Salbutamol use in relation to maintenance bronchodilator efficacy in COPD: a prospective subgroup analysis of the EMAX trial

Abstract

Background: Short-acting β2-agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD.

Methods: The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 μg, once-daily umeclidinium 62.5 μg or twice-daily salmeterol 50 μg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV1), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates.

Results: At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV1 at Week 24 in both SABA subgroups (59-74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: - 0.56 [p < 0.001]; low: - 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day.

Conclusions: In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome.

Funding: GlaxoSmithKline (study number 201749 [NCT03034915]).

Keywords: (3–10): dual bronchodilators; COPD; Lung function; Rescue therapy; SABA; Salbutamol; Symptoms.

Conflict of interest statement

IHB, PWJ, CC and DAL are employees of GlaxoSmithKline (GSK) and hold stocks and shares in GSK. IPN was an employee of GSK at the time of the study, holds stocks and shares in GSK and is a contingent worker on assignment at AstraZeneca. LT is a contingent worker on assignment at GSK. FM has received research grants for participating in multicentre trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols and Novartis. CFV has received grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Mundipharma, Novartis and the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), and has received personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Mundipharma, Novartis, Nuvaira and Teva. LB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. EMK has served on advisory boards, speaker panels or received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance, and has received consulting fees from Cipla and GSK. ELLIPTA and DISKUS are owned by/licensed to the GSK group of companies.

Figures

Fig. 1

Change from baseline in trough FEV1 at Week 24 by baseline SABA usea.CFB change from baseline, CI confidence interval, FEV1 forced expiratory volume in 1 s, LS least squares, SABA short-acting β2-agonist, SAL salmeterol, UMEC umeclidinium, VI vilanterol. aMean SABA use was 3.91 puffs/day and 0.39 puffs/day in the high and low SABA use subgroups, respectively

Fig. 2

Mean (a) SAC-TDI (b) change from baseline E-RS total score by baseline SABA usea. CFB change from baseline, CI confidence interval, ERS Evaluating Respiratory Symptoms: COPD, LS least squares, SABA short-acting β2-agonist, SAC-TDI self-administered computerised Transition Dyspnoea Index, SAL salmeterol, UMEC umeclidinium, VI vilanterol. aMean SABA use was 3.91 puffs/day and 0.39 puffs/day in the high and low SABA use subgroups, respectively

Fig. 3

Mean SABA puffs/day across Weeks 1–24. CI confidence interval, LS least squares, SABA short-acting β2-agonist, SAL salmeterol, UMEC umeclidinium, VI vilanterol

Fig. 4

Risk of a first moderate/severe exacerbation up to Day 168. CI confidence interval, HR hazard ratio, LS least squares, SABA short-acting β2-agonist, SAL salmeterol, UMEC umeclidinium, VI vilanterol

Fig. 5

Relationship between baseline SABA use and treatment differences (UMEC/VI vs UMEC). CI confidence interval, E-RS Evaluating Respiratory Symptoms: COPD, FEV1 forced expiratory volume in 1 s, LS least squares, SABA short-acting β2-agonist, SAC-TDI self-administered computerised Transition Dyspnoea Index, UMEC umeclidinium, VI vilanterol

Fig. 6

Relationship between baseline SABA use and treatment difference (UMEC/VI vs SAL). CI confidence interval, E-RS Evaluating Respiratory Symptoms: COPD, FEV1 forced expiratory volume in 1 s, LS least squares, SABA short-acting β2-agonist, SAC-TDI self-administered computerised Transition Dyspnoea Index, SAL salmeterol, UMEC umeclidinium, VI vilanterol