Efficacy of Proton Pump Inhibitors in Cirrhotic Patients With Acute Variceal Bleeding

Sponsor

West China Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05624229

Collaborator

(none)

672

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Acute Variceal Bleeding (AVB) in patients with liver cirrhosis is a common clinical critical disease.There is little evidence for the effect of PPI use in patients with AVB in liver cirrhosis, and there is no study on the efficacy of PPI combined with standard therapy in patients with AVB.

Condition or Disease	Intervention/Treatment	Phase
Control of Bleed	Drug: Proton Pump Inhibitors	Phase 4

Detailed Description

Acute Variceal Bleeding (AVB) in patients with liver cirrhosis is a common clinical critical disease, with a 6-week mortality rate as high as 20%. Currently, many guidelines recommend the use of vasoactive drugs (terlipressin, somatostatin or octreotide) combined with endoscopic therapy (Endoscopic Variceal Ligation (EVL), endoscopic injection sclerotherapy (EIS) and the use of prophylactic antibiotics for patients with AVB.

Proton pump inhibitor (PPI) is a commonly used antacid agent, which has a significant antacid effect, protects the gastrointestinal mucosa, promotes blood coagulation, healing ulcers, effectively stops bleeding and prevents rebleeding. There is a consensus that PPI should be used before and after endoscopic therapy in patients with non-variceal acute bleeding. However, studies on the efficacy of PPI after EVL are still limited and lack sufficient convincing. In the 2005 Shrestha et al. randomized controlled study, pantoprazole treatment was found to be associated with significantly smaller varicular ulcers 10 days after elective EVL in secondary prevention patients with cirrhosis. Lo et al. 's randomized controlled study in 2013 found that patients with cirrhosis and AVB treated with PPI for 19 days after endoscopic hemostasis had smaller ulcers and fewer overall side effects, but there was no statistically significant difference in 5-day treatment failure, 6-week rebleeding rate and 6-week mortality. In 2017, Chuah et al. included 637 patients with acute bleeding from liver cirrhosis, 80% of whom were treated with acid suppression therapy, and the study found that acid suppression therapy had no significant effect on long-term bleeding and mortality. However, negative effects of PPI have been reported in patients with cirrhosis, such as spontaneous bacterial peritonitis and hepatic encephalopathy. Jepsen et al. found that patients with cirrhosis and ascites had an increased risk of first hepatic encephalopathy with PPI use, and Riggio et al. also found that patients with cirrhosis had an increased risk of hepatic encephalopathy and death with PPI use. Therefore, PPI use in patients with cirrhosis should be more cautious. However, the duration of PPI use in these studies was long, and there are no data to clarify the effect of short-term PPI use.

At present, there is no consensus among the major guidelines on the use of PPI in patients with acute AVB in liver cirrhosis, and the UK guidelines do not recommend the use of PPI unless accompanied by gastrointestinal ulcer. The use of PPI was not mentioned in the guidelines of the American Endoscopic Society and the European Endoscopic Society. The 2021 Baveno 7 guideline clearly proposes that PPI should be stopped immediately once AVB is identified as cirrhosis. The latest meta-analysis in 2022 showed that the use of PPI before endoscopy may reduce the need for endoscopic hemostasis in patients with upper gastrointestinal tract, but there was no sufficient evidence to confirm the effect on clinical outcomes including 30-day mortality and rebleeding. It can be concluded that there is no consensus on the use of PPI in patients with AVB in cirrhosis, and the recommendations of guidelines lack high-quality studies to improve the convincing.

In summary, there is little evidence for the effect of PPI use in patients with AVB in liver cirrhosis, and there is no study on the efficacy of PPI combined with endoscopic therapy in patients with AVB in liver cirrhosis. Therefore, we planned to design a multicenter prospective randomized controlled trial to explore the efficacy of PPI in cirrhotic patients with AVB. In this study, the following questions were investigated: 1. Can PPI reduce the 5-day treatment failure rate in cirrhotic patients with AVB; 2. Can it reduce the 6-week rebleeding rate, mortality, and complications in patients with liver cirrhosis and AVB.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

672 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

Efficacy of Proton Pump Inhibitors in Cirrhotic Patients With Acute Variceal Bleeding

