Real-World Adherence to and Persistence with Vibegron in Patients with Overactive Bladder: A Retrospective Claims Analysis.

INTRODUCTION: Vibegron is a ß3-adrenergic receptor agonist approved for overactive bladder (OAB). This analysis assessed real-world adherence and persistence with vibegron in patients with OAB, along with demographics and clinical characteristics associated with adherence and persistence. METHODS: This retrospective study used the Optum Research Database to identify patients treated with vibegron from April 2021 to August 2022 (identification period). Patients had ≥ 60 days of continuous pharmacy coverage in a commercial or Medicare Advantage plan following the index fill (follow-up). Adherence was assessed as proportion of days covered (PDC) from index to end of follow-up and was defined as PDC ≥ 80%. Persistence was measured as days to discontinuation of therapy (30-day gap) or end of follow-up. Data for adherence and persistence are presented descriptively. Characteristics associated with adherence and persistence were analyzed using multivariable models among patients with medical and pharmacy benefits during the 90 days before index (baseline). RESULTS: Overall, 9992 patients had a vibegron claim during the identification period; 9712 had ≥ 2 months of follow-up. Mean (SD) age was 74.2 (10.7) years; 68.2% were female. Mean (SD) PDC was 0.64 (0.34). Median (95% confidence interval) persistence was 142 (132-153) days. Of the 5073 patients who were ≥ 18 years old with continuous baseline pharmacy and medical benefits ≥ 90 days before index, 2497 (49.2%) were adherent. Patients were more likely to be adherent and persistent if they received a greater days' supply for the index fill and had baseline medication count ≥ 6. Patients were more likely to discontinue if their index copay was > $45. CONCLUSION: Nearly half of the patients initiating vibegron were adherent. Factors associated with adherence and persistence were more likely to be related to prescribing practices than patient characteristics. These results suggest it may be best to follow up with patients approximately 4 to 5 months after initiating treatment with vibegron.

Vibegron is a newer drug for treating overactive bladder. Vibegron was safe and worked well in clinical trials. However, there is no information on use of vibegron in a real-world population that is not a clinical trial. This study looked at how consistently and how long patients took vibegron after starting it. It also looked at what was common in patients who took vibegron consistently. To do this, the study used pharmacy prescription data from April 2021 to August 2022. It examined adherence to the study medication for each patient. Adherence is how many days patients had medication on hand compared to how long they were followed. The study also looked at persistence to the study medication. Persistence is how long a patient takes a medication before they stop taking it. Researchers then examined if there were reasons a patient may or may not take vibegron as prescribed. The study included prescription data for 9712 patients. The average age was 74 years and 68% of patients were female. Patients had their medication 64% of the time (adherence). On average, patients took their medication for 142 days before stopping (persistence). Patients had better adherence and persistence if they received a larger supply of medication at the pharmacy when first prescribed the medication and if they had more medications overall. Patients' age and gender did not affect adherence and persistence. Vibegron may be a good option for patients with overactive bladder. Follow-up with a provider may be considered 4 to 5 months after starting vibegron.

Factors Influencing Medication Selection for Management of Overactive Bladder: Trends and Insights From AUA Quality Registry.

OBJECTIVE: To determine how a patient's demographics, including insurance type, race/ethnicity, gender, and age, may impact the choice of medication prescribed for overactive bladder (OAB). METHODS: We queried the AUA Quality Registry for adults between 2014 and 2020 with a diagnosis of OAB for >1year, excluding neurogenic causes. Variables included age, race/ethnicity, gender, insurance type, medication first prescribed, year of prescription, provider metropolitan status, and provider practice type. Primary outcome was which factors were associated with increased odds of beta-3 prescription as first medication choice. RESULTS: We found 1,453,566 patients with OAB, 641,122 (44.1%) with complete data. Of these, 112,021 (17.5%) were prescribed medication. On multivariate analysis, patients with Medicaid, Medicare, and other/self-pay insurance were less likely to receive a beta-3 vs an anticholinergic compared to private or military insurance. Compared to white patients, Asian, Black, and other races were less likely to receive a beta-3, as were patients outside of metropolitan areas. Age >50, prescriptions after 2014, and nonacademic settings were associated with increased odds of beta-3 prescription. There was no difference between genders. CONCLUSION: Many nonclinical factors, including insurance type and race, may affect which medication is first prescribed for OAB. This is useful for practicing urologists and may help lower barriers to beta-3 prescription through policy change and advocacy.

