Economic Impact of Treatment Options for Hepatic Encephalopathy

Economic Impact of Treatment Options for Hepatic Encephalopathy Carroll B. Leevy, M.D. 1 ABSTRACT Complications of chronic liver disease, such as hepatic encephalopathy (HE), can have a substantial impact on the economic burden of liver disease. In the United States, a report of 162,734 inpatient hospital discharges included HE or unspecified encephalopathy diagnoses in 2004, a 234% increase over data from 1993. Hospital charges for HE and HE-related conditions also increased from 1993 to 2004 in the United States. Mean hospital charges have increased despite a steady reduction in the mean duration of stay, a trend that may reflect advances in treatment. Several studies have provided data about the cost-effectiveness of rifaximin and lactulose as treatments for HE. These studies showed that, although rifaximin costs more per tablet than lactulose, rifaximin is more cost-effective for long-term therapy. Further studies are warranted to more fully evaluate the relative long-term cost-effectiveness of specific HE treatments. KEYWORDS: Hepatic encephalopathy, health care utilization, lactulose, rifaximin National Health Interview Survey data from 1995 (adjusted to 1998) indicate that an estimated 5.5 million individuals in the United States have been diagnosed with chronic liver disease and cirrhosis. 1 These findings, in the absence of more recent data, suggest that the economic burden of chronic liver disease, along with that of associated conditions such as cirrhosis and chronic hepatitis C, is substantial. The total direct cost associated with chronic liver disease, cirrhosis, and chronic hepatitis C was more than $2.1 billion, according to the same adjusted National Health Interview Survey data and also data from Group Health Cooperative of Puget Sound for 1998. Most of that cost resulted from inpatient hospital stays and prescribed medication (Fig. 1). 1 The estimated indirect cost of lost wages due to hospitalization and time associated with visits to physician offices, hospital emergency rooms, and outpatient departments totaled more than $272 million annually for these conditions. 1 Given that these data were based on 1998 estimates, current costs related to chronic liver disease are undoubtedly higher. Complications such as hepatic encephalopathy (HE) are not uncommon in patients with chronic liver disease and contribute to its overall economic burden. HE is a neuropsychiatric syndrome that affects consciousness, cognitive abilities, behavior, and neuromuscular function. Symptoms range from subtle neuropsychological impairment in patients with minimal HE to coma in the most severe cases. 2,3 In studies that reported the prevalence of HE, overt HE developed in 28% to 41% of patients with cirrhosis, 4 6 and minimal HE was found in 22% to 62%. 5,7 10 Up to 51% of patients who undergo placement of transjugular intrahepatic portosystemic shunts for the treatment of complications related to portal hypertension have also been reported to develop HE. 11 13 The economic burden of treating HE varies, depending on the severity of the condition, with more 26 1 New Jersey Medical School Liver Center, Newark, New Jersey. Address for correspondence and reprint requests: Carroll B. Leevy, M.D., New Jersey Medical School Liver Center, 90 Bergen Street, Suite 2100, Newark, NJ 07103. Current Concepts in the Management of Hepatic Encephalopathy; Guest Editor, Emmet B. Keeffe, M.D., M.A.C.P. Semin Liver Dis 2007;27(suppl 2):26 31. Copyright # 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2007-984572. ISSN 0272-8087.

