Evaluation of inhaler technique and achievement and maintenance of mastery of budesonide/formoterol Spiromax® compared with budesonide/formoterol Turbuhaler® in adult patients with asthma: the Easy Low Instruction Over Time (ELIOT) study

Asthma is a worldwide chronic inflammatory disorder of the airways with major adverse effects on affected individuals’ quality of life [1]. Despite advances in therapy, suboptimal asthma control is commonplace and is associated with a substantial socioeconomic burden [2‐6]. The causes of poor asthma control are multifactorial and include several patient-related factors. Smoking, poor treatment adherence, and device handling errors have all been shown to have a negative impact on asthma control [7‐12].

Therapeutic efficacy of inhalation therapy is dependent on the drug(s) reaching the targeted areas of the lower lung [5]. There is a growing body of evidence suggesting that errors in inhaler technique can reduce drug delivery to the lungs and produce poor clinical outcomes [2, 10, 12‐16]. Correct inhaler technique should therefore be considered an essential component in asthma management [5, 10, 14, 17] and has become an integral part of the management strategy set out by the Global Initiative for Asthma (GINA). However, despite the importance of patient training, many healthcare professionals (HCPs) themselves lack proficiency in correct inhaler use, are not confident in demonstrating proper inhaler technique and, consequently, patients are neither taught nor checked in follow-up visits [18‐23]. As a result, poor inhaler technique continues to represent a barrier to achieving optimal asthma control among many patients with asthma, a situation that has not improved over the past 40 years [5, 14, 24‐26].

Although the use of all inhalers involves techniques associated with the preparation of the device, inhalation and post-inhalation behaviors, some steps associated with the correct use of different inhalers are device-specific [2, 14, 27, 28]. The CRITIKAL study, which investigated the association between specific inhaler errors of different devices and asthma outcomes, enabled the identification of specific inhaler technique errors that were associated with lack of asthma control [16]. Other factors shown to be associated with poor asthma control when using the Turbuhaler® were not breathing out before an inhalation, not tilting the head or sealing the lips round the mouthpiece, not using a fast inhalation and no breath-holding after each inhalation [16].

Because inhaler technique errors have implications for disease control and HCPs do not always deliver inhaler technique education [29, 30], it is important that devices are as intuitive as possible. Additionally, many patients express preferences for inhaler devices that they are able to use easily and efficiently [5], but to date, only a few studies have investigated intuitiveness and the maintenance of device mastery with different inhalers by patients with asthma [31‐33].

Combined use of an inhaled corticosteroid (ICS) and a long-acting β2–agonist (LABA) is considered to be recommended for patients with asthma at step 3 or higher of the GINA guidelines [1]. ICS/LABA fixed-dose combinations are available in a range of inhaler devices, including DuoResp® budesonide/formoterol (BF) Spiromax® and Symbicort® (BF) Turbuhaler. In Europe, these two products are approved for use in adult patients with asthma or chronic obstructive pulmonary disease where an inhaled ICS/LABA is indicated [34].

This Easy Low Instruction Over Time (ELIOT) study was a pragmatic trial designed to compare the intuitiveness of BF Spiromax and a real-life comparator, the BF Turbuhaler by assessing achievement and maintenance of correct inhaler technique (mastery), in adult patients with moderate-to-severe asthma.

The ELIOT study was a pragmatic 12-week, 2-stage, multicenter, open-label, randomized, parallel-group study designed to compare the achievement and maintenance of inhaler technique in adults with asthma. It was conducted between May 2014 and March 2015 at 68 centers in the UK. The study was divided into two parts: a cross-sectional phase at Visit 1, followed by a 12-week longitudinal phase with Visit 2 at the end.

In this two-part pragmatic study, Spiromax was associated with higher levels of device mastery compared with Turbuhaler after training in the initial crossover phase. During this phase, patients were significantly less likely to make an HCP-observed error with the empty Spiromax device compared with the empty Turbuhaler device in intuitive use, after reading the patient information leaflet, and after viewing an instructional video. In addition, patients using the empty Spiromax achieved device mastery in fewer steps and made fewer errors overall.

In the longitudinal phase of the study, the proportion of patients maintaining device mastery (absence of HCP-observed errors upon assessment after 12 weeks of device use) was numerically higher with BF Spiromax than with BF Turbuhaler, but not statistically significantly so. However, in the exploratory analysis wherein an independent external expert viewed video recordings of participants’ inhaler usage, higher levels of mastery than were reported by the HCPs were reported, suggesting that HCPs may have had a tendency to over-estimate the number of errors.

