Impact of rifaximin use following an initial overt hepatic encephalopathy hospitalization on rehospitalization and costs.

AIM: To assess the impact of rifaximin (± lactulose) use following discharge of an initial overt hepatic encephalopathy (OHE) hospitalization on OHE rehospitalizations and healthcare costs in a real-world setting. METHODS: Adults (18-64 years) with an OHE hospitalization were identified from MarketScan® Commercial claims (Q4'15-Q2'20), classified into two mutually exclusive treatment cohorts (i.e. rifaximin and no rifaximin treatment), and further stratified into four subgroups based on decreasing quality of care (QoC; i.e. Type 1 - rifaximin without delay post-discharge; Type 2 - rifaximin with delay post-discharge; Type 3 - lactulose only post-discharge; Type 4 - no rifaximin/lactulose treatment post-discharge). The impact of rifaximin use on 30-day and annualized OHE hospitalizations and healthcare costs were assessed between cohorts and by the QoC subgroup. RESULTS: Characteristics were similar between the rifaximin (N = 1,452; Type 1: 1,138, Type 2: 314) and no rifaximin (N = 560; Type 3:337, Type 4: 223) treatment cohorts. The 30-day risk of OHE rehospitalization was lower for the rifaximin vs. no rifaximin treatment cohort (odds ratio 0.56, p < .01) and increased with decreasing QoC. The annual rate of OHE hospitalizations was 59% lower for the rifaximin treatment cohort (incidence rate ratio 0.41, p < .01) and increased with decreasing QoC. Compared to the no rifaximin treatment cohort, the rifaximin treatment cohort had higher pharmacy costs, lower medical costs, and no difference in total healthcare costs. LIMITATIONS: This was a claims-based study subject to common data limitations such as billing inaccuracies or omissions in coded claims. Total healthcare costs were reported from a payer's perspective, which do not capture indirect costs associated with patient burden. CONCLUSIONS: Initiation of rifaximin after an OHE hospitalization was associated with reduced OHE hospitalizations both in the 30-days following and annually. Further, reduced medical costs offset increased pharmacy costs, and no annual cost differences were observed between cohorts.

High rifaximin out-of-pocket costs are associated with decreased treatment retention among patients with hepatic encephalopathy.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is associated with significant morbidity and mortality for those with cirrhosis. Despite the known benefits of rifaximin use for HE, treatment retention remains low. This study aimed to evaluate the impact of out-of-pocket (OOP) rifaximin cost on treatment retention among commercially insured patients in the United States. METHODS: Adult patients with cirrhosis and HE were identified from the IBM MarketScan claims database. Those who began rifaximin treatment between January 1, 2011, and December 1, 2021 were included. Regression models were used to analyze the relationship between patients' 30-day OOP rifaximin cost and rifaximin retention (≥80% eligible days with rifaximin supply) at 180, 360, and 540 days. Models were controlled for patient demographic and clinical characteristics including age, sex, comorbid conditions, Charlson comorbidity index (CCI), and lactulose use. RESULTS: A total of 6839 adult patients were included. Most patients were between 55 and 64 years (57.1%), male (60.4%), and living in urban settings (84.6%). Treatment retention was low for all time periods; retention rates for rifaximin were 42%, 25%, and 16% at 180, 360, and 540 days, respectively. In multivariable analysis, 30-day OOP costs of ≥ $150 were associated with a decreased likelihood of rifaximin retention at 180, 360, and 540 days [relative risk (RR) = 0.67, RR = 0.62, and R = 0.60, respectively]. Younger age was associated with reduced treatment retention for all time periods. Metastatic cancer and depression were associated with reduced treatment retention at 180 days (RR = 0.70 and RR = 0.87, respectively). CONCLUSIONS: Rates of rifaximin treatment retention are low despite the known benefits of rifaximin use for breakthrough HE. High 30-day OOP cost is associated with reduced rifaximin treatment retention.

