Effect of Long-term Carvedilol to Prevent Decompensation or Death in Patients With Asymptomatic Child-Pugh A5 to B8 Cirrhosis and Clinically Significant Portal Hypertension: a Multicenter Double-blind Randomized Control Trial

Prior treatment

• History of overt ascites or encephalopathy \<12 months before inclusion
• Treatment with either diuretics or lactulose or rifaximin \<3 months before inclusion
• Previous transjugular intrahepatic portosystemic shunt (TIPSS) or liver transplantation
• Previous history or active hepatocellular carcinoma
• Concomitant use of Cimétidin
• Concomitant use of class I antiarythmic agents (except lidocaïn) (i.e.cibenzoline, disopyramide, flécaïnide, hydroquinidine méxilétine, propafenone, quinidine)
• Concomitant use of clonidine, méthyldopa, guanfacine, moxonidine, rilménidine
• Concomitant use of fingolimod
• Concomitant use of potent inhibitors (e.g. ketoconazole, HIV protease inhibitors) or inductors (e.g. rifampin, carbamazepine, phenytoin) of CYP3A4 (see appendix 7)

Other illness

• Any history of portal hypertension related bleeding
• Baseline heart rate \<65/min or systolic blood pressure \<100 mm Hg
• Strict indication to selective or nonselective beta-blockers: history of acute myocardial infarction, congestive heart failure
• Strict contraindication to selective or nonselective beta-blockers:
  • decompensated congestive heart failure
  • grade 2 or 3 atrioventricular block
  • sinus node dysfunction without pacemaker
  • severe asthma according to WHO classification \[63\]
  • severe Chronic Obstructive Pulmonary Disease, defined stage 3 or 4 of the GOLD classification, i.e.FEV1\<50% of the predicted value (https://goldcopd.org/)
  • severe Raynaud disease, defined as repetitive episodes of biphasic colour (at least two) of pallor, cyanosis, erythema, in addition to paresthesia or numbness, occurring in both cold and normal environments \[64\].
• Known hypersensitivity to carvedilol

Lab values

• Concomitant use of calcium antagonists: diltiazem, vérapamil and bépridil

Other

• Glomerular filtration rate (CKD-Epi) \< 30 mL/min
• Pregnancy or breastfeeding
• Non ability for participant to comply with the requirements of the study
• Life expectancy \<12 months

• Male or female≥ 18 years of age
• Cirrhosis related to hepatitis C or hepatitis B virus without viral replication for at least 2 years.
  • Or Cirrhosis related to alcohol consumption (active or abstinent) Or Cirrhosis related to metabolic syndrome or cryptogenic with BMI \< 30 kg/m2
• 2 TE-LSM (Fibroscan®) performed in fasting conditions, using either the M or the XL probe \>=25 kPa, within 12 months before inclusion
• Absence of medium or large varices or small varices with red signs at endoscopy within 3 months before inclusion
• Child-Pugh A5 to B8
• Affiliation to a French social security system.
• Written informed consent obtained from the participant or participant's legal representative
• For child-bearing aged women, contraception using oral contraceptive, or intrauterine device or mechanical contraception