Pharmacotherapy for primary biliary cholangitis: an assessment of medication candidacy and rates of treatment.

BACKGROUND: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis. METHODS: All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review of medical records was performed to confirm the diagnosis of primary biliary cholangitis and determine which medications had been prescribed for treatment, as well as candidacy for second-line therapies. RESULTS: A total of 495 patients met inclusion criteria. Notably, 95% of patients were taking ursodeoxycholic acid for treatment of their primary biliary cholangitis, with 67% of patients having disease that was well-controlled on ursodeoxycholic acid monotherapy. In total, 8% of patients were taking obeticholic acid (either as combination or monotherapy). Only 3% would benefit from the addition of a second line therapy but had not yet been offered medication. Only 3% of patients were not on any medication for management of their primary biliary cholangitis. CONCLUSIONS: Ursodeoxycholic acid is a readily available and generally well-tolerated medication that should be offered to all patients with primary biliary cholangitis as first-line therapy. While prior investigations have suggested that up to 30% of patients with primary biliary cholangitis may never have received treatment for the disorder, the present study suggests that patients are generally being managed according to guidelines. Moreover, a significant proportion of patients with primary biliary cholangitis will qualify for second line therapies and prescribers should be aware of the indications to use these medications.

Cost-effectiveness of ursodeoxycholic acid in preventing new-onset symptomatic gallstone disease after Roux-en-Y gastric bypass surgery.

BACKGROUND: The aim was to evaluate the cost-effectiveness and cost-utility of ursodeoxycholic acid (UDCA) prophylaxis for the prevention of symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB) in patients without gallstones before surgery. METHODS: Data from a multicentre, double-blind, randomized placebo-controlled superiority trial were used. Patients scheduled for laparoscopic RYGB or sleeve gastrectomy were randomized to receive 900 mg UDCA or placebo for 6 months. Indicated by the clinical report, prophylactic prescription of UDCA was evaluated economically against placebo from a healthcare and societal perspective for the subgroup of patients without gallstones before surgery who underwent RYGB. Volumes and costs of in-hospital care, out-of-hospital care, out-of-pocket expenses, and productivity loss were assessed. Main outcomes were the costs per patient free from symptomatic gallstone disease and the costs per quality-adjusted life-year (QALY). RESULTS: Patients receiving UDCA prophylaxis were more likely to remain free from symptomatic gallstone disease (relative risk 1.06, 95 per cent c.i. 1.02 to 1.11; P = 0.002) compared with patients in the placebo group. The gain in QALYs, corrected for a baseline difference in health utility, was 0.047 (95 per cent bias-corrected and accelerated (Bca) c.i. 0.007 to 0.088) higher (P = 0.022). Differences in costs were -€356 (95 per cent Bca c.i. €-1573 to 761) from a healthcare perspective and -€1392 (-3807 to 917) from a societal perspective including out-of-pocket expenses and productivity loss, both statistically non-significant, in favour of UDCA prophylaxis. The probability of UDCA prophylaxis being cost-effective was at least 0.872. CONCLUSION: UDCA prophylaxis after RYGB in patients without gallstones before surgery was cost-effective.

Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group.

Variation in clinical practice affects veno-occlusive disease management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation. Disputes about diagnostic criteria, treatment, and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the panel pointed out the need to achieve an early diagnosis, encouraging the adoption of European Society for Blood and Marrow Transplantation criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favor of prophylactic use of ursodeoxycholic acid. As soon as a veno-occlusive disease diagnosis is established, treatment with defibrotide should be started for at least 21 days. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed.

Simplified care-pathway selection for nonspecialist practice: the GLOBAL Primary Biliary Cholangitis Study Group Age, Bilirubin, Alkaline phosphatase risk assessment tool.

BACKGROUND: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients. OBJECTIVE: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC. METHODS: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed. RESULTS: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value. CONCLUSION: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.

A randomized crossover trial to assess therapeutic efficacy and cost reduction of acid ursodeoxycholic manufactured by the university hospital for the treatment of primary biliary cholangitis.