Rethinking Second-Line Therapy for Overactive Bladder to Improve Patient Access to Treatment Options.

Idiopathic overactive bladder (OAB) is a chronic condition that negatively affects quality of life, and oral medications are an important component of the OAB treatment algorithm. Recent literature has shown that anticholinergics, the most commonly prescribed oral medication for the treatment of OAB, are associated with cognitive side effects including dementia. ß3-adrenoceptor agonists, the only alternative oral treatment for OAB, are similar in efficacy to anticholinergics with a more favorable side effect profile without the same cognitive effects. However, there are marked cost variations and barriers to access for OAB medications, resulting in expensive copays and medication trial requirements that ultimately limit access to ß3-adrenoceptor agonists and more advanced procedural therapies. This contributes to and perpetuates health care inequality by burdening the patients with the least resources with a greater risk of dementia. When prescribing these medications, health care professionals are caught in a delicate balancing act between cost and patient safety. Through multilevel collaboration, we can help disrupt health care inequalities and provide better care for patients with OAB.

Are Beta 3 Adrenergic Agonists Now the Preferred Pharmacologic Management of Overactive Bladder?

PURPOSE OF THE REVIEW: This paper discusses the recent evidence supporting beta 3 adrenergic agonists as the preferred pharmacological management of overactive bladder syndrome. RECENT FINDINGS: Mirabegron has a similar efficacy profile to first-line antimuscarinics with favorable adverse effects profile. Treatment of OAB with beta-3 adrenergic agonist should be favored in patients at higher risk of anticholinergic adverse events. The efficacy and tolerability of beta-3 adrenergic agonists are consistently reported in older OAB patients, whether used alone or with other antimuscarinics. Mirabegron is cost-effective in treating OAB unless the symptoms were severe or refractory. Combination therapy of mirabegron and other pharmacotherapy has proven to be efficient in controlling OAB symptoms without inducing serious add-on adverse effects. While beta-3 adrenergic agonists bear favorable advantages in OAB treatment, physicians should perform a thorough and careful pre-treatment planning to optimize treatment benefits and adherence.

Mirabegrona para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica / Mirabegrone for the treatment of storage dysfunction in patients with neurogenic bladder

