Juan G Abraldes1, Candid Villanueva2, Carles Aracil3, Juan Turnes4, Manuel Hernandez-Guerra5, Joan Genesca6, Manuel Rodriguez7, Jose Castellote8, Juan Carlos García-Pagán9, Ferran Torres10, Jose Luis Calleja11, Agustin Albillos12, Jaime Bosch13. 1. Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut D'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain. Electronic address: juan.g.abraldes@ualberta.ca. 2. Department of Gastroenterology, Hospital de Sant Pau, Barcelona, Universidad Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain. 3. Servicio de Gastroenterología, Hospital Universitario Arnau de Vilanova, Institut de Recerca Biomedica, Lleida, Spain. 4. Department of Gastroenterology, Complejo Hospitalario Universitario de Pontevedra, Instituto de Investigación Biomédica, Pontevedra, Spain. 5. Gastroenterology Department, University Hospital of the Canary Islands, Tenerife, Spain. 6. Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Universidad Autònoma de Barcelona, Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain. 7. Liver Unit, Hospital Universitario Central de Asturias, Oviedo, Spain. 8. Unidad de Hepatología, Servicio de Aparato Digestivo, Institut d'Investigació Biomèdica de Bellvitge: Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Spain. 9. Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut D'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain. 10. Biostatistics and Data Management Core Facility, Institut D'Investigacions Biomédiques August Pi i Sunyer, Hospital Clinic Barcelona, Spain and Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. 11. Liver Unit. Hospital U. Puerta de Hierro. Universidad Autònoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain. 12. Department of Gastroenterology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain. 13. Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut D'Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Spain; Swiss Liver Center, Inselspital, Bern, Switzerland. Electronic address: jbosch@clinic.ub.es.
Abstract
BACKGROUND & AIMS: The combination of β-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis. METHODS: We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a β-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding). RESULTS: The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group (P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15-0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group (P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group (P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group (P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis. CONCLUSIONS: In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185.
BACKGROUND & AIMS: The combination of β-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis. METHODS: We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a β-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding). RESULTS: The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group (P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15-0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group (P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group (P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group (P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis. CONCLUSIONS: In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185.
Authors: Martin Janicko; Sylvia Drazilova; Daniel Pella; Jan Fedacko; Peter Jarcuska Journal: World J Gastroenterol Date: 2016-07-21 Impact factor: 5.742