The Impact of Exacerbation History on the Safety and Efficacy of Aclidinium in Patients with Chronic Obstructive Pulmonary Disease and Increased Cardiovascular Risk: ASCENT-COPD Trial.

Purpose Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk. Patients and methods ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study. Results Of 3589 patients, 2156 (60.1%) had ≥1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54-1.16; none: HR 1.27, 95% CI: 0.65-2.47; interaction P=0.233) or all-cause mortality (≥1: HR 1.08, 95% CI: 0.81-1.43; none: HR 0.66, 95% CI: 0.36-1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥1: rate ratio [RR] 0.80, 95% CI: 0.68-0.94; none: RR 0.69, 95% CI: 0.54-0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633). Conclusion In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history. Clinical trial registration ClinicalTrials.gov Identifier: NCT01966107.