Apixaban to Prevent dEcompensation of eArly liver CirrHosis (APEACH)

Research question: Does treatment with the anticoagulant, apixaban reduce decompensation events in patients with alcohol related (ArLD) and/or metabolic-dysfunction and alcohol-associated (MetALD) Childs A liver cirrhosis and portal hypertension? Background: Mortality from liver disease has increased 400% since 1970 with >15000 deaths and 70000 liver related hospitalisations in 2022. Yet, there are no licensed medications proven to reverse cirrhosis or improve long term outcomes. Decompensation of cirrhosis is life changing. Patients with compensated (Childs A) cirrhosis are asymptomatic with unimpaired quality of life and many continue to work. However, those with “decompensated cirrhosis” have ascites, variceal haemorrhage, and hepatic encephalopathy, are very unwell with poor quality of life, require frequent hospitalisations and have only a 2-year median survival. Childs A patients with clinically significant portal hypertension (CSPH), high pressure in the main liver blood vessel-portal vein, are at particularly high risk of decompensation. The scientific and clinical evidence for anticoagulation, the safety of DOACs in cirrhosis and predictable pharmacokinetics (requiring no monitoring) provide strong rationale for a randomised controlled trial (RCT). Aims and objectives: To determine if treatment with apixaban reduces decompensation events in patients with alcohol related and/or MetALD Childs A cirrhosis. Methods: A multicentre double-blind, placebo controlled RCT comparing rate of hepatic decompensation in 1142 patients from up to 55 NHS sites in Childs A cirrhosis with CSPH treated with apixaban or placebo. Key inclusion criteria: Childs A cirrhosis and CSPH defined as (1 of): Liver Stiffness Measurement >20kPa on FibroScan®; If BMI>35, LSM >20kPa and platelets <150; Presence of gastro-oesophageal varices or portal hypertensive gastropathy at endoscopy; Evidence of abdominal collateral circulation, recanalized umbilical vein or varices on cross-sectional imaging; Splenomegaly (>13.5 cm) with platelet count of <150. The active treatment is apixaban 2.5mg bd and the comparator a placebo tablet of identical appearance. Active drug or placebo will be taken for a minimum of 12 months and maximum of 51 months. Proposed sample size: We have estimated an effect size of (Hazard Ratio) 0.65 for apixaban to reduce of decompensation events. Assuming a placebo event rate of 27%, we estimate a sample size of 1142 patients including a 10% allowance for loss to follow up. Statistical Analysis will be intention-to-treat (ITT) and treatment policy estimand. Potential confounders include alcohol use and use of non-selective beta blockers and will be included in stratification. Primary Outcome: Time from randomisation to first decompensation event, defined as: Grade 2 or 3 Ascites according to the International Ascites club, or Spontaneous Bacterial Peritonitis; Grade 2-4 Hepatic Encephalopathy; Variceal Haemorrhage (gastrointestinal bleeding secondary to rupture of varices); Liver Related Death. Timelines for delivery: 9-months set-up and approvals and 19-months to open 55 sites. Planned recruitment completes at 39-months, followed by 12-month follow-up. We conclude with 6-month analyses, manuscript publication and dissemination. The project length is 66 months with an 18-month internal pilot with stop/go criteria for continuation. Anticipated impact: a positive outcome would transform management for patients with cirrhosis.