Beta-blockers Or Placebo for Primary Prophylaxis of oesophageal varices (BOPPP): a blinded, multi-centre, clinical effectiveness and cost-effectiveness randomised controlled trial
Participants with cirrhosis and small varices without evidence of previous bleeding
Current interventions as of 24/04/2026: Oral carvedilol 6.25 mg to 12.5 mg once daily vs oral placebo 1 to 2 tablets once daily Patients who are recruited to the study with small varices will be randomised to either beta-blockers (carvedilol) or a placebo. The randomisation sequence will be generated in an ongoing manner using varying permuted blocks of size 4 to 12, within each site in a 1:1 ratio (Carvedilol: Placebo). Participants will be observed closely for up to 3 years for bleeding from their varices or other complications of cirrhosis or side effects of taking medication. This is the amount of time needed to observe for bleeding when the varices are small. The trialists will review the patients every 6 months including assessing the varices by a camera test called an endoscopy at the beginning and of each year until the study is finished. During the study patients will be involved with the conduct and management of the research, and the trialists will feedback to recruited patients the results at the end. They will assess the barriers and facilitators of doctors in primary care - such as General Practitioners - in adjusting the dose of the tablets to optimise treatment effects, and assess patients’ views on taking part in the trial, and whether the side effects justify the potential benefits of reducing the risk of bleeding. It is estimated that this risk could be reduced from 20% of patients having significant bleeding to 10% over 3 years. The trialists will measure the impact of beta-blockers on the overall costs to the NHS of caring for people with cirrhosis during the trial. They will then assess the impact of treatment on both mortality and quality of life using a combined measure, the Quality Adjusted Life-Year (QALY). They will use a mathematical prediction model to estimate the impact of treatment on costs, mortality and quality of life over a patient’s lifetime. They will assess whether any increased costs are justified by better outcomes fo
Current key inclusion criteria as of 24/04/2026: 1. Age >18 years 2. Cirrhosis and portal hypertension, defined by any two of the following: 2.1. Characteristic clinical examination findings; one or more of: 2.1.1. Jaundice, ascites, caput medusae, spider naevi, palmar erythema, asterixis 2.2. Characteristic liver function tests, haematological panel and coagulation profile abnormalities 2.2.1. hyperbilirubinaemia (serum total bilirubin > 30 umol/l) 2.2.2. thrombocytopenia (platelet count <120 x109 / L) 2.2.3.international normalised raio (INR) > 1.5 NB These blood tests may be normal in well compensated cirrhosis – if cirrhosis is confirmed on other investigations, normal blood tests suggest well compensated disease. 2.3. Characteristic radiological findings; one or more of: 2.3.1. Heterogeneous, small liver with irregular contour 2.3.2. Splenomegaly 2.3.3. Ascites 2.3.4. Varices 2.3.5. Recanalized umbilical vein 2.4. Fibrosis score > stage 4 on liver biopsy 2.5. FibroScan liver stiffness measurement >15 kPa without other explanation 3. Small oesophageal varices – defined as <5mm in diameter or completely disappear on moderate insufflation at gastroscopy within the last 3 months 4. Not received a beta-blocker in the last week 5. Capacity to provide informed consent _____ Previous key inclusion criteria: 1. Age >18 years 2. Cirrhosis and portal hypertension, defined by any two of the following: 2.1. Characteristic clinical examination findings; one or more of: 2.1.1. Jaundice, ascites, caput medusae, spider naevi, palmar erythema, asterixis 2.2. Characteristic liver function tests, haematological panel and coagulation profile abnormalities 2.2.1. hyperbilirubinaemia (serum total bilirubin > 30 umol/l) 2.2.2. thrombocytopenia (platelet count <120 x109 / L) 2.2.3.international normalised raio (INR) > 1.5 NB These blood tests may be normal in well compensated cirrhosis – if cirrhosis is confirmed on other investigations, normal blood tests suggest well compensat
Current key exclusion criteria as of 24/04/2026: 1. Non-cirrhotic portal hypertension 2. Medium/large oesophageal varices (current or history of) 3. Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding 4. Previous variceal haemorrhage 5. Known intolerance to beta blockers 6. Contraindication to beta blocker use: 6.1. Heart rate <50 bpm 6.2. Known 2nd degree or higher heart block 6.3. Sick sinus syndrome 6.4. Systolic blood pressure <85mm Hg 6.5. Chronic airways obstruction (asthma/COPD) 6.6. Floppy Iris Syndrome 6.7. CYP2D6 Poor Metaboliser 6.8. Cardiogenic shock 6.9. History of severe hypersensitivity reaction to beta blockers 6.10. Untreated phaeochromocytoma 6.11. Severe peripheral vascular disease 6.12. Prinzmetal angina 6.13. NYHA IV heart failure 7. Unable to provide informed consent 8. Child Pugh C cirrhosis 9. Already receiving a beta-blocker for another reason that cannot be discontinued 10. Pregnant or lactating women 11. Graft cirrhosis post liver transplantation 12. Evidence of active malignancy without curative therapy planned 13. Women of childbearing potential not willing to use adequate contraception during the period of IMP dosing, if relevant 14. Patients who have been on a CTIMP within the previous 3 months 15. Clinical symptoms consistent with COVID-19 (a high temperature, a new continuous cough or a loss or change to sense of smell or taste) at the time of randomisation _____ Previous key exclusion criteria: 1. Non-cirrhotic portal hypertension 2. Medium/large oesophageal varices (current or history of) 3. Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding 4. Previous variceal haemorrhage 5. Known intolerance to beta blockers 6. Contraindication to beta blocker use: 6.1. Heart rate <50 bpm 6.2. Known 2nd degree or higher heart block 6.3. Sick sinus syndrome 6.4. Systolic blood pressure <85mm Hg 6.5. Chronic airways obstruction (asthma/COPD) 6.6. Floppy Iris Syndrome 6.7.