Clinical and economic outcomes in patients with chronic obstructive pulmonary disease initiating maintenance therapy with tiotropium bromide/olodaterol or fluticasone furoate/umeclidinium/vilanterol.

BACKGROUND: Clinical practice guidelines recommend dual long-acting muscarinic antagonists (LAMAs)/long-acting ß2agonists (LABAs) as maintenance therapy in patients with chronic obstructive pulmonary disease (COPD) and dyspnea or exercise intolerance. Escalation to triple therapy (TT) (LAMA/LABA/inhaled corticosteroid) is conditionally recommended for patients with continued exacerbations on dual LAMA/LABA therapy. Despite this guidance, TT use is widespread across COPD severities, which could impact clinical and economic outcomes. OBJECTIVE: To compare COPD exacerbations, pneumonia events, and disease-related and all-cause health care resource utilization and costs (in 2020 US dollars) in patients initiating fixed-dose combinations of either LAMA/LABA (tiotropium/olodaterol [TIO + OLO]) or TT (fluticasone furoate/umeclidinium/vilanterol [FF + UMEC + VI]). METHODS: This retrospective observational study of administrative claims included patients with COPD aged 40 years or older initiating TIO + OLO or FF + UMEC + VI from June 2015 to November 2019. TIO + OLO and FF + UMEC + VI cohorts in the overall and maintenance-naive populations were 1:1 propensity score matched on baseline demographics, comorbidities, COPD medications, health care resource utilization, and costs. Multivariable regression compared clinical and economic outcomes up to 12 months in FF + UMEC + VI vs TIO + OLO postmatched cohorts. RESULTS: After matching, there were 5,658 and 3,025 pairs in the overall and maintenance-naive populations, respectively. In the overall population, the risk of any (moderate or severe) exacerbation was 7% lower in FF + UMEC + VI vs TIO + OLO initiators (adjusted hazard ratio [aHR] = 0.93; 95% CI = 0.86-1.0; P = 0.047). There was no difference in the adjusted risk of any exacerbation in the maintenance-naive population (aHR = 0.99; 95% CI = 0.88-1.10). Pneumonia risk was not statistically different between cohorts in the overall (aHR = 1.12; 95% CI = 0.98-1.27) and maintenance-naive (aHR = 1.13; 95% CI = 0.95-1.36) populations. COPD- and/or pneumonia-related adjusted total annualized costs (95% CI) were significantly greater for FF + UMEC + VI vs TIO + OLO in the overall ($17,633 [16,661-18,604] vs $14,558 [13,709-15,407]; P < 0.001; differences [% of relative increase] = $3,075 [21.1%]) and maintenancenaive ($19,032 [17,466-20,598] vs $15,004 [13,786-16,223]; P < 0.001; $4,028 [26.8%]) populations, with significantly higher pharmacy costs with FF + UMEC + VI (overall: $6,567 [6,503-6,632] vs $4,729 [4,676-4,783]; P < 0.001; $1,838 [38.9%]; maintenance-naive: $6,642 [6,560-6,724] vs $4,750 [4,676-4,825]; P < 0.001; $1,892 [39.8%]). CONCLUSIONS: A lower risk of exacerbation was observed with FF + UMEC + VI vs TIO + OLO in the overall population but not among the maintenance-naive population. Patients with COPD initiating TIO + OLO had lower annualized costs than FF + UMEC + VI initiators in the overall and maintenance-naive populations. Thus, in the maintenance-naive population, initiation with dual LAMA/LABA therapy per practice guidelines can improve real-world economic outcomes. Study registration number: ClinicalTrials.gov (identifier: NCT05127304). DISCLOSURES: The study was funded by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI). To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, BIPI grants all external authors access to relevant clinical study data. In adherence with the BIPI Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Dr Sethi has received honoraria/fees for consulting/speaking from Astra-Zeneca, BIPI, and GlaxoSmithKline. He has received consulting fees for serving on data safety monitoring boards from Nuvaira and Pulmotect. He has received consulting fees from Apellis and Aerogen. His institution has received research funds for his participation in clinical trials from Regeneron and AstraZeneca. Ms Palli was an employee of BIPI at the time the study was conducted. Drs Clark and Shaikh are employees of BIPI. Ms Buysman and Mr Sargent are employees and Dr Bengtson was an employee of Optum, which was contracted by BIPI to conduct this study. Dr Ferguson reports grants and personal fees from Boehringer Ingelheim during the conduct of the study; grants from Novartis, Altavant, and Knopp; grants and personal fees from AstraZeneca, Verona, Theravance, Teva, and GlaxoSmithKline; and personal fees from Galderma, Orpheris, Dev.Pro, Syneos, and Ionis outside the submitted work. He was a paid consultant for BIPI for this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Tiotropium for children and adolescents with severe asthma.

INTRODUCTION: An important proportion of asthma patients remain uncontrolled despite using inhaled corticosteroids and long-acting beta-agonists. Some add-on therapies, such as tiotropium bromide has been recommended for this subgroup of patients. The purpose of this study was to assess the cost-effectiveness of tiotropium as add-on therapies to ICS + LABA for children and adolescents with uncontrolled allergic asthma. METHODS: A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with severe asthma in Colombia. Total costs and QALYS of two interventions including standard therapy (ICS + LABA), and add-on therapy with tiotropium, were calculated over a time horizon from 6 to 18 years. Probability sensitivity analyses were conducted. RESULTS: For a patient with severe asthma, our Markov model showed that compared to standard therapy, add-on therapy with tiotropium was associated with higher treatment costs and QALY. The incremental cost-effectiveness ratio estimated was US$2,017 in the probabilistic model after Monte-Carlo simulation. Our base-case results were robust to variations in all assumptions and parameters. The incremental net monetary benefit of US$327 with a 95% credible interval of US$396 to US425. CONCLUSION: Add-on therapy with tiotropium was cost-effective when added to usual care in children and adolescents with severe asthma who remained uncontrolled despite treatment with medium or high-dose ICS/LABA. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.

The Efficacy and Cost-Effectiveness of Umeclidinium/Vilanterol versus Tiotropium in Symptomatic Patients with Chronic Obstructive Pulmonary Disease.

