1 Diagnosis and Treatment of Minimal Hepatic Encephalopathy to Prevent Motor Vehicle Accidents: A Cost-Effectiveness Analysis Jasmohan S. Bajaj, 1,2 Steven D. Pinkerton, 3 Arun J. Sanyal, 1 and Douglas M. Heuman 1 Minimal hepatic encephalopathy (MHE) in cirrhosis is associated with impaired driving skills and increased risk of motor vehicle accidents (MVAs). Detection and treatment of MHE has the potential to reduce costs and morbidity associated with MVAs. We conducted a cost-effectiveness analysis to assess the benefits of different strategies of MHE diagnosis and treatment for reducing MVA-related societal costs. The analyses compared five MHE management strategies: (1) presumptive treatment of all cirrhosis patients; (2) diagnosis by neuropsychological exam (NPE) with treatment; (3) diagnosis by standard psychometric tests (SPTs) with treatment; (4) diagnosis by rapid screening using inhibitory control test (ICT) with treatment; and (5) no MHE diagnosis or treatment (status quo). Treatments considered were lactulose or rifaximin, which were assumed to reduce the MVA rate to the level of similarly aged noncirrhosis patients with benefit adjusted for treatment compliance. A Markov model followed a simulated cohort of 1,000 cirrhosis patients without overt hepatic encephalopathy (OHE), from entry into treatment, through MHE development, and later OHE, when they exited the modeled cohort. Follow-up was for 5 years and included biannual MHE testing. The societal cost of a single MVA was estimated at $42,100. All four strategies with lactulose were cost-saving compared with the status quo. Diagnosis with ICT and lactulose was the most cost-effective approach (cost/ MVA prevented: $24,454 ICT; $25,470 SPT; $30,469 presumptive treatment and $33,742 NPE). Net program savings over 5 years ranged from $1.7 to 3.6 million depending on the strategy. Rifaximin therapy was not cost-saving at current prices but would become so at a monthly cost of <$353. Conclusion: Detection of MHE, especially using the ICT, and subsequent treatment with lactulose could substantially reduce societal costs by preventing MVAs. (HEPATOLOGY 2012;55: ) See Editorial on Page 985 Minimal hepatic encephalopathy (MHE) is present in approximately 55% of cirrhosis patients tested. 1-4 MHE increases the risk of development of overt hepatic encephalopathy (OHE) and adversely affects survival. 5 MHE also is associated with impaired driving skills and a significantly higher risk of motor vehicle crashes 6,7 due to the attention and visuomotor coordination deficits associated with this condition. Driving impairment is highly correlated with diminished psychometric performance There are several methods for the diagnosis of MHE, including a comprehensive neuropsychological exam (NPE), standard psychometric batteries, neurophysiological testing, and computerized testing These modalities are usually copyrighted and require psychological Abbreviations: ICT, inhibitory control test; MHE, minimal hepatic encephalopathy; MVA, motor vehicle accident; NPE, neuropsychological exam; OHE, overt hepatic encephalopathy; PHES, Psychometric Hepatic Encephalopathy Score; QOL, quality of life; SPT, standard psychometric test battery. From the 1 Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 2 Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI; 3 Center for AIDS Intervention Research, Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI.. Received August 31, 2011; accepted November 18, Supported, in part, by grant P30MH52776 from the National Institute of Mental Health, by grant U01AT from the National Center for Complementary and Alternative Medicine, by grant R01DK087913, from the National Institute of Diabetes and Digestive and Kidney Diseases, and by an American College of Gastroenterology Junior Faculty Development Award grant. Portions of this article were presented as an oral presentation at the American College of Gastroenterology Annual Meeting in Orlando and the abstract was awarded the ACG Board of Governors Award for Excellence in Clinical Research. 1164
