https://orcid.org/0000-0001-6332-4895
Abstract
Background
In patients with COPD, inhalation ability should be assessed when considering inhaler choice. To evaluate whether the soft mist inhaler (SMI) is suitable for COPD patients irrespective of inhalation ability, the TRONARTO study investigated the efficacy of dual long-acting bronchodilator therapy delivered via the Respimat® SMI on lung function in patients with COPD stratified by inhalation ability. Tiotropium/olodaterol delivered via the SMI was effective both in patients with peak inspiratory flow (PIF) <60 L/min and PIF ≥60 L/min, measured against medium-low resistance.
Methods
This congress compilation summarizes post hoc analyses from the TRONARTO study presented at the annual American Thoracic Society 2022 and European Respiratory Society 2022 meetings. These analyses evaluated PIF in over 200 patients, with PIF measurements taken daily at home for 4 weeks, and in the clinic at baseline, Weeks 2 and 4.
Results
Overall, 57.9% of patients had a PIF range (difference between lowest and highest PIF measurements) <20 L/min (12.4% of patients had PIF range <10 L/min). At-home PIF range decreased over the study period, suggesting that inhaler training/repeated PIF measurements may help to make patients’ inspiratory effort more consistent. Some patient characteristics correlated with lower PIF (female gender, shorter stature, more severe disease, worse airflow obstruction) and lower PIF range (more severe disease). PIF measurements differed between medium-low and high-resistance settings, highlighting the importance of measuring PIF at the resistance of a patient’s inhaler. PIF correlated poorly with spirometry measurements.
Conclusion
As indicated in COPD management guidelines, choice of inhaler is essential to optimize pharmacologic therapies for COPD. Poor inspiratory ability should be viewed as a treatable trait that can help to inform inhaler choice. Inhaler training and consideration of PIF (if patients use a dry powder inhaler) can reduce patient-to-inhaler mismatch, with potential consequences for health status and exacerbation risk.
Introduction
Chronic obstructive pulmonary disease (COPD) is a respiratory condition that requires long-term maintenance treatment for symptom relief and to reduce the risk of exacerbations.Citation1,Citation2 Inhaled bronchodilator therapy is currently the mainstay of COPD treatment, with long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) in combination being recommended as the initial therapy for the majority of symptomatic patients with COPD.Citation2
The three main types of handheld inhalation devices to deliver treatment to patients with COPD are dry powder inhalers (DPIs), pressurized metered-dose inhalers (pMDIs) and soft mist inhalers (SMIs).Citation3,Citation4 The delivery and deposition of medication in the lungs by these devices can be affected by a range of patient-related factors, including, for DPIs, a patient’s peak inspiratory flow (PIF).Citation4,Citation5 If a patient uses their inhaler incorrectly, or has suboptimal PIF, they may not receive the clinically relevant dose to alleviate their symptoms and reduce the risk of exacerbations.Citation3,Citation6
In order to overcome the internal resistance of the inhaler and to separate the drug from its carrier molecule, most DPIs require patients to achieve a PIF of 30–60 L/min depending on the internal resistance of the device, although a PIF of 60 L/min is considered optimal for most devices to disaggregate the powder and produce drug particles of an optimal size.Citation4,Citation7–13 For patients with inadequate PIF, this can result in ineffective drug delivery from DPIs, impacting disease control and health status.Citation6,Citation8,Citation14 pMDIs operate independently of PIF but rely on patients coordinating inhaler activation with the intake of breath.Citation3 SMIs use mechanical energy to generate a slow-moving mist of drug and require slow, coordinated inhalation,Citation3,Citation15,Citation16 though coordination is less of an issue for SMIs as the duration of the aerosol is approximately four times longer than pMDIs.Citation16
The TRONARTO study evaluated the efficacy of drug delivery via the SMI in patients with COPD and different inhalation abilities.Citation17 TRONARTO (NCT04223843) was a Phase IV, randomized, double-blind, placebo-controlled, multicenter, parallel-group study that investigated the efficacy of tiotropium/olodaterol (TIO/OLO) 5 μg/5 μg delivered via the SMI, Respimat® (Boehringer Ingelheim, Ingelheim am Rhein, Germany), on lung function in patients with COPD stratified by inhalation ability (<60 L/min or ≥60 L/min), measured with the In-Check DIAL G16 (Clement Clarke Ltd, Harlow, UK) set at medium-low resistance.Citation17 Included patients were aged ≥40 years, current or ex-smokers, with a spirometry-confirmed diagnosis of moderate-to-severe COPD.Citation17 The TRONARTO study (n=213) showed that treatment with TIO/OLO via the SMI results in significant lung function improvements versus placebo, irrespective of the PIF that a patient can generate.Citation17
