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

Int J Chron Obstruct Pulmon Dis. 2021 Mar 18;16:689-699. doi: 10.2147/COPD.S285068. eCollection 2021.

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.

Publication types

  • Clinical Trial, Phase IV
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Bronchodilator Agents / therapeutic use
  • Cardiovascular Diseases* / diagnosis
  • Disease Progression
  • Double-Blind Method
  • Forced Expiratory Volume
  • Heart Disease Risk Factors
  • Humans
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy
  • Risk Factors

Substances

  • Bronchodilator Agents

Associated data

  • ClinicalTrials.gov/NCT01966107

Grant support

The ASCENT-COPD study was initially funded by Forest Laboratories and later funded by AstraZeneca and Circassia. AstraZeneca was involved in data collection and interpretation, and the development and review of this manuscript. The decision to submit the manuscript for publication was made by the authors.