Background
Inhaled drug delivery is the cornerstone of therapy for the treatment of obstructive chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD) [
1]. The most common devices used to administer aerosolized medication in day-to-day respiratory practice are the pressurized metered-dose inhaler (pMDI) and the dry powder inhaler (DPI). pMDIs are most often prescribed [
2], but patients need to inhale correctly and coordinate breathing and actuation to ensure effective drug delivery [
3‐
6]. In contrast, DPIs are breath-actuated, with most devices relying on a rapid and powerful inhalation manoeuvre for drug delivery, which can be particularly problematic for patients who struggle to inhale forcefully [
6].
Recent advances in inhaler technologies have seen an explosion in the number of devices [
7]. This plethora of devices, however, has led to confusion in their use amongst health-care providers (HCPs) and patients, who may not properly understand how to use inhalers [
8]. Indeed, mastering an inhaler device involves correct preparation and handling of the device before inhalation, and an optimal inhalation technique; an error in any step of this process may lead to inadequate drug delivery to the lungs.
There is no one ‘perfect device’ and several studies have shown that inhaler technique errors made by patients with asthma and COPD are common in real life with both pMDIs and DPIs despite advances in inhaler device technology [
3,
9‐
12]. Although study results vary, estimates of those making inhaler errors range up to 90% of patients irrespective of the device type used [
13,
14]. Most importantly, it is vital to distinguish between ‘critical’ (sometimes defined as ‘essential’ or ‘crucial’) errors, which are likely to significantly impair the delivery of adequate medication to the lungs, and ‘non-critical’ errors, which are likely to result in a reduced amount of drug reaching the lungs compared with that attained using the correct technique [
15,
16].
A recent major cross-sectional study of asthma patients has compared inhaler technique data with data on disease control, in order to determine which errors are most associated with poor health outcomes [
17]. The results of this may provide the most coherent basis for defining and identifying critical errors; however, progress towards fully elucidating these errors is slow.
The societal and health-economic burden of poor inhaler technique is increasingly being recognised [
10]. Worryingly, in three countries (the UK, Spain and Sweden) poor inhaler technique accounted for over €750 million in direct and indirect costs in 2015, for the two most commonly used DPIs [
18]. These cost data, together with the increasing prevalence of obstructive lung diseases and restriction in healthcare spending is propagating the imperative need for inhaler competency (that is, correct and effective inhaler use) [
15].
Recent global position documents from the Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD) both give significant prominence to assessing and correcting poor inhalation technique before escalating drug therapy [
19,
20].
Price et al. proposed the need for policy change and research focusing on current gaps in knowledge: specifically on the association between device errors and health economic and clinical outcomes, and on the patient characteristics associated with a higher frequency of errors [
15]. Indeed, clinicians must recognise that the device itself and its characteristics are at least equally as important as the prescribed drug; and that in future, the choice of drug compound may be considered to be of secondary importance [
3].
The aim of this study was to define ‘critical’ errors and their impact on health outcomes and resource use between 2004 and 2016. This was accomplished through systematically reviewing the scientific literature on inhaler errors made by patients when using pMDIs and DPIs, and the approaches used to assess them -- exploring the relationships between inhaler errors, disease outcomes, quality of life, and healthcare resource use, and associations between patient characteristics and inhaler errors. Given the striking variety of inhaler errors reported in the literature [
11], this paper focuses on critical errors, as these are most likely to have a health impact.
Discussion
The aim of our article was to define ‘critical’ inhaler errors and their impact on health outcomes and resource use; and by doing so, to bring to the attention of physicians the importance of the inhaler device in their daily prescribing in the management of patients with asthma and COPD. Indeed, both GINA and GOLD now highlight the critical importance of assessing inhaler technique to guide appropriate inhaler prescribing, with a concerted drive to educate professionals and patients about the real impact of inhaler errors on the patients’ disease control, as well as on the financial economics of societal health.
To our knowledge this is the first formally registered evidence-based systematic review with a priori clearly formulated questions that documents the wide discrepancies within the literature regarding definitions and descriptions of inhaler errors and their classification as either ‘critical’ or ‘non-critical’. Previous reviews such as that by Basheti et al. focusing on inhaler error checklists have approached these issues [
136], although in a different context.
Astonishingly, we observed 299 different descriptions of critical inhaler errors. Even for the same inhaler device type, different terminology was used between different study authors to describe the same inhaler error, and this may contribute to the confusion observed in clinical practice with regards to best inhaler practice and the limitations in determining associations with inhaler errors [
8]. This heterogeneity and lack of consensus fundamentally hampers the ability to interpret studies with respect to the impact of inhaler errors. Indeed, the different definitions of critical error could be a contributing factor to extremely different conclusions even with the same inhaler device type; as exemplified in the Melani study where MDI users were significantly less likely to commit critical errors relative to DPI users [
10], in contrast to the Batterink study where MDI users were most likely to make critical errors [
25].
