Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease: The ASCENT-COPD Randomized Clinical Trial

Robert A Wise, Kenneth R. Chapman, Benjamin M. Scirica, Deepak L. Bhatt, Sami Z. Daoud, Sofia Zetterstrand, Colin Reisner, Esther Garcia Gil

Research output: Contribution to journalArticle

Abstract

Importance: There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. Interventions: Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. Main Outcomes and Measures: The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. Results: Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]). Conclusions and Relevance: Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year. Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.

Original languageEnglish (US)
Pages (from-to)1693-1701
Number of pages9
JournalJAMA
Volume321
Issue number17
DOIs
StatePublished - May 7 2019

Fingerprint

Chronic Obstructive Pulmonary Disease
Randomized Controlled Trials
Placebos
Disease Progression
Hospitalization
aclidinium bromide
Cardiovascular Diseases
Dry Powder Inhalers
Safety
Muscarinic Antagonists
North America
Urinary Tract Infections
Respiratory Tract Infections
Pneumonia
Outcome Assessment (Health Care)
Morbidity
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease : The ASCENT-COPD Randomized Clinical Trial. / Wise, Robert A; Chapman, Kenneth R.; Scirica, Benjamin M.; Bhatt, Deepak L.; Daoud, Sami Z.; Zetterstrand, Sofia; Reisner, Colin; Gil, Esther Garcia.

In: JAMA, Vol. 321, No. 17, 07.05.2019, p. 1693-1701.

Research output: Contribution to journalArticle

Wise, Robert A ; Chapman, Kenneth R. ; Scirica, Benjamin M. ; Bhatt, Deepak L. ; Daoud, Sami Z. ; Zetterstrand, Sofia ; Reisner, Colin ; Gil, Esther Garcia. / Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease : The ASCENT-COPD Randomized Clinical Trial. In: JAMA. 2019 ; Vol. 321, No. 17. pp. 1693-1701.
@article{39e45782a69947daaebcfa5191b0635b,
title = "Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease: The ASCENT-COPD Randomized Clinical Trial",
abstract = "Importance: There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. Interventions: Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. Main Outcomes and Measures: The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5{\%} CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. Results: Among 3589 patients analyzed (mean age, 67.2 years; 58.7{\%} male), 2537 (70.7{\%}) completed the study. Of these, 69 (3.9{\%}) aclidinium and 76 (4.2{\%}) placebo patients had a MACE (HR, 0.89; 1-sided 97.5{\%} CI, 0-1.23); the expanded MACE definition included 168 (9.4{\%}) aclidinium vs 160 (8.9{\%}) placebo patients with events (HR, 1.03; 1-sided 97.5{\%} CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95{\%} CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95{\%} CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1{\%}]; placebo, 105 events [5.8{\%}]), urinary tract infection (aclidinium, 93 events [5.2{\%}]; placebo, 89 events [5.0{\%}]), and upper respiratory tract infection (aclidinium, 86 events [4.8{\%}]; placebo, 101 events [5.6{\%}]). Conclusions and Relevance: Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year. Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.",
author = "Wise, {Robert A} and Chapman, {Kenneth R.} and Scirica, {Benjamin M.} and Bhatt, {Deepak L.} and Daoud, {Sami Z.} and Sofia Zetterstrand and Colin Reisner and Gil, {Esther Garcia}",
year = "2019",
month = "5",
day = "7",
doi = "10.1001/jama.2019.4973",
language = "English (US)",
volume = "321",
pages = "1693--1701",
journal = "JAMA - Journal of the American Medical Association",
issn = "0098-7484",
publisher = "American Medical Association",
number = "17",

}

TY - JOUR

T1 - Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease

T2 - The ASCENT-COPD Randomized Clinical Trial

AU - Wise, Robert A

AU - Chapman, Kenneth R.

AU - Scirica, Benjamin M.

AU - Bhatt, Deepak L.

AU - Daoud, Sami Z.

AU - Zetterstrand, Sofia

AU - Reisner, Colin

AU - Gil, Esther Garcia

PY - 2019/5/7

Y1 - 2019/5/7

N2 - Importance: There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. Interventions: Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. Main Outcomes and Measures: The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. Results: Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]). Conclusions and Relevance: Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year. Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.

AB - Importance: There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 μg twice daily, in patients with COPD and cardiovascular disease or risk factors. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. Interventions: Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. Main Outcomes and Measures: The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. Results: Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]). Conclusions and Relevance: Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year. Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.

UR - http://www.scopus.com/inward/record.url?scp=85065804092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065804092&partnerID=8YFLogxK

U2 - 10.1001/jama.2019.4973

DO - 10.1001/jama.2019.4973

M3 - Article

C2 - 31063575

AN - SCOPUS:85065804092

VL - 321

SP - 1693

EP - 1701

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0098-7484

IS - 17

ER -