L-Ornitina L-Aspartato en el tratamiento de la encefalopatía hepática / L-Ornithine L-Aspartate in the treatment of hepatic encephalopathy

DESCRIPCIÓN DEL PROBLEMA DE SALUD: La cirrosis es un trastorno crónico del hígado. Los pacientes con esta afección desarrollan por lo general encefalopatía hepática, una complicación que da lugar a un funcionamiento cerebral deficiente. Algunos pacientes con cirrosis desarrollan características clínicas obvias de una alteración en el funcionamiento cerebral, como dificultades con el habla, el equilibrio y el funcionamiento diario; se dice que presentan encefalopatía hepática evidente; los cambios pueden ser transitorios, recurrentes o pueden persistir durante períodos prolongados. Otros pacientes con cirrosis pueden no mostrar cambios obvios, aunque al realizarles pruebas se pueda encontrar que algunos aspectos clínicos de la función cerebral, como la atención y la capacidad para cumplir tareas complejas, presentan un deterioro; se dice que presentan encefalopatía hepática mínima. La razón por la que los pacientes desarrollan encefalopatía hepática es compleja, pero la acumulación en sangre de toxinas de los intestinos, en particular de un compuesto llamado amoníaco, desempeña una función clave. La L-ornitina L-aspartato reduce los niveles de amoníaco en sangre y, por lo tanto, puede tener efectos beneficiosos en los pacientes con encefalopatía hepática o ayudar a interrumpir su desarrollo. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas Pubmed: L-ornithine L-aspartate and/or, Dipeptides [adverse effects, *therapeutic use]; Hepatic Encephalopathy [*drug therapy, mortality, *prevention & control]; Liver Cirrhosis [*complications]; Quality of Life; Randomized Controlled Trials as Topic; Branched Chain Amino Acid Supplementation; Probiotics; Lactulose; Placebo; Lactitol; Antibiotic Therapy. Se filtró la búsqueda a Estudios Clínicos fase III, controlados randomizados, Revisiones Sistemáticas, Meta-análisis, Guías de Práctica Clínica, además se limitó la búsqueda estudios en humanos. También se realizó búsqueda manual en otras bases de datos bibliográficas (Cochrane, NIH, TRIP DATABASE), en buscadores genéricos de internet, agencias de evaluación de tecnologías sanitarias y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas, meta-análisis, estudios clínicos aleatorizados y controlados, guías de práctica clínica, evaluaciones de tecnología sanitaria, evaluaciones económicas y políticas de cobertura de otros sistemas de salud. CONCLUSIONES: Eficacia: L-Ornitina-L-Asparato (LOLA) ha sido utilizada como tratamiento para pacientes con hepatopatía crónica con riesgo de encefalopatía hepática. La evaluación de la eficacia de LOLA en esta población se ha basado en estudios clínicos controlados y aleatorizados. En general, la evidencia disponible sugiere que LOLA puede ser eficaz en la prevención y tratamiento de la encefalopatía hepática en pacientes con hepatopatía crónica. En varios estudios clínicos se ha observado que el uso de LOLA se asocia con una reducción significativa en la incidencia de la encefalopatía hepática y una mejora en la calidad de vida de los pacientes. Por ejemplo, un estudio aleatorizado, doble ciego y controlado con placebo realizado en 2011 demostró que LOLA redujo significativamente la incidencia de encefalopatía hepática en pacientes con cirrosis hepática avanzada. Otro estudio aleatorizado y controlado, publicado en 2015, encontró que el uso de LOLA se asoció con una mejora significativa en la calidad de vida de los pacientes con encefalopatía hepática. Sin embargo, es importante tener en cuenta que algunos estudios han reportado resultados contradictorios, y la evidencia global sobre la eficacia de LOLA es limitada y no concluyente. Además, la mayoría de los estudios han sido realizados en poblaciones específicas y pueden no ser generalizables a otras poblaciones. Seguridad: Según la revisión sistemática y metaanálisis analizados, se concluye que la L-Ornitina-L-Asparato es segura en la dosis recomendada para pacientes con cirrosis hepática y encefalopatía hepática. En los estudios revisados, no se reportaron efectos adversos graves asociados con el uso de LOrnitina-L-Asparato, y los efectos secundarios menores (como diarrea y náuseas) se presentaron en una proporción similar entre el grupo de tratamiento y el grupo de control. Además, otros estudios investigados compararon la seguridad de la L-Ornitina-L-Asparato con la lactulosa (un tratamiento convencional para la encefalopatía hepática) en pacientes con cirrosis hepática y encefalopatía hepática. Los resultados indicaron que la L-Ornitina-L-Asparato y la lactulosa fueron igualmente seguras, y que no hubo diferencias significativas en la frecuencia o gravedad de los efectos adversos entre ambos tratamientos. Conveniencia: Las ventajas de utilizar las diferentes opciones terapéuticas dependen de la condición específica del paciente. Tanto la lactulosa como la rifaximina se administran por vía oral, sin embargo, en casos donde la vía oral está comprometida, las ampollas endovenosas de L-ornitina-L-aspartato se convierten en la opción más viable. Costo: Aunque el costo por tratamiento completo puede ser más alto que otras opciones terapéuticas, la eficacia y seguridad de L-Ornitina-L-Asparato lo convierten en una opción atractiva desde el punto de vista costo-efectividad. Además, si se logra prevenir la encefalopatía hepática, los costos a largo plazo para el tratamiento de esta condición serían mucho mayores. Además, considerando los beneficios que se han demostrado en cuanto a la eficacia y seguridad del tratamiento, especialmente en pacientes con encefalopatía hepática de grado leve a moderado, podemos concluir que el uso de L-Ornitina-L-Aspartato es una opción costo-efectiva para el tratamiento de estos pacientes en el contexto del Instituto Salvadoreño del Seguro Social. Es importante tener en cuenta que la evaluación de costo-efectividad no solo se basa en el costo del tratamiento, sino también en la eficacia y los beneficios que se obtienen a través de su uso. En este caso, se ha demostrado que el uso de L-Ornitina-L-Aspartato tiene un impacto positivo en la reducción de los síntomas de encefalopatía hepática y la calidad de vida de los pacientes, lo que puede justificar su uso en términos de costo-efectividad.

