PharmacoEconomics (2018) 36:809–822 https://doi.org/10.1007/s40273-018-0641-6 SYSTEMATIC REVIEW Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic Impact of Rifaximin 1 2 Guy Neff Woodie Zachry III Published online: 12 April 2018 The Author(s) 2018, corrected publication [May 2018] Abstract favourable pharmacoeconomic proﬁle compared with lac- Background Hepatic encephalopathy (HE), a common tulose (based on the incremental cost-effectiveness ratio). neurologic complication in cirrhosis, is associated with Conclusions In addition to its clinical beneﬁts (e.g. substantial disease and economic burden. Rifaximin is a reduction in the risk of recurrence of overt HE, overt HE- non-systemic antibiotic that reduces the risk of overt HE related hospitalizations, favourable adverse event proﬁle), recurrence and overt HE-related hospitalizations. economic data are favourable for the use of rifaximin in Objective Our objective was to provide an overview of the patients with a history of overt HE. direct HE-related costs and cost beneﬁts of rifaximin, lactulose, and rifaximin plus lactulose. Methods A systematic review of PubMed and relevant Key Points for Decision Makers meeting abstracts was conducted to identify publications since 1 January 2007 reporting economic data related to Hepatic encephalopathy (HE) is associated with HE and rifaximin and/or lactulose. Further, a public data- substantial healthcare utilization (e.g. base and published literature were used to estimate current hospitalizations), which rifaximin has been shown to costs of hospitalization for overt HE, and potential cost reduce (e.g. reduction in risk of overt HE recurrence, savings of HE-related hospitalizations with rifaximin. The reduction in overt HE-related hospitalizations). methodological quality of included studies was evaluated The economic burden of HE on healthcare systems, using the Drummond checklist. including annual hospitalizations for patients with Results A total of 16 reports were identiﬁed for inclusion overt HE, may be mitigated by rifaximin. in the systematic review. Globally, HE-related direct costs ranged from $US5370 to $US50,120 annually per patient. The cost savings and clinical beneﬁts of rifaximin in Rifaximin was associated with shorter hospital stays and patients with cirrhosis have the potential to beneﬁt reduced healthcare costs. Rifaximin also has the potential healthcare decision making regarding management to reduce overt HE-related hospitalization risk by 50% of HE. compared with lactulose. Rifaximin was shown to have a The original version of this article was revised due to a retrospective Open Access Order. 1 Introduction & Guy Neff firstname.lastname@example.org Hepatic encephalopathy (HE) is a common neurologic complication of cirrhosis  and is estimated to affect Florida Research Institute, Florida Digestive Health Specialists, Lakewood Ranch, FL, USA between 30 and 70% of patients with cirrhosis [2, 3]. Cog- nitive impairment experienced by patients with HE ranges Quantym Therapeutic Data, Sarasota, FL, USA 810 G. Neff, W. Z. III from minimal (covert) HE, which is detected using special- experienced another such rehospitalization within 1 year ized testing, to overt HE, which is characterized by clinically . Another Italian study of patients previously hospi- identiﬁable symptoms (e.g. confusion, personality and talized for liver disease estimated that this population behavioural changes, lethargy) [1, 4]. HE negatively impacts experienced a mean of 1.5 HE-related readmissions multiple aspects of the lives of patients (e.g. cognition, annually during the 3-year period from 2006 through employment, ﬁnances) [5, 6] and their caregivers (e.g. per- 2008 . sonal health, ﬁnances, daily life) . HE adversely affects Given the substantial healthcare utilization associated sleep quality and sleep efﬁciency (i.e. time spent sleeping with HE, the aim of this systematic review is to provide an while in bed)  and is associated with learning impairment, overview of the global costs associated with HE and of which may persist even when overt HE symptoms clinically management options that have the potential to decrease resolve [8, 9]. Both general (e.g. physical functioning, social healthcare utilization in a manner that may be beneﬁcial to functioning) and disease-speciﬁc (e.g. disease effects, patients and healthcare institutions. memory) health-related quality-of-life (HRQOL) indicators are aberrantly affected in patients with HE compared with patients without the condition [10, 11]. In one study, 100% of 2 Methods patients with overt HE reported depressive symptoms in the previous 2 weeks, a ﬁnding that had a signiﬁcant negative 2.1 Reference Search association with all domains of the general and disease- speciﬁc HRQOL instruments used to assess patient func- A PubMed search of English language articles available from tioning (p = 0.03 to p \ 0.001) . 