• Switching from a metered-dose to a dry-powder inhaler after a formulary change increased emergency department visits and hospitalizations in people with COPD or asthma.
• The absolute changes in risk were small.
• The findings suggested potential harm from the switch, with the medication, the device, and other factors potentially contributing.

Shifting from a metered-dose inhaler to a dry-powder inhaler for chronic obstructive pulmonary disease (COPD) and asthma in one healthcare system formulary led to increased healthcare utilization, a study showed, suggesting potential harm.

Patients who were switched from budesonide-formoterol metered-dose inhaler (Symbicort) to fluticasone-salmeterol dry-powder inhaler (Wixela Inhub) had 5% more all-cause emergency department visits and more hospitalizations as well — increases of 8% overall, 10% respiratory-related, and 24% pneumonia-related — as compared with pre-change rates in a within-person, self-controlled case series.

The absolute differences in hospitalizations in a matched observational cohort of those who switched and those who didn’t were 0.49 percentage points more for switchers overall, 0.41 percentage points more for respiratory causes, and 0.12 percentage points more for pneumonia over 180 days.

These findings suggested “potential harm and the need to reevaluate this policy change,” researchers led by Alexander Rabin, MD, of the Veterans Affairs Ann Arbor Healthcare System in Michigan, reported in JAMA Internal Medicine

Dry-powder inhalers eliminate the hydrofluorocarbon propellants used in metered-dose inhalers, which could reduce healthcare-related greenhouse gas emissions

However, dry-powder inhalers put different demands on patients “Metered-dose inhalers deliver medication to the lungs independent of inspiratory effort but require patients to coordinate actuation with inhalation, whereas dry-powder inhalers rely on rapid, deep inhalation to minimize oropharyngeal deposition, which may be difficult for patients with diminished lung function,” the researchers explained.

Using the “natural experiment” of the Veterans Health Administration’s formulary change in July 2021, the investigators followed outcomes for all 260,268 patients on combination inhaler therapy for treatment of COPD and asthma both before and after the formulary change.

The primary analysis was a self-controlled case series of the 260,268 patients already on budesonide-formoterol before the formulary change who were switched to fluticasone-salmeterol. Their median age was 71 years, 91% were male, and 69% had COPD, while 32% had asthma.

Findings were “robust” across sensitivity and subgroup analyses, the team reported.

Of these patients who switched inhalers and experienced the adverse outcomes of interest, the findings showed that during treatment with fluticasone-salmeterol dry-powder inhaler therapy there were:

• 10% fewer albuterol fills (incidence rate ratio [IRR] 0.90, 95% CI 0.90-0.91)

• 2% more prednisone fills (IRR 1.02, 95% CI 1.01-1.03)

• 5% more all-cause emergency department visits (IRR 1.05, 95% CI 1.04-1.06)

• 8% more all-cause hospitalizations (IRR 1.08, 95% CI 1.06-1.09)

• 10% increased respiratory-related hospitalizations (IRR 1.10, 95% CI 1.07-1.14)

• 24% more pneumonia-specific hospitalizations (IRR 1.24, 95% CI 1.17-1.31)

To eliminate the risk of temporal confounding with a self-controlled analysis and to be able to generate absolute risk differences, the researchers also completed a cohort study with 167,331 patients who switched to fluticasone-salmeterol dry-powder inhaler therapy matched with 91,226 patients who continued receiving other inhaler therapy.

No difference was seen in 90- or 180-day mortality nor in albuterol or prednisone fills between groups.

Limitations of the study included inability to directly measure inhaler use, the largely older male population, and the focus on relatively short-term outcomes.

“A key question raised by our study is whether the increased incidence of adverse outcomes among patients who switched to the dry-powder fluticasone-salmeterol inhaler was associated with the medication, the device, or other factors. The answer likely involves all three factors,” the investigators suggested.

In terms of the medication, industry-sponsored head-to-head comparisons of the two inhaler combinations have shown similar clinical efficacy, but “other studies indicate that fluticasone is associated with a higher pneumonia risk than budesonide, likely due to its more sustained systemic and local immunosuppressive effects,” Rabin and colleagues wrote.

A relative unfamiliarity with dry-powder inhalers might have decreased tolerance, worsening disease control, while “older patients with COPD may also have struggled to generate sufficient inspiratory force for effective dry-powder drug delivery,” the group added. Forced device switching can decrease medication adherence too, with errors in inhalation technique worsening clinical outcomes.

“Implementation strategies likely play a role in lessening the impact associated with inhaler formulary changes: how transitions are implemented may be as important as the choice of drug or device,” the researchers concluded. “Structured inhaler education and clear patient and health care professional communication during formulary changes are essential to minimize interruptions in care. Regular reassessment of inhalation technique and peak flow monitoring may also improve dry-powder drug delivery among patients who switch to this device class.”