2 HEPATOLOGY, Vol. 55, No. 4, 2012 BAJAJ ET AL or neurological expertise for procuring, administration, and interpretation in the U.S., increasing associated costs and reducing access. 1 An American Association for the Study of Liver Diseases (AASLD) survey demonstrated that the majority of hepatologists were not able to test cirrhosis patients for MHE, partly due to the lack of availability of testing techniques. 14 Highsensitivity tests that can be administered by personnel without specialized expertise, such as the inhibitory control test (ICT), offer a potentially cost-effective method for diagnosing MHE. 6,15,16 The ICT is a computerized test of attention and response inhibition which is inexpensive and is well correlated with driving impairment. 6,9,15 Abnormalities in ICT and standard psychometric tests have been shown to be related to driving offenses and vehicular crashes. 6,17,18 The societal costs associated with motor vehicle accidents (MVAs) include productivity losses, medical expenses, motor vehicle damage, employers uninsured costs, and administrative expenses. 19 The high cost of vehicular accidents estimated at more than $200 billion per year in the United States 20 necessitates investigation of treatable forms of driving impairment, such as MHE. Lactulose therapy has been tested extensively for patients diagnosed with MHE. 13 Lactulose is inexpensive and has been shown to reverse MHE-based performance deficits on psychometric tests. 10,21,22 However, lactulose adherence is relatively poor, in large part due to gastrointestinal adverse effects. 10,21-23 Rifaximin, which also has been used as a therapy for MHE, has a much better adherence profile. Moreover, rifaximin has been shown to improve driving simulator performance in a placebo-controlled randomized trial. 25 We report here the results of a model-based costeffectiveness of MHE diagnosis and subsequent pharmaceutical treatment (lactulose or rifaximin) to reduce MVAs among cirrhosis patients. The analyses compared four potential strategies for diagnosing and treating MHE with a no-treatment alternative. Because the effectiveness of pharmaceutical treatments with respect to reducing accidents among treated patients has not been well established, we conducted extensive sensitivity analyses around this key parameter. The aim was to provide a cost-effectiveness platform for MHE diagnosis and Table 1. Diagnostic Test Parameters Test Cost treatment from a societal perspective and tailored to individual treatment options available in the U.S. Materials and Methods Time (Hours) Base-Case Sensitivity Base-Case Specificity Presumptive treatment $ % 0% Inhibitory control test (ICT) $ % 85% Standard psychometric test (SPT) $ % 85% Neuropsychological examination $ % 100% The cost-effectiveness analysis combined a Markov model of progression from cirrhosis without MHE, to MHE, to OHE, with empirically derived and literature-based estimates of MHE diagnostic tests and treatment parameters and MVA-related parameters. The analysis adopted a societal perspective and included time costs borne by patients, as well as the societal costs associated with MVAs. All future costs and benefits were discounted at a 3% annual rate (0% and 5% in the sensitivity analyses) in accordance with recommended practice. 27 The results are expressed in base-year 2010 dollars. The Markov model followed a simulated cohort of 1,000 cirrhosis patients with compensated liver disease and without OHE, from entry into treatment (at which point they might or might not have MHE), through the potential development of MHE, and later OHE, at which time they exited the modeled cohort. The model assumed that cirrhosis patients were screened for MHE on a semiannual basis. 12,13 State changes within the Markov model also occurred at 6-month intervals. Annual state-transition probabilities, from non-mhe cirrhosis to MHE, and from MHE to OHE, were derived from a published study. 28 Six-month state-transition values were derived from these annual probabilities using the equation: p(6 mo) ¼ 1 (1 p(12 mo)) 0.5. The baseline prevalence of MHE was set to 55%. 2-5,15,21,24,29 The simulated cohort of cirrhosis patients was followed for a total of 5 years. The main analysis compared four diagnostic strategies: (1) presumptive treatment of all cirrhosis Address reprint requests to: Jasmohan S. Bajaj, M.D., M.S., Associate Professor, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, VA fax: Copyright VC 2011 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Nothing to report.