1 January 2007 through 23 June 2017 was conducted using the Patients with a history of HE are at increased risk for following keywords to identify articles for inclusion in the HE recurrence; one study estimated that risk of recurrence review: hepatic encephalopathy, economic, health-related increased by 23% with every unit increase in the number quality of life, cost, cost utility, cost effectiveness, rifaximin, of prior overt HE episodes (hazard ratio (HR) 1.23; 95% lactulose, adherence, and patient-reported outcomes. conﬁdence interval (CI) 1.19–1.29) . It is not Abstracts presented at annual meetings of the American uncommon for patients with overt HE to require hospi- Association for the Study of Liver Diseases (AASLD), the talization to manage the condition [13–15]; indeed, in a European Association for the Study of the Liver (EASL), and prospective study of patients with cirrhosis, overt HE was Digestive Disease Week, between 2014 and 2017 (if avail- the most common cause of patients’ initial liver disease- able), were reviewed for inclusion in the article. The Inter- related hospitalizations . Further, HE was predictive national Society for Pharmacoeconomics and Outcomes of cirrhosis-related rehospitalization (odds ratio (OR) 5.5; Research abstract database  was also searched for inclu- 95% CI 2.0–15.3; p = 0.001) . A study of patients sion of relevant studies published between 2014 and 2017. with cirrhosis in a US hospital system reported that overt Data from the Agency for Healthcare Research and Quality’s HE was the most common cause for rehospitalization in Healthcare Cost and Utilization Project were used to community hospitals compared with tertiary-care hospitals determine annual hospitalizations for patients with HE, which (29.5 vs. 8.6%, respectively) . Furthermore, post-in- were coded according to one of three International Classiﬁ- dex mean annual hospital costs (2010–2013) for patients cation of Diseases, Ninth Revision, Clinical Modiﬁcation with an index hospitalization for complications of cir- (ICD-9-CM) codes for HE: 291.2 (alcoholic dementia, not rhosis, such as HE, were greater for patients rehospital- elsewhere classiﬁed), 348.30 (encephalopathy, not otherwise ized B 30 or [ 30 days than for patients who were not speciﬁed), and 572.2 (hepatic coma) . readmitted and had outpatient costs only ($US73,252 and 62,053 vs. 5719, respectively) . Based on ﬁndings of two independent studies conducted in the USA and 2.2 Inclusion Canada, an estimated 18.1% of patients with cirrhosis who had been hospitalized previously had an HE-related Publications selected for inclusion during formal review were rehospitalization within 30 days, and an estimated those that reported on economic evaluations of patients with 23.7–28.8% of patients reported an HE-related readmis- HE and patients with HE receiving rifaximin, lactulose, or sion within 3 months [18, 19]. A study of patients with rifaximin plus lactulose. Further, studies examining quality of HE-related hospitalizations observed that 38.4% were life (QOL) in patients with HE and HE as an outcome in readmitted within 30 days, and an additional 13.6% re- patients with cirrhosis were considered for inclusion in this entered the hospital within 31–90 days of their last stay review. Studies were excluded if patients included were aged . An Italian study estimated that 42.5% of patients \ 18 years, did not receive rifaximin and/or lactulose, or had with a previous overt HE-related hospitalization minimal (or covert) HE. Narrative reviews were also excluded. Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic… 811 2.3 Assessment of Methodological Quality for each study included in the systematic review were of Economic Studies highly variable . A systematic review of US studies of patients with hepatitis C-related sequelae estimated that The 10-item Drummond checklist was used to evaluate the annual HE-related costs were $US16,430 in the ﬁrst year quality of methods reported for the economic studies and $US3810 annually in subsequent years, although these identiﬁed for inclusion in this systematic review . values are likely an underestimate of current costs, given Criteria for exclusion of economic studies were a combined that many studies included in the systematic review relied lack of economic importance of the research question, on a small single-centre study from 1997 . The broad failure to identify competing alternatives, and outcomes range of economic costs observed are consistent with the not relevant to the current review. No studies identiﬁed for ﬁndings of this systematic review of seven independent inclusion in this review were excluded based on this quality studies examining economic costs associated with HE assessment. worldwide (Table 1)[21, 27–32]: we found a broad range of mean annual hospitalization costs (2012) for patients with HE, with between $US25,634 and $US58,625 repor- 3 Results ted for the USA . 