Bayesian or frequentist: there is no question when comparing single-inhaler triple therapies via network meta-analysis. Focus on fluticasone furoate/umeclidinium/vilanterol fixed-dose combination in chronic obstructive pulmonary disease

Objectives: Single-inhaler triple therapies (SITTs) have never been directly compared in randomized controlled trials (RCTs) in chronic obstructive pulmonary disease (COPD). Cochrane recommends the Bayesian approach for indirect comparisons but a frequentist network meta-analysis (NMA) reported superiority of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) over other SITT. We assessed the most appropriate inference method for NMA characterized by between-study heterogeneity on SITT in COPD. Methods: Bayesian and frequentist NMA were performed on RCTs investigating the effect of SITT on exacerbations and trough forced expiratory volume in the 1st second (FEV1) in COPD. Results: The included RCTs (ETHOS, FULFIL, IMPACT, KRONOS 200812) reported significant between-study heterogeneity (I2 > 99%, p < 0.001). The Bayesian random-effect NMA provided unbiased evidence that FF/UMEC/VI was not superior to other SITT on exacerbations and trough FEV1. The frequentist fixed-effect NMA indicated that FF/UMEC/VI was significantly (p < 0.05) more effective than other SITT, although results were affected by dispersion, asymmetry, and significant risk of bias. Frequentist random-effect NMA provided effect estimates rather similar but not equal to those of Bayesian approach. Conclusion: Indirect comparison should be performed via Bayesian approach instead of frequentist inference with a fixed-effect model. Claiming the superiority of a specific medication over other therapies should be confirmed by findings originating from well-designed RCTs.