1. Short-term effects of combination of satavaptan, a selective vasopressin V 2 receptor antagonist, and diuretics on ascites in patients with cirrhosis without hyponatraemia – a randomized, double-blind, placebo-controlled study P. GINE`S, F. WONG, H. WATSON, R. TERG, R. BRUHA–, J.-P. ZARSKI & F. DUDLEY FOR THE NORMOCAT STUDY INVESTIGATORS Aliment Pharmacol Ther 31, 834–845 R2. JH L / Prof. BH K

2. Background Vaptans (vasopressin V 2 receptor antagonists) are a new family of drugs that act by antagonizing selectively the V 2 vasopressin receptors located in the principal cells of the collecting ducts in the kidney Vasopressin : reabsorption of solute-free water in the collecting ducts, with a marked increase in solute-free water excretion and reduction in urine osmolality, which results in an increase in urine volume

3. Background Short-term effects of combination of satavaptan, a selective vasopressin V 2 receptor antagonist, and diuretics on ascites in patients with cirrhosis with hyponatraemia (<130 mmol ⁄ L)  marked increase in urine volume and solute-free water excretion and reduction in urine osmolality  serum sodium concentration increases and hyponatraemia is reversed  improvement in serum sodium concentration, a reduction in ascites volume Aliment Pharmacol Ther 31, 834–845

4. Background Until now, the effects of the administration of multiple doses of vaptans to patients with cirrhosis and ascites, but without hyponatraemia, have not been explored.

5. Methods Prospective, multicentre, randomized, double-blind, placebo-controlled study designed as a proof-of concept study to test whether satavaptan has effects on ascites in patients with cirrhosis. (April 2004 ~ January 2005) (1) cirrhosis (2) moderate or tense ascites defined as grade 2 or 3 (3) serum sodium concentration (>130 mmol ⁄ L) (4) informed consent.

6. Methods (1) < the age of 19 years (2) serum bilirubin > 8 mg⁄dL (3) prothrombin time 3) (4) platelet count <40000⁄mm3, neutrophil count <1000⁄mm3 (5) Serum creatinine >2 mg⁄dL (6) serum potassium >5.5 mmol⁄L (7) serum sodium >142 mmol⁄L (8) Hepatocellular carcinoma (9) Hepatic encephalopathy > grade 1 (10) bacterial infection or gastrointestinal bleeding (11) large-volume paracentesis (12) administration in the 2 weeks prior to screening of >200mg⁄day of spironolactone and > 80mg⁄day of furosemide (13) Transjugular intrahepatic portosystemic stent shunt (TIPS) (14) Recent myocardial infarction

7. Methods Figure 1. Flowchart of patients included in the study. spironolactone 100 mg ⁄ day furosemide 20-25 mg ⁄ day

8. Methods The primary efficacy end-point : change in body weight from baseline (day 1) to the end of the study treatment period (day 14) Secondary efficacy end-points (1) reduction in body weight > 2 kg (2) abdominal discomfort (3) ascites worsening : therapeutic paracentesis, increase in diuretics or weight gain (> 2 kg) (4) safety and tolerability : in serum and urine osmolality, serum sodium, serum potassium, serum creatinine, estimated glomerular filtration rate (GFR), 24-h urine volume, and electrolyte excretion, thirst index, immunoreactive renin and the plasma levels aldosterone and AVP.

9. Results

11. Table 2. Characteristics and management of ascites before inclusion in the study in the 148 patients included according to the assigned treatment

12. Figure 2. Mean changes in body weight in the four groups -0.36 -2.28 -2.08 -2.46

15. Conclusion The results of the current study show that a 14-day treatment with satavaptan, an orally active highly selective vasopressin V 2 receptor antagonist, in patients with moderately severe cirrhosis and ascites without hyponatraemia treated with low doses of diuretics is associated with a reduction in ascites.