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Chronic obstructive pulmonary disease
Does mixing inhaler devices lead to unchecked inhaler technique errors in patients with COPD? Findings from the cross-sectional observational MISMATCH study
  1. Lars Dijk1,
  2. Marjan Kerkhof1,
  3. Merijn Driessen1,
  4. Yoran H Gerritsma1,
  5. Sinthia Bosnic-Anticevich2,3,
  6. Jaime Correia-de-Sousa4,
  7. P N Richard Dekhuijzen5,
  8. Marika Leving1,
  9. David B Price6,7,
  10. Ioanna Tsiligianni8,
  11. Omar Usmani9,
  12. Huib A M Kerstjens10,11 and
  13. Janwillem W H Kocks1,7,11
  1. 1General Practitioners Research Institute, Groningen, The Netherlands
  2. 2Macquarie University, Sydney, New South Wales, Australia
  3. 3University of Sydney, Woolcock Institute of Medical Research, Sydney, New South Wales, Australia
  4. 4Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
  5. 5Radboud University Nijmegen, Nijmegen, The Netherlands
  6. 6Centre of Academic Primary Care, Division of Applied Health Sciences, Univ Aberdeen, Aberdeen, UK
  7. 7Observational and Pragmatic Research Institute, Singapore
  8. 8Department of Social Medicine, Health Planning Unit, Faculty of Medicine, University of Crete, Rethimno, Greece
  9. 9Airway Disease, National Heart and Lung Institute (NHLI), Imperial College London, London, UK
  10. 10Department of Pulmonology, University Medical Center, Groningen, The Netherlands
  11. 11University Medical Center Groningen, GRIAC Research Institute, Groningen, Netherlands
  1. Correspondence to Dr Janwillem W H Kocks; janwillem{at}gpri.nl

Abstract

Background Patients with chronic obstructive pulmonary disease (COPD) may be prescribed multiple inhalers that require different techniques for optimal performance. Mixing devices has been associated with poorer COPD outcomes suggesting that it leads to inappropriate inhaler technique. However, empirical evidence is lacking.

Aims Compare the nature and frequency of dry powder inhaler (DPI) technique errors in patients with COPD using (1) a single DPI or (2) mixed-devices (a DPI and pressurised metered dose inhaler (pMDI)).

Methods Data from the PIFotal study—a cross-sectional study on Peak Inspiratory Flow in patients with COPD using a DPI as maintenance therapy, capturing data from 1434 patients on demographic characteristics, COPD health status and inhaler technique—were used to select 291 patients using mixed-devices. Frequency matching based on country of residence and DPI device type was used to select 291 patients using a DPI-only for comparison. Predetermined checklists were used for the evaluation of DPI video recordings and complemented with additional errors that were observed in ≥10%. Error proportions were calculated for the (1) individual and total number of errors, (2) number of critical errors and (3) number of pMDI-related errors.

Results The study sample contained 582 patients (mean (SD) age 69.6 (9.4) years, 47.1% female). DPI technique errors were common, but not significantly different between the groups. The majority of patients made at least one critical error (DPI-only: 90.7% vs mixed-devices: 92.8%). Proportions of total, ‘pMDI-related’ and critical errors did not significantly differ between the groups.

Conclusion The nature and frequency of inhaler technique errors did not substantially differ between patients prescribed with a single DPI and mixed-devices. Currently, ‘pMDI-related errors’ in DPI use are not accounted for in existing checklists.

Trial registration number ENCEPP/EUPAS48776.

  • Inhaler devices
  • COPD Pharmacology
  • Pulmonary Disease, Chronic Obstructive

Data availability statement

Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjresp-2023-001821

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Previous literature has shown that the effectiveness of inhaler therapy can be adversely affected by suboptimal inhaler technique. Prescribing multiple inhalers requiring different inhalation technique could worsen this problem and has been associated with worse outcomes in patients with chronic obstructive pulmonary disease (COPD).

