By Will Boggs MD
NEW YORK (Reuters Health) - 8/5/2019
The long-acting muscarinic antagonist (LAMA) aclidinium bromide reduces exacerbations of chronic obstructive pulmonary disease (COPD) without worsening cardiovascular outcomes in high-risk patients, according to results from the ASCENT-COPD randomized clinical trial. "This study reassures that what we've considered foundational therapy in COPD - LAMA bronchodilator - is safe and effective in a real world setting," Dr. Kenneth R. Chapman from University of Toronto, Ontario, Canada told Reuters Health by email.
"There's been a lingering concerning about the cardiovascular safety of anticholinergic bronchodilators, first raised with the short-acting agents and later with the first long-acting agent, tiotropium," he explained. "Several studies have attempted to reassure, but ASCENT is the first trial to tackle the problem head on by recruiting patients with COPD who have either had a significant cardiovascular/cerebrovascular event or have two or more important risk factors for cardiovascular disease."
Dr. Chapman and colleagues at 522 sites in North America investigated the efficacy and cardiovascular safety of aclidinium bromide (400 mcg twice daily) in their placebo-controlled trial of 3630 high-risk patients with moderate to very severe COPD.
The fraction of patients who experienced a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) did not differ significantly between the aclidinium group (3.9%) and the placebo group (4.2%), according to the May 7th online report in JAMA.
The groups did not differ when researchers used an expanded definition of MACE (serious events of heart failure, arrhythmias, or cerebrovascular disease).
The annual rate of moderate to severe exacerbations during the first year of treatment was significantly lower with aclidinium (0.44) than with placebo (0.57) (P<0.001), according to an on-treatment analysis.
The rate of COPD exacerbations requiring hospitalization was also significantly lower with aclidinium (0.07) than with placebo (0.10) (P=0.006).
Rates of treatment-emergent adverse events and serious adverse events were comparable between the groups.
"This question asks about 'this LAMA,' aclidinium, and it may be relevant to focus on this specific agent rather than the whole class," Dr. Chapman said. "Although we usually look at large trials in common diseases and consider the findings applicable to the broad class of drugs, there is one way aclidinium differs from other available LAMAs. It's rapidly hydrolyzed in plasma and should have lowest potential for systemic side effects as a result."
"So we can say after ASCENT that aclidinium has been shown safe and effective, a characteristic particularly relevant if there are concerns about treatment in patients with concomitant cardiovascular disease," he said.
"Like any large multicenter trial of consequence, we've been busy looking at the data for other lessons," Dr. Chapman added. "Without jeopardizing future publications, I'll say that the findings of the overall trial are robust. That is, we see the same results in various sub-populations, independent of background patient characteristics or background medication use."
Dr. James F. Donohue from University of North Carolina, Chapel Hill, who participated in an earlier trial of aclidinium/formoterol in patients with COPD, told Reuters Health by email, "For a number of years there were concerns at FDA (the US Food and Drug Administration) about MACE events with LAMAs, especially if used in high doses. The UPLIFT study and many other LAMA studies have reinforced the safety. Thus, the FDA may ask for additional safety data."
"The ASCENT is particularly reassuring, as these patients had increased cardiovascular risk, but aclidinium was noninferior to placebo in a large well done study over a reasonable period," he said. "Its safety is now well established, and the agent is competitive with other LAMAs."
Forest Laboratories/AstraZeneca/Circassia sponsored the trial, employed 4 of the 8 authors, and had various relationships with the other 4 authors and with Dr. Donohue.