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Considerations for the Cost-Effective Management of Hepatic Encephalopathy
Steven L. Flamm, MD

Considerations for the Cost-Effective Management of Hepatic Encephalopathy

Steven L. Flamm, MD
The AEs associated with treatment may impact adherence rates. Gastrointestinal AEs are common among patients taking lactulose and include bloating, abdominal pain, diarrhea, flatulence, cramping, nausea, and anorexia.7,15 Additionally, the dosing schedule can be complex and may affect treatment adherence. Lactulose is prescribed at a dose intended to achieve 2 to 3 bowel movements per day, but self-titration following discharge may be necessary to achieve the appropriate frequency.7,18 Self-titration can be unclear and difficult for patients and they have trouble with the self-titration process. Adherence of patients to self-titration with lactulose was evaluated and analyzed relative to the time since the index episode. Patients were more adherent immediately following their first bout of HE and became less adherent over time, as indicated by a lack of self-titration to achieve 2 to 3 bowel movements per day. These data highlight the complexity of self-titrating lactulose and managing AEs.18

Cost Considerations for the Management of HE

The economic burden of HE is substantial and is expected to increase given the rising direct costs of hospitalizations, outpatient care, and HE treatment in the United States. Reducing the rate of HE-related hospitalizations is an important measure which has the ability to reduce total cost of HE management. Additionally, the indirect costs of lost working time and productivity also contribute to the financial burden of this disease.

HE is the most common cause of readmission in patients with cirrhosis and is a driver of 30-day and 90-day readmission risks. In an analysis of payer administrative datasets from the Healthcare Cost and Utilization Project for 6 states in the United States, patients with index hospital admissions for cirrhosis (N = 119,722) were analyzed for readmission rates and cause of readmission. The presence of HE in these patients was most strongly associated with readmission within 30 and 90 days compared with any other cirrhotic complication, infection, or renal injury (unadjusted OR, 1.64; 95% CI, 1.56-1.72). Readmissions rates for HE were 18.1% for 30-day readmissions and 28.8% for 90-day readmissions.44  Additionally, of patients without HE at index hospitalization (N = 13,679), 9.7% were readmitted within 30 days with HE as an active complication. In 43.6% of the patients readmitted, HE was the primary billing diagnosis, indicating the large economic burden associated with HE in repeat hospitalizations.44  

In a study of 2075 patients with index cirrhosis-related hospital admissions to a community hospital and 2 regional hospitals over nearly 3 years, 655 patients were readmitted within 30 days of hospitalization. This translated to an overall readmission rate of 32%, and HE-related readmissions within 30 days of hospitalization accounted for 13.6% of all readmissions. Of the 157 readmissions within 30 days to the community hospital, the most common readmission was for HE without obvious infection and ascites or its complications in 29.5% of patients.45  HE was the primary reason for  30-day readmission in 8.6% of the 498 patients readmitted to regional hospitals. In an analysis of hospital readmission costs in this study population with cirrhosis, patients who were not readmitted following index hospitalization had posthospitalization outpatient costs totaling $5719 per patient. The population of patients readmitted within 30 days of hospitalization had the highest overall postindex costs (including outpatient and hospitalization costs following index hospitalization) of $73,252 per patient compared with $62,053 per patient for those readmitted after 30 days following the index hospitalization.45

Reducing the risk of early hospital readmissions is important to the cost-effective management of HE. As up to 40% of hospital readmissions for HE are preventable with appropriate lactulose and rifaximin combination treatment,41 the burden of hospitalization rates in this population can be improved with effective management.46 The potential cost savings of rifaximin prophylaxis in the prevention of repeat hospitalizations for patients with HE can be estimated by extrapolating data on hospitalization outcomes from the phase 3 trial presented earlier (Figure 1).25 As stated previously, an estimated 85.2% of the US population with HE, or 98,673 Americans, were hospitalized with major or extreme disease severity in 2009. Assuming that all patients with major or extreme HE graded disease severity were treated with rifaximin in 2009, hospitalization readmissions within 6 months would occur in 13,420 patients for a repeat OHE episode (13.6%).25  If all patients were not treated with rifaximin, hospitalization would occur in 22,300 patients (22.6%) within 6 months. As discussed, the average inpatient hospitalization cost associated with HE was estimated at $17,812 per patient in 2009. With rifaximin treatment, there would be an estimated decrease of 8880 hospitalizations, which translates to approximately $158 million saved on hospital readmission for HE in 6 months compared with no rifaximin treatment.1,25

