Research ArticleTolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis
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.
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For the SALT study investigators.