CHEST Annual Meeting
CHEST Annual Meeting
October 25, 2019
3 min read

Triple combination COPD therapy beneficial in patients without exacerbation history

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NEW ORLEANS — A subgroup analysis of the KRONOS study showed the reduction in COPD exacerbations observed with the triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler, as compared with a dual bronchodilator, was not driven by patients with a history of prior exacerbations.

In fact, the results of the subgroup analysis, which was restricted to patients without a history of prior exacerbations, were comparable to those from the overall study population, according to Fernando J. Martinez, MD, FCCP, from Weill Cornell Medicine and NewYork-Presbyterian Weill Cornell Medical Center.

“I was surprised when I saw these results; I did not anticipate that to be the case. It’s clear that the effect of this particular triple therapy did not really appear to be dramatically different based on whether a patient has a prior history of exacerbations or not,” he said during a presentation of the data at the CHEST Annual Meeting.

The KRONOS study was designed to evaluate lung function changes, not exacerbations, in low-risk patients with COPD treated with one of four therapies: budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler, glycopyrrolate/formoterol fumarate metered-dose inhaler, budesonide/formoterol fumarate metered-dose inhaler or budesonide/formoterol fumarate dihydrate dry powder inhaler. As such, the 6-month, randomized, double-blind, phase 3 trial, which was conducted for registrational purposes, did not require patients to have a history of exacerbations during the previous year.

“This is important for those of us who are trying to figure out how to use inhaled steroids in this patient population,” Martinez said, noting that controversy persists about whether inhaled corticosteroids are being used appropriately in patients with COPD. “This particular analysis is trying to define whether the benefit that we’ve seen with an inhaled steroid added to dual bronchodilation in the KRONOS study related to the 25% of patients who did have a prior history of exacerbation.”

Approximately three-quarters of the 1,896 patients in the KRONOS modified intention-to-treat population had no history of exacerbations in the previous year. Patient demographics for those who did and those who did not have an exacerbation history were similar and comparable among treatment groups.

In patients without prior exacerbations, the incidence rate ratio (IRR) of moderate or severe exacerbations was 0.52 (95% CI, 0.37-0.72) with triple therapy vs. glycopyrrolate/formoterol fumarate, which was similar to that observed in the overall study population (IRR = 0.48; 95% CI, 0.37-0.64) and in patients with prior exacerbations (IRR = 0.42; 95% CI, 0.26-0.67).


Surprisingly, the number needed to treat to prevent an exacerbation was extremely similar between groups — two among patients with a history of prior exacerbation and three among those with no exacerbation history, according to Martinez.

He noted, however, that differences in the rate of exacerbations were more apparent when comparing triple therapy with the steroid-containing regimens, with greater benefit seen in patients with a history of exacerbations.

Triple therapy also yielded nominally significant improvements in lung function, as compared with budesonide/formoterol fumarate, in patients without prior exacerbations, which was comparable with findings from the overall study population.

Treatment-emergent adverse events among this subgroup were also consistent with those seen in the overall population.

“This analysis is more confusing than instructive for me because, in this particular analysis with this particular triple therapy — understanding that it is not a study designed for exacerbation reduction — there was a clear exacerbation reduction effect with the triple therapy compared with the dual bronchodilator, independent of a prior history of exacerbations,” Martinez said.

“These results were very similar to the overall KRONOS study, with the groups behaving very similarly with regard to prior exacerbation history, and there clearly is a suggestion that a triple therapy has a beneficial effect. So, I still remain somewhat unsure of exactly when we would use the triple therapy.”

He added that additional analyses to tease out differences in populations based on other factors, such as eosinophils, are ongoing. – by Melissa Foster


Martinez FJ. Late Breaking Abstracts. Presented at: CHEST Annual Meeting; Oct. 19-23, 2019; New Orleans.

Disclosures: The KRONOS study was funded by AstraZeneca. Martinez reports he has received grants from AstraZeneca; he has received personal fees and nonfinancial support from the American College of Chest Physicians (CHEST), AstraZeneca, Boehringer Ingelheim, Chiesi, Concert, Continuing Education, Genentech, GlaxoSmithKline, Inova Fairfax Health System, Miller Communications, National Association for Continuing Education, Novartis, Pearl (member of the AstraZeneca Group), PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Roche, Sunovion and Theravance; nonfinancial support from ProterixBio; he has received personal fees from the American Thoracic Society, Columbia University, Haymarket Communications, Integritas, inThought Research, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/Medscape and Western Connecticut Health Network; and he has received grants from NIH.