3.1 Identiﬁcation of Studies 3.3 Management of Hepatic Encephalopathy and Clinical Impact The search for economic studies related to HE that were published since 2007, as well as studies related to the use Management of overt HE includes treating patients with of lactulose and/or rifaximin for the management of HE, acute HE episodes, preventing HE recurrence, and identi- found 133 articles or abstracts, of which 16 were identiﬁed fying and managing precipitating factors associated with for inclusion in this systematic review because they con- development of HE . First-line therapy for patients tained cost data related to overt HE (Fig. 1). Speciﬁcally, experiencing an acute episode of overt HE is the nonab- nine articles (including two systematic reviews) were sorbable disaccharide lactulose, which requires self-titra- identiﬁed as being related to economic costs of overt HE, tion to two to three soft bowel movements per day . and seven articles or abstracts were considered related to Rifaximin is an oral non-systemic antibiotic approved in costs associated with rifaximin and/or lactulose for patients the USA for reduction of risk of overt HE recurrence in with overt HE. Excluded from further review were review adults; the recommended dosing is 550 mg twice daily. articles (excluding systematic reviews) and studies of Guidelines from the AASLD and EASL recommend paediatric patients or minimal or covert HE, as well as rifaximin as add-on therapy to lactulose to reduce the risk studies that included other HE treatments or did not include of overt HE recurrence . economic data. 3.3.1 Lactulose for Hepatic Encephalopathy 3.2 Economic Impact of Hepatic Encephalopathy A meta-analysis of 22 randomized controlled studies demonstrated that nonabsorbable disaccharides (i.e. lactu- Data from the US Nationwide Inpatient Service indicate lose, lactitol) were signiﬁcantly more effective than pla- that the number of HE-related hospitalizations increased cebo or no intervention for the prevention and treatment of annually between 2004 and 2014, excepting 2008 (from HE (relative risk (RR) 0.58; 95% CI 0.48–0.69) . A 95,232 in 2004 to 156,205 in 2014) . Further, in 2014, meta-analysis of 24 randomized controlled studies for patients with a primary diagnosis of HE (ICD-9-CM demonstrated that nonabsorbable disaccharides signiﬁ- diagnosis code 572.2; n = 55,485), unadjusted (for the cantly reduced the risk of mortality compared with placebo medical consumer price index) total costs were estimated at or no intervention (RR 0.59; 95% CI 0.40–0.87) . For approximately $US620 million . These data from the hospitalized patients with end-stage liver disease, lactulose US Nationwide Inpatient Service , and data in pub- use was associated with decreased risk of Clostridium lished studies (Table 1)[21, 25–32], demonstrate the eco- difﬁcile infection (OR 0.48; 95% CI 0.31–0.74; p \ 0.001) nomic impact of HE-related hospitalizations. , which is important given that C. difﬁcile infection is A systematic review of 11 economic costs studies for associated with poor outcomes in hospitalized patients with countries with available data (excluding the USA) pub- cirrhosis (i.e. higher mortality rate, longer hospital stay, lished between 1990 and 2011 estimated mean annual HE- increased hospital costs) . related costs at $US13,270 per patient (range 5370–50,120); the methodologies for collecting cost data 812 G. Neff, W. Z. III Records identified using PubMed Records identified using other sources n = 122 (i.e. meeting abstracts, internet search) n = 11 Records excluded after duplicates removed n = 15 Records excluded after title/abstract Records screened considered to lack relevance to review n = 118 n = 58 Full-text articles evaluated for inclusion Ineligible articles n = 60 Full-text articles excluded for lack of relevance to review n = 44 Reasons for exclusion: Eligible articles • Minimal (covert) HE or condition n = 16 other than HE discussed � Pediatric patient population Economic data related to HE � Rifaximin and/or lactulose n = 9 not examined � Economic or pharmacoeconomic Economic data related to data not included rifaximin and/or lactulose for HE � Review articles other than n = 7 systematic reviews Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta- encephalopathy, economic, health-related quality of life, cost, cost Analyses (PRISMA) diagram detailing the search for records utility, cost effectiveness, rifaximin, lactulose adherence, and patient- pertaining to economic data for hepatic encephalopathy, and admin- reported outcomes. HE hepatic encephalopathy istration of rifaximin and/or lactulose. Search terms included hepatic 3.3.2 Rifaximin for the Management of Hepatic retrospective study, a signiﬁcantly lower percentage of Encephalopathy patients receiving rifaximin and lactulose combination therapy for acute HE were rehospitalized for HE-related Rifaximin is indicated in the USA for reducing the risk of reasons within 6 months compared with patients receiving overt HE recurrence in adults but not for management of an lactulose alone (2.4 vs. 16.2%, respectively; p = 0.03) . acute episode of overt HE. However, in one study, a sig- In a 6-month phase III randomized, double-blind, placebo- niﬁcantly greater percentage of patients receiving rifaximin controlled study in patients with a history of overt HE plus lactulose experienced