Gastroenterology
Volume 136, Issue 5 , Pages 1651-1658 , May 2009

Simvastatin Lowers Portal Pressure in Patients With Cirrhosis and Portal Hypertension: A Randomized Controlled Trial

  • Juan G. Abraldes

      Affiliations

    • Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • ,
  • Agustin Albillos

      Affiliations

    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Unidad I+D Asociada al Centro Nacional de Biotecnología, Universidad Alcalá, Madrid, Spain
    • ,
  • Rafael Bañares

      Affiliations

    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • Servicio de Aparato Digestivo, Sección de Hepatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
    • ,
  • Juan Turnes

      Affiliations

    • Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • ,
  • Rosario González

      Affiliations

    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Unidad I+D Asociada al Centro Nacional de Biotecnología, Universidad Alcalá, Madrid, Spain
    • ,
  • Juan Carlos García–Pagán

      Affiliations

    • Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • ,
  • Jaime Bosch

      Affiliations

    • Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
    • Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
    • Corresponding Author InformationReprint requests Address requests for reprints to: Jaime Bosch, MD, Hepatic Hemodinamic Laboratory, Liver Unit, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. fax: (34) 93-451-52-72

Received 13 August 2008 ,Accepted 22 January 2009.

References 

  1. Bosch J, Abraldes JG, Groszmann RJ. Current management of portal hypertension. J Hepatol. 2003;38:S54–S68
  2. Vargas V, Rimola A, Casanovas T, et al. Applicability of liver transplantation in Catalonia at the end of the millennium (A prospective study of adult patient selection for liver transplantation). Transpl Int. 2003;16:270–275
  3. Abraldes JG, Tarantino I, Turnes J, et al. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology. 2003;37:902–908
  4. D'Amico G, Garcia-Pagan JC, Luca A, et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006;131:1611–1624
  5. Albillos A, Banares R, Gonzalez M, et al. Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis. Am J Gastroenterol. 2007;102:1116–1126
  6. Gluud C, Brok J, Gong Y, et al. Hepatology may have problems with putative surrogate outcome measures. J Hepatol. 2007;46:734–742
  7. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133:481–488
  8. Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet. 1995;346:1056–1059
  9. Thalheimer U, Bosch J, Burroughs AK. How to prevent varices from bleeding: shades of grey—the case for nonselective beta blockers. Gastroenterology. 2007;133:2029–2036
  10. Garcia-Tsao G, D'Amico G, Abraldes JG, et al. Predictive models in portal hypertension. In:  de Franchis R editors. Proceedings of the fourth Baveno International Consensus Workshop on definitions, methodology and therapeutic strategies. Oxford: Blackwell-Science; 2005;p. 47–100
  11. de Franchis R. Evolving consensus in portal hypertension report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2005;43:167–176
  12. Failli P, DeFranco RM, Caligiuri A, et al. Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells. Gastroenterology. 2000;119:479–492
  13. Yu Q, Shao R, Qian HS, et al. Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension. J Clin Invest. 2000;105:741–748
  14. Van de CM, Omasta A, Janssens S, et al. In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats. Gut. 2002;51:440–445
  15. Morales-Ruiz M, Cejudo-Martn P, Fernandez-Varo G, et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology. 2003;125:522–531
  16. Salmeron JM, Ruiz dA, Gines A, et al. Renal effects of acute isosorbide-5-mononitrate administration in cirrhosis. Hepatology. 1993;17:800–806
  17. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology. 2002;35:478–491
  18. Abraldes JG, Rodriguez-Vilarrupla A, Graupera M, et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol. 2007;46:1040–1046
  19. Trebicka J, Hennenberg M, Laleman W, et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology. 2007;46:242–253
  20. Zafra C, Abraldes JG, Turnes J, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004;126:749–755