Racial and ethnic disparities in rifaximin use and subspecialty referrals for patients with hepatic encephalopathy in the United States.

BACKGROUND & AIMS: Rifaximin use in combination with lactulose is associated with a decreased risk of overt hepatic encephalopathy (HE). We sought to determine whether race and ethnicity were associated with rifaximin prescriptions. METHODS: We examined data for a 20% random sample of United States Medicare enrollees with cirrhosis and hepatic encephalopathy treated with outpatient lactulose and Part D prescription coverage from 2011-2019. Beginning at the time of first diagnosis, we evaluated time to first prescription of rifaximin accounting for competing risks (Fine-Gray, yielding subdistribution hazard ratios [sHRs]) and cumulative rifaximin exposure using a gamma hurdle model (yielding exposure length ratios). We aimed to determine the association of race and ethnicity with each outcome, adjusting for demographics, clinical factors, and other features of clinical management. RESULTS: Overall, 29,095 patients were diagnosed with HE and treated with lactulose, of whom 13,272 were prescribed rifaximin. Compared to White patients, Black patients were least likely to receive any prescription for rifaximin (sHR 0.70; 95% CI 0.65-0.76). Asian and Hispanic patients were also less likely to receive rifaximin compared to White patients. Black patients also received fewer doses of rifaximin (exposure length ratio 0.90; 95% CI 0.82-0.98). Hispanic patients also received fewer doses (0.88; 95% CI 0.80-0.98). Out-of-pocket spending on rifaximin per person-year was higher for Black and Hispanic than White patients. Out-of-pocket medication spending was associated with reduced odds of filling a rifaximin prescription. Black and Hispanic patients were least likely to be referred to a gastroenterologist. CONCLUSION: In a national cohort of patients with HE, we observed stark racial and ethnic disparities in the use of rifaximin, an approved therapy for the improvement of HE-specific outcomes. Access to gastroenterologists and cost controls may reduce disparities. LAY SUMMARY: Hepatic encephalopathy is a serious problem that can affect people with cirrhosis. When someone develops hepatic encephalopathy, there are 2 main treatments. The first-line treatment is called lactulose. If episodes of hepatic encephalopathy happen on lactulose, another treatment called rifaximin is recommended. In this study, we found that compared to White patients, Black and Hispanic patients are less likely to be prescribed rifaximin, receive fewer rifaximin refills, spend more on rifaximin, and have less access to subspecialists who are familiar with rifaximin. We conclude that efforts to address the cost of rifaximin and access to gastroenterologists could help improve these disparities.

