Gastroenterology

Gastroenterology

Volume 150, Issue 5, May 2016, Pages 1160-1170.e3
Gastroenterology

Original Research
Full Report: Clinical—Liver
Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis

https://doi.org/10.1053/j.gastro.2016.01.004Get rights and content

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.

Section snippets

Study Design and Oversight

The BLEPS (Bleeding Prevention With Simvastatin) study was an investigator-initiated multicenter, randomized (1:1), placebo-controlled, double-blind, parallel group trial that enrolled patients from 14 Spanish academic centers. The study protocol and amendments were approved by the Spanish national regulatory authority and the Institutional Review Board or Ethics Committee for Clinical Research at each participating center and the coordinating center. Written informed consent was obtained from

Results

The study enrolled 158 participants who were randomized a median of 6 days after the index bleeding (interquartile range [IQR], 5–7 days). Eighty-three were assigned to receive placebo and 75 simvastatin. Supplementary Figure 1 shows the disposition of the patients. During the data blind review, 9 patients were excluded from the safety population (n = 149) because they never received the study medication (6 consent withdrawal before starting treatment, 1 immediate death, 1 immediate rebleeding,

Discussion

In this multicenter double-blind randomized trial in patients with cirrhosis after variceal bleeding, treatment with simvastatin resulted in longer survival than placebo administration (given above standard of care therapy). Simvastatin, however, failed to show superiority over placebo in decreasing the rate of rebleeding or other complications of cirrhosis. The increase in survival achieved by simvastatin was mainly determined by a decrease in mortality derived from rebleeding and infections,

Acknowledgments

The authors acknowledge the following: Data safety monitoring board: J. A. Arnaiz, A. Berzigotti, Jose Rios (statistician). Administrative, technical, or material support: Study supervision: J. A. Arnaiz. Trial manager: J. Pich.

Additional BLEPS Study Investigators: Hospital Vall d’Hebron (Barcelona): Salvador Augustin; Hospital Puerta de Hierro (Madrid): Elba Llop; Hospital Universitario de Canarias (Tenerife): Dalia Morales Arraez, Goretti Hernández Mesa; Hospital Ramon y Cajal (Madrid):

References (55)

  • T.G. Simon et al.

    Statin use is associated with a reduced risk of fibrosis progression in chronic hepatitis C

    J Hepatol

    (2015)
  • P.S. Sorensen et al.

    Simvastatin as add-on therapy to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial

    Lancet Neurol

    (2011)
  • S.T. Kim et al.

    Simvastatin plus capecitabine-cisplatin versus placebo plus capecitabine-cisplatin in patients with previously untreated advanced gastric cancer: a double-blind randomised phase 3 study

    Eur J Cancer

    (2014)
  • I.R. Konings et al.

    The addition of pravastatin to chemotherapy in advanced gastric carcinoma: a randomised phase II trial

    Eur J Cancer

    (2010)
  • G. D'Amico et al.

    Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review

    Gastroenterology

    (2006)
  • J.C. Garcia-Pagan et al.

    Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicenter randomized controlled trial

    Gut

    (2009)
  • S. Augustin et al.

    Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal bleeding

    Hepatology

    (2012)
  • J. Trebicka et al.

    Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

    Hepatology

    (2007)
  • V. La Mura et al.

    Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction

    Hepatology

    (2013)
  • C.Z. Meireles et al.

    Simvastatin prevents liver microvascular dysfunction and attenuates liver injury in rats with biliary cirrhosis submitted to hemorrhage/resuscitation

    Hepatology

    (2013)
  • G. Marrone et al.

    KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins

    Gut

    (2015)
  • nQuery Advisor Version 6.01. Statistical Solutions, Cork, Ireland. 2010. Available at:...
  • International Conference on Harmonization, ICH E9 Statistical principles for clinical trials (CPMP/ICH/363/96)....
  • European Medicines Agency's guidelines on the clinical efficacy and safety of medicines. Available at:...
  • M. Moreno et al.

    Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver

    Am J Physiol Gastrointest Liver Physiol

    (2009)
  • S. Kumar et al.

    Statin use in patients with cirrhosis: a retrospective cohort study

    Digest Dis Sci

    (2014)
  • C. Motzkus-Feagans et al.

    Statin use and infections in veterans with cirrhosis

    Aliment Pharmacol Ther

    (2013)
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    Conflicts of interest The authors disclose no conflicts.

    Funding The Spanish Ministry of Health funded the trial through a competitive peer-reviewed grant. The funding agency had no role in the collection, analysis, or interpretation of the data.

    Author names in bold designate shared co-first authorship.

    Authors share co-first authorship.

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