BACKGROUND: Health care costs are growing faster than the rest of the global economy, according to the World Health Organization (WHO). Countries' health expenditures include paying for general medicine, diagnostic procedures, hospitalizations and surgeries, as well as medications and prescribed treatment. Primary biliary cholangitis (PBC) is a rare autoimmune liver disease and the first line available treatment is ursodeoxycholic acid (UDCA), however, direct and indirect treatment costs are expensive. Main aim of this trial was to assess if the therapeutic efficacy of UDCA manufactured by the university hospital is equivalent to that of standard UDCA and treatment cost reduction in patients with PBC. METHODS: It is a prospective, interventional, randomized, and crossover study in patients diagnosed with PBC. UDCA 300 mg tablets and capsules were developed and manufactured by the university hospital. Thirty patients under treatment with standard UDCA, in stable doses were randomized in sequence A and B, 15 patients in each arm. The groups were treated for 12 weeks and after, the UDCA formulation was changed, following for another 12 weeks of continuous therapy (tablets and capsules / capsules and tablets). Laboratory tests were performed at time T0 (beginning of treatment), T1 (at the 12 week-therapy, before the crossing-over) and T2 (end of treatment). The evaluation was done by comparing the hepatic parameters ALP, GGT, ALT, AST and total bilirubin, also considering the adverse events. The comparison of costs was based on price of the manufactured UDCA and standard UDCA price of the hospital. RESULTS: Hospital reduced 66.1% the PBC treatment costs using manufactured UDCA. There were no differences in the biochemical parameters between sequence (A and B) and tablets or capsules of UDCA formulations applied in the treatment of PBC. CONCLUSIONS: The study showed that there was no significant difference between manufactured UDCA (capsule and tablet) and standard UDCA. Hospital reduced the PBC treatment costs using the manufactured UDCA by the university hospital. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03489889 retrospectively registered on January 12th, 2018; Ethics Committee approved the study (ID: 1.790.088) on October 25th, 2016.

Informe diário de evidências COVID-19: busca realizada em 11 de agosto de 2020 / COVID-19 daily evidence report: search conducted on August 11, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 14 artigos e 5 protocolos.

The value of routine laboratory screening in the neonatal intensive care unit.

BACKGROUND: Healthcare spending is expected to grow faster than the economy over the next decade, and the cost of prematurity increases annually. The aim of this study was to investigate the frequency of intervention after routine laboratory testing in preterm infants. METHODS: This was a retrospective study of preterm infants (≤34 weeks) admitted to the NYU Langone Health NICU from June 2013 to December 2014. Data collected included demographics, results of laboratory tests, and resulting interventions. Intervention after a hemogram was defined as a blood transfusion. Intervention after a hepatic panel was defined as initiation or termination of ursodiol or change in dose of vitamin D. Subjects were stratified into 3 groups based on gestation (<28 weeks, 28-31 6/7 weeks, 32-34 weeks). Chi-square analysis was used to compare the frequency of intervention between the groups. RESULTS: A total of 135 subjects were included in the study. The frequency of intervention after a hemogram was 8.4% in infants <28 weeks, 4.6% in infants 28-31 6/7 weeks, and 0% in infants 32-34 weeks; this difference was found to be statistically significant (p = 0.02). The frequency of intervention after a hepatic panel was 4.2% in infants <28 weeks, 5.7% in infants 28-31 6/7 weeks, and 0% in infants 32-34 weeks, which was not found to be a statistically significant different. CONCLUSION: No interventions were undertaken post-routine laboratory testing in any infant 32-34 weeks and routine testing in this population may be unnecessary. Further studies are needed to elucidate if routine testing affects neonatal outcomes.

Ácido ursodeoxicolico para la profilaxis de síndrome de obstrucción sinusoidal en pacientes post trasplante de células progenitoras hematopoyéticas / Ursodeoxycholic acid for the prophylaxis of sinusoidal obstruction syndrome in post-hematopoietic progenitor cell transplant patients

INTRODUCCIÓN: El síndrome de obstrucción sinusoidal (SOS) es una complicación potencialmente fatal que clásicamente se asocia al trasplante de células progenitoras hematopoyéticos (TPH). Otras causas identificadas son: Irradiación, administración de alcaloides de pirrolizidina presentes en plantas tipo crotalaria y senecio (tés de arbustos medicinales) y otras hierbas (p. ej., consuelda), otras hepatotoxinas (p. ej., dimetilnitrosamina, aflatoxina, azatioprina, algunos antineoplásicos). A. Cuadro clínico: Debido a la elevada morbilidad y mortalidad del SOS, y a los malos resultados obtenidos con la mayoría de las medidas terapéuticas empleadas, la prevención debe tener carácter prioritario. Las medidas preventivas deben dirigirse, en primer lugar, a reducir al máximo el impacto de los factores de riesgo modificables conocidos, siendo uno de éstos el ácido ursodesoxicólico (ursodeoxycholic acid, UDCA por sus siglas en inglés), entre otros. B. Tecnología sanitaria: El Ácido Ursodesoxicolico (UDCA) es un ácido biliar secundario endógeno altamente hidrofilico que interfiere en la suspensión de cristales de colesterol, bloqueando parcialmente su precipitación. Este acido biliar, no tóxico, presenta multiples actividades hepatoprotectoras, de las que destacan las propiedades citoprotectoras, antiapoptoticas e inmunomoduladoras, así como su efecto colerético. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura del ácido ursodeoxicolico en la profilaxis de síndrome de obstrucción sinusoidal. METODOLOGÍA: Se realizó una búsqueda en las principales bases de datos bibliográficas: MEDLINE, LILACS, COCHRANE, así como en buscadores genéricos de Internet incluyendo Google Scholar y TRIPDATABASE. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales de enfermería y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se selecciono una RS y cuatro GPC, no se identificaron evaluaciones de tecnología sanitaria ni evaluaciones económicas de la región. CONCLUSIONES: La evidencia con respecto al ácido ursodeoxicolico en la profilaxis de síndrome de obstrucción sinusoidal es escasa. Basada en una revisión sistemática de ensayos clínicos aleatorizados de alta calidad metodológica, se muestra que UDCA podría prevenir la incidencia de SOS comparado con placebo, no profilaxis o heparina. Además, se encontraron resultados superiores para UDCA con respecto a la mortalidad post-transplante después de 100 días y la mortalidad asociada a SOS. No se encontraron diferencias en la sobrevida global a largo plazo con los mismos comparadores. Tres GPC recomiendan el uso de UDCA en profilaxis de SOS mientras que una GPC no lo recomienda. En general, las GPC que recomiendan UDCA lo hacen mostrando defibrótido como otra opción no preferente para la misma indicación en la profilaxis de SOS. No existen estudios de comparaciones directas o indirectas entre UDCA y defibrotido.

