Tratamento medicamentoso da Doença de Cushing: revisão sistemática da literatura e metanálise
Carregando...
Arquivos
Data
2018-02-22
Autores
Correa, Julia Martins Simões
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
Introdução: Existem quatro medicações disponíveis como tratamento complementar da doença de Cushing: pasireotida, cabergolina, cetoconazol e mifepristone. Contudo, não existe um consenso sobre qual medicação é mais efetiva e segura para o controle dessa neoplasia. Objetivo: comparar a segurança e a efetividade destas quatro medicações no controle de indivíduos com doença de Cushing não curados pela cirurgia, recidivados ou que não puderam realizar esse procedimento. Metodologia: para isso foi realizada uma revisão sistemática de acordo com a metodologia da colaboração Cochrane, no qual seriam incluídos estudos randomizados das comparações destas medicações entre si e fossem avaliados como desfechos primários a remissão do hipercortisolismo por meio da normalização do cortisol livre urinário (CLU), melhora na qualidade de vida, frequência de eventos adversos, melhora das comorbidades e sintomas associadas a essa doença. Foram realizadas três estratégias de busca adaptadas as bases eletrônicas de saúde: EMBASE, PubMed e CENTRAL-Cochrane. Os estudos foram selecionados por dois revisores independentes e os dados extraídos a partir de um formulário padronizado. Resultados: Foram incluídos dez estudos randomizados, um comparando cabergolina versus cetoconazol, e nove avaliando doses diferentes do pasireotida, sendo que oito se referiam ao mesmo protocolo de estudo. A normalização do CLU em seis meses de tratamento foi inferior na cabergolina em relação ao cetoconazol (33% versus 62,5%, respectivamente), porém, com uma qualidade da evidência muito baixa, essa diferença não foi significativa (RR: 0,53, IC 95%: 0,15-1,87). Comparando a dose maior do pasireotida (900μg subcutâneo duas vezes ao dia ou 30mg de liberação lenta intramuscular a cada 28 dias) com uma dose menor (600μg ou 10mg), a normalização do CLU em seis e 12 meses foi de 29% vs 21% e 25% vs 24%, respectivamente, a metanálise não mostrou diferença significativa entre os grupos (RR 1,35, IC 95%: 0,85 a 2,14 e RR 1,12, IC 95% 0,15 a 1,87, respectivamente). Quanto a segurança, ambas as doses do pasireotida ocasionaram diabetes mellitus, sem diferença ente os grupos (frequência de 25% vs 24%, RR 1,12 IC 95%: 0,44 a 2,89). Nessa mesma comparação, houve melhora na qualidade de vida, dos sintomas e das complicações associadas, também sem diferença significativa entre as doses. Conclusão: um único estudo comparativo entre duas drogas foi encontrado (cabergolina versus o cetoconazol), e a taxa de normalização do CLU em seis meses não foi significativamente diferente entre os grupos. A comparação de duas doses do pasireotida (uma dose maior versus uma menor) em seis meses, sem ajuste de dose e 12 meses com ajuste também não foi significativamente diferente. Em relação à segurança, em 12 meses de seguimento, o evento adverso Diabetes Mellitus ocorreu em 25% dos pacientes que utilizaram o pasireotida. Para todos esses achados a qualidade da evidência de acordo com o GRADE (Grading of Recommendations Assessment, Development, and Evaluation foi baixa.