3 1166 BAJAJ ET AL. HEPATOLOGY, April 2012 Table 2. Model Parameter Values Parameter Values* Source Prevalence of MHE among patients 55% (50%-60%) Das et al.(2), Sharma et al.(3), Gitlin et al.(4), Romero-Gomez et al.(5), Rikkers et al.(29) Annual progression: No MHE to MHE 19% (0%-50%) Huang et al.(28) Annual progression: MHE to OHE 23% (0%-50%) Huang et al.(28) Rapid test (ICT) sensitivity 90% (70%-95%) Bajaj et al., Amodio et al.(6,15,16) Rapid test (ICT) specificity 85% (80%-90%) Bajaj et al., Amodio et al.(6,15,16) Standard psychological test (SPT) sensitivity 95% (90%-100%) Weissenborn et al.(35). Standard psychological test (SPT) specificity 85% (80%-90%) Weissenborn et al.(35). Lactulose adherence 70% (50%-90%) Dhiman et al.(10), Prasad et al.(16), Horsmans et al.(18) Rifaximin adherence 95% (90%-99%) Bajaj et al.(25), Sidhu et al.(24), Accidents per year, untreated MHE 0.18 ( ) Bajaj et al. and Gad et al. (6,17,18) Accidents per year, treated/adherent MHE ( ) NHTSA (26) (age ¼ 45-65) Bajaj et al (17) Value of patient time, per hour $19.25 (0-$21.50) Bureau of Labor Statistics (30) (age ¼ 45-65) Economic discount rate 3% (0%-5%) Gold et al.(27) *Base-case value (values examined in sensitivity analyses) MHE: minimal hepatic encephalopathy, OHE: overt hepatic encephalopathy, ICT: inhibitory control test. patients (100% sensitivity); (2) rapid screening using the inhibitory control test (sensitivity ¼ 90% and specificity ¼ 85% based on previous studies 6,15 ): (3) standard psychometric test (SPT) battery (sensitivity ¼ 95% and specificity ¼ 85%); and (4) full NPE (the gold standard : 100% sensitive and specific). Test costs and patient time for the four diagnostic test options were based on the authors experiences at their home institutions 15 (Table 1). The cost for SPT was varied to reflect its use in other countries. Patient time was valued at $19.25 per hour based on Bureau of Labor Statistics averages for persons aged 45 to 64, assuming a 90% employment rate. 30 The analyses assumed that patients who tested MHEpositive would be treated with either lactulose at a monthly cost of $ or rifaximin 550 mg twice daily at a monthly cost of $1,120 to reduce cognitive impairment and, consequently, the likelihood of involvement in an MVA Limited information is available from randomized clinical trials regarding lactulose adherence. 10,21-23 Adherence is greater than 80% in MHE clinical trials, but gastrointestinal adverse effects often force poor compliance or reduction in dosage in patients outside of trials In the main analysis, lactulose adherence was set to 70% (range: 50% to 90%) and rifaximin adherence was set to 95% (range: 90% to 99%). Recent studies have found a 0.17 to 0.19 per-person annual crash rate for patients with MHE, versus no MVAs among cirrhosis patients without MHE. 6,17,18 The analyses assumed that effective pharmaceutical therapy would reduce the crash rate to the baseline level, 0.039, for a similarly aged cohort of persons without cirrhosis, 20 and that patients who developed OHE discontinued driving but those who developed decompensated cirrhosis due to reasons other than OHE were still able to drive. The cost-effectiveness analysis compared the overall cost of MHE diagnosis and treatment (including patient time costs) to the societal savings that are realized by preventing MVAs through effective management of the cognitive impairment observed in MHE patients. The cost-effectiveness ratio for a particular diagnostic strategy (cost per MVA prevented) can be expressed as (C þ Tk) / EAR, where C is the total cost of screening patients for MHE during the 5-year period; T is the total number of treatment months for patients who test (true or false) positive for MHE; k is the cost of treatment, per month; E is the number of effective treatment months (i.e., the number of treatment-adherent months for true positives); A is the number of accidents per month for patients with untreated MHE; and R is the reduction in the accident rate due to