Discussion
Results of the current study suggest that Pulmojet may be easier to learn to use correctly than either the Diskus or Turbohaler for current inhaler users who are switched to a new device. Patients with asthma and/or COPD were significantly less likely to make a nurse-observed serious error with Pulmojet than with Diskus or Turbohaler after receiving training by either the patient information leaflet alone or the leaflet and as-needed additional video instruction. Mastery of the inhalation technique is, therefore, more likely to be readily achieved with Pulmojet than either Diskus or Turbohaler. Designing inhaler devices to make them easier to use and teach is essential for improving long-term outcomes in asthma and COPD, so an important factor to consider when choosing a specific device is whether or not the patient is capable of using it correctly to achieve adequate drug delivery [
25]. Furthermore, the ease of correct use of inhalers and patient preference for device can affect adherence with treatment and clinical outcomes [
1,
5,
7,
14‐
16,
23‐
26].
Patients were not given verbal instructions alongside the patient information leaflet, so the use of the leaflet on its own mimicked common clinical practice (although sometimes patients may be verbally trained as well when prescribed a new device). We found that, for all inhalers tested, fewer serious errors were observed after patients read the patient information leaflet and watched an instructional video than after reading the leaflet alone. Our findings are in line with other reports that written or passive instructions alone, such as the patient information leaflets, are not sufficient to teach correct inhalation technique; and other tools, such as verbal instructions, multimedia educational materials, demonstrations, and practice sessions are needed to improve inhaler device technique [
25‐
35]. Crompton et al. [
26] have also recommended that the teaching of correct inhalation techniques should be tailored to each patient’s needs and preferences; for example, multimedia methods may be more beneficial for younger patients, while one-to-one tuition is more suitable for elderly patients. The fact that errors in device technique remained after the instructional video suggests that instructional videos are useful but may not be adequate to ensure optimal device technique for all patients.
The comparator devices chosen for this study, the Diskus and the Turbohaler, are two of the most frequently prescribed multidose DPI devices worldwide. Previously reported incidence of serious errors ranges from 21–35 % with Diskus and 37–44 % with Turbohaler [
1,
10]. The current device error data (study phase 1) showed a similar incidence for Diskus use (39 %) but greater error rates amongst the Turbohaler users (76 %). The high inhaler technique error rate amongst current pMDI users (92 %) was consistent with previous data [
3].
The Pulmojet device has been designed to release its dose at a low minimum inspiratory flow. In-house measurements have identified that the dose is released from a Pulmojet at ≥25 L/min (unpublished data), which is below the recognised minimum inspiratory flow of the Turbohaler [
36‐
38] and the Diskus [
39]. This ensures efficient de-aggregation of the dose during each inhalation so that drug particles most likely to be deposited into the airways are entrained in the inhaled airstream leaving the device. The Pulmojet inhaler has been designed with audio, visual, and sensory feedback mechanisms to indicate that an adequate inhalation has been performed, a feature appreciated by patients [
40], whereas neither the Turbohaler nor Diskus provides any feedback to the patient that an adequate inspiratory flow has been achieved. Furthermore, because the dose is not released until a set inhalation flow is achieved, the Pulmojet can be held in any orientation during dose preparation.
Patients attending UK primary care practices were recruited for this study, and minimal exclusion criteria other than evidence of recent exacerbation or lower respiratory tract infection were applied to enable the study results to be generalisable to most patients with asthma and/or COPD receiving ICS or fixed-dose combination therapy in routine practice. Asthma, COPD and asthma-COPD were diagnoses made by the patients’ physicians according to their standard clinical practices, and we included both ICS and fixed-dose combinations as both are commonly prescribed for asthma and COPD in clinical practice [
41]. Other strengths of this investigation include the randomised assignment to device training order, assessments made by trained independent nurses, and blinding of data analysts and statisticians. The practical importance of identifying superiority (rather than just non-inferiority) should also be recognised, as despite the ease of use of any one device compared with another, the overall management of chronic respiratory conditions is associated with a complex array of management issues, and hence it would be practically acceptable for a switch in device only if superiority were shown.
We acknowledge several limitations of the current research. Firstly, this was an open-label study that involved subjective assessment, and hence potential nurse bias, although efforts were made to standardise demonstration of devices and training in assessment of serious errors. Secondly, this study focused on self-training techniques (both the patient information leaflet and video are tools that the patient can employ at home); whereas, in practice, healthcare providers might incorporate their own educational style when training device-naïve patients for the first time (ie, the education may not be standardised in real life). Furthermore, although errors were defined by independent expert consensus, they were not validated as being serious. However, in the post-hoc sensitivity analysis restricted to errors that were definitely serious (ie, those that would definitely preclude adequate dose delivery to the lungs), the results remained largely the same. We included “inhalation is not forceful from the start” as a serious error based on the recommendations for DPI use of a recent European Respiratory Society/International Society for Aerosols in Medicine task force [
42].
