SAN DIEGO – The use of aclidinium bromide 400 mcg b.i.d. did not increase the risk of major adverse cardiac events or mortality in patients with moderate to very severe , compared with placebo.
Those are two key findings from thepresented by , at an international conference of the American Thoracic Society. “Cardiovascular risk factors and comorbidities are prevalent in patients with COPD, and about 30% of COPD patients die of cardiovascular disease,” said Dr. Wise, who serves as director of research for the division of pulmonary and critical care medicine at the Johns Hopkins University School of Medicine, Baltimore. “However, patients who have cardiovascular disease are often excluded from, or not enrolled in, COPD clinical trials. Moreover, there has been controversy as to whether or not treatment with a long-acting muscarinic antagonist is associated with an increased risk of cardiovascular events. That’s been seen in randomized trials, meta-analyses, as well as in observational studies.”
Aclidinium bromide 400 mcg b.i.d., administered by the Pressair inhaler, is approved as a maintenance treatment for patients with COPD. However, during the registration studies, there were not an adequate number of cardiovascular events in order to ascertain clearly whether or not the drug was associated with increased risk, Dr. Wise said. Therefore, he and his associates in the ASCENT COPD study set out to assess the long-term cardiovascular safety profile of aclidinium 400 mcg b.i.d. in patients with moderate to very severe COPD at risk of major adverse cardiovascular events (MACE) for up to 3 years (). For the randomized, placebo-controlled, parallel-group study, patients received treatment with aclidinium bromide or a placebo inhaler of similar appearance. The study was designed to be terminated when at least 122 patients experienced an adjudicated MACE. The primary safety endpoint was time to first MACE during follow-up of up to 3 years, while the primary efficacy endpoint was the rate of moderate to severe exacerbations per patient per year during the first year of treatment.
To be included in the study, patients had to be at least 40 years of age with moderate to very severe stable COPD, have a smoking history of at least 10 pack-years, and have at least one of the following significant risk factors: cerebrovascular disease; coronary artery disease; peripheral vascular disease, or history of claudication; or at least two atherothrombotic risk factors (male at least 65 years of age, female at least 70 years of age; waist circumference of at least 40 inches among males or at least 38 inches among females; an estimated glomerular filtration rate of less than 60 mL/min and microalbuminuria; dyslipidemia; or hypertension).
The researchers randomized 1,791 patients to the aclidinium group and 1,798 to the placebo group. Their mean age was 67 years, and about 60% of patients had an exacerbation in the preceding year. Nearly two-thirds of patients (63%) were receiving concomitant long-acting beta 2-agonists (LABA) or LABA/inhaled corticosteroid therapy. In addition, 44% of patients entered the study with a history of a prior cardiovascular event plus at least two atherothrombotic risk factors, 52% reported at least two atherothrombotic risk factors without any prior cardiovascular events, and 4% had a history of a prior cardiovascular event only.
Dr. Wise reported that aclidinium did not increase the risk of MACE in patients with moderate to very severe COPD with significant cardiovascular risk factors, compared with placebo (hazard ratio 0.89; P = .469); non-inferiority was concluded as the upper bound of the 95% confidence interval was less than 1.8). In terms of all-cause mortality, aclidinium did not increase the risk of death, compared with placebo (HR 0.99; P = .929).
During the first year of treatment, Dr. Wise and his associates also observed a 22% reduction in COPD exacerbation rate for aclidinium vs. placebo groups (HR 0.44 vs. 0.57, respectively; P less than .001), and a 35% reduction in the rate of COPD exacerbations leading to hospitalizations (HR 0.07 vs. 0.10; P = .006). “The reduction in exacerbation risk was similar, whether or not patients had an exacerbation in the past year,” Dr. Wise said. He reported being a consultant to, and receiving research support from, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and ContraFect.
SOURCE: Wise, R., et al., , ATS 2018.