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John R Hurst,1 Kevin Gruffydd-Jones,2 Mousumi Biswas,3 Deniz Guranlioglu,4 Martin Jenkins,4 Neda Stjepanovic,5 Arushi Bamrara6 1UCL Respiratory, University College London, London, UK; 2GP, Box Surgery, Box, Wiltshire, UK; 3AstraZeneca, Gaithersburg, MD, USA; 4AstraZeneca, Cambridge, UK; 5AstraZeneca Gothenburg, Mölndal, Sweden; 6Parexel International, Punjab, IndiaCorrespondence: John R Hurst Email j.hurst@ucl.ac.ukBackground: This literature review assessed comparative efficacy and safety of long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) fixed-dose combinations (FDCs) in patients with COPD and moderate-to-very severe airflow limitation, using evidence from direct (head-to-head) and indirect treatment comparisons.Methods: Two systematic literature reviews were conducted to identify direct comparisons (head-to-head randomized controlled trials [RCTs]) and indirect comparisons (network meta-analyses [NMAs]; indirect treatment comparisons; meta-analyses) in patients with COPD with moderate-to-very severe airflow limitation. Study/Analysis characteristics, eligibility criteria, patient characteristics, and overall conclusions were extracted from relevant publications. The review of indirect comparisons focused on NMAs reporting efficacy outcomes at 12 and 24 weeks of treatment (established durations of symptomatic studies in COPD recommended by regulators).Results: Direct comparisons: Four RCTs that provided head-to-head comparisons of LAMA/LABA FDCs were identified, and these varied in their study design, included patient population and reported endpoints. While some differences in lung function outcomes were noted, where assessed, LAMA/LABA FDCs had comparable efficacy in improving symptoms, health status, exacerbations, and comparable safety profiles. However, the differences in study methodology and patient characteristics between these studies made it difficult to draw generalizable conclusions regarding the comparative effectiveness of LAMA/LABA FDCs from the direct comparisons alone. Indirect comparisons: Six NMAs were identified that reported indirect comparisons between LAMA/LABA FDCs; five of these were within the pre-defined scope of this review. Although the scope of each NMA varied, all five concluded that LAMA/LABA FDCs were generally comparable in terms of lung function improvements, patient-reported outcomes, and safety (where assessed).Conclusion: Although there were some inconsistencies between the outcomes of RCTs and NMAs for lung function, the totality of lung function, symptoms, exacerbations, and safety data suggests that currently available LAMA/LABA FDCs have comparable efficacy and safety in patients with COPD and moderate-to-very severe airflow limitation.Keywords: chronic obstructive pulmonary disease, direct evidence, indirect treatment comparisons, LAMA/LABA, efficacy, safety