This article summarizes post hoc analyses from the TRONARTO data set, which addresses the variation in PIF over time, comparisons between at-home and in-clinic measurements of PIF, associations between PIF and expiratory spirometry measures, and patient characteristics. Daily PIF measurements from over 200 patients participating in TRONARTO were included in these post hoc analyses.Citation17
Presentation 1: The Variability of Peak Inspiratory Flow: Analyses of the TRONARTO Population
Mahler DA, Watz H, Ritz J, Gardev A, Shaikh A, Drummond MB.Citation18
This post hoc analysis evaluated PIF variability in the 209 patients (of 213 randomized) who had available at-home PIF measurements in the TRONARTO study. Patients measured their PIF daily for 4 weeks at home, using an In-Check DIAL G16 device set to medium-low resistance. All PIF values were analyzed and the variability between PIF values (all patients, all days) was assessed, as well as within-patient PIF range. Data were pooled for all patients irrespective of treatment (TIO/OLO or placebo) or PIF stratum at screening.
From this analysis, three patient subgroups were identified based on the recorded daily PIF values. One in five patients consistently had a PIF <60 L/min (“can’t do”, where patients had consistently poor inspiratory ability to optimally operate DPIs of medium-low resistance), one in three patients had values above and below 60 L/min (“can and sometimes do”, where patients’ inspiratory ability was sufficient to operate DPIs of medium-low resistance on some but not all days) and half of patients consistently achieved a PIF ≥60 L/min (“can and consistently do”, where patients had consistently sufficient inspiratory ability to operate DPIs of medium-low resistance) ().
Figure 1 Patient subgroups based on self-measured PIF readings.
Analysis of the overall distribution of PIF measurements showed that individual PIF values most commonly fell between 50 and <60 L/min (). In addition, over the 4-week study period, the most common PIF range (difference between a patient’s highest and lowest PIF values) was 10–<20 L/min (). Overall, 12.4% of patients had a PIF range of <10 L/min over the 4-week period; 57.9% had a PIF range of <20 L/min, 86.1% had a PIF range of <30 L/min, and 13.9% had a PIF range of >30 L/min.
Figure 2 (a) overall distribution of PIF values and (b) range between highest and lowest PIF value (by PIF subgroup based upon self-measured PIF readings over 28 days).
Clinical Implications
In patients with COPD, PIF can be variable in the home setting. Some patients have consistently adequate PIF, whereas others have variable or consistently low PIF, which is suboptimal for medium-low-resistance DPI devices. Considering this variability, if a patient uses a DPI, it is advisable to assess PIF at each clinic visit to ensure that patients are matched with their inhalers effectively. Patients with variable PIF could be considered for inhaler training to avoid potential inadequate dosing. Patients with consistently low PIF should be offered an alternative device with an active drug delivery mechanism, such as an SMI, pMDI, or nebulizer.
Presentation 2: TRONARTO Post Hoc Analysis: Factors Affecting Peak Inspiratory Flow (PIF) Variability
Mahler DA, Watz H, Emerson-Stadler R, Ritz J, Shaikh A, Drummond MB.Citation19
This post hoc analysis evaluated the relationship between patient characteristics and PIF variability in 213 patients with COPD randomized in the TRONARTO study. Patients were stratified into quartiles according to their PIF range (ie, the difference between their minimum and maximum PIF values), derived from at-home daily PIF measurements. These quartiles were tested for trend against baseline characteristics including age, gender, stature and disease severity (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2 vs 3). Additionally, differences between in-clinic PIF (single measurements at baseline, Week 2 and Week 4) and at-home PIF (mean average of aggregated at-home PIF values during the week closest to each clinic visit) were compared, overall and by PIF strata from the original TRONARTO study (<60 L/min or ≥60 L/min). Lastly, weekly PIF range (using the 28 days of at-home measurements), and weekly population means and standard errors (SEs) were calculated. For PIF range, a test for trend with study duration was performed.
