SMART Therapy for Asthma: Press Gas or Hit the Brakes?

HONOLULU — Although single maintenance and reliever therapy (SMART, or MART) marks a new chapter in asthma treatment, its advocates acknowledged practical limitations during a debate at the CHEST annual meeting hosted by the American College of Chest Physicians.

“SMART therapy is recommended. It is effective and it is simple and there is no doubt about that,” said Shahid Sheikh, MD, of Nationwide Children’s Hospital in Columbus, Ohio. He noted however, that it comes with costs and patients may experience insurance issues trying to get multiple inhalers every month.

After all, without an official FDA approval for use on a daily and as-needed basis for moderate to severe persistent asthma, SMART therapy — use of a single inhaler containing inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) formoterol for both maintenance and quick reliever therapy — is squarely off-label.

Budesonide/formoterol (Symbicort), the one such formulation embraced for SMART, is officially only FDA approved as maintenance, not as-needed acute therapy in asthma.

This is despite SMART therapy receiving a strong backing from national guidelines nearly 3 years ago, and being known to reduce severe asthma exacerbations compared with using ICS alone or with LABA alone, as described by Jerry Krishnan, MD, PhD, of University of Illinois Chicago, who took the pro-SMART position of the debate.

Sheikh cautioned against opening the floodgates to maintenance-reliever therapy in one inhaler and made the case that regulatory approval may not necessarily be the right thing to do.

Since 2022, the Global Initiative for Asthma (GINA) group has endorsed as-needed ICS/formoterol in people with mild asthma, even though the effectiveness of ICS or SMART is less clear in these people than in those with moderate-severe asthma.

Sheikh cited an estimate that it would cost at least $1.5 million to prevent one hospitalization in a low-risk population with mild asthma requiring no more than one inhaler a year. This is too high a cost, he suggested to the audience at CHEST.

What’s more, with an ICS/formoterol inhaler costing approximately $500, a new indication for SMART for the 13 million Americans with intermittent asthma in the U.S. alone would certainly burden healthcare systems, Sheikh said. “Worldwide there are 130 million patients with intermittent asthma. You can do the math.”

Overtreatment with corticosteroids may also be a concern if patients exceed the SMART allowance for up to 12 puffs of ICS/formoterol a day.

Krishnan argued that “if you’re preventing severe exacerbations, then you’re reducing actually using systemic therapies. There are studies that have shown that if you use SMART therapy, you end up overall having less systemic corticosteroid use for a 12-month period, where obviously the dose is substantially higher.”

The usual prescribing for budesonide/formoterol (160/4.5 mcg) is, for step 3 therapy, one inhalation once or twice a day and another inhalation as-needed for symptoms; for step 4 therapy, it is two inhalations twice a day plus one inhalation as-needed for symptoms, according to Krishnan.

“Now are there chances somebody will overuse it and get in trouble? Absolutely. You can see that for any medication that has been prescribed,” he said.

Sheikh noted the risk of overuse if the patient is not improving. It remains to be seen if such overuse causes QTc issues and arrhythmias, he said, adding that the literature on SMART is comprised of studies testing different doses and largely with dry powder inhalers, not the metered-dose inhalers that are the norm in the U.S.

Further adding to the complexity of therapy is that SMART is usually given only in outpatient settings, whereas inpatient care follows separate guidelines, the speaker said.

There is also the question of whether relying on this strategy can lead to delays in giving oral steroids to people who really need them, he added.

Krishnan cautioned that SMART does not refer to ICS and any LABA in one inhaler, but formoterol specifically. He emphasized that formoterol is unlike short-acting beta agonists (SABAs) and other LABAs, being more like a hybrid with both SABA- (rapid onset of bronchodilation) and LABA-like effects (long-acting bronchodilation).

The first generic version of budesonide/formoterol was FDA approved in 2022.

SMART was first endorsed by the NHLBI National Asthma Education and Prevention Program guidelines in late 2020, when the group gave this single-inhaler approach a strong recommendation with high certainty for patients 12 years of age or older and moderate certainty for 4 to 11 years of age requiring step 3 and step 4 therapy for asthma.

“The most important part of these guidelines, and any guidelines is that if your patient is doing fine, please leave them alone,” Sheikh said to audience applause and laughter. “Because at the end, the outcomes may not be what we desired.”

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