International Journal of COPD (Mar 2021)

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

  • Wise RA,
  • Chapman KR,
  • Scirica BM,
  • Daoud SZ,
  • Lythgoe D,
  • Garcia-Gil E

Journal volume & issue
Vol. Volume 16
pp. 689 – 699

Abstract

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Robert A Wise,1 Kenneth R Chapman,2 Benjamin M Scirica,3,4 Sami Z Daoud,5 Dan Lythgoe,6 Esther Garcia-Gil7 1Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA; 5Late-Stage Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 6Statistics, Phastar, Chiswick, London, UK; 7Respiratory & Immunology, BioPharmaceuticals Medical, AstraZeneca, Barcelona, SpainCorrespondence: Robert A WiseMedicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USAEmail [email protected]: 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, aclidinium, MACE, mortality

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