J Hepatol 2011 Oct 23 [Epub ahead of print].

Patients with advanced cirrhosis frequently develop dilutional hyponatremia due to impairment of their renal ability to eliminate solute-free water.1 Although the pathophysiology of this disorder is multifactorial, an increased hypersecretion of arginine vasopressin (AVP) is a major factor.2 The nonosmotic secretion of AVP in cirrhosis is thought to be due to arterial splanchnic vasodilation and arterial underfilling, leading to activation of the baroreceptors that regulate the release of AVP.3 The prevalence of hyponatremia in cirrhosis, as defined by a serum sodium level of 135 mmol/L is reported to be 49%, with the prevalence rates of serum sodium levels of 130, 125, and 120 mEq/L being 21.6%, 5.7%, and 1.2%, respectively.4 In most patients with cirrhosis, hyponatremia is usually asymptomatic because it develops slowly. However, there are several lines of evidence that hyponatremia is a risk factor for the development of hepatic encephalopathy, and that it predicts a poor quality of life independent of liver function.5 In addition, hyponatremic patients who proceed to liver transplantation appear to have an increased risk of neurologic injuries, renal failure, and infections in the immediate posttransplant period, and have a reduced short-term survival posttransplantation.6 Hyponatremia also predicts short-term mortality in cirrhotic patients awaiting liver transplantation, independently of Model for End-stage Liver Disease (MELD) score.7,8 It has thus been proposed that serum sodium data should be integrated into the MELD scoring system in order to improve its prognostic accuracy.9

The principle of the management of hypervolemic hyponatremia is to induce a negative water balance, with the aim of normalizing the increased total body water, which would result in an improvement in serum sodium concentration. Fluid restriction (1-1.5 L/day) is the most widely accepted nonpharmacological therapy, but its efficacy is very limited. The administration of hypertonic sodium chloride has been common in severe hypervolemic hyponatremia, but its effect is only partial and short lived; moreover, additional expansion of fluid can worsen ascites and edema. The administration of albumin appears to improve serum sodium concentration due to an improvement in circulatory function, with suppression of the sodium and water-retaining system, including AVP, but data supporting its use are limited.10

The pathophysiologically oriented treatment of hyponatremia focuses on inhibiting the actions of AVP. One of the first drugs used to treat hypervolemic hyponatremia was demeclocycline, which inhibits the tubular effect of AVP, thereby increasing solute-free water clearance; however, its nephrotoxic potential has led to its abandonment.11 In recent years, the pharmacological approach to the treatment of hyponatremia has made a step forward with the discovery of vaptans, a new class of drugs that are able to increase free water excretion. They work as antagonists of the V₂ receptors of vasopressin, which are located in the principal cells of the renal collecting duct.12 Tolvaptan, an orally active, selective V₂ receptor antagonist, induces the excretion of electrolyte-free water without electrolyte excretion.13 The US Food and Drug Administration (FDA) has approved this agent for the treatment of hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH), cardiac failure, and cirrhosis, and the European Medicines Agency has approved its use for SIADH. These approvals were based on the results of several randomized, placebo-controlled, multicenter clinical trials,14-17 one of which-the Study of Ascending Levels of Tolvaptan (SALT), published in the New England Journal of Medicine in 200615-investigated the effects of tolvaptan in hyponatremic patients with SIADH, cardiac failure, or cirrhosis. The findings of these trials indicated that tolvaptan effectively improved serum sodium levels. However, the authors did not provide a separate efficacy analysis stratified according to the disease associated with hyponatremia, and so the actual effects of tolvaptan in hyponatremic patients with cirrhosis could not be ascertained from that study. Given that tolvaptan is the only oral vaptan approved for the management of hyponatremia, its efficacy in the population of patients with cirrhosis is of interest to practicing clinicians. Therefore, we provide herein the results of a subgroup analysis of the SALT trials, e-published in the Journal of Hepatology, evaluating the efficacy and safety of tolvaptan in hyponatremic patients with liver cirrhosis.18

The study of Cárdenas et al (reported in this issue) examined cirrhotic patients with hyponatremia who received 15 mg of oral tolvaptan (n=63; increased to 30 or 60 mg if needed) or placebo (n=57) once daily for 30 days. Primary endpoints were changes in serum sodium concentration at 4 and 30 days of therapy. Tolvaptan was found to be associated with a marked and significant increase in serum sodium concentration compared to placebo at day 4 (absolute average increases of 4.7 vs. 0.3 mmol/L, respectively) and at day 30 (4.2 vs. 1.3 mmol/L, respectively). The proportion of patients on tolvaptan whose serum sodium normalized (i.e., >135 mmol/L) at day 4 was 41%, as compared to 11% for placebo; at day 30 these proportions were 33% and 19%, respectively. Although more than a half of patients in the tolvaptan group did not achieve normalization, with the proportions still being >3- to 1.5-fold greater than for the placebo group. The serum sodium levels had returned to pretreatment values at 1 week after stopping treatment. Interestingly, the administration of tolvaptan was associated with a significant improvement in the scores of the mental component of the medical outcomes study 12-item short-form general health survey. This suggests that correcting hyponatremia improves the quality of life in patient with liver cirrhosis.

Another clinically relevant finding was that combining tolvaptan with diuretics did not lead to renal insufficiency. However, other clinical outcomes such as ascites resolution and changes in the degree of hepatic encephalopathy were not assessed. Tolvaptan was found to be safe, with no significant differences in adverse events compared to the placebo group. Side effects that were more frequent in the tolvaptan group were dry mouth and thirst. An infrequent, yet important adverse event was gastrointestinal bleeding, whose incidence was higher in the tolvaptan group than in the placebo group (9.5% vs. 1.8%, respectively). The underlying source of the bleeding was probably esophageal varices, but this was unclear in the event descriptions. The increased risk of bleeding was discussed during the FDA review of tolvaptan, which led to it being attributed to the effect of tolvaptan on vitamin-K-dependent clotting factors and platelet function.13,19

In conclusion, oral tolvaptan for 1 month significantly improved the serum sodium levels and health-related quality of life in hyponatremic patients with liver cirrhosis. Tolvaptan did not lead to renal insufficiency, even when the drug was given with diuretics. Although the side effects were comparable to those observed in placebo-treated patients, tolvaptan was associated with a higher incidence of gastrointestinal bleeding. These findings indicate that further study is warranted into the use of tolvaptan in order to evaluate its long-term risks and benefits in hyponatremic patients with cirrhosis.