Budget impact of optimizing rifaximin-α use for the prevention of recurrent hepatic encephalopathy in The Netherlands.

AIMS: Rifaximin-α as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-α remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-α as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer's perspective. MATERIALS AND METHODS: A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness. RESULTS: Treating eligible HE patients with rifaximin-α in addition to lactulose saves €4,487 and costs €249 per patient over a 5-year period compared with lactulose monotherapy from hospital and healthcare payer's perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligible patients are currently being treated with rifaximin-α. Optimizing rifaximin-α use by treating all eligible patients with the rifaximin-α + lactulose could save more than 3,000 hospital admissions, almost 15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treatment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from a Dutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer's perspective. CONCLUSIONS: Next to a clinical perspective, also from an economic perspective, wider prescription of rifaximin-α adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer's perspective, costs increase with addition of rifaximin-α due to relative better survival causing relatively higher drug and liver transplantation-related costs.

Hospitalizations and healthcare costs associated with rifaximin versus lactulose treatment among commercially insured patients with hepatic encephalopathy in the United States.

AIMS: To assess healthcare costs and hospitalization rates associated with rifaximin therapy versus lactulose alone among patients at risk for hepatic encephalopathy (HE). METHODS AND MATERIALS: IBM Marketscan Commercial and Optum's de-identified Clinformatics Data Mart databases were used separately to identify commercially insured HE patients treated with rifaximin or lactulose alone, using an algorithm developed with clinical experts. HE-related hospitalizations were defined based on an algorithm using diagnosis codes and diagnosis-related group codes. HE-related/all-cause hospital admissions/days and healthcare costs were compared between rifaximin and lactulose episodes using incidence rate ratios and adjusted cost differences. RESULTS: In Marketscan, there were 13,515 [Optum: 5,217] rifaximin episodes and 9,946 [4,897] lactulose alone episodes included. Yearly rates of HE-related hospital admissions decreased by 33% [34%] when treated with rifaximin versus lactulose alone, and rates of HE-related hospital days similarly decreased by 43% [57%]. Yearly rates of all-cause hospital admissions decreased by 27% [27%]; rates of all-cause hospital days decreased by 33% [37%] during rifaximin episodes versus lactulose alone. This translated to $2,417 [$2,301] and $173 [$397] lower total mean medical costs and HE-related hospital costs per-patient-per-month, respectively (p < .05). Despite increased pharmacy costs associated with rifaximin, there was no change in total healthcare costs. Patients adherent to rifaximin incurred $2,891 [$2,340] lower total healthcare costs than non-adherent patients. In a simulated plan of 1 million lives, if 50% of HE patients treated with lactulose alone had rifaximin added on and were adherent to rifaximin therapy, the total cost savings would be $7.5 [$6.1] million per year ($0.62 [$0.50] per-member-per-month). CONCLUSIONS: Patients incurred significantly lower rates of HE-related and all-cause hospitalizations during rifaximin versus lactulose episodes, resulting in lower facility and professional costs. Cost savings may be possible if rifaximin adherence is improved in HE patients. LIMITATIONS: The study is subject to limitations common to claims-based analyses.

A retrospective study of drug utilization and hospital readmissions among Medicare patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a complication occurring in patients with cirrhosis and is associated with neuropsychiatric and motor abnormalities. Symptomatic HE episodes almost always require hospitalization and the frequent recurrence of episodes is associated with poor prognosis and increased medical costs. The utilization of existing therapies for management of HE and adherence to them has yet to be evaluated using real-world claims data.The aim of this study was to evaluate HE drug regimens and adherence and their association with hospital readmissions in Medicare Advantage plan patients.This was a retrospective cohort study of patients discharged from a HE-related hospitalization or emergency room visit. Based on subsequent enrollment in the plan they were categorized into cohorts of 1 month, 3, and 6 months follow-up, and medication regimen was evaluated within the first month. The drugs evaluated included lactulose, rifaximin, and neomycin. Multivariable logistic regression was conducted to evaluate the association of drug regimen and medication adherence measured as proportion of days covered with HE readmissions.There were 347 patients hospitalized for HE with 184 patients having 30-day enrollment and either a drug refill or an outpatient visit in this duration. Medications were not refilled by 67 (36.4%) patients. Various drug regimens had different adherence with mean (standard deviation) proportion of days covered ranging from 0.56 (0.29) to 0.82 (0.16) at 3 months and 0.48 (0.3) to 0.77 (0.15) at 6 months. The results of logistic regression at 3 and 6 months did not show a significant association of medication use or medication adherence with hospital readmissions.Despite availability of therapy, medication utilization was alarmingly low after discharge of patients from HE-related hospitalization. Medication adherence was also low, which may affect the rate of recurrence and costs associated with readmissions. Efforts are needed in both care coordination of these patients to ensure they are prescribed appropriate medications and to enhance adherence to them.

