October 01, 2019
"The primary recommendation we made is against the use of quick-relief medication — short-acting beta-agonists, or SABA — which has been the first-line treatment for asthma for 50 years," said Helen Reddel, MBBS, PhD, from the Woolcock Institute of Medical Research in Sydney, Australia, who is chair of the GINA science committee.
For safety reasons, short-acting beta-agonists alone are no longer recommended for the quick relief of asthma symptoms, according to the 2019 GINA pocket guide.
The guidelines state that "GINA recommends that all adults and adolescents with asthma should receive ICS [inhaled corticosteroid]-containing controller treatment, to reduce their risk of serious exacerbations and to control symptoms."
For mild asthma, GINA recommends as-needed low-dose formoterol — a long-acting beta-agonist — and, if formoterol is not available, then low-dose inhaled corticosteroids taken whenever a short-acting beta-agonist is taken.
A Paradox for Patients
"The paradox we need to explain is that a short-acting beta-agonist can save your life, but it can also kill you," Reddel told Medscape Medical News.
Until now, daily low-dose inhaled corticosteroids have been recommended for the prevention of mild asthma, along with beta-agonist rescue therapy when needed (J Asthma Allergy. 2010;3:169-176).
But few patients with mild asthma manage adherence to a daily regimen, Reddel explained.
"A daily low dose is highly effective and reduces hospitalization by one-third and results in half the deaths," Reddel told a packed audience here at the European Respiratory Society 2019 International Congress. However, "adherence is only around 25% to 35%, and it is much lower in Australia."
Patients prefer reacting when needed rather than using maintenance therapy as a precaution, she said. "They think, 'I have control,' but we know this increases their risk of death."
"These changes are not hasty," she assured the audience, explaining that they are driven by a long history of warnings, as outlined in a summary of the changes (Eur Respir J. 2019;53:1901046).
Building Up to the New Recommendations
Two previous reports raised the alarm that short-acting beta-agonists alone might do more harm than good after the isoprenaline and fenoterol asthma epidemics of the 1960s and 1970s.
A 1994 study showed that the risk for asthma death escalates drastically when a patient uses 1.4 canisters (20,000 µg each) per month of inhaled beta-agonists (Am J Respir Crit Care Med. 1994;149[3 Pt 1]:604-610).
And a 2001 study showed that use of nebulized bronchodilators or oral steroids is significantly more likely to cause asthma death (Am J Respir Crit Care Med. 2001;163:12-18). In fact, the blood of patients who died had salbutamol concentrations 2.5 times higher than that of control subjects.
In 2014, GINA started calling for precautions, saying that short-acting beta-agonist treatment should be restricted to asthma patients who have symptoms no more than twice a month and who have no risk factors for exacerbation, but noted that more evidence was needed. Reddel was involved in two subsequent studies that looked at this issue.
In 2018, a study showed a 64% reduction in severe exacerbations with the combination of the corticosteroid budesonide plus formoterol, compared with terbutaline, a short-acting beta-agonist (N Engl J Med. 2018;378:1865-1876).
Another 2018 study showed that the budesonide plus formoterol combination used on an as-needed basis was noninferior to budesonide maintenance therapy for patients with severe exacerbations (N Engl J Med. 2018;378:1877-1887).
Since then, more studies have shown that the combination of inhaled corticosterioids plus formoterol on an as-needed basis effectively relieves symptoms. "We published the guidelines in April with evidence from 7000 patients, Reddel told Medscape Medical News. "And we now have data from nearly 10,000 patients."
A recent study from New Zealand, which showed that as-needed budesonide plus formoterol is superior to maintenance low-dose budesonide plus an as-needed reliever inhaler (Lancet. 2019;394:919-928), provides evidence that supports the new recommendations.
That research will be presented at the congress by one of the investigators, Christina Baggott, MBChB, from the Medical Research Institute of New Zealand in Wellington.
"These guidelines will help circumvent some reliever overuse and preventer underuse," she said.
"We have already seen results of the SYGMA1 [NCT02149199] and SYGMA2 [NCT02224157] studies," she told Medscape Medical News. However, "we were surprised that we got significant results — just significant — showing superiority" for as-needed budesonide plus formoterol.
Clinicians need to sit down with their patients to discuss the best regimen for them, she explained. "What are your priorities? What do you prefer?" Are you the kind of person who likes to take something every day, or someone who likes to react more when you have a symptom?
Further Precautions Proposed
"Using a long-acting beta-agonist without an ICS in asthma is clearly unsafe," said Sebastian Johnston, MBBS, PhD, from Imperial College London, who presented data on the drugs.
And evidence "suggests that overusing a short-acting beta-agonist without an ICS is also clearly unsafe. I suspect that it kills people with asthma," he added.
But Johnston said he thinks the GINA precaution should go a step further to ensure that patients don't have the opportunity to take a short-acting beta-agonist on its own.
Beta-agonists, "for safety reasons, should be banned and replaced with beta-agonist–ICS combination therapy in the same inhaler so that patients cannot take a beta-agonist without at the same time taking a steroid," he said.
However, he did acknowledge that is a controversial idea.
Reddel reports financial relationships with AstraZeneca, GlaxoSmithKline, Novartis, Teva, Mundipharma, and Boehringer Ingelheim. Johnston has disclosed no relevant financial relationships. Baggott reports receiving educational fees from AstraZeneca and Boehringer.