INTRODUÇÃO: A bexiga neurogênica é um termo aplicado ao mau funcionamento da bexiga urinária e do esfíncter urinário, devido à disfunção neurológica que resulta de trauma, doença ou lesão interna ou externa. Alguns pacientes com disfunção neurogênica do trato urinário inferior apresentam sintomas que se relacionam com o armazenamento prejudicado de urina, como o aumento da frequência de micção, urgência urinária e incontinência urinária. PERGUNTA: Qual a eficácia e a segurança da mirabegrona para disfunção de armazenamento em pacientes adultos com bexiga neurogênica? TECNOLOGIA: Mirabegrona. EVIDÊNCIAS CIENTÍFICAS: Na busca de evidências foram recuperadas 121 referências, das quais três estudos foram incluídos, sendo um ECR e duas séries de casos. Quanto à qualidade metodológica, as séries de casos apresentaram alto risco de viés, enquanto o ECR apresentou risco de viés incerto, uma vez que o artigo não descreve como foi realizada a alocação e cegamento dos participantes e avaliadores. Os principais desfechos de eficácia foram volume cistométrico, volume residual, episódios de urgência, episódios de incontinência, número de absorventes, I-QoL e escore. Além destes, os estudos relataram também eventos adversos. Com relação ao volume cistométrico, mirabegrona 50 mg/dia apresentou aumento de 183,50 (DP=121,60) ml na linha de base para 238,81 (DP=150,56) ml após quatro semanas de tratamento. No grupo de pacientes que recebeu placebo houve redução de 210,44 (DP=135,34) ml na linha de base para 167,56 (DP=102,96) ml após 4 semanas de tratamento (p=0,016). Outros dois estudos relataram o desfecho, porém sem grupo comparador (séries de casos); nesses, a comparação do desfecho pós intervenção versus antes da intervenção não apresentou resultados significativos. Uma única série de caso avaliou o desfecho volume residual. De acordo com esse estudo, o volume residual foi 83,4 (92,2) mL na linha de base; de 56,8 (61,4) mL em quatro semanas; e de 78,8 (113,3) mL em 12 semanas. Não houve diferença dos valores de seguimento em relação à linha de base. Em comparação com placebo, a mirabegrona promoveu melhorar significativas em qualidade de vida e funcionalidade, após quatro semanas de estudo (p = 0,0013 e p=0,0001, respectivamente para os escores I-QoL e PPBC). Eventos adversos foram mais frequentes no grupo que recebeu mirabegrona. No entanto, os estudos não fornecem maiores detalhes quanto à diferença entre grupos. AVALIAÇÃO ECONÔMICA: Considerando-se os custos da mirabegrona e o resultado de qualidade de vida fornecido por um dos estudos incluídos e dados de expectativa de vida global de pacientes com trauma de coluna, obteve-se a estimativa de anos de vida ajustados por qualidade (do inglês, Quality Adjusted Life Years ­ QALY) para esta população. Construiu-se um modelo determinístico comparando a mirabegrona e o placebo. Observou-se que mirabegrona, em dose de 50 mg, foi a estratégia dominada, com razão de custo-efetividade incremental de R$ 471,89/QALY/mês. Na análise de sensibilidade observou-se que, independentemente do ganho de utilidade promovido pela mirabegrona, esta sempre foi a estratégia dominada. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário adotou a perspectiva do SUS e um horizonte temporal de cinco anos (2020-2024). O custo do tratamento limitou-se ao valor de aquisição dos medicamentos obtidos do Banco de Preços em Saúde. Dada a ausência de dados específicos para indivíduos com bexiga neurogênica, foram consideradas as quatro principais causas de bexiga neurogênica: doença de Parkinson, esclerose múltipla, acidente vascular cerebral e danos na coluna vertebral. No cenário base, considerou-se a incorporação apenas da mirabegrona. Deste modo, a estimativa de impacto orçamentário, decorrente da incorporação da mirabegrona, após cinco anos, foi de R$ 11.273.255.511,53. Cenário alternativo foi elaborado considerando as porcentagens de uso dos agentes antimuscarínicos obtidas de uma publicação do Sistema de Saúde Inglês (NHS). Com isso, a estimativa de impacto orçamentário neste cenário decorrente da incorporação dos antimuscarínicos e mirabegrona seria de R$ 2.095.249.966,02 no primeiro ano de incorporação. Após cinco anos de incorporação esse valor seria de R$ 10.679.375.762,42 de reais. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: foram realizadas buscas no ClinicalTrials.gov e Cortellis™, a fim de localizar potenciais medicamentos para o tratamento de pacientes adultos com bexiga neurogênica. Não foram encontrados medicamentos nas fases de desenvolvimento clínico, contudo foi detectado a fesoterodina em estudo para pacientes pediátricos com incontinência urinária de causa neurológica. CONSIDERAÇÕES GERAIS: Os estudos mostraram eficácia da mirabegrona no controle dos sintomas de incontinência, principalmente aumento do volume cistométrico, qualidade de vida (IQoL) e funcionalidade (PPBC) em pacientes com dano permanente de coluna vertebral e esclerose múltipla. Porém, cabe salientar que dois desses estudos eram séries de casos sem grupo comparador e um ECR com amostra pequena e com risco de viés incerto. Ademais o impacto orçamentário calculado foi superior a dez bilhões de reais após cinco anos da incorporação. Dessa forma, ainda não existe evidência suficiente que permita a recomendação da mirabegrona para pacientes com bexiga neurogênica. RECOMENDAÇÃO PRELIMINAR: A Conitec, em sua 82ª reunião ordinária, no dia 09 de outubro de 2019, recomendou a não incorporação no SUS da mirabegrona para o tratamento da bexiga neurogênica. Além do aspecto financeiro, considerou-se, primordialmente, a ausência de benefício clínico significante e baixa qualidade metodológica dos estudos avaliados. CONSULTA PÚBLICA: Foram recebidas cinco contribuições, sendo três advindas do formulário de experiência e opinião e as outras duas, via formulário técnico-científico. Dentre as contribuições por experiência e opinião, duas discordaram da recomendação preliminar e uma não concordou nem discordou. Em relação as contribuições técnico-científicas, as duas discordaram sobre a recomendação preliminar. A Conitec entendeu que não houve argumentação suficiente para alterar a sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 85º reunião ordinária, no dia 04 de fevereiro de 2020, deliberaram, por unanimidade, por recomendar a não incorporação no SUS da mirabegrona para o tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica. DECISÃO: Não incorporar a mirabegrona para tratamento da disfunção de armazenamento em pacientes com bexiga neurogênica, no âmbito do Sistema Único de Saúde - SUS, conforme a Portaria nº 9, publicada no Diário Oficial da União nº 49, seção 1, páginas 187 e 188, em 12 de março de 2020.

