Gastroenterology

Gastroenterology

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

Clinical—Liver, Pancreas, and Biliary Tract
Simvastatin Lowers Portal Pressure in Patients With Cirrhosis and Portal Hypertension: A Randomized Controlled Trial

https://doi.org/10.1053/j.gastro.2009.01.043Get rights and content

Background & Aims

Simvastatin improves liver generation of nitric oxide and hepatic endothelial dysfunction in patients with cirrhosis, so it could be an effective therapy for portal hypertension. This randomized controlled trial evaluated the effects of continuous simvastatin administration on the hepatic venous pressure gradient (HVPG) and its safety in patients with cirrhosis and portal hypertension.

Methods

Fifty-nine patients with cirrhosis and portal hypertension (HVPG ≥12 mm Hg) were randomized to groups that were given simvastatin 20 mg/day for 1 month (increased to 40 mg/day at day 15) or placebo in a double-blind clinical trial. Randomization was stratified according to whether the patient was being treated with β-adrenergic blockers. We studied splanchnic and systemic hemodynamics and variables of liver function and safety before and after 1 month of treatment.

Results

Simvastatin significantly decreased HVPG (−8.3%) without deleterious effects in systemic hemodynamics. HVPG decreases were observed in patients who were receiving β-adrenergic blockers (−11.0%; P = .033) and in those who were not (−5.9%; P = .013). Simvastatin improved hepatic, fractional, and intrinsic clearance of indocyanine green, showing an improvement in effective liver perfusion and function. No significant changes in HVPG and liver function were observed in patients receiving placebo. The number of patients with adverse events did not differ significantly between groups. No patient was withdrawn from the study based on adverse events.

Conclusions

Simvastatin decreased HVPG and improved liver perfusion in patients with cirrhosis. These effects were additive with those of β-adrenergic blockers. The beneficial effects of simvastatin should be confirmed in long-term clinical trials for portal hypertension.

Section snippets

Patients and Methods

The present study was a prospective, randomized, multicenter trial performed at 3 university hospitals in Spain with wide experience in research in portal hypertension. The final protocol was approved by the Ethics Committee of each participating hospital and the Spanish Ministry of Health. The Ethics Committee of the Hospital Clinic (Barcelona) acted as the external safety monitoring board of the study. The study was conducted following the principles of the Declaration of Helsinki (revised in

Results

A total of 29 patients were randomized to receive placebo and 30 patients were randomized to receive simvastatin between March 2004 and February 2007. One patient from the placebo group did not complete the study because of side effects. Three wrong inclusions (baseline HVPG, <12 mm Hg) were excluded from the analysis before breaking the treatment codes, but were maintained for safety analysis. One of these patients received placebo and 2 patients received simvastatin. Therefore, the final

Discussion

This double-blind, randomized, controlled trial showed that 1-month simvastatin administration significantly decreased HVPG in patients with cirrhosis and severe portal hypertension. Although moderate, the magnitude of this effect has potential clinical relevance. Indeed, simvastatin reduced HVPG of 10% or greater in 40% of the patients, a value shown to protect against bleeding in patients with early portal hypertension,23 and 32% had an HVPG reduction of 20% or greater to less than 12 mm Hg.

Acknowledgment

The authors want to acknowledge the contribution of Mónica González, MD, and Cristina Ripoll, MD, in recruiting and following up patients for this study.

References (43)

  • J.G. Abraldes et al.

    Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats

    J Hepatol

    (2007)
  • C. Zafra et al.

    Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

    Gastroenterology

    (2004)
  • R. Banares et al.

    Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis

    Hepatology

    (2002)
  • R. Mastai 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)
  • M. Kiszka-Kanowitz et al.

    Blood volume distribution in patients with cirrhosis: aspects of the dual-head gamma-camera technique

    J Hepatol

    (2001)
  • V. Andreu et al.

    Total effective vascular compliance in patients with cirrhosisEffects of propranolol

    J Hepatol

    (2002)
  • J.C. Barbare et al.

    Intrinsic hepatic clearance and Child-Turcotte classification for assessment of liver function in cirrhosis

    J Hepatol

    (1985)
  • U. Ritzel et al.

    Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers

    J Hepatol

    (2002)
  • R. Vuppalanchi et al.

    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)
  • S. Khorashadi et al.

    Incidence of statin hepatotoxicity in patients with hepatitis C

    Clin Gastroenterol Hepatol

    (2006)
  • J. Bosch et al.

    Current management of portal hypertension

    J Hepatol

    (2003)

    • Cited by (0)

    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.

    View full text
    Copyright © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.