SACRED: Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis: Statins and Cirrhosis: Reducing Events of Decompensation

David E Kaplan, Rajni Mehta, Guadalupe Garcia-Tsao, Jeffrey Albrecht, Ayse Aytaman, Gyorgy Baffy, Jasmohan Bajaj, Ruben Hernaez, Kristel Hunt, George Ioannou, Kay Johnson, Fasiha Kanwal, Tae-Hoon Lee, Alexander Monto, Prashant Pandya, Douglas Schaubel, Tamar H Taddei, David E Kaplan, Rajni Mehta, Guadalupe Garcia-Tsao, Jeffrey Albrecht, Ayse Aytaman, Gyorgy Baffy, Jasmohan Bajaj, Ruben Hernaez, Kristel Hunt, George Ioannou, Kay Johnson, Fasiha Kanwal, Tae-Hoon Lee, Alexander Monto, Prashant Pandya, Douglas Schaubel, Tamar H Taddei

Abstract

Background/aims: The development of decompensation in cirrhosis demarcates a marked change in the natural history of chronic liver disease. HMG-CoA reductase inhibitors (statins) exert pleiotropic effects that reduce inflammation and fibrosis as well as improve vascular reactivity. Retrospective studies uniformly have associated statin utilization with improved outcomes for patients with cirrhosis. Prospective human studies have shown that statins reduce portal hypertension and reduce death in patients with decompensated cirrhosis after variceal hemorrhage when added to standard therapy with an acceptable safety profile. This proposal aims to extend these findings to demonstrate that simvastatin reduces incident hepatic decompensation events among cirrhotic patients at high risk for hepatic decompensation.

Methods: We will perform the SACRED Trial (NCT03654053), a phase III, prospective, multi-center, double-blind, randomized clinical trial at 11 VA Medical Centers. Patients with compensated cirrhosis with clinically significant portal hypertension will be stratified based upon the concomitant use of nonselective beta-blockers and randomized to simvastatin 40 mg/day versus placebo for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Ancillary studies will evaluate patient-reported outcomes and pharmacogenetic corollaries of safety and/or efficacy.

Conclusion: Statins have a long track-record of safety and tolerability. This class of medications is generic and inexpensive, and thus, if the hypothesis is proven, there will be few barriers to widespread acceptance of the role of statins to prevent decompensation in patients with compensated cirrhosis. ClinicalTrials.gov Identifier: NCT03654053.

Keywords: Cirrhosis; Clinical trial; HMG-CoA reductase inhibitor; Human; Prospective; Veterans.

Conflict of interest statement

Declaration of Competing Interest

None.

Copyright © 2021. Published by Elsevier Inc.

Figures

Fig. 1.
Fig. 1.
Study Schema.
Fig. 2.
Fig. 2.
ANTICIPATE Nomogram for stratification of patient risk for Clinically Significant Portal Hypertension (CSPH).
Fig. 3.
Fig. 3.
Schema for Assessment and Management of Muscle Symptoms.