There are four medications available for the medical treatment of Cushing’s disease: pasireotide, cabergoline, ketoconazole and mifepristone. However, there is no consensus as to the most effective or safe medication. Objective: The aim of this systematic review was to compare these four medications in patients with Cushing’s disease who did not achieve disease control after transsphenoidal surgery, in recurrence cases, or in individuals no candidate for surgery. Methodology: We performed a systematic review according to Cochrane collaboration to include randomized studies comparing these four medications. The primary outcomes were normalization of urinary free cortisol (UFC), quality of life, adverse events and improvement of comorbidities and symptoms related to this condition. Search strategies were applied to the following electronic database: Medline, EMBASE and CENTRAL - Cochrane. Studies were selected by two independent reviewers and data were extracted using a standard form. Results: Ten studies were included, one that compared cabergoline versus ketoconazole, and nine that performed indirect comparisons between two different dosages of pasireotide, although eight referred to the same study protocol. Normalization of UFC in six months of treatment with cabergoline was worst than with ketoconazole (33% versus 62.5%, respectively). However, in the meta-analysis this difference was not statistically significant (RR: 0.53, 95% CI: 0.15- 1.87). Pasireotide 900μg/30mg when compared to pasireotide 600μg/10mg to the normalization of UFC in six and 12 months, presented cure rates of 29% vs 21% e 25% vs 24%, respectively. The meta-analysis did not show significant difference between the groups in six (RR: 1.35 95%CI: 0.85 a 2.14) and in 12 months (RR: 1.12, 95%CI 0.15 a 1.87). Concerning safety, including both groups, 25% of patients using pasireotide presented Diabetes Mellitus without significant difference between the groups (RR: 1.12 95%CI (0.44 a 2.89). Pasireotide was associated with improvement of quality of life, symptoms and comorbidities, although with non-significant differences between dosages. Conclusion: we found a single comparative study between two drugs (cabergoline versus ketoconazole), and the UFC normalization rate at six months was not significantly different between the groups. The comparison of two doses of pasireotide (one higher versus one lower dose) at six months, no dosis adjustment, and 12 months after dosis adjustment was also not significantly different. Regarding safety, at 12 months of the follow-up, the adverse event Diabetes Mellitus occurred in 25% of the patients who used pasireotide. For all these findings the quality of evidence according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was very low.
There are four medications available for the medical treatment of Cushing’s disease: pasireotide, cabergoline, ketoconazole and mifepristone. However, there is no consensus as to the most effective or safe medication. Objective: The aim of this systematic review was to compare these four medications in patients with Cushing’s disease who did not achieve disease control after transsphenoidal surgery, in recurrence cases, or in individuals no candidate for surgery. Methodology: We performed a systematic review according to Cochrane collaboration to include randomized studies comparing these four medications. The primary outcomes were normalization of urinary free cortisol (UFC), quality of life, adverse events and improvement of comorbidities and symptoms related to this condition. Search strategies were applied to the following electronic database: Medline, EMBASE and CENTRAL - Cochrane. Studies were selected by two independent reviewers and data were extracted using a standard form. Results: Ten studies were included, one that compared cabergoline versus ketoconazole, and nine that performed indirect comparisons between two different dosages of pasireotide, although eight referred to the same study protocol. Normalization of UFC in six months of treatment with cabergoline was worst than with ketoconazole (33% versus 62.5%, respectively). However, in the meta-analysis this difference was not statistically significant (RR: 0.53, 95% CI: 0.15- 1.87). Pasireotide 900μg/30mg when compared to pasireotide 600μg/10mg to the normalization of UFC in six and 12 months, presented cure rates of 29% vs 21% e 25% vs 24%, respectively. The meta-analysis did not show significant difference between the groups in six (RR: 1.35 95%CI: 0.85 a 2.14) and in 12 months (RR: 1.12, 95%CI 0.15 a 1.87). Concerning safety, including both groups, 25% of patients using pasireotide presented Diabetes Mellitus without significant difference between the groups (RR: 1.12 95%CI (0.44 a 2.89). Pasireotide was associated with improvement of quality of life, symptoms and comorbidities, although with non-significant differences between dosages. Conclusion: we found a single comparative study between two drugs (cabergoline versus ketoconazole), and the UFC normalization rate at six months was not significantly different between the groups. The comparison of two doses of pasireotide (one higher versus one lower dose) at six months, no dosis adjustment, and 12 months after dosis adjustment was also not significantly different. Regarding safety, at 12 months of the follow-up, the adverse event Diabetes Mellitus occurred in 25% of the patients who used pasireotide. For all these findings the quality of evidence according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was very low.
Descrição
Palavras-chave
doença de cushing, revisão sistemática, cabergolina, pasireotida, cetoconazol, mifepristone, cushing’s disease, pasireotide, cabergoline, ketoconazole, mifepristone, systematic review