Anticoagulation in Liver Fibrosis in Patients With Hepatitis C Virus Infection
Condition: Liver Fibrosis
MeSH terms: Infections; Hepatitis C; Virus Diseases; Hepatitis; Liver Cirrhosis; Fibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Patients who have been treated for hepatitis C virus (HCV) infection who have failed to
      respond to anti-viral treatment are often concerned about their ongoing liver disease and are
      therefore looking for alternative treatments which might prevent fibrosis progression. This
      view is endorsed by patient representative groups (including Charles Gore at the HepC Trust)
      who have welcomed this trial protocol.

      The study is a single centred, prospective, open labelled design. Practical as well as safety
      concerns dictated that the study could not be conducted in a blinded fashion, since patients
      taking anticoagulation require monitoring. The study consisted of two 8 week phases: Phase 1
      and Phase 2. Phase 1 (observation phase, 0 to 8 weeks) and Phase 2 (treatment phase with
      warfarin anticoagulation, 8 to 16 weeks). Study completed at end of Phase 2.
    

Detailed description: 
      Background:

      Convincing evidence exists outlining a role for the coagulation system in the pathogenesis of
      liver fibrosis. In vivo and in vitro studies have suggested a role for thrombin and FXa in
      activating hepatic stellate cells and epidemiological studies have demonstrated that
      prothrombotic states accelerate liver fibrosis (Wright et al., 2003).

      Hence if prothrombotic states accelerate liver fibrosis, conversely anticoagulation should
      slow liver fibrosis. Animal studies have confirmed this (Anstee et al., 2008; Duplantier et
      al., 2004), and confirmed the beneficial effect of inhibiting the coagulation cascade. The
      number of patients with HCV infection on anticoagulants is small and there is no published
      case series. Similarly there are problems assessing disease progression using patients with
      haemophilia and HCV infection. The therapeutic use of anticoagulation to prevent fibrosis in
      humans is not without precedent, and warfarin has demonstrated a survival benefit in
      pulmonary fibrosis (Kubo et al., 2005).

      The antifibrotic potential of warfarin anticoagulation needs to be formally assessed in the
      setting of a clinical trial using patients with documented liver fibrosis. Most previous
      human studies of antifibrotics have taken place in patients with chronic HCV infection who
      have failed anti-viral therapy, as they are a model of progressive fibrosis (Anstee et al.,
      2009).

      Study aims:

        1. To evaluate if any potential effect on the progression of liver fibrosis in patients
           infected with Hepatitis C virus, with moderate severity liver fibrosis is demonstrable
           with anticoagulation.

        2. To evaluate the safety of anticoagulation in patients infected with Hepatitis C virus
           infection, with moderate severity liver fibrosis.

      Patients:

      The study was approved by the St. Mary's Hospital Ethics committee and conducted in
      accordance with the principles of the Declaration of Helsinki. Potential participants were
      identified via the departmental Hepatitis C database. All potential candidates were screened
      for the inclusion and exclusion criteria.

      Inclusion criteria:

      Patients were eligible for inclusion if they were aged greater than 17 years of age, had
      evidence of active Hepatitis C viral replication (HCV RNA PCR positive), ALT of greater than
      40 iu/ml, a modified histology activity index fibrosis score (Ishak et al., 1995) of greater
      than 2 but less than 5 on liver biopsy within the last five years, and had failed antiviral
      therapy for Hepatitis C in the last 5 years.

      Exclusion criteria:

      Patients requiring anticoagulation for existing clinical indications; standard
      contraindications to anticoagulation (active peptic ulcer disease, past history of
      haemorrhagic stroke, thrombocytopaenia, platelets count < 100 x109 /L); clinical evidence of
      portal hypertension; known cerebrovascular abnormalities; HIV antibody positive; alcohol
      abuse (> 40 units/week); menhorragia and pregnancy.

      Potential qualifying subjects were initially contacted by telephone to be informed about the
      study and arrange a formal screening visit. During the screening visit, entry criteria were
      confirmed and all patients who agreed to participate were required to give written informed
      consent.

      Study design:

      The study employed a single centred, prospective, open labelled design. Practical as well as
      safety concerns dictated that the study could not be conducted in a blinded fashion, since
      patients taking anticoagulation require monitoring. The study consisted of two 8 week phases:
      Phase 1 and Phase 2.

      Phase 1 (Week 0 to Week 8) Phase 1 of the study consisted of 8 weeks of observation, which
      commenced following a baseline visit at week 0. At the baseline study routine blood tests and
      non-invasive markers of fibrosis were performed. No placebo was given during the observation
      period. At week 8 patients underwent their second study visit during which routine blood
      tests and evaluation with non-invasive markers of fibrosis were repeated. The week 8 study
      visit marked the completion of Phase 1, following which patients entered Phase 2 of the
      study.

      Phase 2 (Week 8 to Week 16) Phase 2 of the study consisted of 8 weeks of anticoagulation with
      warfarin. In previous animal studies (Anstee et al., 2008), warfarin anticoagulation to
      achieve a whole blood clotting of twice the normal range was sufficient to retard fibrosis
      significantly, hence the international normalised ration (INR) was aimed to be maintained
      between 2 to 3 during the treatment period. Patients were given a standard induction regimen
      of warfarin in keeping with the outpatient warfarin loading protocol of the hospital's
      anticoagulation clinic. Warfarin was supplied by the hospital pharmacy. Routine INR
      monitoring and warfarin dosing was undertaken by the anticoagulation clinic on a weekly
      basis. Patients were monitored at these visits for any adverse events related to the
      treatment. At week 16, following 8 weeks of anticoagulation, a further study visit was
      organised. Routine bloods tests and non-invasive markers of fibrosis were performed at this
      visit, which marked the completion of each patient's participation in the study.
    

Intervention name(s): Warfarin
Intervention type(s): Drug
Intervention MeSH terms: Warfarin
Intervention model: Single Group Assignment
Intervention model description: The study employed a single centred, prospective, open labelled design. Practical as well as safety concerns dictated that the study could not be conducted in a blinded fashion, since patients taking anticoagulation require monitoring. The study consisted of two 8 week phases: Phase 1 and Phase 2.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatic fibrosis; anticoagulation; Coumarin; Warfarin; Chronic hepatitis C virus infection