complete reversal of an acute (n = 299), rifaximin reduced the risk of breakthrough HE overt HE episode compared with those receiving lactulose by 58% (HR 0.42; 95% CI 0.28–0.64; p \ 0.001) com- alone after 10 days (76.2 vs. 43.9%, respectively; pared with placebo; of note, 91% of patients in each group p = 0.004) . Rifaximin plus lactulose was associated received concomitant lactulose . Twice-daily rifaximin with decreased mortality compared with lactulose alone improved sleep quality after 28 days in patients with a (23.8 vs. 49.1%; p \ 0.05) . In addition, rifaximin has history of HE . Finally, a meta-analysis of 12 random- demonstrated efﬁcacy for reducing the risk of overt HE ized controlled studies of patients with minimal or overt recurrence. In a Greek study, rifaximin decreased the risk HE demonstrated that rifaximin signiﬁcantly decreased the of overt HE recurrence (p = 0.03) and improved survival risk of mortality compared with lactulose/lactitol, other (p = 0.01) in patients with alcohol-related decompensated antibiotics, or placebo (RR 0.64; 95% CI 0.43–0.94) . cirrhosis compared with patients not receiving rifaximin A retrospective chart review of patients with overt HE during a 5-year period . In a US single-centre demonstrated the durability of rifaximin for the Included Eligibility Screening Identification Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic… 813 Table 1 Economic costs associated with hepatic encephalopathy Study; country; perspective Population Outcome(s) Cost(s) Irish et al. ; USA; payer Pts with HE-related hospitalization Mean no. of hospitalizations: Mean hospitalization costs: perspective in 2012; Medicare claims database 2.4 $US25,364–58,625 (n = 1113) Mean duration of hospitalization: 5.9 days Mean no. of outpatient visits: 11.0 Poovorawan et al. ; Thailand; Pts with cirrhosis (ICD-10 code Mean ± SD duration of HE- Mean ± SD hospitalization costs: payer perspective K74)-related hospitalization in related hospitalization: THB44,606 ± 71,001; 2010 (n = 92,301 admissions) 9.1 ± 10.9 days $US1394 ± 2219 Pts with HE (n = 5292) Mortality during Total healthcare costs: hospitalization: 32% THB58,134 ± 79,763; $US1817 ± 2493 Roggeri et al. ; Italy; payer Pts with C 1 overt HE-related Mortality Mean ± SD direct costs of single perspective hospitalization between 1 January overt HE recurrence-related During index hospitalization 2011 and 31 December 2011 hospitalization : €3361 ± 1286; (n = 82; 21.5%) (n = 381) $US3838 ± 1469 During hospitalization at Total annual costs for pts with 1-year follow-up (n = 22; (n = 124) and without (n = 172) 5.8%) overt HE recurrence: €21,272 Mean ± SD duration of ($US24,293) vs. €12,098 overt HE recurrence- ($US13,816), respectively related hospitalization: (p \ 0.001) 9 ± 7 days Mean ± SD annual hospitalization cost with recurrence vs. no recurrence: €18,970 ± 16,652 vs. €10,196 ± 22,182 Mean ± SD annual drug cost with recurrence vs. no recurrence: €1633 ± 1807 vs. €1173 ± 1657 Mean ± SD annual diagnostic and therapeutic procedure costs with recurrence vs. no recurrence: €669 ± 974 vs. €729 ± 1519 Benkovic´ et al. ; Croatia; payer Pts with malnutrition and HE in Total healthcare costs: €1,019,994 perspective 2012 (n = 945) Mean healthcare costs/pt: €1344 Lee et al. ; China; payer Pts with HE (ICD-9-CM diagnosis Mean ± SD HE-related healthcare perspective code 572.2) associated with costs benzodiazepine use enrolled in Hospitalization: NTD6987 ± 419; previous (2005–2009) and current $US231 ± 14 (2009–2012) clinical studies at Outpatient visits: NTD812 ± 99; single hospital (n = 322) $US27 ± 3 ER visits: NTD4170 ± 641; $US138 ± 21 Overall medical costs: NTD11,970 ± 210; $US396 ± 7 814 G. Neff, W. Z. III Table 1 continued Study; country; perspective Population Outcome(s) Cost(s) Andersen et al. ; Denmark; Pts with cirrhosis with previous HE- Survival (B 20 months from Median (range) costs provider perspective related hospitalization receiving baseline; rehabilitation Rehospitalization at study outpatient rehabilitation (2009; group vs. control group): hospital n = 19) vs. pts not receiving 84 vs. 36%, respectively; Rehabilitation group: DKK52,266 rehabilitation (i.e. control group; p = 0.01 (0–409,402); $US9643 2008; n = 14) (0–75,535) Control group: DKK51,266 (0–410,128); $US9459 (0–75,669) Rehospitalization at any hospital Rehabilitation group: DKK84,730 (0–409,402); $US15,633 (0–75,535) Control group: DKK84,395 (0–471,562); $US15,571 (0–87,004) El Khoury et al. ; Brazil, Pts with HE related to HCV Mean (range) global HE-related Canada, Asia-paciﬁc region, infection costs (2010 values): $US13,270 Europe (systematic review); (5370–50,120) Studies published between January payer (n = 3 studies) and provider 1990 and January 2011 (n =11 (n = 7 studies) perspective; studies) perspective unknown for 1 study El Khoury et al. ; USA Pts with HE associated with HCV Mean HE-related costs (2010 (systematic review); provider infection values) perspective (n = 5 studies) Studies published between 1997 and Year 1: $US16,430 2007 (n =5) Year 2: $US3810 