Multicriteria Decision Analysis Applied to the Clinical Use of Pharmacotherapy for Overactive Bladder Symptom Complex.

CONTEXT: The nonspecific storage symptom complex overactive bladder (OAB) is an important clinical condition in functional urology. Until recently, pharmacological therapy comprised antimuscarinic drugs, but more recently beta 3 agonists have added to the available agents. Traditional reporting of efficacy and safety of these agents relies upon regulatory placebo-controlled studies. There remains no head-to-head comparison of existing agents in the contemporary literature. Contemporary conclusions on comparative efficacy and safety drawn from the use of these agents are based on systematic reviews of the literature and associated meta-analyses. OBJECTIVE: In this study, we used the analytical model of multicriteria decision analysis (MCDA) to compare contemporary pharmacotherapy for OAB. EVIDENCE ACQUISITION: Efficacy and safety data from published, randomised, placebo-controlled trials of antimuscarinic antagonists, the beta 3 agonist, and the combination of an antimuscarinic and beta 3 agonist were used to populate the MCDA model. EVIDENCE SYNTHESIS: Experts assessed weights of the relative importance of favourable and unfavourable effects, which provided a common measure of benefits and safety that were combined in the MCDA model to give an overall ranking of the OAB drugs. RESULTS: When benefits are judged as more important than safety, fesoterodine 4 or 8mg used in a flexible dosing pattern provides the most favourable therapeutic option, over a wide sensitivity analysis relating to benefits and harms. CONCLUSIONS: In our analysis using an MCDA model, in both the flexible dosing pattern of fesoterodine and the solifenacin combination with mirabegron, the benefit-safety balance is better in terms of benefits and/or safety than any of the other available OAB drugs. Caution in interpretation of the data has to be expressed as the fesoterodine data are based on a flexible dosing regimen, which adds an additional dimension of personalising therapy. PATIENT SUMMARY: Overactive bladder (OAB) is a common condition with a significant impact on the quality of life. Possible symptoms include the following: (1) urgency-a compelling desire to urinate, which is difficult to defer; (2) urgency urinary incontinence-urgency leading to incontinence episodes; (3) frequency-increased frequency of wanting to pass urine; and (4) nocturia-increase in instances of getting up at night to urinate. To date, the mainstay of therapy for OAB has been antimuscarinic drugs and, more recently, the beta 3 agonist mirabegron. Ten international experts in urology, obstetrics, gynaecology, healthy ageing, and data analysis compared the benefit-risk balance of 14 OAB drugs licensed in Europe. The experts considered the importance of a favourable effect on the above four symptoms and also potential for side effects, but only three of these side effects, constipation, dry mouth, and dizziness, showed clinically relevant differences among the six drugs they considered. The observations recorded here suggest interesting differences between drugs across a wide range of possible trade-offs between benefit and safety. The different recruitment criteria used for each study may influence the results seen, so they need to be treated with caution. Comparison of flexibly dosed fesoterodine studies with fixed-dose fesoterodine studies introduces an additional potential bias; definitive conclusions can be drawn only if enough comparable placebo-controlled flexible dosing studies with other drugs were available.

Efficacy and Safety of Combination Pharmacotherapy for Patients with Overactive Bladder: A Rapid Evidence Assessment.