Quality improvement programs are designed to reduce readmission risk and offer more effective treatment to patients with HE. Lower 30-day readmission risk for HE was demonstrated when implementing a quality improvement program using electronic decision support (default ordering of treatments at the point of care) for clinicians for improved uptake of higher dose and frequency of lactulose and routine use of rifaximin for OHE.44,46 Implementing quality improvement programs also requires business planning for costs and cost effectiveness of an intervention, including competitive analysis with available alternatives.46

Cost-effective analysis of agents used in the management of HE was conducted using a model developed from the perspective of a third-party payer in the United States. This model was designed to account for direct costs of medications and hospitalization as well as indirect costs, cirrhosis-related costs (eg, ascites, liver transplantation, outpatient care), and nonmedication costs (eg, doctor visits, laboratory tests). The model assumed that the population was for patients with 50% subclinical HE and 50% OHE. The following 6 treatment strategies were considered in the model for patients naïve to treatment for HE: no treatment, lactulose monotherapy, lactitol monotherapy, neomycin monotherapy, rifaximin monotherapy, and lactulose with crossover to rifaximin if the patient could not tolerate lactulose or had poor response (rifaximin salvage).47 Of the 6 treatment options, lactulose monotherapy and rifaximin salvage therapy were most balanced in outcomes; these treatments were less expensive and more effective. Although lactulose monotherapy was the least expensive treatment, with $56,967 in the total lifetime combined cost of care, rifaximin salvage was the most effective treatment option, with 6.9 life-years and 5.3 quality-adjusted life-years gained from treatment.47

In a retrospective review of 39 patients with HE treated with lactulose or rifaximin from January 2004 to November 2005, secondary prophylaxis with rifaximin reduced the number of hospitalizations and length of hospital stays in patients with previous OHE compared with lactulose treatment.5,26 Reduced rates of hospitalization and emergency department (ED) visits from rifaximin treatment were related to lower overall total cost of therapy compared with lactulose. Aggregating the costs of hospitalizations, ED visits, and drug costs, the mean total cost of therapy for patients treated with lactulose was $13,285 per patient compared with $9958 per patient treated with rifaximin. Treatment with rifaximin resulted in a mean cost difference per patient of $3327 compared with lactulose.5 Using data extrapolated from this study, if all 39 patients enrolled selected rifaximin treatment over lactulose, this group would have total savings of nearly $170,000 per year (Figure 3).5

Indirect costs, such as physician office visits and drug compliance, were not analyzed in this study. These excluded indirect costs suggest that rifaximin may offer potentially greater cost savings than calculated in this analysis.5 This study utilized charges associated with the 200-mg formulation of rifaximin in the cost of therapy assessments, where the drug cost of rifaximin is more expensive than the drug cost of lactulose ($662 vs $50, respectively).5   Notably, when directly comparing mg-to-mg costs, the 550-mg formulation of rifaximin is less expensive than the 200-mg formulation. As this 550-mg formulation was not accounted for in the analysis, rifaximin has the potential to offer savings additional to those demonstrated in this study.

In a study of 145 patients who received at least 6 months of lactulose followed by at least 6 months of rifaximin, HE treatment cost outcomes from the lactulose and rifaximin treatment periods were compared. Compared with the rifaximin treatment period, hospital charges exceeded $42,000 more per patient during the lactulose period ($56,635 vs $14,222). This difference in cost was likely attributed to fewer incidences of hospitalizations and shorter lengths of hospital stay.27


Cost-effective management of HE is essential, as the combined direct and indirect medical costs of this condition represent a large economic burden for individuals, healthcare systems, and society. Additionally, OHE is often recurrent, and each episode contributes to the overall burden of this disease. Although CHE does not typically require hospitalization, patients living with this condition may still experience associated quality-of-life reductions caused by neurocognitive and physical decline. Regarding the economic burden of medications, studies have shown that rifaximin in combination with lactulose may be a cost-effective treatment option that reduces hospitalizations and improves adherence to maintenance therapy.

According to the 2014 AASLD/EASL practice guidelines for HE in chronic liver disease, rifaximin is recommended as an effective add-on therapy for the prevention of recurrence of OHE is patients treated with lactulose. Alternative options include PEG and antibiotics such as neomycin, metronidazole, and vancomycin. While these agents have been historically used for HE treatment, they have fallen out of favor due to limited recent studies and a relatively poor risk–benefit profile. At present, rifaximin therapy appears to offer greater potential efficacy, safety, and cost benefits when compared with lactulose through its associated reduction in hospitalizations, enhanced patient quality of life, and improved adherence attributable to a favorable AE profile.