effective treatment. The cost-effectiveness ratio can be interpreted as the total (gross) cost per MVA prevented by the screening strategy when MHE-positive diagnoses are followed by a specific treatment protocol. National Highway and Traffic Administration data estimate the average societal cost per MVA to be $42, Consequently, the net cost of a testing/ treatment strategy equals (C þ Tk) ($42,100)EAR. If this value is negative, then the diagnostic/treatment strategy is cost-saving (i.e., the monetary benefits of the testing and treatment program exceed the costs). When more than one diagnostic strategy is cost-saving, the preferred strategy is the one with the smaller net cost because it generates greater societal savings. If no strategy is cost-saving, the preferred strategy is the one with the smallest cost-effectiveness ratio. Naturally, if one strategy is cost-saving and another is not, the one that generates societal savings is preferred over the one with a positive net cost.
4 HEPATOLOGY, Vol. 55, No. 4, 2012 BAJAJ ET AL Table 3. Cost-Effectiveness of MHE Screening and Treatment with Lactulose: Main Results over 5 Years Table 2 lists key modeling parameters, values used in the analyses, and the sources of these parameter values. One-way (univariate) analyses were conducted for all key parameters to account for uncertainty in basecase estimates. Additional sensitivity analyses were conducted as needed. Results Presumptive Treatment Inhibitory Control Test Standard Psychometric Neuropsychological Battery Exam Total program cost ($) 6.3M 4.9M 5.2M 6.9M Screening/testing 0 49, , M costs ($) Patient time costs ($) 0 11,976 23, ,952 Treatment costs ($) 6.3M 4.9M 4.9M 3.8M Accidents prevented Societal savings ($) 8.7M 8.5M 8.6M 8.7M Net program cost ($) -2.4M -3.6M -3.4M -1.7M Cost per accident prevented ($) 30,469 24,454 25,470 33,742 The results of the main analysis for lactulose therapy are presented in Table 3. Diagnosis of MHE followed by lactulose therapy was cost-saving for all four of the diagnostic strategies considered in the analyses compared with the status quo of no testing or treatment. Rapid screening using ICT was the most cost-effective of the diagnostic strategies, just marginally ahead of the SPT. The cost per accident prevented in this scenario ($24,454 over the 5-year analysis period) was considerably less than the societal cost associated with a single MVA ($42,100). Screening 1,000 patients at 6-month intervals and treating MHE-positive patients with lactulose would cost $4.9 million and prevent 202 crashes over 5 years. During this time the rapid ICT screening plus lactulose treatment scenario would generate $8.5 million in crash-related savings, for a net savings of $3.6 million. Similar results were obtained for the standard tests, which was just slightly less costeffective than the ICT (Table 3). ICT remained costeffective even when the SPT was reduced to $35; if the cost of SPT reduced below $35, then it became the most cost-effective strategy. The remaining diagnostic strategies (presumptive treatment and comprehensive NPE) each prevented more crashes than rapid ICT screening or standard tests, but did so at substantially greater costs. MHE diagnosis followed by lactulose therapy remained cost-saving for all four diagnostic strategies and for all of the parameter values examined in the univariate sensitivity analyses (Table 4), with two exceptions. The results were somewhat sensitive to the lactulose adherence rate, which was varied from 50% to 90%, and to the MHE and OHE progression rates. However, this uncertainty did not change the costeffectiveness rankings of the four diagnostic screening options. The main analysis assumed that effective and adherent MHE treatment would reduce the crash rate from 0.18 to the baseline level, 0.039, for a similarly aged Table 4. 