How are inhalers used for the management of asthma?
Management of asthma involves a series of stepwise therapies depending on the severity of the disease. Initial therapy typically starts with as needed short-acting inhaler therapy (step 1), and a daily low- to medium-dose inhaled steroids is added for better asthma control when needed (step 2). Subsequently, a bronchodilator known as long-acting beta2-agonist (LABA), which causes the passages of the airways to expand and relax so that breathing difficulty is reduced, is typically added to inhaled steroids if needed (steps 3 and 4).
What are the options when asthma is not controlled with a combination of inhaled steroids and LABA?
Current guidelines recommend a higher-dose of inhaled steroids or adding another bronchodilator known as long-acting muscarinic antagonist (LAMA), (i.e. triple inhaled therapy) (step 5), when asthma is not controlled with medium-dose inhaled steroids and LABA dual inhaled therapy.
How did we answer the question?
We collected and analysed data from 17 studies, including a total of 17,161 adolescents and adults with uncontrolled asthma, using a special method called a network meta-analysis, which enabled us to simultaneously compare multiple inhaler groups.
What did we find?
Triple inhaled therapy (i.e, inhaled steroids + LABA + LAMA) reduces asthma flare-ups, but not asthma-related hospitalisations. High-dose triple therapy, not medium-dose triple, is likely to be better tolerated due to less side effects compared to dual inhaled therapy (i.e. inhaled steroids + LABA).
Triple therapy may improve symptom and quality of life scores compared to dual therapy but not enough to be perceived by those being on it.
Higher than medium-dose inhaled steroids in dual inhaled therapy are unlikely to result in any additional benefit or harm.
Conclusions
Triple inhaled therapy, especially high-dose formulations, reduces asthma flare-ups and is likely to be better tolerated due to less side effects compared to dual therapy.
Triple inhaled therapy may or may not to improve symptoms or quality of life compared to dual therapy.
Increasing the strength of inhaled steroids from medium to high dose is likely beneficial in triple inhaled therapy but probably not in dual therapy.
Immuno modulators, which are injectable medications, or other options may be considered if asthma symptoms are not well controlled or for those requiring asthma-related hospitalisations despite being on medium-dose dual inhaled therapy.
Medium-dose and HD triple therapies reduce steroid-requiring asthma exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA especially in those with a history of asthma exacerbations in the previous year. High-dose triple therapy is likely superior to MD triple therapy in reducing steroid-requiring asthma exacerbations.
Triple therapy is unlikely to result in clinically meaningful improvement in symptoms or quality of life compared to dual therapy considering the MCIDs.
High-dose triple therapy, but not MD triple, results in a reduction in all-cause AEs and likely reduces dropouts due to AEs compared to MD-ICS/LABA. Triple therapy results in little to no difference in all-cause or asthma-related SAEs compared to dual therapy.
HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, although long-term safety of higher rather than MD-
ICS remains to be demonstrated given the median duration of included studies was six months.
The above findings may assist deciding on a treatment option when asthma is not controlled with MD-ICS/LABA.
Current guidelines recommend a higher-dose inhaled corticosteroids (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination therapy.
To assess the effectiveness and safety of dual (ICS/LABA) and triple therapies (ICS/LABA/LAMA) compared with each other and with varying doses of ICS in adolescents and adults with uncontrolled asthma.
We searched multiple databases for pre-registered randomised controlled trials (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022.
We searched studies, including adolescents and adults with uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, comparing dual and triple therapies. We excluded cluster- and cross-over RCTs.
We conducted a systematic review and network meta-analysis according to the previously published protocol. We used Cochrane’s Screen4ME workflow to assess search results and Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome was steroid-requiring asthma exacerbations and asthma-related hospitalisations (moderate to severe and severe exacerbations).
We included 17,161 patients with uncontrolled asthma from 17 studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The quality of included studies was generally good except for some outcomes in a few studies due to high attrition rates.
Medium-dose (MD) and high-dose (HD) triple therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) (high-certainty evidence), but not asthma-related hospitalisations, compared to MD-ICS/LABA.
High-dose triple therapy likely reduces steroid-requiring asthma exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], [moderate certainty]). Subgroup analyses suggest the reduction in steroid-requiring exacerbations associated with triple therapies may be only for those with a history of asthma exacerbations in the previous year but not for those without.
High-dose triple therapy, but not MD triple, results in a reduction in all-cause adverse events (AEs) and likely reduces dropouts due to AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). Triple therapy results in little to no difference in all-cause or asthma-related serious adverse events (SAEs) compared to dual therapy (high certainty).
The evidence suggests triple therapy results in little or no clinically important difference in symptoms or quality of life compared to dual therapy considering the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA.