Elsevier

Journal of Hepatology

Volume 56, Issue 3, March 2012, Pages 571-578
Journal of Hepatology

Research Article
Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis

https://doi.org/10.1016/j.jhep.2011.08.020Get rights and content

Background & Aims

Tolvaptan is a vasopressin V2-receptor antagonist that improves serum sodium concentration by increasing renal solute-free water excretion. Specific data on the safety and efficacy of tolvaptan in patients with cirrhosis and hyponatremia has not been exclusively evaluated.

Methods

This sub-analysis of the Study of Ascending Levels of Tolvaptan trials examined cirrhotic patients with hyponatremia who received 15 mg oral tolvaptan (n = 63; increased to 30 or 60 mg if needed) or placebo (n = 57) once-daily for 30 days. At baseline, 44% had mild hyponatremia (serum sodium 130–134 mmol/L), 56% had marked hyponatremia (serum sodium <130 mmol/L), 85% had cirrhosis due to alcohol and/or hepatitis B/C, and 80% were Child-Pugh class B/C.

Results

Tolvaptan was effective in raising serum sodium. Average daily area under the curve for serum sodium was significantly greater in the tolvaptan group from baseline to day 4 (p <0.0001) and day 30 (p <0.0001). This superiority was maintained after stratification by baseline hyponatremia (mild and marked), estimated glomerular filtration rate (⩽60 ml/min and >60 ml/min), or serum creatinine levels (<1.5 mg/dl and ⩾1.5 mg/dl). Hyponatremia recurred 7 days after discontinuation of tolvaptan. Mean mental component summary scores of the SF-12 health survey improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, p = 0.02). Major side effects due to tolvaptan were dry mouth and thirst. Gastrointestinal bleeding occurred in 10% and 2% of patients in the tolvaptan and placebo group, respectively (p = 0.11). Adverse event rates, withdrawals, and deaths were similar in both groups.

Conclusions

One month of tolvaptan therapy improved serum sodium levels and patient-reported health status in cirrhotic patients with hyponatremia. Hyponatremia recurred in tolvaptan-treated patients after discontinuation.

Introduction

Patients with cirrhosis may retain fluids due to an abnormal regulation of extracellular fluid volume leading to increased renal sodium and solute-free water re-absorption. In some patients, excessive solute-free water retention may lead to hyponatremia occurring in the setting of this expanded extracellular fluid volume. This type of hyponatremia is known as dilutional or hypervolemic hyponatremia and usually occurs in patients with advanced cirrhosis [1], [2]. In cirrhosis, splanchnic vasodilation secondary to sinusoidal portal hypertension leads to arterial underfilling, which in turn unloads high-pressure baroreceptors that stimulate a non-osmotic hypersecretion of arginine vasopressin (AVP), thereby leading to solute-free water retention and hyponatremia [2], [3]. Hyponatremia in cirrhosis has been linked to hepatic encephalopathy, impaired quality of life, and poor short-term prognosis [4], [5].

Restricting fluids to 1–1.5 liters per day had been, until recently, the only available method for managing hypervolemic hyponatremia. However, this method has very limited efficacy in improving serum sodium levels [6], [7]. Other treatments, such as demeclocycline or urea, are not approved by the Food and Drug Administration (FDA) or by the European Medicines Agency (EMEA), are slow to correct serum sodium, and are potentially nephrotoxic in cirrhosis [8], [9], [10]. The administration of hypertonic saline solution is not recommended because additional expansion of the extracellular fluid worsens edema and ascites and, with over-rapid correction, can induce osmotic demyelination [3], [6]. Additionally, hypertonic saline solution infusion lacks a controlled safety database and a consensus on infusion rate. Most importantly, none of the prior therapeutic options addresses the underlying pathophysiology of the hyponatremia, which is related to increased AVP levels.