Author affiliations: Northwestern University, Feinberg School of Medicine, Chicago, IL.
Funding source: This publication was sponsored by Salix Pharmaceuticals.
Author disclosures: Steven L. Flamm MD, reports serving as a consultant or advisory board member for and receiving lecture fees from Salix Pharmaceuticals.
Authorship information:  Concept and design; analysis and interpretation of data; and critical revision of the manuscript for important intellectual content.
Address correspondence to: E-mail:
1. Stepanova M, Mishra A, Venkatesan C, Younossi DM. In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol. 2012;10(9):1034-1041.e1. doi: 10.1016/j.cgh.2012.05.016.
2. Scaglione S, Kliethermes S, Cao G, et al. The epidemiology of cirrhosis in the United States: a population-based study. J Clin Gastroenterol. 2015;49(8):690-696. doi: 10.1097/MCG.0000000000000208.
3. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by AASLD and EASL. American Association for the Study of Liver Diseases website. Published 2014. Accessed December 18, 2017.
4. Romero-Gómez M, Boza F, García-Valdecasas MS, García E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol. 2001;96(9):2718-2723. doi: 10.1111/j.1572-0241.2001.04130.x.
5. Neff G. Pharmacoeconomics of hepatic encephalopathy. Pharmacotherapy. 2010;30(5 Pt 2):28S-32S. doi: 10.1592/phco.30.pt2.28S.
6. Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management of hepatic encephalopathy in the hospital. Mayo Clin Proc. 2014;89(2):241-253. doi: 10.1016/j.mayocp.2013.11.009.
7. Suraweera D, Sundaram V, Saab S. Evaluation and management of hepatic encephalopathy: current status and future directions. Gut Liver. 2016;10(4):509-519. doi: 10.5009/gnl15419.
8. Rathi S, Dhiman RK. Managing encephalopathy in the outpatient setting. Clin Liver Dis. 2016;8(6):150-155. doi: 10.1002/cld.590.
9. Bismuth M, Funakoshi N, Cadranel JF, Blanc P. Hepatic encephalopathy: from pathophysiology to therapeutic management. Eur J Gastroenterol Hepatol. 2011;23(1):8-22. doi: 10.1097/MEG.0b013e3283417567.
10. NeSmith M, Ahn J, Flamm SL. Contemporary understanding and management of overt and covert hepatic encephalopathy. Gastroenterol Hepatol (N Y). 2016;12(2):91-100.
11. Stewart CA, Malinchoc M, Kim WR, Kamath PS. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl. 2007;13(10):1366-1371. doi: 10.1002/lt.21129.
12. Wong RJ, Aguilar M, Gish RG, Cheung R, Ahmed A. The impact of pretransplant hepatic encephalopathy on survival following liver transplantation. Liver Transpl. 2015;21(7):873-880. doi: 10.1002/lt.24153.
13. Patidar KR, Thacker LR, Wade JB, et al. Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization. Am J Gastroenterol. 2014;109(11):1757-1763. doi: 10.1038/ajg.2014.264.
14. Lactulose [prescribing information]. Amityville, NY: Hi-Tech Pharmacal Co, Inc; 2017.
15. Elwir S, Rahimi RS. Hepatic encephalopathy: an update on the pathophysiology and therapeutic options. J Clin Transl Hepatol. 2017;5(2):142-151. doi: 10.14218/JCTH.2016.00069.
16. Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2016;4:CD003044. doi: 10.1002/14651858.CD003044.pub3.
17. Luo M, Li L, Lu CZ, Cao WK. Clinical efficacy and safety of lactulose for minimal hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol. 2011;23(12):1250-1257. doi: 10.1097/MEG.0b013e32834d1938.
18. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther. 2010;31(9):1012-1017. doi: 10.1111/j.1365-2036.2010.04257.x.
19. Polyethylene glycol 3350 [prescribing information]. Braintree, MA: Braintree Laboratories, Inc; 2013.
20. Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vs polyethylene glycol 3350—electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial. JAMA Intern Med. 2014;174(11):1727-1733. doi: 10.1001/jamainternmed.2014.4746.
21. Conn HO, Leevy CM, Vlahcevic CR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. a double blind controlled trial. Gastroenterology. 1977;72(4 Pt 1):573-583.
22. Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis. 2013;28(2):307-312. doi: 10.1007/s11011-013-9383-5.