Background: Both long-acting muscarinic antagonists (LAMAs) and long-acting ß2-agonists (LABAs) are widely used in the treatment of chronic obstructive pulmonary disease (COPD). A novel LAMA/LABA combination of umeclidinium/vilanterol (UMEC/VI; 62.5 µg/25 µg) is approved for chronic obstructive pulmonary disease (COPD) treatment. Objective: This study aimed to assess the efficacy and cost-effectiveness of UMEC/VI versus tiotropium (TIO) 18 µg in symptomatic patients with COPD from the perspective of the Chinese National Healthcare System. Methods: A simple analysis included three studies in the meta-analysis that compared UMEC/VI with TIO. A Markov model was developed to estimate the cost-effectiveness of UMEC/VI compared with TIO treatment in symptomatic patients with COPD. First, utilities, clinical efficacy, and adverse events obtained from the literature were utilized as model inputs. Costs were from Chinese average data, including local data. Costs were expressed in dollars based on 2020 prices. Then, the model outputs including drug costs, other medical costs, and total costs, and quality-adjusted life years (QALYs) were estimated. Costs and outcomes were discounted at a 5% annual rate. Furthermore, incremental cost-effective ratios (ICERs) were analyzed. Finally, the influences of changing parameters on the uncertainty of the results were assessed by means of one-way and probabilistic sensitivity analyses. Results: This study revealed that UMEC/VI treatment had a higher rate of clinical efficacy in comparison with TIO, and the differences in the rate of adverse events between the two treatments were not significant. The results indicated that UMEC/VI was superior to TIO, which provided an increase in QALYs (0.002) and a total cost savings of $765.67 per patient over 3 years. In the base case, the ICER of UMEC/VI is -$397468.04/QALY compared with TIO, suggesting that UMEC/VI may be considered a dominant option over TIO. According to the Chinese medical system, the probability of UMEC/VI being cost-effective was 61.6% at a willingness-to-pay (WTP) of $31554/QALY. Sensitivity analyses confirmed that the results were robust. Conclusion: UMEC/VI could be considered a cost-effective treatment compared with TIO in symptomatic COPD patients from the Chinese National Healthcare System perspective. These results may help decision-makers in China when making judgements on which treatments to administer.

Cost-effectiveness of single-inhaler extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium in patients with uncontrolled asthma in England.

BACKGROUND: In patients with asthma that is uncontrolled by a medium- or high-dose inhaled corticosteroid (ICS) plus long-acting ß2-agonist (LABA), a maintenance therapy option is the addition of a long-acting muscarinic agonist, either via multiple inhalers, or single-inhaler triple therapy (SITT). One SITT is the extrafine formulation of beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G). We used data from two 52-week clinical trials (TRIMARAN and TRIGGER), both conducted in adults with asthma uncontrolled by ICS/LABA, to investigate the cost-effectiveness of BDP/FF/G. METHODS: A Markov cohort state transition model (focusing on exacerbations) was used to investigate the cost-effectiveness of medium- or high-dose BDP/FF/G vs medium- or high-dose BDP/FF, and high-dose BDP/FF/G vs high-dose BDP/FF + tiotropium. The model analysed cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER), and was developed from the England National Health Service perspective (2020 costs). Uncertainty of the inputs was estimated using one-way and probabilistic sensitivity analyses. RESULTS: Both medium- and high-dose BDP/FF/G were cost-effective vs BDP/FF, with ICERs of £12,224 and £15,587 per QALY gained. High-dose BDP/FF/G was dominant vs BDP/FF + tiotropium, as it was both cheaper and gained QALYs. Sensitivity analyses were consistent with the base model: medium- and high-dose BDP/FF/G had 94.3% and 88.3% likelihoods to be cost-effective vs BDP/FF; high-dose BDP/FF/G had 100% likelihood to be a dominant strategy vs BDP/FF + tiotropium. CONCLUSIONS: Both medium- and high-dose BDP/FF/G were cost-effective vs medium- and high-dose BDP/FF in adults with asthma that was uncontrolled by ICS/LABA. In addition, high-dose BDP/FF/G was a dominating strategy to high-dose BDP/FF + tiotropium. CLINICALTRIALS: GOV: NCT02676076 and NCT02676089.

Cost­effectiveness of tiotropium versus omalizumab for uncontrolled allergic asthma.

OBJECTIVE: In patients with uncontrolled asthma, despite management with high doses of inhaled corticosteroids, the additional use of omalizumab and tiotropium is recommended. Omalizumab is an expensive medication and doubts arise as to whether the benefit of this drug outweighs the additional expense of the drug. The purpose of this study was to assess the cost-effectiveness of tiotropium versus omalizumab as add-on therapies to ICS + LABA for patients with uncontrolled allergic asthma. METHODS: A probabilistic Markov model was created to estimate the cost and quality-adjusted life years (QALYs) of patients with uncontrolled allergic asthma in Colombia. Total costs and QALYs of three interventions including standard therapy (ICS + LABA), add-on therapy with tiotropium, and add-on therapy with omalizumab, were calculated over a 10-year time horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000. RESULTS: The model showed that tiotropium was associated with lower cost than standard therapy and omalizumab (US$5590 vs. US$5693 vs. U$18,154 average annual cost per patient), and higher QALYs (11.8 vs. 11.3 vs. 11.9) average per patient), showing dominance respect to standard therapy. The probability that tiotropium provides a more cost-effective use of resources compared with standard therapy exceeds 99% for willingness-to-pay threshold. CONCLUSION: Add-on therapy with tiotropium was a cost-effective alternative to omalizumab and standard therapy for uncontrolled allergic asthma. Our study provides evidence that should be used by decision-makers to improve clinical practice guidelines and should be replicated to validate their results in other middle-income countries.

Two cases of chronic obstructive pulmonary disease evaluated by dynamic-ventilatory digital radiography for pulmonary function and assessment of treatment efficacy.

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Cost-effectiveness of the fixed-dose combination tiotropium/olodaterol versus tiotropium monotherapy or a fixed-dose combination of long-acting ß2-agonist/inhaled corticosteroid for COPD in Finland, Sweden and the Netherlands: a model-based study.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) guidelines advocate treatment with combinations of long-acting bronchodilators for patients with COPD who have persistent symptoms or continue to have exacerbations while using a single bronchodilator. This study assessed the cost-utility of the fixed dose combination of the bronchodilators tiotropium and olodaterol versus two comparators, tiotropium monotherapy and long-acting ß2 agonist/inhaled corticosteroid (LABA/ICS) combinations, in three European countries: Finland, Sweden and the Netherlands. METHODS: A previously published COPD patient-level discrete event simulation model was updated with most recent evidence to estimate lifetime quality-adjusted life years (QALYs) and costs for COPD patients receiving either tiotropium/olodaterol, tiotropium monotherapy or LABA/ICS. Treatment efficacy covered impact on trough forced expiratory volume in 1 s (FEV1), total and severe exacerbations and pneumonias. The unit costs of medication, maintenance treatment, exacerbations and pneumonias were obtained for each country. The country-specific analyses adhered to the Finnish, Swedish and Dutch pharmacoeconomic guidelines, respectively. RESULTS: Treatment with tiotropium/olodaterol gained QALYs ranging from 0.09 (Finland and Sweden) to 0.11 (the Netherlands) versus tiotropium and 0.23 (Finland and Sweden) to 0.28 (the Netherlands) versus LABA/ICS. The Finnish payer's incremental cost-effectiveness ratio (ICER) of tiotropium/olodaterol was €11 000/QALY versus tiotropium and dominant versus LABA/ICS. The Swedish ICERs were €6200/QALY and dominant, respectively (societal perspective). The Dutch ICERs were €14 400 and €9200, respectively (societal perspective). The probability that tiotropium/olodaterol was cost-effective compared with tiotropium at the country-specific (unofficial) threshold values for the maximum willingness to pay for a QALY was 84% for Finland, 98% for Sweden and 99% for the Netherlands. Compared with LABA/ICS, this probability was 100% for all three countries. CONCLUSIONS: Based on the simulations, tiotropium/olodaterol is a cost-effective treatment option versus tiotropium or LABA/ICS in all three countries. In both Finland and Sweden, tiotropium/olodaterol is more effective and cost saving (ie, dominant) in comparison with LABA/ICS.

