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: 11.19). 07/2008; 48(1):204-13. DOI: 10.1002/hep.22293
Source: PubMed

ABSTRACT 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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    • "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.
    Metabolic Brain Disease 03/2013; 28. DOI:10.1007/s11011-013-9384-4 · 2.40 Impact Factor
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    • "Additionally, the development of hypernatremia (serum sodium concentration >145 mmol/L) due to increased solute-free water excretion not compensated by water intake did not occur. These potential risks of treatment did not occur in the present study and they have not appeared to be a problem in other studies using vasopressin V2 receptor antagonists in patients with cirrhosis and ascites [7] [17] [19]. "
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    ABSTRACT: 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. 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. 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 (<1.5mg/dl and ≥ 1.5mg/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. 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.
    Journal of Hepatology 03/2012; 56(3):571-8. DOI:10.1016/j.jhep.2011.08.020 · 10.40 Impact Factor
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    • "Five non-peptide antagonists are now at various stages in randomized controlled trials (RCTs) (Table 1). Some of them have also been tested in cirrhotic patients with the aim of correcting hyponatremia [11] [14], and in some cases, to reduce oedema. The rationale for the latter indication is that by increasing free water excretion, vaptans can cause a moderate hypovolemia and thus induce oedema reabsorption. "
    Journal of Hepatology 08/2010; 53(2):225-7. DOI:10.1016/j.jhep.2010.04.003 · 10.40 Impact Factor
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