Background
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.
Objectives
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.
Search methods
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 We contacted trial authors for further information and requested details regarding the possibility of unpublished trials.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.
Selection criteria
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 We included full texts, s and unpublished data.
Data collection and analysis
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.
Main results
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).
Authors' conclusions
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.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy and safety of single combined (long‐ or short‐acting beta₂ agonist plus an inhaled ...corticosteroid (ICS)) inhaler only used as needed in people with mild asthma.
In people with mild asthma poor adherence to regular therapy is common and increases the risk of exacerbations, morbidity and mortality. The use of fixed-dose combination inhalers containing an ...inhaled corticosteroid (ICS) and a fast-acting β
-agonist (FABA) is established in moderate asthma, but they may also have potential utility in mild asthma.
To evaluate the efficacy and safety of single combined FABA/ICS inhaler only used as needed in people with mild asthma.
Cochrane meta-analysis of available trial data.
Children aged 12+ and adults with mild asthma.
We searched the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE and Embase, ClinicalTrials.gov and the WHO trials portal on 19 March 2021.
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 included randomised controlled trials (RCTs) and cross-over trial. We excluded trials shorter than 12 weeks. We included full texts, abstracts and unpublished data.
We used Cochrane's standard methodological procedures and applied the GRADE approach to assess the evidence.
We included six studies from which 9657 participants contributed to the meta-analyses. All used dry powder budesonide and formoterol as the combination inhaler. Two studies included children aged 12+ years and two studies were open-label.
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 with 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). Changes in asthma control were small and less than the minimal clinically important difference (MCID). FABA/ICS as required was associated with reductions in fractional exhaled nitric oxide, probably reducing the odds of an adverse event (OR 0.82, 95% CI 0.71 to 0.95) and may reduce total systemic steroid dose (mean difference (MD) -9.90, 95% CI -19.38 to -0.42).
There may be little or no difference in the number of people with asthma exacerbations requiring systemic steroids 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 with 65 (95% CI 49 to 86) out of 1000 in the 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). Changes in asthma control were small and less than MCID. Adverse events and total systemic corticosteroid doses were similar between groups. FABA/ICS as required was likely associated with less average daily exposure to ICS than those on regular ICS (MD -154.51 mcg/day, 95% CI -207.94 to -101.09).
FABA/ICS as required is clinically effective in adults and adolescents with mild asthma and reduced exacerbations, hospital admissions or unscheduled healthcare visits and exposure to systemic corticosteroids and probably reduces adverse events compared with FABA as required alone. 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 associated with increased adverse events.
Cognitive deficits are a recognised component of Parkinson's disease (PD). However, particularly within the domain of short-term memory, it is unclear whether these impairments are masked, or caused, ...by patients' dopaminergic medication. The effect of medication on pure maintenance in PD patients has rarely been explored, with most assessments examining maintenance intercalated between other executive tasks. Moreover, few studies have utilised methods that can measure the quality of mental representations, which can enable the decomposition of recall errors into their underlying neurocognitive components. Here, we fill this gap by examining pure maintenance in PD patients in high and low dopaminergic states. Participants had to encode the orientation of two stimuli and reproduce these orientations after a short (2 s) or long (8 s) delay. In addition, we also examined the performance of healthy, age-matched older adults to contextualise these effects and determine whether PD represents an exacerbation of the normal ageing process. Patients showed improved recall OFF compared to ON their dopaminergic medication, but only for long-duration trials. Moreover, PD patients OFF their medication actually performed at a level superior to age-matched controls, indicative of a paradoxical enhancement of memory in the low dopaminergic state. The application of a probabilistic model of response selection suggested that PD patients made fewer misbinding errors in the low, compared with high, dopaminergic state for longer-delay trials. Thus, unexpectedly, the mechanisms that prevent memoranda from being corrupted by misbinding over time appear to be enhanced in PD patients OFF dopaminergic medication. Possible explanations for this paradoxical effect are discussed.
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