Tiotrópio para tratamento da asma moderada e grave em pacientes adultos e crianças (com idade de 6 anos ou mais) / Tiotropium for the treatment of moderate and severe asthma in adult and child patients (aged 6 years or older)

CONTEXTO: A asma é uma doença complexa, de apresentação variável, com uma prevalência elevada. A OMS estima que existam cerca de 235 milhões de pessoas com asma no mundo, sendo que ocorrem em torno de 250 mil mortes por ano no mundo, devido a esta doença. A asma pode ser classificada como intermitente, persistente leve, persistente moderada e persistente grave. A asma grave é aquela que mais frequentemente se associa a óbitos. Estudos indicam que de 5 a 10% dos portadores de asma apresentam a forma grave. O Protocolo Clínico e Diretriz Terapêutica (PCDT) atual de Asma foi aprovado e publicado no ano de 2013. Este recomenda o uso de altas doses de corticosteroide inalatório associado a Beta2 agonistas de longa duração e no caso não haver controle com esses medicamentos, este sugere aumentar a dose destes medicamentos e associar corticoide oral. Do ano da publicação do PCDT de asma até este momento, surgiram opções terapêuticas para os portadores de asma grave, como a utilização de tiotrópio, um anticolinérgico, que atua como antimuscarínico de longa duração. TECNOLOGIA: tiotrópio. EVIDÊNCIAS CIENTÍFICAS: A literatura disponível, dá suporte ao uso do tiotrópio como um complemento ao padrão de tratamento em pessoas com asma moderada e grave, com controle inadequado da doença. Esses tratamentos melhoram o VEF1 e o controle da asma (ACQ). Não houve, no entanto, diferença observada para os desfechos exacerbações (com uso de corticosteroide oral), exacerbação com hospitalização, qualidade de vida e uso de corticosteroide oral. Os efeitos adversos foram semelhantes naqueles que usaram tiotrópio ou que não o utilizaram. A qualidade das evidências foi considerada alta para a maior parte dos desfechos (função pulmonar, qualidade de vida, controle de sintomas e efeitos adversos) na população adulta e baixa a moderada para evidência referente a crianças e adolescentes. AVALIAÇÃO ECONÔMICA: Em avaliação anterior à consulta pública, foi identificada ausência de diferença significativa entre os desfechos de eficácia e segurança com grupos tratados com e sem tiotrópio adição de tiotrópio. Foi então realizada uma análise de custo-minimização, que resultou em custo médio por indivíduo ao ano de R$ 2.566,80. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Em avaliação anterior à consulta pública e considerando o menor valor de compra feito pelo DLOG, o impacto incremental seria de R$ 981.009.093,38 a uma taxa de difusão de 30% a 50% e de R$ 1.715.357.742,83 com difusão de 60% a 80%, em cinco anos (2021-2025). Já considerando o preço proposto pela empresa fabricante do medicamento no relatório nº 585 da Conitec, o impacto incremental poderia variar de cerca de R$ 578,5 milhões a R$ 1 bilhão, em cinco anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Em busca nas bases ClinicalTrials.gov e Cortellis™ foram localizadas duas tecnologias em fase 3 de estudo, ambas sem registro no FDA, EMA e Anvisa. O masatinibe é um inibidor de tirosina quinase em investigação para asma grave não controlada por corticoides orais (>5mg/dia) e alta dose de corticoides inalatórios + LABA, cujos resultados preliminares sugerem superioridade do masatinibe em comparação o placebo para redução do número de exacerbações. Já o tepelizumabe é um anticorpo monoclonal humanizado que se se liga à linfopoietina estromal tímica, citocina possivelmente relacionada à hiperresponsividade das vias aéreas, IgE, eosinofilia e à patofisiologia da asma. Este medicamento está sendo avaliado como terapia adjuvante na asma moderada a grave em pacientes adultos e adolescentes. No que diz respeito ao tiotrópio, foram encontrados dois pedidos de patente, sendo que um deles foi arquivado e o outro, negado. CONSIDERAÇÕES: As evidências existentes na literatura, até o momento, são, em geral, de boa qualidade e sugerem que o tiotrópio é eficaz na melhora da função pulmonar (avaliada através do VEF1 e dos sintomas da asma- alterações estatisticamente significativas entre os grupos com e sem o tiotrópio), porém a magnitude destes 'ganhos' parece ser muito baixa e não ter reflexo clínico. Em consonância com esta possibilidade, o uso deste medicamento, em relação a exacerbações, hospitalizações e qualidade de vida, não apresentou significância estatística. Para o desfecho redução no uso e dose de corticosteroide não foi encontrada literatura específica dentro dos critérios pré-estabelecidos. Por fim, o tiotrópio mostrou-se um medicamento com um bom nível de segurança. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec, em sua 95ª Reunião Ordinária, realizada no dia 04 de março de 2021, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação do tiotrópio para a indicação avaliada. Para tomar a decisão a Conitec considerou que há escassez de evidências que demonstrem a superioridade do tiotrópio frente ao tratamento já disponível no SUS (combinação de LABA + CI ­ formoterol + budesonida) e que a incorporação do tiotrópio resultaria em impacto orçamentário vultoso ao sistema de saúde. CONSULTA PÚBLICA: A consulta pública nº 21 ficou vigente no período entre 22/03/2021 e 12/04/2021. Foram recebidas 1.195 contribuições, sendo 456 pelo formulário para contribuições técnico-científicas e 740 pelo formulário para contribuições sobre experiência ou opinião. Em comum, tanto contribuições técnico-científicas quanto sobre experiência ou opinião foram, na maioria, discordantes da recomendação preliminar da Conitec; e reforçaram a importância de consideração de diretrizes nacionais e internacionais, principalmente, Global Initiative for Asthma (GINA) e da Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). A maioria das contribuições técnico-científicas apresentava desfechos e estudos já contemplados no relatório inicial ou inelegíveis, considerando os critérios de inclusão e exclusão elaborados com especialistas (p.ex. estudos observacionais ou revisões não sistemáticas). Principalmente no tocante à avaliação econômica e análise de impacto orçamentário, a maioria argumentou que tiotrópio é mais econômico que omalizumabe, opção disponível no SUS para pacientes com asma alérgica grave. Omalizumabe não foi definido como comparador na pergunta norteadora deste relatório, pois não havia sido incorporado no SUS na ocasião de elaboração da pergunta, bem como porque sua indicação (asma alérgica grave) abrange um subgrupo dos pacientes com asma moderada e grave. Alguns profissionais de saúde sugeriram ainda que a população elegível da análise de impacto orçamentário estava superdimensionada. Nas contribuições sobre experiência de pacientes, profissionais, familiares ou pessoas interessadas no tema, eles opinam principalmente sobre a melhora da capacidade pulmonar, o aumento da qualidade de vida, diminuição de crises e internações e diminuição de outros medicamentos como corticoides, além de evitar a progressão para uso de imunobiológicos. Sobre os efeitos negativos do tiotrópio, pessoas que tiveram experiência com a tecnologia relataram, principalmente, boca seca e tosse, taquicardia, aumento da pressão intraocular, porém a maioria relata que os efeitos colaterais são muito leves e raros. Após síntese e análise das contribuições e anexos, foi incluído um ensaio clínico randomizado à revisão sistemática com meta-análise deste relatório, que não modificou significativamente as conclusões quanto à evidência científica. Considerando a premissa de diferença entre os tratamentos em termos de efetividade, uma análise de custo-efetividade foi realizada e identificou, para anos de vida ajustados pela qualidade (QALY), que a incorporação do tiotrópio ao tratamento padrão leva a uma RCEI de R$ 2.849,23 por QALY adicional, quando comparado ao TRATAMENTO padrão em crianças, adolescentes e adultos com asma moderada a grave. Quanto à atualização da análise de impacto orçamentário considerando população elegível menor, a adição de tiotrópio resultaria em impacto de R$ 254.361.850 para o período de 5 anos. RECOMENDAÇÃO FINAL DA CONITEC: O Plenário da Conitec, em sua 97ª Reunião Ordinária, realizada no dia 05 de maio de 2021, deliberou por unanimidade recomendar a não incorporação do tiotrópio para o tratamento de crianças, adolescentes e adultos com asma moderada e grave não controlada. Para tomar a decisão, a Conitec considerou que, ao passo que há evidência do benefício do tiotrópio considerando função pulmonar e outros desfechos intermediários, há escassez de evidências que demonstrem a superioridade do tiotrópio frente ao tratamento já disponível no SUS (combinação de LABA + CI ­ formoterol + budesonida), considerando desfechos primordiais, como exacerbações graves, hospitalização ou qualidade de vida. Foi assinado o Registro de Deliberação nº 607/2021. Decisão: não incorporar o tiotrópio para tratamento da asma moderada e grave em pacientes adultos e crianças (com idade de 6 anos ou mais), no âmbito do Sistema Único de Saúde ­ SUS, conforme Portaria nº 19, publicada no Diário Oficial da União nº 103, Seção 1, página 118, em 2 de junho de 2021.