Ácido ursodesoxicólico para colangite biliar primária / Ursodeoxycholic acid for primary biliary cholangitis

INTRODUÇÃO: A colangite biliar primária (CBP) é uma doença hepática autoimune colestática rara, caracterizada por inflamação e destruição progressiva dos ductos interlobulares de pequeno e médio calibre, colestase que provoca fadiga e prurido debilitantes, podendo evoluir para fibrose, cirrose, doença hepática terminal e morte. Estudos epidemiológicos de base populacional de diversos países mostrou taxas de incidência que variam de 0,33 a 5,8 por 100 mil habitantes por ano e taxas de prevalência 1,91 a 40,2 por 100 mil habitantes por ano. Atualmente, o SUS oferece apenas alternativas para o tratamento dos sintomas da doença hepática terminal (cirrose), e não possui nenhuma alternativa terapêutica com idicação para CBP. TECNOLOGIA: Ácido Ursodesoxicólico (Ursacol®). PERGUNTA: O uso de ácido ursodesoxicólico (AUDC) é eficaz e seguro em pacientes com colangite biliar primária quando comparado às opções disponíveis atualmente no SUS? EVIDÊNCIAS CIENTÍFICAS: Com base nos critérios de inclusão, na estratégia de busca e nas referências dos artigos selecionados, foram incluídos 13 estudos, 10 já incluídos pelo demandante e três pela Secretaria-Executiva da CONITEC. Mortalidade foi avaliada por seis estudos, três observaram que não houve diferença estatisticamente significante entre AUDC e placebo, em outros três estudos os resultados foram variados. A sobrevida global foi avaliada por três estudos que concluíram que a sobrevida observada foi significativamente (P< 0.001) maior no grupo tratado com AUDC quando comparado ao previsto pelo modelo de Mayo ou grupo não tratado. Os resultados de sobrevida livre de transplante (SLT) de quatro estudos puderam ser meta-analisados, e o tratamento com AUDC apresentou aumento do tempo de SLT no acompanhamento de longo prazo a partir do quinto ano de tratamento, com resultados estatisticamente significantes para os anos 5, 8 e 10 (p< 0,01). Não houve diferença estatisticamente significantes nas meta-análises para proporção de eventos adversos graves quando se comparou AUDC com placebo/não tratamento. AVALIAÇÃO ECONÔMICA: O demandante delineou em sua proposta um estudo de custo-efetividade do AUDC como opção de tratamento em pacientes com CBP sintomáticos. O estudo demonstrou uma RCEI de R$ 9,32 mil por ano livre de transplante salvo e R$ 13,26 mil por ano de vida salvo, quando comparado ao placebo. O modelo possui limitações na fonte de dados de eficácia, no levantamento dos custos e no horizonte temporal usado no modelo que limitam a interpretação do resultado. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A partir das premissas adotadas pelo demandante, o impacto orçamentário incremental com a incorporação do AUDC no SUS seria de R$11,77 milhões no primeiro ano e de R$98,52 milhões no acumulado de cinco anos. Entretanto, análise possui limitações quanto à estimativa da população e a previsão de custos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As buscas apontaram haver quatro potenciais medicamentos nas fases 3 ou 4 de desenvolvimento clínico para a indicação terapêutica considerada. Destes, o ácido obeticólico e selaldelpar lisina parecem estar num horizonte mais próximo, dado que obtiveram registro sanitário no FDA e/ou EMA nos últimos dois anos. RECOMENDAÇÃO DA CONITEC: Os membros presentes em sua 68º reunião ordinária, no dia 05 de julho de 2018, deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável à incorporação do AUDC para tratamento de pacientes com CBP. CONSULTA PÚBLICA: Foram recebidas 25 contribuições técnico-científicas e 140 contribuições de experiência e opinião durante o período de consulta pública, entre 04 de agosto a 23 de agosto de 2018. Dentre as contribuições, a maioria foram contrárias à recomendação da CONITEC. Os principais argumentos enviados pela empresa fabricante foram: alto custo do medicamento, única opção terapêutica para CBP, melhroa dos parâmetros hepáticos, recomendação de agências internacionais, mudança da história natural da doença e redução dos eventos adversos. O plenário da CONITEC entendeu a necessidade de modificar sua recomendação inicial e deliberaram, por unanimidade, por recomendar a incorporação no SUS do AUDC para CBP. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 68ª reunião ordinária, no dia 04 de julho de 2018, deliberaram, por unanimidade, por recomendar a incorporação do AUDC para tratamento de pacientes com Colangite Biliar Primária. Foi assinado o Registro de Deliberação nº 355/2018. DECISÃO: A Portaria nº 47, de 16 de outubro de 2017, tornou pública a decisão de incorporar o ácido ursodesoxicólico para colangite biliar, no âmbito do Sistema Único deSaúde - SUS. Publicada no Diário Oficial da União nº 200, seção 1, página 44.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial).