    WHAT THIS STUDY ADDS

    • This study showed that, irrespective of the type of device(s) prescribed, patients with COPD reveal poor dry powder inhaler (DPI) technique in general and are also likely to make inhaler technique errors that are currently not accounted for in DPI-specific checklists.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • The results from this study provide evidence to support changes to potential refinement of inhaler-specific checklists, as patients with COPD seem to be prone to a mismatch between their inhaler technique and prescribed inhaler device.

    Introduction

    Chronic obstructive pulmonary disease (COPD) is a common chronic lung disease that is characterised by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities.1 Pharmacological therapy can reduce COPD symptoms, reduce the frequency and severity of exacerbations, and improve health status and exercise tolerance. Inhaled drug therapy is the cornerstone of treatment of COPD. However, use of inhaler devices can be challenging, potentially leading to critical errors that can reduce drug delivery to the lungs.2 3 Therefore, correct inhaler technique is fundamental for effective therapy in both asthma and COPD.2–4

    There is a wide range of inhalers for COPD on the market, each with its own required technique. There are three principal types of inhalers, which require differing techniques for optimal performance: dry powder inhalers (DPIs), pressurised metered dose inhalers (pMDIs) and soft mist inhalers (SMIs). While DPIs are breath-actuated, and therefore, require the patient to generate sufficient peak inspiratory flow by inhaling forcefully and rapidly, pMDIs and SMIs are less dependent on a patient’s inspiratory ability but require patients to have a proper actuation-inhalation technique, ensuring that actuation follows a slow inhalation (when not using a spacer).5 There are also substantial differences in dose preparation, for example, suspension pMDIs need to be shaken before dose administration, but shaking a primed DPI may, in some devices, lead to falling out powder and therefore a reduction of administered powder during the inhalation manoeuvre.

    Handling errors are likely to increase when patients use a combination of inhalers that require different techniques, yet prescribing both a DPI and a pMDI simultaneously is common in the treatment of COPD.4 For example, the number of inhaler devices used substantially increased the risk of making ‘critical’ errors that affected drug delivery in a Swedish real-life population of patients with COPD.6 Furthermore, a mixture of devices requiring dissimilar techniques has also been associated with worse COPD outcomes (eg, higher rate of exacerbations).7

    The PIFotal COPD study, a cross-sectional multicountry observational study performed in a primary care setting, made video recordings of the inhaler technique of 1434 patients with COPD when using their DPI.8 These videos were scored for correctness of the steps required to achieve a good inhaler technique for the specific DPI-device based on device-specific checklists. Within the PIFotal study, specific combinations of errors related to the inhalation manoeuvre (ie, not breathing out to empty the lungs before the inhalation, insufficient inspiratory effort, no breath-hold for at least 6 s after the inhalation) were deemed clinically relevant based on their association with worse health outcomes.9

    Assessing the handling for individual devices, on the basis of standardised checklists, is primarily focused on ensuring that every step required for delivery of medication is correct. Beyond the bounds of a priori defined errors of interest, it is conceivable that patients may perform actions with a DPI that are part of a pMDI’s required technique—and vice versa. Hence, it would be of interest for clinical research/practice to consider all sets of errors that may affect drug delivery but are not accounted for in predetermined checklists. More insights in all potential errors may provide additional guidance for future selection of inhaler devices in these already complex patients.

    Therefore, in the current analysis, we aimed to compare the nature and frequency of inhaler technique errors, by describing all errors observed rather than using predetermined checklists, between two groups of patients with COPD using either (1) a single DPI or (2) a combination of a DPI and a pMDI.

