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

Abstract

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.

Keywords: COPD; COPD exacerbation; MACE; aclidinium; mortality.

Conflict of interest statement

RAW reports personal fees from AstraZeneca during the conduct of the study; personal fees from AbbVie, Anaptsys Bio, AstraZeneca/MedImmune, Bristol Myers Squibb, Chimerix, Circassia, ContraFect, Galderma, GlaxoSmithKline, Kamada, Kinevant, Kiniksa, Merck, Novartis, Pneuma, Propeller Health, Pulmonx, Roche, Sunovion, and Verona, outside the submitted work; and research grants from AstraZeneca/MedImmune, Boehringer Ingelheim, and Pearl Therapeutics, outside the submitted work. KRC reports personal fees from AstraZeneca, Boehringer Ingelheim, CIHR-GSK Research Chair in Respiratory Health Care Delivery (UHN), CSL Behring, Genentech, Grifols, Kamada, Merck, Novartis, Roche, and Sanofi; and grants from Amgen, AstraZeneca, Bayer, Baxter, Boehringer Ingelheim, CSL Behring, Genentech, GlaxoSmithKline, Grifols, Kamada, Mereo Biopharma, Novartis, Regeneron, Roche, Sanofi, Shire, and Vertex, during the conduct of the study. BMS is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. He reports consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Eisai, Elsevier Practice Update Cardiology, Esperion, Hamni, Lexicon, Medtronic, Merck, NovoNordisk, outside the submitted work; grants from Eisai, Merck, Novartis, NovoNordisk, and Pfizer Inc, outside the submitted work; and equity in Health[at]Scale. SZD and EG-G are employees of AstraZeneca. DL is an employee of PHASTAR and former consultant statistician to AstraZeneca. The authors report no other conflicts of interest in this work.

© 2021 Wise et al.

Figures

Figure 1

Patient flow in the ASCENT randomized clinical trial. aPatients were randomized in error. bFor safety outcomes, 70.7% of patients had completed the 3-year study or were currently enrolled in the study when it was stopped; for efficacy outcomes, 67.3% of patients had completed 12 months of treatment or were in their first year of treatment when the study was stopped. The median exposure times for aclidinium vs placebo were: 770.0 and 736.5 days with a history of ≥1 exacerbation and 410.0 and 386.0 days without exacerbation history, respectively.

Figure 2

Time to first adjudicated MACE (A) and risk of MACE (B) up to 3 years in patients with and without an exacerbation history. Cox regression model with factors, including treatment, exacerbation history, and their interaction, as well as adjusting for other baseline factors (see Statistical Considerations). An HR >1 indicated higher risk of MACE with aclidinium and an HR <1 indicated lower risk of MACE with aclidinium.

Figure 3

Time to all-cause mortality event (A) and risk of all-cause mortality (B) up to 3 years based on vital status in patients with and without an exacerbation history. Cox regression model with factors, including treatment, exacerbation history, and their interaction, as well as adjusting for other baseline factors (see Statistical Considerations). An HR >1 indicated higher risk of all-cause mortality with aclidinium and an HR <1 indicated lower risk of all-cause mortality with aclidinium.

Figure 4

Time to first moderate or severe COPD exacerbation (A), moderate or severe COPD exacerbation rate during the first year (B), and COPD exacerbation treatments (C) (on-treatment analysis). Negative binomial model with factors, including treatment, exacerbation history, and their interaction. An RR >1 indicated higher risk of exacerbation with aclidinium and an RR <1 indicated lower risk of exacerbation with aclidinium.

Figure 5

Change from baseline in morning (trough) FEV1 during the first year (on-treatment analysis). Baseline = average of two pre-dose values prior to administration of first dose, or one value if only one is available, or pre-dose bronchodilator value at screening if both are missing. Change in baseline FEV1 (least square mean ± standard error) analysis is based on a mixed model for repeated measures with pre- and post-bronchodilator FEV1 values at screening, and baseline FEV1 as factors. On-treatment analysis included all patients who completed 1 year or were on-treatment when the study was stopped.