Meeting News

ASCENT-COPD: Aclidinium shows continued success in chronic obstructive pulmonary disease

DALLAS — Aclidinium reduces moderate to severe exacerbations without increasing cardiovascular event risk in patients with chronic obstructive pulmonary disease, regardless of beta-blocker use or background treatment with long-acting beta-agonists with or without an inhaled corticosteroid, new data presented at the American Thoracic Society International Conference suggest.

As Healio Pulmonology previously reported, an on-treatment analysis published in JAMA showed significantly lower annual rates of moderate to severe COPD exacerbations and exacerbations requiring hospitalization in patients treated with aclidinium (Tudorza, AstraZeneca and Circassia), as compared with placebo, during the first year of treatment. The risk for the primary safety composite outcome of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, also did not differ significantly between the treatment and placebo groups over 3 years.

“Despite some early concerns about the use of anticholinergics generally, and more recently long-acting muscarinic agonists (LAMAs), and their safety in patients, when we look at a high-risk population in terms of cardiovascular disease, we don’t see a safety signal, at least with this particular anticholinergic,” Kenneth Chapman, MD, MSc, professor of medicine at the University of Toronto and director of the Asthma Airway Center at the University Health Network, told Healio Pulmonology.

Benefits in beta-blocker users

In one of the new analyses presented at the ATS International Conference, Chapman and colleagues specifically evaluated outcomes in patients who were using beta-blockers at baseline, including 627 in the aclidinium group and 642 in the placebo group.

They found that the risk for MACE was not increased with aclidinium, as compared with placebo, in both patients on beta-blockers (HR = 1.01; 95% CI, 0.62-1.64) and those not on beta-blockers (HR = 0.8; 95% CI, 0.51-1.24), with no significant difference between beta-blocker users and nonusers (P = .483).

Similarly, the all-cause mortality risk was no higher with aclidinium than placebo in both beta-blocker users (HR = 1.13; 95% CI, 0.68-1.74) and nonusers (HR = 0.89; 95% CI, 0.62-1.26), with no substantial difference in risk between beta-blocker users and non-users (P = .352).

Moreover, aclidinium, as compared with placebo, reduced the moderate or severe COPD exacerbation rate by 25% in beta-blocker users (HR = 0.75; 95% CI, 0.6-0.94) and 21% in nonusers (HR = 0.79; 95% CI, 0.67-0.93), with no difference in treatment effect (P = .753). Aclidinium also delayed time to first moderate or severe COPD exacerbation in both groups.

Interestingly, Chapman said, both beta-blocker users and nonusers had improved forced expiratory volume in 1 second (FEV1) from baseline with aclidinium vs. placebo at all visits, but beta-blocker users benefited more from treatment than nonusers (average improvements, 99 mL vs. 69 mL; P for interaction = .041).

Although the researchers are still analyzing this surprising finding, Chapman noted that it “makes terrific pharmacologic sense.”

“A common background therapy for many of our patients at baseline included long-acting beta-agonist (LABA) with an inhaled corticosteroid. It’s sensible to say that patients taking a beta-blocker for prevention of myocardial reinfarction, for instance, blunted the benefit of the beta-agonist in their regimen so they did not achieve optimal control with that single agent, and those patients then benefited from the LAMA, which bronchodilates by a different mechanism,” he told Healio Pulmonology.

Treatment effect against background therapy

In another analysis presented at the meeting, the researchers also sought to assess the effects of aclidinium in the context of background therapy with LABA with or without inhaled corticosteroid therapy.

Of the 2,285 patients on a LABA with or without an inhaled corticosteroid in the study, 1,127 were assigned aclidinium and 1,158 were assigned placebo.

Among those receiving a LABA with or without an inhaled corticosteroid at baseline, aclidinium, as compared with placebo, significantly reduced the rate of moderate to severe exacerbations per patient per year (RR = 0.76; 95% CI, 0.65-0.89) and the rate was similar to that seen in the overall population (RR = 0.78; 95% CI, 0.68-0.89).

The same was true for patients receiving a concomitant LABA with or without inhaled corticosteroids in the aclidinium group vs. the placebo group (RR = 0.77; 95% CI, 0.66-0.89).