    Methods

    Data source and permissions

    Data from the cross-sectional observational real-world PIFotal COPD study were used.8 10 These data were collected between October 2020 and May 2021 in 102 sites across five European countries (Greece, the Netherlands, Poland Portugal, Spain) and Australia. The MISMATCH study was conducted according to standards recommended for observational research11 and the use of the PIFotal COPD data was approved by the PIFotal data governance committee and the Anonymous Data Ethics Protocols and Transparency committee—an independent body of experts and regulators commissioned by the Respiratory Effectiveness Group reviewed and approved the protocol.12 Patients’ consent to use their data for future studies was obtained. The MISMATCH study was registered with the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP/EUPAS48776).13

    Study design

    Two study groups were created with patients that either used a single DPI (ie, ‘DPI-only’) or used a combination of a DPI and pMDI (ie, ‘mixed-devices’). Balanced 1:1 frequency matching was applied based on country of residence, the device-type and the number of doses that can be loaded into the device (single dose capsule vs multiple dose), to minimise the potential confounding effects of these factors on the comparison of the DPI technique errors between the groups.

    Inclusion and exclusion criteria

    In the PIFotal COPD study, inclusion/exclusion criteria were limited to ensure a real-world setting as much as possible. Participants were included in the analysis if the following criteria were met: a clinical diagnosis of COPD, aged 40 years or older at the time of their PIFotal study visit and treated with a DPI as maintenance therapy for their COPD for at least 3 months. Participants were excluded from the study if they were participating in clinical trials with COPD medication, if they had an exacerbation in the 6 weeks prior to the study visit or if they had a life-threatening disease with a life expectancy <6 months. In the MISMATCH study, only participants were included in the analysis who provided written informed consent for use of their video/data for future research. Therefore, Australian patients were excluded from this analysis.

    Inhaler technique

    Patients’ inhaler technique when using their DPI was observed and documented by video recording which was rated offline for errors by two independent reviewers for correctness. To describe all errors, rather than using predetermined checklists only, a sample of 100 DPI videos was selected from the mixed-devices group to observe all types of inhalation actions that were made and that may affect lung deposition. To account for the variety/number of device-specific inhalation actions, one-third (n=33) of the videos was randomly selected from single-dose capsule-based DPIs while the remainder was randomly selected from the eligible multiple-dose DPIs (n=67). The standard list of device-specific errors (online supplemental table 1) to be scored in the full population was complemented with additional errors that were observed at least in 10% of the patients who were eligible for making that specific error with their device. An overview of all new errors added can be found in table 1.

    View this table:
    Table 1

    Overview of additional errors supplemented to the prespecified checklist

    The device-specific checklists that were added on in this study were based on predefined instruction protocols by the Netherlands Lung Alliance (www.inhalatorgebruik.nl), or, if unavailable, the Aerosol Drug Management Improvement Team (www.inhalers4u.org) We scored whether the error was observed, and each inhaler technique error could therefore either be scored as ‘yes’ (error) or ‘no’ (no error), or marked as ‘not applicable’.

    The reassessment of all videos was done separately by two trained researchers. Differences between the two independent observers were resolved by discussion. Unfortunately, data on the inter-rater reliability were not captured. However, the videos were distributed among assessors and evaluated in batches of approximately 20 videos. When researchers could not reach consensus, a third independent expert arbitrated.

    Adherence, health status and exacerbations

    Adherence was calculated based on the answers on the 10-item Test of Adherence to Inhalers (TAI-10).14 Items could be scored 1–5 points each. Only if participants scored the maximum number of points on all items (total 50 points), he or she was considered adherent. The TAI questionnaire has been validated in patients with COPD and asthma and correlated with electronic adherence (≥80%).14

    COPD-related health status was measured with the 10-item self-administered Clinical COPD Questionnaire (CCQ),15 consisting of three domains: symptoms, functional status and mental health. The CCQ-score is the mean score of 10 item-scores, where each item is scored on a 7-point Likert scale indicating the severity of symptoms.

    Moderate exacerbations were defined as exacerbations treated with oral corticosteroids or antibiotics without hospital admission and severe exacerbations were defined as exacerbations requiring hospital admission.

