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Statins After Variceal Bleeding Are Beneficial, but Still an Unexplained Mystery?

  • Priscilla Pollo-Flores
    Affiliations
    Internal Medicine Department, Fluminense Federal University, Niteroi, Rio de Janeiro, Brazil
    Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil
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  • Jonel Trebicka
    Affiliations
    Department of Internal Medicine I, Goethe University Frankfurt, Frankfurt, Germany
    Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
    European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
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      Dear Editors:
      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),
      • Zafra C.
      • et al.
      • Abraldes J.G.
      • et al.
      • Pollo-Flores P.
      • et al.
      this study is the first randomized controlled trial reporting a survival benefit of statins in liver disease.
      • Abraldes J.G.
      • et al.
      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. The following points need attention.
      The decrease in hepatic venous pressure gradient (HVPG) has been the “golden calf” of the treatment of portal hypertension, especially with respect to bleeding. Several studies with shorter duration than the present trial have demonstrated that 1 or 3 months of statin therapy decreases HVPG,
      • Abraldes J.G.
      • et al.
      ,
      • Pollo-Flores P.
      • et al.
      which was more pronounced in patients with previous variceal bleeding and HVPG >12 mm Hg.
      • Pollo-Flores P.
      • et al.
      Similar data were recently published for NSBB response.
      • Villanueva C.
      • et al.
      The assessment of hemodynamic response of NSBB and statins might have been an important information in this study and might represent a limitation in the interpretation of the results. This might have been the case because especially after variceal bleeding, hemodynamic response to treatment seems to be important for the outcome of patients and should have been part of the stratification of the groups, as shown recently in another study investigating variceal rebleeding.
      • Sauerbruch T.
      • et al.
      Moreover, statin therapy over 3 months could more effectively reduce the shunt flow as assessed by azygos flow measurements in patients with previous esophageal variceal bleeding and/or high-risk esophageal varices.
      • Pollo-Flores P.
      • et al.
      These clinical data are in line with experimental evidence that statins in cirrhotic portal hypertension decrease shunt flow, but in portal vein obstruction may lead to the opposite effects.
      • Uschner F.E.
      • et al.
      Therefore, even though patients with complete portal vein thrombosis (PVT) were excluded form the study, still there were a number of patients with partial PVT and this information is missing at baseline. Even though the numbers were low, still PVT developed or progressed more in the statin arm, which might deserve a little more thorough analysis of the data and/or consideration in future studies. This is of particular importance because PVT and higher shunting might provoke bleeding—and the bleeding rate was unchanged in the statin arm—but the intrahepatic effects of statins improved survival in these patients.
      Indeed, even though the reader gets the impression that statins beneficially influenced the course of liver disease in this trial, the data do not entirely support them. On the one hand, statin therapy decreased the rate of fatal rebleeding and infections—key features of progression of liver disease—and Model for End-Stage Liver Disease scores tended to improve, but hard data on liver fibrogenesis and/or inflammation are lacking, even though suggested in nonhuman animal studies.
      • Trebicka J.
      • et al.
      This again stresses the importance of liver biopsy or other noninvasive techniques (eg, magnetic resonance imaging) in the setting of clinical trials.
      Myopathy, and less commonly, rhabdomyolysis, are known adverse effects of statin and are rare in normal circumstances: ∼2–3 cases/year per 100,000 patients treated.
      • Collins R.
      • et al.
      However, in this trial it was relatively frequent. The reasons might be related to the dose of statins or genetic predisposition (eg, SCLO1B1 polymorphism), but also to alcoholic etiology of liver disease, which was the most prevalent in this study.
      • Hou Q.
      • et al.
      Therefore, the etiology of the patients matters even though portal hypertension develops in any etiology. Moreover, the authors discussed the choice of the specific drug as a reason for increased adverse effects. Atorvastatin showing more potent effects on stellate cell activation and activity, the main profibrogenic and contractile cell in the liver,
      • Trebicka J.
      • et al.
      ,
      • Trebicka J.
      • et al.
      ,
      • Klein S.
      • et al.
      seems not to be related to myopathy in patients with SCLO1B1 polymorphisms.
      In summary, this excellent trial represents a giant step in the treatment of portal hypertension. Moreover, it teaches us that several points should be kept in mind in the design of another trial on statins such as including patients with severe portal hypertension, stratifying for HVPG response and PVT, assessing fibrosis and inflammation, and choosing the appropriate members of a drug category.
      We congratulate the authors again on this fantastic and stimulating study.

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