Azithromycin vs Roflumilast: Lowering COPD Exacerbation Risk

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Adults diagnosed with active chronic obstructive pulmonary disease (COPD) initiating maintenance azithromycin demonstrate a lower risk of experiencing a first moderate or severe exacerbation compared to those prescribed roflumilast.1 In a target trial emulation evaluating Optum Clinformatics Data Mart database records from March 2011 to August 2024, researchers propensity-matched 7,550 patients aged 40 years or older receiving oral azithromycin with an equal cohort receiving roflumilast (mean age: 69.7 years; 56% women).1

“I will be more likely now to reach for azithromycin,” stated lead researcher William B. Feldman, MD, MPH, PhD.1 Emphasizing the clinical necessity of the study, Feldman added: “Ultimately, COPD can be a debilitating disease, and we not only need new therapies to treat patients, but we also need more evidence to guide decision-making for therapies that are currently available. This most recent study fits within a broader research portfolio that my co-authors and I have been working on to advance this evidence base.”1

Comparative Efficacy and Clinical Outcomes

Patients treated with azithromycin experienced fewer moderate or severe COPD exacerbations per person-year compared to those on roflumilast (1.1 vs 1.3 events/person-year).1 Azithromycin significantly reduced the risk of a first moderate exacerbation, as well as first all-cause hospital admission or death. However, no statistically significant difference was observed between the two drugs regarding the risk of a first severe exacerbation or overall all-cause mortality.1

Subgroup Analysis and Alignment with Ongoing Research

Subgroup evaluation confirmed a reduced risk of first moderate or severe exacerbations with azithromycin across almost all baseline cohorts, except for two specific populations.1

“Clinical guidelines recommend either maintenance azithromycin or roflumilast for patients with COPD who experience exacerbations despite maximal inhaler therapy,” Feldman noted. “We were interested in completing this study because there is not much evidence for physicians regarding which treatment to select.”1

Addressing how these findings complement the randomized controlled RELIANCE trial, Feldman stated: “Our study will complement findings from RELIANCE in two key ways. One, our data will be available to guide clinicians while we await results from RELIANCE, and two, we examined a broad range of patients with COPD who received azithromycin or roflumilast in routine clinical practice (not just those who would meet the inclusion/exclusion criteria of RELIANCE).”1

In a sub-cohort of 2,454 patients who strictly met the inclusion criteria for the RELIANCE trial (yielding 714 propensity-matched pairs), azithromycin maintained a reduced risk for first all-cause hospital admission or mortality (HR = 0.83; 95% CI, 0.72–0.95; NNT = 15).1 While trends favored azithromycin for moderate and severe exacerbations within this subgroup, the confidence intervals crossed the null value.1

Expert Perspective on Clinical Utility and Safety

Commenting on the implications for practice, Mike Hess, MPH, RRT, RPFT, highlighted that non-specialists are generally more familiar with azithromycin than roflumilast. Hess pointed out that while roflumilast is effective, it is “notorious for having fairly common (and uncomfortable) gastrointestinal side effects, often leading people to discontinue treatment despite the potential benefit.”1

However, Hess emphasized the need to carefully monitor the safety profile of long-term macrolide therapy, specifically pointing to risks such as hearing loss and QT prolongation. Additionally, Hess identified non-adherence and patient misunderstanding as critical hurdles: “Antibiotics are often associated with short-term treatment for acute illness, and people may not have realized that azithromycin was being prescribed for the long haul. That may present an unnecessary barrier to maximum benefit.”1

“More studies are needed to understand the competing safety profiles of these drugs in routine clinical practice,” Feldman concluded. “In general, we need more research examining how to optimize the care of patients with COPD.”1

References

1. Portela GT, Feldman WB, et al. Comparative effectiveness of azithromycin versus roflumilast in COPD exacerbation prevention. BMJ. 2026;394:e100111. doi:10.1136/bmj-2026-100111