5-Year Sensitivity Analysis Results: Cost per Accident Prevented ($)* Parameter (Base-Case Value) PT ICT SPT NPE MHE prevalence (55%) 50% 32,405 25,421 26,546 35,697 60% 28,685 23,562 24,478 31,939 Annual progression: No MHE to MHE (19%) 0% 42,929 32,221 33,768 45,647 50% 23,485 20,332 21,022 26,821 Annual progression: MHE to OHE (23%) 0% 25,930 22,122 22,773 27,988 50% 38,874 28,852 30,506 44,396 ICT sensitivity (90%) 70% N/A 24,804 N/A N/A 95% N/A 24,390 N/A N/A ICT specificity (85%) 80% N/A 25,596 N/A N/A 90% N/A 22,997 N/A N/A SPT sensitivity (95%) 90% N/A N/A 25,559 N/A 100% N/A N/A 25,390 N/A SPT specificity (85%) 80% N/A N/A 26,494 N/A 90% N/A N/A 24,162 N/A Lactulose adherence (70%) 50% 42,657 34,236 35,658 47,238 90% 23,698 19,020 19,810 26,243 Accidents per year, untreated MHE (0.180) ,795 26,321 27,414 36, ,451 22,835 23,783 31,507 Accidents per year, treated MHE (0.039) ,225 23,456 24,430 32, ,823 25,541 26,602 35,241 Value of patient time, per hour ($19.25) $0 30,469 24,395 25,354 31,717 $ ,469 24,461 25,483 33,978 Economic discount rate (3%) 0% 30,403 24,511 25,499 33,561 5% 30,512 24,417 25,451 33,860 PT: presumptive treatment; ICT: inhibitory control test; SPT: standard test battery; NPE: neuropsychological examination; MHE: minimal hepatic encephalopathy; OHE: overt hepatic encephalopathy. *Base-case results (cost per accident prevented): $30,469 for presumptive treatment; $24,454 for ICT; $25,470 for SPT; and $33,742 for neuropsychological exam.
5 1168 BAJAJ ET AL. HEPATOLOGY, April 2012 Table 5. Cost-Effectiveness of MHE Screening and Treatment with Rifaximin: Main Results over 5 Years Presumptive Treatment Inhibitory Control Test Standard Psychometric Battery Neuropsychological Exam Total program cost ($) 46.9M 36.5M 37.0M 31.2M Screening/testing 0 49, , M costs ($) Patient time costs ($) 0 11,976 23, ,952 Treatment costs ($) 46.9M 36.5M 36.7M 28.0M Accidents prevented Societal savings ($) 11.8M 11.6M 11.7M 11.8M Net program cost ($) 35.1M 25.0M 25.3M 19.5M Cost per accident prevented ($) 167, , , ,760 Fig. 1. Cost per accident prevented for the four diagnostic strategies considered in the analyses when combined with lactulose treatment. The ICT plus lactulose treatment is cost-saving for 44% and greater reductions in the accident rate for MHE patients. Larger accident rate reductions are necessary to achieve cost savings in the SPT battery, the NPE, and the presumptive treatment plus lactulose scenarios. cohort of persons without cirrhosis that is, that it would reduce the accident rate by 78.3%. Although rifaximin has been shown to improve simulator performance, the effectiveness of lactulose or rifaximin treatment with respect to reducing crashes among treated patients has not been well established. Therefore, we conducted an additional sensitivity analysis around this key parameter. As illustrated in Fig. 1, ICT screening plus lactulose treatment would remain cost-saving even if the reduction in crash rates were as small as 46%, rather than 78.3% as assumed in the base-case analysis. The results of the analyses for rifaximin therapy differed substantively from those for lactulose in two main respects (Table 5). First, the NPE rather than ICT was the most cost-effective of the four screening strategies, and second, none of the four screening strategies was cost-saving when paired with rifaximin treatment due to the high monthly cost of this treatment. The cost per crash prevented ranged from $111,760 for the NPE to more than $167,000 for presumptive treatment. We conducted a threshold analysis to determine by how much the monthly cost of rifaximin would need to be reduced in order for screening plus rifaximin treatment to be cost-saving. This analysis indicated that ICT plus rifaximin would be cost-saving if rifaximin cost no more than $353 per month. Of note, at this cost, ICT was the most cost-effective of the four diagnostic strategies, as shown in Fig. 2. Discussion There are no current guidelines for the diagnosis or treatment of MHE in patients with cirrhosis, despite ample evidence that patients with MHE have a higher rate of motor vehicle crashes, poor quality of life (QOL), and increased progression to OHE. 5 The results of the preceding analyses indicate that diagnosis of MHE followed by lactulose therapy could result in substantial societal cost savings by preventing MVAs among MHE patients. In contrast, because of its high monthly cost, treatment with rifaximin is unlikely to generate overall cost savings unless the rifaximin monthly cost is substantially reduced. 28 The results also suggest that, when combined with lactulose treatment, screening using the ICT or a standard test battery is more cost-effective than either presumptive treatment of all cirrhosis patients or conducting comprehensive NPE to detect MHE. Fig. 2. Cost per accident prevented for the four diagnostic strategies considered in the analyses when combined with rifaximin treatment. The ICT plus rifaximin treatment would be cost-saving if the monthly cost of rifaximin were less than $353 (cf., $348 for the SPT battery; $342 for an NPE; and $281 for presumptive treatment).