BACKGROUND: The number of bariatric interventions for morbid obesity is increasing worldwide. Rapid weight loss is a major risk factor for gallstone development. Approximately 11 % of patients who underwent Roux-en-Y gastric bypass develop symptomatic gallstone disease. Gallstone disease can lead to severe complications and often requires hospitalization and surgery. Ursodeoxycholic acid (UDCA) prevents the formation of gallstones after bariatric surgery. However, randomized controlled trials with symptomatic gallstone disease as primary endpoint have not been conducted. Currently, major guidelines make no definite statement about postoperative UDCA prophylaxis and most bariatric centers do not prescribe UDCA. METHODS: A randomized, placebo-controlled, double-blind multicenter trial will be performed for which 980 patients will be included. The study population consists of consecutive patients scheduled to undergo Roux-en-Y gastric bypass or sleeve gastrectomy in three bariatric centers in the Netherlands. Patients will undergo a preoperative ultrasound and randomization will be stratified for pre-existing gallstones and for type of surgery. The intervention group will receive UDCA 900 mg once daily for six months. The placebo group will receive similar-looking placebo tablets. The primary endpoint is symptomatic gallstone disease after 24 months, defined as admission or hospital visit for symptomatic gallstone disease. Secondary endpoints consist of the development of gallstones on ultrasound at 24 months, number of cholecystectomies, side-effects of UDCA and quality of life. Furthermore, cost-effectiveness, cost-utility and budget impact analyses will be performed. DISCUSSION: The UPGRADE trial will answer the question whether UDCA reduces the incidence of symptomatic gallstone disease after Roux-en-Y gastric bypass or sleeve gastrectomy. Furthermore it will determine if treatment with UDCA is cost-effective. TRIAL REGISTRATION: Netherlands Trial Register (trialregister.nl) 6135 . Date registered: 21-Nov-2016.

Primary Biliary Cholangitis: Medical and Specialty Pharmacy Management Update.

BACKGROUND: Chronic liver disease and cirrhosis are a leading cause of morbidity and mortality in the United States. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis and which has been designated an orphan condition, is a chronic autoimmune disease resulting in the destruction of the small bile ducts in the liver. Without effective treatment, disease progression frequently leads to liver failure and death. Until May 2016, the only FDA-approved treatment for PBC was ursodiol (UDCA), an oral hydrophilic bile acid, which can slow progression of liver damage due to PBC. However, 1 out of 3 patients taking UDCA has an inadequate biochemical response, leading to increased risk of disease progression, liver transplantation, and mortality. Given this unmet clinical need, new therapies are in development for the treatment of PBC. To provide pharmacists with an overview of the latest research on the pathophysiology of PBC and potential new treatment options and to highlight medical and specialty pharmacy approaches to managing access to drugs to treat orphan diseases such as PBC, a 2-hour satellite symposium was presented in conjunction with the 2015 Academy of Managed Care Pharmacy (AMCP) Nexus meeting. Although obeticholic acid was approved by the FDA for the treatment of PBC in May 2016, this development occurred after the symposium presentation. The symposium was supported by an independent educational grant from Intercept Pharmaceuticals and was managed by Analysis Group. Robert Navarro, PharmD, moderated the CPE-accredited symposium titled "Medical and Specialty Pharmacy Management Update on Primary Biliary Cirrhosis." Expert panelists included Christopher L. Bowlus, MD; James T. Kenney, RPh, MBA; and Gary Rice, RPh, MS, MBA, CSP. OBJECTIVE: To summarize the educational satellite symposium presentations and discussions. SUMMARY: Autoimmune liver diseases, including PBC, are responsible for 15% of all liver transplants performed and an equal percentage of deaths related to liver disease. UDCA is the only FDA-approved therapy for treatment of PBC and is considered the standard of care. Nevertheless, many patients do not respond to UDCA, creating the need for new therapeutic options to improve clinical outcomes for PBC patients with inadequate response to treatment. While several agents are being studied in combination with UDCA, monotherapy with the novel agent obeticholic acid, a farnesoid X receptor agonist, has also shown promising results. Health plans are anticipated to assign any newly introduced therapy for the treatment of PBC to specialty pharmacy given its orphan disease status. This assignment enables the health plan to receive disease education, which is particularly important when new drugs are indicated for orphan diseases, and assistance with designing appropriate prior authorization criteria. The clinical value of any new therapeutic options that will inform formulary decisions and prior authorization criteria will be assessed based on evidence of efficacy, safety, and tolerability, among other factors, such as the potential to reduce or delay medical resource utilization (e.g., liver transplant). Key considerations for prior authorization of a new therapy will be determining which PBC patients are appropriate candidates for the new therapy and developing criteria for that determination. These are likely to include clinical diagnostic criteria and degree of response to prior treatment with UDCA. Initially, any new therapy would likely be positioned as noncovered until appropriate prior authorization criteria are established. CONCLUSIONS: PBC is a chronic liver disease with significant morbidity and mortality, as well as a significant burden on the health care system if the disease progresses to the point at which a liver transplant is needed. Although UDCA, the current standard of care, has improved outcomes for many patients, others have an inadequate response to this treatment. This symposium discussed these issues and also addressed the overall treatment paradigm for orphan drug therapies, key implications for patient management, and the role of specialty pharmacy management and any associated needs both in general and specifically for new therapeutic options for PBC.

