Effectiveness of Adjunctive Drug Therapy to Endoscopic Stenting in Liver Cirrhosis Complicated by Refractory Variceal Bleeding

AIM OF THE STUDY. Comparative clinical analysis of the efficacy of terlipressin and octreotide as additional drug therapy to mechanical hemostasis with nitinol stent in patients with liver cirrhosis complicated by bleeding from esophageal varices refractory to endoscopic treatment.

MATERIAL AND METHODS. Thirty-one patients with liver cirrhosis complicated by esophageal variceal bleeding refractory to endoscopic treatment , in whose complex treatment program, as a first-line life­saving measure, hemostasis with a self-expanding hemostasis was performed nitinol stent were randomly assigned to two groups. In group A, 20 patients were treated with terlipressin as an adjuvant to mechanical hemostasis, and in group B, 11 patients were treated with octreotide. Unpaired Student’s t-test was used for statistical analysis of the results. Graphs for assessing the survival function of patients for 8 weeks after the end of treatment were constructed using the Kaplan-Meier method.

RESULTS. In the acute observation period terlipressin and octreotide were equally effective in treating refractory variceal bleeding. In the subacute observation period, the administration of octreotide was generally accompanied by a greater number of side effects (54.5%) than terlipressin (30.0%) (p=0.453). In the remote observation period, 8-week survival in the group of patients receiving terlipressin was higher than in the group of patients receiving octreotide.

CONCLUSION. Terlipressin is as effective as octreotide as an adjunct to endoscopic stenting in drug therapy for liver cirrhosis complicated by esophageal variceal bleeding refractory to endoscopic treatment. At the same time, terlipressin has a greater effect than octreotide on reducing 8-week mortality, which approaches statistical significance. In this regard, terlipressin may be the vasoactive drug of choice in acute refractory variceal bleeding.

1. Fortune BE, Garcia-Tsao G, Ciarleglio M, Deng Y, Fallon MB, Sigal S, et al. Vapreotide Study Group. Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study. J Clin Gastroenterol. 2017;51(5):446–453. PMID: 27779613 https://doi.org/10.1097/MCG.0000000000000733

2. Escorsell À, García-Pagán JC, Bosch J. Esophageal Stents for Acute Variceal Bleeding: Expanding the Possibilities. Dig Dis Sci. 2018;63(2):275–276. PMID: 29255994 https://doi.org/10.1007/s10620-017-4854-x

3. Garcia-Pagán JC, Di Pascoli M, Caca K, Laleman W, Bureau C, Appenrodt B, et al. Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study. J Hepatol. 2013;58(1):45–50. PMID: 22940408 https://doi.org/10.1016/j.jhep.2012.08.020

4. Shertsinger AG, Zhao AV, Ivashkin VT, Maevskaya MV, Pavlov ChS, Vertkin AL, et al. Treatment of Bleedings from Varicose Veins of the Esophagus and Stomach. Annals of HPB Surgery. 2013;18(3):110–129 (In Russ.).

5. de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743–752. PMID: 26047908 https://doi.org/10.1016/j.jhep.2015.05.022

6. Manukyan GV, Shertsinger AG, Zhigalova SB, Semenova TS, Martirosyan RA. Primary Prevention of Bleeding from Esophageal and Gastric Varices in Patients With Portal Hypertension. Annals of HPB Surgery. 2016;21(2):93–104. (In Russ.) https://doi.org/10.16931/1995-5464.2016293-104

7. de Mattos ÂZ, Terra C, Farias AQ, Bittencourt PL; Alliance of Brazilian Centers for Cirrhosis Care–the ABC Group. Primary prophylaxis of variceal bleeding in patients with cirrhosis: A comparison of different strategies. World J Gastrointest Endosc. 2021;13(12):628–637. PMID: 35070024 https://doi.org/10.4253/wjge.v13.i12.628

8. Zia HA, Aby ES, Rabiee A. An Update on the Management of Esophageal Variceal Hemorrhage. Clin Liver Dis (Hoboken). 2021;18(4):179–183. PMID: 34745574 https://doi.org/10.1002/cld.1108

