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There was a notable gap in effectiveness between metered-dose and dry-powder formulations of single-inhaler triple therapy for chronic obstructive pulmonary disease (COPD), according to real-world data.

Metered-dose inhaler budesonide-glycopyrrolate-formoterol (Breztri Aerosphere) was associated with a higher risk of a first moderate or severe COPD exacerbation (HR 1.09, 95% CI 1.04-1.14) compared with the dry-powder competitor fluticasone-umeclidinium-vilanterol (Trelegy Ellipta) over median follow-ups of 88 and 113 days, respectively, in a propensity score-matched analysis of claims data from the U.S.

The excess risk with budesonide-glycopyrrolate-formoterol was consistent when researchers separated moderate versus severe COPD exacerbations.

"Our study may provide reassurance to health systems seeking to decrease greenhouse gas emissions by reducing use of metered-dose inhalers, because the single-inhaler triple therapy with the lower carbon footprint ... was also associated with slightly improved clinical outcomes," stated William Feldman, MD, DPhil, MPH, of Brigham and Women's Hospital and Harvard Medical School, both in Boston, and colleagues in .

"Given the added climate impact of metered-dose inhalers, health systems seeking to decrease use of these products may consider steps to promote further prescribing of fluticasone-umeclidinium-vilanterol compared with budesonide-glycopyrrolate-formoterol in people with COPD," they concluded.

The authors reported no safety signal for either inhaler in terms of first admissions to hospital with pneumonia (HR 1.00, 95% CI 0.91-1.10).

Both budesonide-glycopyrrolate-formoterol and fluticasone-umeclidinium-vilanterol provide the guideline-recommended combination of inhaled corticosteroid-long acting muscarinic antagonist (LAMA)-long acting β-agonist (LABA).

The main issue is that budesonide-glycopyrrolate-formoterol is a twice-daily metered-dose inhaler that can benefit COPD patients -- some older studies suggested a lower risk of less pneumonia -- but is known to release hydrofluoroalkane-134a.

This propellant "has 1,430 times the global warming potential as carbon dioxide and contributes to greenhouse gas emissions from metered-dose inhalers that are 20 times greater than the emissions from dry-powder inhalers during the lifecycles of these products," according to Feldman's group.

The other single-inhaler on the market for COPD triple therapy, fluticasone-umeclidinium-vilanterol, is a dry-powder inhaler that does not contain hydrofluoroalkane-134a.

In a 2024 JAMA report, other researchers showed that out of 69.8 million inhaler claims for CMS beneficiaries in 2022, metered-dose inhalers accounted for 49 million claims and 98.3% of their associated carbon dioxide equivalent emissions.

Feldman's team theorized that in the present study, fluticasone-umeclidinium-vilanterol could have resulted in slightly fewer COPD exacerbations as a result of its once-daily dosing (which facilitates better adherence), its simpler operation not requiring timed breaths, or the drugs themselves.

The jury is still out because budesonide-containing dry-powder inhalers for COPD are not on the U.S. market -- and therefore not available for a comparison of dry-powder inhalers containing budesonide versus fluticasone furoate, the investigators noted.

In any case, "Feldman and colleagues' study provides assurance to patients and clinicians when choosing a dry-powder inhaler over a metered-dose inhaler of LABA-LAMA-inhaled corticosteroid in a single inhaler, if clinically appropriate and preferred, with respect to its effectiveness, safety, and carbon footprint," according to Meng-Ting Wang, of National Yang Ming Chiao Tung University in Taipei, Taiwan, and Chen Wei Lin, of Safeway Pharmacy in Lynden, Washington.

"Incorporating an environmentally friendly inhaler into practice needs to be weighed against clinical appropriateness and patients' preferences. More evidence is needed to assess clinical outcomes associated with metered-dose inhalers versus dry-powder inhalers and to develop strategies to safely transition patients with COPD from metered-dose inhaler to dry-powder inhaler based triple therapy," they urged in an .

Feldman and colleagues used U.S. claims gathered through Optum's de-identified Clinformatics Data Mart.

Eligible patients had COPD, were ages 40 or older, and were new initiators of these inhalers from 2021 to 2023. They were allowed to be on monotherapy or dual therapy during the year before cohort entry, but were excluded if they had received either study inhaler or an inhaled corticosteroid-LAMA-LABA combination via separate inhalers.

The cohort included 87,751 individuals, from which investigators pulled 20,388 matched pairs. Average age was 70.8 years, approximately 55% were women, and 73.0% were white, while 12.8% were Black.

The authors acknowledged that some residual confounding was possible due to the study's observational design. "Metered-dose inhalers may be preferred in patients with frailty and poor inspiratory force, and such patients could have been more likely to have exacerbations in follow-up," they explained.

As such, Wang and Lin urged that future research be done on metered-dose inhaler versus dry-powder inhaler triple therapy that controls for the differences of individual drugs and patients' inspiratory flow rates.

Other important study limitations included a lack of analysis of other safety risks of triple therapy (e.g., oral thrush, osteoporosis, and adrenal insufficiency), the high rate of non-persistence to medication, and short follow-up durations.

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