Stepanova et al. ; USA; payer Pts with HE-related hospitalizations Mean ± SD duration of HE- Total HE-related hospitalization perspective between 2005 and 2009 related hospitalization charges (n = 111,090) 2005: 8 ± 0.2 days 2005: $US4.677 billion 2009: 8.5 ± 0.2 days 2009: $US7.254 billion Mean no. procedures Mean HE-related hospitalization charges 2005: 1.9 ± 0.1 2005: $US 46,663 ± 2180 2009: 2.2 ± 0.1 2009: $US63,107 ± 3244 In-hospital mortality Mean HE-related costs per pt 2005: 15.6% 2005: $US16,512 ± 709 2009: 14.4% 2009: $US17,812 ± 764 DKK Danish krone, ER emergency room, HCV hepatitis C virus, HE hepatic encephalopathy, ICD-9-CM International Classiﬁcation of Diseases, Ninth Revision, Clinical Modiﬁcation, ICD-10 ICD, Tenth Revision, mo month, NTD New Taiwan dollars, pt patient, SD standard deviation, THB Thai baht Exchange rate €1.00 = $US1.1420 maintenance of HE remission, as 81.2% of 149 patients lactulose who experienced breakthrough HE, 42.9 and receiving monotherapy (mean duration 255 days) and 38.9% required hospitalization for overt HE, respectively, 66.7% of 54 patients receiving rifaximin and lactulose and 14.3 and 27.8% required hospitalization for dehydra- combination therapy (mean duration 205 days) did not tion and overt HE, respectively . In another US single- experience HE recurrence during 1 year of follow-up . centre study, rifaximin signiﬁcantly reduced the odds of In that study, of the 28 (18.8%) patients receiving rifaximin rehospitalization within 30 days in patients with overt HE monotherapy and the 18 (33.3%) receiving rifaximin with (OR 0.39; 95% CI 0.16–0.87; p = 0.02) . Rifaximin Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic… 815 was associated with a decrease in hospitalizations ; in in a single-centre retrospective study of patients with HE one study, 30-day and 6-month rehospitalization rates in receiving lactulose twice daily for C 6 months, followed patients with HE receiving rifaximin 550 mg twice daily by rifaximin alone three times daily for C 6 months (31 vs. were 9.4 and 15.6%, respectively . Patients with HE 92%, respectively; p \ 0.001) . In that study, during who were crossed over from placebo to receive open-label the C 6-month timeframe, lactulose was associated with a rifaximin in a randomized controlled trial had a numeric greater number of hospitalizations than was rifaximin alone decrease in HE-related hospitalizations within 6 months, (1.6 vs. 0.5, respectively; p \ 0.001) as well as longer although signiﬁcance was not achieved (0.36 vs. 0.57 duration of hospitalization (7.3 vs. 2.5 days; p \ 0.001) events/person-years of exposure; p = 0.4) . In a phase and higher hospitalization costs per patient ($US56,635 vs. III randomized controlled trial of patients with a history of 14,222; year 2005 values; payer perspective) . Data overt HE (n = 299), rifaximin 550 mg twice daily reduced from a single-centre retrospective study of patients the risk of HE-related hospitalization by 50% compared receiving lactulose monotherapy found that dehydration with placebo during a 6-month period (HR 0.50; 95% CI and failure to adhere to therapy were predictors of HE 0.29–0.87; p = 0.01); overall, 13.6 and 22.6% of patients, recurrence . A US single-centre retrospective study of respectively, experienced HE-related hospitalizations . patients hospitalized for HE indicated that lactulose use In a long-term open-label study, rifaximin was associated after initial hospitalization was a signiﬁcant factor associ- with decreased rates of overt HE- and all-cause-related ated with rehospitalization within 90 days (OR 8.6; 95% CI hospitalizations for C 2 years compared with patients 1.1–66.7; p = 0.03); however, rifaximin use posthospital- receiving placebo for C 6 months (historical comparison ization was not signiﬁcantly associated with risk of group) . A single-centre retrospective study reported rehospitalization within 90 days (OR 1.2; 95% CI 0.7–2.2; that patients with more severe liver disease (i.e. Model for p =0.3). End-Stage Liver Disease (MELD) score [ 20; n = 43) The adverse effects associated with lactulose, including receiving rifaximin plus lactulose for C 6 months had a diarrhoea, abdominal pain, and bloating, were associated lower mean number of HE-related hospitalizations than did with nonadherence to lactulose and resulted in a failure to patients with a MELD score \ 20 (n = 49; 1.6 vs. 2.5 adequately titrate lactulose to the appropriate number of hospitalizations, respectively) . However, retrospective daily bowel movements ; in one study, failure to analysis of a US pharmacy claims database (1 January properly titrate lactulose was a common cause of pre- 2006 through 30 June 2015) found no difference in overt ventable rehospitalization in patients with HE who were HE-related hospitalizations between rifaximin plus lactu- readmitted within 1 month of their last hospital stay . A lose vs. lactulose monotherapy (16.0 vs. 15.3%, respec- signiﬁcantly greater percentage of patients experienced tively; p = 0.8) . Furthermore, there was no signiﬁcant diarrhoea, ﬂatulence, and