Estudo custo-utilidade e do impacto orçamentário das anticitocinas Adalimumabe, Etanercepte e Infliximabe no tratamento da artrite reumatoide no Estado do Paraná

Orientador : Prof. Dr. Roberto PontaroloCoorientador : Prof. Dr. Cassyano Januário CorrerDissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas. Defesa: Curitiba,22/09/2011Bibliografia: fls. 79-80Área de concentração: Insumos, medicamentos e correlatosResumoIntrodução: Foram avaliadas três anticitocinas utilizadas para o tratamento da artrite reumatoide. Essas drogas, chamadas de biológicas, fazem parte do grupo de medicamentos da atenção especializada e são fornecidos à população pelo Sistema Único de Saúde (SUS). Foi realizada uma avaliação econômica das anticitocinas e seu impacto orçamentário no Paraná, tomando como ano-base o ano de 2008. Objetivo: O objetivo desse trabalho foi definir se as anticitocinas adalimumabe, etanercepte e infliximabe apresentam diferenças de custo-efetividade para tratar da artrite reumatoide nãocontrolada, sob a perspectiva do SUS. Também se buscou determinar qual dessas alternativas terapêuticas apresenta melhor relação custo-utilidade e qual seria o impacto econômico da exclusão de algum(uns) desse(s) medicamento(s) do Programa de Atenção Especializada do Ministério da Saúde ou do crescimento do número de pacientes cadastrados que usam esses medicamentos, considerando as alternativas atualmente padronizadas no sistema. Metodologia: Dados de eficácia, segurança e tolerabilidade do uso das drogas foram obtidos de revisões sistemáticas e metanálises. O custo dos medicamentos foi calculado utilizando-se os preços pagos pelo Centro de Medicamentos do Paraná nas compras realizadas por licitações em 2008; outros custos diretos envolvidos no tratamento, como insumos e monitoração dos tratamentos foram obtidos da tabela do Sistema de Informação Ambulatorial do SUS - SIA/SUS, disponibilizada pelo DATASUS. O modelo de Markov foi utilizado para realizar a avaliação econômica. Valores como o escore de utilidade dos pacientes em cada estágio do tratamento foi calculado a partir dos valores de HAQ (Health Assesment Questionnaire) antes e depois do tratamento obtidos das mesmas revisões sistemáticas. Para o cálculo da relação custo-utilidade foi considerado horizonte temporal de 10 anos e ciclos de seis meses. A taxa de desconto aplicada foi de 5%. Foram realizadas análises de sensibilidade, variando a eficácia e o custo dos tratamentos. O impacto orçamentário das anticitocinas no Paraná foi calculado através da criação de diferentes cenários, considerando a taxa média de novos pacientes com artrite reumatoide incluídos no programa do SUS para receberem anticitocinas. Resultados: A avaliação de custo-utilidade, medida em Reais/Ano de Vida Ajustado por Qualidade (QALY) ganho, gerou os seguintes valores (em R$/QALY): 511.633,00, 437.486,00 e 657.593,00 para o adalimumabe, etanercepte e infliximabe, respectivamente. A análise de custo incremental resultou em 307.793,00 e 259.200,00, para o adalimumabe e para o etanercepte, considerando como comparador-base o infliximabe. As análises de sensibilidade somente levaram a alterações na ordem das relações custo-utilidade para variações da ordem de 15$ 8.500.000,00, quando comparado ao ano de 2008. Isso representa um aumento anual de 3,3% dos gastos da SESA-PR com medicamentos. Conclusão: Observou-se uma grande discrepância entre os valores de custo-utilidade dos medicamentos; o tratamento com infliximabe custa aproximadamente 70% a mais por QALY, em comparação com o etanercepte. Essas informações devem ser avaliadas pelos tomadores de decisão para melhor alocação dos recursos. É interessante que as três opções de tratamento continuem sendo disponibilizadas por motivos de diferenças nas respostas clínicas dos pacientes, cabendo aos gestores estaduais e aos médicos a decisão do tratamento para cada paciente individualmente.Abstract: Background: Three anticitokines for treating rheumatoid arthritis (RA) were evaluated. These drugs, called biological drugs, are part of a group of medicines known as "specializated care medicines" due to their high costs and are provided by SUS, the Brazilian health system. An economic evaluation of anticitokines ant its budget impact to Paraná, taking as reference the year of 2008. Aims: To define if the anticitokines adalimumab, etanercept and infliximab are different, in terms of cost-utility, to treat noncontrolled rheumatoid arthritis, within SUS's perspective. Also sought to determine which one of these therapeutic alternatives presents the best cost-utility relationship and what is the budget impact of exclusion of one or more of these drugs or of the increasing of number of patients registered to receive them, considering the standardized alternatives. Methodology: Efficacy, safety and tolerability data involved in these drugs using were obtained from actual and high quality systematic reviews and meta-analyses. The costs of the drugs were calculated using the prices payied by CEMEPAR (public organ responsible for medicine management on Paraná); other direct costs involved in treatment, such as insumes used and treatment monitoring were obtained from a public databank (SIA/SUS). Markov modeling was used to do the economic evaluation of the drugs. The utility of patients within each state of treatment was calculated using values of HAQ (Health Assessment Questionnaire) before and after the treatment obtained from the same systematic reviews. For calculus of cost-utility relationship, a time horizon of 10 years was used, with 6 months markov cycles. The discount rate was of 5%. Sensitivity analyses were made varying the effectiveness and cost of each treatment. The budget impact of anticitokines use in Paraná was estimated by creation of different frameworks, considering the mean rate of new RA patients receiving adalimumab, etanercept or infliximab. Results: Cost-effectiveness analysis (in Reais/Quality-Adjusted Life Years, or QALY, gained) led to the following values: 511.633,00, 437.486,00 and 657.593,00 for adalimumab, etanercept and infliximab treatment, respectively. Incremental cost-utility relationship resulted in 307.793,00 and 259.200,00 for adalimumabe and etanercept, respectively). Sensitivity analysis did not impact significantly on final result of cost-utility analyses. In budget impact analysis, making a estimation of the number of new patients for 2009, based on the last trimester of 2008, it was noticed that, considering patients included for treatment with anticitokines, it would increase resource needed of R$ 8.500.000,00, approximately, when compared to 2008. This represents an annual increase of 3.3% of the government spending with medicines. Conclusion: A difference between the cost-utility values of the drugs was noticed; the treatment with infliximab costs almost 70% more per QALY than etanercept. These informations must be analyzed by the decision-makers to better resource allocation in the public health system. It is interesting that the three drug options continue to be disponibilized, since there are different clinical responses among the patients, leading to the gestores and to the physicians the role to decide the treatment for each patient individually

A review of the application of hollow-fiber liquid-phase microextraction in bioanalytical methods - a systematic approach with focus on forensic toxicology

Over the past three decades, many studies employing hollow-fiber liquid-phase microextraction (HF-LPME) bioanalytical methods have been published. The basic mechanism of extraction relies on the migration of the analytes through a liquid membrane sustained in the pores of the walls of a porous hollow fiber, and from there into an acceptor phase present in the lumen of the fiber. The mass transfer occurs by passive diffusion and it can be enhanced by using a carrier or applying an electrical potential across the phases. This type of extraction method presents many advantages over classical techniques, such as high preconcentration factor, clean extracts, and a green chemistry approach. Due to its advantages, and considering that no study systematically compiled the characteristics of the published methods in one single accessible source of information, the aim of this systematic review is to assess the data regarding bioanalytical methods, compile, and analyse the studies published until up to October of 2017. The data source used for the systematic review were Pubmed, Web of Science, and Science Direct, and 171 studies were included in the final review by two independent reviewers, resulting in a reliable and accessible source of information about bioanalytical methods employing HF-LPME

Medico-legal death investigation systems – Brazil

Investigation of death differs between countries and whether deaths are natural or unnatural. This article aims to describe the investigation of both natural and unnatural deaths in Brazil, a federation formed by 26 States plus the Federal District. Although the Brazilian States are self-governing, death investigation follows some standardised processes throughout the country. Some deaths require little to no investigation, such as natural deaths that occur under the supervision of a medical doctor; in these cases, the body can be released directly to the funeral services. Other deaths are investigated more thoroughly, such as suspicious deaths with non-identified body. Such cases usually involve more parties, such as the Military Police, the Judicial Police, Forensic Experts, Prosecutors, and a Judge. Reports from Forensic Experts, such as Forensic Pathologists, Forensic Toxicologists, and Crime Scene Investigators, are compiled together with other documents within the inquiry process and are critical to the success of the investigation. The Forensic Experts normally work in the Medico-Legal Institutes or in the Criminalistics Institutes and they may or may not be part of the Judicial Police force, depending on the State; in some States, they are part of another institution called Scientific Police. A crucial step in the process of death investigation is the chain of custody, which has evolved greatly in Brazil in the past few years. However, the investigation process may still take years to be completed due to the lack of resources and investment in the involved parties, especially the Polices forces

Efficacy, safety and tolerability of using abatacept for the treatment of rheumatoid arthritis