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Standard group Early treatment is mainly aimed at correcting hypovolemic shock, preventing gastrointestinal bleeding-related complications (infection, electrolyte acid-base disorder, hepatic encephalopathy, etc.), effective control of bleeding, monitoring vital signs and urine output. Medical treatment included initiation and maintenance of vasoactive agents (terlipressin, somatostatin, octreotide, depending on the participating institution) as soon as possible for 2 to 5 days, and prophylactic antibiotics (preferably ceftriaxone sodium or quinolones) by intravenous infusion for 5 days. Endoscopic intervention was performed within 12 hours after presentation and generally no longer than 24 hours. PPI was stopped immediately after endoscopic treatment. Early TIPS is determined according to the technology and concept of each unit. Child-pugh score 7 points with active bleeding under endoscopy or Child-pugh score ≤13 points can be considered.	Drug: Proton Pump Inhibitors PPI infusion stopped in standard group after endoscopy while continue to use for 5 days in experimental group Other Names: Omeprazole Esomeprazole Rabeprazole Pantoprazole Ilaprazole
Experimental: Standard group+PPI PPI was continued after endoscopic therapy for 5 days.	Drug: Proton Pump Inhibitors PPI infusion stopped in standard group after endoscopy while continue to use for 5 days in experimental group Other Names: Omeprazole Esomeprazole Rabeprazole Pantoprazole Ilaprazole

Arm

Intervention/Treatment

Placebo Comparator: Standard group

Early treatment is mainly aimed at correcting hypovolemic shock, preventing gastrointestinal bleeding-related complications (infection, electrolyte acid-base disorder, hepatic encephalopathy, etc.), effective control of bleeding, monitoring vital signs and urine output. Medical treatment included initiation and maintenance of vasoactive agents (terlipressin, somatostatin, octreotide, depending on the participating institution) as soon as possible for 2 to 5 days, and prophylactic antibiotics (preferably ceftriaxone sodium or quinolones) by intravenous infusion for 5 days. Endoscopic intervention was performed within 12 hours after presentation and generally no longer than 24 hours. PPI was stopped immediately after endoscopic treatment. Early TIPS is determined according to the technology and concept of each unit. Child-pugh score 7 points with active bleeding under endoscopy or Child-pugh score ≤13 points can be considered.

Drug: Proton Pump Inhibitors

PPI infusion stopped in standard group after endoscopy while continue to use for 5 days in experimental group

Other Names:

Omeprazole

Esomeprazole

Rabeprazole

Pantoprazole

Ilaprazole

Experimental: Standard group+PPI

PPI was continued after endoscopic therapy for 5 days.

Drug: Proton Pump Inhibitors

PPI infusion stopped in standard group after endoscopy while continue to use for 5 days in experimental group

Other Names:

Omeprazole

Esomeprazole

Rabeprazole

Pantoprazole

Ilaprazole

Outcome Measures

Primary Outcome Measures

5-day treatment failure rate [5 days]
Failure of initial hemostasis Initial hemostasis was defined as not achieving a 24h bleeding-free period within the first 48h after treatment together with stable vital signs based on Baveno consensus criteria. UGI bleeding occurred after initial hemostasis and within 5 days after enrollment was defined as early rebleeding. UGI bleeding was proven to be from esophageal varices.

Secondary Outcome Measures

Rebleeding within 42 days [42 days]
Rebleeding within 42 days
Mortality within 42 days [42 days]
Mortality within 42 days
Rescure treatment [42 days]
TIPs, re-endoscopy, surgery, etc
Compilcations [42 days]
Chest pain, reflux, nausea, vomiting, dysphagia, ulcer perforation, diarrhea, abdominal pain, headache, hepatic encephalopathy, spontaneous peritonitis, etc

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Liver cirrhosis.
The etiology of portal hypertension is cirrhosis.
Patients presenting with acute esophageal variceal bleeding proven by emergency endoscopy within 24 hours.
Be willing to participate in this clinical study, comply with the study requirements and sign the informed consent

Exclusion Criteria:

non-cirrhotic portal hypertension
the time from admission to endoscopy was more than 24 hours
patients with peptic ulcer or gastroesophageal reflux disease requiring PPI therapy
PPI use for more than 2 weeks before admission
received endoscopic or interventional therapy within the previous 4 weeks
PPI allergy
Chronic renal insufficiency (CKD stage 3-5)
Severe cardiopulmonary dysfunction (such as heart failure grade 3-4, respiratory failure, etc.)
Hepatocellular carcinoma (Barcelona Clinic Liver Cancer (BCLC) stage C and D)
other advanced malignancies (life expectancy less than 6 months)
Pregnancy