Clinical trial NCT02271295: Impact on Morbidity and Mortality of Prophylactic Dosing of Low Molecular Heparin in Child-Pugh B Cirrhotic Patients
Official title: Impact on Morbidity and Mortality of Prophylactic Dosing of Low Molecular Weight Heparin in Child-Pugh B Cirrhotic Patients: a Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE3
Conditions: Cirrhosis
Keywords: Cirrhosis
Child B
decompensation
mortality
portal thrombosis
anticoagulation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2014-10-22
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Morbidity and mortality at 24 months
timeFrame: 24 months
Secondary outcomes:
measure: Mortality liver-related or not at 24 months
timeFrame: 24 months
measure: Adverse events at 24 months
timeFrame: 24 months
measure: Liver function and fibrosis at 24 months
timeFrame: 24 months
measure: Thrombosis at 24 months
timeFrame: 24 months
measure: Compliance
timeFrame: 24 months
measure: Survival rate without completion
timeFrame: 30 months
measure: Portal hypertension parameters
timeFrame: 24 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Saint Antoine
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Armelle Poujol-Robert
role: PRINCIPAL_INVESTIGATOR
References: