Efficacy of Statin Association With Standard Treatment in Prevention of Recurrent Hemorrhage in Patient With Cirrhosis and Variceal Bleeding

A Randomized, Multicenter,Double Blind,Controlled With Placebo Trial About Efficacy of Statin Association With Standard Treatment in Prevention of Recurrent Hemorrhage in Patient With Liver Cirrhosis and Variceal Bleeding

This is a prospective, double blind controlled trial in which patients with esophagic variceal bleeding treated with standard therapy (endoscopic variceal ligation(EVL) + B-blockers), will be randomized to receive statins or placebo. They will be followed up during 12 months to determinate whether statins are effective in prevention of variceal bleeding recurrence and evaluate patient survival.

Randomization will be stratified according to the degree of hepatic insufficiency, assessed by the Child-Pugh classifications (A,B or C).

Study Overview

• Status: Completed
• Conditions: Cirrhosis; Hypertension, Portal; Portal Vein Thrombosis; Bleeding Esophageal Varices
• Intervention / Treatment: Drug: Simvastatin; Drug: Placebo

Detailed Description

A mayor cause of cirrhosis-related morbility and mortality is the development of variceal hemorrhage, a direct consequence of portal hypertension. In addition, survivors of an episode of active bleeding have a 70 % risk of recurrent hemorrhage within two years of the bleeding episode and the highest risk it is situated in the first six weeks after the hemorrhage episode.

The recommended treatment in AASLD guidelines is the combination of non selective Betablockers with endoscopic treatment with EVL, with high recurrence (30% in 2 years).

The hypothesis of this study is that statins are candidates for improving portal hypertension treatment in patients with cirrhosis, improving vascular function as well as preventing venous thrombotic events.

Patients with liver cirrhosis and variceal bleeding with standard treatment will be stratified and after randomized to undergo either statins (20 mg for 15 days, and after 40 mg/day) or placebo. They will be followed up for 12 months.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Alicante, Spain
    • Hospital Universitario de Alicante
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Universitario del Mar
  • Barcelona, Spain
    • Hospital de la Vall d'Hebron
  • Barcelona, Spain, 08005
    • Hospital Clínic
  • Barcelona, Spain, 089016
    • Hospital German Trias i Pujol
  • Madrid, Spain
    • Hospital Ramón y Cajal
  • Madrid, Spain
    • Hospital Gregorio Marañón
  • Tenerife, Spain
    • Hospital Universitario de Canarias
  • Asturias
    • Oviedo, Asturias, Spain
      • Complejo Universitario Central de Asturias
  • Barcelona
    • L´Hospitalet del LLobregat, Barcelona, Spain
      • Hospital Universitari Bellvitge
    • Sabadell, Barcelona, Spain
      • Corporació Sanitària Parc Taulí
  • Catalunya
    • LLeida, Catalunya, Spain
      • Hospital Arnau de Vilanova
  • Galicia
    • Pontevedra, Galicia, Spain
      • Complejo Hospitalario Pontevedra
  • Madrid
    • Majadahonda, Madrid, Spain
      • Hospital Puerta del Hierro

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients between 18 and 80 years old.
• Clinical criteria and/or analytical, ultrasound and/or liver biopsy consistent with the diagnosis of liver cirrhosis.
• Hematemesis or melenas within 7 days prior to study inclusion.

• Variceal bleeding. Endoscopic diagnosis:

  • Active variceal bleeding.
  • Clot or platelet cluster or,
  • Esophageal varices associated to red blood in esophagogastric lumen in the absence of other sources of bleeding.
• Patients with standard treatment for prevention of recurrence of variceal bleeding (EVL+B Blockers,Propanolol).
• Women of childbearing age should have a urine pregnancy test negative for 7 days before commencement of treatment and postmenopausal women must have amenorrhea for at least 12 months to be considered not fertile. Potential childbearing women and men must commit to use adequate contraception prior to joining the study and during it.
• Written informed consent to participate in the study.

Exclusion Criteria:

• Pregnancy or lactation
• Presence multiple hepatocellular carcinoma or only diameter> 5 cm.
• Renal failure ( Creatinine > 2 mg/dl)
• Advanced liver disfunction (Child Pugh > 13 points)
• Contraindication for statins.
• Patients HIV treated with antiretroviral therapy.
• Pre-treatment with portosystemic shunt ( surgical or percutaneous).
• Bleeding due to gastric varices.
• Patients with total portal vein thrombosis or portal cavernomatosis.
• Patients previously treated with endoscopic variceal ligation and B- Blockers (before index episode).
• Patients previously treated with statins ( one month before the study).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard therapy + Simvastatin; Standard therapy: Endoscopic variceal ligation (EVL)+ B Blockers (Propanolol titrated until achieve maximum tolerated dose); Simvastatin (20 mg for 15 days and after 40 mg/day until the end of the study)	Drug: Simvastatin; Simvastatin 20 mg for 15 days, then 40 mg until the end of the study.; Other Names: Simvastatina; Simvastatina Ratiopharm
Placebo Comparator: Standard therapy + placebo; Standard therapy: Endoscopic variceal ligation (EVL)+ B Blockers (Propanolol titrated maximum tolerated dose).; Placebo	Drug: Placebo; Simvastatin placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Recurrence of variceal bleeding and patient survival	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Bleeding severity in both arms.	12 months
Appearance or progression of Portal Hypertension complications	12 months
Appearance or progression of Portal Vein Thrombosis	12 months
Need for alternative treatments (transjugular intrahepatic portosystemic shunt [TIPS], surgery)	12 months
Incidence of adverse events of statin treatment	12 months

Collaborators and Investigators

• Sponsor: Juan A. Arnaiz
• Investigators: Principal Investigator: Jaume Bosch, MD, Hospital Clínic

Publications and helpful links

General Publications

• Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, Genesca J, Rodriguez M, Castellote J, Garcia-Pagan JC, Torres F, Calleja JL, Albillos A, Bosch J; BLEPS Study Group. Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis. Gastroenterology. 2016 May;150(5):1160-1170.e3. doi: 10.1053/j.gastro.2016.01.004. Epub 2016 Jan 14.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: March 29, 2010
• First Submitted That Met QC Criteria: March 29, 2010
• First Posted (Estimate): March 30, 2010

Study Record Updates

• Last Update Posted (Estimate): March 19, 2015
• Last Update Submitted That Met QC Criteria: March 18, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Gastrointestinal Diseases; Liver Diseases; Embolism and Thrombosis; Esophageal Diseases; Fibrosis; Hemorrhage; Liver Cirrhosis; Esophageal and Gastric Varices; Thrombosis; Hypertension, Portal; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: BLEPS; 2009-016500-24 (EudraCT Number)