The findings of the cross-sectional phase support the hypothesis that patients may find it easier to attain mastery of Spiromax compared with Turbuhaler. Fewer errors were observed with both devices when patients received tuition by reading the patient information leaflet and watching the instructional video (step 3; verbal instruction and demonstration given) than after reading the leaflet alone (step 2; no verbal instructions given). Device mastery at step 2 was achieved in a significantly greater proportion of patients using Spiromax versus Turbuhaler, but rates of achievement of device mastery were markedly increased following viewing of the instructional video at step 3.

In a ‘real-world’ setting, many patients may not have access to video instructions, or they may be of variable quality. In contrast, all patients should receive the patient leaflet, so maximizing patient mastery of inhaler technique using this resource is an important objective. The outcomes of this study are in agreement with previously published findings that passive instructions alone (such as reading the patient information leaflet) are not as effective as verbal instructions or demonstration (such as watching an instructional video) in teaching patients correct inhaler technique, specifically in patients using inhalers for the first time [40‐43]. Other instructional tools for the training of correct inhaler technique should be considered, including verbal instructions and multimedia educational materials (e.g. a link to a website-based instructional video could be included in the patient information leaflet). Demonstrations and practice sessions should also be considered in clinical practice to maximize the number of patients with correct inhaler technique [5, 31, 32, 41, 44‐47]. Overall, in order to improve device mastery, HCPs should consider a range of factors including the inhaler type, the patient, the educator/teacher, and the method of teaching [48].

Possible reasons why the longitudinal phase mastery results (based on HCP-observed errors) did not demonstrate a significant difference between the two devices include the fact that many longitudinal phase participants had previous experience of using the Turbuhaler (albeit more than 6 months prior to the study), whereas none had used the Spiromax. Cross-sectional studies [16, 24, 25] have reported a much higher frequency of errors with Turbuhaler than that observed in this study. Another possible explanation is the frequent telephone follow-up of patients, a situation rather different from normal clinical practice, which could have had an impact on the proportion of patients maintaining correct technique. Maintenance of correct device technique may be influenced by patient motivation. Previous studies, in which patients received intensive inhaler technique education in a community pharmacy setting, and had their technique checked 1 month later back at the pharmacy, showed correct technique in about 45 to 60% of patients at this time [31, 45].

It could also be argued that HCP assessment is prone to human observational errors. The discrepancy between HCP-reported error rates and those obtained through independent expert assessment of video-recorded use that was observed in our exploratory analysis suggests that HCPs may be conservative with patient assessments or lack experience and require training in assessment themselves, potentially resulting in over-estimation of error rates. In real-life clinical settings, it could be beneficial for external experts to review each patient’s inhaler technique with HCPs. The implementation of such assessment in busy clinics would be a challenge, and if this is not feasible, HCPs should ensure that they maintain their own inhaler technique mastery and periodically review each other’s technique. In the future, smartphone apps (including video recording of inhalation technique at home or augmented reality facial mapping) could become an option, as well as new technologies incorporating electronic sensors to inhalers. This study therefore highlights the potential for technology-assisted methods to enhance teaching and assessment of inhaler technique. Our findings also suggest that HCPs should receive training on inhaler technique and its evaluation, to ensure that they monitor their patients in a standardized manner reflecting the approach of an inhalation device expert.

Another important aspect of this study was the analysis of specific aspects of device mastery such as dose preparation. Spiromax was associated with significantly higher levels of dose preparation mastery in the cross-sectional phase compared with Turbuhaler and significantly fewer HCP-observed errors after the longitudinal phase. Errors in dose preparation can significantly impair effective delivery of drug to the lungs, leading to a risk of inadequate treatment dosing (or even no drug dose) [5, 8, 14, 46]. Previous studies have reported that dose preparation errors are device-specific whereas errors in inhalation maneuvers are usually observed across different devices of a particular type (in this study, both devices were DPIs) [24, 25, 49]. Studies in which dose preparation errors have been specifically examined report error rates of between 24 and 49% with Turbuhaler in patients who use this device for their regular medication [16, 49] and in 16.7% of people who are using Turbuhaler for the first time and have read the patient leaflet [43]. The findings of the latter study are consistent with the outcomes from our research, in that both studies found that (1) Spiromax was associated with a lower rate of dose preparation errors compared with Turbuhaler, and (2) maximal device mastery is achieved after HCP education and demonstration [43]. Research shows that when patients learn correct inhaler technique and adhere to treatment for 7 days, they are more likely to maintain device mastery over time [50].

It has recently been shown that not using a fast inhalation when using dry powder inhalers is one of the principal errors related to a greater incidence of poor asthma control [16]. Dose emission from a DPI is affected by inhalation flow, but the extent of variability differs between devices, so that it may be beneficial to use an inhaler with low variability [51].