FEV1 also improved from baseline with aclidinium, as compared with placebo, from week 4 to 78 (P < .001), and numerical improvements were observed at week 104 (39 mL) and week 156 (53 mL) — improvements that were comparable to those seen in the overall population (range, 54 mL to 91 mL; P < .001 for all).

Numerical improvements from baseline were seen in COPD Assessment Test scores with aclidinium vs. placebo at all time points in those on a LABA with or without an inhaled corticosteroid at baseline and in the overall study population up to week 130.

Robust findings

The randomized, double-blind, parallel-group ASCENT-COPD trial, which included 3,589 patients (mean age, 67.2 years; 58.7% men), was unique in its goal of evaluating a specific outcome in COPD in a more realistic population.

“Typically, when an inhaled LAMA is tested, the study has a very homogenous, clean population of patients — meaning many of the patients with common comorbidities are excluded. However, it was quite the opposite with ASCENT. We went out to enrich the population with patients who had, as well as COPD, cardiovascular disease or risk factors for cardiovascular disease,” Chapman said.

Consequently, these data are reassuring and suggest that a LAMA should be considered as part of the treatment regimen in patients with COPD in whom cardiovascular risk is a concern, he added.

“The first glance through the data indicated that the overall outcomes of ASCENT were true whether the patient is on an inhaled corticosteroid, a LABA or nothing else. We’re also now looking at the outcome relative to baseline patient characteristics, such as exacerbation tendency, and once again, the results seem to be the same. All of this is very encouraging. The last thing you want is to go through the data and discover that some tiny subset of patients was responsible for your major outcomes. However, we seem to have very robust findings,” Chapman said. – by Melissa Foster

Reference s :

Chapman KR. Abstract 2443.

Wise RA. Abstract 2451. Both presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

For more information:

Kenneth R. Chapman, MD, MSc, can be reached at ken.chapman.airways@gmail.com.

Disclosure s: ASCENT-COPD was initially funded by Forest Laboratories and later funded by AstraZeneca and Circassia. Chapman reports he received reimbursement from AstraZeneca for the study. Wise reports he has received personal fees from Aradigm, AstraZeneca, Bonti, Circassia, Contrafect, Denali, Kinks’, 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.

DALLAS — Aclidinium reduces moderate to severe exacerbations without increasing cardiovascular event risk in patients with chronic obstructive pulmonary disease, regardless of beta-blocker use or background treatment with long-acting beta-agonists with or without an inhaled corticosteroid, new data presented at the American Thoracic Society International Conference suggest.

As Healio Pulmonology previously reported, an on-treatment analysis published in JAMA showed significantly lower annual rates of moderate to severe COPD exacerbations and exacerbations requiring hospitalization in patients treated with aclidinium (Tudorza, AstraZeneca and Circassia), as compared with placebo, during the first year of treatment. The risk for the primary safety composite outcome of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, also did not differ significantly between the treatment and placebo groups over 3 years.

“Despite some early concerns about the use of anticholinergics generally, and more recently long-acting muscarinic agonists (LAMAs), and their safety in patients, when we look at a high-risk population in terms of cardiovascular disease, we don’t see a safety signal, at least with this particular anticholinergic,” Kenneth Chapman, MD, MSc, professor of medicine at the University of Toronto and director of the Asthma Airway Center at the University Health Network, told Healio Pulmonology.

Benefits in beta-blocker users

In one of the new analyses presented at the ATS International Conference, Chapman and colleagues specifically evaluated outcomes in patients who were using beta-blockers at baseline, including 627 in the aclidinium group and 642 in the placebo group.

They found that the risk for MACE was not increased with aclidinium, as compared with placebo, in both patients on beta-blockers (HR = 1.01; 95% CI, 0.62-1.64) and those not on beta-blockers (HR = 0.8; 95% CI, 0.51-1.24), with no significant difference between beta-blocker users and nonusers (P = .483).

Similarly, the all-cause mortality risk was no higher with aclidinium than placebo in both beta-blocker users (HR = 1.13; 95% CI, 0.68-1.74) and nonusers (HR = 0.89; 95% CI, 0.62-1.26), with no substantial difference in risk between beta-blocker users and non-users (P = .352).