ECONOMIC IMPACT OF TREATMENT OPTIONS FOR HE/LEEVY 27 Figure 1 Total direct cost (millions, US dollars) of chronic liver disease, cirrhosis, and chronic hepatitis C. Data are from the 1995 National Health Interview Survey (adjusted to 1998) and Group Health Cooperative of Puget Sound for 1998. *No visits to the emergency room for hepatitis C were reported by the National Hospital Ambulatory Medical Care Survey in 1998. (From American Gastroenterological Association. The Burden of Gastrointestinal Diseases. Chapter 5: Hepatobiliary and pancreatic disorders. Available at: www.gastro.org/user-assets/documents/burden-report.pdf. Accessed January 5, 2007.) severe cases requiring management in an intensive care unit. 11 The economic impact may also depend on the specific treatment administered. This article presents an overview of the economic burden of HE and reviews the cost-effectiveness of two treatments for HE: the nonabsorbable disaccharide lactulose and the nonabsorbable antibiotic rifaximin. ECONOMIC IMPACT OF HE Estimates of the economic burden of inpatient hospital treatment for HE can be obtained from the Nationwide Inpatient Sample (NIS), a collection of databases developed as part of the Healthcare Cost and Utilization Project (HCUP) and sponsored by the Agency for Healthcare Research and Quality. 12 The NIS database contains data from 8 million hospital stays each year and discharge information from 1004 hospitals in 37 states. Specific health care utilization data for HE and HE-related conditions are tracked using codes listed in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Based on data from the NIS database, the number of hospitalizations for a principal diagnosis of HE (code 572.2) or unspecified encephalopathy (code 348.30) steadily increased during the period from 1993 to 2004 (Fig. 2). 12 Hospitalizations for HE-related conditions, including alcoholic cirrhosis (code 571.2; Fig. 2), and nonalcoholic cirrhosis (code 571.5) also increased during this time period. 12 The total number of discharges for a principal diagnosis of HE (code 572.2) or unspecified encephalopathy (code 348.30) increased 180%, from 18,154 in 1993 to 50,962 in 2004 (Table 1). All-listed diagnoses of HE, which encompass all diagnoses that coexisted with HE or unspecified encephalopathy at the time of admission or that developed during the hospital stay and affected treatment or duration of stay, increased 234%, from 48,729 in 1993 to 162,734 in 2004 (Table 1). 12 The difference in principal and all-listed diagnoses for HE suggests that HE is infrequently coded as the principal diagnosis and that the reported prevalence may be underestimated. One factor that may have contributed to the increase in conditions related to chronic liver disease, including HE, is an increase in viral hepatitis cases. The number of outpatient clinic visits for chronic hepatitis C increased from 756,774 in 2000 to 1,237,708 in 2002, an Figure 2 Trends in hospitalization for principal diagnoses of HE (code 572.2) in the United States from 1993 to 2004. HE, hepatic encephalopathy. (From Agency for Healthcare Research Quality. HCUPnet: Healthcare Cost and Utilization Project. Available at: http://hcupnet.ahrq.gov/hcupnet.jsp?id=dbe1ccf502e0c25d &Form=SelQUERYTYPE&JS=Y&Action=%3E%3ENext%3E% 3E&_QUERYTYPE=Trends. Accessed February 2007.)

28 SEMINARS IN LIVER DISEASE/VOLUME 27, SUPPLEMENT 2 2007 Table 1 Hospital Discharges for HE or Unspecified Encephalopathy in the United States, 2004 Diagnosis (ICD-9-CM Code) Principal Diagnoses All-Listed* Hepatic encephalopathy (572.2) 42,269 98,669 Encephalopathy, unspecified (348.30) 8693 64,065 Total 50,962 162,734 *Includes all diagnoses that coexisted at the time of admission or that developed during the hospital stay and affected treatment or duration of stay. Data from Agency for Healthcare Research Quality. HCUPnet: Healthcare Cost and Utilization Project. Available at: http://hcupnet. ahrq.gov/hcupnet.jsp?id=dbe1ccf502e0c25d&form=selquery TYPE&JS=Y&Action=%3E%3ENext%3E%3E&_QUERYTYPE= Trends. Accessed February 2007. HE, hepatic encephalopathy; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification. increase that was likely due to increased awareness among patients and health care providers. 13 To estimate the potential future impact of chronic hepatitis C, Wong and colleagues conducted a Markov statistical simulation based on 1991 data from the National Health and Nutrition Examination Survey III. 14 These authors predicted that, between the years 2010 and 2019, deaths due to hepatitis C related chronic liver disease would total 181,300 for the 10-year period, a 2-fold increase over the number of deaths reported in 1991. As with hospital discharges, aggregate hospital charges (i.e., the national bill ) for primary diagnoses of HE (code 572.2) and unspecified encephalopathy (code 348.30) also increased, from approximately $216 million in 1993 to more than $1.1 billion in 2004. 12 Based on 2004 data from the NIS database, patients with a principal diagnosis of HE or unspecified encephalopathy incurred mean charges per hospital stay of $22,236 and $24,378, respectively (Table 2). The NIS database does not provide data on the duration of hospital stay and associated charges for all-listed diagnoses; consequently, these charges may be estimated from charges associated with related conditions. Although such an estimate is likely to be exaggerated, the data suggest that principal diagnoses of conditions that may lead to or coexist with HE, such as portal hypertension and cirrhosis, were associated with costly hospital stays (Table 2). 12 The combined mean charges per hospital stay for principal diagnoses of HE (code 572.2) and unspecified encephalopathy (code 348.30) increased 90% from $11,910 in 1993 to $22,607 in 2004 (Fig. 3). 