FormalPara Key Summary Points

Why carry out the study?

High carbon footprint of pressurized metered-dose inhalers (pMDI) devices increases the pressure to prefer dry powder inhalers (DPI) in treatment of COPD, but sufficient inspiratory effort is needed to use DPIs.

There is concern among clinicians whether patients with COPD are able to generate sufficient inspiratory flow to use DPIs successfully.

What was learned from the study?

In this work, we show 99% of the patients generated sufficient inspiratory flow rate to operate Easyhaler DPI. Additionally, inspiratory capability of the patient cannot be predicted from parameters easily available in a clinical setting.

Our results show that inspiratory flow rate does not limit use of Easyhaler among patients with COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disorder characterized by severe airflow limitation and hence is often treated with inhaled bronchodilators and in some phenotypes corticosteroids [1]. Inhalation is the preferred route of administration and there has been an active discussion about sustainability of inhaler therapy and its clinical implications. The devices available for use differ drastically in terms of carbon footprint. Propellant containing pressurized metered-dosed inhalers (pMDI) devices have 20–40 fold greater carbon footprint compared to propellant-free dry powder inhalers (DPIs) [2]. Recently, there was an urgent call for immediate actions against global warming in health care from many of the leading biomedical journals [3] and WHO has identified reducing greenhouse gas emissions as one of the ten avenues which health care workers should utilize to reduce global warming. In the United Kingdom, the propellants from pMDIs account for approximately 13% of the National Health Services carbon footprint related to the delivery of care [4].

As with any medical device, correct handling of the inhaler is a prerequisite for successful therapy. Depending on the device, it may include dose preparation or actuation as well as the inhalation maneuver. The nature of the inhalation maneuver depends heavily on the used device. The pMDI utilizes pressurized propellant to aerosolize the formulation and deliver the dose. They require considerable coordination between actuation of the device and precise breathing pattern for successful inhalation [5]. DPIs use the energy from the patients inspiratory effort to de-agglomerate the formulation into respirable particles [6]. For accurate and consistent delivery with medium-high and high resistance DPIs, the peak inspiratory flow during the inhalation maneuver should in general reach a flow rate of 30 l/min or higher, but there are device specific requirements [7]. The vast majority of patients are able to generate sufficient inspiratory flow rates despite the inhaler resistance [8].

The aims of this study were to analyze pooled data from clinical studies including 246 patients with COPD to find possible clinical predictors for PIF and to assess whether the patients with COPD had difficulties in generating sufficient PIF with a high resistance DPI Easyhaler® (Orion Pharma, Espoo, Finland).

Methods

Patients

Only patients with a documented diagnosis of COPD were included. We combined data from three studies; two randomized, multicenter, crossover, open-label studies carried out in Estonia and Finland [9, 10] [ClinicalTrials.gov identifiers NCT04147572 and NCT01424137], as well as one Investigator Initiated Trial (Malmberg), which was approved by the Ethics Committee of the Helsinki University Central Hospital [11].

Figure 1 shows subject selection to this study from the pooled population of the original clinical trials.

Fig. 1
figure 1

Eligible subjects were chosen from the pooled population according to the flow chart

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The study protocols were reviewed by regional ethical committees according to their region of conduct and were conducted according to the Declaration of Helsinki. Written informed consent was obtained from each subject prior to the study.

PIF Measurements

The Easyhaler comes in two inhaler versions, namely, the standard Easyhaler, currently used in in products with a single active ingredient, and the center-slot Easyhaler, currently used in fixed-dose combination products. Design of the aerosolization engine is different in these two device variants, and as a result they differ in internal air flow resistance. The results with the different devices are not directly comparable. For this work, we have only used the data on the standard variant. The standard Easyhaler has a higher air flow resistance and thus the same patient using the center-slot device would achieve higher inspiratory flow rates.

The PIFEH measurements have been described in detail elsewhere [11]. Shortly, the inspiratory flow parameters were measured using SpiroMaster MX Spirometer (Medikro, Kuopio, Finland). Three inspiratory profiles were recorded and the inhalation with highest PIF was analyzed. All other inspiratory parameters were analyzed from the same profile where the PIF was acquired.

Statistical Methods

The demography and baseline characteristics of the patients are shown in Table 1. The primary endpoint was peak inspiratory flowrate (PIF) through the Easyhaler. General linear models were used to investigate independent predictive factors of PIF and their coefficients. First, the univariate relationships of PIF with different predictive variables were constructed. Second, a multivariate model was constructed using the same variables that were used in univariate models.

