Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites?

Table 1 Main characteristics of randomized double-blind, placebo-controlled trials on vaptans for patients with liver cirrhosis

Ref.	V2RA	Dose	Additional diuretics	Max treatment duration	No of patients vaptan(control)	Efficacy outcome	Main results
Guyader et al[54]	Lixivaptan	25, 50, 100, 200, 300 mg/d	None (withheld for 48 h)	24 h	22 (5)	Daily urine output, urine osmolality, serum osmolality, serum Na	A significant dose-related increase in daily urine output and a dose-related decrease in urine osmolality together with significant increases in serum osmolality, Na, and vasopressin levels
Gerbes et al[55]	Lixivaptan	100, 200 mg/d	Yes? (no detailed information available）	7 d	40 (20)	Serum sodium concentration, urine osmolality, body weight	Normalization of serum Na 27% (100 mg/d group) 50% (200 mg/d group); a significant reduction in urine osmolality and body weight	Fluid intake was restricted to 1000 mL/d
Wong et al[56]	Lixivaptan	50, 250, 500 mg/d	Yes	8 d	25 (8)	Free water clearance, serum sodium	Significant dose related increases in free water clearance and serum Na without changes in orthostatic blood pressure and serum creatinine levels	Fluid intake was restricted to 1500 mL/d
Schrier et al[63]	Tolvaptan	15, 30, 60 mg/d	Yes	30 d	63 (57) Salt 1 and Salt 2 study including other causes of hyponatremia	Serum Na	Effective in increasing serum Na concentrations at day 4 and day 30
Thuluvath et al[58]	RWJ-351647	1, 2, 5 mg (single oral doses)	Spironolactone 100 mg/d + furosemide 40 mg/d	24 h	18 (6)	Urine volume, free water excretion, urine osmolality	Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose	No changes in either serum chemistry or plasma AVP and renin levels
Ginès et al[59]	Satavaptan	5, 12.5, 25 mg/d	Spironolactone 100 mg/d	14 d	82 (28)	Body weight, abdominal girth, serum Na	Reduction in body weight and abdominal girth with improvements in serum Na
Ginès et al[60]	Satavaptan	5, 12.5, 25 mg/d	Spironolactone 100 mg/d + furosemide 20-25 mg/d	14 d	113 (35)	Change in body weight The percentage of patients with a weight loss > 2 kg	Significant reduction in body weight; percentage of patients with a weight loss > 2 kg was greater
Wong et al[61]	Satavaptan	5, 12.5, 25 mg/d	Spironolactone 100 mg/d	12 wk	115 (36)	Prevention of recurrent ascites after LVP (1) median time to first paracentesis (2) frequency of paracenteses (3) mean increase in ascites	Significant decrease in the frequency of paracenteses; No significant difference of mean increase in ascites
Cárdenas et al[64]	Tolvaptan	15, 30, 60 mg/d	Spironolactone < 200 mg/d + furosemide < 80 mg/d	30 d	63 (57)	Serum Na (average daily area under the curve for serum Na); mental component summary scores of the SF-12 health survey	Improvement in serum Na levels and patient-reported health status without severe adverse effects	Sub-analysis of the SALT-1 and SALT-2 trials
Wong et al[62]	Satavaptan	5, 10 mg/d	Study 1 (None); Study 2 (one or more diuretics); Study 3 (withheld during the first 12 wk)	52 wk	720 (478)	Prevention of recurrent ascites after LVP (1) cumulative number of LVPs during the first 12 wk (2) reccurrence of ascites, defined as LVP and/or weight increase of > 4 kg (3) cumulative increase in ascites estimated	Not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints; slight advantages noted in delaying ascites formation and improvement of serum Na concentration in patients with hyponatremia	(Study 3) a higher rate of all-cause mortality, mostly associated with complications of cirrhosis in combination with diuretics
Okita et al[67]	Tolvaptan	7.5, 15 or 30 mg/d	Furosemide ≥ 40 mg/d + spironolactone ≥ 25 mg/d or furosemide ≥ 20 mg/d + spironolactone ≥ 50 mg/d	7 d	77 (27)	Body weight, abdominal circumference	7.5-30 mg/d reduced body weight and abdominal circumference 7.5 mg/d showed the maximum changes together with preferable tolerability
Sakaida et al[68]	Tolvaptan	7.5 mg/d	furosemide ≥ 40 mg/d + spironolactone ≥ 25 mg/d or furosemide ≥ 20 mg/d + spironolactone ≥ 50 mg/d	7 d	84 (80)	Change in body weight from baseline; changes in abdominal circumference and ascites volume: improvement rates of lower limb edema and ascites-related clinical symptoms	change in body weight; -0.44 kg in the placebo group vs -1.95 kg in the tolvaptan group; higher improvement rates of limb edema and ascites-related clinical symptoms	Improve hyponatremia and derease body weight regardless of serum albumin level

All major studies are summarized in this table. In general, short-term effects of vaptans on hyponatremia and ascites are evident. Long-term effects are still controversial.