Long-acting antimuscarinic therapy in patients with chronic obstructive pulmonary disease receiving beta-blockers

Abstract

Background: Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users.

Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year.

Results: Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62-1.64]; non-user: 0.80 [0.51-1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78-1.64]; non-user: 0.89 [0.62-1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60-0.94, P = 0.013]; non-user: 0.79 [0.67-0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL-147 mL] versus 69 mL [42 mL-97 mL]; interaction P = 0.041).

Conclusions: This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity.

Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://ichgcp.net/clinical-trials-registry/NCT01966107 .

Keywords: Aclidinium; Beta-adrenergic antagonists; Cardiac risk; Exacerbations.

Conflict of interest statement

KRC received 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, Baxter, Boehringer Ingelheim, CSL Behring, Genentech, Grifols, GlaxoSmithKline, Kamada, Novartis, Roche, Sanofi, and Shire, during the conduct of the study. RAW received personal fees from AstraZeneca, during the conduct of the study; personal fees from AbbVie, AnaptysBio, AstraZeneca/MedImmune, Circassia, ContraFect, Galderma, GlaxoSmithKline, Kamada, Kinevant, Kiniksa, Merck, Novartis, Pneuma, Propeller Health, Pulmonx, Roche, Sunovion, and Verona; and grants from AstraZeneca/MedImmune, Boehringer Ingelheim, and Pearl Therapeutics, outside of the submitted work. BMS received an Institutional research grant to Brigham and Women’s Hospital from AstraZeneca during the conduct of the study; consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Eisai, Elsevier Practice Update Cardiology, Esperion, Hanmi, Lexicon, Medtronic, Merck, and Novo Nordisk; equity in Health[at]Scale; and grants from Eisai, Merck, Novartis, Novo Nordisk, and Pfizer, outside of the submitted work. DLB discloses the following relationships—Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Takeda. SZD is an employee of AstraZeneca. DL is an employee of Phastar and former consultant statistician to AstraZeneca. EGG was an employee and shareholder of AstraZeneca at the time of the study and is now an employee of Almirall S.A., Barcelona, Spain.

© 2021. The Author(s).

Figures

Fig. 1

Kaplan–Meier plot (a) and Cox regression analysis (b) of time to first adjudicated MACE. Cox proportional hazards model with baseline CV risk group, smoking status, treatment group and baseline beta-blocker use as factors. Interaction P = 0.48. CI confidence interval, CV cardiovascular, HR hazard ratio, MACE major adverse cardiovascular event, N total number of patients, n total number of patients experiencing event

Fig. 2

Kaplan–Meier plot (a) and Cox regression analysis (b) of all-cause mortality. Cox proportional hazards model with baseline CV risk group, smoking status, treatment group and baseline beta-blocker use as factors. Interaction P = 0.35. CI confidence interval, CV cardiovascular, HR hazard ratio, N total number of patients, n total number of patients experiencing event

Fig. 3

Moderate-to-severe COPD exacerbation rate during first year of treatment (a), Kaplan–Meier plot (b) and Cox regression analysis (c) of time to first moderate-to-severe COPD exacerbation. Cox proportional hazards model with treatment group, baseline ICS use, baseline COPD severity, smoking status, 1-year exacerbation history and beta-blocker use at baseline as factors. Moderate-to-severe COPD exacerbation rate during first year of treatment interaction P = 0.75; Cox regression analysis interaction P = 0.83. CI confidence interval, COPD chronic obstructive pulmonary disease, HR hazard ratio, ICS inhaled corticosteroids, N total number of patients, n total number of patients experiencing event

Fig. 4

Change from baseline in morning pre-dose (trough) FEV1 in beta-blocker users and non-users. Baseline was the average of two pre-dose values prior to administration of first dose, or one value if only one was available, or pre-dose bronchodilator value at screening if both were missing. Change in baseline FEV1 (LS mean ± standard error) analysis was based on a mixed model for repeated measures with pre- and post-bronchodilator values at screening, baseline FEV1 as covariates, and treatment group, smoking status, baseline ICS use, baseline beta-blocker use and visits as fixed effects. On-treatment analysis during the first year included patients who completed 1 year or were on-treatment when the study dropped off. FEV1 forced expiratory volume in 1 s, ICS inhaled corticosteroids, LS least squares