Efficacy and Safety of Rifaximin Versus Placebo or Other Active Drugs in Critical ill Patients With Hepatic Encephalopathy

Xianghui Han, Zhanyang Luo, Wenyi Wang, Peiyong Zheng, Tian Li, Zubing Mei, Jianyi Wang, Xianghui Han, Zhanyang Luo, Wenyi Wang, Peiyong Zheng, Tian Li, Zubing Mei, Jianyi Wang

Abstract

Objective: Rifaximin has been approved for use as a first-line therapy for secondary prophylaxis of hepatic encephalopathy (HE). This article is to update existing evidence on efficacy and safety of rifaximin treatment and prevention for HE. Methods: We systematically searched multiple databases until January 31 2021. The studies compared rifaximin vs. placebo or other active drugs (i.e., nonabsorbable disaccharides, other antibiotics, L-ornithine-L-aspartate (LOLA), and probiotics) for patients with overt HE (OHE), minimal HE (MHE), and recurrent HE. Results: Twenty-eight randomized controlled trials with a total of 2979 patients were included. Compared with the controls, rifaximin significantly reduced HE grade (OHE: RR = 1.11, 95% CI = 1.02-1.21), improved the cognitive impairments (MHE: RR = 1.82, 95% CI = 1.12-2.93) and prevented the risk of HE recurrent episodes (RR = 1.33, 95% CI = 1.18-1.49). No statistical difference was observed in mortality between rifaximin and their controls (RR = 0.82, 95% CI = 0.54-1.24). The incidence of total adverse events in rifaximin-treated groups was significantly lower than that in the controls during the treatment period (RR = 0.73, 95% CI = 0.54-0.98). In addition, rifaximin treatment was better than other active drugs in improving psychometric indicators (mental state, flapping tremor and portosystemic encephalopathy (PSE) index) and reducing the risk of rehospitalization in HE patients. Conclusion: Rifaximin therapy is effective and well-tolerated in different types of HE, which might be recommended as an alternative to conventional oral drugs in clinical settings.

Keywords: efficacy; hepatic encephalopathy; meta-analysis; rifaximin; safety.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Han, Luo, Wang, Zheng, Li, Mei and Wang.

Figures

FIGURE 1
FIGURE 1
Flowchart of study screen in this meta-analysis.
FIGURE 2
FIGURE 2
Risk of bias graph: reviewers’ judgments about each risk of bias item presented as percentages across all included studies (A). Risk of bias summary: reviewers’ judgments about each risk of bias item for each included study according to the Cochrane Collaboration’s “Risk of Bias” tool, the green circle with “plus” sign representing low risk of bias, the yellow circle with “question mark” sign representing unclear risk of bias and the red circle with “minus” sign representing high risk of bias (B).
FIGURE 3
FIGURE 3
Funnel plots evaluating publication bias for different outcomes: (A) OHE improvement, (B) prevention of recurrent HE, (C) blood ammonia level, (D) mortality, (E) total adverse events, (F) abdominal pain, and (G) diarrhea.
FIGURE 4
FIGURE 4
Forest plot of randomized controlled trials on rifaximin vs. placebo or other active drugs on the OHE improvement (A), MHE reversal (B), and prevention of recurrent HE (C).
FIGURE 5
FIGURE 5
Forest plot of randomized controlled trials on rifaximin treatment for HE. The outcome measure was mortality. The control groups received placebo or other active drugs.
FIGURE 6
FIGURE 6
Forest plot of randomized controlled trials on the safety of rifaximin treatment for HE. The outcome measures included total adverse events, abdominal pain, diarrhea, nausea, vomiting and fatigue. The control groups received placebo or other active drugs. (A) Total adverse events; (B) Abdominal pain; (C) Diarrhea; (D) Nausea; (E) Vomiting; (F) Fatigue.

