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.

Figure 1.. Patient Flow in the ASCENT-COPD Randomized Clinical Trial

COPD indicates chronic obstructive pulmonary disease. ^aFor safety outcomes, 70.7% of patients had completed the 3-year study or were currently enrolled in the study at the time the study 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. ^bPatients were randomized in error.

Figure 2.. Risk of MACE and Time to First Adjudicated MACE (On-Study Analysis)

HR indicates hazard ratio; MACE, major adverse cardiovascular event. Estimates of HRs and 1-sided 97.5% CIs comparing aclidinium with placebo were derived using the Cox proportional hazard model with treatment group, baseline cardiovascular severity, and smoking status as factors. Observations were censored for Kaplan-Meier curve. An HR >1.0 indicates higher risk of MACE with aclidinium and an HR <1.0, lower risk of MACE with aclidinium. The vertical dashed line indicates the margin of noninferiority, 1.8. The median exposure time (including time after treatment discontinuation) was 495 days (interquartile range, 369-893 days) for aclidinium and 478 days (interquartile range, 357-869 days) for placebo.

Figure 3.. Moderate to Severe COPD Exacerbations During the First Year and Time to First Moderate to Severe Exacerbation (On-Treatment Analysis)

COPD indicates chronic obstructive pulmonary disease; RR, rate ratio. A, Least-squares means from a negative binomial regression model, with treatment group, baseline inhaled corticosteroid use, baseline COPD severity, history of ≥1 exacerbation in the past 12 months, and smoking status as factors; the log of the exposure time adjusted for the time the patients experienced exacerbations was an offset variable. B, Cox regression analysis. Observations were censored for Kaplan-Meier curve. Log-rank P = .001 comparing aclidinium with placebo, stratified by baseline COPD severity and smoking status. There were 574 patients (32.5%) with events in the aclidinium group and 631 (35.6%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.73-0.92; P<.001). Median observation time was 321 days (interquartile range, 121.5-365 days) for aclidinium and 283 days (interquartile range, 96-365 days) for placebo. A unique exacerbation was one that occurred 7 or more days after completion of treatment with corticosteroids or antibiotics for a previous event.