Advantages vary with single- and multiple-inhaler therapies for patients with asthma

Key takeaways:

• Use of a single inhaler with albuterol and corticosteroids as needed reduced exacerbations by 26%.
• As-needed albuterol and inhaled corticosteroids in separate inhalers reduced annual exacerbations by 0.13.

WASHINGTON — The use of single-inhaler and multiple-inhaler therapies for asthma control as needed offers a variety of pros and cons, according to a presentation at the American Thoracic Society International Conference.

However, both approaches still reduce asthma exacerbations, Juan Carlos Cardet, MD, MPH, assistant professor of internal medicine, division of allergy and immunology, University of South Florida Morsani College of Medicine, said during his presentation.

Patients with mild asthma may use single-inhaler inhaled corticosteroids (ICS) with short-acting beta agonists (SABA) as needed, Cardet said, based on the 6-month, double-blind, placebo-controlled BEST trial of 455 adults aged 18 to 65 years with mild asthma.

Juan Carlos Cardet

“The as-needed use of ICS and SABA was as effective as regular use of ICS plus as-needed SABA in terms of peak flow and asthma exacerbation, and both superior to as-needed SABA alone,” Cardet said.

As-needed ICS/SABA treatment also had a less cumulative ICS dose at 17.4 mg than regular ICS use at 18.5 mg (P < .001) and fewer exacerbations than regular use of combination ICS and SABA treatment.

“It comes with less extra ICS, it’s easy to use, and it’s consistent with the existing paradigm of using rescue albuterol,” Cardet said.

This strategy also is approved for controlled therapy in a few countries and soon will be clinically available in the United States, he added. However, Cardet continued, safety and efficacy data are limited, and there have not been any studies involving dry powder inhalers.

The MANDALA trial comprised 3,132 patients aged 12 years and older with uncontrolled moderate to severe asthma who received a medium to high dose of ICS alone or a low to high dose of ICS plus a long-acting beta agonist (LABA) through 112 weeks.

“The higher dose of ICS combined in a single inhaler with albuterol had a 26% reduction in exacerbations relative to albuterol alone,” Cardet said.

Although ICS albuterol is available in a few countries outside the United States, Cardet continued, it is not indicated for as-needed use.

“ICS SABA in a single inhaler is expected to be clinically available in the U.S. in 2024,” Cardet said.

In the BASALT study of 342 adults whose mild to moderate asthma was well controlled with a low-dose ICS and albuterol in separate inhalers, patients received adjustments in their treatment based on physician directives, on their fractional exhaled nitric oxide totals, or on other symptoms.

“There was no significant difference,” Cardet said. “Treatment failure rates were similar across all three groups but were numerically lowest in the ICS plus SABA group for half of the cumulative dose.”

But safety and efficacy data again were limited, and there were no studies involving dry powder inhalers, Cardet said, in addition to other complications.

“There’s the issue of carrying two separate inhalers, which may be confusing or cause nonadherence in patients, and ICS alone is not approved for as-needed use,” Cardet said.

The randomized, single-blind, 15-month PREPARE study of 1,201 Black and “Latinx” patients with moderate to severe asthma also provided evidence for the use of albuterol and ICS in separate inhalers, Cardet said.

Patients using patient-advocated, reliever-triggered inhaled corticosteroids (PARTICS) plus usual care (n = 600) took one puff of their ICS with each puff or albuterol or five puffs of their ICS for each albuterol nebulization.

Compared with participants who followed usual care (n = 601), patients using this intervention experienced an approximately 15% reduction in hazards for exacerbations with little extra ICS use, which Cardet said was significant.

“Or put another way, 0.13 fewer severe exacerbations per person per year, and this effect came at 1.1 additional ICS inhalers compared to usual care,” Cardet said.

The intervention and control groups both had improvements in asthma control, Cardet continued, but only the intervention group had a significant change that was superior to the minimal clinically important difference of 3 in their Asthma Control Test score.

Both groups showed improvements in asthma-related quality of life based on their Asthma Symptom Utility Index scores, but only the intervention group experienced improvements that were superior to the minimum clinically important difference of 0.09, Cardet said.

“PARTICS also resulted in about a 20% reduction in days lost from work, school or usual activities due to asthma compared to the usual-care only group,” Cardet said.

Specifically, the intervention group reported 13.4 days lost, and the control group reported 16.8 days lost (P = .013).

The PREPARE study further noted that PARTICS enabled patients to continue nebulization, including two-thirds of its participants.

“In an ancillary study done with qualitative interviews on 40 nebulizer users from PREPARE, we found that regular use was common at an average of 3.5 times per week, ranging from less than daily to more than six times per day,” Cardet said.

These patients usually had a longstanding history of nebulizer use, mostly at home, sharing their nebulizer with family or friends, Cardet said.

“Most participants preferred nebulizers over inhalers or puffers for severe asthma symptoms and often used them as an attempt to prevent going to the ER or as a strategy to mitigate inhaler costs,” Cardet said.

But while this treatment is easy to use and approved in a few countries, Cardet cautioned, it only has been studied among patients with poorly controlled asthma. Evidence also does not extrapolate well into well-controlled asthma, Cardet said, in addition to the lack of studies with dry powder inhalers.

“This strategy of single inhaler ICS SABA is not studied in patients reliant on rescue nebs, and there can be potential errors in technique and nonadherence due to having multiple inhalers,” Cardet continued. “And ICS alone is not approved for as-needed rescue use, which might cause difficulties in obtaining medication for this strategy in some patients.”

The efficacy of all these strategies compared with other strategies for as-needed ICS is unknown as well, Cardet said, but he expects head-to-head trials to begin soon.

References:

• Calhoun WJ, et al. JAMA. 2012;doi:10.1001/2012.jama.10893.
• Israel E, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2118813.
• Papi A, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa063861.
• Papi A, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2203163.

For more information:

Juan Carlos Cardet, MD, MPH, can be reached at jcardet@usf.edu.