Abstract
BackgroundTo determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics.MethodsIn the present placebo-controlled, randomized, double-blinded, multicentre clinical trial, patients with cirrhotic ascites who failed to adequately respond to a combination of an aldosterone antagonist plus an orally administered loop diuretic were randomly placed at a 4:2:1 ratio into 3 groups [the 15 mg/day tolvaptan group (N = 301), 7.5 mg/day tolvaptan group (N = 153) and placebo group (N = 76)] for 7 days of treatment. The effects and safety were evaluated on days 4 and 7. A change in body weight from baseline on day 7 of treatment was the primary endpoint.ResultsThe administration of 7.5 or 15 mg/day tolvaptan significantly decreased body weight from baseline on day 7 of treatment compared to that with placebo treatment (P = 0.026; P = 0.001). For the secondary endpoints, changes in abdominal circumference from baseline and improvements in ascites were markedly different in the treatment groups and the placebo group on day 7 (P7.5 = 0.05, P15.0 = 0.002 and P7.5 = 0.037, P15.0 = 0.003), but there was no difference between the 7.5 mg/day and 15 mg/day dosage groups. The 24-h cumulative urine volume was higher in the 7.5 mg/day and 15 mg/day tolvaptan groups than the placebo group (P = 0.002, P < 0.001) and was greater in the 15 mg/day tolvaptan group than the 7.5 mg/day tolvaptan group (P = 0.004). Sodium serum concentrations were higher in patients with hyponatraemia after tolvaptan treatment, with no significant difference between the two dosage groups. The incidence of serious adverse drug reactions was not different between the groups (P = 0.543).ConclusionsTolvaptan treatment at 7.5 mg per day might be a good therapeutic choice for Chinese cirrhotic patients with ascites who did not achieve satisfactory clinical responses to previous treatment regimens with combination therapy with an aldosterone antagonist and an orally administered loop diuretic.Trial registrationNCT01349348. Retrospectively registered May 2011.
Highlights
To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics
Clinical characteristics and demographic parameters of enrolled patients Of the 639 enrolled patients from 39 centres who insufficiently responded to primary at least 4 days of combination therapy with routine diuretic treatments, 535 were eligible to participate in the trial, with 76, 154 and 305 patients randomly allocated to the placebo, 7.5 mg or 15 mg tolvaptan groups, respectively
The difference in body weight changes on day 7 for the 7.5 mg tolvaptan and placebo groups was − 0.8 kg and − 1.0 kg for the 15 mg tolvaptan and the placebo groups (Table 2)
Summary
To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics. The underlying pathophysiological mechanisms involved in cirrhotic ascites are complex and remain to be fully elucidated. Drugs that suppress these neurohormones should be used to treat cirrhotic ascites patients. Aldosterone antagonists, such as spironolactone, administered alone or together with a loop diuretic, such as furosemide, are recommended as the first-line treatment [2]. In September 2013, Japan approved 7.5 mg/day tolvaptan for the treatment of patients with ascites who failed to adequately respond to conventional diuretics [8]. The Japan Liver Cirrhosis guidelines recommend the treatment of ascites with a dosage range from 3.75 to 7.5 mg/day [9]
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