Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites
Tolvaptan for Hyponatremia in Cirrhotic Patients With Ascites
The purpose of the study is to investigate the efficacy and safety for the management of
 hyponatremia and ascites in patients with liver cirrhosis.
Patients with advanced cirrhosis frequently develop dilutional hyponatremia due to impairment
 of their renal ability to eliminate solute-free water. Although the pathophysiology of this
 disorder is multifactorial, an increased hypersecretion of arginine vasopressin (AVP) is a
 major factor. The prevalence of hyponatremia in cirrhosis, as defined by a serum sodium level
 of 130 mmol/L is reported to be about 20%, and there are several lines of evidence that
 hyponatremia is a risk factor for the development of hepatic encephalopathy, and that it
 predicts a poor quality of life independent of liver function. Hyponatremia also predicts
 short-term mortality in cirrhotic patients awaiting liver transplantation. The principle of
 the management of hypervolemic hypona- tremia is to induce a negative water balance, with the
 aim of normalizing the increased total body water, which would result in an improvement in
 serum sodium concentration. Fluid restriction is the most widely accepted nonpharmacological
 therapy, but its efficacy is very limited. The administration of hypertonic sodium chloride
 has been common in severe hypervolemic hyponatremia, but its effect is only partial and short
 lived; moreover, additional expansion of fluid can worsen ascites and edema. Therefore, the
 pathophysiologically oriented treatment of hyponatremia focuses on inhibiting the actions of
 AVP. Recently, antagonists of the V2 receptors of vasopressin has been proposed to manage
 hyponatremic patients, such as heart fauilure, syndrome of inappropriate antidiuretic hormone
 or liver cirrhosis. Especially, a lot of hyponatremic patients with cirrhosis had ascites,
 and some of them had intractable ascites. In these patients, antagonists of the V2 receptors
 of vasopressin including tolvaptan might have beneficial effect in enhancing not only
 hyponatremia , but also ascites
Inclusion Criteria:

 1. 20 years of age or older

 2. Patients with cirrhosis as diagnosed by liver biopsy or a combination of laboratory
 (thrombocytopenia), radiologic (cirrhotic feature of liver, splenomegaly, collateral
 shunt on US, CT, or MRI) and endoscopic findings (gastoesophageal varices or portal
 hypertensive gastropathy)

 3. ≥ Grade 2 ascites who have already been treated with restricted salt diet within 3
 month

 4. Hyponatremia (Serum sodium ≥120 mEq/L and ≤130 mEq/L)

 5. Written informed consent

 Exclusion Criteria:

 1. Hypovolemic hyponatremia (Patients with hypotension or chronic heart failure)

 2. Serum potassium concentration > 5.5 mEq/L

 3. Serum bilirubin > 5.0 mg/dL

 4. Blood coagulation factor < 40% or international normalized ratio (INR) > 2.3

 5. Platelet count < 30,000/mm3

 6. Serum creatinine > 3 mg/dL

 7. Treatment within 2 weeks with vasopressin anlogues

 8. Systolic blood pressure <80 mmHg

 9. History of gastrointestinalesophageal varix bleeding variceal hemorrhage

 10. Spontaneous bacterial peritonitis

 11. Hepatic encephalopathy ≥ grade 3

 12. History of Hepatocellular carcinoma treatment within 3month or viable tumor Viable
 hepatocellular carcinoma

 13. Liver transplant

 14. Previous treatment with transjugular intrahepatic portosystemic stent shunt (TIPS)

 15. History of significant cardiac diseases such as recent myocardial infarction or
 ischemic diseases within 1 year of screening

 16. Prolonged QTc interval of > 500 ms based on electrocardiography

 17. Treatment within 2 weeks with substances or drugs that may either induce or
 significantly inhibit cytochrome P450 3A (ketoconazole, clarithromycin, erythromycin,
 fluconazole, diltiazem, verapamil, etc)

 18. Pregnant or breast feeding

 19. Patients with galactose intolerance or malabsorption (as production of the drug
 contains lactose)

 20. HbA1Cc ≥ 9 %

 21. Serious medical illness (e.g. heart failure, severe pulmonary disorders, alcohol
 dependence, malignant tumors, etc)