The Health Care Burden of Hepatic Encephalopathy.

Hepatic encephalopathy is a major neuropsychiatric complication of liver disease that affects 30% to 40% of cirrhotic patients. Hepatic encephalopathy is characterized by a brain dysfunction that is associated with neurologic complications. Those complications are associated with cognitive impairments, which negatively impacts patients' physical and mental health. In turn, hepatic encephalopathy poses a substantial economic and use burdens to the health care system. This article reviews the multidimensional aspects of the health care burden posed by hepatic encephalopathy.

Long-Term Management: Modern Measures to Prevent Readmission in Patients with Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a frequent indication for hospitalization and represents a common manifestation of portal hypertension and decompensated liver disease that contributes to hospital readmissions. Multiple new techniques are being evaluated to assist in preventing readmissions in these high-risk patients. Techniques to improve medication adherence are paramount. The use of telemedicine and on-demand patient assessment is likely to diminish hospitalizations for HE. Wearable technology has the potential to assist in HE diagnosis and prevent HE progression, with an anticipated diminution in hospital readmissions. This article discusses current and potential future techniques to improve outcomes in these vulnerable patients.

Social Impact of Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a multifaceted disorder, with effects stretching far beyond office visits and hospitalizations. Patients with HE suffer from varying degrees of altered consciousness, intellectual disability, and personality changes. A large social impact exists for patients with HE. Quality of life and activities of daily living, such as work capacity, driving ability, and sleep quality, have been shown to be affected. Additionally, caregiver and financial burdens are highly prevalent. Multiple tools exist to assess quality of life, including the CLD-Q questionnaire. Common treatments for HE, including rifaximin and lactulose, have been shown to improve overall quality of life.

Evaluation of the cost-effectiveness of rifaximin-α for the management of patients with hepatic encephalopathy in the United Kingdom.

OBJECTIVE: Rifaximin-α 550 mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt hepatic encephalopathy (OHE) and the risk of hepatic encephalopathy (HE)-related hospitalizations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin-α 550 mg twice daily plus lactulose versus lactulose alone in United Kingdom (UK) cirrhotic patients with OHE. METHOD: A Markov model was built to estimate the incremental cost-effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data was sourced from a randomized controlled trial (RCT) and an open-label maintenance study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-α on hospital admissions and length of stay for cirrhotic patients with OHE was from four single-center UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was 5 years. RESULTS: The average cost per patient was £22,971 in the rifaximin-α plus lactulose arm and £23,545 in the lactulose arm, a saving of £573. The corresponding values for benefit were 2.35 quality adjusted life years (QALYs) and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay. CONCLUSION: Rifaximin-α 550 mg twice daily in patients with recurrent episodes of OHE was estimated to generate cost savings and improved clinical outcomes compared to standard care over 5 years.

Systematic Review of the Economic Burden of Overt Hepatic Encephalopathy and Pharmacoeconomic Impact of Rifaximin.