References

    1. Al Sibae M. R., McGuire B. M. (2009). Current Trends in the Treatment of Hepatic Encephalopathy. Ther. Clin. Risk Manag. 5 (3), 617–626. 10.2147/tcrm.s4443
    1. American Association for the Study of Liver D. (2014). Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J. Hepatol. 61 (3), 642–659. 10.1016/j.jhep.2014.05.042
    1. Aqeel A. R., Butt B., Naveed H., Arshad A. (2018). A Randomized Triple Blind, Placebo-Controlled Trial to Determine Effectiveness of Rifaximin in Preventing Hepatic Encephalopathy in Patients with Chronic Liver Disease. Indo Am. J. Pharm. Sci. 5 (4), 2728–2732.
    1. Bajaj J. S., Heuman D. M., Wade J. B., Gibson D. P., Saeian K., Wegelin J. A., et al. (2011). Rifaximin Improves Driving Simulator Performance in a Randomized Trial of Patients with Minimal Hepatic Encephalopathy. Gastroenterology 140 (2), 478–e1. 10.1053/j.gastro.2010.08.061
    1. Bass N. M., Mullen K. D., Sanyal A., Poordad F., Neff G., Leevy C. B., et al. (2010). Rifaximin Treatment in Hepatic Encephalopathy. N. Engl. J. Med. 362 (12), 1071–1081. 10.1056/NEJMoa0907893
    1. Bucci L., Palmieri G. C. (1993). Double-blind, Double-Dummy Comparison between Treatment with Rifaximin and Lactulose in Patients with Medium to Severe Degree Hepatic Encephalopathy. Curr. Med. Res. Opin. 13 (2), 109–118. 10.1185/03007999309111539
    1. Cai X. J., Wang L., Hu C. M. (2018). Efficacy of Different Drugs in the Treatment of Minimal Hepatic Encephalopathy: A Network Meta-Analysis Involving 826 Patients Based on 10 Randomized Controlled Trials. J. Cel Biochem 119 (10), 8336–8345. 10.1002/jcb.26886
    1. Conn H. O., Leevy C. M., Vlahcevic Z. R., Rodgers J. B., Maddrey W. C., Seeff L., et al. (1977). Comparison of Lactulose and Neomycin in the Treatment of Chronic portal-systemic Encephalopathy. A Double Blind Controlled Trial. Gastroenterology 72 (4 Pt 1), 573–583. 10.1016/s0016-5085(77)80135-2
    1. Dhiman R. K., Thumburu K. K., Verma N., Chopra M., Rathi S., Dutta U., et al. (2020). Comparative Efficacy of Treatment Options for Minimal Hepatic Encephalopathy: A Systematic Review and Network Meta-Analysis. Clin. Gastroenterol. Hepatol. 18 (4), 800–e25. 10.1016/j.cgh.2019.08.047
    1. Eltawil K. M., Laryea M., Peltekian K., Molinari M. (2012). Rifaximin vs. Conventional Oral Therapy for Hepatic Encephalopathy: a Meta-Analysis. World J. Gastroenterol. 18 (8), 767–777. 10.3748/wjg.v18.i8.767
    1. Fera G., Agostinacchio F., Nigro M., Schiraldi O., Ferrieri A. (1993). Rifaximin in the Treatment of Hepatic Encephalopathy. Eur. J. Clin. Res. 4 (1), 57–66.
    1. Ferenci P. (2017). Hepatic Encephalopathy. Gastroenterol. Rep. (Oxf) 5 (2), 138–147. 10.1093/gastro/gox013
    1. Festi D., Mazzella G., Orsini M., Sottili S., Sangermano A., Li Bassi S., et al. (1993). Rifaximin in the Treatment of Chronic Hepatic Encephalopathy; Results of a Multicenter Study of Efficacy and Safety. Curr. Ther. Res. 54, 598–609. 10.1016/s0011-393x(05)80681-2
    1. Flamm S. L., Mullen K. D., Heimanson Z., Sanyal A. J. (2018). Rifaximin Has the Potential to Prevent Complications of Cirrhosis. Therap Adv. Gastroenterol. 11, 1756284818800307. 10.1177/1756284818800307