Oral selective antagonists of AVP that bind to the V2 receptor of the principal cells of the renal collecting ducts are effective in increasing serum sodium levels in hypervolemic hyponatremia [11]. Tolvaptan, an orally active, selective, nonpeptide V2 antagonist, induces the excretion of electrolyte-free water without increasing the total level of electrolyte excretion. This agent is approved for the treatment of dilutional hyponatremia associated with SIADH, cardiac failure or cirrhosis by the FDA in the United States, for SIADH by the EMEA in Europe, and for diuretic-resistant volume overload in heart failure by the Ministry of Health in Japan. Pivotal studies of tolvaptan enrolled patients with hyponatremia due to SIADH, cardiac failure, and cirrhosis have been conducted. The results of these pivotal studies indicate that tolvaptan effectively improves serum sodium levels in these patients [12], [13]. In these studies, no evaluation was performed on the disease responsible for hyponatremia. Thus, there is lack of data on the specific effects of tolvaptan in patients with cirrhosis and hyponatremia. Given that tolvaptan is the only oral vaptan approved for management of hyponatremia, its efficacy in the population of patients with cirrhosis is of interest to practicing clinicians. Therefore, the current study reports a sub-analysis of the tolvaptan pivotal studies evaluating the efficacy and safety of tolvaptan in patients with cirrhosis and hyponatremia.

Section snippets

Patients

This report represents an analysis of patients with cirrhosis enrolled in two prospective, multicenter, randomized, placebo-controlled, double-blind, phase 3 studies (study of ascending levels of tolvaptan in hyponatremia 1 and 2 [SALT1 and SALT2]; Clinicaltrials.gov registration numbers NCT00072683 and NCT00201994). SALT1 and 2 examined the effects of tolvaptan (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan) on hypervolemic and euvolemic hyponatremia of diverse etiology, including congestive

Study patients

The demographic and baseline characteristics of patients in the two treatment groups were similar. Liver and renal function tests, as well as serum sodium concentration at the time of randomization, are shown in Table 1. Sodium levels between 131–135 meq/L are not uncommon in patients with Child A cirrhosis as impairment of solute-free water excretion can develop in those with mild ascites and edema [1], [2]. About half of these subjects had mild and half more severe hyponatremia. In those with

Discussion

The results of this analysis of the SALT studies indicate that use of the oral vasopressin V2 receptor antagonist tolvaptan for 30 days increases serum sodium concentration in hyponatremic patients with cirrhosis. The administration of tolvaptan was also associated with a significant increase in urine output and fluid intake and a negative fluid balance 24 h after the initial dose when compared to placebo, as well as a significant improvement in the SF-12 health survey MCS scores at day 30.

Conflict of interest

Andrés Cárdenas is a consultant for Otsuka Pharmaceuticals, Orphan Therapeutics and GlaxoSmithKline. Pere Ginès is a consultant for Otsuka Pharmaceuticals, Ferring International, Ikaria Pharmaceuticals, and Novashunt AG. Frank Czerwiec and John Ouyang are employees of Otsuka Pharmaceutical Development & Commercialization, Inc. Nezam Afdhal is an Investigator for Otsuka Pharmaceuticals. Paul Marotta was an investigator for Otsuka. Mónica Guevara has no conflicts of interest to disclose. CIBEREHD

Writing assistance

Anne Sexton, MD (Independent Contractor with Otsuka), assisted in clinical data preparation and review. David Norris, Ph.D. (Ecosse Medical Communications, LLC, Princeton, NJ, USA), provided editorial assistance during the preparation of the manuscript.

Financial support

This work was sponsored and supported by Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville Maryland, USA.

References (22)

  • F. Carrilho et al.

    Renal failure associated with demeclocycline in cirrhosis

    Ann Intern Med

    (1977)
  • Cited by (116)

    • Hyponatremia in Cirrhosis

      2022, Clinics in Liver Disease
    • Hyponatremia and Liver Transplantation: A Narrative Review

      2022, Journal of Cardiothoracic and Vascular Anesthesia
    • Clinical Implications, Evaluation, and Management of Hyponatremia in Cirrhosis

      2022, Journal of Clinical and Experimental Hepatology
    View all citing articles on Scopus

    For the SALT study investigators.

    View full text