BACKGROUND: Hepatic encephalopathy (HE), a common neurologic complication in cirrhosis, is associated with substantial disease and economic burden. Rifaximin is a non-systemic antibiotic that reduces the risk of overt HE recurrence and overt HE-related hospitalizations. OBJECTIVE: Our objective was to provide an overview of the direct HE-related costs and cost benefits of rifaximin, lactulose, and rifaximin plus lactulose. METHODS: A systematic review of PubMed and relevant meeting abstracts was conducted to identify publications since 1 January 2007 reporting economic data related to HE and rifaximin and/or lactulose. Further, a public database and published literature were used to estimate current costs of hospitalization for overt HE, and potential cost savings of HE-related hospitalizations with rifaximin. The methodological quality of included studies was evaluated using the Drummond checklist. RESULTS: A total of 16 reports were identified for inclusion in the systematic review. Globally, HE-related direct costs ranged from $US5370 to $US50,120 annually per patient. Rifaximin was associated with shorter hospital stays and reduced healthcare costs. Rifaximin also has the potential to reduce overt HE-related hospitalization risk by 50% compared with lactulose. Rifaximin was shown to have a favourable pharmacoeconomic profile compared with lactulose (based on the incremental cost-effectiveness ratio). CONCLUSIONS: In addition to its clinical benefits (e.g. reduction in the risk of recurrence of overt HE, overt HE-related hospitalizations, favourable adverse event profile), economic data are favourable for the use of rifaximin in patients with a history of overt HE.

Considerations for the cost-effective management of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric complication commonly associated with liver disease, namely cirrhosis. The inability of the liver to metabolize ammonia results in a buildup of ammonia, which can cross the blood-brain barrier and cause significant neurocognitive impairment. Up to 80% of patients with cirrhosis will experience HE and a large proportion of these patients are at high risk of recurrent HE. There are several factors to consider when developing a cost-effective approach to managing HE, such as patient compliance, the adverse event (AE) profile of drug therapy, efficacy of drug therapy, and relative cost-benefits of drug therapy. Pharmacologic agents used for HE treatment and prevention are commonly associated with gastrointestinal AEs, namely diarrhea. While these AEs are mild in nature, they can be bothersome and lead to patient noncompliance, which increases the patient's risk of HE. Furthermore, the complex dosing schedule and self-titration requirement of lactulose, a first-line agent, can be confusing to a patient. A patient's noncompliance with self-titration may result in underuse, increasing the patient's risk of HE, or overuse, increasing the patient's risk of severe AEs. HE imposes a significant economic burden to the patient, patients' caregivers, healthcare systems, and society. HE not only negatively impacts a patient's morbidity and mortality, but also impacts the patient's psychological and social functioning and overall quality of life. HE can impact the patient's ability to work, resulting in reduced productivity and lost wages. A patient with HE may require hospitalization, which accounts for a substantial proportion of costs associated with HE. Given the social and financial burden of HE, cost-effective management of HE is crucial. Early prevention is important to minimize the societal and economic costs associated with HE.

Eficacia y seguridad de rifaximina alfa en pacientes con encefalopatia hepatica refractaria al uso de lactulosa / Efficacy and safety of rifaximin alfa in patients with hepatic encephalopathy refractory to the use of lactulose

INTRODUCCIÓN: Antecedentes: El presente dictamen responde a la solicitud de evaluación del uso del petitorio de Rifaximina alfa en pacientes con encefalopatia hepática refractaria al uso de lactulosa. Aspectos Generales: Se estima que aproximadamente 5.5 millones de personas en los Estados Unidos sufren de cirrosis hepática, una causa de movilidad y mortalidad tanto en este país como en el mundo. La encefalopatia hepática o encefalopatía portosistemica constituye una complicación de la cirrosis hepática y falla de la función neuropsiquiátrica asociada con falla en la función hepática. A pesar que la condición es frecuentemente diagnosticada aún no existe un claro entendimiento de la patogénesis. Sin embargo, se estipula que se puede deber a un incremiento en las concentraciones de amoniaco en vista que el higado ya no es capaz de eliminar las toxinas de la sangre causando así toxicidad en el cerebro. Puede presentarse como episodios agudos o crónicamente a largo plazo. Tecnología Sanitaria de Interés: La Rifaximina alfa es un agente antimicrobiano con un amplio espectro de acción sobre Bacterias Gram-positivas y Gram- negativas, tanto aerobias como anaerobais. La característica de Rifaximina alfa es su forma polimorfa alfa y su escasa absorción en el tracto gastrointestinal (inferior a 1%), lo cual favorece la concentración del fármaco en el intestino y sobre todo, en las heces en forma activa. METODOLOGÍA: Estrategia de Búsqueda: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de Rifaximina alfa para el tratamiento de pacientes con encefalopatía hepática con resistencia (falla) al tratamiento estándar con lactulosa. La búsqueda se inicio revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras com la Food and Drug Administration (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriomente se buscaron Guías de Práctica Clínica a través de los metabuscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline), The National Guuideline of Clearinghouse, y Health Systems Evidence. Finalmente. se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica. RESULTADOS: Sinopsis de la Evidencia: En la presente sinopsis se describe la evidencia disponible que sustenta la eficacia y seguridad de Rifaximina alfa para el tratamiento de pacientes con encefalopatia hgepática refractarios al tratamiento estándar con lactulosa. CONCLUSIONES: A la fecha, no se ha evaluado la eficacia y seguridad de Rifazimina alfa como monoterapia ni en pacientes refractarios a lactulosa, por lo que la evidencia encontrada responde la pregunta PICO de manera indirecta. Actualmente no existe alternativa de tratamiento a lactulosa en el Petitorio Farmacológico de EsSalud, por lo que es necesario contar con una alternativa de tratamiento para así evitar el deterioro de la calidad de vida del paciente, dadas las limitaciones en las funciones cognitiva y psicomotriz a la que la enfermedad conlleva. El Instituto de Evaluacioón de Tecnologías en Salud e Investigación-IETSI, aprueba el uso de Rifaximina alfa en pacientes con encefalopatía hepática refractaria al uso de lactulosa. El presente Dicatamen Preliminar tiene una vigencia de dos años a partir de su fecha de publicación.