  21. Bosch J, Garcia-Pagan JC, Berzigotti A, et al. Measurement of portal pressure and its role in the management of chronic liver disease. Semin Liver Dis. 2006;26:348–362
  22. Navasa M, Bosch J, Mastai R, et al. Measurement of hepatic blood flow, hepatic extraction and intrinsic clearance of indocyanine green in cirrhosis (Comparison of a non-invasive pharmacokinetic method with measurements using hepatic vein catheterization). Eur J Gastroenterol Hepatol. 1991;3:305–312
  23. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353:2254–2261
  24. Bosch J, Mastai R, Kravetz D, et al. Effects of propranolol on azygos venous blood flow and hepatic and systemic hemodynamics in cirrhosis. Hepatology. 1984;4:1200–1205
  25. Banares R, Moitinho E, Matilla A, et al. Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology. 2002;36:1367–1373
  26. Mastai R, Bosch J, Navasa M, et al. Effects of alpha-adrenergic stimulation and beta-adrenergic blockade on azygos blood flow and splanchnic haemodynamics in patients with cirrhosis. J Hepatol. 1987;4:71–79
  27. Kiszka-Kanowitz M, Henriksen JH, Moller S, et al. Blood volume distribution in patients with cirrhosis: aspects of the dual-head gamma-camera technique. J Hepatol. 2001;35:605–612
  28. Huonker M, Schumacher YO, Ochs A, et al. Cardiac function and haemodynamics in alcoholic cirrhosis and effects of the transjugular intrahepatic portosystemic stent shunt. Gut. 1999;44:743–748
  29. Andreu V, Perello A, Moitinho E, et al. Total effective vascular compliance in patients with cirrhosis (Effects of propranolol). J Hepatol. 2002;36:356–361
  30. Barbare JC, Poupon RE, Jaillon P, et al. Intrinsic hepatic clearance and Child-Turcotte classification for assessment of liver function in cirrhosis. J Hepatol. 1985;1:253–259
  31. Caesar J, Shaldon S, Chiandussi L, et al. The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clin Sci. 1961;21:43–57
  32. Lee JS, Semela D, Iredale J, et al. Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?. Hepatology. 2007;45:817–825
  33. DeLeve LD, Wang X, Guo Y, et al. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology. 2008;48:920–930
  34. Garcia-Pagan JC, Feu F, Bosch J, et al. Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis (A randomized controlled study). Ann Intern Med. 1991;114:869–873
  35. Ritzel U, Leonhardt U, Nather M, et al. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers. J Hepatol. 2002;36:454–458
  36. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology. 2005;41:690–695
  37. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci. 2005;329:62–65
  38. Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol. 2006;4:902–907
  39. Stojakovic T, Putz-Bankuti C, Fauler G, et al. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology. 2007;46:776–784
  40. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology. 2006;44:466–471
  41. Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology. 2007;46:1453–1463
  42. O'Leary JG, Chan JL, McMahon CM, et al. Atorvastatin does not exhibit antiviral activity against HCV at conventional doses: a pilot clinical trial. Hepatology. 2007;45:895–898
  43. Argo CK, Loria P, Caldwell SH, et al. Statins in liver disease: a molehill, an iceberg, or neither?. Hepatology. 2008;48:662–669

 J.G.A. and A.A. contributed equally to this work and share first authorship.

 Conflicts of interest The authors disclose no conflicts. The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety (specifically serious adverse events as defined in federal guidelines) have been confirmed independently by a biostatistician (Juan G. Abraldes, MD) who is not employed by the corporate entity. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis.

 Funding Supported by Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, and the Spanish Ministry of Science and Innovation (grants CM0300123, 05/1285, 05/0519, and 06/0623). The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is funded by the Instituto de Salud Carlos III. The trial sponsor had no involvement in the design of the trial, collection and analysis of the data, or writing of the report.

 Trial registration number: NCT00594191.

PII: S0016-5085(09)00144-9

doi: 10.1053/j.gastro.2009.01.043

Gastroenterology
Volume 136, Issue 5 , Pages 1651-1658 , May 2009

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