Patients with more severe disease were found to have a significantly lower PIF range than those with moderate disease (GOLD 3 vs 2; P=0.01), but no other baseline characteristic showed a trend with PIF range ().
Table 1 Trend Analysis for Baseline Characteristics Across the PIF Range Quartiles
The mean (SE) difference between PIF measured at home versus in the clinic decreased between clinic visits (). Over the study period, the mean PIF in the overall population increased slightly from baseline (65.97 L/min) to Week 4 (69.52 L/min), though the change was not statistically significant. In contrast, the weekly PIF range (difference between minimum and maximum daily PIF measurements for each patient) and variance (SE) declined significantly with study week (11.35 L/min [SE 0.50] at Week 1 to 8.78 L/min [SE 0.39] at Week 4 [test-of-trend P=0.0001]) ().
Figure 3 Difference in PIF between at-home and in-clinic visits.a
Figure 4 Mean PIF, weekly PIF range and variance (SE) in the overall population by study week.
Clinical Implications
Previous research has shown that certain COPD patient phenotypes are more likely to have lower PIF,Citation20 but to our knowledge, there is little known about factors associated with PIF variability. In our analysis, with the exception of disease severity constraining a patient’s PIF range, no other baseline characteristic was found to predict PIF range. This finding highlights the difficulty in predicting which patients will have variable PIF performance by the usual clinical characteristics available to the healthcare professional.
A comparison of in-clinic versus at-home PIF measurements showed that if a patient had low PIF at their clinic visit (before regular PIF measurements were made), they were likely to generate an even lower PIF reading when at home. If a physician is concerned that a patient’s PIF at home will not be sufficient for their inhaler, they should offer the patient an alternative device to avoid a potential mismatch between a patient’s inspiratory ability and their inhaler’s airflow requirement, thereby avoiding potentially compromising a patient’s health status. Within-patient PIF range reduced over the 4-week analysis period, suggesting that with training/repeated PIF measurements, patients could become more consistent in their inspiratory effort. Appropriate training in a real-world setting warrants further exploration.
Presentation 3: Relationship Between Peak Inspiratory Flow and Patient Characteristics: Analysis of Trends from the TRONARTO Population
Drummond MB, Watz H, Ritz J, Gardev A, Shaikh A, Mahler DA.Citation21
This post hoc analysis investigated the potential association between baseline characteristics and PIF in the 213 patients with COPD who were randomized in the TRONARTO study. At baseline, post-bronchodilator PIF was measured in the clinic with the patient in a seated position using the In-Check DIAL G16 at medium-low and high resistance. Triplicate readings were taken and the highest PIF value was recorded at each resistance setting. Patients were then stratified into six groups (PIF: <30, 30–<45, 45–<60, 60–<80, 80–<100 and ≥100 L/min) according to their highest PIF against medium-low resistance, and a test of trend was carried out against various baseline characteristics.
Female gender (P=0.0013), shorter stature (P=0.0008), more severe disease (GOLD stage 3 vs GOLD 2; P=0.0056), worse airflow obstruction (post-bronchodilator forced expiratory volume in 1 second [FEV1] [P<0.0001] and percent predicted FEV1 [P=0.0122]) were found to be significantly associated with lower PIF; no trends were observed for age or body mass index ().
Table 2 Trend Analysis for Baseline Characteristics Across the PIF Subcategories
In a linear regression analysis, a strong correlation was observed between baseline PIF measurements at the medium-low- and high-resistance settings (correlation coefficient, R=0.766) (). However, PIF measurements were not equal at the different resistance settings, with high-resistance measurements having 64% of the value of medium-low-resistance measurements. In a separate regression analysis, a weak correlation was observed between baseline PIF and FEV1 or forced vital capacity (FVC) (correlation coefficients, 0.303 and 0.365, respectively []). and were created using locally estimated scatterplot smoothing.
Figure 5 Correlation of PIF recorded at medium-low and high resistance.
Figure 6 Correlation of PIF with FVC and FEV1.