CONTEXT: Oral pharmacotherapy consisting of antimuscarinics, ß3-adrenoreceptor agonists, or combinations of these agents forms the mainstay of overactive bladder (OAB) management. OBJECTIVE: To evaluate the efficacy and safety of combination therapy in patients with OAB. EVIDENCE ACQUISITION: A literature search was conducted in June 2018 using Embase, MEDLINE, and Cochrane databases via Ovid and relevant congress abstracts. Studies reporting the efficacy/safety of two antimuscarinics or a ß3-adrenoreceptor agonist plus an antimuscarinic were included. EVIDENCE SYNTHESIS: Publications reported on clinical efficacy, safety, and health-related quality of life (HRQoL) for mirabegron (M) plus solifenacin (S) from three 12-wk randomised controlled trials (RCTs)-SYMPHONY, SYNERGY, and BESIDE-and a 12-mo RCT, SYNERGY II. SYMPHONY reported statistically significant improvements in clinical symptoms and HRQoL with combination therapy versus solifenacin 5 mg (S5) and placebo. In SYNERGY, there were consistent improvements in urinary incontinence (UI) episodes/24 h and micturitions/24 h (coprimary endpoints), and in secondary efficacy parameters with mirabegron 25 mg (M25) + S5 and mirabegron 50 mg (M50) + S5 versus respective monotherapies. In patients with an inadequate response to S5 monotherapy (BESIDE), greater improvements in UI (primary endpoint) were noted for M50 + S5 versus S5 (p = 0.001). Combination therapy was noninferior to solifenacin 10 mg (S10) for reduction in UI and superior to S10 for improvement in micturition frequency (p < 0.001), and resulted in greater improvements from baseline in OAB-5 Dimension scores versus S5 and S10 (p < 0.01). In SYNERGY II, clinically meaningful and sustained improvements in clinical outcomes were observed for M50 + S5 versus M50 or S5. Combination therapy was well tolerated in all four trials. The incidence of adverse events (AEs) was similar across groups, and there were no notable differences in the incidence of specific AEs. Positive efficacy outcomes were observed in five studies of dual antimuscarinic therapy (trospium + solifenacin). CONCLUSIONS: Mirabegron plus solifenacin provides effective, well-tolerated treatment for patients with OAB. Limited data for dual antimuscarinic therapy suggest a benefit in patients with moderate-to-severe symptoms. PATIENT SUMMARY: Overactive bladder (OAB) is treated with medicines called antimuscarinics, such as solifenacin, propiverine, or trospium, or another ß-adrenoreceptor agonist medicine called mirabegron, which works in a different way. We looked at published scientific studies of patients with OAB treated with mirabegron plus solifenacin together, or with two antimuscarinics. We found that mirabegron plus solifenacin can help reduce symptoms and improve quality of life. Patients tolerate this treatment well, with few patients experiencing side effects.

Mirabegrona para o tratamento de incontinência urinária de urgência (IUU) / Mirabegrone for the treatment of Urinary Urinary Incontinence (UUI)

