Multicenter prospective randomized trial of the effect of rivaroxaban on survival and development of complications of portal hypertension in patients with cirrhosis

INTERVENTION: Trade Name: Xarelto 10 mg Product Name: Rivaroxaban Pharmaceutical Form: Tablet INN or Proposed INN: RIVAROXABAN CAS Number: 366789‐02‐8 Current Sponsor code: BAY 59‐7939 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Liver cirrhosis Therapeutic area: Diseases [C] ‐ Digestive System Diseases [C06] PRIMARY OUTCOME: Main Objective: Survival free of: transplant and decompensations / complications of PHT. Primary end point(s): 1. Survival free of transplant. Secondary Objective: 1. To evaluate the efficacy in preventing portal thrombosis (PT).; 2. To evaluate the efficacy in preventing complications of portal hypertension (PHT); 3. To evaluate the safety of rivaroxaban in patients with liver cirrhosis (LC); 4. To evaluate the incidence of HCC.; 5. To assess the effect on liver fibrosis by non‐invasive methods.; 6. To evaluate the effect on hepatocellular function (Child‐Pugh and MELD); 7. To correlate levels of anti‐Xa and Rivaroxaban on efficacy and safety; 8. To evaluate the effect of Rivaroxaban on HVPG (in a Substudy: CIRROXABAN‐CATSHEP, in 65 patients).; 9. To assess if Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical findings. Timepoint(s) of evaluation of this end point: At month 24 SECONDARY OUTCOME: Secondary end point(s): Key secondary enpoints:; 1. Bleeding episode due to portal hypertension.; 2. Hepatic encephalopathy grade II or higher.; 3. Ascitic decompensation: In patients without ascites, decompensation defined as "de novo" clinically detectable ascites; whereas in those with previous ascites is considered end‐point for worsening ascites if required: a) perform two or more evacuative paracentesis in the following six months, or b) the completion of a TIPS.; Secondary enpoints:; 1. Development of portal vein thrombosis detected by ultrasound and confirmed by CT angiography or MRI ngiography.; 2. Development of complications of portal hypertension (anamnesis, physical examination, ultrasound and fibrogastroscopy).; 3. Security of rivaroxaban in patients with liver cirrhosis. History and clinical evaluation of bleeding and monitoring of hematocrite. Evaluation of liver function.; 4. Incidence of HCC by semiannual ultrasound.; 5. To correlate levels of Rivaroxaban and antiXa to the efficacy and safety of the drug.; Rivaroxaban 6. Effect on hepatic venous pressure gradient (HVPG) Determination of HVPG at baseline and 12 months rivaroxaban or placebo (in a Substudy CIRROXABAN‐CATSHEP of 65 patients).; 7. Effect of rivaroxaban on liver fibrosis assessed by liver elastography measured by FibroScan and / or ARFI at baseline and every six months conditions. Effect on fibroscan and / or splenic ARFI.; 8. Effect of Rivaroxaban on hepatocellular function estimated by the Child‐Pugh scores and MELD.; 9. Assess Rivaroxaban reduces bacterial translocation and proinflammatory cytokines. Correlation with clinical events. Timepoint(s) of evaluation of this end point: At month 24 INCLUSION CRITERIA: a. Aged between 18 and 75 years of both sexes. b. Clinical and / or laboratory criteria, ultrasound and / or liver biopsy compatible with the diagnosis of viral cirrhosis (If HBV: HBV‐DNA must be negative; if HCV: SVR should be at least for 6 months prior to enrollment); alcohol (in the last 6 months: in men less than 60 g daily intake in women less than 40 g); NASH and cryptogenic. c. Presence of clinically significant portal hypertension (CSPHT) defined by clinical criteria (presence of esophageal varices or ascites), elastography (liver Fibroscan® ? 21 kPa) or hemodynamic (HVPG ? 10 mmHg) d. Mild to moderate hepatic impairment defined by Child‐Pugh of 7‐10 points. e. Written informed consent to participate in the study Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 160 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subject