Evolving paradigm of asthma management: GINA 2019–2020 updates
Short-acting β-agonists (SABAs) have been used in step 1 treatment of asthma and as rescue medication for the past 30 years, but their overuse has been associated with adverse outcomes. Increasing evidence of the benefits of combination therapy with inhaled corticosteroid (ICS) and fast-onset long-acting β-agonist (LABA) in preventing asthma exacerbations has prompted the Global Initiative for Asthma (GINA) to update the treatment strategy on asthma management. In a recent webinar, Professor J Mark FitzGerald of the University of British Columbia, Canada, provided insights into new directions for asthma management and highlighted fundamental changes in the GINA 2019–2020 reports.
GINA 2019–2020 updates
“One of the major updates in the GINA 2019 and 2020 reports is that SABA-only therapy is no longer described as step 1 treatment. Instead, as-needed low-dose combination of ICS and formoterol is recommended as both controller and reliever therapy in mild asthma. The change is supported by results of randomized controlled trials comparing ICS-formoterol combination therapy with SABA-only therapy and with regular low-dose ICS maintenance plus as-needed SABA in exacerbation prevention,” said FitzGerald. [Global Initiative for Asthma Report 2020, https://ginasthma.org/gina-reports/]
Patients with mild asthma remain at risk of exacerbation
Disease severity is one of the risk factors for asthma exacerbation. According to a UK population-based cohort study (n=424,326), exacerbation rates increased with increasing asthma severity. However, over 30 percent of patients aged 18–54 years and over 50 percent of those aged ≥55 years with mild asthma still experience exacerbations. “There is clear evidence showing that [even] patients with mild asthma are prone to exacerbations, and a significant minority of them will progress to more severe forms of asthma,” noted FitzGerald. [Thorax 2018;73:313-320]
SABA overuse and disease progression
Researchers have identified some treatment paradoxes that may have contributed to the overuse of SABA and underuse of ICS in the current management of asthma. “Asthma is a disease of chronic airway inflammation with increased inflammation during exacerbations. When we prescribed SABA alone as step 1 treatment, the medication provided instant relief of symptoms in most cases. It is cheap and patients used it only when symptoms worsened. However, when SABA was not controlling their symptoms, they were advised to use an ICS fixed-dose regimen and to minimize SABA use at step 2 and onwards. They were confused because ICS did not provide immediate relief, and they continued to perceive SABA as the medication that provided benefit. The disparity between patients’ understanding of asthma control and their actual symptoms resulted in poor disease control and poor outcomes,” explained Fitzgerald. [Eur Respir J 2017;50:1701103]
A study that followed up 70,829 patients aged 14–45 years with mild asthma for 10 years identified inappropriate use of SABA as one of the most influential determinants for disease progression (odds ratio [OR], 1.79; 95 percent confidence interval [CI], 1.68 to 1.90; p<0.001). Although the majority of patients remained at a mild stage of asthma, 8 percent progressed to moderate or severe asthma over 10 years. “Interestingly, ICS-LABA combination therapy was protective against progression to moderate or severe asthma when compared with ICS monotherapy [OR, 0.92; 95 percent CI, 0.87 to 0.97],” pointed out FitzGerald. [J Allergy Clin Immunol Pract 2018;6:2024-2032]
SABA overuse linked to increased exacerbation and mortality
Data from Swedish national registries, which followed up 365,324 asthma patients for an average of 85.4 months, showed that higher numbers of collected SABA canisters were associated with increased risk of exacerbation (3–5 canisters: hazard ratio [HR], 1.26; 95 percent CI, 1.24 to 1.28) (6–10 canisters: HR, 1.44; 95 percent CI, 1.41 to 1.46) (≥11 canisters: HR, 1.77; 95 percent CI, 1.72 to 1.83). Higher SABA use also showed a dose-dependent association with increased risk of all-cause, respiratory-related and asthma-related mortality. (Figure 1) [Eur Respir J 2020;55:1901872]
As-needed budesonide-formoterol reduces exacerbations in mild asthma
The phase III, double-blind, randomized SYGMA-1 study (n=3,849) compared the efficacy and safety of as-needed budesonide-formoterol combination therapy with as-needed SABA alone (terbutaline) and with twice-daily ICS (budesonide) plus as-needed SABA (terbutaline) in patients with mild asthma over the course of 52 weeks. “As-needed budesonide-formoterol was superior to as-needed SABA in asthma symptom control [OR, 1.14; 95 percent CI, 1.00 to 1.30; p=0.046]. Importantly, it resulted in a substantially lower daily ICS load [83 percent lower] when compared with ICS maintenance therapy,” noted FitzGerald. [N Engl J Med 2018;378:1865-1876]
SYGMA-2 was a phase III, double-blind, randomized study (n=4,215) that compared the efficacy and safety of as-needed budesonide-formoterol and twice-daily maintenance therapy with budesonide plus as-needed terbutaline in mild asthma over 52 weeks. Results showed that as-needed budesonide-formoterol was noninferior to budesonide maintenance therapy in terms of annualized rate of severe exacerbations (0.11 vs 0.12; rate ratio, 0.97). Consistent with SYGMA-1, the median daily metered dose of ICS was lower in the budesonide-formoterol vs budesonide maintenance group (66 µg vs 267 µg). [N Engl J Med 2018;378:1877-1887]
Another 52-week, randomized, open-label, controlled trial in adult patients with mild asthma (n=668) also showed a similar annualized exacerbation rate between as-needed budesonide-formoterol and budesonide maintenance therapy (0.195 vs 0.175; p=0.65). Notably, the number of severe exacerbations was lower in the budesonide-formoterol group than in the budesonide maintenance group. (Figure 2) [N Engl J Med 2019;380:2020-2030]
In an open-label, randomized controlled, pragmatic trial (n=890) (PRACTICAL study), patients with mild to moderate asthma previously treated with SABA for symptom relief with or without maintenance ICS received either as-needed budesonide-formoterol or maintenance budesonide plus as-needed terbutaline. After 52 weeks of treatment, patients receiving as-needed budesonide-formoterol had a significantly decreased exacerbation rate as well as a 42 percent reduction in mean daily steroid load compared with those receiving budesonide maintenance therapy. (Figure 3) “With the as-needed combination therapy, there was no difference in underlying airway inflammation in terms of fraction of exhaled nitric oxide even when the patients were using only half as much ICS, when compared with ICS monotherapy,” added FitzGerald. [Lancet 2019;394:919-928]
Patients with mild asthma are still at risk of exacerbations. SABA-only therapy, previously prescribed as step 1 treatment, is associated with adverse outcomes. ICS is the cornerstone of asthma treatment because it treats the underlying airway inflammation. New data show that as-needed ICS-LABA (budesonide-formoterol) combination therapy significantly reduces the risk of severe exacerbation vs as-needed SABA alone or ICS maintenance therapy, with a lower daily ICS load compared with ICS maintenance.
In addition, as-needed budesonide-formoterol can improve patients’ adherence because it provides rapid symptom relief and reduces exacerbation risk without the need for daily use, especially in patients with mild asthma and infrequent symptoms.
Maintenance and as-needed ICS-LABA combination therapy is preferred for patients with persistent asthma with a history of exacerbation, and represents a new treatment strategy as recommended in the updated GINA report.