The lack of consensus between researchers extends to the use of differing inhaler technique checklists. As the checklists used are not standardized, even within individual inhaler device types, comparing error rates between or within inhaler device types is unfeasible. Future research can and should adopt more consistent inhaler technique checklists, as the manufacturers’ instructions are available to form a basis for a checklist in almost all cases.
We observed several important factors, including older age, education status, lack of previous inhaler instruction, and lower socioeconomic class, which were all associated with high inhaler error frequency. In addition, inhaler technique interventions were found to decrease error frequency, and have positive impacts on disease and patient outcomes, as has previously been described in the literature by Basheti et al. [
137].
However these findings were not reflected in all studies, likely due to differences in study design and populations. For example, both interventional and observational studies were included, there were different inhaler devices included (i.e. pMDI or DPI), and wide ranging population sizes (between 46 and 6512 individuals), thereby limiting our ability to directly compare the results.
Interestingly, a significant association with error frequency was found for some comorbidities that are known to be strongly correlated with age, such as obesity, heart disease, or cognitive impairment [
48,
79,
80]; but despite this, only around a third of studies that examined age itself reported a significant association with error frequency.
Our systematic review identified studies showing an association between inhaler errors and poor asthma control and COPD disease stability. This is in line with a recent individual study that has demonstrated that inhaler errors affect drug delivery [
138]. Sulaiman showed in a laboratory environment that deliberately making certain inhaler errors led to a reduced amount of drug reaching the bloodstream [
138]. However, the limited quantity of disclosed research in this area may suggest that the term “critical” is being overused, with only a weak basis for categorising errors as such.
In a recent real-world study by Molimard in 2935 patients an increased risk of COPD exacerbation among patients who made a critical inhaler error, was confirmed [
139]. A further study by Price determined that the error of “insufficient respiratory effort” was associated with increased asthma exacerbation rate, as well as decreased control in general [
140].
Importantly, we identified eight economic models which linked inhaler errors to economic burden, of which one study by Roggeri demonstrated a specific link between critical errors and resource use, leading to an excess cost of many thousands of Euros per 100 patients making critical errors [
127,
128]. Indeed, recently Lewis and colleagues showed that poor inhalation technique led to approximately ¾ billion euros in direct and indirect costs for just two DPI inhalers used over 1 year [
18].
Previous literature has also demonstrated that poor disease outcomes are linked with worsened QoL and increased resource use and economic burden through increased physician consultation time and lost productivity (Additional file
1: Table S3) [
141‐
146]. Therefore, the issue of inhaler errors is important to address due to the downstream effects on patients, healthcare systems and society.
Our findings clearly illustrate inhaler technique can be affected by the level of instruction from HCPs. It is therefore important to interpret clinical trial results with caution, given that their controlled environment (where all patients are instructed in inhaler use) may not be representative of clinical practice in real life. This issue is especially important in the context of different inhaler devices that may have ergonomic designs and functions, as raised by Scichilone et al. in a 2015 review [
147]. The key message here is that in day-to-day practice, it may be an efficient strategy to provide patients at higher risk of errors with additional specifically tailored in-depth support with their inhaler use, to ensure they are confident with the correct technique.
Greater attention is clearly needed on the routine review of inhaler technique in the patient population as a whole, as a recent study by Sanchis reported rates of common inhaler errors to be static over a period of several decades [
11], and data also show that despite optimally prescribed inhaled therapy, levels of asthma control and COPD disease stability remain poor [
18,
145].
In comparison with a previously published systematic review only on DPI inhaler errors, our review encompasses a wider range of device types including the most commonly used inhaler device, the pMDI [
14]. Whilst Lavorini et al. included data on critical errors and provided a definition of a critical error, their study focused on the incidence of errors and the possible implications for clinical effectiveness of inhalers [
14]. A key strength of our review is that it integrates the link between inhaler errors and disease outcomes and QoL, and provides a systematic overview of how these critical inhaler errors are being assessed and measured.
Direct comparisons and synthesis of the data were challenging due to mixed methodologies (such as observational cross-sectional, or interventional cross-over designs, and designs intended for descriptive or qualitative analysis), different patient populations, and varied endpoints. Yet, despite these differences we observed clear trends in our data. However, due to the vast differences between studies, this review did not examine clinical outcomes by device, but this is an important area for future research.