Ácido ursodesoxicólico para o tratamento da hepatopatia crônica criptogênica / Ursodeoxycholic acid for the treatment of chronic cryptogenic liver disease

CONTEXTO: A hepatopatia é um termo empregado para designar um conjunto de doenças que acometem o fígado. Segundo a Classificação Internacional de Doenças 10a versão (CID-10), compreende as doenças de CID-10 K70 a K77. A hepatopatia crônica criptogênica refere-se a doença hepática sem etiologia conhecida (K73.9) (1). Além dessas, existem as doenças hepáticas de origem viral (CID-10 B15-B19) (2). As principais doenças hepáticas crônicas (DHC) são: hepatite viral (B15-B19), alcoólica (K70) ou autoimune (K75.4), doença hepática gordurosa não alcoólica (DHGNA) (K76.0), cirrose hepática (K74) e carcinoma hepatocelular (C22.0). A cirrose, doença difusa do fígado, é considerada estágio próprio da evolução de diversas doenças hepáticas crônicas e pode evoluir para insuficiência hepática e carcinoma hepatocelular. TECNOLOGIA: Ácido ursodesoxicólico (Ursacol®). PERGUNTA: Ácido ursodesoxicólico é eficaz e seguro para o tratamento da hepatopatia crônica criptogênica? EVIDENCIAS: Não foram encontrados estudos que avaliassem o ácido ursodesoxicólico para o tratamento de doenças hepáticas crônicas de etiologia desconhecida. Foi incluída uma revisão sistemática que avaliou o uso de ácido ursodesoxicólico para o tratamento da cirrose biliar primária, sua indicação em bula no FDA. Os resultados mostraram não haver diferença significativa no efeito entre o ácido ursodesoxicólico e placebo ou "não intervenção" para mortalidade por todas as causas; mortalidade por todas as causas ou transplante de fígado; eventos adversos graves ou eventos adversos não graves. O ácido ursodesoxicólico não influenciou o número de pacientes com prurido ou com fadiga. A pressão portal, varizes, varizes hemorrágicas, ascite e encefalopatia hepática não foram significativamente afetadas pelo ácido ursodesoxicólico. O ácido ursodesoxicólico diminuiu significativamente a concentração sérica de bilirrubina e a atividade da fosfatase alcalina sérica em comparação com placebo ou nenhuma intervenção. Ácido ursodeoxicólico também pareceu melhorar os níveis séricos de gama-glutamil transferase, aminotransferases, colesterol total e concentração de imunoglobulina M plasmática. O ácido rsodesoxicólico pareceu ter um efeito benéfico sobre a agravamento do estágio histológico. Os autores concluíram que os resultados da revisão sistemática não demonstraram quaisquer benefícios significativos de ácido rsodesoxicólico na mortalidade por todas as causas, transplante de fígado, prurido, ou fadiga em pacientes com cirrose biliar primária. O ácido ursodesoxicólico demonstra ter um efeito benéfico sobre as medidas bioquímicas do fígado e na progressão histológica em comparação com o grupo controle. CONCLUSÕES: Não existem evidencias diretas para o uso de ácido ursodesoxicólico para o tratamento de hepatopatia crônica criptogênica. Nos casos de hepatopatias que apresentam comprometimento colestático crônico, o ácido ursodesoxicólico melhora os parâmetros bioquímicos e histológico sem, entretanto, trazer benefícios nos desfechos de mortalidade por todas as causas, mortalidade por todas as causas ou transplante hepático, fadiga e prurido.

Cost and health consequences of treatment of primary biliary cirrhosis with ursodeoxycholic acid.

