Beta-blockers for Oesophageal Varices
Beta-blockers for Oesophageal Varices
To determine if carvedilol reduces the rate of variceal haemorrhage in patients with
 cirrhosis and small oesophageal varices
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.
Inclusion Criteria:

 1. Age >18 years

 2. 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

 3. 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.

 4. Not received a beta-blocker in the last week

 5. Capacity to provide informed consent

 Exclusion Criteria:

 1. Non-cirrhotic portal hypertension

 2. Medium/large oesophageal varices (current or history of), defined as >5 mm in diameter

 3. Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding

 4. Previous variceal haemorrhage

 5. Red signs accompanying varices at endoscopy

 6. Known intolerance to beta blockers

 7. 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

 8. Unable to provide informed consent

 9. Child Pugh C cirrhosis

 10. Already receiving a beta-blocker for another reason that cannot be discontinued

 11. Graft cirrhosis post liver transplantation

 12. Evidence of active malignancy without curative therapy planned

 13. Pregnant or lactating women

 14. Women of child bearing potential not willing to use adequate contraception during the
 protocol of IMP dosing

 15. Patients who have been on a CTIMP within the previous 3 months