Effects of Satavaptan, a Selective Vasopressin V2 Receptor Antagonist, on Ascites and Serum Sodium in Cirrhosis with Hyponatremia: A Randomized Trial

Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Catalunya, Spain.
Hepatology (Impact Factor: 11.06). 07/2008; 48(1):204-13. DOI: 10.1002/hep.22293
Source: PubMed


Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin receptor antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective vasopressin V(2) receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium < or =130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 mg, 12.5 mg, or 25 mg once daily) versus placebo. Duration of treatment was 14 days and all patients received spironolactone at 100 mg/day. Satavaptan treatment was associated with improved control of ascites, as indicated by a reduction in body weight (mean change at Day 14 was +0.49 kg [+/-4.99] for placebo versus +0.15 kg [+/-4.23], -1.59 kg [+/-4.60] and -1.68 kg [+/-4.98] for the 5 mg, 12.5 mg, and 25 mg doses, respectively; P = 0.05 for a dose-effect relationship overall) and a parallel reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium (mean change from baseline to day 5 was 1.3 +/- 4.2, 4.5 +/- 3.5, 4.5 +/- 4.8, and 6.6 +/- 4.3 mmol/L for the placebo group and the groups on satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively; P < 0.01 for all compared to placebo). Thirst was significantly more common in patients treated with satavaptan compared to those treated with placebo, whereas the frequency of other adverse events was similar among groups. CONCLUSION: The V(2) receptor antagonist satavaptan improves the control of ascites and increases serum sodium in patients with cirrhosis, ascites, and hyponatremia under diuretic treatment.

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Available from: Hugh Robert Watson, Oct 14, 2014
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    • "Satavaptan and lixivaptan have been evaluated in several trials of hyponatraemia, including in cirrhotic patients, who showed an improvement in hyponatraemia and no serious adverse events compared with placebo [31, 32, 36]. Long-term data on the use of vaptans in cirrhosis is limited but, in trials of SIADH, both satavaptan and tolvaptan had lasting effects and maintained near-normonatremia when continued for one year [37]. "
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    ABSTRACT: Hyponatraemia is a common complication of advanced cirrhosis related to an impairment in the renal capacity for eliminating solute-free water, causing a retention of water that is disproportionate to the retention of sodium, thus leading to a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatraemia is a non-osmotic hypersecretion of arginine vasopressin (AVP) or antidiuretic hormone from the neurohypophysis, related to circulatory dysfunction. Hyponatraemia in cirrhosis is associated with increased morbidity and mortality. Hyponatraemia is also associated with increased morbidity and impaired short-term survival after transplantation. The current standard of care based on restricting fluids to 1-1.5 L/day is rarely effective. Other approaches, such as albumin infusion and the use of vaptans-which act by specifically antagonizing the effects of AVP on the V2 receptors located in the kidney tubules-have been evaluated for their role in the management of hyponatraemia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatraemia; however their use in patients with end-stage liver disease is limited by hepatotoxic effects of some of these drugs. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited.
    Full-text · Article · Feb 2014
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    • "Hyponatraemia in patients with decompensated cirrhosis has been found to be associated with impaired performance on cognitive function tests indicative of minimal hepatic encephalopathy (HE)(Cordoba et al. 2009; Guevara et al. 2010; Riggio et al. 2008) and has been suggested to be a predisposing factor for overt HE (Guevara et al. 2009). Vasopressin V 2 receptor antagonists , selectively antagonising the renal vasopressin receptors, cause an increase in solute-free water excretion and serum sodium concentration (Gerbes et al. 2003; Ginès et al. 2008). Improvement in the mental components of health-related quality of life scores following correction of hyponatraemia by a V 2 receptor antagonist has been reported (Cardenas et al. 2012; Schrier et al. 2006), but no large studies of effects on the incidence of HE have been undertaken. "
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    ABSTRACT: Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.
    Full-text · Article · Mar 2013 · Metabolic Brain Disease
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    • "Vaptans are distal tubular V2 receptor antagonists. Recently, Gerbes et al. [74] and Wong et al. [76] with lixivaptan, Schrier et al. [77] with tolvaptan, and Ginès et al. [78] with satavaptan demonstrated clinically and statistically significant amelioration of low serum sodium levels in a large majority of the sample studied despite heterogeneity in duration of treatment and study design. "
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    ABSTRACT: Mortality in cirrhosis is consequent of decompensation, only treatment being timely liver transplantation. Organ allocation is prioritized for the sickest patients based on Model for End Stage Liver Disease (MELD) score. In order to improve survival in patients with high MELD score it is imperative to preserve them in suitable condition till transplantation. Here we examine means to prolong life in high MELD score patients till a suitable liver is available. We specially emphasize protection of airways by avoidance of sedatives, avoidance of Bilevel Positive Airway Pressure, elective intubation in grade III or higher encephalopathy, maintaining a low threshold for intubation with lesser grades of encephalopathy when undergoing upper endoscopy or colonoscopy as pre transplant evaluation or transferring patient to a transplant center. Consider post-pyloric tube feeding in encephalopathy to maintain muscle mass and minimize risk of aspiration. In non intubated and well controlled encephalopathy, frequent physical mobility by active and passive exercises are recommended. When renal replacement therapy is needed, night-time Continuous Veno-Venous Hemodialysis may be useful in keeping the daytime free for mobility. Sparing and judicious use of steroids needs to be borne in mind in treatment of ARDS and acute hepatitis from alcohol or autoimmune process.
    Full-text · Article · Jul 2012
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