abdominal pain with lactulose reduction in the risk of an overt HE episode between the compared with rifaximin alone (p \ 0.001, for each com- two groups (HR 1.04; 95% CI 0.81–1.28) . These parison) . Further, a meta-analysis of eight controlled ﬁndings are currently limited to presentation in abstract clinical studies demonstrated that rifaximin had a more form, and it is unclear why these data differ from the favourable safety proﬁle than lactulose, as the risks of positive data noted above. The abstract authors speculated diarrhoea and abdominal pain were signiﬁcantly less with that this difference may be related to unobserved con- rifaximin than with lactulose (diarrhoea RR 0.11; 95% CI founding . Overall, data support that rifaximin is 0.04–0.31; p \ 0.0001; abdominal pain RR 0.34; 95% CI effective for reducing all-cause- and HE-related hospital- 0.14–0.83; p = 0.02; both adverse events together RR 0.19; izations in patients with a history of overt HE. 95% CI 0.10–0.37; p \ 0.00001) . Nonadherence to lactulose, in part related to adverse events, appeared to play 3.4 Impact of Therapy on Hepatic Encephalopathy a role in HE recurrence and HE-related rehospitalization, Costs and Outcomes both events that are associated with economic costs that may be avoidable in some patients. Rifaximin and lactulose combination therapy has been In the UK, healthcare resource utilization was signiﬁ- shown to signiﬁcantly decrease the duration of hospital cantly decreased after initiation of rifaximin compared with stays vs. lactulose alone (5.8 ± 3.4 vs. 8.2 ± 4.6 days; before initiation of rifaximin (Table 2)[55, 56]. In one p = 0.001) , even given the higher monthly drug cost study, use of rifaximin (with 87% of patients receiving of rifaximin vs. lactulose [48, 49]. Congly and Leise  concomitant lactulose) to reduce the risk of overt HE suggested a favourable economic impact of rifaximin on decreased mean annual inpatient admission costs compared hospitalizations. Lactulose was associated with signiﬁ- with the year prior to rifaximin (12,522 per year before cantly worse adherence (i.e. taking C 75% of doses as rifaximin vs. 5915 per year after rifaximin; provider prescribed by patient self-report) compared with rifaximin perspective)  (Table 3)[55, 57–62]. When considering 816 G. Neff, W. Z. III Table 2 Effects of rifaximin on healthcare resource utilization [55, 56] Study; country Centre Data Outcomes (prior to rifaximin vs. with rifaximin ) (pts), n collection Month 3 Month 6 Month 12 Orr et al. 2016 7 (326) 2014 Mean all-cause Mean all-cause Mean all-cause b b b , UK hospitalizations : 1.2 vs. 0.6 hospitalizations : 1.6 vs. 1.0 hospitalizations : 2.1 vs. 1.6 (p \ 0.001) (p \ 0.001) (p = 0.001) b b b Mean hospital LOS (d) : Mean hospital LOS (d) : Mean hospital LOS (d) : 24.4 vs. 11.5 (p \ 0.001) 15.8 vs. 7.4 (p \ 0.001) 20.7 vs. 9.7 (p \ 0.001) Aspinall et al. 11 July 2008– Not reported Mean hospitalizations: 2.2 vs. Mean hospitalizations: 2.7 vs. 2016 , UK (145) May 2014 1.0 (p \ 0.001) 1.7 (p = 0.002) Total inpatient bed days: 28.6 Total inpatient bed days: 31.7 vs. 11.9 (p \ 0.001) vs. 16.4 (p \ 0.001) Critical care bed days/pt: 7.9 Critical care bed days/pt: 11.3 vs. 2.0 (p = 0.046) vs. 2.4 (p = 0.017) ER visits/pt: 1.9 vs. 1.0 ER visits/pt: 2.4 vs. 1.8 (p \ 0.001) (p = 0.099) d day, ER emergency room, LOS length of stay, pt patient Time points for outcomes assessed after rifaximin was initiated n = 158 the annual cost of rifaximin at the time of the study 4 Discussion (3379), the mean annual cost savings per patient were 3228 . In this systematic review, the global economic costs In France, rifaximin plus lactulose had a favourable associated with HE-related healthcare utilization are sum- pharmacoeconomic proﬁle compared with lactulose marized for the past 10 years. Patients with HE, regardless monotherapy, based on a societal willingness-to-pay cost- of geographic location, present a substantial economic effectiveness threshold of €27,000 (Table 3); the incre- burden on the healthcare infrastructure, and annual hospi- mental cost-effectiveness ratio of rifaximin to lactulose talizations for patients with HE can be quite costly to the was €18,517 per each quality-adjusted life-year gained healthcare system. Mean duration of hospital stay related to over 5 years, suggesting that rifaximin in combination with HE ranged between 5.9  and 9 days [21, 27] in the lactulose was a cost-effective treatment for patients with a literature, with a mean of 2.4 yearly hospitalizations for history of at least two HE episodes . In the USA and patients with HE . A study of patients previously other countries, clinically relevant beneﬁts of rifaximin hospitalized for liver disease showed a mean 1.5 HE-re- (e.g. reduction in hospitalizations, decreased mortality rate, lated readmissions annually . Overall, data suggest that reversal of HE symptoms, maintenance of remission of initiating rifaximin therapy early in the hospital setting HE) have been demonstrated in pharmacoeconomic studies could lead to decreased length of