Title: Beta-blockers or placebo for primary prophylaxis of oesophageal varices (BOPPP study)
Funder: Department of Health and Social Care

Abstract: Cirrhosis or liver scarring is an important problem in healthcare in the United Kingdom. 60,000 patients are living with this disease and about 11,000 people every year will die because of it. There are several ways in which patients with this severe form of liver disease become unwell or die and bleeding from the oesophagus or stomach is one. Cirrhosis causes pressure changes inside the abdomen and swelling of veins in the oesophagus (called “varices”) which can bleed catastrophically. We know that when varices are large we need to treat them with medication called beta-blockers to reduce the pressure in the varices. If the varices are small, we are not sure if we need to treat with beta-blockers and this study aims to address this uncertainty. _x000D_ _x000D_ Patients who are recruited to the study with small varices will be randomised to either beta-blockers or a placebo. We will observe them closely for 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. We will review the patients every 6 months including assessing the varices by a camera test called an endoscopy at the beginning and each year until the study is finished. _x000D_ _x000D_ During the study patients will be involved with the conduct and management of the research, and we will feedback to recruited patients the results at the end. We 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. We estimate this risk could be reduced from 20% of patients having significant bleeding to 10% over 3 years._x000D_ _x000D_ We will measure the impact of beta-blockers on the overall costs to the NHS of caring for people with cirrhosis during the trial. We will then assess the impact of treatment on both mortality and quality of life using a combined measure, the Quality Adjusted Life-Year (QALY). We will use a mathematical prediction model to estimate the impact of treatment on costs, mortality and quality of life over a patient’s lifetime. We will assess whether any increased costs are justified by better outcomes for patients and represent good value for money for the NHS budget. _x000D_ _x000D_ Finally, we will publish the results of the study in the medical literature and discuss the findings at medical conferences, patient groups and with charities involved in helping patients with cirrhosis such as the British Liver Trust._x000D_ _x000D_ _x000D_ * PPI lay advisory group contributed to the wording of this summary.

Lay abstract: Study design: Multicentre, blinded, randomised controlled trial (RCT) of non-selective beta blockade (NSBB) v placebo in patients with small oesophageal varices (OVs). _x000D_ _x000D_ Setting: Secondary and tertiary care centres with endoscopy and gastroenterology services._x000D_ _x000D_ Strategy for reviewing literature: This is a commissioned call._x000D_ _x000D_ Target population: Patients with cirrhosis and small OVs._x000D_ _x000D_ Inclusion Criteria: Cirrhosis (defined by two of clinical, biochemical, radiological and/or histological criteria), grade 1 OVs without red signs at screening or surveillance endoscopy, no episode of previous overt upper GI bleeding attributed to OVs._x000D_ _x000D_ Exclusion Criteria: Age <18, unable to give informed consent, unable to undergo screening gastroscopy, pregnancy/lactating, history of overt upper GI bleeding attributed to OVs, previous portosystemic shunt, gastroduodenal ulceration, already on a beta-blocker, requirement for betablockade (known portal hypertension/decompensation/cardiovascular disease), known allergy/intolerance/contraindication to beta-blockers, baseline heart rate (HR) <50bpm, baseline systolic blood pressure <85mmHg, active malignancy._x000D_ _x000D_ Intervention: Placebo or carvedilol 6.25mg once daily dose adjusted to 12.5mg after a week if tolerated or if HR <50-55 bpm is reached._x000D_ _x000D_ 1o outcome: Variceal haemorrhage within 3 years, cost-effectiveness._x000D_ _x000D_ 2o outcomes: All-cause mortality, increase in OV grade, hospitalisation with decompensated cirrhosis, MELD score increase, development of overt hepatic encephalopathy (HE), ascites, jaundice, renal impairment, HCC, myocardial infarction, liver transplantation._x000D_ _x000D_ Study visits: Screening, randomisation, week 1 following initiation of investigative product for dose escalation, telephone call at 6 weeks and then every 6 months._x000D_ _x000D_ Health technology being assessed: Carvedilol. _x000D_ _x000D_ Measurements of costs and outcomes: Variceal bleeding will be recorded at presentation, or hospital record, at year 3. 2o outcomes will be recorded from hospital records, case report form (CRF), or mortality registry. Health care costs will be assessed using hospital records and CRF. Quality Adjusted Life Expectancy will be estimated from quality of life measurement at 6 monthly intervals using the EQ-5D-5L. Cost-utility will be determined at 3 years, and at lifetime using a Markov model._x000D_ _x000D_ Power calculation: Assuming 18% of recruited placebo patients will develop variceal bleeding by 3 years (median 4 years) follow up, and carvedilol will achieve a clinically important hazard ratio of 0.60. For 90% power, 1200 patients in total (600 per allocation group) required to be randomised detect a difference with a two-sided significance level of 0.05._x000D_ _x000D_ Difference between current and planned care pathways: IMP, health related quality of life questionnaire._x000D_ _x000D_ Project timetable and recruitment rate: Initial scoping study at King’s College Hospital of (160 patients) then further 18 months of recruitment of patients (aim-1200 patients over the 2-year period), with at least 3 years follow up._x000D_ _x000D_ Expertise in team: KCH hosts the largest comprehensive clinical hepatology service in Europe and draws on national referral pathways to enhance study recruitment. King’s Clinical Trial Unit (KCTU) have extensive methodological, trial design, statistics, health economics and qualitative research, with a proven track record of delivering large multi-centre RCTs. A UK wide collaborative group have pledged support to this study.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL