Quantitative analysis of efficacy and safety of LABA/LAMA fixed-dose combinations in the treatment of stable COPD

Abstract

Objective: This study aimed to quantitatively compare the efficacy and safety of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for the treatment of stable chronic obstructive pulmonary disease (COPD), especially in terms of their loss of efficacy in lung function.

Methods: Randomized controlled clinical trials of LABA/LAMA FDCs for the treatment of stable COPD were comprehensively searched for in public databases. Pharmacodynamic models were established to describe the time course of the primary outcome [trough forced expiratory volume in the first second (FEV₁)]. Secondary outcomes [COPD exacerbations, St. George's Respiratory Questionnaire (SGRQ), Transition Dyspnoea Index (TDI), and rescue medication use] and safety outcomes [mortality, serious adverse events (SAEs), and withdrawals due to adverse events (AEs)] were also compared via a meta-analysis.

Results: A total of 22 studies involving 16,486 participants were included in this study. The results showed that in terms of primary outcome (change from baseline in trough FEV₁), the efficacy of vilanterol/umeclidinium was the highest, while the efficacy of formoterol/aclidinium was the lowest, with a maximum effect value (E_max) of 0.185 L [95% confidence interval (CI): 0.173-0.197 L] and 0.119 L (95% CI: 0.103-0.135 L), respectively. The efficacy of other drugs, such as formoterol/glycopyrronium, indacaterol/glycopyrronium, and olodaterol/tiotropium, were comparable, and their E_max values were 0.150-0.177 L. Except for vilanterol/umeclidinium, the other four LABA/LAMA FDCs showed a certain degree of loss of efficacy. Compared with the efficacy at 2 days, the trough FEV₁ (L) relative to baseline at 24 weeks decreased by 0.029-0.041 L. In terms of secondary outcomes, the efficacy of different LABA/LAMA FDCs was similar in TDI and rescue medication use. However, formoterol/aclidinium was better in preventing the COPD exacerbations, while vilanterol/umeclidinium was the best in terms of SGRQ. In addition, different LABA/LAMA FDCs and placebo had similar safety outcomes.

Conclusion: The present findings may provide necessary quantitative information for COPD medication guidelines.

Keywords: LABA/LAMA fixed-dose combinations; chronic obstructive pulmonary disease; model-based meta-analysis; trough forced expiratory volume in 1 second.

Figure 1.

Flow chart for study identification and selection.

Figure 2.

Visual predictive check of the final model of the change from baseline in predose(trough) FEV₁ (L). The points represent observed change from baseline in predose(trough) FEV₁ (L), and symbol size is proportional to sample size. Points linked by a line are from the same arm. Purple lines are the model-predicted fifth, 50th, and 95th percentiles of the change from baseline in predose(trough) FEV₁ (L).

Figure 3.

Predicted typical time course of the change from baseline in predose(trough) FEV₁ (L) of each drug and placebo.