stay . Furthermore, (Table 3)[55, 57–62]. Finally, applying the 50% reduction the cost savings estimated for rifaximin vs. lactulose, while in HE-related hospitalizations attributable to rifaximin by based on published estimates of numbers affected, support Bass et al.  to the 22,931 HE-related hospitalizations at the idea that reducing the risk of hospitalization in patients $US63,107 annual inpatient charges per episode reported with HE would signiﬁcantly reduce the economic burden to by Stepanova et al.  reveals a potential inpatient cost healthcare systems for this condition. Indeed, the incre- avoidance for the payer of [ $US723 million annually in mental costs of rifaximin are outweighed by the potential the USA (2009 values). However, this cost avoidance savings in healthcare costs. potential must be considered within the context of charges Irish et al.  demonstrated that patients with HE as a valuation vs. actual costs, any additional costs of enrolled in a government-sponsored healthcare programme therapy, potential cost savings for other direct medical had an average of 11 outpatient visits annually. The liter- costs and indirect costs, the potential increases in both the ature suggests that rifaximin may provide better control of incidence and the cost of HE-related hospitalizations since HE symptoms and, in turn, may reduce not only hospital- 2009, and the number of patients treated. ization-related costs and duration of hospital stay but also other healthcare-related costs, especially if rifaximin use translates into reduced need for ambulatory follow-up Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic… 817 Table 3 Pharmacoeconomic proﬁle of rifaximin Country Patient characteristics Endpoint(s) and model Outcomes Belgium Recurrent overt HE ICER, derived from QALY Lactulose (SOC)  Markov state transition model Average cost (2010): €44,190 1.9 QALY/pt Average cost effectiveness: €23,258/QALY Rifaximin ? lactulose Average cost: €31,262 2.5 QALY/pt Average cost effectiveness: €12,505/QALY ICER: €21,547/QALY for rifaximin ? lactulose vs. lactulose France  History of overt HE (C 2 ICER, derived from QALY Lactulose (SOC) episodes); currently in Markov state transition model 2 years remission Cost: €5503 0.967 QALY/pt 5 years Cost: €8555 1.778 QALY/pt Rifaximin ? lactulose 2 years Cost: €7639 1.078 LY/pt 5 years Cost: €14,411 2.094 QALY ICER 2 years: €19,187/QALY for rifaximin ? lactulose vs. lactulose 5 years: €18,517/QALY for rifaximin ? lactulose vs. lactulose Netherlands Recurrent overt HE ICER, derived from QALY Lactulose (SOC)  Markov state transition model Average cost (2010): €82,968 1.89 QALY/pt Rifaximin ? lactulose Average cost: €88,386 2.45 QALY/pt ICER (5 years): €9576/QALY for rifaximin ? lactulose vs. lactulose Sweden  Recurrent overt HE ICER, derived from QALY Lactulose (SOC) Markov state transition model Average cost (2012): €42,522 1.83 QALY/pt Rifaximin ? lactulose Average cost: €32,667 2.38 QALY/pt ICER (5 years): €17,918/QALY for rifaximin ? lactulose vs. lactulose UK  Overt HE Cost analysis of rifaximin Mean annual emergency inpatient admission costs, 1 year before vs. 1 year after rifaximin: 12,522 vs. 5915, respectively (2013/2014 costs) 818 G. Neff, W. Z. III Table 3 continued Country Patient characteristics Endpoint(s) and model Outcomes UK  Recurrent overt HE ICER, derived from QALY Lactulose (SOC) Markov state transition model Average cost (2012): 23,545 1.83 QALY/pt Rifaximin Average cost: 22,971 2.36 QALY/pt ICER 5 years: 1083/QALY for rifaximin vs. lactulose 10 years: 4470/QALY for rifaximin vs. lactulose Lifetime: 7215/QALY for rifaximin vs. lactulose USA  Recurrent overt HE Costs (drug costs, Rifaximin ? lactulose vs. lactulose hospitalizations, liver Life expectancy improved with rifaximin ? lactulose vs. transplant) lactulose (lifetime, 5.7 vs. 2.8 years) Outcomes (hospitalizations, Opportunity for liver transplant improved 2-fold with rifaximin LY, QALY) ? lactulose vs. lactulose Hospitalizations were decreased with rifaximin ? lactulose vs. lactulose over 6 mo (0.27/pt vs. 0.51/pt) Lifetime cost of rifaximin: $US 59,777 $US 20,287/LY for rifaximin ? lactulose vs. lactulose $US 26,672/QALY for rifaximin ? lactulose vs. lactulose HE hepatic encephalopathy, ICER incremental cost-effectiveness ratio, LY life-years, QALY quality-adjusted life years, SOC standard of care In this study, costs were compared before and after initiation of rifaximin [39, 45]. However, more research is needed to conﬁrm and the world were included [25, 26]. Further, as shown in quantify the extent to which rifaximin use may reduce Table 4, most of the cost data presented in the current healthcare-related costs. systematic review did not undergo adjustment (e.g. to Rifaximin with or without lactulose is associated with medical consumer price index), restricting head-to-head improvement in both the number and the duration of hos- comparisons. Finally, while the pharmacoeconomic bene- pitalizations in patients with HE [55, 56]. Further, studies ﬁts of rifaximin appear to be favourable, a more