BACKGROUND: Long-term use of ursodeoxycholic acid (UDCA) is the recommended therapy in primary biliary cirrhosis (PBC). The lifetime effectiveness and cost-effectiveness of UDCA in PBC have, however, not been assessed. AIM: To estimate the health outcomes and lifetime costs of a Norwegian cohort of PBC patients on UDCA. METHODS: Norwegian PBC patients (n = 182) (90% females; mean age 56.3 ± 8.9 years; Mayo risk score 4.38) who were included in a 5-year open-label study of UDCA therapy were subsequently followed up for up to 11.5 years. The lifetime survival was estimated using a Weibull survival model. The survival benefit from UDCA was based on a randomised clinical trial from Canada, comparing the effect of non-UDCA and UDCA. Survival and costs of standard care vs. standard care plus UDCA were simulated in a Markov model with death and liver transplantation as major events, invoking transition of a patient's state in the model. RESULTS: The gain in life expectancy for a PBC patient on UDCA compared with standard care was 2.24 years (1.19 years discounted). The lifetime treatment costs were EUR 151,403 and EUR 157,741 (EUR 102,912 and EUR 115,031 discounted) for patients with and without UDCA respectively. A probabilistic sensitivity analysis indicated an 82% probability that UDCA entails both greater life expectancy and lower costs than standard care. CONCLUSIONS: The results of this study indicate that UDCA therapy is a dominant strategy as it confers reduced morbidity and mortality, as well as cost savings, compared with standard therapy.

Stereological assessment of placental morphology in intrahepatic cholestasis of pregnancy.

OBJECTIVE: To apply stereology for the detection of possibly morphological abnormalities in placentas of women with intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: Prospective case-control study of placentas from untreated and UDCA-treated ICP, respectively, and normal pregnancies, examined for morphological differences by systematic random sampling generated by computerized stereology methodology. MAIN OUTCOME MEASURES: Volume of placenta, surface area of terminal villi and capillaries, volume fraction of collagen, number of syncytial knots, and chorangiosis. RESULTS: Surface area of terminal villi and capillaries, and number of syncytial knots were higher in placentas from all ICP, as compared to controls (p < 0.01). A reduction of collagen was found in placentas from UDCA-treated ICP, both in comparison to placentas from untreated ICP and controls (p < 0.05). CONCLUSION: ICP affects the placenta morphologically as shown by increased terminal villous and capillary surface area, and number of syncytial knots.

Cost-effectiveness analysis of cholecystectomy during Roux-en-Y gastric bypass for morbid obesity.

BACKGROUND: Controversy exists regarding the use of concurrent cholecystectomy during Roux-en-Y gastric bypass performed for morbid obesity. METHODS: A decision model was developed to evaluate the cost-effectiveness of current strategies: routine concurrent cholecystectomy, Roux-en-Y gastric bypass alone with or without postoperative ursodiol therapy, and selective cholecystectomy based on preoperative findings on ultrasonography. Probabilities were obtained from a comprehensive literature review. Costs and hospital days were obtained from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. One-way sensitivity analyses were performed. RESULTS: The least expensive strategy was to perform RYGB alone without preoperative ultrasonography, with an average cost (over RYGB costs) of $537 per patient. RYGB with concurrent cholecystectomy had a cost of $631. Selective cholecystectomy based on preoperative ultrasonography was dominated by the other 2 strategies. Our model was most sensitive to the probability of developing gallbladder-related symptoms after RYGB alone. When the incidence of gallbladder-related symptoms was <4.6%, the dominant strategy was to perform a RYGB alone without preoperative ultrasonography. For values >6.9%, performing concurrent cholecystectomy at the time of the RYGB was superior to other strategies. When ursodiol was used, the least expensive strategy was to perform a concurrent cholecystectomy during RYGB. CONCLUSION: The main factor determining the most cost-effective strategy is the incidence of gallbladder-related symptoms after RYGB. The use of ursodiol was associated with an increase in cost that does not justify its use after RYGB. Finally, selective cholecystectomy based on preoperative ultrasonography was dominated by the other strategies in the scenarios evaluated.

Eficácia e segurança de ácido ursodesoxicólico no o tratamento de cirrose biliar primária / Efficacy and safety of ursodeoxycholic acid in the treatment of primary biliary cirrhosis / Eficacia y seguridad de ácido ursodesoxicólico en el tratamiento de la cirrosis biliar primaria

