GINA 2019–2020 updates: Improving management of mild asthma with as-needed ICS/LABA
Inhaled short-acting β2-agonist (SABA) therapy has been the mainstay of treatment for asthma. The Global Initiative for Asthma (GINA) now recommends as-needed use of low-dose inhaled corticosteroid (ICS)–containing controller treatment to prevent exacerbations and control symptoms of mild asthma. At a recent webinar, Professor Helen Reddel of University of Sydney, Australia, discussed GINA’s fundamental updates in management of mild asthma in primary care and the role of as-needed ICS/long-acting
β2 adrenoceptor agonist (LABA) combination therapy (eg, budesonide-formoterol) as a preferred controller in
adults and adolescents aged ≥12 years with mild asthma.
Risks of regular use or overuse of SABA
“For years, SABA inhalers have been the mainstay of treatment for patients with asthma as they provide rapid symptom relief,” said Reddel.
Nevertheless, a randomized study (n=55) showed that regular use of inhaled terbutaline (500–1,000 µg QID) was associated with a temporary increase in morning peak flows (p<0.01) and a greater-than-expected rise in evening peak flows for the first 2 days of treatment (p<0.001) vs placebo, suggestive of development of tolerance to SABA. Rebound bronchoconstriction was also observed, reflected by a fall in morning peak flows on treatment withdrawal (p<0.05) vs placebo. These effects were likely mediated by β-receptor downregulation. An increase in eosinophilic airway inflammation (p=0.049) was also observed with regular use of terbutaline (1 mg QID) vs placebo in a randomized crossover study (n=52). [Respir Med 2000;94:767-771; Am J Respir Crit Care Med 2000;161:1459-1464]
“A treatment paradox thus exists with regular SABA use, and patients often feel the need for extra doses of SABA,” said Reddel.
“SABA use, even at a level not often regarded as excessive, may also pose harm to patients. The use of ≥1.4 SABA canisters [20,000 µg each] per month was shown to be associated with a drastic increase in risk of asthma-related death. At the same time, paediatric use of ≥3 SABA canisters per year and adult use of ≥2 SABA canisters per quarter was associated with a doubled risk of asthma-related emergency department visit or hospitalization vs patients using <3 and <2 SABA canisters, respectively, after adjustment for asthma severity,” she continued. [Am J Respir Crit Care Med 1994;149:604-610; Ann Allergy Asthma Immunol 2012;109:403-407]
Results of the webinar poll in Hong Kong (n=110) showed that 45 percent of clinicians were very likely and 45 percent were likely to discuss the risks of SABA overuse and over-reliance with their asthma patients.
AEs of oral CS
“Emerging evidence on the adverse effects [AEs] of oral corticosteroids [OCS] is also of concern,” said Reddel.
For example, a US population-based cohort study showed that use of a single short course of OCS was associated with a significant increase in rates of sepsis (incidence rate ratio [IRR], 5.30; 95 percent confidence interval [CI], 3.80 to 7.41; p<0.001), venous thromboembolism (IRR, 3.33; 95 percent CI, 2.78 to 3.99; p<0.001) and fracture (IRR, 1.87; 95 percent CI, 1.69 to 2.07; p<0.001) within the first 30 days. [BMJ 2017;357:j1415]
Similarly, a long-term observational study of patients with active asthma showed that OCS users had an increased risk of osteoporosis/osteoporotic fracture (adjusted hazard ratio [aHR], 3.11; 95 percent CI, 1.87 to 5.19), pneumonia (aHR, 2.68; 95 percent CI, 2.30 to 3.11) and cardio-/cerebrovascular diseases (aHR, 1.53; 95 percent CI, 13.6 to 1.72) compared with non-OCS users. There was a dose-response relationship between cumulative OCS exposure and adverse outcomes, such as type 2 diabetes, for those with ≥4 lifetime OCS courses (aHR, 1.37; 95 percent CI, 1.18 to 1.58). [J Asthma Allergy 2018;11:193-204]
As-needed budesonide-formoterol reduces exacerbation, controls symptoms
In 2019, GINA updated its guidelines to recommend the use of as-needed low-dose ICS-formoterol combination therapy (ie, budesonide-formoterol) as a preferred controller option for asthma step 2 treatment in adults and children aged ≥12 years. [https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf; Ann Allergy Asthma Immunol 2020;124:311-313]
“The decision was made based on four high-quality clinical trials,” stressed Reddel.
SYGMA 1 & 2 trials
In the 12-month, double-blind SYGMA 1 trial, patients aged ≥12 years (n=3,836; mean age, 39.6 years; female, 61.1 percent) with mild asthma were randomized (1:1:1) to receive placebo BID plus as-needed terbutaline 0.5 mg (terbutaline group; n=1,277), placebo BID plus as-needed combination of budesonide 200 µg and formoterol 6 µg (budesonide-formoterol group; n=1,277), or budesonide BID plus as-needed terbutaline (budesonide maintenance group; n=1,282). An initial run-in period of 2–4 weeks with as-needed terbutaline alone was included. [N Engl J Med 2018;378:1865-1876]
At baseline, patients had uncontrolled asthma symptoms (mean five-item Asthma Control Questionnaire [ACQ-5] score, 1.57), with a mean bronchodilator reversibility and mean forced expiratory volume in 1 second (FEV1) of 14.6 percent and 84.18 percent, respectively.