Cost-Effectiveness of Tiotropium in Elderly Patients with Severe Asthma Using Real-World Data.

BACKGROUND: Tiotropium has the potential to alleviate asthmatic symptoms caused by the aging of lungs. However, few studies have focused on specific treatments for elderly patients with asthma. OBJECTIVES: To estimate the cost-effectiveness of adding tiotropium to inhaled corticosteroids and long-acting beta-agonists in elderly patients with severe asthma using real-world data. METHODS: Phase I was a retrospective cohort study using the National Health Insurance claims data to measure clinical and economic outcomes. In phase II, a Markov model was constructed to evaluate cost-effectiveness from Korean health care system perspective, based on phase I, including 2 health states, and an asthma exacerbation event. We estimated cost given in 2018 US dollars, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Subgroup analyses for patients with poorly controlled symptoms (frequent short-acting beta-agonist users; frequent exacerbators) were performed. RESULTS: In elderly patients with severe asthma, the incremental cost and effectiveness in the tiotropium group compared with the inhaled corticosteroid and long-acting beta-agonist group were $2281 and 0.038 QALYs, respectively. The incremental cost-effectiveness ratio was $60,074/QALY, indicating that the addition of tiotropium is not a cost-effective alternative. Meanwhile, 2 subgroups with poorly controlled symptoms showed that adding tiotropium is a cost-effective alternative (frequent short-acting beta-agonist users $4078/QALY; frequent exacerbators $8332/QALY). CONCLUSIONS: Tiotropium shows a higher cost-effectiveness profile when applied to elderly patients with uncontrolled symptoms. These results using real-world evidence provide information beyond the clinical outcomes reported by randomized controlled trials, providing a complementary ground in establishing the reimbursement criteria of tiotropium for elderly patients with severe asthma.

Costs, exacerbations and pneumonia after initiating combination tiotropium olodaterol versus triple therapy for chronic obstructive pulmonary disease.

Aim: To compare health plan-paid costs, exacerbations and pneumonia outcomes for patients with chronic obstructive pulmonary disease (COPD) initiating combination tiotropium olodaterol (TIO + OLO) versus triple therapy (TT: long-acting muscarinic antagonist + long-acting ß2 agonists + inhaled corticosteroid). Patients & methods: COPD patients initiating TIO + OLO or TT between 1 January 2014 and 30 June 2016 were identified from a managed care Medicare database and balanced for baseline characteristics using inverse probability of treatment weighting before assessment of outcomes. Results: Annual COPD-related and all-cause costs were US$4118 (35%) and US$5384 (23%) lower for TIO + OLO versus TT (both p ≤ 0.001). TIO + OLO patients had nearly half the severe exacerbations (8.3 vs 15.5%; p = 0.014) and pneumonia was also less common (18.9 vs 30.9%; p < 0.001). Conclusion: TIO + OLO was associated with improved economic and COPD health outcomes versus TT.

Tiotropium in asthma: From bench to bedside.

