Apixaban to Prevent Decompensation of Early Liver Cirrhosis Trial

• Apixaban 2.5 mg twice daily (Drug): Participants randomised to this arm will receive Apixaban 2.5mg twice daily
• Placebo (Drug): Placebo will be given as oral tablet and taken twice daily

Primary outcomes

• Time from randomisation to first decompensation event, assessed up to 49 months [Time from randomisation to first decompensation event, assessed up to 49 months]: First decompensation event is defined as at least one of the following: Grade 2 or 3 ascites according to the International Club of Ascites (ICA), or spontaneous bacterial peritonitis; Grade 2-4 hepatic encephalopathy; variceal haemorrhage (gastrointestinal bleeding secondary to rupture of varices); and liver-related death measured using METHOD at 6-monthly trial follow-up visits and throughout the trial, when location study teams become aware of these events, as decompensation normally involves hospitalisation

Secondary outcomes

• Time from randomisation to first decompensation event, assessed up to 49 months [Time from randomisation to first decompensation event, assessed up to 49 months]: Time to event for individual decompensation events measured at 6-monthly follow-up visits, assessed up to 49 months
• Time to development of grade 1 (small volume) ascites [Time from randomisation assessed up to 49 months]: Small volume ascites
• Assessment of safety of anticoagulation in Childs A cirrhosis patients [Time from randomisation assessed up to 49 months]: Assessment of safety of anticoagulation in Childs A cirrhosis patients, including incidence of clinically relevant combined major bleeding and non-major bleeding during trial treatment period
• Time to all-cause mortality [Time from randomisation assessed up to 49 months]
• Time to portal vein thrombosis or other thromboembolic events [Time from randomisation assessed up to 49 months]
• Incidence of cardiac events [Time from randomisation assessed up to 49 months]
• Alcohol use [Time from baseline assessed up to 49 months]: Alcohol use will be determined by patient reporting on AUDIT-C questionnaire
• Health-related quality of life assessed using EQ-5D-5L questionnaire [Time from randomisation assessed up to 49 months]

Other outcomes

• Changes in FibroScan® liver stiffness measurement values, splenic elastography, and ELF values as an exploratory outcome [Time from baseline assessed up to 49 months]: This will be performed in scan performed and technology available
• Progression or requirement for TIPSS or transplant as an exploratory outcome [Time from randomisation assessed up to 49 months]
• Time to diagnosis of hepatocellular carcinoma [Time from randomisation assessed up to 49 months]
• Disease progression, comparing changes in MELD and scores between beginning and end of trial [Time from randomisation assessed up to 49 months]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Liver cirrhosis secondary to alcohol, with or without associated metabolic risk factors, i.e. Alcohol related liver disease (ARLD) or metabolic dysfunction-associated steatotic liver disease, where there has been a significant history of alcohol consumption (MetALD)
2. Cirrhosis will be based on histology, or clear radiological evidence, e.g. nodular or heterogeneous liver or non-invasive testing (e.g. Fibroscan®, or Enhanced Liver Fibrosis (ELF) test
3. Childs A Cirrhosis (Participants with a previous episode of decompensated cirrhosis who have now recompensated can be included)
4. Participants with no hepatic encephalopathy or low-grade hepatic encephalopathy (Grade 0 or 1) taking lactulose and/or rifaximin
5. Aged ≥18 years
6. Clinical evidence of portal hypertension, defined as any 1 of:

   * Evidence of abdominal collateral circulation, recanalised umbilical vein or varices on imaging
   * Asymptomatic ascites (trace only) seen around the liver on imaging in patients who are not taking diuretics
   * Liver stiffness measurement >20kPa on FibroScan®/ Vibration- Controlled Transient Elastography (VCTE) (where BMI <35)
   * Presence of Gastro-oesophageal varices at endoscopy
   * Hepatic venous pressure gradient ≥ 10mmHg

Or Platelet count < 150,000 μL AND any 1 of:

* Spleen size >13 cm in length
* Liver stiffness measurement >20kPa on FibroScan®/VCTE (where BMI >35)
* Presence of portal hypertensive gastropathy at endoscopy

Exclusion Criteria:

1. Evidence of decompensation (e.g. ascites requiring treatment other than a thin rim around liver on imaging, as above) (Evidence of decompensation as follows: Grade 2 or 3 Ascites, Grade 2 - 4 Hepatic Encephalopathy, Variceal Haemorrhage)
2. Causes for cirrhosis other than alcohol, including those with MASLD who have never drunk alcohol above government recommended levels (14 units/week)
3. Pre-existing splanchnic vein thrombosis (portal, splenic, mesenteric, and hepatic veins)
4. Use of (and need for) anticoagulation or dual antiplatelet therapy or clopidogrel
5. Platelets <50x109/L at screening
6. Moderate-severe renal impairment defined as eGFR <30ml/min at screening
7. Recent variceal bleed or untreated large varices
8. Malignancy in last 2 years if unlikely to survive trial because of comorbidity in the location PI's opinion
9. Hepatocellular carcinoma
10. Severe cardiac failure1 or Chronic Obstructive Pulmonary Disease (COPD)
11. Pregnancy
12. INR >1.7 (After vitamin K correction) at screening
13. Previous hypersensitivity reaction to Apixaban

• Alastair O'Brien, Principal investigator, Queen Mary University of London