References

    1. Kaplan DE, Chapko MK, Mehta R, et al.Healthcare costs related to treatment of hepatocellular carcinoma among veterans with cirrhosis in the United States, Clin. Gastroenterol. Hepatol. (July262017), 10.1016/j.cgh.2017.07.024.
    1. Kaplan DE, Dai F, Aytaman A, et al.Development and performance of an algorithm to estimate the child-turcotte-pugh score from a national electronic healthcare database, Clin. Gastroenterol. Hepatol. (July152015), 10.1016/j.cgh.2015.07.010.
    1. Beste LA, Leipertz SL, Green PK, Dominitz JA, Ross D, Ioannou GN, Trends in burden of cirrhosis and hepatocellular carcinoma by underlying liver disease in US veterans, 2001–2013, Gastroenterology. 149 (6) (November 2015), 10.1053/j.gastro.2015.07.056, 1471–1482 e5.
    1. El-Serag HB, Hampel H, Javadi F, The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence, Clin. Gastroenterol. Hepatol. 4 (3) (March 2006) 369–380.
    1. Jepsen P, Lash TL, Vilstrup H, The clinical course of alcoholic cirrhosis: development of comorbid diseases. A Danish nationwide cohort study, Liver Int. (April282016), 10.1111/liv.13151.
    1. Blais P, Lin M, Kramer JR, El-Serag HB, Kanwal F, Statins are underutilized in patients with nonalcoholic fatty liver disease and dyslipidemia, Dig. Dis. Sci. 61 (6) (June 2016) 1714–1720, 10.1007/s10620-015-4000-6.
    1. Sadowitz B, Maier KG, Gahtan V, Basic science review: statin therapy—part I: the pleiotropic effects of statins in cardiovascular disease, Vasc. Endovasc. Surg. 44 (4) (May 2010) 241–251, 10.1177/1538574410362922.
    1. Vieira JM Jr., Mantovani E, Rodrigues LT, et al.Simvastatin attenuates renal inflammation, tubular transdifferentiation and interstitial fibrosis in rats with unilateral ureteral obstruction, Nephrol. Dial. Transplant. 20 (8) (August 2005) 1582–1591, 10.1093/ndt/gfh859.
    1. Yamamoto C, Fukuda N, Jumabay M, et al.Protective effects of statin on cardiac fibrosis and apoptosis in adrenomedullin-knockout mice treated with angiotensin II and high salt loading, Hypertens. Res. 34 (3) (March 2011) 348–353, 10.1038/hr.2010.243.
    1. Tokunaga T, Ikegami T, Yoshizumi T, et al.Beneficial effects of fluvastatin on liver microcirculation and regeneration after massive hepatectomy in rats, Dig. Dis. Sci. 53 (11) (November 2008) 2989–2994, 10.1007/s10620-008-0241-y.
    1. El-Ashmawy NE, El-Bahrawy HA, Shamloula MM, Ibrahim AO, Antifibrotic effect of AT-1 blocker and statin in rats with hepatic fibrosis, Clin. Exp. Pharmacol. Physiol. 42 (9) (September 2015) 979–987, 10.1111/1440-1681.12446.
    1. Abraldes JG, Rodriguez-Vilarrupla A, Graupera M, et al.Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats, J. Hepatol. 46 (6) (2007) 1040–1046, 10.1016/j.jhep.2007.01.020.
    1. Moreno M, Ramalho LN, Sancho-Bru P, et al.Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver, Am. J. Physiol. Gastrointest. Liver Physiol. 296 (2) (February 2009) G147–G156, 10.1152/ajpgi.00462.2007.
    1. Busnelli M, Manzini S, Froio A, et al.Diet induced mild hypercholesterolemia in pigs: local and systemic inflammation, effects on vascular injury - rescue by high-dose statin treatment, PLoS One 8 (11) (2013), e80588, 10.1371/journal.pone.0080588.
    1. La Mura V, Pasarin M, Meireles CZ, et al.Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction, Hepatology. 57 (3) (March 2013) 1172–1181, 10.1002/hep.26127.
    1. Zhang W, Wu J, Zhou L, Xie HY, Zheng SS, Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway, Indian J. Exp. Biol. 48 (12) (December 2010) 1167–1174.
    1. El-Serag HB, Johnson ML, Hachem C, Morgana RO, Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes, Gastroenterology 136 (5) (May 2009) 1601–1608, 10.1053/j.gastro.2009.01.053.
    1. Kaplan DE, Serper MA, Mehta R, et al.Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis, Gastroenterology 156 (6) (May 2019) 1693–1706, 10.1053/j.gastro.2019.01.026, e12.
    1. Motzkus-Feagans C, Pakyz AL, Ratliff SM, Bajaj JS, Lapane KL, Statin use and infections in veterans with cirrhosis, Aliment. Pharmacol. Ther. 38 (6) (September 2013) 611–618, 10.1111/apt.12430.
    1. Mohanty A, Tate JP, Garcia-Tsao G, Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C-related compensated cirrhosis, Gastroenterology. 150 (2) (February 2016) 430–440, 10.1053/j.gastro.2015.10.007, e1.
    1. Abraldes JG, Villanueva C, Aracil C, et al.Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce Rebleeding but increases survival in patients with cirrhosis, Gastroenterology 150 (5) (May 2016) 1160–1170, 10.1053/j.gastro.2016.01.004, e3.
    1. Kumar S, Grace ND, Qamar AA, Statin use in patients with cirrhosis: a retrospective cohort study, Dig. Dis. Sci. 59 (8) (August 2014) 1958–1965, 10.1007/s10620-014-3179-2.
    1. Chang FM, Wang YP, Lang HC, et al.Statins decrease the risk of decompensation in hepatitis B virus- and hepatitis C virus-related cirrhosis: a population-based study, Hepatology. 66 (3) (September 2017) 896–907, 10.1002/hep.29172.
    1. Stokkeland K, Lageborn CT, Ekbom A, et al.Statins and angiotensin-converting enzyme inhibitors are associated with reduced mortality and morbidity in chronic liver disease, Basic Clin. Pharmacol. Toxicol. 122 (1) (January 2018) 104–110, 10.1111/bcpt.12844.