The objective is to provide an update on the clinical efficacy, safety and tolerability of the use of abatacept for treating rheumatoid arthritis. A systematic review (up to June 2011) followed by meta-analyses was performed. Randomized controlled clinical trials comparing abatacept at a dose of 10 mg/kg with a placebo, both with concomitant methotrexate, were used. Only high- or moderate-quality studies were included. The efficacy was evaluated based on changes in the ACR, DAS and HAQ; safety was assessed based on serious adverse events, serious infections, malignancies and deaths; tolerability was evaluated based on the withdrawals due to adverse events, serious adverse events and lack of efficacy. All these parameters were evaluated within one year of treatment. Nine studies met the inclusion criteria, comprising 4,219 patients. For all of the efficacy parameters, the abatacept group had better results than the placebo group, except in the case of HAQ improvement >0.3, which presented no statistically significant difference. None of the safety parameters presented a significant difference between the groups. The tolerability parameters were also similar between groups, with the exception of withdrawals due to lack of efficacy. For this criterion, the abatacept group presented favorably compared to the control group. Abatacept showed a higher efficacy compared to placebo without significant differences between the abatacept and control group in terms of safety

Efficacy, safety and tolerability of using abatacept for the treatment of rheumatoid arthritis

The objective is to provide an update on the clinical efficacy, safety and tolerability of the use of abatacept for treating rheumatoid arthritis. A systematic review (up to June 2011) followed by meta-analyses was performed. Randomized controlled clinical trials comparing abatacept at a dose of 10 mg/kg with a placebo, both with concomitant methotrexate, were used. Only high- or moderate-quality studies were included. The efficacy was evaluated based on changes in the ACR, DAS and HAQ; safety was assessed based on serious adverse events, serious infections, malignancies and deaths; tolerability was evaluated based on the withdrawals due to adverse events, serious adverse events and lack of efficacy. All these parameters were evaluated within one year of treatment. Nine studies met the inclusion criteria, comprising 4,219 patients. For all of the efficacy parameters, the abatacept group had better results than the placebo group, except in the case of HAQ improvement >;0.3, which presented no statistically significant difference. None of the safety parameters presented a significant difference between the groups. The tolerability parameters were also similar between groups, with the exception of withdrawals due to lack of efficacy. For this criterion, the abatacept group presented favorably compared to the control group. Abatacept showed a higher efficacy compared to placebo without significant differences between the abatacept and control group in terms of safety.O objetivo foi fornecer dados atualizados sobre eficácia clínica, segurança e tolerabilidade do uso de abatacepte para o tratamento da artrite reumatoide. Realizaram-se uma revisão sistemática (com dados até junho/2011) e metanálises. Somente estudos clínicos controlados randomizados comparando o abatacepte (10 mg/kg) com placebo, ambos com uso concomitante de metotrexato, foram incluídos; todos possuíam qualidade alta ou moderada. A eficácia foi avaliada baseando-se em mudanças no ACR, DAS e HAQ; a segurança foi avaliada pelos eventos adversos e infecções graves, malignidades e mortes e a tolerabilidade pelo abandono do tratamento devido a eventos adversos (graves ou não) e falta de eficácia. Todos esses parâmetros foram avaliados ao final de um ano de tratamento. Nove estudos se adequaram aos critérios de inclusão, envolvendo 4219 pacientes. Em todos os parâmetros avaliados, o grupo tratado com abatacepte obteve melhores resultados, exceto para a melhora (>;0,3) no HAQ (sem diferença estatisticamente significativa). Nenhum critério de segurança ou tolerabilidade apresentou diferença significativa entre os grupos, com exceção dos abandonos devido à falta de eficácia (grupo abatacepte apresentou resultados favoráveis em relação ao controle). O abatacepte possui maior eficácia quando comparado com o placebo, sem diferença significativa entre os grupos em termos de segurança

Application of a urine and hair validated LC-MS/MS method to determine the effect of hair colour on the incorporation of 25B-NBOMe, 25C-NBOMe and 25I-NBOMe into hair in the rat.

NBOMes are a group of new psychoactive substances derived from phenethylamines. Recreational abuse is thought to have begun in 2010 and they are commonly associated with the “club drug” scene. They are administered in liquid form or as blotters due to their high potency. An LC-MS/MS method was validated using SWGTOX parameters for the detection of 25B-, 25C- and 25I-NBOMe using 25B-NBOMe-D3 as internal standard for urine and hair. Calibration graphs with R2 values >0.99 were observed for urine and hair for concentrations ranging from 0.1 -100 ng/mL and 0.025-2.5 ng/mg respectively. Urine LODs ranged from 5-25 pg/mL and had an LOQ of 50 pg/mL. Hair LOD and LOQs ranged from 3-5 pg/mg and 6.25-12.5 pg/mg respectively. Intra and inter-day precision was <20% and accuracy was within ± 20% for both matrices. The method was shown to be selective for both exogenous and endogenous compounds. No matrix effects were observed for either matrix. LLE recovery ranged from 90-103% for urine samples and SPE recovery ranged from 80-107% for hair samples. Long-Evans rats (n=55) were administered 25B-, 25C- or 25I-NBOMe at doses ranging from 30-300 µg/kg over a period of 10 days. Rats were shaved prior to their first dose and re-shaved after the 10-day period. Hair was separated by colour (black: n=55 and white: n=55) and analysed using the validated LC-MS/MS method to assess the impact hair colour has on the incorporation of these drugs. All drugs were successfully detected in black hair. 25B-NBOMe from rats receiving the highest dose and 25C-NBOMe from rats receiving the medium and high doses were quantified in white hair. 25I-NBOMe was detected but fell below the limit of quantification. A dose-dependent concentration increase was observed in the black hair. All pooled urine samples tested positive for their expected NBOMes

Economic evaluation of treatments for chronic hepatitis B

The aim of this study was to conduct a cost-utility study of adefovir, entecavir, interferon alpha, pegylated interferon alpha, lamivudine and tenofovir for chronic hepatitis B in the context of Brazilian Public Health Care System. A systematic review was carried out for efficacy and safety. Another review was performed to collect utility data and transition probabilities between health states. A Markov model was developed in a time horizon of 40 years with annual cycles for three groups of: HBeAg positive, HBeAg negative, and all patients. These strategies were compared to a fourth group that received no treatment. Discount rates of 5% were applied and sensitivity analyses were performed. Tenofovir offered the best cost-utility ratio for the three evaluated models: U$397, U$385 and U$384 (per QALY, respectively, for HBeAg positive, negative, and all patients). All other strategies were completely dominated because they showed higher costs and lower effectiveness than tenofovir. The sequence of cost-utility in the three models was: tenofovir, entecavir, lamivudine, adefovir, telbivudine, pegylated interferon alpha, and interferon alpha. In the sensitivity analysis, adefovir showed lower cost-utility than telbivudine in some situations. The study has some limitations, primarily related to the creation of scenarios and modeling. In this study, tenofovir presented the best cost-utility ratio. The results obtained in this study will be valuable in decision-making and in the review of the clinical protocol, mainly involving the allocation of available resources for health care

Safety of biologics approved for the treatment of rheumatoid arthritis and other autoimmune diseases: a disproportionality analysis from the FDA Adverse Event Reporting System (FAERS)

Introduction: The molecular and pharmacological complexity of biologic disease-modifying antirheumatic drugs used for the management of rheumatoid arthritis (RA) favors the occurrence of adverse drug reactions (ADRs), which should be constantly monitored in post-marketing safety studies. Objective: The aim of this study was to identify signals of disproportionate reporting (SDR) of clinical relevance related to the use of biologic drugs approved for RA and other autoimmune diseases. Methods: All suspected ADRs registered in the FDA Adverse Event Reporting System between January 2003 and June 2016 were collected. The reporting odds ratio was used as a measure of disproportionality to identify possible SDRs related to biologics. Those involving important medical events and designated medical events (DME) were prioritized. Results: In total, 2602 SDRs were prioritized. The most commonly reported were ‘Infections and infestations’ (32.2%) and ‘Neoplasms benign, malignant, and unspecified’ (20.4%), and were mainly related to use of infliximab (25.3%, p &lt; 0.001, and 28.8%, p = 0.002, respectively). Sixty-three signals involving DMEs were identified, most of which were related to rituximab (n = 27), and were mainly due to ‘blood disorders’. Amongst the DMEs detected for more than one biologic, ‘intestinal perforation’ and ‘pulmonary fibrosis’ were related to most of them. Conclusions: The results of this study highlight possible safety issues associated with biologics, whose relationship should be more thoroughly investigated. Our results contribute to future research on the identification of clinically relevant risks associated with these drugs, and may help contribute to their rational and safe use

Effect of a Pharmaceutical Care Program on quality of life and satisfaction with pharmacy services in patients with type 2 diabetes mellitus

The aim is to evaluate the humanistic outcomes in type 2 diabetic patients by the adoption of pharmacotherapy follow-up in community pharmacies. Controlled, non-randomized, 12-months trial; n=161 patients distributed into control and intervention groups; 6 community pharmacies involved, all in the Curitiba city region, in the state of Paraná were used. The health-related quality of life (HRQoL) and the satisfaction index were determined using both the DQOL assessment tool, which measures HRQoL, and the satisfaction evaluation tool (QSSF). Interventions on 119 negative therapeutic outcomes were done (2.3/patient [SD=1.6]); the most commonly found problems were related to ineffectiveness of pharmacotherapy (68.1%). The Intervention-Group showed a significant improvement in HRQoL compared with the Control Group (0.08 vs -0.01, respectively; p=0.036). Satisfaction and impact domains presented the most significant improvement (0.13 vs 0.00 [p=0.030] and 0.07 vs -0.04 [p=0.033], respectively). After adjusting for baseline variables, the difference in improvement scores between groups on the QSSF was attributed to the allocation of patients in the intervention group. Pharmacotherapy follow-up of type 2 diabetic patients in community pharmacies can improve the HRQoL and satisfaction of patients.O objetivo foi avaliar os resultados humanísticos de pacientes com diabetes tipo 2, por meio da adoção de acompanhamento farmacoterapêutico nas farmácias comunitárias. Utilizaram-se: ensaio controlado, não-randomizado, de 12 meses; n=161 pacientes, distribuídos entre Grupo Controle e de Intervenção, e 6 farmácias comunitárias, todas na região da cidade de Curitiba, Estado do Paraná. A qualidade de vida relacionada à saúde (HRQoL) e o índice de satisfação foram determinados utilizando a ferramenta de avaliação DQOL, que mede a HRQoL, e a ferramenta de avaliação da satisfação (QSSF). Intervenções em 119 resultados terapêuticos foram efetuadas (2,3/paciente [SD=1,6]. Os problemas mais comumente encontrados foram aqueles relacionados à ineficácia da farmacoterapia (68,1%). O Grupo de Intervenção mostrou melhoria significativa da HRQoL em comparação ao Grupo Controle (0,08 versus 0,00 [p=0,030 e 0,07 versus -0,04 [p=0,033], respectivamente). Após o ajuste da linha base das variáveis, a diferença na contagem de melhoramento entre os grupos no QSSF foi atribuída à alocação de pacientes no Grupo de Intervenção. O acompanhamento farmacoterapêutico em pacientes de diabetes tipo 2 em farmácias comunitárias pode melhorar a HRQoL e a satisfação dos pacientes

Insulin analogues versus human insulin in type 1 diabetes: direct and indirect meta-analyses of efficacy and safety

Todos os pacientes com Diabetes Mellitus (DM) tipo 1 recebem insulina. Neste estudo, avaliaram-se eficácia, segurança e tolerabilidade de insulinas humanas e análogas. Realizou-se uma revisão sistemática e meta-análise, de acordo com o preconizado pela Colaboração Cochrane. Na ausência de estudos clínicos comparando insulinas entre si, realizaram-se meta-análises de comparações indiretas a fim de estabelecer diferenças entre tratamentos ativos. Incluíram-se estudos de 1995 a 2010. Resultados de HbA1c, episódios de hipoglicemia e hipoglicemia noturna foram extraídos e analisados. Após leitura de resumos e, posteriormente, de artigos na íntegra, selecionaram-se 35 ensaios clínicos randomizados, totalizando 4206 pacientes utilizando insulina análoga de longa duração e 5733 pacientes insulina análoga de curta duração. Os resultados não demonstraram diferença estatisticamente significativa para redução de HbA1c entre glargina e detemir (uma vez ao dia) comparados a NPH. No entanto, insulina detemir utilizada duas vezes ao dia reduz a HbA1c (-0.14% [95% CI: -0.21 to -0.08]; pAll patients with Diabetes Mellitus (DM) receive insulin therapy. In this study, we evaluated the efficacy, safety and tolerability of human insulin and insulin analogues. We performed a systematic review of the literature and a meta-analysis according to the Cochrane Collaboration methodology. In the absence of clinical studies comparing insulins, we performed a mixed treatment comparison to establish the differences between the active treatments. We included studies published from 1995 to 2010. HbA1c results, episodes of hypoglycemia and nocturnal hypoglycemia data were extracted and analyzed. Thirty-five randomized clinical trials were selected after examining the abstract and a full text review. These studies included 4,206 patients who received long-acting insulin analogues and 5,733 patients who received short-acting insulin analogues. Pooled data regarding efficacy indicated no significant differences in HbA1c values between glargine or detemir (once daily) and NPH insulin. However, a twice-daily dose of detemir produced differences in HbA1c values that favored detemir (-0.14% [95% CI: -0.21 to -0.08];