OBJECTIVE: Tiotropium is a long-acting muscarinic antagonist approved for maintenance treatment of asthma in children, adolescents, and adults in the United States, and recommended as add-on treatment for uncontrolled asthma despite treatment with inhaled corticosteroids and/or long-acting beta-2 agonists. This review traces the journey of tiotropium from its historical origins through early preclinical testing to human clinical trials and real-life studies. DATA SOURCES: A search was performed in PubMed using search terms 'tiotropium' and 'asthma.' Relevant references cited in those articles were reviewed. STUDY SELECTIONS: English language articles published from December 2008-December 2018 were screened. Articles evaluating the efficacy, cost-effectiveness, real-life evidence, and steroid-sparing effect of tiotropium with inadequately controlled asthma were included. RESULTS: Anticholinergics have a long history of use in the treatment of obstructive airway diseases. Evidence indicates that tiotropium's mechanism of action consists of bronchodilation and diminished mucus secretion, with preclinical evidence suggesting an anti-inflammatory effect as well. Phase 2 and 3 clinical trials have demonstrated that tiotropium is efficacious and safe, resulting in significant improvements in lung function in adults, adolescents, and children across asthma severities. Emerging evidence suggests that add-on tiotropium might potentially enable reductions in inhaled corticosteroid dose in patients with uncontrolled asthma. Further, tiotropium is a cost-effective treatment option that is also effective in the clinical practice setting. CONCLUSIONS: An increasing body of evidence indicates that tiotropium can play a significant role in the treatment of patients with uncontrolled asthma.

Long-term cost-effectiveness of the fixed-dose combination of tiotropium plus olodaterol based on the DYNAGITO trial results.

PURPOSE: Combinations of long-acting bronchodilators are recommended to reduce the rate of COPD exacerbations. Evidence from the DYNAGITO trial showed that the fixed-dose combination of tiotropium + olodaterol reduced the annual rate of total exacerbations (P<0.05) compared with tiotropium monotherapy. This study aimed to estimate the cost-effectiveness of the fixed-dose combination of tiotropium + olodaterol vs tiotropium monotherapy in COPD patients in the French setting. PATIENTS AND METHODS: A recently developed COPD patient-level simulation model was used to simulate the lifetime effects and costs for 15,000 patients receiving either tiotropium + olodaterol or tiotropium monotherapy by applying the reduction in annual exacerbation rate as observed in the DYNAGITO trial. The model was adapted to the French setting by including French unit costs for treatment medication, COPD maintenance treatment, COPD exacerbations (moderate or severe), and pneumonia. The main outcomes were the annual (severe) exacerbation rate, the number of quality-adjusted life-years (QALYs), and total lifetime costs. RESULTS: The number of QALYs for treatment with tiotropium + olodaterol was 0.042 higher compared with tiotropium monotherapy. Using a societal perspective, tiotropium + olodaterol resulted in a cost increase of +€123 and an incremental cost-effectiveness ratio (ICER) of €2,900 per QALY compared with tiotropium monotherapy. From a French National Sickness Fund perspective, total lifetime costs were reduced by €272 with tiotropium + olodaterol, resulting in tiotropium + olodaterol being the dominant treatment option, that is, more effects with less costs. Sensitivity analyses showed that reducing the cost of exacerbations by 34% increased the ICER to €15,400, which could still be considered cost-effective in the French setting. CONCLUSION: Treatment with tiotropium + olodaterol resulted in a gain in QALYs and savings in costs compared with tiotropium monotherapy using a National Sickness Fund perspective in France. From the societal perspective, tiotropium + olodaterol was found to be cost-effective with a low cost per QALY.

Characteristics and health care resource use of subjects with COPD in the year before initiating LAMA monotherapy or LAMA+LABA combination therapy: A U.S. database study.

PURPOSE: To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting ß2-adrenergic agonist (LABA) therapy. DESIGN: This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database. METHODOLOGY: Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment. Data were collected in the year before the index date and included comorbidities, medication use, COPD-related costs, health care resource use, and exacerbations. RESULTS: Of 5,311 eligible subjects, 2,057 initiated LAMA therapy (LAMA cohort) and 191 initiated LAMA+LABA therapy (LAMA+LABA cohort). The Charlson comorbidity index was slightly lower in the LAMA+LABA cohort than the LAMA cohort (mean±SD: 0.63±1.13 vs. 0.66±1.28), but the number of prescriptions was higher (mean±SD: 42.9±23.2 vs. 30.5±27.2). The LAMA+LABA cohort had higher short-acting inhaled ß2 agonist (56.0% vs. 35.7%), oral corticosteroid (37.7% vs. 32.6%), and home oxygen therapy use (14.1% vs. 3.2%) than the LAMA cohort. Total medical costs were greater in the LAMA+LABA cohort than the LAMA cohort (mean±SD: $3,320.40±4085.9 vs. $1,226.20±3602.9), although emergency department ($11.00±66.8 vs. $30.70±259.2) and outpatient visit ($39.60±163.1 vs. $41.70±424.3) costs were lower. Resource use and exacerbation incidence were similar between cohorts. CONCLUSION: In this first look, subjects with COPD initiating LAMA or LAMA+LABA therapy exhibited different clinical and resource use characteristics in the year before treatment. Subjects receiving LAMA+LABA were older, with higher COPD co-medication use, more prescriptions, and associated higher pharmacy costs compared with subjects initiating LAMA. These differences may reflect a higher severity of COPD in those starting LABA+LAMA treatment.

Clinical and economic outcomes associated with the use of fluticasone propionate 250 mcg and salmeterol 50 mcg combination versus tiotropium bromide 18 mcg as initial maintenance treatment for chronic obstructive pulmonary disease in managed care.

AIMS: To examine the clinical and economic outcomes associated with the use of long-acting bronchodilators for initial maintenance treatment of chronic obstructive pulmonary disease (COPD) by analyzing health insurance claims data in the US. METHODS: A retrospective, observational, matched cohort study used health insurance claims data (January 2008 to June 2013) to assess COPD-related outcomes for subjects aged ≥40 years. Subjects were assigned to a study cohort according to the first observed prescription fill for a long-acting bronchodilator (fluticasone propionate 250 mcg/salmeterol 50 mcg [FSC] or tiotropium bromide 18 mcg [TIO]). The analysis period for each subject comprised a 1-year pre-index date and 1-year post-index date. Primary outcome measure was total COPD-related costs per-patient per-year (PPPY) during the follow-up period. Secondary outcome measures included COPD-related exacerbations and the components of COPD-related costs. RESULTS: Overall, 24,040 subjects were identified; the analysis sample consisted of 19,090 subjects (9,545 per cohort) with no significant differences between cohorts. Mean COPD-related total costs PPPY were numerically lower among the FSC cohort; however, the difference was not statistically significant ($2,224 [±4,108] vs $2,352 [±3,721], p = .057). There was no difference between cohorts for COPD-related medical costs (p = .894). COPD-related pharmacy costs were significantly, yet modestly, lower in the FSC cohort compared with the TIO cohort ($1,160 [±1,106] vs 1,275 [±1,110], p < .001). There were no statistically significant differences in the rate or number of exacerbations between the matched cohorts. LIMITATIONS: While propensity scoring achieved balance in baseline characteristics, some residual confounding unobserved in the database may be present. CONCLUSIONS: Few clinical and economic differences between subjects initiating maintenance therapy with FSC or TIO were observed.