    1. Zafra C, Abraldes JG, Turnes J, et al.Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis, Gastroenterology. 126 (3) (March 2004) 749–755.
    1. Abraldes JG, Albillos A, Banares R, et al.Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial, Gastroenterology. 136 (5) (May 2009) 1651–1658, 10.1053/j.gastro.2009.01.043.
    1. Kim RG, Loomba R, Prokop LJ, Singh S, Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis, Clin. Gastroenterol. Hepatol. 15 (10) (October 2017) 1521–1530, 10.1016/j.cgh.2017.04.039, e8.
    1. Pose E, Napoleone L, Amin A, et al.Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial, Lancet Gastroenterol. Hepatol. 5 (1) (January 2020) 31–41, 10.1016/S2468-1253(19)30320-6.
    1. Group SC, Link E, Parish S, et al.SLCO1B1 variants and statin-induced myopathy—a genomewide study, N. Engl. J. Med. 359 (8) (August 21 2008) 789–799, 10.1056/NEJMoa0801936.
    1. Voora D, Shah SH, Spasojevic I, et al.The SLCO1B1*5 genetic variant is associated with statin-induced side effects, J. Am. Coll. Cardiol. 54 (17) (October 20 2009) 1609–1616, 10.1016/j.jacc.2009.04.053.
    1. Bakar NS, Neely D, Avery P, Brown C, Daly AK, Kamali F, Genetic and clinical factors are associated with statin-related myotoxicity of moderate severity: a case-control study, Clin. Pharmacol. Ther. 104 (1) (July 2018) 178–187, 10.1002/cpt.887.
    1. Nguyen KA, Li L, Lu D, et al.A comprehensive review and meta-analysis of risk factors for statin-induced myopathy, Eur. J. Clin. Pharmacol. 74 (9) (September 2018) 1099–1109, 10.1007/s00228-018-2482-9.
    1. Santos PC, Soares RA, Nascimento RM, et al.SLCO1B1 rs4149056 polymorphism associated with statin-induced myopathy is differently distributed according to ethnicity in the Brazilian general population: Amerindians as a high risk ethnic group, BMC Med. Genet. 12 (October 12 2011) 136, 10.1186/1471-2350-12-136.
    1. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J, Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American association for the study of liver diseases, Hepatology 65 (1) (January 2017) 310–335, 10.1002/hep.28906.
    1. Molokhia M, Bhatia S, Nitsch D, Genetic determinants of statin-associated myopathy, Perinat. Med. 5 (5) (September 2008) 481–494, 10.2217/17410541.5.5.481.
    1. Abraldes JG, Garcia-Tsao G, The design of clinical trials in portal hypertension, Semin. Liver Dis. 37 (1) (February 2017) 73–84, 10.1055/s-0036-1597891.
    1. Ripoll C, Groszmann R, Garcia-Tsao G, et al.Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis, Gastroenterology. 133 (2) (August 2007) 481–488, 10.1053/j.gastro.2007.05.024.
    1. Groszmann RJ, Garcia-Tsao G, Bosch J, et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, N. Engl. J. Med. 353 (21) (November 24 2005) 2254–2261, 10.1056/NEJMoa044456.
    1. D’Amico G, Pasta L, Morabito A, et al.Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients, Aliment. Pharmacol. Ther. 39 (10) (May 2014) 1180–1193, 10.1111/apt.12721.
    1. Augustin S, Pons M, Maurice JB, et al.Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease, Hepatology. 66 (6) (December 2017) 1980–1988, 10.1002/hep.29363.
    1. Abraldes JG, Bureau C, Stefanescu H, et al.Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study, Hepatology. 64 (6) (December 2016) 2173–2184, 10.1002/hep.28824.
    1. Singh S, Muir AJ, Dieterich DT, Falck-Ytter YT, American Gastroenterological Association Institute technical review on the role of elastography in chronic liver diseases, Gastroenterology 152 (6) (May 2017) 1544–1577, 10.1053/j.gastro.2017.03.016.
    1. Stone NJ, Robinson JG, Lichtenstein AH, et al.2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines, J. Am. Coll. Cardiol. 63 (25 Pt B) (July 1 2014) 2889–2934, 10.1016/j.jacc.2013.11.002.
    1. Chen PY, Tsiatis AA, Causal inference on the difference of the restricted mean lifetime between two groups, Biometrics. 57 (4) (December 2001) 1030–1038, 10.1111/j.0006-341x.2001.01030.x.
    1. Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA, The National Lipid Association’s muscle safety expert P. an assessment by the statin muscle safety task force: 2014 update, J. Clin. Lipidol. 8 (3 Suppl) (May-Jun 2014) S58–S71, 10.1016/j.jacl.2014.03.004.
    1. Chalasani N, Regev A, Drug-induced liver injury in patients with preexisting chronic liver disease in drug development: how to identify and manage? Gastroenterology 151 (6) (December 2016) 1046–1051, 10.1053/j.gastro.2016.10.010.
    1. Peto R, Pike MC, Armitage P, et al.Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples, Br. J. Cancer 35 (1) (January 1977) 1–39.
    1. Zohar S, Teramukai S, Zhou Y, Bayesian design and conduct of phase II single-arm clinical trials with binary outcomes: a tutorial, Contemp. Clin. Trials 29 (4) (July 2008) 608–616, 10.1016/j.cct.2007.11.005.
    1. El-Sherif O, Jiang ZG, Tapper EB, et al.Baseline factors associated with improvements in decompensated cirrhosis after direct-acting antiviral therapy for hepatitis C virus infection, Gastroenterology 154 (8) (June 2018) 2111–2121, 10.1053/j.gastro.2018.03.022, e8.
    1. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB, Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents, Gastroenterology 153 (4) (October 2017) 996–1005, 10.1053/j.gastro.2017.06.012, e1.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir