Associate Professor of Medicine and an attending physician in the Division of Pulmonary, Critical Care, Sleep Medicine, Clinical Immunology & Allergy at UCLA. He also serves as director of the Pharmaceutical Policy & Outcomes Lab.

William Feldman, MD

In an emulated target trial using nationwide health claims data, patients with 

chronic obstructive pulmonary disease (COPD)

 who started maintenance azithromycin had a lower risk of moderate or severe exacerbations than those started on roflumilast, according to William B. Feldman, MD, MPH, PhD, a pulmonologist and health services researcher at UCLA Health. Feldman told HCPLive the analysis, published in 

, drew on Optum Clinformatics claims data from March 2011 to August 2024 and centered on a primary analysis of 7550 propensity-score-matched pairs.

“This was a target trial emulation where we used a large longitudinal healthcare claims database to ask the question of whether we see different clinical outcomes in patients with COPD who receive azithromycin versus roflumilast,” Feldman said, noting both drugs are approved to prevent exacerbations but had never been compared head-to-head. He said the study, pre-registered on the Open Science Framework, used propensity score matching across a range of covariates, along with sensitivity analyses, to limit confounding inherent to observational data. Results are also expected soon from RELIANCE, an ongoing randomized controlled trial directly comparing the 2 therapies; Feldman said his findings are meant to complement, not substitute for, that trial.

William Feldman, MD: Azithromycin Over Roflumilast in Real World COPD Data

In a secondary analysis restricted to the 2454 patients who met RELIANCE's inclusion and exclusion criteria, propensity matching yielded 714 pairs, and azithromycin was again associated with a lower risk of first all-cause hospitalization or death (hazard ratio, 0.83; 95% CI, 0.72-0.95; number needed to treat, 15; 95% CI, 9-46) compared with roflumilast.

 Feldman said prespecified subgroup analyses, including by prior COPD hospitalization and eosinophil count, showed broadly consistent treatment effects, an important distinction now that biologic therapies are available for patients with elevated eosinophils who would not otherwise be candidates for azithromycin or roflumilast.

How should clinicians interpret the findings?

Feldman was careful to flag the study's limits. The analysis measured only exacerbation risk, not safety: azithromycin carries known risks of QT prolongation and hearing changes, while roflumilast is more commonly associated with gastrointestinal side effects, neither of which was captured in the claims data. Follow-up time was also shorter than ideal, he said, since many patients discontinued therapy before the 1 to 2 years he would have preferred to observe.

Feldman said the findings are meant to help guide treatment decisions while clinicians and patients await RELIANCE's results. “In COPD, we don’t get a lot of new therapies that hit the market,” he said. “So I think really drilling down into the kind of optimal treatment algorithms with therapies that we have is quite important.”

Feldman WB, et al. Comparative effectiveness of azithromycin versus roflumilast in patients with chronic obstructive pulmonary disease: emulated target trial. 

 2026;394:e100111. doi:10.1136/bmj-2026-100111

Krishnan JA, Holbrook JT, Sugar EA, et al. Rationale and design of the roflumilast or azithromycin to prevent COPD exacerbations clinical trial. 

 2026;13(1):17-28. doi:10.15326/jcopdf.2025.0669

Articles

Nationwide claims-based target trial emulation compared maintenance azithromycin versus roflumilast for COPD exacerbation prevention using Optum Clinformatics data (2011–2024). In 7550 propensity-score–matched pairs, azithromycin initiation was associated with lower risk of moderate or severe exacerbations. A RELIANCE-eligible subset (714 matched pairs) similarly favored azithromycin for first all-cause hospitalization or death (HR 0.83; NNT 15). Interpretation is constrained by observational confounding, limited follow-up due to discontinuation, and lack of captured safety outcomes.

Feldman, of UCLA Health, discusses a target trial emulation finding azithromycin outperformed roflumilast at preventing COPD exacerbations.