Aclidinium Bromide Not Shown to Increase COPD Patient Cardiovascular Risk

Robert A. Wise, MD

Concerns that long-acting muscarinic antagonist (LAMA) therapy drive major adverse cardiovascular event (MACE) risks in patients with chronic obstructive pulmonary disease (COPD) may not be as substantiated as once thought.

New results from the ASCENT-COPD trial show that LAMA aclidinium bromide (Tudorza Pressair) was noninferior to placebo in three-year MACE risk among randomized patients with COPD. Investigators also reported in the AstraZeneca-supported trial that COPD exacerbations among treated patients were reduced over the first year of care.

Led by Robert A. Wise, MD, of the Johns Hopkins University School of Medicine, investigators sought to establish more affirmative data on the conflicting belief that LAMAs or even short-acting muscarinic antagonists (SAMAs) could drive MACE risk in COPD patients. They noted that meta-analyses and epidemiological studies have shown an increased risk of cardiovascular events in treated patients, while large-scale clinical trials of LAMAs such as tiotropium have not evidenced such an associated risk.

“Short-term studies of aclidinium have demonstrated decreased annual rates of exacerbation compared with placebo after 3 to 6 months of treatment, but this has not been established beyond 6 months,” they noted.

Investigators did not return a request for comment at the time of publication.

Wise and colleagues randomized 3630 patients to receive either aclidinium (n= 1812) or place (n= 1818) administered via dry-powder inhaler, twice-daily, for up to 3 years. Patients were assessed from 522 North America sites, and were required to have been diagnosed with moderate to very severe COPD, as well as a history of either cardiovascular disease or at least 2 atherothrombic risk factors. Primary safety endpoint was time to first MACE over up to 3 years, and primary efficacy endpoint was annual COPD exacerbation rate during the first year of treatment.

Mean patient age was 67.2 years old, and 58.7% were male. Just 2537 (70.7%) had completed the trial. Among them, 69 (3.9%) patients on aclidinium reported a MACE, compared to 76 (4.2%) patients on placebo (HR 0.86; one-sided 97.5% CI: 0-1.23). In patient time to first MACE or serious cardiovascular event, aclidinium again reported noninferiority to placebo (HR 1.03; one-sided 97.5% CI: 0-1.28).

Investigators noted that patients who were taking inhaled corticoid steroids (ICS) or dual ICS-LABA at baseline reported lower exacerbation rates with aclidinium versus placebo—just the same as patient not on baseline ICS nor ICS-LABA.

Patients on aclidinium also reported a lower rate of severe COPD exacerbations (0.44) than placebo (0.57; P< .001), as well as rate of exacerbations which required hospitalization (0.07 vs 0.10; P= .006). Common adverse events among all patients including pneumonia, urinary tract infection, and upper respiratory tract infection.

The “long-standing controversy” surrounding research into LAMA’s role in MACE risk among COPD patients has not only influenced the rate of patients administered the therapy at COPD diagnosis or worsening condition, but it’s affected the makeup of clinical trials. Wise and colleagues noted patients with cardiovascular comorbidities and renal impairment have been frequently excluded from LAMA therapy studies. These findings give that practice pause.

“Because patients with COPD exacerbations are at higher risk of subsequent MACE and all-cause mortality, it might be hypothesized that the reduction in exacerbations seen with aclidinium might be reflected in a reduction in cardiovascular events or the exploratory outcome of all-cause mortality,” investigators wrote.

However, such a conclusion was not found in the ASCENT-COPD trial. The findings, particularly among this particular COPD patient population, allowed for risk-benefit comparisons and evidence against the belief of harm surrounding LAMAs.

“By enrolling patients with increased cardiovascular risk and continuing the study until an adequate number of adjudicated MACE had occurred, the study demonstrated that aclidinium was noninferior to placebo with respect to the risk of a new MACE,” the team concluded.

The study, “Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease,” was published online in JAMA.