12 Interestingly, this increase was associated with a decrease in the mean duration of stay; the combined mean duration of stay for HE and unspecified encephalopathy decreased from 8.2 days in 1993 to 5.6 days in 2004, a reduction of 32% (Fig. 3 and Table 2). 12 The decrease in the duration of hospital stay may reflect advances in HE treatment. As noted, the NIS database has several limitations, including the potential for underestimating the costs associated with HE due to the lack of complete hospital data (e.g., duration of stay, hospital charges) for all-listed diagnoses. Nevertheless, the data suggest that direct costs associated with HE contribute to the overall costs of chronic liver disease. 12 COST-EFFECTIVENESS OF RIFAXIMIN VERSUS LACTULOSE The nonabsorbable disaccharide lactulose is the mainstay treatment for HE, although antibiotics, such as neomycin and metronidazole, are also commonly prescribed. 11 The nonabsorbable antibiotic rifaximin has been licensed in Europe for the treatment of various conditions, including HE, for 20 years. 15,16 In the United States, where rifaximin is currently approved for the treatment of travelers diarrhea caused by noninvasive strains of Escherichia coli, 15 a randomized, double-blind, placebo-controlled phase III investigation of the efficacy of rifaximin for the treatment of HE is ongoing. The cost-effectiveness of rifaximin for the treatment of HE has most often been compared with that of lactulose. 17 19 One retrospective chart review conducted at a single center included 145 patients with HE; these patients had not undergone liver transplantation and had received treatment with lactulose 60 ml/d for at least 6 months, followed by treatment with rifaximin 1200 mg/d for at least 6 months. 19 Table 2 Hospital Stay Data for HE-Related Conditions* in the United States, 2004 Diagnosis (ICD-9-CM Code) Total Number of Discharges Mean Duration of Stay (d) Mean Charges ($) Hepatic encephalopathy (572.2) 42,269 5.4 22,236 Encephalopathy, unspecified (348.30) 8693 6.6 24,378 Portal hypertension (572.3) 3219 5.3 28,766 Cirrhosis Alcoholic (571.2) 53,134 6.4 32,598 Nonalcoholic (571.5) 37,400 6.5 36,259 *Principal diagnoses only. Data from Agency for Healthcare Research Quality. HCUPnet: Healthcare Cost and Utilization Project. Available at: http://hcupnet.ahrq.gov/ HCUPnet.jsp?Id=DBE1CCF502E0C25D&Form=SelQUERYTYPE&JS=Y&Action=%3E%3ENext%3E%3E&_QUERYTYPE=Trends. Accessed February 2007. HE, hepatic encephalopathy; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

ECONOMIC IMPACT OF TREATMENT OPTIONS FOR HE/LEEVY 29 Figure 3 Trends in hospital charges and length of hospital stay for principal diagnosis of HE (code 572.2) and other types of encephalopathy (codes 348.30) from 1993 to 2004 in the United States. HE, hepatic encephalopathy. (From Agency for Healthcare Research Quality. HCUPnet: Healthcare Cost and Utilization Project. Available at: http://hcupnet.ahrq.gov/hcupnet.jsp?id=dbe1cc F502E0C25D&Form=SelQUERYTYPE&JS=Y&Action=%3E%3ENext%3E%3E&_QUERYTYPE=Trends. Accessed February 2007.) During the rifaximin treatment period, patients had significantly fewer hospitalizations (p < 0.001) and shorter hospital stays (p < 0.001) (Table 3). Hospital charges were approximately 4 times lower during the rifaximin treatment period than during the lactulose treatment period, a difference that may have been attributable to shorter stays associated with lower posttreatment severity of HE with rifaximin (Table 3). Another retrospective study evaluated the costs of treatment for 39 patients with stage 2 HE awaiting liver transplantation who had received lactulose 60 g/d or rifaximin 1200 mg/d. 17 The total number of hospitalizations and the average length of stay favored rifaximin (Table 3). The total drug cost per month was higher for rifaximin ($620) than for lactulose ($50). However, the mean total cost per year for hospitalization, emergency room visits, and drug treatment was 40% lower for patients who received rifaximin than for those who received lactulose; in addition, the mean annual total cost of therapy per patient was $5327 lower with rifaximin. The authors suggested that the initially lower economic cost associated with lactulose was negated when long-term costs, which included the cost of hospitalization, were taken into consideration. In addition to these retrospective studies reporting hospital and cost outcomes, Spiegel et al conducted a hypothetical analysis based on a systematic literature review and statistical modeling to evaluate the costeffectiveness of HE treatments. 18 This study evaluated the cost-effectiveness of 6 treatment strategies: rifaximin, lactulose, lactitol, neomycin monotherapy, lactulose Table 3 Studies Comparing Cost-Effectiveness of Rifaximin with Lactulose Outcome Parameter Rifaximin (1200 mg/d) Leevy 19 Patients, n 145 145 Hospitalizations, n, mean 0.5* 1.6 Duration per hospitalization, days, mean 2.5* 7.3 Lactulose (60 g/d) Hospital charges per patient, $ y 14,222 56,635 HE stage 3 or 4 9 (6)* 36 (25) posttreatment, n (%) Asterixis posttreatment, n (%) 91 (63)* 135 (93) Neff et al 17 Patients, n 15 24 Hospitalizations, n 3 19 Duration per hospitalization, days, mean 3.5 z 5.0 Annual cost of therapy 7958 13,285 per patient, $, mean Total annual costs, $, mean 119,372 318,839 *p < 0.001 versus lactulose. y Calculated in 2005 dollars based on 2003 data from the HCUP for a principal diagnosis of HE (572.2). p < 0.0001. Calculation took into account annual cost of hospitalization, emergency room visits, and drug costs. Data from Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 2007;52:737 741; and Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 2006;38:3552 3555. HE, hepatic encephalopathy.