Another limitation is the fact that this study does not provide insight into maintenance of inhaler mastery or its impact on disease control. Learning to correctly handle a device is a continuous process and inhaler technique can decline over time [
34], so it would be interesting to determine whether the superior results in inhaler technique observed with Pulmojet vs. Diskus and Turbohaler are maintained after a period of use and whether this is associated with better disease control. Moreover, patients considered as first-time users with regard to the Diskus or Turbohaler devices could potentially have used them in the past, more than 1 year before their inclusion in the study. In such cases, it is possible that any differences with the Pulmojet device would have been minimised or, conversely, that for patients switched at some time preceding the prior year from Diskus or Turbohaler because they could not handle it well, a comparison with Pulmojet would lead to a relatively favourable outcome for Pulmojet. However, we believe that patients using these devices previous to the 1 year were few if any. Finally, all enrolled patients were current inhaler users and hence our findings may not apply to patients prescribed an inhaler for the first time.
Competing interests
The study was funded by Zentiva, Prague, Czech Republic, and was performed in compliance with Good Clinical Practice. Zentiva played no role in the conduct of the study. Henry Chrystyn has no shares in any pharmaceutical companies. He has received sponsorship to carry out studies, together with some consultant agreements and honoraria for presentation, from several pharmaceutical companies that market inhaled products. These include Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Innovata Biomed, Meda, Napp Pharmaceuticals, Mundipharma, NorPharma, Norvartis, Orion, Sanofi, Teva, Truddell Medical International, UCB and Zentiva. Research sponsorship has also been received from grant awarding bodies (EPSRC and MRC). He owns 50 % of Inhalation Consultancy Ltd.
David B Price has Board Membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva. Consultancy: Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva, and Zentiva; Grants/Grants Pending with UK National Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva, and Zentiva; Payments for lectures/speaking: Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, SkyePharma, Takeda, and Teva; Payment for manuscript preparation: Mundipharma and Teva; Patents (planned, pending or issued): AKL Ltd.; Payment for the development of educational materials: GlaxoSmithKline, Novartis; Stock/Stock options: Shares in AKL Ltd which produces phytopharmaceuticals and owns 80 % of Research in Real Life Ltd and its subsidiary social enterprise Optimum Patient Care; received Payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva; Funding for patient enrolment or completion of research: Almirall, Chiesi, Teva, and Zentiva; Peer reviewer for grant committees: Medical Research Council (2014), Efficacy and Mechanism Evaluation programme (2012), HTA (2014); and Received unrestricted funding for investigator-initiated studies from Aerocrine, AKL Ltd, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva.
Mathieu Molimard has Board Membership and Consultancy with Almirall, AstraZeneca, BMS, GlaxoSmithKline, Lundbeck, Mundipharma, Novartis Pharma, Otsuka, Pfizer, Stallergen, Zentiva; received payment for travel/accommodations/meeting expenses from Novartis Pharma.
John Haughney has received reimbursements for attending symposia, fees for speaking, organising educational events, funds for research or fees for consulting from Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Mundipharma, Novartis and Teva.
Sinthia Bosnic-Anticevich has received reimbursements for attending meetings, fees for speaking, or consultancy from Mundipharma and Teva.
Federico Lavorini has received reimbursements for attending meetings, fees for speaking, or consultancy from: AstraZeneca, Boehringer Ingelheim, Chiesi, Mundipharma, GSK and Zentiva.
John Efthimiou has received fees for consultancy or speaking from GlaxoSmithKline, Oxagen, Sanofi, 3 M Pharmaceuticals, Vectura, and Zentiva.
Dawn Shan, Erika Sims, Anne Burden, and Catherine Hutton are employees of Research in Real Life, which conducted this study and which has conducted paid research in respiratory disease on behalf of the following other organizations in the past 5 years: Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva.
Nicolas Roche has received over the past 3 years (i) fees for speaking, organising education, participation in advisory boards or consulting from 3M, Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, MSD-Chibret, Mundipharma, Novartis, Pfizer, Sandoz, Sanofi, Stallergenes, Takeda, Teva; (ii) research grants from Novartis, Boehringer Ingelheim and Pfizer.
Authors’ contributions
HC, DBP, and ES led the study design process; DS is responsible for data collection; AB conducted the analyses. HC, DBP, MM, JH, SB-A, FL, JE, DS, ES, AB, CH, NR participated in the interpretation of the data, drafting and critical revision of the manuscript, and decision to submit the manuscript for publication. All authors read and approved the final manuscript.