    1. Guyatt G. H., Oxman A. D., Vist G. E., Kunz R., Falck-Ytter Y., Alonso-Coello P., et al. (2008). GRADE: an Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations. Bmj 336 (7650), 924–926. 10.1136/bmj.39489.470347
    1. Higgins J., Greeni S. (2011). Cochrane Handbook for Systematic Reviews of Interventions. version 5.1.0 [updated March 2011]. Oxford, United Kingdom: The Cochrane collaboration. .
    1. Higuera de la Tijera F., Servín-Caamaño A. I., Salas-Gordillo F., Pérez-Hernández J. L., Abdo-Francis J. M., Camacho-Aguilera J., et al. (2018). Primary Prophylaxis to Prevent the Development of Hepatic Encephalopathy in Cirrhotic Patients with Acute Variceal Bleeding. Can. J. Gastroenterol. Hepatol. 2018, 3015891–3015910. 10.1155/2018/3015891
    1. Hu W., Tang S. H. (2013). Rifaximin in the Treatment of Chronic Hepatic Encephalopathy: a Meta-Analysis. Chin. Hosp. Pharm. J. 33 (17), 1444–1449.
    1. Jiang Q., Jiang X. H., Zheng M. H., Jiang L. M., Chen Y. P., Wang L. (2008). Rifaximin versus Nonabsorbable Disaccharides in the Management of Hepatic Encephalopathy: a Meta-Analysis. Eur. J. Gastroenterol. Hepatol. 20 (11), 1064–1070. 10.1097/MEG.0b013e328302f470
    1. Song K., Lee K., Kim M., Paik Y., Moon B., Yoon S., et al. (2000). “The Clinical Efficacy of Rifaximin in the Treatment or Hepatic Encephalopathy (Comparison with Lactulose). Hepatology.
    1. Kimer N., Krag A., Møller S., Bendtsen F., Gluud L. L. (2014). Systematic Review with Meta-Analysis: the Effects of Rifaximin in Hepatic Encephalopathy. Aliment. Pharmacol. Ther. 40 (2), 123–132. 10.1111/apt.12803
    1. Li T., Providencia R., Mu N., Yin Y., Chen M., Wang Y., et al. (2021). Association of Metformin Monotherapy or Combined Therapy with Cardiovascular Risks in Patients with Type 2 Diabetes Mellitus. Cardiovasc. Diabetol. 20 (1), 30. 10.1186/s12933-020-01202-5
    1. Loguercio C., Federico A., De Girolamo V., Ferrieri A., Del Vecchio Blanco C. (2003). Cyclic Treatment of Chronic Hepatic Encephalopathy with Rifaximin. Results of a Double-Blind Clinical Study. Minerva Gastroenterol. Dietol 49, 53–62.
    1. Mas A., Rodés J., Sunyer L., Rodrigo L., Planas R., Vargas V., et al. (2003). Comparison of Rifaximin and Lactitol in the Treatment of Acute Hepatic Encephalopathy: Results of a Randomized, Double-Blind, Double-Dummy, Controlled Clinical Trial. J. Hepatol. 38 (1), 51–58. 10.1016/s0168-8278(02)00350-1
    1. Massa P., Vallerino E., Dodero M. (1993). Treatment of Hepatic Encephalopathy with Rifaximin: Double Blind, Double Dummy Study versus Lactulose. Eur. J. Clin. Res. 4 (1), 7–18.
    1. Mekky M. A., Riad A. R., Gaber M. A., Abdel-Malek M. O., Swifee Y. M. (2018). Rifaximin versus Metronidazole in Management of Acute Episode of Hepatic Encephalopathy: An Open Labeled Randomized Clinical Trial. Arab J. Gastroenterol. 19 (2), 76–79. 10.1016/j.ajg.2018.06.001
    1. Miglio F., Valpiani D., Rossellini S. R., Ferrieri A. (1997). Rifaximin, a Non-absorbable Rifamycin, for the Treatment of Hepatic Encephalopathy. A Double-Blind, Randomised Trial. Curr. Med. Res. Opin. 13 (10), 593–601. 10.1185/03007999709113333