CONTEXTO: O termo incontinência urinária (IU) refere-se à queixa de qualquer perda de urina, que pode ser involuntária, provocada pelo indivíduo ou descrita por um cuidador. A IU é uma condição que afeta dramaticamente a qualidade de vida, comprometendo o bem-estar físico, emocional, psicológico e social. A IU pode acometer indivíduos de todas as idades, de ambos os sexos e de todos os níveis sociais e econômicos. A IUU ocorre como consequência da hiperatividade detrusora, em que o músculo detrusor apresenta contração involuntária. Várias situações podem levar a hiperatividade detrusora, desde uma infecção urinária que irrita a mucosa vesical até uma alteração, identificável ou não, da inervação vesical. Os sintomas mais comuns associados a IUU são urgência miccional, polaciúria e noctúria. TECNOLOGIA: Mirabegrona (Myrbetric® - Astellas). PERGUNTA: Qual a eficácia e a segurança do uso de mirabegrona para o tratamento de indivíduos adultos com incontinência urinária de urgência? Evidências científicas: Para essa análise 22 estudos foram incluídos, entre eles revisões sistemáticas de ECR, com meta-análise direta e indireta, e ECR não inclusos nas revisões sistemáticas. Os desfechos primários avaliados foram redução de número de episódios de IU/dia; redução de episódios de urgência/dia; redução de episódios de IUU/dia; redução do número de micções/dia; e taxa de cura (redução de 100% dos episódios de IU/dia). No geral, para qualquer um dos desfechos primários avaliados, a mirabegrona foi mais eficaz que o placebo. Em geral, para todos os desfechos primários avaliados, a solifenacina foi superior à mirabegrona. Geralmente, quando a mirabegrona é associada à solifenacina (5 ou 10 mg), a associação apresenta melhores resultados de eficácia. A mirabegrona apresentou perfil geral de eventos adversos semelhantes aos do placebo. Considerando os eventos adversos relacionados ao tratamento, a o perfil de segurança da mirabegrona também foi semelhante ao dos antimuscarínicos avaliados. No entanto, a frequência de ocorrência de boca seca, foi superior nos antimuscarínicos em relação à mirabegrona. A qualidade geral do corpo da evidência, apesar de advinda de revisões sistemáticas e ECRs, é baixa, haja vista a grande heterogeneidade e o alto risco de viés presente na maioria dos estudos aqui avaliados. Ademais, precisamos levar em conta a significância clínica dos desfechos avaliados. Em geral, para os desfechos avaliados em redução de números de episódios, esse foram menores do que 1/dia. AVALIAÇÃO ECONÔMICA: A Análise de custo efetividade foi feita para os desfechos redução de episódios de IU/dia; redução de episódios de urgência/dia; e redução do número de micções/dia. O cenário base foi aquele no qual os pacientes recebiam cuidados para o acompanhamento da IU, disponível no SUS. Os cenários alternativos foram os seis utilizados na AIO. Para qualquer um dos desfechos analisados, as RCEI foram menores para solifenacina e para oxibutinina. Os desfechos de eficácia foram superiores paras as comparações entre oxibutinina versus placebo e para solifenacina versus placebo. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A AIO foi feita na perspectiva do SUS e considerou um horizonte temporal de cinco anos. Os dados sobre a população elegível foram claculados por meio de estimavas populacionais presentes no site do IBGE, os quais foram associados à prevalência de IUU, obtida de uma revisão sistemática. Para essa análise, seis cenários foram avaliados: 1) todos os medicamentos seriam incorporados com um Marketshare específico (33% para a tolterodina; 28% para a solifenacina; 17% oxibutinina; 17% mirabegrona; e 4% darifenacina); 2) apenas a tolterodina seria incorporada; 3) apenas a solifenacina seria incorporada; 4) apenas a oxibutinina seria incorporada; 5) apenas a mirabegrona seria incorporada; e 6) apenas a darifenacina seria incorporada. Esses cenários passaram por análise de sensibilidade para verificação da influência da variação da prevalência. Os cenários com menor impacto orçamentário foram aqueles com 100% de oxibutinina e 100% de solifenacina. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As pesquisas apontaram não haver novos medicamentos nas fases 3 ou 4 de desenvolvimento clínico para o tratamento da incontinência urinária de urgência. CONSIDERAÇÕES: Atualmente não existem alternativas farmacológicas para o tratamento da IUU no SUS. A evidência analisada por meio deste relatório, mostra que a mirabegrona apresenta boa eficácia em relação ao placebo, sendo semelhante à maioria dos antimuscarínicos comparados. A exceção é a solifenacina que, em geral, apresentou melhores resultados de eficácia que a mirabegrona. A qualidade geral do corpo da evidência, apesar de advinda de revisões sistemáticas e ECRs, é baixa, haja vista a grande heterogeneidade e o alto risco de viés presente na maioria dos estudos aqui avaliados. Ademais, precisamos levar em conta a significância clínica dos desfechos avaliados. Em geral, para os desfechos avaliados em redução de números de episódios, esse foram menores do que 1 episódio/dia. Ademais, apesar do valor baixo das RCEI, para os desfechos avaliados, o impacto orçamentário em cinco anos é enorme, o que pode inviabilizar a incorporação de tal fármaco. A mirabegrona demonstrou ser menos eficaz do que a solifenacina e mais onerosa ao sistema de saúde. RECOMENDAÇÃO PRELIMINAR: Pelo exposto, a CONITEC, em sua 76ª reunião ordinária, no dia 04 de abril de 2019, recomendou a não incorporação no SUS da mirabegrona para o tratamento de incontinência urinária de urgência. Foram considerados os seguintes aspectos: as evidência disponíveis são de qualidade muito baixa; os resultados apresentam pouca relevância clínica, com a redução de um episódio de IUU ou menos; estão disponilibizadas no SUS outras opções não farmacológicas, como fisioterapia e cirurgias; além do alto custo do medicamento para o baixo benefício apresentado. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: A Consulta Pública nº 28/2019 foi realizada entre os dias 09/05/2019 e 28/05/2019. Foram recebidas 9 contribuições, sendo 4 pelo formulário para contribuições técnico-científicas e 5 pelo formulário para contribuições sobre experiência ou opinião, essas últimas foram excluídas por abordarem um tema diferente ou por não conter informação (em branco). Dentre as contribuições técnico-científicas, somente uma era alusivas às evidências clínicas. Foi enviado um parecer técnico-científico pela empresa Astellas Farma Brasil, que ressaltou a inexistência de medicamentos disponíveis na rede pública para o tratamento da Síndrome da Bexiga Hiperativa. No momento, o SUS disponilibiza outras opções não farmacológicas, como fisioterapia e cirurgias. A CONITEC entendeu que não houve argumentação suficiente para alterar sua recomendação inicial de não incorporação deste medicamento. RECOMENDAÇÃO FINAL: Os membros da CONITEC presentes na 78ª reunião ordinária, no dia 06 de junho de 2019, deliberaram por unanimidade recomendar a não incorporação da mirabegrona para incontinência urinária de urgência (IUU). Foi assinado o Registro de Deliberação nº 455/2019. DECISÃO: Não incorporar a mirabegrona para incontinência urinária de urgência, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 34, publicada no Diário Oficial da União nº 123, seção 1, página 240, em 28 de junho de 2019.