30 SEMINARS IN LIVER DISEASE/VOLUME 27, SUPPLEMENT 2 2007 Table 4 Summary of Cost-Effectiveness of Rifaximin versus Lactulose in the Treatment of HE Measure Cost-Effectiveness Frequency and duration of hospitalizations Hospitalization charges Total drug cost per month Total cost of hospitalization, emergency room visits, and drug costs rifaximin < lactulose rifaximin < lactulose rifaximin > lactulose rifaximin < lactulose Data from Leevy CB, Phillips JA. Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 2007;52:737 741; and Neff GW, Kemmer N, Zacharias VC, et al. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 2006;38:3552 3555. HE, hepatic encephalopathy. followed by rifaximin, and no treatment. Patients were 50 years of age and had either stage 1 (minimal) or stage 2 HE. The total lifetime combined cost of care was estimated to be lowest for lactulose ($56,967) and highest for rifaximin ($75,671). Treatment with lactulose followed by rifaximin was calculated to be the most effective with regard to discounted cost per life-years gained (6.9 life-years vs 3.86 life-years for no treatment), but it was less cost-effective than lactulose monotherapy. The authors concluded that rifaximin is not cost-effective as first-line therapy but that it may be highly costeffective when used as salvage therapy for patients who do not respond to lactulose. 18 To date, the findings of this study have only been published as a meeting abstract and have not yet appeared in a peer-reviewed journal. Because this study was a hypothetical modeling analysis based on a narrow patient population, it is difficult to draw conclusions about the direct cost of rifaximin compared with other treatments or about the costeffectiveness of these HE treatments in patients with moderate or severe HE. In summary, rifaximin appears to be more costeffective than lactulose. 17 19 Two retrospective chart reviews showed that rifaximin treatment resulted in lower health care utilization and costs compared with lactulose (Table 4) 17 19 and suggested that rifaximin may provide long-term economic benefit. CONCLUSION The economic burden of chronic liver disease, cirrhosis, and chronic hepatitis C is substantial, contributing to estimated annual direct costs of more than $2.1 billion and indirect costs of more than $272 million. In recent years, HE diagnoses and charges for inpatient HE treatment have increased, raising the overall economic impact of chronic liver disease. An increase in hospital charges for inpatient HE treatment has been coupled with a decrease in the mean duration of hospital stays for HE treatment. The reason for the trend toward shorter hospital stays is unclear, but advances in HE treatment may play a role. The costs associated with HE treatment can affect the overall economic burden of the condition. Studies of the cost-effectiveness of specific HE treatments are lacking, but several published studies have compared the cost-effectiveness of the nonabsorbable disaccharide lactulose with that of the nonabsorbable antibiotic rifaximin. These studies showed that, although rifaximin costs more per month than lactulose, rifaximin therapy is associated with lower hospital utilization, hospital charges, and overall cost than lactulose. Over the course of long-term therapy, rifaximin was found to be more cost-effective than lactulose. In conclusion, when the long-term economic benefits of various HE treatments are considered, a higher short-term economic burden of newer treatments may provide greater overall economic benefits over the long term. ABBREVIATIONS HCUP Healthcare Cost and Utilization Project HE hepatic encephalopathy ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification NIS Nationwide Inpatient Sample REFERENCES 1. American Gastroenterological Association. The Burden of Gastrointestinal Diseases. Chapter 5: Hepatobiliary and pancreatic disorders. Available at: www.gastro.org/user-assets/ Documents/burden-report.pdf. Accessed January 5, 2007 2. Mas A. Hepatic encephalopathy: from pathophysiology to treatment. Digestion 2006;73(suppl 1):86 93 3. Abou-Assi S, Vlahcevic ZR. Hepatic encephalopathy: metabolic consequence of cirrhosis often is reversible. Postgrad Med 2001;109:52 60, 63 4. Amodio P, Del Piccolo F, Petteno E, et al. 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