Comparing the Efficacy and Safety Profile of Triple Fixed-Dose Combinations in COPD: A Meta-Analysis and IBiS Score

Abstract

Background: Triple fixed-dose combination (FDC) therapy is recommended in severe chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations and/or symptoms not controlled by dual FDCs. Since no randomized controlled trials (RCTs) have directly compared the different inhaled corticosteroid/long-acting β2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) FDCs, we performed a meta-analysis to compare the impact of the current available ICS/LABA/LAMA FDCs in COPD. Methods: A meta-analysis was performed by connecting beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide or glycopyrrolate (BDP/FOR/GLY), budesonide (BUD)/GLY/FOR, and fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI) FDCs via ICS/LABA or LABA/LAMA FDCs arms. The safety and efficacy profiles were investigated, and the Implemented Bidimensional Surface under the cumulative ranking curve analysis (IBiS) was carried out. Protocol registration: CRD42022301189. Results: Data from 21,809 COPD patients were extracted from the ETHOS, IMPACT, KRONOS, and TRILOGY studies. No significant (p > 0.05) differences were detected across the triple FDCs with respect to the risk of exacerbation, trough forced expiratory volume in the first second (FEV1), transition dyspnea index (TDI), St. George’s Respiratory Questionnaire (SGRQ), risk of serious adverse events (SAEs), cardiovascular (CV) SAEs, pneumonia, and all-cause mortality. According to IBiS score, BDP/FOR/GLY 200/12/25 µg twice daily (BID) was the FDC reporting the best combined efficacy/safety profile (area 41.41%), although FF/UMEC/VI 100/62.5/25 µg once daily (QD) showed the greatest efficacy profile (50.54%). The protection against mortality related to the dose of ICS. Conclusions: All triple FDCs are effective and safe in COPD regardless of the regimen of administration (twice daily vs. once daily), with no relevant difference in the risk of CV SAEs and pneumonia.

Letter to the Editor Regarding “Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis”

“…Given the methodological issues, selective reporting of fixed-effects model results, and failure to disclose the random-effects model results, which we believe to be not significant per our replicate analysis, we do not agree with Ismaila et al that FF/UMEC/VI showed statistically significant improvements in annualized moderate/severe exacerbation rates versus budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) [1]. Notably, their finding contradicts four other peer-reviewed NMA publications, including two from independent researchers [8,9], all of which used random-effects models to account for heterogeneity and reported no significant exacerbation rate differences between triple therapies in patients with chronic obstructive pulmonary disease [8][9][10][11].…”

A Response to: Letter to the Editor Regarding “Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-analysis”

“…• Study designs: RCTs with a minimum duration of 8 weeks; Marshall et al commented on the differences between our findings and those of four other NMA studies [13][14][15][16]. The Ferguson et al [17] and Bourdin et al [16] publications assume therapeutic equivalency of the ICS/LABA or LAMA/LABA therapies (an assumption that is not supported by head-to-head evidence), which may contribute towards differences in findings and the magnitude of effects reported.…”

“…As part of the study selection for this triple therapy NMA, we included studies conducted in populations that were consistent with the licensed indication for COPD triple therapy: ''indicated as a maintenance treatment in adult patients with moderate-to-severe COPD who are not adequately treated by a combination of an ICS and a LABA or combination of a LABA and a LAMA'' [12][13][14]. The comprehensive systematic literature review (SLR) identified RCTs conducted in adults aged C 40 years with a COPD diagnosis, including the relevant triple therapy studies that are presented specifically within the respective Summary of Product Characteristics (SmPCs) of the licensed triple therapies.…”

“…The NMA studies mentioned by Marshall et al [13][14][15][16] presented results from a Bayesian RE model. These studies have not presented sufficient details on their statistical analyses to facilitate reproducibility of the models used.…”

“…These two assumptions would mean that we are testing the benefit of adding different LAMA (to ICS/LABA) or different ICS (to LAMA/LABA). Differences between alternative LAMA/LABA combinations [ 2 , 9 , 17 , 18 ] or ICS/LABA combinations [ 19 , 20 ] have previously been demonstrated, and it has been suggested that the clinical impact of triple combination therapies may be modulated by the pharmacological characteristics of the individual components [ 14 ]. We also propose that differences in efficacy observed between triple therapies in our NMA may be attributed to differences in the component molecules.…”