Systematic literature review of clinical trials evaluating pharmacotherapy for overactive bladder in elderly patients: An assessment of trial quality.

AIMS: Overactive bladder (OAB) disproportionately affects older-aged adults, yet most randomized controlled trials (RCTs) underrepresent patients ≥65. This systematic literature review (SLR) identified RCTs evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly patients with OAB, and compared study quality across trials. METHODS: MEDLINE® , Embase® , and Cochrane Collaboration Central Register of Clinical Trials databases were searched from inception through April 28, 2015 to identify published, peer-reviewed RCT reports evaluating ß-3 adrenergic agonists or muscarinic antagonists in elderly OAB patients (either ≥65 years or study-described as "elderly"). To assess study quality of RCT reports, we focused on internal/external validity, assessed via two scales: the validated Effective Public Health Practice Project [EPHPP]): Quality Assessment Tool for Quantitative Studies, and a tool commissioned by the Agency for Healthcare Research and Quality (AHRQ). RESULTS: Database searches yielded 1380 records that were then screened according to predefined inclusion/exclusion criteria. We included eight papers meeting study criteria. Despite scientific community efforts to improve RCT reporting standards, published reports still include incomplete and inconsistent reporting-of subject attrition, baseline patient characteristics, inclusion/exclusion criteria, and other important details. Only three of the eight OAB RCTs in this review received quality ratings of Strong (EPHPP) or Fair (AHRQ) and were multicenter with large samples. CONCLUSIONS: Despite the prevalence of OAB among older age individuals, relatively few RCTs evaluate OAB treatments explicitly among elderly subjects. The findings from this quality assessment suggest some areas for improvement in both conduct and reporting of future RCTs assessing OAB treatment in elderly.

Comprehensive Assessment of Coronary Plaque Progression With Advanced Intravascular Imaging, Physiological Measures, and Wall Shear Stress: A Pilot Double-Blinded Randomized Controlled Clinical Trial of Nebivolol Versus Atenolol in Nonobstructive Coronary Artery Disease.

BACKGROUND: We hypothesized that nebivolol, a ß-blocker with nitric oxide-mediated activity, compared with atenolol, a ß-blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease. METHODS AND RESULTS: In this pilot double-blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow-up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low-WSS segments in the nebivolol cohort (P=0.06). Low-WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high-WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin-capped fibroatheromas per vessel. Importantly, after adjusting for ß-blocker, low-WSS segments remained significantly associated with lumen loss and plaque progression. CONCLUSION: Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low-WSS segments in the nebivolol arm. Both ß-blockers had similar effects on oxidative stress, microvascular function, and endothelial function. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

A quantitative benefit-risk assessment approach to improve decision making in drug development: Application of a multicriteria decision analysis model in the development of combination therapy for overactive bladder.

