Impact on Morbidity and Mortality of Prophylactic Dosing of Low Molecular Heparin in Child-Pugh B Cirrhotic Patients (Childbenox)

Impact on Morbidity and Mortality of Prophylactic Dosing of Low Molecular Weight Heparin in Child-Pugh B Cirrhotic Patients: a Randomized Controlled Study

Thrombosis occurring in the small intrahepatic, as well as in the large vessels is involved in the progression of cirrhosis. Anticoagulation could reduce morbidity and mortality in cirrhotic patients

Study Overview

• Status: Suspended
• Conditions: Cirrhosis
• Intervention / Treatment: Drug: Enoxaparine

Detailed Description

Cirrhosis is the end-stage of all chronic liver diseases. Cirrhosis is a critical step in the natural history of liver disease, as it is associated with the occurrence of complications (so-called decompensation) and death. Life expectancy varies from 12-14 years in patients with compensated cirrhosis, to 2-4 years after decompensation.

Cirrhosis is associated with thrombosis of the intrahepatic portal and hepatic venous systems leading to parenchymal extinction (atrophy), liver dysfunction and portal hypertension. Regeneration in the areas without microthrombosis, and inflammation are powerful factors inducing liver cancer. Portal and hepatic venous thrombosis have been shown to participate in remodeling the liver architecture and are associated with a worsening outcome. Thrombosis in cirrhosis is thought to result from a procoagulant state due to an imbalance between pro and anticoagulant factor plasma levels, inflammation in and around blood vessels, and a marked slowing down of venous blood flow. Heparin administration, in animal models of liver fibrosis, decreases extra cellular matrix protein synthesis and fibrous tissue deposition. Recently, a reduction in liver decompensation and mortality has been shown in Child-Pugh B7-C10 cirrhotic patients assigned to receive a low dose of enoxaparin (4000IU/d), a low molecular weight heparin, for 48 weeks, compared to patients receiving no anticoagulation therapy.

These results are in line with the hypothesis of a protective role of anticoagulation in liver disease progression and a strong association between thrombosis and liver fibrosis.

So the main objective of the study is to compare the effect of a 2-year low dosing of Enoxaparin (4000 IU/day) versus no treatment on morbidity and mortality in patients with Child B7-C10 cirrhosis.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Hôpital Saint Antoine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥18 and ≤75 years old
• A diagnosis of cirrhosis based on liver biopsy or on the combination of clinical, laboratory and imaging criteria
• Compensated Child-Pugh B7-C10
• Any of the following causal factors : past but controlled excessive alcohol intake (<30g/d for men and <20g/d for women), HCV infection without viral replication, HBV infection without viral replication on therapy, metabolic syndrome, biliary cirrhosis, auto-immune cirrhosis, hemochromatosis, cryptogenetic cirrhosis

Exclusion Criteria:

• Ascites, portal hypertensive bleeding or encephalopathy within the last 3 months prior to enrolment
• Hepatocellular carcinoma non considered in remission
• Budd Chiari syndrome non considered in remission
• Liver transplantation
• F2 or F3 varices without treatment in accordance with recommended guidelines (B-blockers, ligation or both)
• Portal vein thrombosis
• Transjugular intrahepatic portosystemic shunt
• Known extra-hepatic malignancies
• PT<35%
• Platelet count<50,000/mm3
• Haemoglobin level < 9g/dl
• Serum Albumin < 20g/L
• A bone mineral density T score of less than -4.0 at the lumbar spine or total hip
• Known HIV infection
• Ongoing anticoagulation or antiaggregation
• Renal insufficiency defined by creatinine clearance<60ml/mn
• Conditions at risk for spontaneous bleeding (except for portal hypertension) or hemostatic abnormalities not related to cirrhosis
• Pregnancy or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enoxaparine; 69 Child Pugh B7-C10, cirrhotic patients receiving anticoagulation treatment (daily subcutaneous injection of enoxaparin 4000UI/day) during 24 months	Drug: Enoxaparine; Enoxaparine 4000UI/day during 24 months; Other Names: LOVENOX® 4000UI/day
No Intervention: Control; 69 Child Pugh B7-C10, cirrhotic patients not receiving anticoagulation treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Morbidity and mortality at 24 months	To compare the effect of a 2-year low dosing of Enoxaparin (4000 IU/day) versus no treatment on morbidity and mortality in patients with Child B7-C10 cirrhosis.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality liver-related or not at 24 months	Two year overall survival and two year liver related survival considering non-liver death as a competive event.	24 months
Adverse events at 24 months	percentage of bleeding episodes not reported to portal hypertension, percentage of heparin induced thrombocytopenia, variation of bone mineral density (M24-M0/M0) and percentage of occurrence of osteoporosis at dual energy X-ray absorptiometry	24 months
Liver function and fibrosis at 24 months	Variation of liver function tests (M24-M0/M0): PT, albumin and T bilirubin levels, Child-Pugh and MELD score; Variation of non-invasive tests of liver fibrosis (M24-M0/M0): fibrometer and cirrhometer scores, liver stiffness measurement using transient elastography.	24 months
Thrombosis at 24 months	Occurrence of portal vein (PV) thrombosis at Doppler ultrasound evaluation performed every 3 months or CT scan performed at M-1 and M24 (appendix 2) or hepatocellular carcinoma at Doppler ultrasound evaluation performed every 3 months or CT scan performed at M-1 and M24 and confirmed according to EASL recommendations	24 months
Compliance	record of unused packaging and information about compliance in a patient diary	24 months
Survival rate without completion	Survival rate without complication 6 months after completion of treatment as well as variation of liver function and portal hypertension parameters, occurrence of PV thrombosis, occurrence of bacterial infections	30 months
Portal hypertension parameters	Variation of portal hypertension parameters (M24-M0/M0): platelets count, esophageal varices size at endoscopic evaluation	24 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Armelle Poujol-Robert, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2015
• Primary Completion (Anticipated): July 2, 2019
• Study Completion (Anticipated): July 2, 2019

Study Registration Dates

• First Submitted: October 20, 2014
• First Submitted That Met QC Criteria: October 20, 2014
• First Posted (Estimate): October 22, 2014

Study Record Updates

• Last Update Posted (Actual): February 27, 2018
• Last Update Submitted That Met QC Criteria: February 26, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: mortality; Cirrhosis; anticoagulation; decompensation; Child B; portal thrombosis
• Additional Relevant MeSH Terms: Pathologic Processes; Fibrosis; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Enoxaparin
• Other Study ID Numbers: P130926; AOM 13606 (Other Grant/Funding Number: Ministry of Health)