    Statistical analysis

    Patient characteristics (including demographic variables, maintenance therapy, comorbidities, COPD-related health status and the number of exacerbations in the past 12 months) and the frequency of all inhaler technique errors were described for the total study population, and the likelihood of making the errors was estimated as an OR comparing frequencies observed in both groups (DPI-only vs mixed-devices).

    Moreover, the proportion of errors was calculated and compared between the groups. For this article, the proportions were calculated for (1) the total number of DPI technique errors, (2) the number of ‘pMDI-related’ errors and (3) the number of ‘critical’ DPI technique errors while using a DPI (table 2).

    View this table:
    Table 2

    Combinations of errors used for the analysis

    For each outcome-predictor combination, a binomial multilevel regression model was fitted, allowing for a random effect at the level of the participant’s country of residence (n=5). We corrected for overdispersion in the data by including an observation level random effect.16 With these models, we estimated the ORs and 95% CIs for error proportions in the mixed-devices group compared with the DPI-only group. The models were weighted for the number of errors that could be made with the used device (ie, denominator of the proportion) and device type (ie, single-dose capsule vs multidose DPI) was added as fixed effect to the model. We estimated the bias potential of candidate confounders by estimating the relative change in coefficient of the fixed effect under study (DPI-only vs mixed-devices group) after adding the candidate to the unadjusted model. Candidate confounders were then sorted by bias potential in descending order and included in the model one by one. Whenever the bias was ≥5%, the candidate confounder was retained in the model. An overview of all candidate confounders can be found in online supplemental table 2. Sensitivity analyses were carried out to investigate potential modifying effects of country of residence (eg, due to country-specific guidelines/inhaler instructions) by including it as a fixed effect, as well as an interaction term between country of residence and the fixed effect under study (DPI-only vs mixed-devices group). For the analysis, we used complete cases.

    The level of statistical significance was set at p<0.05. The sample size was determined by the number of eligible patients in the PIFotal dataset according to the inclusion criteria and by the number of patients who could be matched to a patient in the comparison group.

    All statistical analyses were performed in R V.4.0.5 17 in the Rstudio IDE (V.7.2.576).18

    Patient and public involvement

    No patients were directly involved in the conceptualisation and design of the study. A scientific advisory board has been set up to provide advice on the study protocol, the conduct of the study, statistical analysis and interpretation of the data. All members of the scientific advisory board are distinguished researchers and/or clinicians in the field of respiratory medicine and care for patients with COPD. We plan on sharing our findings with clinicians, patients and the public.

    Results

    Study population

    After applying the inclusion and exclusion criteria, a total of 582 participants with COPD from Greece, the Netherlands, Poland, Portugal and Spain were eligible for this study (figure 1). The devices used for the evaluation of the DPI video recordings are shown in table 3. Of these participants, 47.1% were female and the mean (SD) age was 69.6 (9.4) years. The level of COPD airflow obstruction was available for 304 participants and classified as GOLD severity I in 76 (25.0%), II in 150 (49.3%), III in 56 (18.4%) and IV in 22 (7.2%). A capsule DPI as primary inhaler was used in 45.5% of the participants. Participant characteristics are shown in table 4 and online supplemental table 3.

    Figure 1
    Figure 1

    Flow diagram showing study groups derived from the PIFotal study.10 DPI, dry powder inhaler.

    View this table:
    Table 3

    Overview of primary dry powder inhalers (DPIs) used for the evaluation of the video recordings

    View this table:
    Table 4

    Overview of participant characteristics

    Significant differences (in percentages) between the groups were found in maintenance therapy (eg, more triple therapy in mixed-devices group), years since diagnosis (higher in mixed-devices group), concomitant asthma (more in mixed-devices group), forced expiratory volume in 1 s (lower in mixed-devices group), number of moderate exacerbations in the previous year and CCQ (higher in mixed-devices group) (table 4).

    Nature and frequency of inhaler technique errors

    In general, the presence and nature of the inhaler technique errors in DPI use was not significantly different between the groups (figure 2).