TECNOLOGIA: Ácido ursodesoxicólico. INDICAÇÃO: Cirrose biliar primária. CARACTERIZAÇÃO DA TECNOLOGIA: Ácido biliar natural que tem ação colagoga e colerética. PERGUNTA: O uso do ácido ursodesoxicólico é mais eficaz e seguro em comparação às alternativas terapêuticas existentes no tratamento de pacientes com cirrose biliar primária? BUSCA E ANÁLISE DE EVIDÊNCIAS CIENTÍFICAS: Foram pesquisadas as bases The Cochrane Library, Centre for Reviews and Dissemination, Tripdatabase, Medline e LILACS. Incluíram-se revisões sistemáticas (RS) que comparassem o ácido ursodesoxicólico com as alternativas terapêuticas existentes para o tratamento cirrose biliar primária. Avaliações de Tecnologias de Saúde (ATS) foram pesquisadas em sites de agências nacionais e internacionais. A qualidade da evidência foi avaliada pelo sistema GRADE. RESUMO DOS RESULTADOS DOS ESTUDOS SELECIONADOS: Foram selecionadas oito RS, sendo uma sobre a segurança do medicamento. Os estudos incluíram pacientes em todos os estágios da doença. Foi observado benefício do uso do ácido ursodesoxicólico em relação aos marcadores de função hepática, especialmente a bilirrubina total, observável com seis meses de uso. Entretanto, não houve benefício do uso de ácido ursodesoxicólico em relação à mortalidade e/ou transplante hepático, fadiga, prurido e complicações hepáticas. Quanto à evolução histológica da doença, só foi observada desaceleração em pacientes nos estágios I-II. O medicamento é, em geral, bem tolerado pelos pacientes, sendo o evento adverso mais freqüente a diarréia. Em pacientes em estádios III-IV há risco de descompensação do quadro hepático. Não foram encontradas ATS sobre o ácido ursodesoxicólico. RECOMENDAÇÕES: Pacientes com cirrose biliar primária têm sobrevida que varia de quatro a vinte anos dependendo do estágio no qual a doença é diagnosticada. O ácido ursodesoxicólico, por melhorar os níveis de marcadores hepáticos parece ter efeito benéfico sobre a evolução histológica em pacientes em estádios I-II. Porém essa análise não foi foco central das RS incluídas, de forma que o uso de ácido ursodesoxicólico é fracamente recomendado para pacientes em estádios iniciais desde que sejam considerados responsivos à essa terapia em até, no máximo, seis meses de uso. Em caso de resposta favorável, o tempo de uso pode ser estendido até quando for necessário. Para pacientes com cirrose biliar primária em estádios III-IV recomenda-se fortemente a não utilização do medicamento, pois não há evidência de benefício e há risco de descompensação do quadro clínico.(AU)

TECHNOLOGY: Ursodeoxicholic acid. INDICATION: Primary biliary cirrhosis. CHARACTERIZATION OF THE TECHNOLOGY: A natural biliary acid with cholagogue and choleretic effects. QUESTION: Is ursodeoxycholic acid more effective and safer than other available therapies for primary biliary cirrhosis? SEARCH AND ANALYSIS OF SCIENTIFIC EVIDENCE: We searched The Cochrane Library, Centre for Reviews and Dissemination, Tripdatabase, Medline and LILACS databases aiming to find systematic reviews comparing ursodeoxycholic acid with therapeutic alternatives for the treatment primary biliary cirrhosis. Health Technology Assessments (HTA) were searched on the websites of national and international agencies. Quality of the evidence and strength of recommendation were evaluated using the GRADE system. SUMMARY OF RESULTS OF SELECTED STUDIES: We selected eight systematic reviews, one about the drug's safety. All studies included patients in all stages of the disease. Beneficial effect was observed with the use of ursodeoxycholic acid in relation to markers of liver function, especially total bilirubin, observable within six months of use. However, there was no benefit of using the drug in relation to mortality or liver transplantation, fatigue, pruritus, and liver complications. Histological progression of the disease was only decelerated in patients in stages I-II. The drug is generally well tolerated by patients, the most common adverse event been diarrhea. In patients with stage III-IV there is the risk of hepatic decompensation. There were no HTA on ursodeoxycholic acid. RECOMMENDATIONS: Patients with primary biliary cirrhosis may live from four to twenty years depending on the stage at which the disease is diagnosed. For improving the levels of hepatic markers, ursodeoxycholic acid seems to have a beneficial effect on histological progression in patients with stages I-II. However, this analysis was not the central focus of the systematic reviews included so that the use of ursodeoxycholic acid is weakly recommended for patients in early stages that are considered responsive to this therapy after a maximum of six months of use, which than can be stended for as long as it is needed. For patients with primary biliary cirrhosis in stages III-IV it is strongly recommended not to use the drug because there is no evidence of benefit and there is risk of clinical decompensation.(AU)