A multicriteria decision analysis (MCDA) approach was developed and used to estimate the benefit-risk of solifenacin and mirabegron and their combination in the treatment of overactive bladder (OAB). The objectives were 1) to develop an MCDA tool to compare drug effects in OAB quantitatively, 2) to establish transparency in the evaluation of the benefit-risk profile of various dose combinations, and 3) to quantify the added value of combination use compared to monotherapies. The MCDA model was developed using efficacy, safety, and tolerability attributes and the results of a phase II factorial design combination study were evaluated. Combinations of solifenacin 5 mg and mirabegron 25 mg and mirabegron 50 (5+25 and 5+50) scored the highest clinical utility and supported combination therapy development of solifenacin and mirabegron for phase III clinical development at these dose regimens. This case study underlines the benefit of using a quantitative approach in clinical drug development programs.

Cost-Effectiveness of Mirabegron Compared with Antimuscarinic Agents for the Treatment of Adults with Overactive Bladder in the United Kingdom.

BACKGROUND: Mirabegron, a first-in-class selective oral ß3-adrenoceptor agonist, has similar efficacy to most antimuscarinic agents and a lower incidence of dry mouth in patients with overactive bladder (OAB). OBJECTIVES: To evaluate the cost-effectiveness of mirabegron 50 mg compared with oral antimuscarinic agents in adults with OAB from a UK National Health Service perspective. METHODS: A Markov model including health states for symptom severity, treatment status, and adverse events was developed. Cycle length was 1 month, and the time horizon was 5 years. Antimuscarinic comparators were tolterodine extended release, solifenacin, fesoterodine, oxybutynin extended release and immediate release (IR), darifenacin, and trospium chloride modified release. Transition probabilities for symptom severity levels and adverse events were estimated from a mirabegron trial and a mixed treatment comparison. Estimates for other inputs were obtained from published literature or expert opinion. Quality-adjusted life-years (QALYs) and total health care costs, including costs of drug acquisition, physician visits, incontinence pad use, and botox injections, were modeled. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Base-case incremental cost-effectiveness ratios ranged from £367 (vs. solifenacin 10 mg) to £15,593 (vs. oxybutynin IR 10 mg) per QALY gained. Probabilistic sensitivity analyses showed that at a willingness-to-pay threshold of £20,000/QALY gained, the probability of mirabegron 50 mg being cost-effective ranged from 70.2% versus oxybutynin IR 10 mg to 97.8% versus darifenacin 15 mg. A limitation of our analysis is the uncertainty due to the lack of direct comparisons of mirabegron with other agents; a mixed treatment comparison using rigorous methodology provided the data for the analysis, but the studies involved showed heterogeneity. CONCLUSIONS: Mirabegron 50 mg appears to be cost-effective compared with standard oral antimuscarinic agents for the treatment of adults with OAB from a UK National Health Service perspective.

Economic evaluation of pharmacological treatments for overactive bladder from the perspective of the UK National Health Service.

OBJECTIVE: To evaluate the costs and outcomes associated with different sequences of oral anti-muscarinic agents and the selective ß(3)-adrenoceptor agonist, mirabegron, for the treatment of overactive bladder (OAB). METHODS: A Markov model with monthly cycle length and time horizon up to 3 years was designed to compare two different sequences of up to three lines of oral therapy for OAB. Patients who discontinued one oral medication could switch to another oral medication or could discontinue treatment. Patients whose symptoms were not controlled were considered for botulinum toxin or sacral nerve stimulation. Outcomes were measured by (a) number of patients with controlled symptoms (no incontinence episodes and <8 micturitions per 24 h); (b) patients with no incontinence episodes per 24 hours; and (c) patients with <8 micturitions per 24 h. RESULTS: Including a third-line oral medication before considering other treatment options improved all patient outcomes, irrespective of the specific drugs used. A three-line sequence including two generic (oxybutynin first line and tolterodine extended-release second line) and one branded drug (solifenacin 5 mg third line) resulted in inferior patient outcomes at costs similar to a sequence of branded drugs (mirabegron first line, solifenacin 5 mg second line, solifenacin 10 mg third line): controlled patients (generic 29.6/1000 vs branded 38.7/1000); patients with no incontinence episodes (103.6/1000 vs 123.7/1000); patients with <8 micturitions (228.7/1000 vs 262.1/1000). Annual treatment costs per patient were similar (generic £1299 vs branded £1385). CONCLUSIONS: In the treatment of OAB, low-cost generic treatments are not necessarily more cost-effective than branded drugs, primarily because a better efficacy and tolerability balance improves both symptom control and persistence.