Moreover, aclidinium, as compared with placebo, reduced the moderate or severe COPD exacerbation rate by 25% in beta-blocker users (HR = 0.75; 95% CI, 0.6-0.94) and 21% in nonusers (HR = 0.79; 95% CI, 0.67-0.93), with no difference in treatment effect (P = .753). Aclidinium also delayed time to first moderate or severe COPD exacerbation in both groups.

PAGE BREAK

Interestingly, Chapman said, both beta-blocker users and nonusers had improved forced expiratory volume in 1 second (FEV1) from baseline with aclidinium vs. placebo at all visits, but beta-blocker users benefited more from treatment than nonusers (average improvements, 99 mL vs. 69 mL; P for interaction = .041).

Although the researchers are still analyzing this surprising finding, Chapman noted that it “makes terrific pharmacologic sense.”

“A common background therapy for many of our patients at baseline included long-acting beta-agonist (LABA) with an inhaled corticosteroid. It’s sensible to say that patients taking a beta-blocker for prevention of myocardial reinfarction, for instance, blunted the benefit of the beta-agonist in their regimen so they did not achieve optimal control with that single agent, and those patients then benefited from the LAMA, which bronchodilates by a different mechanism,” he told Healio Pulmonology.

Treatment effect against background therapy

In another analysis presented at the meeting, the researchers also sought to assess the effects of aclidinium in the context of background therapy with LABA with or without inhaled corticosteroid therapy.

Of the 2,285 patients on a LABA with or without an inhaled corticosteroid in the study, 1,127 were assigned aclidinium and 1,158 were assigned placebo.

Among those receiving a LABA with or without an inhaled corticosteroid at baseline, aclidinium, as compared with placebo, significantly reduced the rate of moderate to severe exacerbations per patient per year (RR = 0.76; 95% CI, 0.65-0.89) and the rate was similar to that seen in the overall population (RR = 0.78; 95% CI, 0.68-0.89).

The same was true for patients receiving a concomitant LABA with or without inhaled corticosteroids in the aclidinium group vs. the placebo group (RR = 0.77; 95% CI, 0.66-0.89).

FEV1 also improved from baseline with aclidinium, as compared with placebo, from week 4 to 78 (P < .001), and numerical improvements were observed at week 104 (39 mL) and week 156 (53 mL) — improvements that were comparable to those seen in the overall population (range, 54 mL to 91 mL; P < .001 for all).

Numerical improvements from baseline were seen in COPD Assessment Test scores with aclidinium vs. placebo at all time points in those on a LABA with or without an inhaled corticosteroid at baseline and in the overall study population up to week 130.

Robust findings

The randomized, double-blind, parallel-group ASCENT-COPD trial, which included 3,589 patients (mean age, 67.2 years; 58.7% men), was unique in its goal of evaluating a specific outcome in COPD in a more realistic population.

PAGE BREAK

“Typically, when an inhaled LAMA is tested, the study has a very homogenous, clean population of patients — meaning many of the patients with common comorbidities are excluded. However, it was quite the opposite with ASCENT. We went out to enrich the population with patients who had, as well as COPD, cardiovascular disease or risk factors for cardiovascular disease,” Chapman said.

Consequently, these data are reassuring and suggest that a LAMA should be considered as part of the treatment regimen in patients with COPD in whom cardiovascular risk is a concern, he added.

“The first glance through the data indicated that the overall outcomes of ASCENT were true whether the patient is on an inhaled corticosteroid, a LABA or nothing else. We’re also now looking at the outcome relative to baseline patient characteristics, such as exacerbation tendency, and once again, the results seem to be the same. All of this is very encouraging. The last thing you want is to go through the data and discover that some tiny subset of patients was responsible for your major outcomes. However, we seem to have very robust findings,” Chapman said. – by Melissa Foster

Reference s :

Chapman KR. Abstract 2443.

Wise RA. Abstract 2451. Both presented at: American Thoracic Society International Conference; May 17-22, 2019; Dallas.

For more information:

Kenneth R. Chapman, MD, MSc, can be reached at ken.chapman.airways@gmail.com.

Disclosure s: ASCENT-COPD was initially funded by Forest Laboratories and later funded by AstraZeneca and Circassia. Chapman reports he received reimbursement from AstraZeneca for the study. Wise reports he has received personal fees from Aradigm, AstraZeneca, Bonti, Circassia, Contrafect, Denali, Kinks’, 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.

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