Clinical Implications
In this population of patients with moderate-to-severe COPD, factors such as female gender, shorter stature, more severe disease and worse airflow obstruction were significantly associated with lower PIF. Although PIF at medium-low resistance strongly correlated with PIF at high resistance, the PIF measurements at the two resistance settings were not equal. Hence, PIF readings measured at different resistances are not interchangeable, highlighting the importance of measuring PIF at the resistance of the patient’s inhaler in order to ensure a good match between patients and their DPIs. In linear regression, PIF measurements showed a poor correlation with FVC and FEV1, indicating that patient expiratory ability (ie, spirometry measurements) should not be used to predict inspiratory ability.
Discussion
COPD is a complex, heterogeneous condition that is associated with a high personal and societal burden.Citation2 There is increasing recognition that a precision-medicine approach would be beneficial in COPD to deliver treatments that are targeted to the individual needs of patients.Citation22–25 To this end, it is valuable to identify “treatable traits”, which have been defined as traits that are clinically relevant and associated with specific outcomes, easily identifiable and measurable, and treatable.Citation23 Key to the success of this approach is that any treatable trait should be evaluable objectively by means of a biomarker.Citation23
In COPD, airflow limitation and muscle deconditioning are treatable traits, which can be assessed using the biomarkers of FEV1 and exercise testing (eg, 6-minute walk test), and treated with bronchodilators and pulmonary rehabilitation, respectively.Citation22,Citation23,Citation26 Similarly, poor inspiratory ability can be considered a treatable trait, assessed using PIF as a biomarker, and optimally managed by matching a patient’s inspiratory ability with the most appropriate inhaler device and offering self-management education and digital behavioral change interventions (including electronic monitoring devices or automated text messages) to improve the consistency of inhalation effort.Citation22,Citation27
The GOLD report 2023 highlights the importance of inhalation ability, with DPIs described as unsuitable for patients unable to perform a forceful and deep maneuver.Citation2 Suboptimal PIF is associated with poor outcomes, as shown by results from previous studies.Citation6,Citation8,Citation28 The PIFotal cross-sectional observational study assessed the impact of PIF, inhalation technique errors and medication adherence on patient-reported outcomes in ~1400 patients with COPD in the primary care setting who had been using a DPI for COPD maintenance therapy for ≥3 months.Citation6 In the PIFotal cohort, 29% had suboptimal PIF; 16% were able to generate optimal PIF when inhaling maximally but not through typical inhalation maneuvers (“can, but will not do”) and 13% were incapable of generating the sufficient PIF required for their device under either maximal or typical inhalation maneuvers (“cannot do”).Citation6 Suboptimal PIF in the PIFotal study was associated with significant reductions in health status (lower scores on the Clinical COPD questionnaire).Citation6 Although no significant association was found between suboptimal PIF and moderate and severe exacerbations, participants with suboptimal PIF had a 73% higher rate of severe exacerbations compared with those with optimal PIF.Citation6 These results are in line with previous studies, which found an association between reduced PIF and an increased risk of acute exacerbations of COPD.Citation7,Citation8
Results from the TRONARTO post hoc analyses support the need to identify patients with low PIF, if a DPI is being considered, in order to make the most informed choice of inhaler that matches the patient’s clinical inspiratory phenotype. In our analyses, some patients had consistently adequate inspiratory ability as assessed by daily measurement of PIF; however, as many as one in three had variable PIF readings and one in five had consistently low PIF readings,Citation18 which are suboptimal for medium/low-resistance DPI devices. Patients with variable PIF should be considered for inhaler training in order to avoid inadequate dosing and consequent poor outcomes. In patients with consistently low PIF, inhalers requiring a specific degree of effort should be avoided and an active device preferred, such as an SMI, pMDI, or nebulizer. In one study comparing delivery of LAMA monotherapy via SMI versus DPIs, SMI users had fewer exacerbations and a lower risk of re-admission following hospitalization,Citation29 suggesting the potential benefits of an active drug delivery system. Similarly, another study found that the LAMA/LABA combination of TIO/OLO was associated with higher therapeutic effects on lung function and symptoms compared with LAMA/LABA combinations delivered by DPI.Citation30 Given the differences in lung deposition between SMIs and DPIs,Citation31 it is possible that the higher drug deposition associated with SMIs may translate into better clinical outcomes for patients who are not well suited to DPI devices.
