Beta-blockers for Oesophageal Varices

Study Overview
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Brief Summary
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To determine if carvedilol reduces the rate of variceal haemorrhage in patients with cirrhosis and small oesophageal varices

Detailed Description
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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. The investigators know that when varices are large, treatment can be initiated with medication called beta-blockers to reduce the pressure in the varices. If the varices are small, the medical community is not sure if treatment with beta-blockers will work. This study aims to address this uncertainty. Patients who are recruited to the study with small varices will be randomised to either beta-blockers or a placebo. Research sites will observe patients 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. Research sites 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. During the study, patients will be involved with the conduct and management of the research. Patient will also be notified on the trial results at the end of the study. The barriers and facilitators in adjusting the dose of the tablets to optimise treatment effects primary care will be along with patients' views on taking part in the trial, and whether the side effects justify the potential benefits of reducing the risk of bleeding. The investigators estimate this risk could be reduced from 20% of patients having significant bleeding to 10% over 3 years. The investigators will measure the impact of beta-blockers on the overall costs to the National Health Service (NHS) of caring for people with cirrhosis during the trial, and will also assess the impact of treatment on both mortality and quality of life using a combined measure, the Quality Adjusted Life-Year (QALY). The investigators will use a mathematical prediction model to estimate the impact of treatment on costs, mortality and quality of life over a patient's lifetime and will assess whether any increased costs are justified by better outcomes for patients and represent good value for money for the NHS budget. Finally, the results of the study will be published 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.

Official Title
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Beta-blockers or Placebo for Primary Prophylaxis of Oesophageal Varices (BOPPP Trial). A Blinded, Multi-centre, Clinical Effectiveness and Cost-effectiveness Randomised Controlled Trial

Conditions
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Cirrhoses, Liver, Oesophageal Varices

Intervention / Treatment
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* Drug: Carvedilol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Cirrhosis and portal hypertension, defined by any 2 of the following: A) Characteristic clinical examination findings; one or more of i) liver function tests ii) haematological panel iii) coagulation profile abnormalities B) Characteristic radiological findings; one or more of i) heterogeneous, small liver with irregular contour ii) splenomegaly iii) ascites iv) varices v) recanalized umbilical vein C) Fibrosis score > stage 4 on liver biopsy D) FibroScan liver stiffness measurement >15 kilo Pascal without other explanation Small oesophageal varices diagnosed within the last 3 months,- defined as <5 mm in diameter or varices which completely disappear on moderate insufflation at gastroscopy. Not received a beta-blocker in the last week Capacity to provide informed consent Exclusion Criteria: Non-cirrhotic portal hypertension Medium/large oesophageal varices (current or history of), defined as >5 mm in diameter Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding Previous variceal haemorrhage Red signs accompanying varices at endoscopy Known intolerance to beta blockers Contraindication to beta blocker use i) Heart rate <50 bpm ii) Known 2nd degree or higher heart block iii) Sick sinus syndrome iv) Systolic blood pressure <85 mm Hg v) Chronic airways obstruction (asthma/COPD) vi) Floppy Iris Syndrome vii) CYP2D6 Poor Metaboliser viii) History of cardiogenic shock ix) History of severe hypersensitivity reaction to beta-blockers x) Untreated phaeochromocytoma xi) Severe peripheral vascular disease xii) Prinzmetal angina xiii) New York Heart Association IV heart failure Unable to provide informed consent Child Pugh C cirrhosis Already receiving a beta-blocker for another reason that cannot be discontinued Graft cirrhosis post liver transplantation Evidence of active malignancy without curative therapy planned Pregnant or lactating women Women of child bearing potential not willing to use adequate contraception during the protocol of IMP dosing Patients who have been on a CTIMP within the previous 3 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Carvedilol<br>6.25 mg or 12.5 mg if tolerated | Drug: Carvedilol<br>* Oral tablet<br>|
| Placebo Comparator: Oral Placebo<br> | Drug: Carvedilol<br>* Oral tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variceal bleeding | Time to first variceal haemorrhage | 3 years | 
| Health Economic assessment | Assess the cost effectiveness of early intervention with non specific beta blockers in this patient population. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variceal bleed rate | Number of variceal bleeds by allocation | 1 and 3 years | 
| Variceal bleeding needing intervention | Number of patients that progress to medium/large varices requiring clinical intervention | 3 years | 
| Composite of variceal bleed rate and bleeding needing intervention | Composite of variceal bleed rate and bleeding needing intervention. i.e. Unit less measure of rate of ((Number of patients who bled) PLUS (Number of patients who progressed without bleeding)) / (Number of patients in that arm at randomisation) at 3 years ranging from 0 to 1 | 3 years | 
| Clinical decompensation | Number of patients with clinical decompensation (spontaneous bacterial peritonitis, new ascites, new hepatic encephalopathy) in the active and inactive IMP groups | 3 years | 
| Child Pugh Score for Cirrhosis mortality | Child Pugh Score for Cirrhosis mortalityin the active and inactive IMP groups. Range 5-15. Higher scores represent worse outcomes. | 3 years | 
| Model for end-stage liver disease (MELD) score | MELD score in the active and inactive IMP groups.Range 6-40. Higher scores represent worse outcomes. | 3 years | 
| Survival (Overall, liver related, cardio-vascular related) | Survival (Overall, liver related, cardio-vascular related) | 3 years | 
| Quality of life assessment | Quality of life score using EQ5D-5L in the active and inactive IMP groups. Range 5-25. Higher scores represent worse outcomes. | 3 years |