Aclidinium bromide safe for COPD patients at risk of CV events
Aclidinium bromide does not increase the risk of major adverse cardiac event (MACE) in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) who also had significant cardiovascular (CV) risk factors, according to the phase IV ASCENT COPD* study presented at ATS 2018.
“CV risk factors and comorbidities are prevalent in patients with COPD. About 30 percent of patients with COPD die from CV disease. However, patients with significant CV disease are often excluded from COPD clinical trials,” said Professor Robert Wise of Johns Hopkins University School of Medicine, Baltimore, Maryland, US.
Whether treatment with an inhaled muscarinic antagonist such as aclidinium bromide is associated with an increased risk of CV events remains controversial, both in randomized clinical trials and meta-analysis, he said.
“Aclidinium bromide is approved in the US as a maintenance treatment of COPD. However, during the registration studies, there were not adequate number of CV events to ascertain whether the drug was associated with an increased CV risk,” Wise added.
In the phase IV ASCENT COPD study, the primary safety endpoint of time to first MACE — a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke — did not increase with aclidinium bromide compared with placebo (hazard ratio [HR], 0.89, 95 percent confidence interval [CI], 0.64–1.23; p=0.469). The upper bound of the CI was 1.23, which met the prespecified noninferiority criterion of <1.80. [ATS 2018, abstract A7711]
Specifically, risk reductions were seen for both components of nonfatal MI and stroke (HRs, 0.72 and 0.74, respectively) while the HR for CV death was 1.34 (95 percent CI, 0.74–2.42), which Wise attributed to the low number of events and thus, unable to demonstrate noninferiority.
There was also no increase in the risk of all-cause mortality with aclidinium bromide vs placebo (HR, 0.99; p=0.929). When asked about how important this outcome is, Wise said, “CV mortality is a competing event for respiratory death or other causes of death — one way of increasing cardiac-specific mortality would be to decrease respiratory or noncardiac mortality. That’s why the all-cause mortality analysis is very important to determine whether there was an effect there.”
In the multicentre, double-blind, parallel-group phase IV study, 3,589 patients (mean age 67.2 years, 58.7 percent male) with moderate-to-very severe stable COPD (mean post-bronchodilator FEV1** predicted, 47.7 percent) to receive aclidinium bromide 400 µg twice daily or placebo. Sixty-three percent of patients were treated with concomitant long-acting β2-agonist (LABA) or LABA/inhaled corticosteroid. About half of the patients had ≥2 atherothrombotic risk factors (52.0 percent) or this plus prior CV event (43.9 percent).
Aclidinium bromide significantly reduced the primary efficacy endpoint of moderate-to-severe COPD exacerbation rate during the first year of treatment by 22 percent compared with placebo (0.44 vs 0.57; p<0.001).
Also, exacerbation rate leading to hospitalization was significantly reduced by 35 percent with aclidinium bromide vs placebo (0.07 vs 0.10; p=0.006)
“The reduction in exacerbation risk was similar regardless of whether or not patients had an exacerbation in the past year,” said Wise.