The impact on hospital resource utilisation of treatment of hepatic encephalopathy with rifaximin-α.

BACKGROUND & AIMS: Rifaximin-α reduces the risk of recurrence of overt hepatic encephalopathy. However, there remain concerns regarding the financial cost of the drug. We aimed to study the impact of treatment with rifaximin-α on healthcare resource utilisation using data from seven UK liver treatment centres. METHODS: All seven centres agreed a standardised data set and data characterising clinical, demographic and emergency hospital admissions were collected retrospectively for the time periods 3, 6 and 12 months before and following initiation of rifaximin-α. Admission rates and hospital length of stay before and during therapy were compared. Costs of admissions and drug acquisition were estimated using published sources. Multivariate analyses were carried out to assess the relative impact of various factors on hospital length of stay. RESULTS: Data were available from 326 patients. Following the commencement of rifaximin, the total hospital length of stay reduced by an estimated 31-53%, equating to a reduction in inpatient costs of between £4858 and £6607 per year. Taking into account drug costs of £3379 for 1-year treatment with rifaximin-α, there was an estimated annual mean saving of £1480-£3228 per patient. CONCLUSIONS: Initiation of treatment with rifaximin-α was associated with a marked reduction in the number of hospital admissions and hospital length of stay. These data suggest that treatment of patients with rifaximin-α for hepatic encephalopathy was generally cost saving.

Bispectral index monitoring for diagnosis and assessment of severity of hepatic encephalopathy in cirrhotic patients.

BACKGROUND: Recent evidence suggests that bispectral index may aid in the diagnosis of hepatic encephalopathy. We evaluated its utility to diagnose, grade and monitor clinical course of hepatic encephalopathy in patients with cirrhosis. METHODS: 200 patients (70.5% males, mean age 39.5±9.1 years) with cirrhosis and 20 healthy controls were enrolled prospectively. Cirrhotic patients were divided into groups based on encephalopathy grades I-IV assessed by West Haven criteria; minimal encephalopathy was assessed by psychometric tests. Bispectral index was measured at baseline and after one week of lactulose therapy in patients with overt encephalopathy, and after 3 months in patients with minimal encephalopathy. RESULTS: Bispectral index scores were significantly different in patients with different grades of encephalopathy; 79.5±4.2, 67.5±4.3, 56.4±3.5, 44.8±3.9 and 85.0±4.3 respectively for grade I, II, III, IV overt and minimal hepatic encephalopathy, but similar (92.6±3.7 vs 93.75±2.8) in cirrhotics without encephalopathy and healthy controls. Bispectral scores' cut off values for minimal and overt encephalopathy grade I, II, III, IV were 90.5 and 77.5, 70.5, 60.5, 50.5, respectively. Changes in bispectral index after treatment corresponded to cut-off scores for grades of overt and minimal hepatic encephalopathy. CONCLUSIONS: Bispectral index was found to be useful in diagnosis, grading and monitoring of treatment response in cirrhotic patients with hepatic encephalopathy.