6 HEPATOLOGY, Vol. 55, No. 4, 2012 BAJAJ ET AL We used NPE as the gold standard because it involves an evaluation of multiple dimensions including psychologist interview, detailed cognitive testing, mood, psychiatric, and substance abuse disorder assessments. This is usually performed as part of pretransplant evaluation and gives a deeper appreciation of factors that could confound the ultimate cognitive testing results. Before performing the ICT or SPT, this information is sought from the medical record or patient interview to exclude confounders. Therefore, this was used as the standard to which the smaller cognitive batteries are compared. The standard batteries vary between investigators and studies but are a collection of several recommended cognitive tests such as number connection test- A/B, digit symbol, and block design tests which are also components of the Psychometric Hepatic Encephalopathy Score (PHES). 1,35 Although these tests are recommended and validated for diagnosis of MHE, most components do not have norms for the U.S. population. 36 In addition, in the U.S. a psychologist is required to procure, administer, and interpret the results, adding to the barriers in testing. Therefore, unlike other countries, the use of standard tests for the diagnosis of MHE clinically remains difficult in the U.S. Tests such as the ICT have been used that, unlike standard psychologistadministered test batteries, are not copyrighted. 6 The ICT costs less than an SPT battery because it can be administered by clinical assistants with minimal training. 15 Similar results were obtained for the ICT and SPT in this study, indicating that both are cost-saving and could potentially be used depending on the availability of expertise and norms. ICT remained cost-effective compared with SPT even when the cost of SPT was reduced to less than $35; this would be applicable in other countries provided all other parameters, e.g., cost for rifaximin and lactulose, was the same. Another possible strategy, especially in populations that have a high prevalence of MHE, would be to presumptively treat every cirrhosis patient with lactulose or rifaximin without prior diagnostic testing. Although this strategy is theoretically appealing, the adverse effects of lactulose are associated with poor adherence even in OHE patients who have significant symptoms from their encephalopathy. 34,37 It is unlikely that patients with MHE most of whom do not suffer from any specific symptoms and have poor insight would be adherent on a medication with these adverse effects. 38 Adherence would potentially be higher on rifaximin; however, this strategy is limited by the associated costs, which are the highest for the presumptive treatment with rifaximin category. Adherence would also be expected to increase if patients impaired psychometric performance were demonstrated to them. 39 Therefore, the additional step of testing (e.g., using the ICT or an SPT battery) and selectively treating only those impaired would not only increase adherence but also avoid the unnecessary adverse effects or costs of therapy in those who do not have cognitive abnormalities. There is ample evidence regarding the use of rifaximin in the therapy of both MHE and OHE. 24,25,40 It is well tolerated and had good efficacy in these conditions. However, the cost of rifaximin therapy is almost 10 times that of lactulose. 