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Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis

Published:January 13, 2016DOI:https://doi.org/10.1053/j.gastro.2016.01.004

      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.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), HR (hazard ratio), IQR (interquartile range), MELD (Model for End-Stage Liver Disease), NSBB (nonselective β-blocker)
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      Linked Article

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          We read with interest the recent study describing reduced mortality in patients with recent variceal hemorrhage treated with simvastatin.1 This important study is the first that aims to prospectively evaluate a role for statin therapy in improving outcomes for patients with advanced cirrhosis. The study is supported by preclinical work showing an approximately 10% reduction in hepatic venous pressure gradient in simvastatin treated patients with cirrhosis2 and a number of retrospective analyses.
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          I read with interest the article by Abraldes et al1 regarding the addition of simvastatin to standard therapy for the prevention of variceal rebleeding in patients with cirrhosis.1 The authors demonstrated that the addition of simvastatin to standard therapy could not prevent rebleeding, but increased survival in these cirrhotic patients. We should applaud their work for the remarkable improvement in survival by the addition of simvastatin in cirrhotic patients with history of variceal bleeding.
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          Abraldes et al1 offer a new perspective on prevention of variceal bleeding. Their multicenter clinical trial randomized 69 patients with cirrhosis to simvastatin (40 mg/d). Two patients with advanced cirrhosis developed rhabdomyolysis during simvastatin therapy, and this is higher than expected. In a large epidemiologic study, the average incidence of rhabdomyolysis was 0.49 per 10,000 person-years of treatment with simvastatin.2 The authors indicate that genetic variants that reduce the expression of organic anion transporter (SLCO1B) are a risk factor for simvastatin-induced myopathy.
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      • Statins After Variceal Bleeding Are Beneficial, but Still an Unexplained Mystery?
        GastroenterologyVol. 161Issue 6
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          First, we congratulate Abraldes et al for their excellent study and wonderful paper. Although other studies from the same group and others have shown that statins decrease hepatic resistance and portal pressure even on top of nonselective beta-blockers (NSBBs),1–3 this study is the first randomized controlled trial reporting a survival benefit of statins in liver disease.4 Besides this important finding, this paper might teach us important lessons regarding the perfect design of a clinical trial to improve the understanding of the effects of drugs, as well as to elaborate on patient selection.
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