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

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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.