RESUMO Objetivo: Avaliar o efeito do tratamento com a combinação de três moduladores da proteína cystic fibrosis transmembrane conductance regulator (CFTR, reguladora de condutância transmembrana em fibrose cística) - elexacaftor + tezacaftor + ivacaftor (ETI) - sobre desfechos clínicos importantes em indivíduos com fibrose cística. Métodos: Revisão sistemática e meta-análise de ensaios clínicos randomizados que compararam o uso de ETI em indivíduos com fibrose cística com pelo menos um alelo F508del com o uso de placebo ou de um comparador ativo como outras combinações de moduladores da CFTR. O estudo foi realizado seguindo as recomendações Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) e a metodologia Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO). Foram realizadas buscas nos seguintes bancos de dados: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials e ClinicalTrials.gov, desde a sua criação até 26 de dezembro de 2022. O risco de viés foi avaliado por meio da ferramenta de risco de viés da Cochrane, e a qualidade das evidências foi determinada com base no sistema Grading of Recommendations Assessment, Development and Evaluation (GRADE). Resultados: Foram identificados 54 estudos na busca primária. Destes, 6 preencheram os critérios de inclusão e foram analisados (1.127 pacientes: 577 pacientes intervenção e 550 pacientes controle). A meta-análise revelou que o uso de ETI aumentou o VEF1 em porcentagem do previsto [diferença de risco (DR): +10,47%; IC95%: 6,88-14,06], reduziu o número de exacerbações pulmonares agudas (DR: −0,16; IC95%: −0,28 a −0,04) e melhorou a qualidade de vida (DR: +14,93; IC95%: 9,98-19,89) e o IMC (DR: +1,07 kg/m2; IC95%: 0,90-1,25). Os eventos adversos não diferiram entre os grupos (DR: −0,03; IC95%: −0,08 a 0,01), e nenhum dos estudos relatou óbitos. Conclusões: Nossos achados demonstram que o tratamento com ETI melhora substancialmente os desfechos clinicamente significativos centrados no paciente. Objetivo CFTR, CFTR (CFTR (ETI Métodos metaanálise meta análise Fdel F del MetaAnalyses Meta Analyses PRISMA (PRISMA studied interventions PICO. PICO . (PICO) dados MEDLINE EMBASE ClinicalTrialsgov ClinicalTrials gov ClinicalTrials.gov 2 2022 Assessment GRADE. GRADE (GRADE) Resultados 5 primária Destes 1.127 1127 1 127 (1.12 57 55 controle. controle controle) VEF diferença DR (DR) +10,47% 1047 10 47 IC95% IC95 IC 6,8814,06, 6881406 6,88 14,06 , 88 14 06 6,88-14,06] (DR −0,16 016 0 16 028 28 −0,2 −0,04 004 04 +14,93 1493 93 9,9819,89 9981989 9,98 19,89 9 98 19 89 9,98-19,89 107 07 +1,0 kg/m2 kgm2 kgm kg m2 m 0,901,25. 090125 0,90 1,25 90 25 0,90-1,25) −0,03 003 03 008 08 −0,0 0,01, 001 0,01 01 0,01) óbitos Conclusões paciente (PICO 202 (GRADE 1.12 112 12 (1.1 +10,47 104 4 IC9 8814 6,8814,06 688140 688 6,8 1406 14,0 8 6,88-14,06 −0,1 02 −0, 00 +14,9 149 9819 9,9819,8 998198 998 9,9 1989 19,8 9,98-19,8 +1, kg/m 901 0,901,25 09012 090 0,9 125 1,2 0,90-1,25 0,0 20 1.1 11 (1. +10,4 881 6,8814,0 68814 68 6, 140 14, 6,88-14,0 −0 +14, 981 9,9819, 99819 99 9, 198 19, 9,98-19, +1 0,901,2 0901 09 0, 1, 0,90-1,2 1. (1 +10, 6,8814, 6881 6,88-14, − +14 9,9819 9981 9,98-19 0,901, 0,90-1, ( +10 6,8814 6,88-14 9,981 9,98-1 0,901 0,90-1 6,881 6,88-1 9,98- 0,90- 6,88-