    Figure 2
    Figure 2

    OR (and frequency) of inhaler technique errors in patients with COPD using mixed-devices compared with patients using a DPI only. The size of the rectangle indicates the frequency of the errors. COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; pMDI, pressurised metered dose inhaler.

    Additional errors (supplemented to the prespecified checklists, listed in table 1) were common in both group, such as exhaling through the device before (7% in mixed-devices vs 3% in DPI-only group) or after the first inhalation (18% in mixed-devices vs 13% in DPI-only group). Inhaling unnecessarily multiple times through the device was common (19% in mixed-devices vs 16% in DPI-only group). In both groups, more than 60% of the patients with capsule DPIs did not check powder residue at the end of the inhalation, and about 10% of the patients primed the inhaler more times than necessary.

    Regarding the critical errors (table 2), ‘no breath-hold (at least 6 s)’ was more likely to occur in the mixed-devices group (80%) compared with the DPI-only group (70%). The frequency of insufficient inspiratory effort was higher in the mixed-devices compared with the DPI-only group (48% vs 42%), yet without reaching significance. Not breathing out completely before inhalation was observed in more than three-quarters of both the DPI-only and mixed-devices group (77% and 78%, respectively)

    The pMDI-related error ‘shaking of the device’ was more frequently observed before priming (6% in mixed-devices; 3% in DPI-only) than after (2% in mixed-devices, 3% in DPI-only) priming without significant differences between the groups. Pressing the button while inhaling through the device was observed in 11% of the mixed-devices and 8% of the DPI-only group.

    Adjusted differences in error proportions between the groups

    The total error proportion and the pMDI-related error proportion was not significantly different between the groups (figure 3).

    Figure 3
    Figure 3

    Differences between the groups in the proportion of (1) total number of DPI technique errors, (2) pMDI-related errors while using a DPI and (3) critical DPI technique errors. ORs were adjusted for the following confounders: total errors: concomitant asthma; CCQ; maintenance therapy; body mass index; smoking status; number of moderate exacerbations in the previous year. pMDI-related errors: maintenance therapy; CCQ; smoking status; age. Critical errors: CCQ; maintenance therapy; number of moderate exacerbations in the previous year; smoking status.

    Regarding the proportion of critical errors, 37.5% of patients in the mixed-devices group and 30.2% of patients in the DPI-only group made all the critical errors that could be observed (online supplemental table 4). In the unadjusted analysis (not adjusted for additional confounders), the mixed-devices group were more likely to make a higher proportion of critical errors compared with the DPI-only group (OR 1.34, 95% CI (1.07 to 1.69), p=0.01). The association did not remain significant after adjusting for potential confounding factors (OR 1.27, 95% CI (0.98 to 1.65), p=0.07, figure 3).

    Sensitivity analyses

    The OR of making critical errors in the mixed-devices groups as compared with the DPI-only group was significantly (p=0.04) greater in Portugal (OR 2.56, 95% CI (1.07 to 6.10)) than in the other countries (OR 1.24, 95% CI (0.97 to1.60)). The associations for the total errors and pMDI-related errors were not significantly different across the countries.

    Discussion

    Principal findings

    This study in primary care patients with COPD showed that DPI technique errors are common, both in patients using a DPI-only and in patients using mixed-devices. On top of high error frequencies identified based on steps listed on standard checklists, this study demonstrated that patients with COPD—irrespective of whether devices are mixed or not—tend to make errors that are usually not covered by predetermined DPI checklists. Patients with COPD using mixed-devices did not make more errors compared with patients using a single DPI, although the unadjusted analysis showed a higher proportion of ‘critical’ inhaler technique errors in patients prescribed with mixed-devices as compared with patients using a DPI-only.

