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Statin exposure is associated with reduced development of acute-on-chronic liver failure in a Veterans Affairs cohort

  • Author Footnotes
    † Co-first authors
    Nadim Mahmud
    Correspondence
    Corresponding author. Address: 3400 Civic Center Boulevard, 4th Floor, South Pavilion, Philadelphia, PA 19104, USA, Tel.: 215-349-8222, fax: 215-349-5915.
    Footnotes
    † Co-first authors
    Affiliations
    Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA

    Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Leonard David Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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  • Author Footnotes
    † Co-first authors
    Sara Chapin
    Footnotes
    † Co-first authors
    Affiliations
    Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • David S. Goldberg
    Affiliations
    Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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  • K. Rajender Reddy
    Affiliations
    Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Tamar H. Taddei
    Affiliations
    Division of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA

    VA Connecticut Healthcare System, West Haven, CT, USA
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  • David E. Kaplan
    Affiliations
    Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
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  • Author Footnotes
    † Co-first authors
Published:January 20, 2022DOI:https://doi.org/10.1016/j.jhep.2021.12.034

      Highlights

      • Of 84,963 U.S. Veterans with cirrhosis, 8,558 (10.1%) were hospitalized with ACLF.
      • Binary statin exposure was associated with a 38% reduced hazard of developing ACLF.
      • Increasing dose exposure was associated with a progressively reduced hazard of ACLF.
      • Statin-exposed patients with ACLF had more kidney and less liver or brain failures.

      Backgrounds & Aims

      There is a need to identify therapies that prevent the development of acute-on-chronic liver failure (ACLF) in patients with cirrhosis. This study sought to evaluate the association between statin exposure and the risk of developing ACLF in a large national cohort of patients with cirrhosis.

      Methods

      We performed a retrospective cohort study of patients diagnosed with cirrhosis within the Veterans Health Administration from 2008 and 2018. Patients were stratified into 3 groups based on statin exposure (statin naïve, existing statin user, and new statin initiator). Cox proportional hazards regression models with inverse probability treatment weighting and marginal structural models were utilized to comprehensively address potential confounding in estimating the association between time-updated statin exposure and first occurrence of high-grade ACLF.

      Results

      The cohort included 84,963 patients, of whom 26.9% were on a statin at baseline. A total of 8,558 (10.1%) patients with cirrhosis were hospitalized with high-grade ACLF over a median follow-up time of 51.6 months (IQR 27.5–81.4). Time-updated statin use was associated with a significant reduction in the hazard of developing ACLF (hazard ratio [HR] 0.62, 95% CI 0.59-0.65, p <0.001). Increasing doses of statin were associated with progressively reduced hazard of developing ACLF (HR 0.75, 95% CI 0.66-0.86, p <0.001 for <20 mg vs. 0 mg of time-updated statin exposure, in simvastatin equivalents; HR 0.61, 95%, CI 0.58-0.64, p <0.001 for >20 mg vs. 0 mg statin exposure). Furthermore, every additional 5 months of statin exposure was associated with a 9% reduced hazard of high-grade ACLF (HR 0.91, 95% CI 0.90-0.92, p <0.001).

      Conclusions

      In this large, retrospective, cohort study in patients with cirrhosis, statin use was significantly associated with reduced development of high-grade ACLF.

      Lay summary

      Statin therapy has been shown to have numerous beneficial effects in patients with chronic liver disease. This study demonstrated a strong association between statin therapy and a reduced risk of acute-on-chronic liver failure development in patients with cirrhosis. The results of this study support the promising role that statins may play in future prevention of acute-on-chronic liver failure in patients with cirrhosis.

      Graphical abstract

      Keywords

      Linked Article

      • Statin Exposure is Associated with Reduced Development of Acute-on-chronic Liver Failure in a Veterans Affairs Cohort
        Journal of Clinical and Experimental HepatologyVol. 12Issue 6
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          This was a retrospective study that evaluated the association between the risk of developing acute on chronic liver failure (ACLF) in patients with cirrhosis and exposure to statins. The data were collected from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) cohort.1 The study included 84,963 patients with cirrhosis. Patients with Fibrosis-4 score2 (FIB-4) < 1.45, less than six months of follow-up and less than two outpatient visits in the index year were excluded. Among these patients, 26.9% patients were on statins at baseline.
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