Eficacia y seguridad del uso de bromuro de tiotropio como monoterapia en el tratamiento de pacientes con epoc de los grupos C y D / Efficacy and safety of the use of tiotropium bromide as monotherapy in the treatment of patients with C and D epoc groups

INTRODUCCIÓN: El presente dictamen presenta la evaluación de tecnología de la eficacia y seguridad de bromuro de tiotropio en el tratamiento de enfermedad pulmonar obstructiva crónica de los grupos C y D. La enfermedad pulmonar obstructiva crónica (EPOC) es una obstrucción de las vías aéreas con síntomas respiratorios persistentes que puede llevar a discapacidad y a una disminución de la calidad de vida. Los síntomas más comunes incluyen disnea, tos y/o producción de esputo. En la actualidad, el EPOC es una de las principales causas de morbimortalidad en el mundo, siendo la cuarta causa de muerte más frecuente, y por lo tanto un problema de salud pública de alta relevancia. Actualmente, EsSalud cuenta con corticosteroides inhalados (ICS), broncodilatadores agonistas de receptores ß de acción corta (SABA) y de acción larga (LABA), y con agentes antagonistas de receptores muscarínicos de acción corta (SAMA). Sin embargo, existe una fracción de pacientes en quienes las exacerbaciones y síntomas persisten a pesar del tratamiento con dichos agentes, y en quienes se requiere la evaluación de otros esquemas terapéuticos. TECNOLOGÍA SANITARIA DE INTERÉS: Los aspectos generales del bromuro de tiotropio se encuentran descritas al detalle en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N. ° 033-SDEPFYOTS-DETS-IETSI-2017. Brevemente, la acción del bromuro de tiotropio también llamado únicamente tiotropio, se da a nivel de vías áreas, donde inhibe los receptores muscarínicos de músculo liso (M 1 a M 5 ), lo cual tiene como resultado la broncodilatación. A los medicamentos de su clase se les conoce como antagonistas muscarínicos de acción prolongada (LAMA, por sus siglas en inglés). METODOLOGÍA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de bromuro de tiotropio en el tratamiento de EPOC en las bases de datos de PubMed, TRIPDATABASE, The Cochrane Library y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como Organización mundial de la Salud (OMS), National Institute for Health and Care Excellence (NICE), Scottish Medicines Consortium (SMC), Canadian Agency for Drugs and Technologies in Health (CADTH), Instituto de efectividad clínica y sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); y especializados en neumología como American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Asociación Latinoamericana de Tórax (ALAT), National Heart, Lung and Blood Institute (NHLBI), British Thoracic Society (BTS). RESULTADOS: Las GPC emiten recomendaciones en relación al uso de LAMA en general, solo una menciona tiotropio en específico. Así, ambas recomiendan el uso de LAMA en el manejo de EPOC estable, pero dentro de un esquema con LABA/ICS o LABA, mas no contempla la alternativa de su uso como monoterapia en la población de interés (i.e. grupos C y D). Adicionalmente, las recomendaciones en ambos casos se basan en evidencia indirecta y opinión de expertos, es decir, evidencia de bajo nivel. CONCLUSIONES: Las GPC emiten recomendaciones en relación al uso de LAMA en general, solo una menciona tiotropio en específico. Así, ambas recomiendan el uso de LAMA en el manejo de EPOC estable, pero dentro de un esquema con LABA/ICS o LABA, mas no como monoterapia en la población de interés (i.e. grupos C y D). Adicionalmente, las recomendaciones en ambos casos se basan en evidencia indirecta y opinión de expertos, es decir, evidencia de bajo nivel. En cuanto a la RS con MA, ésta muestra resultados inconsistentes entre las herramientas que evaluaron calidad de vida (i.e. SGRQ, EQ-5D y CRQ), donde para SGRQ el beneficio es estadísticamente significativo, aunque modesto, mientras que para EQ-5D y CRQ las diferencias no son estadísticamente significativas. Por otra parte, muestra que el uso de tiotropio disminuye el riesgo de exacerbaciones en solo 22 % y que existe heterogeneidad moderada entre los estudios (>50 %); y no se observaron diferencias en las hospitalizaciones ni en la mortalidad entre tiotropio y placebo. Si bien los resultados mencionados muestran cierto beneficio modesto del uso de tiotropio, estos dan cuenta de los efectos sobre la población general con EPOC, es decir, que incluye todos los grados de severidad, es posible que para los casos más graves como son los incluidos en la pregunta PICO (grupos C y D), estos resultados sobreestimen el ya modesto e inconsistente efecto de tiotropio en comparación con placebo en dichos grupos específicos. Esto está en línea con las recomendaciones de las GPC, las cuales no contemplan el uso de tiotropio como monoterapia para dichos grupos. En relación a los eventos adversos, no se observaron diferencias frente a placebo. El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de bromuro de tiotropio como monoterapia en pacientes con EPOC de los grupos C y D.

External Validation of Health Economic Decision Models for Chronic Obstructive Pulmonary Disease (COPD): Report of the Third COPD Modeling Meeting.

OBJECTIVES: To validate outcomes of presently available chronic obstructive pulmonary disease (COPD) cost-effectiveness models against results of two large COPD trials-the 3-year TOwards a Revolution in COPD Health (TORCH) trial and the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial. METHODS: Participating COPD modeling groups simulated the outcomes for the placebo-treated groups of the TORCH and UPLIFT trials using baseline characteristics of the trial populations as input. Groups then simulated treatment effectiveness by using relative reductions in annual decline in lung function and exacerbation frequency observed in the most intensively treated group compared with placebo as input for the models. Main outcomes were (change in) total/severe exacerbations and mortality. Furthermore, the absolute differences in total exacerbations and quality-adjusted life-years (QALYs) were used to approximate the cost per exacerbation avoided and the cost per QALY gained. RESULT: Of the six participating models, three models reported higher total exacerbation rates than observed in the TORCH trial (1.13/patient-year) (models: 1.22-1.48). Four models reported higher rates than observed in the UPLIFT trial (0.85/patient-year) (models: 1.13-1.52). Two models reported higher mortality rates than in the TORCH trial (15.2%) (models: 20.0% and 30.6%) and the UPLIFT trial (16.3%) (models: 24.8% and 36.0%), whereas one model reported lower rates (9.8% and 12.1%, respectively). Simulation of treatment effectiveness showed that the absolute reduction in total exacerbations, the gain in QALYs, and the cost-effectiveness ratios did not differ from the trials, except for one model. CONCLUSIONS: Although most of the participating COPD cost-effectiveness models reported higher total exacerbation rates than observed in the trials, estimates of the absolute treatment effect and cost-effectiveness ratios do not seem different from the trials in most models.