thorough conducted in different countries demonstrated that rifax- analysis is warranted to provide a current estimate of imin combined with lactulose had a more favourable cost- savings to the US healthcare system. Any such study uti- effectiveness proﬁle than lactulose alone [55, 57–62]. It lizing more current estimates of the number of patients should be noted that the data presented in some of these with cirrhosis and HE should employ sensitivity analyses studies are in the form of meeting abstracts [32, 56, 58–62], representing higher prevalence estimates, given that the thus limiting the details presented regarding study design prevalence of cirrhosis and overt HE is likely underesti- and outcomes (Table 4)[21, 25–32, 55–62]. mated  for several reasons, including nonspeciﬁc ICD- A limitation of the current systematic review is that 10 diagnosis coding. available data originate from multiple countries and often involve different timeframes. Variances in healthcare sys- tems worldwide may limit the generalizability of the eco- 5 Conclusions nomic ﬁndings to a single country. Guidelines from the AASLD and EASL recommend lactulose as ﬁrst-line Rifaximin, either alone or in combination with lactulose, therapy and rifaximin as add-on therapy for reducing the improved outcomes in patients with HE compared with risk of recurrence of overt HE . Another limitation of the lactulose alone. Rifaximin (with or without lactulose) current review is the paucity of economic data published decreased healthcare resource utilization in patients with for management of overt HE. This review included any overt HE and was associated with a favourable pharma- publications meeting inclusion criteria since 2007; thus, coeconomic proﬁle compared with lactulose alone. Eco- two systematic reviews of costs in the USA and the rest of nomic data are favourable for use of rifaximin (with or Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic… 819 Table 4 Quality assessment of economic studies Study Well- Comprehensive Evidence of Important and Outcomes and Outcomes Outcomes and Incremental analysis Sensitivity Conclusions deﬁned description of programme’s relevant outcomes costs measured and costs costs adjusted of outcomes and costs analysis justiﬁed by question competing effectiveness for each alternative accurately in valued (e.g. of alternatives performed the evidence alternatives identiﬁed appropriate units credibly discounting) performed Andersen No Yes Yes Yes Yes Not clear No No No Yes et al. 2013  Benkovic Yes Yes Yes Yes Yes Yes No No No Yes et al. 2014  Berni et al. Yes Yes Yes Yes Yes Yes Yes Yes Not clear Yes 2015  Berni et al. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 2015  Bozkaya Yes Yes Yes Yes Yes Yes Not clear Yes Not clear Yes et al. 2014  El Khoury Yes Yes Yes Yes Yes Yes Yes No No Yes et al. 2012  El Khoury Yes Yes Yes Yes Yes Yes Yes No No Yes et al. 2012  Irish et al. Yes Yes Yes Yes Yes Not clear Not clear Not clear No Yes 2015  Kabeshova Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes et al. 2015  Lee et al. Yes Yes Yes Yes Yes Yes No No No Yes 2014  Orr et al. Yes Yes Yes Yes Yes Yes No No No Yes 2016  Poole et al. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 2015  Poovorawan Yes Yes Yes Yes Yes Yes No No No Yes et al. 2015  Roggeri Yes Yes Yes Yes Yes Yes No No No Yes et al. 2015  Stepanova Yes Yes Yes Yes Yes Yes Yes No Not clear Yes et al. 2012  820 G. Neff, W. Z. III without lactulose) for reducing the risk of overt HE recurrence in patients with a history of overt HE. There- fore, reducing the risk of recurrence of overt HE (e.g. with rifaximin) to reduce hospital readmission should be a consideration at discharge for adults with cirrhosis who were hospitalized due to overt HE. Data availability statement Data sharing information is not applicable to this article as no datasets were generated or analysed during the current study. Author contributions GN and WZ contributed to the concept and objective of the article, established the parameters around the sys- tematic review, and interpreted and critiqued the data. GN and WZ were involved in drafting and commenting on the article and approved the ﬁnal version for submission. Guarantor: GN acts as the guarantor for this work. Compliance with Ethical Standards Funding Technical editorial assistance was provided, under the direction of the authors, by Mary Beth Moncrief, PhD, and Sophie Bolick, PhD, Synchrony Medical Communications, LLC, West Chester, PA, USA. Funding for this support was provided by Salix Pharmaceuticals, Bridgewater, NJ, USA. Conﬂict of interest GN and WZ have no potential conﬂicts of interest that are relevant to the content of this article and neither they nor their respective institutions received funding for the manuscript. Salix Pharmaceuticals did not actively participate in content devel- opment but reviewed the manuscript for scientiﬁc accuracy. As dis- closed in the funding statement, Salix Pharmaceuticals provided support for technical editorial assistance. 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