    Interpretations and comparison with previous studies

    The MISMATCH study focused on all actions performed when using a DPI that could potentially affect drug delivery, including actions that are part of the required technique for a pMDI. To this end, inhaler checklists were supplemented with a list of additional errors frequently observed in a subset of 100 video recordings. This data-driven, empirical, approach is unique as most of the currently available literature identified errors solely based on a priori defined, not necessarily data-driven, DPI-specific checklists.2 The frequency of the additional errors (eg, exhaling through the DPI, multiple inhalations through the device, shaking of the DPI) warrants the need for more awareness among healthcare professionals (HCPs) of these potential device-handling errors and discrepancy between the patients’ inhaler technique and the prescribed device. A practical implication of this finding is that during a check-up of inhaler technique, HCPs should be encouraged to ask the patient to demonstrate their day-to-day manoeuvre with their own device (or a placebo-device). This may reveal unexpected handling errors, or those that are not covered by standard checklists, potentially reducing the treatment efficacy. The GOLD guidelines recommend regular inhaler technique assessments, and that it should be part of the management cycle in the adjustment of a patient’s pharmacological treatment. In view of this recommendation, it is pivotal to note that 78% of the patients in this study did not receive inhaler technique instructions a year before the study visit. This is a missed opportunity, as previous research showed that a one-time educational demonstration and correction of inhaler technique reduces the proportion of patients making inhaler technique errors with a detrimental impact on the delivery of the drug to the lung (eg, incorrect dose preparation and loading), persistent after a follow-up period of 1 year.19

    There is a wide range of inhalers for COPD on the market, each with its own required technique. Previous studies showed that mixing inhaler devices could lead to more inhaler technique errors due to the confusion and mismatch between inhaler technique instructions between devices.7 19–22 We could not confirm these results. Evidence showed that patients with asthma using a combination of DPIs were more likely to perform all ‘essential’ inhaler technique steps correctly compared with patients prescribed with mixed-devices (DPI plus pMDI), 68% vs 54%, respectively. The authors argued that, whenever possible, HCPs should prescribe only one type of inhaler.23 However, for the DPIs in their study, only two steps of the inhaler technique (correct priming of the device and inhaling forcefully and deeply) were considered, whereas the MISMATCH study focused on all actions that are part of the DPI technique. Another explanation for not confirming these results is that both groups in the current study were matched on the DPI. Device type, rather than the use of multiple inhalers, has been found to be a relevant factor associated with incorrect inhaler technique in patients with COPD.24 Additionally, it should be acknowledged that information on previous device use was not captured in this study. For instance, it might be that some patients in the DPI-only group previously used another type of device at the time of their diagnosis, such as a pMDI for their rescue medication as needed, but that they switched to a DPI as maintenance therapy when the disease worsened—or that guidelines changed over the years. Previous device prescription may influence the current device handling of the patient and, thus, should be considered when HCPs are trying to select the most appropriate inhaler for the patient with COPD.

    Multiple inhaler technique steps may be interrelated and contribute to worse outcomes, as evidenced by the combination of ‘critical’ errors associated with COPD health status (listed in table 2).9 Not sufficiently breathing out to empty the lungs before the inhalation may hamper the generation of sufficient inspiratory flow due to lack of inhaled volume25—a fundamental step for dose emission since DPIs are flow-dependent. Aforementioned errors may affect the capability for sufficient breath-hold time—essential for particles to be deposited in the peripheral areas by sedimentation.26 The current study observed a tendency towards a higher proportion of these ‘critical’ errors in the mixed-devices compared with the DPI-only group. A possible explanation of the observed difference is the discrepancy between breathing manoeuvre instructions of DPIs and pMDIs. The generic instruction for DPIs is to inhale as fast and deeply as possible, whereas patients using a pMDI are instructed to breathe in slowly and steadily given that pMDIs are less dependent on a patient’s inspiratory ability. However, this finding should be interpreted with caution, as it could—in general—have been biased by the higher disease severity in the mixed-devices group. Increased disease severity has been associated with lower inspiratory muscle strength27 and reduced peak inspiratory flow28 in patients with COPD, potentially contributing to the proportion of these ‘critical’ errors. The same applies to the observed country-specific differences since, in general, Portuguese patients in the mixed-devices group had significantly (p<0.001) worse health status compared with the other countries (mean (SD) CCQ 3.09 (1.26) vs 2.11 (1.08), respectively). The definition of ‘critical’ errors was based on the association of prespecified inhaler technique errors on COPD health-status,9 therefore, excluding the list of new ‘additional’ errors defined in the current study. Future larger studies should investigate whether the additional errors observed in this study are associated with poor COPD outcomes and should be deemed ‘critical’.

