Background
Asthma is the most common respiratory illness. Many people with asthma have mild asthma, but still remain at risk of severe asthma exacerbations, which often result in the use of oral steroids. Mild asthma is commonly treated with preventative inhalers, which contain a steroid used to reduce inflammation in the airways, and with reliever inhalers, which relax the muscles of the airways causing quick relief of asthma symptoms. Combination inhalers contain both the preventative steroid and the reliever, simplifying treatment and ensuring steroids are always given alongside the immediate relief of symptoms.
Review question
We examined the findings of clinical trials to assess the use of combination inhalers in the treatment of mild asthma when taken on an as-needed, symptom-driven basis.
Study characteristics
We searched for studies up to March 2021. Results were collected from six studies which compared use of a combination inhaler used on an as-needed basis with either as-needed reliever-only therapy or daily treatment with a low dose preventative inhaler.
Key findings
We found that combination inhalers used as-needed when compared with reliever-only treatment reduced severe exacerbations requiring tablet steroids and rates of emergency admission to hospital with asthma symptoms. Differences in other measures relating to symptom control and lung function were too small to be clinically important. Rates of severe exacerbations were similar between patients on daily preventative steroid inhalers and those using combination inhalers as-needed. People using combination inhalers had lower rates of hospital admission and lower total inhaled steroid dose, whilst the differences in lung function and asthma symptom control were not clinically significant.
This review found the use of combination inhalers used when the patient experiences asthma symptoms was beneficial in reducing severe exacerbations when compared to stand-alone reliever therapy in mild asthma. In addition to this the use of combination inhalers used on an as-needed basis was associated with a reduction in hospital admissions and total inhaled steroid dose when compared with regularly-taken low dose preventative inhaler therapy.
Quality of the evidence
The studies which contributed data were well-designed and robust, although two were open-label (participants knew which treatment they were getting), with some potential for bias, so the evidence was generally of moderate-to-high quality.
We found FABA/ICS as required is clinically effective in adults and adolescents with mild asthma. Their use instead of FABA as required alone reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events. FABA/ICS as required is as effective as regular ICS and reduced asthma-related hospital admissions or unscheduled healthcare visits, and average exposure to ICS, and is unlikely to be associated with an increase in adverse events.
Further research is needed to explore use of FABA/ICS as required in children under 12 years of age, use of other FABA/ICS preparations, and long-term outcomes beyond 52 weeks.
Asthma affects 350 million people worldwide including 45% to 70% with mild disease. Treatment is mainly with inhalers containing beta₂-agonists, typically taken as required to relieve bronchospasm, and inhaled corticosteroids (ICS) as regular preventive therapy. Poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. Fixed-dose combination inhalers containing both a steroid and a fast-acting beta₂-agonist (FABA) in the same device simplify inhalers regimens and ensure symptomatic relief is accompanied by preventative therapy. Their use is established in moderate asthma, but they may also have potential utility in mild asthma.
To evaluate the efficacy and safety of single combined (fast-onset beta₂-agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma.
We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 19 March 2021.
We included randomised controlled trials (RCTs) and cross-over trials with at least one week washout period. We included studies of a single fixed-dose FABA/ICS inhaler used as required compared with no treatment, placebo, short-acting beta agonist (SABA) as required, regular ICS with SABA as required, regular fixed-dose combination ICS/long-acting beta agonist (LABA), or regular fixed-dose combination ICS/FABA with as required ICS/FABA. We planned to include cluster-randomised trials if the data had been or could be adjusted for clustering. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data.
Two review authors independently extracted data. We analysed dichotomous data as odds ratios (OR) or rate ratios (RR) and continuous data as mean difference (MD). We reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence. Primary outcomes were exacerbations requiring systemic steroids, hospital admissions/emergency department or urgent care visits for asthma, and measures of asthma control.
We included six studies of which five contributed results to the meta-analyses. All five used budesonide 200 μg and formoterol 6 μg in a dry powder formulation as the combination inhaler. Comparator fast-acting bronchodilators included terbutaline and formoterol. Two studies included children aged 12+ and adults; two studies were open-label. A total of 9657 participants were included, with a mean age of 36 to 43 years. 2.3% to 11% were current smokers.
FABA / ICS as required versus FABA as required
Compared with as-required FABA alone, as-required FABA/ICS reduced exacerbations requiring systemic steroids (OR 0.45, 95% CI 0.34 to 0.60, 2 RCTs, 2997 participants, high-certainty evidence), equivalent to 109 people out of 1000 in the FABA alone group experiencing an exacerbation requiring systemic steroids, compared to 52 (95% CI 40 to 68) out of 1000 in the FABA/ICS as-required group. FABA/ICS as required may also reduce the odds of an asthma-related hospital admission or emergency department or urgent care visit (OR 0.35, 95% CI 0.20 to 0.60, 2 RCTs, 2997 participants, low-certainty evidence).
Compared with as-required FABA alone, any changes in asthma control or spirometry, though favouring as-required FABA/ICS , were small and less than the minimal clinically-important differences. We did not find evidence of differences in asthma-associated quality of life or mortality. For other secondary outcomes FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reduces the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95, 2 RCTs, 3002 participants, moderate-certainty evidence) and may reduce total systemic steroid dose (MD -9.90, 95% CI -19.38 to -0.42, 1 RCT, 443 participants, low-certainty evidence), and with an increase in the daily inhaled steroid dose (MD 77 μg beclomethasone equiv./day, 95% CI 69 to 84, 2 RCTs, 2554 participants, moderate-certainty evidence).
FABA/ICS as required versus regular ICS plus FABA as required
There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroid with FABA/ICS as required compared with regular ICS (OR 0.79, 95% CI 0.59 to 1.07, 4 RCTs, 8065 participants, low-certainty evidence), equivalent to 81 people out of 1000 in the regular ICS plus FABA group experiencing an exacerbation requiring systemic steroids, compared to 65 (95% CI 49 to 86) out of 1000 FABA/ICS as required group. The odds of an asthma-related hospital admission or emergency department or urgent care visit may be reduced in those taking FABA/ICS as required (OR 0.63, 95% CI 0.44 to 0.91, 4 RCTs, 8065 participants, low-certainty evidence).
Compared with regular ICS, any changes in asthma control, spirometry, peak flow rates (PFR), or asthma-associated quality of life, though favouring regular ICS, were small and less than the minimal clinically important differences (MCID). Adverse events, serious adverse events, total systemic corticosteroid dose and mortality were similar between groups, although deaths were rare, so confidence intervals for this analysis were wide. We found moderate-certainty evidence from four trials involving 7180 participants that FABA/ICS as required was likely associated with less average daily exposure to inhaled corticosteroids than those on regular ICS (MD -154.51 μg/day, 95% CI -207.94 to -101.09).