Participants were instructed to take two inhalations twice daily, and the preparation of the second dose formed an important part of the device mastery assessment. Many of the inhalation 2 errors were due to patients making two inhalations from the first dose that was prepared, instead of preparing a second dose. They made a second inhalation either without closing and opening the cap of the Spiromax inhaler or without rotating the base of the Turbuhaler. Patients were observed to make this type of error with both Spiromax and Turbuhaler with a similar frequency, suggesting that they may have misinterpreted the dosing instructions or had never properly been instructed. Further studies are therefore required to investigate if this is a problem that needs to be addressed. The role of HCPs in ensuring that patients are fully aware of all steps required, including those that apply when taking a second dose if applicable, and directing patients to suitable training material, must therefore be emphasized.

Patients are more likely to prefer a device that they consider easy to use and that they can use correctly, and patient satisfaction with an inhaler is correlated with clinical outcomes [5, 10, 17, 44, 48, 52]. Hence, selecting the correct inhaler device by matching the patient with the inhaler that they prefer and find more intuitive to use could potentially lead to improved adherence, better clinical outcomes and reduced costs for care [5, 13, 28, 48, 53].

Although the between-group difference was small, patient-reported PASAPQ scores for Spiromax and Turbuhaler were significantly in favor of the empty Spiromax (PASAPQ score 89.8 vs. 85.7 for Turbuhaler; p < 0.001), indicating higher device preference with Spiromax. Similar findings were reported in two recent studies [43, 54]. One of these was a clinical study comparing BF Spiromax with BF Turbuhaler in patients with asthma; PASAPQ scores showed that patients preferred the Spiromax device for its performance and that they were more willing to continue therapy with Spiromax beyond the 12-week study period [54]. In the other study, device preference questionnaire results from inhaler-naïve Finnish volunteers showed that the majority of participants found Spiromax easier to use than Easyhaler or Turbuhaler and, if they were prescribed an inhaler, they would prefer Spiromax [43]. In our study, device preference was only assessed in the cross-sectional phase. It would be relevant to know whether device preference or satisfaction was maintained after 12 weeks of using the active inhaler (i.e. by repeating the PASAPQ at the end of the study and comparing the outcomes with the cross-sectional phase).

One strength of the current study is the assessment of the maintenance of device mastery, which has been addressed in very few other pragmatic studies in asthma [31, 32, 45]. This begins to address a gap in the literature and provides a preliminary insight into the possible impact of inhaler technique and mastery on disease control. For a formal assessment, adjustment for confounding factors such as adherence will be required. Our study suggests that maintaining good inhaler technique could provide benefits to patients receiving high-dose ICS medication, as the daily dose of beclomethasone dipropionate-equivalent ICS in patients enrolled in this study was 800–2000 μg (fixed or free combinations with LABA). Dose modification and alternative choices for improving asthma control are generally limited in these patients. Another strength of this pragmatic study was the assessment of patients in real-life scenarios. In general, randomized clinical trials (RCTs) provide evidence from narrowly defined patient groups representing subsets of the real-life patient population; co-morbidities and lifestyle factors are not usually captured. Findings from pragmatic trials provide additional insight from a broader asthma population and can be combined with findings from conventional RCTs to provide a comprehensive picture of treatment efficacy and outcomes [55]. Among the limitations of this study are the open-label design, potential confounding associated with 4-weekly follow-up acting as a reminder to patients, and the subjective nature of some assessments such as HCP observations making it inherently prone to a degree of bias and personal judgment. The 4-weekly follow-up calls, in particular, may have had a positive influence on patients’ device mastery, as previous research has shown that regular follow-up of patients affects device mastery over time [31, 50]. A regimen requiring two doses to be taken twice daily also represents a dosing frequency greater than that typically found in the clinic, where patients more usually administer one dose, twice daily. In addition, the findings are not necessarily applicable to mild asthma which was outside of the scope of this study.

In the cross-sectional phase of this study, Spiromax was associated with higher levels of device mastery compared with Turbuhaler in adult patients with moderate-to-severe asthma. No significant overall difference between the devices was observed by HCP assessment of inhaler technique in the longitudinal phase, though Spiromax users were observed to make fewer dose preparation errors than those using Turbuhaler. An exploratory investigation involving external expert assessment of inhalation technique by video reported higher levels of maintenance of device mastery during the longitudinal phase with Spiromax versus Turbuhaler. Improvements in asthma control, similar with both devices, were observed over 12 weeks of BF treatment, despite low adherence levels in both study groups. In accordance with previous studies, device preference was higher with Spiromax than with Turbuhaler. This study supports the use of active (e.g. verbal) training to minimize the likelihood of inhalation errors. Our findings also highlight the possible value of independent assessment using video to assist HCPs in evaluating patients’ device mastery.