Evaluation of COPD Treatments: A Multicriteria Decision Analysis of Aclidinium and Tiotropium in the United States.

BACKGROUND: Comparisons of the use of aclidinium bromide and tiotropium bromide for the treatment of chronic obstructive pulmonary disease often concentrate on key end points (exacerbations) at the expense of other benefits and risks. Multicriteria decision analysis (MCDA) can help overcome this by using stakeholder preferences to combine multiple end points into an overall value estimate. OBJECTIVES: To evaluate the use of aclidinium bromide twice daily via Pressair™ (AstraZeneca Pharmaceuticals LP, Wilmington, DE) and of tiotropium once daily via HandiHaler® (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) from the perspective of patients using MCDA. METHODS: Literature reviews and clinician engagement were used to identify value criteria. Performance of criteria was estimated from a clinical trial and clinician opinion. Scores and swing weights came from six clinicians who, during a 2-day workshop, reflected their patients' preferences. Scenario and sensitivity analyses were used to explore uncertainty in model designs and inputs. RESULTS: Fourteen criteria, covering clinical effectiveness, safety, and convenience of the treatments of chronic obstructive pulmonary disease, were identified. Exacerbations and device preloading were identified as the most important to patients; the least important was rescue medication use. Tiotropium's higher overall clinical effectiveness score was offset by aclidinium's better performance on safety and convenience outcomes. The MCDA generated a -42 (worst performance) to 100 (best performance) scale. The net impact of benefits over risks of aclidinium (38.5) exceeded that of tiotropium (13.2), and patients preferred aclidinium 79.7% of the time. CONCLUSIONS: When considering clinical benefits and risks, aclidinium and tiotropium generate similar value to patients, but when convenience criteria are considered, aclidinium may be preferred. Further work is required to replicate these results, including eliciting preferences directly from patients.

Eficacia y seguridad del uso de bromuro de tiotropio en el tratamiento de pacientes con asma severa no controlada con ics/laba y ltra, y no tributarios a teofilina / Efficacy and safety of the use of tiotropium bromide in the treatment of patients with severe asthma not controlled with ics / laba and ltra, and not tributaries to theophylline

INTRODUCCIÓN: El presente dictamen presenta la evaluación de tecnología de la eficacia y seguridad de bromuro de tiotropio en el tratamiento de dolor neuropático. El asma es una enfermedad respiratoria crónica que se manifiesta de manera heterogénea entre los que la padecen, usualmente caracterizada por inflamación crónica de las vías aéreas. El asma puede ser clasificado como leve, moderada o severa. La severidad del asma se evalúa de manera retrospectiva y está en función del tratamiento requerido para controlar los síntomas y exacerbaciones. La prevalencia global de asma se ha estimado entre 1% y 16% en la población entre 13 y 14 años de edad, aunque varían entre países por la ausencia de una definición de asma universal. En cuanto a la población adulta general, en Estados Unidos, la prevalencia de asma se estima cerca al 8%, mientras que la prevalencia de asma en adultos mayores de 65 años se encuentra entre 4% y 8%. El asma severa se da en 5-10% del total de casos de asma. TECNOLOGIA SANITARIA DE INTERÉS: El bromuro de tiotropio, también llamado únicamente tiotropio, es un agente anticolinérgico de acción prolongada que presenta afinidad especifica por los receptores muscarínicos (M 1 a M 5 ), particularmente por los subtipos M 1 y M 3 . La acción del bromuro de tiotropio se da a nivel de vías áreas, donde inhibe los receptores muscarínicos de músculo liso, lo cual tiene como resultado la broncodilatación. A los medicamentos de su clase se les conoce como antagonistas muscarínicos de acción prolongada (LAMA, por sus siglas en inglés). METODOLOGIA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de de bromuro de tiotropio en el tratamiento de asma severa en las bases de datos de PubMed, TRIPDATABASE, The Cohrane Library y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como Organización mundial de la Salud (OMS), National Institute for Health and Care Excellence (NICE), Scottish Medicines Consortium (SMC), Canadian Agency for Drugs and Technologies in Health (CADTH), Instituto de efectividad clínica y sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); y especializados en neumología como American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Asociación Latinoamericana de Tórax (ALAT), National Heart, Lung and Blood Institute (NHLBI), British Thoracic Society (BTS). RESULTADOS: En la actualidad el Petitorio Farmacológico de EsSalud cuenta con ICS, LABA, LTRA y teofilina para el tratamiento de pacientes con asma severa. Sin embargo, existe un grupo de pacientes en quienes el tratamiento con dosis máximas de ICS más LABA y terapia complementaria con LTRA o teofilina no ha logrado controlar la enfermedad, en ellos se requiere contar con otras alternativas de tratamiento. Adicional a ello, existen pacientes para quienes alguna de las terapias complementarias está contraindicada, dejando de ser una opción adicional de tratamiento. En este contexto, se ha solicitado al IETSI la evaluación del uso fuera del petitorio de bromuro de tiotropio. El bromuro de tiotropio, también llamado únicamente tiotropio, es un agente anticolinérgico de acción prolongada que presenta afinidad especifica por los receptores muscarínicos (M 1 a M 5 ). La acción del fármaco se da a nivel de vías áreas, donde inhibe los receptores muscarínicos del músculo liso, generando broncodilatación. A los medicamentos de su clase se les conoce como antagonistas muscarínicos de acción prolongada (LAMA, por sus siglas en inglés). A la fecha (Julio 2017) la evidencia identificada en relación al uso de bromuro de tiotropio en el tratamiento de asma severa corresponde a dos GPC (GINA 2017 y BTS/SIGN 2016), una ETS (SMC), un documento de consejo (NICE), un metanálisis (MA), y dos ECAs gemelos (PrimoTinA I y II). Las GPC de GINA y BTS/SIGN son homogéneas en sus recomendaciones. Así, ambas GPC mencionan el uso de tiotropio como una alternativa de tratamiento complementario en pacientes con asma pobremente controlada a pesar del uso de dosis máximas de ICS más LABA, al mismo nivel que el uso de LTRAs o teofilina. Dichas recomendaciones responden indirectamente a la pregunta PICO de interés del dictamen en la medida en que no especifican el uso consecutivo de las alternativas mencionadas frente a ausencia de mejoría de los síntomas, por lo que no hacen referencia específicamente a la población de interés del dictamen. Tanto el MA como los ensayos gemelos PrimoTinA I y II evidencian que el uso de tiotropio como terapia complementaria no ofrece ningún beneficio sobre el uso de ICS/LABA en cuanto a las variables de relevancia clínica como la ocurrencia de exacerbaciones, la calidad de vida y el control de la enfermedad, en pacientes con asma severa. Ambos estudios (el MA y los ensayos) constituyen evidencia indirecta para responder a la pegunta PICO ya que incluyen únicamente a la población de asmáticos que ha recibido ICS/LABA o solo ICS, mientras que la población de la pregunta PICO incluye también a aquellos que han recibido además LTRAs y no son tributarios a teofilina. A pesar de ser evidencia indirecta, es posible aplicar dichos resultados a la población de interés del dictamen ya que se observan resultados no favorables en una población que ha recibido menos líneas de tratamiento, por lo que se esperaría que en una población que ha pasado por más tratamientos este resultado negativo se mantenga. A manera de información adicional de relevancia, los elaboradores de las guías resaltan que para pasar a una siguiente alternativa de tratamiento es necesario corroborar la adherencia a los tratamientos empleados previamente, así como la ausencia de factores externos irritantes que puedan provocar exacerbaciones y la presencia de comorbilidades no controladas apropiadamente. Asimismo, hacen hincapié en que se debe evaluar la técnica empleada por los pacientes al usar el inhalador, ya que ello influye grandemente en la eficacia del fármaco. CONCLUSIÓN: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de bromuro de tiotropio en pacientes con asma severa no controlada con ICS/LABA y LTRAs y no tributarios a teofilina.