9. Pedretti G, Elia G, Calzetti C, Magnani G, Fiaccadori F. Octreotide versus terlypressin in acute variceal hemorrhage in liver cirrhosis. Emergency control and prevention of early rebleeding. Clin Investig. 1994;72(9):653–659. PMID: 7849442 https://doi.org/10.1007/BF00212982

10. Eramishantsev AK, Shertsinger AG, Kitsenko EA. Portal’naya gipertenziya. In: Klinicheskaya khirurgiya. In 3 vol. Vol. 2. Moscow: GEOATR-Media Publ.; 2009:626–665.

11. De Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol. 2005;43(1):167–176. PMID: 15925423 https://doi.org/10.1016/j.jhep.2005.05.009

12. Rebrova OYu. Statisticheskiy analiz meditsinskikh dannykh: primenenie paketa prikladnykh programm STATISTICA. Moscow: Media Sfera Publ.; 2006.

13. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Statist Assoc. 1958;53(282):457–481. https://doi.org/10.2307/2281868

14. Anisimov AYu, Loginov AV, Ibragimov RA, Anisimov AA. Endoscopic Hemostasis With Self-Expanding Nitinol Stents (Literature Review). Annals of HPB Surgery. 2020;25(1):94–105. https://doi.org/10.16931/1995-5464.2020194-105

15. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022;76(4):959–974. PMID: 35120736 https://doi.org/10.1016/j.jhep.2022.03.024

16. 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. 2017;65(1):310–335. PMID: 27786365 https://doi.org/10.1002/hep.28906

17. Zhou X, Tripathi D, Song T, Shao L, Han B, Zhu J, et al. Terlipressin for the treatment of acute variceal bleeding: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018;97(48):e13437. PMID: 30508958 https://doi.org/10.1097/MD.0000000000013437

18. Ioannou GN, Doust J, Rockey DC. Systematic review: Terlipressin in acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther. 2003;17(1):53–64. PMID: 12492732 https://doi.org/10.1046/j.1365-2036.2003.01356.x

19. Dell’Era A, de Franchis R. Iannuzzi F. Acute variceal bleeding: Pharmacological treatment and primary/secondary prophylaxis. Best Pract Res Clin Gastroenterol. 2008;22(2):279–294. PMID: 18346684 https://doi.org/10.1016/j.bpg.2007.11.001

20. Wells M, Chande N, Adams P, Beaton M, Levstik M, Boyce E, et al. Meta-analysis: Vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther. 2012;35(11):1267–1278. PMID: 22486630 https://doi.org/10.1111/j.1365-2036.2012.05088.x

21. Seo YS, Park SY, Kim MY, Kim JH, Park JY, Yim HJ, et al. Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage. Hepatology. 2014;60(3):954–963. PMID: 24415445 https://doi.org/10.1002/hep.27006

22. Ioannou GN, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage. Cochrane Database Syst Rev. 2003;(1):CD002147. PMID: 12535432 https://doi.org/10.1002/14651858.CD002147

23. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W; Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922–938. PMID: 17879356 https://doi.org/10.1002/hep.21907

24. Jenkins SA, Baxter JN, Corbett WA, Shields R. The effects of somatostatin analogue SMS 201-995 on hepatic hemodynamics in the cirrhotic rat. Br J Surg. 1985;72(11):864–867. PMID: 2866012 https://doi.org/10.1002/bjs.1800721105

25. Christiansen J, Ottenjann R, Von Arx F. Placebo-controlled trial with the somatostatin analogue SMS 201-995 in peptic ulcer. Gastroenterology. 1989;97(3):568–574. PMID: 2666249 https://doi.org/10.1016/0016-5085(89)90626-4

26. Hung TH, Tsai CC, TsenK GC, Hsieh YH, Tseng CW. No mortality difference following treatment with terlipressin or somatostatin in cirrhotic patients with gastric variceal hemorrhage. Saudi J Gastroenterol. 2016;22(3):220–225. PMID: 27184641 https://doi.org/10.4103/1319-3767.182458