    Another large database study (n=23 494) found that patients using multiple devices were more likely to be non-adherent to their prescribed therapy compared with patients using a single device.29 This suggests that simpler treatment regimens may be preferred by patients with COPD. In the MISMATCH study, the prevalence of non-adherence (measured with the TAI-questionnaire14) did not differ between both groups and was not identified as a relevant confounder in the association with the proportion of errors. With proper inhaler technique as fundamental aspect of medication adherence, this study highlights that an understanding of the patients’ day-to-day use and attitudes and beliefs with regard to their inhaler therapy is paramount when selecting the appropriate device for the patient. By using real-time data on inhaler technique, smart inhaler programmes have the potential to optimise self-management, enhance inhaler technique and ultimately improve disease outcomes.30

    A strength of the MISMATCH study is that it was carried out on a real-life, multinational, COPD patient population, including a variety of DPIs. Furthermore, the results of the data-driven approach provide strong empirical evidence for a set of ‘additional’ errors that are currently not recognised in inhaler technique checklists. The sensitivity analysis showed that the proportion of errors were not substantially different across the countries, pointing towards the generalisability of the findings. Although this was a post hoc, observational study, a key strength of the study was the matching procedure based on patients’ device-type and country of residence. Moreover, the analysis was adjusted for a comprehensive set of potential confounders based on the literature and clinical expertise, such as age31 and treatment adherence.32

    Because this study used the video ecordings and data from a previously conducted study, only data collected at that time were used in the MISMATCH study. Some potential factors may warrant further investigation. First, information about previous device use, years since asthma (or first) diagnosis, and the use of a spacer in combination with a pMDI were not captured. The latter is relevant to clarify some of the errors potentially related to the multiple breath method, such as breathing out through the device after the first inhalation (observed in 18% of mixed-device cluster, figure 2). Second, missing GOLD severity data resulted in an inability to eliminate potential confounding by disease severity—although proxies of disease severity were included in the adjusted models, such as the score on the CCQ and exacerbation rate. We cannot draw any conclusion about a causal effect based on this observational study. However, the use of mixed devices could potentially serve as a proxy for unstable COPD—as indicated by higher CCQ scores compared with DPI-only users, and for instance, the need for pMDI rescue medications. Third, SMIs were not included in the analysis although these devices, in terms of inhaler technique, could be considered rather similar to pMDIs. The low sample (n=35, 2.4%) of patients in the PIFotal dataset using an SMI in combination with their DPI suggested that these patients may had a special indication, which would have been difficult to evaluate. Lastly, the PIFotal study8 only videorecorded the patients while using their primary DPI. As a potential mismatch between DPI and pMDI instructions could be reciprocal, it would be interesting to investigate whether cross-over effects might be observed when patients in the mixed-devices group use their pMDI—or to compare the mixed-devices group with patients using two or more devices requiring similar inhaler technique (eg, two or more aerosol delivery devices).

    Greater emphasis for more careful consideration to be given to the choice of prescribed inhaler devices in COPD has been called for in the literature.33 The results from this study provide evidence to support changes to potential refinement of inhaler-specific checklists, as patients with COPD seem to be prone to a mismatch between their inhaler technique and prescribed inhaler device. This potential mismatch should be a further consideration when HCPs are prescribing (additional) inhaler therapies.