26 Therefore, we found in our analysis that in contrast to the findings for lactulose, the comprehensive NPE was the most cost-effective diagnostic strategy when combined with rifaximin therapy (although it was not cost-saving). This finding is due to the high cost of rifaximin, which in turn places a premium on reducing the number of patients who test false-positive and are unnecessarily started on rifaximin. The analyses assumed 100% specificity for NPEs, which reduced the number of false-positives to zero. The supplementary threshold analysis indicated that ICT followed by rifaximin treatment would be cost-saving if the monthly cost of rifaximin was reduced to no more than $353 per month. Of note, at this cost ICT rather than the NPE was the most costeffective of the four diagnostic strategies. Despite uncertainties in several key parameter values, the results of the analysis were quite robust. When combined with lactulose therapy, all four diagnostic strategies were cost-saving for all but a small number of the parameter values examined in the univariate sensitivity analyses. However, if all model parameters were set to their least favorable values, screening plus lactulose might no longer be cost-saving. Given the generous margins of the sensitivity analyses, this is not likely to be a concern. The limitations of the assumptions, specifically regarding reduction in MVA with lactulose or rifaximin, are evident. However, a trial that actually randomizes MHE patients into placebo or drug, given the prior background evidence, and follows them up for several years for possible MVA development is likely to be very expensive and impossible to conduct ethically. Therefore, extensive sensitivity parameters around assumptions around which there are no specific data available were made. The cost-effectiveness analyses focused on MVAs as an objective endpoint that is known to be associated with the attention deficits and psychometric impairments present in MHE. 6 Other clinically relevant endpoints of MHE therapy could include development of OHE, improvement of health-related QOL (HRQOL),
7 1170 BAJAJ ET AL. HEPATOLOGY, April 2012 and employment. The analyses did not consider potential improvements in the HRQOL of patients diagnosed with MHE and subsequently treated because an objective endpoint such as MVA was preferred. 21,24,25 And the results of the analyses presented above indicate that diagnosis and treatment of MHE can be cost-saving when the potential reduction in MVAs is considered. These assumptions are based solely on the practice, logistic, and research constraints that exist in the U.S. and cannot be readily applied to countries in which standard batteries are freely available or where medications other than lactulose and rifaximin are in widespread use. We also did not include neurophysiological modalities such as EEG or evoked potentials because they require neurological expertise with added costs. Critical flicker frequency was also not considered, even though it has good validity in MHE, because of its lack of availability of norms and equipment required to use it. However, it is well known that MHE affects several aspects of cognition and all testing strategies can detect some variant of the spectrum of the neurocognitive impairment in cirrhosis. We only included the ones that are being used in clinical research in the U.S. at this time. The analyses provide strong evidence that the development and implementation of effective strategies to diagnose and treat MHE could save society money by reducing the incidence of MVAs among MHE patients. Further investigation into the societal cost of cognitive dysfunction in cirrhosis is important to encourage routine diagnosis and therapy of MHE beyond the research setting. References 1. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, HEPATOLOGY 2002;35: Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 2001;16: Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007; 47: Gitlin N, Lewis DC, Hinkley L. The diagnosis and prevalence of subclinical hepatic encephalopathy in apparently healthy, ambulant, nonshunted patients with cirrhosis. J Hepatol 1986;3: Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar- Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96: Bajaj JS, Hafeezullah M, Hoffmann RG, Saeian K. Minimal hepatic encephalopathy: a vehicle for accidents and traffic violations. Am J Gastroenterol 2007;102: Wein C, Koch H, Popp B, Oehler G, Schauder P. Minimal hepatic encephalopathy impairs fitness to drive. HEPATOLOGY 2004;39: Watanabe A, Tuchida T, Yata Y, Kuwabara Y. Evaluation of neuropsychological function in patients with liver cirrhosis with special reference to their driving ability. Metab Brain Dis 1995;10: Bajaj JS, Hafeezullah M, Hoffmann RG, Varma RR, Franco J, Binion DG, et al. Navigation skill impairment: another dimension of the driving difficulties in minimal hepatic encephalopathy. HEPATOLOGY 2008; 47: Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000;45: Ortiz M, Jacas C, Cordoba J. Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 2005;42 (Suppl):S Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, et al. Review article: the design of clinical trials in hepatic encephalopathy an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther 2011;33: Mullen K, Ferenci P, Bass NM, Leevy CB. An algorithm for the management of hepatic encephalopathy. Semin Liver Dis 2007;27: Bajaj JS, Etemadian A, Hafeezullah M, Saeian K. Testing for minimal hepatic encephalopathy in the United States: an AASLD survey. HEPA- TOLOGY 2007;45: Bajaj JS, Hafeezullah M, Franco J, Varma RR, Hoffmann RG, Knox JF, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008;135: e Amodio P, Ridola L, Schiff S, Montagnese S, Pasquale C, Nardelli S, et al. Improving the inhibitory control task to detect minimal hepatic encephalopathy. Gastroenterology 2009;139: , 518 e Bajaj JS, Saeian K, Schubert CM, Hafeezullah M, Franco J, Varma RR, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. HEPATOLOGY 2009;50: Gad YZ, Zaher AA, Moussa NH, El-Desoky AE, Al-Adarosy HA. Screening for minimal hepatic encephalopathy in asymptomatic drivers with liver cirrhosis. Arab J Gastroenterol 2011;12: Sharma BR. Road traffic injuries: a major global public health crisis. Public Health 2008;122: Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. HEPATOLOGY 2007;45: Watanabe A, Sakai T, Sato S, Imai F, Ohto M, Arakawa Y, et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. HEPATOLOGY 1997;26: Horsmans Y, Solbreux PM, Daenens C, Desager JP, Geubel AP. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997;11: Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 2011;106: Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA, et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 2011;140: e Bajaj JS, Riggio O. Drug therapy: rifaximin. HEPATOLOGY 2011;52: Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-Effectiveness in Health and Medicine. Oxford, UK: Oxford University Press; 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 HEPATOLOGY, Vol. 55, No. 4, 2012 BAJAJ ET AL Rikkers L, Jenko P, Rudman D, Freides D. Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 1978;75: Riggio O, Ridola L, Pasquale C, Nardelli S, Pentassuglio I, Moscucci F, et al. Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy. Clin Gastroenterol Hepatol 2010;9: Red Book ed. Montvale, NJ: Thomson Healthcare Inc., Kalaitzakis E, Bjornsson E. Lactulose treatment for hepatic encephalopathy, gastrointestinal symptoms, and health-related quality of life. HEPA- TOLOGY 2007;46: ; author reply Kalaitzakis E, Simren M, Olsson R, Henfridsson P, Hugosson I, Bengtsson M, et al. Gastrointestinal symptoms in patients with liver cirrhosis: associations with nutritional status and health-related quality of life. Scand J Gastroenterol 2006;41: 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: Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34: Iduru S, Mullen KD. The demise of the pencil? New computer-assisted tests for minimal hepatic encephalopathy. Gastroenterology 2008;135: Conn H. Hepatic Encephalopathy: Management with Lactulose and Related Carbohydrates. East Lansing, MI: Medi-Ed Press; Bajaj JS, Saeian K, Hafeezullah M, Hoffmann RG, Hammeke TA. Patients with minimal hepatic encephalopathy have poor insight into their driving skills. Clin Gastroenterol Hepatol 2008;6: ; quiz Bajaj JS, Thacker LR, Heuman DM, Gibson DP, Sterling RK, Todd Stravitz R, et al. Driving simulation can improve insight into impaired driving skills in cirrhosis. Dig Dis Sci 2011 [Epub ahead of print]. 40. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: