Investigation of two treatment regimens in adults with mild asthma
Introduction In adults with mild-moderate asthma, poor adherence to daily maintenance inhaled corticosteroids (ICS) leads to increased asthma symptoms and risk of asthma exacerbations. There is evidence that symptom-driven use of a combination ICS plus a fast-onset long-acting beta2-agonist (LABA) inhaler taken as needed may be an alternative to daily maintenance ICS plus as-needed short-acting beta2-agonists (SABA). Through four studies: The PRACTICAL study (a randomised controlled trial) and three sub-studies nested within it, this thesis aims to investigate the efficacy of as-needed ICS-formoterol (a fast-onset LABA), exposure to and patterns of ICS and beta2-agonist use, and patient preferences for and priorities concerning their asthma management. Methods The PRACTICAL study was a 52 week, open label, parallel group, multicentre, superiority, randomised controlled trial conducted at 15 sites throughout New Zealand. Adults aged 18-75 with a diagnosis of asthma who were taking SABA for symptom relief with or without low dose maintenance ICS were recruited. Participants were randomised 1:1 to either as-needed budesonide-formoterol (200/6mcg) one actuation for symptom relief or budesonide (200mcg) one actuation twice a day plus as-needed terbutaline (250mcg) two actuations for symptom relief. A sub-group of 110 participants had electronic inhaler monitors attached to their study inhalers which captured the time and date of every inhaler actuation. At their final study visit a total of 407 participants were eligible to complete a survey on their treatment preferences and experiences of their study randomised treatment, and a discrete choice experiment to determine their priorities for attributes of asthma management including; treatment regimen, shortness of breath, steroid dose and likelihood of an asthma flare-up. Results The PRACTICAL study found the rate of severe exacerbations per patient per year was lower in participants randomised to as-needed budesonide-formoterol than participants randomised to maintenance budesonide (absolute rate per patient per year 0.119 vs 0.172; relative rate 0.69; 95%CI 0.48-1.00; p=0.049). Within the electronic monitoring sub-study, exposure to ICS was significantly lower in the group randomised to as-needed budesonide-formoterol with a mean daily ICS dose of 176.0mcg versus 302.5mcg in those randomised to maintenance budesonide (difference -126.5mcg per day; 95%CI -171.0 to -81.9; p<0.001). Use of as-needed budesonide-formoterol was associated with extended periods of no ICS use (median 156 days vs 22 days respectively) and more days where ≥4, 6 or 8 actuations of ICS were taken than maintenance budesonide. Participants’ preference for either as-needed or maintenance treatment was strongly associated with randomised treatment; 90% randomised to as-needed budesonideformoterol preferred their randomised treatment compared to 60% of those randomised to maintenance budesonide, odds ratio for association between randomised treatment and preference was 13.3 (95%CI 7.1 to 24.7; p<0.001). The DCE found that amount of shortness of breath was the most important attribute of asthma treatment to all participants. However, the relative importance of other attributes, particularly type of treatment regimen, varied depending on whether the participants had previously stated a preference for as-needed or maintenance treatment. Discussion In adults with mild-moderate asthma, as-needed budesonide-formoterol is more effective at preventing severe asthma exacerbations than maintenance budesonide at a significantly lower exposure to ICS, despite long periods of no ICS use. This suggests that timing of ICS dose and titrating it in response to symptoms is more important than total dose. If participants have experienced as-needed budesonide-formoterol, they prefer it over maintenance budesonide suggesting this new approach to asthma treatment will be acceptable to patients. Control of shortness of breath was the most important attribute of asthma treatment to all patients. However, participants who preferred as-needed treatment were more willing to trade-off likelihood of an asthma flare up and steroid dose for their preferred treatment regimen. Knowledge of patient preferences and priorities for treatment, together with knowledge of regimen characteristics can be used in discussion with patients to determine the most appropriate regimen for them.