As-needed budesonide-formoterol led to 14 percent improvement in the primary outcome of symptom control (measured according to the percentage of electronically recorded weeks with well-controlled asthma) vs as-needed terbutaline (mean, 34.4 percent vs 31.1 percent; odds ratio, 1.14; 95 percent CI, 1.00 to 1.30; p=0.046).
In addition, severe exacerbations were reduced by 64 percent with as-needed budesonide-formoterol vs as-needed terbutaline (annualized exacerbation rate [AER], 0.07 vs 0.20; rate ratio [RR], 0.36; 95 percent CI, 0.27 to 0.49; p<0.001), and by 17 percent with as-needed budesonide-formoterol vs budesonide maintenance (AER, 0.07 vs 0.09; RR, 0.83; 95 percent CI, 0.59 to 1.16; p=0.28) (Figure 1).
The time to first severe exacerbation was also significantly prolonged with as-needed budesonide-formoterol vs as-needed terbutaline (HR, 0.44; 95 percent CI, 0.33 to 0.58; p<0.001) and budesonide maintenance (HR, 0.90; 95 percent CI, 0.65 to 1.24; p=0.52). (Figure 2)
Similar results in terms of AER of severe exacerbations were observed with as-needed budesonide-formoterol vs budesonide maintenance (AER, 0.11 vs 0.12; RR, 0.97; 95 percent CI, 0.78 to 1.20; p=0.75) in the SYGMA 2 trial (n=4,176), designed in parallel with SYGMA 1 but with a more pragmatic approach without daily reminders for maintenance medication. [N Engl J Med 2018;378:1877-1887]
In both SYGMA 1 and SYGMA 2, patients treated with as-needed budesonide-formoterol were exposed to far less ICS than those receiving budesonide maintenance (median metered daily ICS dose: 57 µg vs 340 µg in SYGMA 1, 66 µg vs 267 µg in SYGMA 2). [N Engl J Med 2018;378:1865-1876; N Engl J Med 2018;378:1877-1887]
Novel START & PRACTICAL trials
A consistent benefit in reducing severe exacerbations with as-needed budesonide-formoterol vs as-needed albuterol 100 µg (AER, 0.195 vs 0.400; relative rate, 0.49; 95 percent CI, 0.33 to 0.72; p<0.001) was demonstrated in the Novel START trial (n=668). Furthermore, the fractional exhaled nitric oxide (FENO) level was significantly reduced in the as-needed budesonide-formoterol vs albuterol group (ratio of geometric means, 0.83; 95 percent CI, 0.75 to 0.91). [N Engl J Med 2019;380:2020-2030]
In the PRACTICAL trial (n=885), as-needed budesonide-formoterol was noninferior to budesonide maintenance plus as-needed terbutaline with respect to severe exacerbations (AER, 0.119 vs 0.172; relative rate, 0.69; 95 percent CI, 0.48 to 1.00; p=0.049). Prespecified analysis showed that the benefit of as-needed budesonide-formoterol with respect to severe exacerbations was independent of baseline inflammatory characteristics (ie, logarithm FENO [pinteraction=0.68] and eosinophil count [pinteraction=0.95], suggesting that inflammatory profiling is not needed for prescription of as-needed ICS-formoterol treatment. [Lancet 2019;394:919-928; https://ginasthma.org/wp-content/uploads/2019/06/GINA-2019-main-report-June-2019-wms.pdf]
“The 12-month open-label Novel START and PRACTICAL trials were designed without the use of placebo BID to better reflect real-world asthma management in the clinic,” noted Reddel. [N Engl J Med 2019;380:2020-2030; Lancet 2019;394:919-928]
“The safety profile of budesonide-formoterol is well established, with no new signs among patients with mild asthma use as-needed budesonide-formoterol for an average of 3–4 times per week,” she added.
As-needed budesonide-formoterol relieves symptoms, prevents exercise-induced bronchoconstriction
“ICS-LABA combinations, such as budesonide-formoterol, can be used as-needed for symptom relief in adults and adolescents aged ≥12 years with persistent asthma, based on results of a recent meta-analysis showing an association between maintenance and reliever therapy [MART] and reduction in risk of asthma exacerbations compared with the same dose or a higher dose of ICS and LABA as controller therapy [same dose, risk ratio, 0.68; 95 percent CI, 0.58 to 0.80] [higher dose, risk ratio 0.77; 95 percent CI, 0.60 to 0.98],” said Reddel. [JAMA 2018;319:1485-1496]
Low-dose as-needed budesonide-formoterol can also be considered prior to exercise. In a 6-week randomized trial in 66 patients with asthma, as-needed budesonide-formoterol was as effective as regular budesonide in decreasing exercise-induced bronchoconstriction, as shown by a similar maximum post-exercise FEV1 fall between the two groups, with a superior effect vs as-needed terbutaline. The total budesonide dose was approximately 2.5 times lower in the budesonide-formoterol vs regular budesonide group. [Thorax 2014;69:130-136]