Effects of satavaptan, a selective vasopressin V2 receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia

Abstract

for the HypoCAT study investigators* 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 <130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 T he development of ascites in cirrhosis is the result of an abnormal regulation of the extracellular fluid volume that causes a positive fluid balance due to a persistently increased renal sodium and water reabsorption. Several lines of evidence indicate that this renal dysfunction is related to impairment in circulatory function characterized by splanchnic arterial vasodilation, secondary to sinusoidal portal hypertension. This causes a reduction in the effective arterial blood volume and a subsequent homeostatic activation of vasoconstrictor and sodium-retaining and water-retaining systems, including the renin-angiotensin-aldosterone system, the sympathetic nervous system, and vasopressin, which are responsible for sodium and water retention. 1,2 According to this pathogenesis, the pharmacological approach to treatment of ascites has been based on the administration of spironolactone, a drug that antagonizes the effect of aldosterone, which reduces the increased extracellular fluid volume by increasing renal sodium and water excretion. 3 However, a significant proportion of patients with ascites either do not respond to spironolactone or require the administration of high doses of the drug, which increases the risk of From the

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“…1), 18 trials met the eligibility criteria or reported data for an eligible subgroup. Two trials assessed conivaptan, 13,14 four assessed lixivaptan, [15][16][17][18] three assessed satavaptan [19][20][21] and nine assessed tolvaptan. [22][23][24][25][26][27][28][29] There were no RCTs published assessing other known interventions such as urea, sodium tablets or mannitol.…”

“…Otsuka (manufacturer of tolvaptan and funder of this review) provided information for six trials of tolvaptan vs placebo and the authors of two further trials responded. 14,20 A summary of the characteristics of the included trials is presented in Table 1. All 18 trials were randomized multicentre trials.…”

“…Some trials reported data for a specific population and others included patients with various underlying causes. Three trials assessed hyponatraemia in patients with SIADH, 15,21,22 four assessed hyponatraemia in patients with congestive heart failure, [24][25][26][27] two assessed hyponatraemia in patients with cirrhosis, 17,20 and one assessed hyponatraemia in patients with cancer. 28 The other eight trials assessed hyponatraemia in patients with a range of underlying conditions.…”

“…11 The majority of trials did not report this and therefore studies using this method of imputation were categorized as having an unclear risk of bias. Two trials had low risk of bias, 14,20 five had high risk of bias 21,23,27,28 and 11 did not report adequate detail and were categorized as unclear risk of bias indicating that there is a substantial risk of bias across the data set as a whole. There were no significant differences between the fixed-and random-effects results for any outcome assessed.…”

Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

“…Although the agent has demonstrated utility in animal models and improved clinical outcomes in patients with SIADH or cirrhosis [65][66][67][68], its efficacy in CHF patients has yet to be determined.…”