Apreciación crítica del estudio "Cost-effectiveness analysis of glycopyrronium versus tiotropium and fixed-dose combinations (formoterol/budesonide and salmeterol/fluticasone) for copd in the colombian health care system" / Critical appraisal of the study "Cost-effectiveness analysis of glycopyrronium versus tiotropium and fixed-dose combinations (formoterol/budesonide and salmeterol/fluticasone) for COPD in the Colombian health care system"

INTRODUCCIÓN: El Instituto de Evaluación Tecnológica en Salud ­ IETS mediante el contrato interadministrativo No. 243 de 2016 suscrito con el Ministerio de Salud y Protección Social (MinSalud) acordó realizar una apreciación crítica de las evaluaciones de tecnologías enviadas por terceros y que fueran priorizadas por dicho Ministerio. Entre las tecnologías priorizadas se encuentra el glicopirronio (Seebri®) para pacientes con Enfermedad Pulmonar Obstructiva Crónica (EPOC), medicamento nominado por Novartis de Colombia S.A. En este documento se presenta los resultados de la apreciación crítica de la evaluación económica "Cost-effectiveness analysis of glycopyrronium versus tiotropium and fixed-dose combinations (formoterol/budesonide and salmeterol/fluticasone) for COPD in the Colombian health care system" y los resultados de los nuevos análisis realizados por el IETS. Para adelantar esta apreciación crítica, se contrastó la metodología propuesta en el estudio nominado por la industria con las recomendaciones del manual metodológico para la elaboración de evaluaciones económicas del IETS. En los casos en los cuales se identificaran diferencias, el IETS realizó el respectivo ajuste y calculó nuevamente la efectividad y costos de las tecnologías incluidas en la evaluación, empleando la plantilla de Excel con el modelo remitido por Novartis de Colombia S.A. como base para realizar los cálculos. HORIZONTE TEMPORAL: Aunque el horizonte temporal de 5 años con ciclos trimestrales parece adecuado, se deben mencionar algunos detalles. En primer lugar, en varios apartes de los informes se menciona que la medición de las exacerbaciones del EPOC se debe realizar a las 52 semanas de iniciado el tratamiento según expertos clínicos y la práctica clínica del American Thoracic Society. Esto genera un conflicto con los ciclos de 3 meses, ya que parecerían muy cortos para tener en cuenta la temporalidad de este desenlace. Adicionalmente, en el modelo de Excel se puede apreciar que los resultados presentados en el informe, corresponden a un horizonte temporal de 10 años y no de 5, lo que genera una incongruencia entre lo mencionado en el informe y lo plasmado en el modelo. PERSPECTIVA: A pesar de que en el informe se menciona la perspectiva del sistema de salud colombiano, en el archivo de Excel se indica una perspectiva social de Suecia. Aunque es posible que esto no afecte los resultados y que sea una cuestión de etiquetas del archivo de Excel, es recomendable modificarlo para tener mayor consistencia entre los documentos enviados. CÁLCULO E INTERPRETACIÓN DE RESULTADOS: Respecto a los resultados el informe indica que para la comparación entre glicopirronio y salmeterol/fluticasona no se puede extraer una conclusión sobre su costo-efectividad debido a que tienen una efectividad y costos muy similares, sin adicionar ninguna explicación adicional. Aunque no poder concluir sobre la costo-efectividad de una alternativa puede ser factible metodológicamente, es necesario realizar una justificación exhaustiva al respecto, especialmente sobre las limitaciones de información. Por otro lado, en la situación presentada, también puede ser factible calcular la RICE, a pesar de que las alternativas tengan similares costos y AVAC. Esto puede justificarse con el argumento de que se debe verificar si ese pequeño aumento en los costos justifica el pequeño aumento en la efectividad. Si se decantara por esta opción, se deberían ordenar las alternativas no dominadas (en este caso glicopirronio y salmeterol/fluticasona) de menor a mayor costo y calcular la RICE para la alternativa más costosa. En la tabla 6 se presentan estos cálculos, en donde se puede observar una RICE de $9.157.617 a favor de salmeterol/fluticasona. Asumiendo un umbral entre 1 y 3 veces el PIB per cápita del país, esto implicaría que la tecnología costo-efectiva sería salmeterol/fluticasona. CONCLUSIONES: Los resultados de esta apreciación crítica permiten concluir que existen limitaciones importantes en el desarrollo metodológico de esta evaluación económica y la confianza en sus conclusiones. Se resalta la falta de inclusión de alternativas potencialmente relevantes (sin justificar su exclusión), la falta de claridad sobre las fuentes y método de cálculo de las ponderaciones de utilidad, probabilidades de transición y costos, la falta de congruencia de la evaluación económica con los resultados del reporte de efectividad y seguridad y la decisión de no concluir sobre la comparación entre glicopirronio y salmeterol/fluticasona. En varios de los análisis realizados en esta apreciación crítica y en la actualización de precios de las alternativas se encuentra que glicopirronio no es una alternativa costoefectiva comparada con salmeterol/fluticasona y formoterol/budesonida. Por esto, no se recomienda que las conclusiones de este estudio sean utilizadas para la toma de decisiones de MinSalud. En su lugar, se recomienda realizar una evaluación económica de novo en donde se incluyan todos los comparadores relevantes y se superen las limitaciones encontradas en este reporte, para poder determinar si glicopirronio es una alternativa costo-efectiva para el país.