Impact of prior and concurrent medication on exacerbation risk with long-acting bronchodilators in chronic obstructive pulmonary disease: a post hoc analysis

BackgroundSymptomatic patients with chronic obstructive pulmonary disease (COPD) and low exacerbation risk still have disease instability, which can be improved with better bronchodilation. We evaluated two long-acting bronchodilators individually and in combination on reducing exacerbation risk and the potential impact of concurrent medication in these patients.MethodsIntegrated post hoc intent-to-treat (ITT) analysis of data from two large 24-week, randomized placebo (PBO)-controlled trials (NCT01313637, NCT01313650). Symptomatic patients with moderate-to-very-severe COPD with/without an exacerbation history were randomized (2:3:3:3) to once-daily: PBO, umeclidinium/vilanterol (UMEC/VI 62.5/25g [NCT01313650] or 125/25g [NCT01313637]), UMEC (62.5 [NCT01313650] or 125g [NCT01313637]) or VI (25g) via the ELLIPTA inhaler. Medication subgroups were segmented by treatment status at screening: a) maintenance-naive or on maintenance medications, b) inhaled corticosteroid [ICS]-free or ICS-treated, c) low or high albuterol use based on median run-in use (<3.6 or3.6 puffs/day). Time to first moderate/severe exacerbation (Cox proportional hazard model) and change from baseline in trough forced expiratory volume in 1s (FEV1; mixed model repeated measures) were analyzed. Safety was also assessed.ResultsOf 3021 patients (ITT population; UMEC/VI: n=816; UMEC: n=825; VI: n=825; PBO: n=555), 36% had a recent exacerbation history, 33% were maintenance-naive, 51% were ICS-free. Mean baseline albuterol use was 5.1 puffs/day. In the ITT population, UMEC/VI, UMEC, and VI reduced the risk of a first exacerbation versus PBO by 58, 44, and 39%, respectively (all p<0.05). UMEC/VI provided significant risk reductions versus PBO in all subgroups. VI had no benefit versus PBO in maintenance-naive, ICS-free, and low rescue use patients and was significantly less effective than UMEC/VI in these subgroups. UMEC had no significant benefit versus PBO in maintenance-naive and ICS-free patients. All bronchodilators improved FEV1 versus PBO, and UMEC/VI significantly improved FEV1 versus both monotherapies across all populations studied (p<0.05). All bronchodilators were similarly well tolerated.ConclusionsResults suggest that UMEC/VI reduces exacerbation risk versus PBO more consistently across medication subgroups than UMEC or VI, particularly in patients with no/low concurrent medication use. Confirmed prospectively, these findings may support first-line use of dual bronchodilation therapy in symptomatic low-risk patients.