The long-acting muscarinic antagonist (LAMA) aclidinium bromide significantly reduced the rates of COPD exacerbation* without increasing the risk of major adverse cardiovascular events (MACE) compared with placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and increased cardiovascular (CV) risk, according to the results of the ASCENT-COPD** trial presented at ATS 2019.

“Outcomes of this trial add data to the longstanding controversy over the [CV] safety of LAMAs in COPD,” said the researchers, citing evidence reflecting an increased CV risk following LAMA therapy. [Eur Respir J 2013;42:606-615; Thorax 2013;68:48-56; JAMA Intern Med 2013;173:1175-1185] “[However, this could have been due] to the exclusion of patients with CV comorbidities … in COPD clinical trials of LAMA therapy,” they explained.

The study included a 2-week run-in period followed by a double-blind treatment phase involving 3,589 participants (mean age 67.2 years, 58.7 percent male) with COPD (mean COPD assessment test score, 20.7/40) and high CV risk (95.9 percent with at least two atherothrombotic risk factors, 47.7 percent with CV disease history). Participants were randomized 1:1 to receive aclidinium bromide 400 μg twice daily via a multidose dry-powder inhaler or a matching placebo. About 71 percent completed the 3-year study. [JAMA 2019;321:1693-1701; ATS 2019, abstract A2443/P209]

The primary safety end point was achieved as reflected by the lower rate of adjudicated composite MACE (CV death, nonfatal myocardial infarction [MI], and nonfatal stroke) among aclidinium bromide vs placebo recipients (3.9 percent vs 4.2 percent), corresponding to a Cox regression hazard ratio (HR) of 0.89 (one-sided 97.5 percent confidence interval [CI]***, 0–1.23).

Evaluation of the MACE subcomponents revealed that the rates of nonfatal MI (1.6 percent vs 2.1 percent, HR, 0.72, one-sided 97.5 percent CI, 0–1.18) and nonfatal stroke (1.0 percent vs 1.3 percent, HR, 0.74, one-sided 97.5 percent CI, 0–1.36), but not CV death (1.5 percent vs 1.1 percent, HR, 1.34, one-sided 97.5 percent CI, 0–2.42), were significantly lower with aclidinium bromide vs placebo.

Despite the increased risk of CV death, the study was not powered to evaluate cause-specific mortality, the researchers pointed out. Moreover, the number of events was small, the CIs were wide, and the risks of the other MACE subcomponents were lower with aclidinium bromide. There was also no between-group difference in the exploratory outcome of all-cause mortality as reflected in the sensitivity analysis (HR, 0.99, two-sided 95 percent CI, 0.76–1.28; p=0.901), they added. Nonetheless, the individual safety assessment should be interpreted with caution as the risk of CV death cannot be excluded.

The rate of moderate-to-severe COPD exacerbations was also significantly reduced in the first year with aclidinium bromide vs placebo (0.44 vs 0.57, rate ratio [RR], 0.78, two-sided 95 percent CI, 0.68–0.89; p<0.001), as was the rate of exacerbations requiring hospitalization (0.07 vs 0.10, RR, 0.65, two-sided 95 percent CI, 0.48–0.89; p=0.006).

The most common treatment emergent adverse event (TEAE) reported was pneumonia, which occurred at comparable rates between the aclidinium bromide and the placebo arms. Other common TEAEs were urinary tract infection (5.2 percent vs 5.0 percent) and upper respiratory tract infection (4.8 percent vs 5.6 percent). The most common serious AEs were pneumonia (3.7 percent vs 3.2 percent), atrial fibrillation (1.3 percent vs 1.0 percent), and congestive heart failure (1.2 percent vs 1.0 percent).

These results support those of a pooled analysis of six trials showing no evidence of increased CV risk with aclidinium bromide in individuals with moderate-to-severe COPD. [Chronic Obstr Pulm Dis 2015;3:435-445] The US Food and Drug Administration has also established that current data do not support an increased risk of stroke, MI, or death associated with the LAMA tiotropium in patients with COPD. [N Engl J Med 2010;363:1097-1099]

Overall, the reduced exacerbation and comparable AE rates underscore the potential of aclidinium bromide in the management of COPD, noted the researchers. Moreover, given the reduced CV risk associated with aclidinium bromide in a cohort with baseline CV risk, the findings highlight the study drug’s CV safety in this setting, they added.