    1. Moher D., Liberati A., Tetzlaff J., Altman D. G. (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement. Bmj 339 (jul21 1), b2535–b. 10.1136/bmj.b2535
    1. Munir F., Waseem M., Mazhar M. U. (2018). Study to Know the Rifaximin Efficacy in Hepatic Encephalopathy Prevention in Cirrhosis of Liver. Indo American J. Pharma. Sci. 5 (6), 5675–5680.
    1. Neff G. W., Barrett A. C., Bortey E., Paterson C., Forbes W. P. (2013). Su1300 Efficacy and Tolerability of Rifaximin in Hepatitis C Patients with Recurrent Hepatic Encephalopathy. Gastroenterology 144 (5), S–451. 10.1016/s0016-5085(13)61667-4
    1. Paik Y. H., Lee K. S., Han K. H., Song K. H., Kim M. H., Moon B. S., et al. (2005). Comparison of Rifaximin and Lactulose for the Treatment of Hepatic Encephalopathy: a Prospective Randomized Study. Yonsei Med. J. 46 (3), 399–407. 10.3349/ymj.2005.46.3.399
    1. Parini P., Cipolla A., Ronchi M., Salzetta A., Mazzella G., Roda E. (1992). Effect of Rifaximin and Paromomycin in the Treatment of portal-systemic Encephalopathy. Curr. Ther. Res. 52 (1), 34–39. 10.1016/S0011-393X(05)80433-3
    1. Pedretti G., Calzetti C., Missale G., Fiaccadori F. (1992). Rifaximin versus Neomycin on Hyperammoniemia in Chronic portal Systemic Encephalopathy of Cirrhotics. A Double-Blind, Randomized Trial. Ital. J. Gastroenterol. 23, 175–178.
    1. Ridola L., Cardinale V., Riggio O. (2018). The burden of Minimal Hepatic Encephalopathy: from Diagnosis to Therapeutic Strategies. Ann. Gastroenterol. 31 (2), 151–164. 10.20524/aog.2018.0232
    1. Riggio O., Masini A., Efrati C., Nicolao F., Angeloni S., Salvatori F. M., et al. (2005). Pharmacological Prophylaxis of Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt: a Randomized Controlled Study. J. Hepatol. 42 (5), 674–679. 10.1016/j.jhep.2004.12.028
    1. Romero-Gómez M., Córdoba J., Jover R., del Olmo J. A., Ramírez M., Rey R., et al. (2007). Value of the Critical Flicker Frequency in Patients with Minimal Hepatic Encephalopathy. Hepatology 45 (4), 879–885. 10.1002/hep.21586
    1. Sanyal A., Younossi Z. M., Bass N. M., Mullen K. D., Poordad F., Brown R. S., et al. (2011). Randomised Clinical Trial: Rifaximin Improves Health-Related Quality of Life in Cirrhotic Patients with Hepatic Encephalopathy - a Double-Blind Placebo-Controlled Study. Aliment. Pharmacol. Ther. 34 (8), 853–861. 10.1111/j.1365-2036.2011.04808.x
    1. Sarwar S., Muhyuddin B., Aleem A., Nadeem M. A. (2019). Primary Prophylaxis of Hepatic Encephalopathy in Decompensated Cirrhosis: Low Dose vs. Full Dose Rifaximin. Pak J. Med. Sci. 35 (5), 1446–1450. 10.12669/pjms.35.5.549
    1. Scarpignato C., Pelosini I. (2005). Rifaximin, a Poorly Absorbed Antibiotic: Pharmacology and Clinical Potential. Chemotherapy 51 (Suppl. 1), 36–66. 10.1159/000081990
    1. Sharma K., Pant S., Misra S., Dwivedi M., Misra A., Narang S., et al. (2014). Effect of Rifaximin, Probiotics, and L-Ornithine L-Aspartate on Minimal Hepatic Encephalopathy: a Randomized Controlled Trial. Saudi J. Gastroenterol. 20 (4), 225–232. 10.4103/1319-3767.136975