    Conclusion

    Irrespective of the type of device(s) prescribed, patients with COPD reveal poor DPI technique in general and are also likely to make inhaler technique errors that are currently not accounted for in DPI-specific checklists. Future research is needed to assess the potential impact of these errors on clinical outcomes, as this may help to refine inhaler checklists and could provide additional guidance for device selection in patients with COPD. For optimal COPD treatment in primary care, it is important to assess a patient’s inhaler technique, with the optimal checklist, to minimise the potential negative consequences of a mismatch between the patient’s technique and their prescribed inhaler(s).

    Data availability statement

    Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and the MISMATCH study was conducted according to standards recommended for observational researchand the use of the PIFotal COPD data was approved by the PIFotal data governance committee and the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee—an independent body of experts and regulators commissioned by the Respiratory Effectiveness Group reviewed and approved the protocol. Patients’ consent to use their data for future studies was obtained. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    The members of the MISMATCH study group would like to acknowledge Titia Klemmeijer (founder of the IMIS foundation; ‘Inhalatie Medicatie Instruction School’) for her assistance in formulating the list of additional errors, and Chantal Arling, Thomas le Rutte & Landy Torre for their time and efforts to perform the reassessments of the video recordings. Finally, they would like to thank the participants who generously gave their time to participate in the PIFotal study and provided informed consent to use their video/data for future research.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Twitter @GerritsmaYoran

    • Contributors LD, MK and JWHK conceptualised the study. LD, MK, MD and YG analysed the data. All authors ensured the accuracy of the analysis. All authors edited and approved the final manuscript. The corresponding author attested that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. JWHK is the guarantor.

    • Funding This work was supported by Chiesi Pharmaceuticals. The PIFotal study was cofunded by Boehringer Ingelheim.

    • Competing interests LD, MK, MD, YG and ML were employed by the General Practitioners Research Institute (GPRI) at the time of the study. In the past 4 years (2019–2022), GPRI conducted investigator-initiated and sponsor-initiated research funded by non-commercial organisations, academic institutes and pharmaceutical companies (including AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, Novartis and Teva). SB-A has received grants from TEVA, and personal fees from TEVA, Boehringer Ingelheim, AstraZeneca, GSK, Sanofi and Mylan. JC-d-S reports or personal fees from AstraZeneca, Bial, Boehringer Ingelheim, GSK, Medinfar, Mundipharma and Sanofi. PNRD has received grants and personal fees from TEVA, Boehringer Ingelheim, AstraZeneca, GSK, Chiesi, Focus Care, and Glenmark. HAMK has performed consultancies for, received unrestricted research and educational grants from, and has participated in clinical trials on a per patient fee basis for: AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Novartis. All renumerations were non personal and were received by his institution. DBP reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Theravance and Zentiva (Sanofi Generics); grants from the British Lung Foundation, Respiratory Effectiveness Group, UK National Health Service, and AKL Research and Development; personal fees from Cipla, GlaxoSmithKline, Kyorin, Merck, Mundipharma, Airway Vista Secretariat, EPG Communication Holdings, FIECON, Fieldwork International, OM Pharma SA, PeerVoice, Phadia AB, Spirosure, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, and WebMD Global; non-financial support from Efficacy and Mechanism Evaluation programme and Health Technology Assessment; stock/stock options from AKL Research and Development, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); and 5% shareholding in Timestamp, which develops adherence monitoring technology. IT reports grants and personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Menarini, Novartis, Chiesi and Elpen. OU reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Edmond Pharma, Chiesi and GSK; grants from Edmond Pharma; and personal fees from Napp, Mundipharma, Sandoz, Takeda, Cipla, COVIS, Novartis, Mereobiopharma, Orion and Menarini. JWHK reports grants, personal fees and non-financial support from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants and personal fees from Chiesi, grants, personal fees and non-financial support from GSK, non-financial support from Mundi Pharma, grants and personal fees from Teva, personal fees from MSD, personal fees from COVIS Pharma, grants from Valneva outside the submitted work; and JWHK holds <5% shares of Lothar Medtec and 72.5% of shares in the General Practitioners Research Institute.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.