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Comparative Study
. 2025 May 14;22(5):e1004596.
doi: 10.1371/journal.pmed.1004596. eCollection 2025 May.

The comparative effectiveness and safety of fluticasone-salmeterol via metered-dose versus dry powder inhalers for COPD: A new user cohort study

Brandon J Demkowicz  1   2 , Kevin Rader  1 , Shirley V Wang  2   3 , Aaron S Kesselheim  2   3 , William B Feldman  2   3   4
Affiliations
Comparative Study

The comparative effectiveness and safety of fluticasone-salmeterol via metered-dose versus dry powder inhalers for COPD: A new user cohort study

Brandon J Demkowicz et al. PLoS Med. .

Abstract

Background: Fluticasone-salmeterol is available in both metered-dose and dry powder inhaler formulations for the treatment of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers are associated with substantially higher greenhouse gas emissions than dry powder inhalers; however, data on their comparative effectiveness and safety in COPD remain limited. We aimed to compare the effectiveness and safety of fluticasone-salmeterol delivered via metered-dose inhaler (Advair HFA) versus dry powder inhaler (Advair Diskus) among patients with COPD treated in routine care.

Methods and findings: We conducted a retrospective cohort study using Optum's de-identified Clinformatics DataMart (January 1, 2007 to November 30, 2023). The study included 202,052 commercially insured patients aged 40 years or older with COPD who had continuous insurance coverage for 180 days prior to cohort entry and had not initiated any inhaled corticosteroid-long-acting β₂-agonist during that period. Patients receiving fluticasone-salmeterol via a metered-dose inhaler (exposure) were compared to those receiving these drugs via a dry powder inhaler (referent), with stabilized inverse probability of treatment weighting applied for covariate adjustment. The primary effectiveness outcome was the incidence of first moderate or severe COPD exacerbation within 365 days of cohort entry. The primary safety outcome was the incidence of first pneumonia hospitalization during the same period. Use of fluticasone-salmeterol via metered-dose inhaler was associated with a similar hazard of first moderate or severe COPD exacerbation (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.99 to 1.08) and first pneumonia hospitalization (HR, 1.06; 95% CI, 0.98 to 1.14) compared to the dry powder inhaler. Primary study limitations include potential residual confounding despite weighting and short follow-up times.

Conclusions: In this cohort study comparing two brand-name fluticasone-salmeterol inhalers prescribed for COPD in routine clinical practice, effectiveness and safety outcomes were similar for patients receiving metered-dose and dry powder versions.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: BJD reports employment for Health Advances, a private healthcare strategy consulting firm. SVW reports ad hoc consulting for Exponent Inc and MITRE, a federally funded research and development center for the Centers for Medicare and Medicaid. ASK serves on the editorial board of PLOS Medicine. ASK and WBF report serving as consultants for Alosa Health. WBF has served as an expert witness in litigation against inhaler manufacturers.

Figures

Fig 1
Fig 1. Cohort composition.
This graphical representation of cohort composition shows how exclusion criteria were applied prior to cohort entry.
Fig 2
Fig 2. Weighted Kaplan–Meier plot for first moderate or severe COPD exacerbation.
This figure shows the probability of experiencing no moderate or severe COPD exacerbation in the 365 days of follow-up for patients in the CBPS-IPTW-adjusted cohort. The blue curve represents new users of Advair HFA (exposure) while the red curve represents new users of Advair Diskus (referent). Bands represent 95% confidence intervals. The proportionality assumption of the Cox model did not appear violated in the primary effectiveness analysis given a null Schoenfeld residual test (p = 0.2) and parallel curves on the LML plot (S3 Fig).
Fig 3
Fig 3. Weighted Kaplan–Meier plot for first pneumonia hospitalization.
This figure shows the probability of experiencing no pneumonia hospitalization in the 365 days of follow-up for patients in the CBPS-IPTW-adjusted cohort. The blue curve represents new users of Advair HFA (exposure) while the red curve represents new users of Advair Diskus (referent). Bands represent 95% confidence intervals. The proportionality assumption of the Cox model may not hold for the primary safety analysis given a significant Schoenfeld residual test (p = 0.029), though the parallel curves on the LML plot (S4 Fig) suggest that the violation may be minor.
Fig 4
Fig 4. Sensitivity analyses for first moderate or severe COPD exacerbation.
This figure shows the hazard ratios and 95% confidence intervals of first moderate or severe COPD exacerbation in new users of fluticasone-salmeterol metered-dose (Advair HFA) versus dry powder (Advair Diskus) inhalers across a range of prespecified sensitivity analyses. Hazard ratios greater than 1 mean that patients receiving fluticasone-salmeterol metered-dose inhalers have a higher hazard of first moderate or severe COPD exacerbation. *The output of the Cox-based model with death as a competing risk is a risk ratio rather than a hazard ratio, with bootstrap-generated confidence intervals.
Fig 5
Fig 5. Subgroup analyses for first moderate or severe COPD exacerbation.
This figure shows the hazard ratios and 95% confidence intervals of first moderate or severe COPD exacerbation in new users of fluticasone-salmeterol metered-dose (Advair HFA) versus dry powder (Advair Diskus) inhalers across a range of prespecified subgroup analyses. Hazard ratios greater than 1 mean that patients receiving fluticasone-salmeterol metered-dose inhalers have a higher hazard of first moderate or severe COPD exacerbation.
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