ABSTRACT Objective: To evaluate the effect of treatment with the combination of three cystic fibrosis transmembrane conductance regulator (CFTR) modulators-elexacaftor+tezacaftor+ivacaftor (ETI)-on important clinical endpoints in individuals with cystic fibrosis. Methods: This was a systematic review and meta-analysis of randomized clinical trials that compared the use of ETI in individuals with CF and at least one F508del allele with that of placebo or with an active comparator such as other combinations of CFTR modulators, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and the Patients of interest, Intervention to be studied, Comparison of interventions, and Outcome of interest (PICO) methodology. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to December 26th, 2022. The risk of bias was assessed using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We retrieved 54 studies in the primary search. Of these, 6 met the inclusion criteria and were analyzed (1,127 patients; 577 and 550 in the intervention and control groups, respectively). The meta-analysis revealed that the use of ETI increased FEV1% [risk difference (RD), +10.47%; 95% CI, 6.88-14.06], reduced the number of acute pulmonary exacerbations (RD, −0.16; 95% CI, −0.28 to −0.04), and improved quality of life (RD, +14.93; 95% CI, 9.98-19.89) and BMI (RD, +1.07 kg/m2; 95% CI, 0.90-1.25). Adverse events did not differ between groups (RD, −0.03; 95% CI, −0.08 to 0.01), and none of the studies reported deaths. Conclusions: Our findings demonstrate that ETI treatment substantially improves clinically significant, patient-centered outcomes. Objective (CFTR modulatorselexacaftor+tezacaftor+ivacaftor modulatorselexacaftortezacaftorivacaftor modulators elexacaftor+tezacaftor+ivacaftor elexacaftor tezacaftor ivacaftor ETIon Methods metaanalysis meta analysis Fdel F del MetaAnalyses Meta Analyses PRISMA (PRISMA studied interventions PICO (PICO methodology databases MEDLINE EMBASE Trials ClinicalTrialsgov ClinicalTrials gov 26th th 2022 riskofbias tool Assessment GRADE. GRADE . (GRADE) Results 5 search these 1,127 1127 1 127 (1,12 patients 57 55 respectively. respectively respectively) FEV1 FEV RD, RD , (RD) +10.47% 1047 10 47 95 CI 6.8814.06, 6881406 6.88 14.06 88 14 06 6.88-14.06] (RD −0.16 016 0 16 028 28 −0.2 −0.04, 004 −0.04 04 −0.04) +14.93 1493 93 9.9819.89 9981989 9.98 19.89 9 98 19 89 9.98-19.89 107 07 +1.0 kg/m2 kgm2 kgm kg m2 m 0.901.25. 090125 0.90 1.25 90 25 0.90-1.25) −0.03 003 03 008 08 −0.0 0.01, 001 0.01 01 0.01) deaths Conclusions significant patientcentered patient centered outcomes modulatorselexacaftor elexacaftortezacaftorivacaftor 202 (GRADE 1,12 112 12 (1,1 +10.47 104 4 8814 6.8814.06 688140 688 6.8 1406 14.0 8 6.88-14.06 −0.1 02 2 −0. 00 +14.9 149 9819 9.9819.8 998198 998 9.9 1989 19.8 9.98-19.8 +1. kg/m 901 0.901.25 09012 090 0.9 125 1.2 0.90-1.25 0.0 20 1,1 11 (1, +10.4 881 6.8814.0 68814 68 6. 140 14. 6.88-14.0 −0 +14. 981 9.9819. 99819 99 9. 198 19. 9.98-19. +1 0.901.2 0901 09 0. 1. 0.90-1.2 1, (1 +10. 6.8814. 6881 6.88-14. − +14 9.9819 9981 9.98-19 + 0.901. 0.90-1. ( +10 6.8814 6.88-14 9.981 9.98-1 0.901 0.90-1 6.881 6.88-1 9.98- 0.90- 6.88-