Terlipressin vs. Somatostatin in Cirrhotic Patients With Acute Variceal Bleeding and Renal Dysfunction

Overall, 64 cirrhotic patients with a diagnosis of AVB and RD will be enrolled. Renal dysfunction is defined as serum creatinine (SCr) level >1.5 mg/dl at admission. They will be stratified according to the severity of liver dysfunction (i.e., Child-Pugh class A, B, and C) and degree of SCr level elevation \[i.e., 1.5-2mg/dl (133-177 μmol/L), 2-3 mg/dl (177-265 μmol/L), and ≥3 mg/dl (265 μmol/L)\], and then randomly assigned to terlipressin group and somatostatin group at a ratio of 1:1. The primary study endpoint is renal function recovery after 5-day treatment. Secondary endpoints include incidence of AKI within 7 days, 5-day failure to control bleeding, requirement of renal replacement therapy, TIPS, liver transplantation, and kidney transplantation within 6 weeks, 6-week mortality, 6-week rebleeding, and incidence of adverse events within 6 weeks.

• 2-4 mg of terlipressin (Drug), also known as Terlivaz: Participants receive 2-4 mg of terlipressin by continuous intravenous infusion every 12 hours, with a maximum treatment course of 5 days.
• 3 mg of somatostatin (Drug), also known as Stilamin: Participants receive 3 mg of somatostatin by continuous intravenous infusion every 12 hours, with a maximum treatment course of 5 days.

Primary outcomes

• Renal function recovery [6 weeks]: The renal function recovery is defined as SCr level ≤ 1.5 mg/dl (133 μmol/L) in two consecutive measurements with an interval of at least 2 hours between them.

Secondary outcomes

• Incidence of AKI within 7 days [7 days]: Clinical symptoms related to AKI occur and SCr levels increase after the treatment. The diagnosis of AKI should meet any one of the following conditions: 1) an increase in SCr level of ≥ 0.3 mg/dl (26.5 μmol/L) within 48 hours; 2) an increase in SCr level to ≥ 1.5 times the baseline value within 7 days; 3) a urine output of < 0.5 ml/kg per hour for a continuous 6 hours.
• 5-day failure to control bleeding [5 days]: The 5-day failure to control bleeding is defined as failure to achieve effective control of AVB or occurrence of rebleeding within 5 days after treatment.
• Kidney replacement therapy rate [6 weeks]: Participants undergo dialysis or continuous kidney replacement therapy due to failure to recover renal function after treatment.
• Transjugular intrahepatic portosystemic shunt (TIPS) treatment rate [6 weeks]: Participants undergo transjugular intrahepatic portosystemic shunt (TIPS) treatment.
• Liver and kidney transplantation treatment rate [6 weeks]: Participants undergo liver and kidney transplantation treatment.
• 6-week mortality rate [6 weeks]: The 6-week mortality rate is defined as the all-cause mortality rate over 6 weeks.
• 6-week rebleeding rate [6 weeks]: The 6-week rebleeding rate is defined as the rebleeding rate within 6 weeks after successful AVB hemostasis.
• Adverse events [6 weeks]: Adverse events will be monitored, including nausea, abdominal pain, diarrhea, arrhythmia, dyspnea, and hyponatremia that may be caused by terlipressin, as well as nausea, abdominal pain, diarrhea, hypoglycemia, and allergies that may be caused by somatostatin. The incidence of adverse events is defined as rate of adverse reactions secondary to terlipressin or somatostatin, endoscopic therapy or interventional procedures during study periods.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* patients have a definite diagnosis of live cirrhosis and AVB;
* patients present with renal dysfunction at admission;
* patients' age 18-70 years old;
* patients or relatives can sign the informed consent form.

Exclusion Criteria:

* patients have non-variceal upper gastrointestinal bleeding;
* patients have hepatorenal syndrome- acute renal injury (HRS-AKI);
* patients have structural kidney injury;
* patients have chronic kidney disease;
* patients received kidney replacement therapy before enrollment;
* patients have a history of liver transplantation or TIPS;
* patients have acute liver failure or acute-on-chronic liver failure;
* patients have hepatic or renal malignant tumor;
* patients have severe diseases of the heart, lungs, and brain;
* patients have contraindications for experimental drugs;
* patients are in pregnancy or lactation;
* patients participated in other clinical studies within 3 months before enrollment;
* patients have other conditions that investigators deem unsuitable for enrollment in the study.

• Results publication: Xu X, Liu B, Lin S, Li B, Wu Y, Li Y, Zhu Q, Yang Y, Tang S, Meng F, Chen Y, Yuan S, Shao L, Bernardi M, Yoshida EM, Qi X. Terlipressin May Decrease In-Hospital Mortality of Cirrhotic Patients with Acute Gastrointestinal Bleeding and Renal Dysfunction: A Retrospective Multicenter Observational Study. Adv Ther. 2020 Oct;37(10):4396-4413. doi: 10.1007/s12325-020-01466-z. Epub 2020 Aug 28. PMID 32860184
• Results publication: Walker S, Kreichgauer HP, Bode JC. Terlipressin vs. somatostatin in bleeding esophageal varices: a controlled, double-blind study. Hepatology. 1992 Jun;15(6):1023-30. doi: 10.1002/hep.1840150609. PMID 1350562
• Results publication: Zhou X, Tripathi D, Song T, Shao L, Han B, Zhu J, Han D, Liu F, Qi X. Terlipressin for the treatment of acute variceal bleeding: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018 Nov;97(48):e13437. doi: 10.1097/MD.0000000000013437. PMID 30508958
• Results publication: Xu X, Tang C, Linghu E, Ding H; Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Digestive Endoscopy, Chinese Medical Association. Guidelines for the Management of Esophagogastric Variceal Bleeding in Cirrhotic Portal Hypertension. J Clin Transl Hepatol. 2023 Dec 28;11(7):1565-1579. doi: 10.14218/JCTH.2023.00061. Epub 2023 Oct 17. PMID 38161497

• Xingshun Qi, MD, Principal investigator, Department of Gastroenterology, General Hospital of Northern Theater Command
• Qianqian Li, Principal investigator, Department of Gastroenterology, General Hospital of Northern Theater Command
• Rong Li, Principal investigator, Department of Gastroenterology, General Hospital of Northern Theater Command