Furthermore, only a handful of the reviewed studies directly addressed patient outcomes and the economic burden of inhaler errors. Therefore, further research and potential health-economic modelling to understand the relationship between inhaler technique and disease outcomes, and the subsequent impact on societal healthcare systems, is vitally required.
Although the present study shows associations between inhaler errors and patient outcomes through a review of chronic obstructive respiratory diseases as a whole, future research may be able to probe further into the two diseases (asthma and COPD). For example, the generally older age, poor prognosis and comorbidities of COPD patients may influence the degree to which their QoL is increased by improvements in technique and control [
148]. The substantially higher prevalence of comorbidities among COPD patients, relative to asthma patients, also likely impacts inhaler technique and patient QoL [
148].
With the variety of definitions identified in our review, difficulties arise in determining whether a particular inhaler type is inherently more vulnerable to critical inhaler errors. Consistent use of our proposed definition and categorization by all researchers internationally would transform this area of research and greatly facilitate quantitative and objective comparison between devices, providing a clearer indication of the associated error rates. This would revolutionise everyday clinical practice, where reliable comparisons of error rates would greatly help physicians and aid informed treatment decisions, ensuring the most appropriate device is prescribed for the individual patient with clear implications for personalised patient management. Further research into the association of patient characteristics with error rate could examine “health literacy”, a patient’s insight into their own treatment and health system, and determine if poor knowledge is a risk factor for poor technique [
115,
149‐
151].
It is clear that inhaler errors have an effect on disease outcomes, and ultimately patient outcomes and economic burden. This in turn will have an impact on overall disease management and affect not only patients but also the wider healthcare system. These findings are increasingly important given the plethora of devices available to HCPs and patients, and highlight the importance of inhaler mastery in managing and treating asthma and COPD.
There is increasing evidence to suggest that correct inhaler technique (mastery) is fundamental for effective therapy, and that inhaler device type and mastery play important roles in improving adherence, clinical outcomes, quality of life, and use of healthcare resources. Evidence suggests that prescribers should consider patients’ mastery of technique (or lack thereof) and ease of use before changing the dose of inhaled medications, switching to a different inhaler, or adding other treatments to the regimen of patients with poorly controlled asthma. Recent international asthma guidelines highlight the importance of testing and ensuring mastery, alongside checking adherence, before increasing or changing therapy.
Conclusions
In conclusion, the multitude of definitions cited within the literature indicates that there is an urgent need for a consensus in the way in which critical (and non-critical) inhaler errors are defined. We propose defining a critical inhaler error as an action or inaction that in itself would have a definite detrimental impact on the delivery of the drug to the lung, in contrast to a non-critical error which we would define as an action or inaction that in combination with other factors may, or may not, contribute to ineffective delivery of the drug to the lung.
We advocate that there is a real need for an independent international panel of inhalation experts to collectively determine, through evidence and consensus, the definitions of critical and non-critical inhaler errors. If done for each device type, this would demystify the current confusion within the respiratory community.
We also propose that future studies classify individual errors into categories such as inhalation manoeuvre, dose preparation, inhaler handling, device-specific or generic, in order to make comparison and analysis simpler in order to ultimately help healthcare professionals help their patients.
Acknowledgements
We would like to thank Alison Saunders, Iván Viejo Viejo and Rebecca Forster for their support in quality checking and co-ordinating this manuscript and Robin Wyn for editorial assistance.
Competing interests
In the last 5 years, Omar S. Usmani and/or his department received research grants, unrestricted educational grants, and/or fees for lectures and advisory board meetings from Aerocrine, Astra Zeneca, Boehringer Ingelheim, Chiesi, Cipla, Edmond Pharma, GlaxoSmithKline, Napp, Mundipharma International, Prosonix, Sandoz, Takeda, Zentiva.
In the last 5 years, Federico Lavorini received fees for lectures and advisory board meetings from Astra Zeneca, Boehringer Ingelheim, Chiesi, Cipla, Menarini International, TEVA, Zentiva.
In the last 3 years, Richard Dekhuijzen and/or his department received research grants, unrestricted educational grants, and/or fees for lectures and advisory board meetings from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma International, Novartis, Takeda and Teva.
William Dunlop and Jonathan Marshall are employees of Mundipharma International Ltd., United Kingdom.
Emily Farrington and Louise Heron are employees of Adelphi Values Ltd., UK. Adelphi Values Ltd. received funding from Mundipharma International Ltd. to support this research.
The authors do not report any conflict of interest with regards to the contents of this study other than those stated.