    1. Sidhu S. S., Goyal O., Mishra B. P., Sood A., Chhina R. S., Soni R. K. (2011). Rifaximin Improves Psychometric Performance and Health-Related Quality of Life in Patients with Minimal Hepatic Encephalopathy (The RIME Trial). Am. J. Gastroenterol. 106 (2), 307–316. 10.1038/ajg.2010.455
    1. Sidhu S. S., Goyal O., Parker R. A., Kishore H., Sood A. (2016). Rifaximin vs. Lactulose in Treatment of Minimal Hepatic Encephalopathy. Liver Int. 36 (3), 378–385. 10.1111/liv.12921
    1. Suzuki K., Endo R., Takikawa Y., Moriyasu F., Aoyagi Y., Moriwaki H., et al. (2018). Efficacy and Safety of Rifaximin in Japanese Patients with Hepatic Encephalopathy: A Phase II/III, Multicenter, Randomized, Evaluator-Blinded, Active-Controlled Trial and a Phase III, Multicenter, Open Trial. Hepatol. Res. 48 (6), 411–423. 10.1111/hepr.13045
    1. Tapper E. B., Halbert B., Mellinger J. (2016). Rates of and Reasons for Hospital Readmissions in Patients with Cirrhosis: A Multistate Population-Based Cohort Study. Clin. Gastroenterol. Hepatol. 14 (8), 1181–e2. 10.1016/j.cgh.2016.04.009
    1. Wahib A. A., El-Deen Salem M. N., Ahmed M. A., El-Dessouky Y. M., El-Tiby D. M., El-Mola K., et al. (2014). Evaluation of Rifaximin in Management of Hepatic Encephalopathy. J. Egypt. Soc. Parasitol. 44 (3), 677–685. 10.12816/0007871
    1. Wang F., Song M., Lu X., Zhu X., Deng J. (2021). Gut Microbes in Gastrointestinal Cancers. Semin. Cancer Biol. S1044-579X, 00098–105. 10.1016/j.semcancer.2021.03.037
    1. Wang Y. F. (2015). Rifaximin Prevents Recurrence of Hepatic Encephalopathy: a Meta-Analysis. Chin. J. Gastroenterol. Hepatol. 24 (9), 1133–1136.
    1. Weissenborn K., Bokemeyer M., Krause J., Ennen J., Ahl B. (2005). Neurological and Neuropsychiatric Syndromes Associated with Liver Disease. Aids 19 (Suppl. 3), S93–S98. 10.1097/01.aids.0000192076.03443.6d
    1. Wu D., Wu S. M., Lu J., Zhou Y. Q., Xu L., Guo C. Y. (2013). Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-Analysis. Gastroenterol. Res. Pract. 2013, 236963. 10.1155/2013/236963
    1. Yang G. (2013). Observation of Rifaximin for Treatment of Hepatic Encephalopathy. Int. J. Dig. Dis. 33 (2), 139–141.
    1. Zhang F., Liu L., Zhang C., Ji S., Mei Z., Li T. (2021). Association of Metabolic Syndrome and its Components with Risk of Stroke Recurrence and Mortality: A Meta-Analysis. Neurology 97 (7), e695–e705. 10.1212/WNL.0000000000012415
    1. Zhang F., Wang K., Du P., Yang W., He Y., Li T., et al. (2021). Risk of Stroke in Cancer Survivors: A Meta-Analysis of Population-Based Cohort Studies. Neurology 96 (4), e513–e26. 10.1212/WNL.0000000000011264
    1. Zhu G. Q., Shi K. Q., Huang S., Wang L. R., Lin Y. Q., Huang G. Q., et al. (2015). Systematic Review with Network Meta-Analysis: the Comparative Effectiveness and Safety of Interventions in Patients with Overt Hepatic Encephalopathy. Aliment. Pharmacol. Ther. 41 (7), 624–635. 10.1111/apt.13122
    1. Zhuo G. Y., Xiang T., Zhang P. Y., Zhang X. D., Luo L., Zhang J. M., et al. (2019). Effects of Rifaximin versus Nonabsorbable Disaccharides in Hepatic Encephalopathy. GastroHep 1 (1), 22–32. 10.1002/ygh2.207

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