TECNOLOGÍA: Ácido ursodesoxicólico. INDICACIÓN: Cirrosis biliar primaria. CARACTERIZACIÓN DE LA TECNOLOGÍA: Ácido biliar natural que tiene la acción y la bilis colerético. PREGUNTA: ¿El uso de ácido ursodesoxicólico es más eficaz y más seguro en comparación con otros enfoques terapéuticos existentes para el tratamiento de pacientes con cirrosis biliar primaria? BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: Se hicieron búsquedas en las bases de datos The Cochrane Library, Centre for Reviews and Dissemination (CRD), Tripbase, Medline (via Pubmed) y en LILACS. Se incluyeron revisiones sistemáticas (RS) que compararon ácido ursodesoxicólico con las alternativas de tratamiento existente de la cirrosis biliar primaria. Se realizaron búsquedas por Evaluaciones de Tecnologías Sanitarias (ETS) en los sitios de las agencias internacionales y de la Red Brasileña de Evaluación de Tecnologías Sanitarias. La calidad de la evidencia y la fuerza de la recomendación se evaluaron utilizando el sistema GRADE. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Fueron seleccionados ocho RS, una sobre la seguridad de los medicamentos. El estudio incluyó pacientes en todas las etapas de la enfermedad. Fue observado beneficio con el uso de ácido ursodesoxicólico en relación a los marcadores de la función hepática, especialmente la bilirrubina total, observable con seis meses de uso. Sin embargo, no hubo ningún beneficio de la utilización de ácido ursodesoxicólico sobre la mortalidad y/o trasplante de hígado, fatiga, prurito y complicaciones hepáticas. Con relación a la evolución histológica de la enfermedad sólo se observó desaceleración en pacientes en los estadios I-II. El medicamento es, en general, bien tolerado por los pacientes, siendo el efecto secundario más frecuente la diarrea. En pacientes con estadios III-IV existe riesgo de descompensación del cuadro hepático. No fueron encontradas ETS. RECOMENDACIONES: Los pacientes con cirrosis biliar primaria tienen supervivencia de cuatro a veinte años, dependiendo de la etapa en que se diagnostica la enfermedad. El ácido ursodesoxicólico, por mejorar los niveles de los niveles de los marcadores hepáticos parece tener un efecto benéfico sobre los resultados histológicos en pacientes en estadios I-II. Sin embargo, este análisis no fue el foco central de las RS, de manera que el uso de ácido ursodesoxicólico es débilmente recomendable para pacientes en los estadios iniciales si fueran sensibles a esta terapia dentro de seis meses de uso. En caso de una respuesta positiva, el tiempo de uso se puede extender hasta sea necesario. Para los pacientes con cirrosis biliar primaria en estadios III-IV se recomienda no utilizar el medicamento, porque no hay evidencia de beneficio y hay riesgo de descompensación clínica.(AU)

Estimation of recurrence of colorectal adenomas with dependent censoring using weighted logistic regression.

In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial.

A contemporary analysis of parenteral nutrition-associated liver disease in surgical infants.

BACKGROUND/PURPOSE: Despite advances in pediatric nutritional support and a renewed focus on management of intestinal failure, there are limited recent data regarding the risk of parenteral nutrition (PN)-associated liver disease in surgical infants. This study investigated the incidence of cholestasis from PN and risk factors for its development in this population. METHODS: A retrospective review was performed of all neonates in our institution who underwent abdominal surgery and required postoperative PN from 2001 to 2006. Cholestasis was defined as 2 conjugated bilirubin levels greater than 2 mg/dL over 14 days. Nonparametric univariate analyses and multivariate logistic regression were used to model the likelihood of developing cholestasis. Median values with range are presented. RESULTS: One hundred seventy-six infants met inclusion criteria, and patients received PN for 28 days (range, 2-256 days). The incidence of cholestasis was 24%. Cholestatic infants were born at an earlier gestational age (34 vs 36 weeks; P < .01), required a 3-fold longer PN duration (76 vs 21 days; P < .001), had longer inpatient stays (86 vs 29 days; P < .001), and were more likely to be discharged on PN. The median time to cholestasis was 23 days. Cholestasis was an early development; 77% of cholestatic infants developed cholestasis by 5 weeks of PN exposure. On multivariate regression, only prematurity was significantly associated with development of cholestasis (P < .05). CONCLUSION: In this analysis, the development of PN-associated liver disease occurred early in the course of exposure to PN. These data help to define the time course and prognosis for PN-associated cholestasis in surgical infants.

Cholestasis in neonatal intensive care unit: incidence, aetiology and management.

AIM: Prevalence, aetiology, management and outcome of cholestasis were evaluated in infants admitted to neonatal intensive care unit (NICU). METHODS: Medical records of all infants admitted to two Italian level III NICUs from January 2005 to August 2007 were retrospectively reviewed. The role of ursodeoxycholic acid (UDCA) therapy was also investigated. RESULTS: Twenty-seven of 1289 enrolled infants developed cholestasis. In 25 infants, cholestasis had a multifactorial basis, while in two, no aetiology was found. UDCA did not significantly affect clinical and biochemical course of cholestasis. During a period of 12 months, eight cholestatic infants died, one underwent liver transplantation and 18 fully recovered. CONCLUSION: Infants admitted in NICU have a rate of cholestasis higher than that reported in the general population of live births; in most cases, cholestasis is associated to multiple risk factors and shows a favourable outcome. UDCA does not seem to affect clinical course of cholestasis in this setting.

Bear bile: dilemma of traditional medicinal use and animal protection.

Bear bile has been used in Traditional Chinese Medicine (TCM) for thousands of years. Modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. However, extensive consumption of bear bile made bears endangered species. In the 1980's, bear farming was established in China to extract bear bile from living bears with "Free-dripping Fistula Technique". Bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. Efforts are now given by non-governmental organizations, mass media and Chinese government to end bear farming ultimately. At the same time, systematic research has to be done to find an alternative for bear bile. In this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in English and Chinese databases. We examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from TCM. We then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future.