Abstract

Research Article

Addition of Simvastatin to Carvedilol and Endoscopic Variceal Ligation improves rebleeding and survival in patients with Child-Pugh A and B class but not in Child Pugh C class

Sanjeev Kumar Jha*, Kuldeep Saharawat, Ravi Keshari, , Praveen Jha, Shubham Purkayastha and Ravish Ranjan

Published: 20 September, 2019 | Volume 3 - Issue 1 | Pages: 020-026

Background: Even with current standard treatment after variceal bleeding which includes combination of nonselective b-blockers and repeated endoscopic variceal ligation, the risk of rebleeding and mortality are high. Statins exhibit an antifibrotic effect and improves HVPG. We evaluated whether addition of simvastatin to carvedilol plus EVL therapy reduces variceal rebleeds or death in patients with cirrhosis.

Method: Patients with a variceal bleed 5 to 10 days before were randomly assigned to groups A [carvedilol (n = 69)] or group B [carvedilol (maximum dose - 12.5mg), and simvastatin (40mg/day) (n = 65)]. Primary end points were variceal rebleeding or death. Secondary end points were new complications of portal hypertension and serious adverse effects of drugs.

Results: During a mean follow-up of 49.05 ± 25.74 weeks, composite end point i.e. rebleeding or death developed in 23 patients (33.3%) in group A and 12 patients (18.5%) in group B [HR for simvastatin = 0.512; 95% CI: 0.254 – 1.030; p = 0.06]. In subgroup analysis by excluding patients of Child C class, 18 patients (34.6%) in group A and 7 patients (13.6%) in group B developed composite end point [HR for simvastatin = 0.369; 95% CI: 0.154 – 0.887; p = 0.026]. 17.4% and 15.4% patients in group A and B developed additional secondary complication [HR = 0.86; 95% CI: 0.345-2.161; p = 0.75). No simvastatin induced significant adverse effects were found.

Conclusion: Addition of simvastatin to carvedilol and EVL may reduce the rebleeding and death in patients with less advance liver disease.

Read Full Article HTML DOI: 10.29328/journal.acgh.1001010 Cite this Article Read Full Article PDF

References

  1. Abraldes JG, Tandon P. Therapies: Drugs, Scopes and Transjugular Intrahepatic Portosystemic Shunt-When and How? Dig Dis. 2015; 33: 524-533. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26159269
  2. Graham DY, Smith JL. The course of patients after variceal hemorrhage. Gastroenterology. 1981; 80: 800-809. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6970703
  3. Garcia-Pagan JC, Villanueva C, Albillos A, Bañares R, Morillas R, 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; 58: 1144-1150. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19218249
  4. Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, et al. Portal Hypertension Collaborative Group. Hepatic venous pressure gradient predict clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007; 133: 481-488. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17681169
  5. Vorobioff J, Picabea E, Villavicencio R, Puccini V, Rossi O, et al. Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients. Hepatology. 1987; 7: 648-653. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/3610045
  6. Lebrec D, Hillon P, Munoz C, Goldfarb G, Nouel O, Benhamou JP. The effect of propranolol on portal hypertension in patients with cirrhosis: a hemodynamic study. Hepatology. 1982; 2: 523-527. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/6981575
  7. Sinagra E, Perricone G, Amico MD, Tin F. Systematic review with meta-analysis: the hemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis. Aliment Pharmacology Therapy. 2014; 39: 557-568. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24461301
  8. Lo GH, Chen WC, Wang HM, Yu HC. Randomized controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. J Gastroenterology Hepatology. 2012; 27: 1681-1687. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22849337
  9. Thomas Reiberger, Gregor Ulbrich, Arnulf Ferlitsch, Berit Anna Payer, Philipp Schwabl, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with hemodynamic non-response to propranolol. Gut. 2013; 62: 1634-1641. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23250049
  10. Martin Janicko, Sylvia Drazilova, Daniel Pella, Jan Fedacko, Peter Jarcuska. Pleiotropic effects of statins in the diseases of the liver. World J Gastroenterol. 2016; 22: 6201-6213. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27468210
  11. Marrone G, Maeso-Díaz R, García-Cardena G, Abraldes JG, García-Pagán JC, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut. 2015; 64: 1434-1443. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25500203
  12. Abraldes JG, Albillos A, Bañares R, Turnes J, González R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology. 2009; 136: 1651-1658. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19208350
  13. de Franchi R, Baveno VI. Expanding consensus in portal hypertension Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. Journal of Hepatology. 2015; 63: 743-752. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26047908
  14. Pollo-Flores P, Soldan M, Santos UC, Kunz DG, Mattos DE, et al. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: A randomized controlled trial. Dig Liver Dis. 2015; 47: 957-963. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26321186
  15. Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, 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. 2016; 150: 1160-1170. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26774179
  16. Trebicka J, Hennenberg M, Laleman W, Shelest N, Biecker E, et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology. 2007; 46: 242-253. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17596891
  17. La Mura V, Pasarin M, Meireles CZ, Miquel R, Rodríguez-Vilarrupla A, et al. Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology. 2013; 57: 1172-1181. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23184571
  18. Zafra C, Abraldes JG, Turnes J, Berzigotti A, Fernández M, et al. Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis. Gastroenterology. 2004; 126: 749-755. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14988829
  19. 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. 2009; 136: 1601-1608. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19208359
  20. Motzkus-Feagans C, Pakyz AL, Ratliff SM, Bajaj JS, Lapane KL. Statin use and infections in Veterans with cirrhosis. Aliment Pharmacol Ther. 2013; 38: 611-618. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23889738
  21. Kaplan DE. The Use of Statins in Patients with Cirrhosis. Gastroenterol Hepatol. 2018; 14: 485-487.
  22. Armitage J,Bowman L, Wallendszus K, Bulbulia R, Rahimi K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet. 2010; 376: 1658-1669. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21067805

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