Budesonide/formoterol reliever a preferred option for preventing severe exacerbations in mild-to-moderate asthma
The PRACTICAL study investigated the real-world efficacy of budesonide/formoterol (inhaled corticosteroid [ICS]/long-acting β2-agonist [LABA]) combination reliever therapy in mild-to-moderate asthma. The results, presented by the study’s lead author, Dr Jo Hardy of the Medical Research Institute of New Zealand, at the European Respiratory Society (ERS) International Congress 2019, demonstrated superiority of budesonide/formoterol reliever vs low-dose budesonide maintenance plus as-needed terbutiline (short-acting β2-agonist [SABA]) in preventing severe asthma exacerbations. Dr Christer Janson of the Uppsala University, Sweden, presented new data from the SABINA programme, highlighting SABA overuse and the associated increase in mortality risk in a nationwide Swedish asthma cohort (HERA).
“Maintenance ICS treatment can reduce the significant burden of morbidity and mortality in patients with mild-to-moderate asthma. However, in real-world clinical practice, adherence to maintenance ICS is very poor,” said Hardy.
“Budesonide/formoterol combination given as sole reliever therapy, titrated according to symptoms, could be an alternative strategy to overcome the problem of poor adherence,” she suggested.
The SYGMA 1 and 2 randomized controlled trials demonstrated that as-needed budesonide/formoterol reliever therapy was noninferior to maintenance ICS plus SABA reliever in reducing severe exacerbations in patients with mild asthma, whereas the real-world Novel START study showed that as-needed budesonide/formoterol reliever was superior to maintenance ICS plus SABA reliever in reducing severe exacerbation risk. [N Engl J Med 2018;378:1865-1876; N Engl J Med 2018;378:1877-1887; N Engl J Med 2019;380:2020-2030]
PRACTICAL is the second trial designed to reflect real-world practice, comparing budesonide/formoterol anti-inflammatory reliever therapy with current standard of care in mild-to-moderate asthma.
This was a 52-week, randomized, open-label, parallel group trial conducted across 15 facilities in New Zealand. Eligible participants were adults aged 18–75 years who met the criteria for Global Initiative for Asthma (GINA) step 2 treatment. These included patients using SABA for symptom relief with or without maintenance low to moderate doses of ICS in the previous 12 weeks. [Hardy J, et al, ERS 2019; Lancet 2019;394:919-928]
Patients were randomized to receive reliever therapy with budesonide/formoterol 200 mg/6 mg turbuhaler (one inhalation as needed) (n=437), or maintenance budesonide 200 mg turbuhaler (one inhalation twice daily) plus terbutiline 250 mg turbuhaler (two inhalations as needed) (n=448). Electronic inhaler usage monitors were attached to all the inhalers of a subset of study participants. Patients were seen six times over the course of the year.
The primary outcome was the number of severe asthma exacerbations per patient per year. Severe exacerbations were defined as the use of systemic corticosteroids for ³3 days for worsening asthma, or an admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids.
Key secondary outcomes included time to first severe exacerbation, time to first moderate or severe exacerbation, asthma control as measured by the five-question Asthma Control Questionnaire (ACQ-5), on-treatment forced expiratory volume in 1 second (FEV1), fractional exhaled nitric oxide (FENO) level, and withdrawals due to treatment failure.
“At study entry, the mean ACQ-5 score was 1.1,” noted Hardy. “About 12 percent of patients reported a severe exacerbation in the previous 12 months, and 70 percent were taking an ICS at baseline.” (Table)
Budesonide/formoterol reliever more effective at preventing severe exacerbations
The rate of severe exacerbations was significantly lower with as-needed budesonide/formoterol than budesonide maintenance plus as-needed terbutiline therapy (absolute rate, 0.119 vs 0.172; relative rate, 0.69; 95 percent confidence interval [CI], 0.48 to 1.00; p=0.049). [Lancet 2019;394:919-928]
Patients receiving as needed budesonide/formoterol therapy also achieved longer time to first severe (and moderate or severe) exacerbation than those on budesonide maintenance plus reliever terbutiline. (Figure 1)
“Prespecified subgroup analysis showed no evidence of effect modification with respect to severe exacerbations based on various baseline subgroups, including FENO level, blood eosinophil count and ICS use,” remarked Hardy.
“Across all time points, there was no difference in asthma control as measured by ACQ-5 between the two treatment groups [mean difference, 0.06; 95 percent CI, -0.005 to 0.12; p=0.07]. This is important and reassuring, suggesting that the inherent concern about symptom control with the budesonide/formoterol regimen is not clinically important,” she commented.
The available evidence supports the 2019 GINA step 2 recommendation that budesonide/formoterol reliever therapy is an alternative to maintenance low-dose ICS plus SABA reliever. “Of these two regimens, budesonide/formoterol reliever therapy may be the preferred option for the prevention of severe exacerbations in mild-to-moderate asthma,” concluded Hardy.
SABA overuse and inadequate asthma control
“Despite significant advances in asthma care during the last two decades, asthma control remains suboptimal worldwide. No further decline in global asthma mortality rates has been seen in recent years,” said Janson. [J Allergy Clin Immunol Pract 2015;3:734-742; Lancet 2017;390:935-945]
“Inadequately controlled asthma is thought to be the result of over-reliance on SABA relievers and underuse of maintenance ICS treatment, leading to under-treatment of the underlying inflammatory pathology,” he continued. [Eur Respir J 2017;50:1701103] “Hence, it is important to explore the impact of patients’ use of SABA relievers on clinical outcomes.”
SABINA programme: New data from a Swedish asthma cohort
The SABINA programme aims to describe prescribing patterns of SABA and its potential effects on asthma control across multiple countries. As part of the SABINA programme, the HERA observational cohort study investigated the association between SABA use and mortality in a Swedish asthma population. Using nationwide data from drug and patient registries, 365,324 asthma patients aged 12–45 years who were prescribed two medications for obstructive lung disease during a 12-month period between 2006–2014 were identified. [Janson C, et al, ERS 2019, abstract PA2554]
Patients were categorized based on the number of SABA canisters collected (0–2, 3–5, 6–10, 11+) during the first year (baseline). Data were collected during follow-up, which lasted up to 9 years. SABA overuse was defined as collecting ³3 canisters during the baseline year.
“Baseline patient characteristics were similar between different SABA use groups, except for exacerbation rates, which increased with frequent SABA usage,” commented Janson.
Almost a third of asthma patients overuse SABA
“A total of 30.4 percent of asthma patients collected ³3 SABA canisters during the baseline year,” reported Janson. “To further compound the problem, 28 percent of the SABA overusers did not receive any ICS, and another 39 percent were only using low-dose ICS.” [Ekstrom M, et al, ERS 2019]
SABA overuse associated with dose-dependent increase in mortality risk
Survival analysis of follow-up data revealed a significant association between SABA overuse and mortality. “When adjusted for comorbidities, maintenance asthma treatment, baseline exacerbations, sex and age, overall mortality risk increased by 26 percent for patients receiving 3–5 canisters and 66 percent for patients receiving 6–10 canisters. In the group with the highest use of SABA, the risk more than doubled. This trend was also noticeable in respiratory-related mortality and asthma-related mortality, with increase in risks proportional to the magnitude of SABA overuse,” noted Janson. (Figure 2) [Janson C, et al, ERS 2019, abstract OA2105]
The SABINA Swedish cohort study found SABA overuse in about 30 percent of asthma patients. SABA overuse was associated with dose-dependent increases in all-cause, respiratory- and asthma-related mortality risks. “These findings emphasize that monitoring SABA usage (and decreasing SABA overuse) should be a key strategy in improving asthma management,” said Janson.