Reinforcing the need for inhaler training or switching of inhaler where appropriate, our research showed that if patients have low PIF readings in the clinic, their PIF is likely to be even lower at home, when not being observed or supervised by their healthcare provider.Citation19 We also found that inspiratory ability is weakly correlated with expiratory ability, and that the PIF required for one device is not interchangeable for another device with different internal resistance.Citation21 Consistent with our findings, a previous study did not find a strong association between PIF and expiratory ability.Citation9 In a recent systematic review, however, low PIF did show a positive correlation with reduced FEV1 in 9 of 14 papers.Citation20
From our data, PIF variability was not associated with specific patient characteristics, except for disease severity (more severe disease associated with lower PIF range).Citation19 Low PIF, however, was found to be associated with specific characteristics (female gender, shorter stature, more severe disease and worse airflow obstruction).Citation21 These data are in agreement with a recent review of the literature, which evaluated the relationship between PIF and patient and disease characteristics.Citation20 According to this literature review, low PIF correlated with female gender, shorter height and greater disease severity, as well as other factors such as increased age and decreased handgrip/inspiratory muscle strength.Citation20 Importantly, these clinical characteristics have no clear thresholds that can be used to clearly identify an individual with low PIF, highlighting the need to measure PIF directly and repeatedly.
Conclusion
These post hoc analyses of findings from the TRONARTO study provide insights supporting the important role of PIF as an indicator of inspiratory ability, which we believe should be considered a treatable trait informing inhaler choice in patients with COPD.
We have demonstrated that PIF can be variable in the home setting and that some patients consistently achieve optimal or suboptimal inspiratory effort required for DPIs. Unlike the PIF value (L/min), which can be associated with patient characteristics, such as female gender, shorter stature, more severe disease and worse airflow obstruction, PIF variability is harder to predict. Consideration of PIF if the patient is using a DPI can therefore help to inform inhaler choice to optimize clinical benefit from inhaled therapies by avoiding mismatches between patients and their inhalers.
Abbreviations
COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; PIF, peak inspiratory flow; pMDI, pressurized metered-dose inhaler; SE, standard error; SMI, soft mist inhaler; TIO/OLO, tiotropium/olodaterol.
Data Sharing Statement
To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in a peer-reviewed journals and regulatory and once reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major Regulatory Authorities. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.
Ethics Approval and Informed Consent
The TRONARTO study protocol was reviewed and approved by the respective independent review boards and ethics committees of the participating sites: 26 in Germany and the United States of America beginning January 8, 2020 and ending September 29, 2020 (for full details, see Supplementary Table 1). The TRONARTO study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.
Consent for Publication
All authors provide their consent for publication of this manuscript and all related contents. All patients provided their informed consent when entering the TRONARTO study.
Author Contributions
The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. All authors 1) made a significant contribution to the work reported, whether through conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; 2) took part in drafting, revising or critically reviewing the article; 3) gave final approval of the version to be published; 4) agreed on the journal to which the article was submitted; and 5) agreed to be accountable for all aspects of the work. The authors received no compensation related to the development of the manuscript.
Disclosure
MBD reports research grants from the National Institutes of Health, Department of Defense, American Lung Association, Boehringer Ingelheim, Midmark and Teva unrelated to this work. He reports personal consulting fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Teva, Midmark, Verona, Optimum Patient Care, Chiesi, Becker Pharma and Polarean unrelated to this work. HW reports grants, personal fees and other support from Boehringer Ingelheim during the conduct of the study. Outside the submitted work, HW received grants, personal fees and other support from AstraZeneca, Chiesi, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Sanofi, and Novartis. JR is an employee of Syneos Health working on behalf of Boehringer Ingelheim. AG, RE-S and AS are employees of Boehringer Ingelheim. DAM reports fees for advisory boards from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Teva, Theravance, Verona and Viatris; royalties from Salem Media Group – COPD: Answers to Your Questions (2015); work with pharmaceutical companies on the use of BDI/TDI; participation in speaker’s bureau for AstraZeneca, Boehringer Ingelheim and Teva; and https://www.donaldmahler.com – an educational website for those with COPD and their families. The authors report no other conflicts of interest in this work.
Acknowledgments
These post hoc analyses were sponsored by Boehringer Ingelheim International GmbH. Medical writing assistance, in the form of the preparation and revision of the manuscript, was supported financially by Boehringer Ingelheim and provided by Paul Todd, PhD, at Meditech Media, under the authors’ conceptual direction and based on feedback from the authors.
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