23. Tarao K, Ikeda T, Hayashi K, et al. Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut. 1990;31(6):702-706. doi: 10.1136/gut.31.6.702.
24. Rifaximin [prescribing information]. Morrisville, NC: Salix Pharmaceuticals, Inc; 2015.
25. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071-1081. doi: 10.1056/NEJMoa0907893.
26. Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplantat Proc. 2006;38(10):3552-3555. doi: 10.1016/j.transproceed.2006.10.107.
27. Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci. 2007;52(3):737-741. doi: 10.1007/s10620-006-9442-4.
28. Mullen KD, Sanyal AJ, Bass NM, et al. Rifaximin is safe and well tolerated for long-term maintenance of remission from overt hepatic encephalopathy. Clin Gastroenterol Hepatol. 2014;12(8):1390-1397.e2. doi: 10.1016/j.cgh.2013.12.021.
29. Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol. 2012;18(8):767-777. doi: 10.3748/wjg.v18.i8.767.
30. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458-1463. doi: 10.1038/ajg.2013.219.
31. Nguyen DL, Morgan T. Protein restriction in hepatic encephalopathy is appropriate for selected patients: a point of view. Hepatol Int. 2014;8(2):447-451. doi: 10.1007/s12072-013-9497-1.
32. Al Sibae MR, McGuire BM. Current trends in the treatment of hepatic encephalopathy. Ther Clin Risk Manag. 2009;5(3):617-626. doi: 10.2147/TCRM.S4443. 
33. ExeGi Pharma. Visbiome Clinical Experience: Adult. Visbiome website.
34. Ong JP, Aggarwal A, Krieger D, et al. Correlation between ammonia levels and the severity of hepatic encephalopathy. Am J Med. 2003;114(3):188-193. doi: 10.1016/S0002-9343(02)01477-8.
35. Aldridge DR, Tranah EJ, Shawcross DL. Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. J Clin Exp Hepatol. 2015;5(suppl 1):S7-S20. doi: 10.1016/j.jceh.2014.06.004.
36. Bajaj JS, Wade JB, Gibson DP, et al. The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Am J Gastroenterol. 2011;106(9):1646-1653. doi: 10.1038/ajg.2011.157.
37. Groeneweg M, Moerland W, Quero JC, Hop WC, Krabbe PF, Schalm SW. Screening of subclinical hepatic encephalopathy. J Hepatol. 2000;32(5):748-753.
38. Poordad FF. Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther. 2007;25(suppl 1):3-9. doi: 10.1111/j.1746-6342.2006.03215.x.
39. Moscucci F, Nardelli S, Pentassuglio I, et al. Previous overt hepatic encephalopathy rather than minimal hepatic encephalopathy impairs health-related quality of life in cirrhotic patients. Liver Int. 2011;31(10):1505-1510. doi: 10.1111/j.1478-3231.2011.02598.x
40. Volk ML, Tocco RS, Bazick J, Rakoski MO, Lok AS. Hospital readmissions among patients with decompensated cirrhosis. Am J Gastroenterol. 2012;107(2):247-252. doi: 10.1038/ajg.2011.314.
41. Bass NM, Feagan B. Emerging issues in gastroenterology and hepatology. Gastroenterol Hepatol (N Y). 2009;5(8 Suppl 17):3-20.
42. Neff G. Factors affecting compliance and persistence with treatment for hepatic encephalopathy. Pharmacotherapy. 2010;30(5):22S-27S. doi: 10.1592/phco.30.pt2.22S.
43. Bajaj JS, Heuman DM, Wade JB, et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology. 2011;140(2):478-487.e1. doi: 10.1053/j.gastro.2010.08.061.
44. Tapper EB, Halbert B, Mellinger J. Rates of and reasons for hospital readmissions in patients with cirrhosis: a multistate population-based cohort study. Clin Gastroenterol Hepatol. 2016;14(8):1181-1188.e2. doi: 10.1016/j.cgh.2016.04.009.
45. Chirapongsathorn S, Krittanawong C, Enders FT, et al. Incidence and cost analysis of hospital admission and 30-day readmission among patients with cirrhosis [published online January 18, 2018]. Hepatol Commun. doi: 10.1002/hep4.1137. 
46. Tapper EB, Finkelstein D, Mittleman MA, Piatkowski G, Chang M, Lai M. A quality improvement initiative reduced 30-day rate of readmission for patients with cirrhosis. Clin Gastroenterol Hepatol. 2016;14(5):753-759.doi: 10.1016/j.cgh.2015.08.041.
47. Huang E, Esrailian E, Spiegel BM. The cost-effectiveness and budget impact of competing therapies in hepatic encephalopathy—a decision analysis. Aliment Pharmacol Ther. 2007;26(8):1147-1161. doi: 10.1111/j.1365-2036.2007.03464.x.

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