory test values were evaluated. The CYP3A5*3/*3 genotype was associated with a higher plasma concentration of tolvaptan but not with its metabolic ratios. The ABCB1 3435C > T, 2677G > T/A and 1236C > T polymorphisms affected neither tolvaptan pharmacokinetics nor its metabolism. Plasma 4β‐OHC/TC and 25‐OHD concentration were not correlated with plasma tolvaptan concentration. In a stratified analysis based on CYP3A5 genotype, plasma 4β‐OHC/TC had a negative correlation with plasma tolvaptan concentration in the patients with the CYP3A5*1 allele, while the plasma concentration of 25‐OHD did not. The CYP3A5*3/*3 genotype was associated with a higher serum sodium level in the patients with volume overload. The plasma concentration of 25‐OHD had a positive correlation with the serum total bilirubin level. In conclusion, CYP3A5*3 but not ABCB1 genotypes elevated tolvaptan plasma exposure in heart failure patients. CYP3A5‐deficient patients treated with tolvaptan had a higher serum sodium level. The CYP3A5 genotype altered the relationship between plasma tolvaptan and 4β‐OHC.

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Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment

Abstract: A daily dosage of 7.5 mg or less was recommended to prevent hypernatremia in short- as well as long-term tolvaptan treatment, and mainly elderly patients were at risk for hypernatremia.

Cited by 29 publications

References 26 publications

RETRACTED: Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current Clinical Practice?

RETRACTED: Vasopressin Receptor Antagonists for the Correction of Hyponatremia in Chronic Heart Failure: An Underutilized Therapeutic Option in Current Clinical Practice?

Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart Failure

Impact of CYP3A5 genotype on tolvaptan pharmacokinetics and their relationships with endogenous markers of CYP3A activity and serum sodium level in heart failure patients

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