Optimal treatment of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric complication of acute or chronic liver disease with symptoms encompassing a continuum from mild confusion to coma. Both covert and overt HE have a significant impact on quality of life and healthcare related costs. The pathophysiology of HE is multifactorial and there is general consensus that ammonia and inflammation act synergistically to cause astrocyte swelling and cerebral edema. Current management strategies include the identification of precipitating factors and the initiation of pharmacologic therapies aimed at modulating intestinal flora and reducing levels of ammonia and other gut-derived toxins. Lactulose and rifaximin are two commonly used treatments for the management of HE. This article will review the optimal management of hepatic encephalopathy.

Branched-chain amino acid supplementation in adults with cirrhosis and porto-systemic encephalopathy: systematic review.

BACKGROUND & AIMS: Branched-chain amino acid supplementation in porto-systemic encephalopathy remains controversial. Here, we examined the systematic review evidence for their effect on encephalopathy, hepatic decompensation, survival, infection, hospital stay and quality of life, and review data on adherence, side-effects and cost/economic evaluation. METHODS: Four electronic databases were searched from 1980 to June 2011, with an update search in two databases in July 2013. Hand-searching was performed of references lists from included trials and six conference proceedings from 2005 to 2010. We included randomised controlled trials of branched chain amino acids versus other nutritional supplements in adults with cirrhosis and porto-systemic encephalopathy. Data extraction and quality assessment were performed by two independent assessors. Meta-analysis was performed if data were sufficient. RESULTS: The search identified nine randomised controlled trials (436 patients in total) of branched-chain amino acid therapy for ≥2 weeks' duration. The overall quality of trials was poor. At meta-analysis, a significant improvement in the grade of encephalopathy was demonstrated in favour of branched-chain amino acids compared to other nutritional supplements (Risk Ratio 2.6, 95% Confidence Interval 1.7-3.9, p < 0.001, 2 trials, n 122) but no significant difference was found for either resolution or worsening of encephalopathy, gastrointestinal bleeding, survival or infection. Limited data suggested no difference in health-related quality of life, ascites or admission to hospital. Studies did not include cost data or economic evaluations. Side-effects appeared mild and gastrointestinal in nature. CONCLUSIONS: Branched-chain amino acids might improve porto-systemic encephalopathy but more robust trials are needed to determine their role.

Update on management of patients with overt hepatic encephalopathy.

Hepatic encephalopathy (HE) is a multifactorial neuropsychiatric disease that affects patients with cirrhosis. We review the clinical impact, pathogenesis, evaluation, management, and prevention of overt HE in patients with cirrhosis. Articles published between January 1960 and November 2012 were acquired through a MEDLINE search of different combinations of the terms hepatic encephalopathy, pathophysiology, treatment, prophylaxis, prevention, prognosis, and recurrence. The Healthcare Cost and Utilization Project database was used to obtain prevalence and cost information related to hospitalizations of patients with HE. The literature describes significant morbidity and mortality of HE in patients with cirrhosis. Overt HE develops in 30% to 45% of patients with cirrhosis and is associated with a substantial pharmacoeconomic burden, particularly HE-related hospitalizations. The development of HE in patients with cirrhosis portends a worsened prognosis and is incorporated into the Child-Pugh classification of the severity of liver disease. In the hospitalized patient, the development of HE is associated with precipitating events (eg, gastrointestinal bleeding, dehydration, infection), and in some patients, its course is characterized by frequent and severe relapses. In addition, hospitalized patients with overt HE have a 3.9-fold increased mortality risk. Patient management employs nonabsorbable disaccharides, the nonsystemic antibiotic rifaximin, or both, to treat acute HE episodes and prevent HE relapse. In open-label trials, use of the nonabsorbable disaccharide lactulose reduced the risk of overt HE recurrence in patients compared with no-lactulose control groups for ≤ a median of 14 months. In a randomized, placebo-controlled trial, rifaximin 550 mg twice daily was more effective in maintaining HE remission compared with placebo and was associated with a reduction in HE-related hospitalizations. Recent advances in treatment and preventative therapies may reduce the personal, societal, and economic impact of this disorder.

Antibiotics for the treatment of hepatic encephalopathy.

The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.