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Aclidinium does not increase cardiovascular risk in COPD

In patients with moderate to severe chronic obstructive pulmonary disease and increased cardiovascular risk, aclidinium did not increase the risk for major cardiovascular events and decreased COPD exacerbations compared with treatment with a placebo, according to the ASCENT-COPD trial published in JAMA.

“There has been controversy over the cardiovascular safety of long-acting bronchodilators in patients with COPD. Observational studies have shown an increase in cardiac events soon after starting these agents. On the other hand, randomized controlled trials have shown no increase in cardiovascular morbidity although patients with active cardiac disease may not participate in these trials,” Robert A. Wise, MD, professor of medicine at Johns Hopkins University School of Medicine, wrote in an email to Healio Pulmonology.

“The ASCENT-COPD trial was designed to test whether aclidinium, a widely available, long-acting antimuscarinic bronchodilator (LAMA) was safe in patients with underlying cardiovascular disease or multiple risk factors. We also wanted to compare benefit in terms of reduction in COPD exacerbations with risk in the same population.

No increase in cardiovascular risk

In the study, 3.9% of the 1,812 patients randomly assigned treatment with aclidinium vs. 4.2% of the 1,818 patients assigned placebo experienced the primary composite safety outcome of an adjudicated MACE, defined as a cardiovascular death, nonfatal myocardial infarction or nonfatal stroke. The HR was 0.89 (one-sided 97.5% CI, 0-1.23), which did not cross the prespecified noninferiority margin of 1.8.

Similarly, a secondary safety analysis using an expanded definition of MACE that included heart failure, arrhythmias and cerebrovascular events showed comparable outcomes between patients treated with aclidinium vs. placebo (9.4% vs. 8.9%; HR = 1.03; one-sided 97.5% CI, 0-1.28).

The multicenter, randomized, placebo-controlled, double-blind, parallel-design trial included patients with moderate to very severe COPD and elevated cardiovascular risk. Nearly all patients (95.6%) had at least two atherothrombotic risk factors and 47.7% had a history of cardiovascular disease.

The mean patient age was 67.2 years, 58.7% were men, 56.5% were former smokers and 85.3% had symptomatic disease or moderate to severe airflow limitation. Sixty percent had one or more COPD exacerbations in the previous year.

More than half (56.8%) of patients used inhaled corticosteroids, usually in combination with a long-acting beta-agonist (LABA; 51.2%), before the study. Nearly two-thirds (64.2%) of patients used an inhaled corticosteroid during the study, usually in combination with a LABA (59.4%).

Patients received aclidinium (Tudorza, AstraZeneca and Circassia) or placebo by dry-powder inhaler (Genuair or Pressair, AstraZeneca) twice daily for as long as 3 years.

Reduced COPD exacerbations

Aclidinium also demonstrated positive effects on COPD exacerbations.

In the on-treatment analysis, the aclidinium group, as compared with the placebo group, had a significantly lower annual rate of moderate to severe COPD exacerbations during the first year of treatment (0.44 vs. 0.57; rate ratio = 0.78; two-sided 95% CI, 0.68-0.89; P < .001). The rate of COPD exacerbations requiring hospitalization was also lower with aclidinium vs. placebo (0.07 vs. 0.1; rate ratio = 0.65 two-sided 95% CI, 0.48-0.89; P = .006).

Further, subgroup analyses demonstrated consistent treatment effect across all subgroups, except in patients with forced expiratory volume (FEV₁) greater than 50%.

“We found that the relative reduction in exacerbations was the same whether the patients came into the study with a prior exacerbation or not,” Wise said. “We also found that the added benefits of aclidinium were similar in patients who were already on dual therapy with an inhaled corticosteroid/LABA as well as those who were not.”

Adverse event rates were comparable between the treatment and placebo groups. The most common treatment-related events, which occurred in at least 5% of patients, were pneumonia, urinary tract infection and upper respiratory tract infection. The most common serious adverse events, which occurred in at least 1% of patients, were pneumonia, atrial fibrillation, congestive heart failure and coronary artery disease. Dry mouth and urinary retention were uncommon in both the treatment and placebo groups.

Current conclusions

The researchers acknowledged several study limitations. For instance, the point estimate for cardiac death was numerically higher with aclidinium, but the study was not powered for cause-specific mortality. The small number of events and the wide confidence intervals are also potential issues

Nevertheless, the trial helps resolve the controversy over safety of LAMAs in COPD, according to the researchers.

“Aclidinium did not pose an increased risk of major adverse cardiovascular events in patients with COPD who are at increased risk for such events,” Wise told Healio Pulmonology. – by Melissa Foster

Disclosures: The study was initially funded by Forest Laboratories and later funded by AstraZeneca and Circassia. Wise reports he has received personal fees from Aradigm, AstraZeneca, Bonti, Circassia, Contrafect, Denali, Kiniksa, Merck, Mylan, Novartis, Pneuma, Propeller Health, Pulmonx, Regeneron, Roche, Spiration, Sunovion, Syneos, Theravance and Verona; grants from Pearl Therapeutics; and grants and personal fees from AstraZeneca/MedImmune, Boehringer Ingelheim and GlaxoSmithKline. Please see the study for all other authors’ relevant financial disclosures.