Table 1 Baseline characteristics
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Patient and Public Involvement

In this work, we pooled three already completed clinical trials and therefore patients or public were not involved in the design or execution of this study.

Results

A summary of the baseline characteristics is found in Table 1. Figure 2 shows the relationship of peak inspiratory flow rate requirement for the Easyhaler (PIFEH) and age (A), BMI (B), forced expiratory volume in 1 s (C), or degree of obstruction (FEV1/FVC, D). The dashed line shows the PIFEH level of 30 l/min, which is required to successfully use the Easyhaler. Mean PIFEH was 56.9 l/min. Out of 246 patients, only three failed to achieve sufficient PIFEH

Fig. 2
figure 2

Dependence of peak inspiratory flow (PIF) through the Easyhaler on age (R2 = 2.5%), body mass index (R2 = 0.09%), forced expiratory volume in 1 s (R2 = 13%), and degree of obstruction (FEV1/FVC, R2 = 5%). The horizontal line at 30 l/min represents the peak inspiratory flow rate requirement of the Easyhaler

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To find possible predictors of PIF, we built univariate models from age, BMI, and lung function parameters to assess how well they predicted PIFEH. The best degree of determination (R2) was with PEF, which only explained 14% of the variation seen in PIFEH. It was closely followed by FEV1 and FVC explaining 13% of the variation. As all of the lung function parameters showed strong collinearity with their relationship to PIFEH and there was no clear best candidate in terms of degree of determination, we chose FEV1 due to its clinical availability and its direct medical relevance to patients with COPD.

Using FEV1, age, gender, and BMI, we built a linear regression model for prediction of PIFEH (Table 2). Only FEV1 and female gender were statistically significant to a low PIF. The degree of determination of the model was only 18%.

Table 2 Linear regression model for prediction of peak inspiratory flow rate through the Easyhaler
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Discussion

In the present study, we found that almost all of the patients with COPD included were able to achieve the PIF of 30 l/min, which is needed to use the Easyhaler successfully. A low PIF was associated with female gender and a low FEV1 but the explanatory value was too low to be clinically meaningful.

As the pressure to favor DPIs over pMDIs due to environmental reasons has increased, there has been some concern among clinicians on the clinical implications [12]. As a result, there has been an on-going effort to identify meaningful clinical factors that would predict ability of the patient to use their inhaler device. However, based on our results and the literature, parameters commonly determined in clinical practice such as age, gender, BMI, or lung function parameters have not been useful in prediction of PIF performance [13, 14]. In accordance with the literature, we were unable to identify any variable that would be useful in identifying the potential for failure in daily clinical practice.

Fortunately, the inability of the patients to achieve sufficient PIF through their DPI seems to be rare. In our study, the mean PIFEH was 56.9 l/min and 99% of the patients were able to inhale through the device with sufficient effort. The patient population included a significant number of patients with severe air flow limitation as assessed by FEV1. While there are reports indicating suboptimal inspiratory flow rates with DPIs, in many cases the PIF limit in the studies is set far higher than what the manufacturers recommend for their devices. Represas-Represas et al. studied PIF with In-Check Dial training device and concluded that 27.9% of the patients had suboptimal PIF [14]. However, in the study, 26 out of 42 failures come from medium-high resistance devices, which is a heterogeneous group in their PIF requirements. The authors used a PIF limit of 60 l/min for this resistance range. For example, the Turbuhaler requires PIF of 60 l/min, while the center-slot variant of the Easyhaler with similar resistance requires flow rate of only 30 l/min. From Fig. 2 it can be concluded that with a limit of 30 l/min, the vast majority of patients would have succeeded (30 l/min difference is > 2 SD) even with the standard variant and would achieve higher flow rates with center-slot variant due to difference in resistance. Also, in a study by Malmberg et al., over 99% of 380 patients with asthma or COPD were able to achieve sufficient PIF with medium-high and high resistance devices and there was no significant difference between patients with asthma or patients with COPD [13]. Al-Showair and colleagues showed that 57% of 163 patients with COPD had a PIF less than 30 l/min with Handihaler [15], but the finding was not confirmed in our recent study, where only two out of 200 subjects failed [9]. Represas-Represas et al. concluded that none of the patients with pMDI failed to reach the correct PIF range, which is in conflict with the results of Haughney et al. [16] where approximately 30% of the patients with asthma inhaled too forcefully from their pMDI devices even after teaching and coaching by health care professionals. In several studies, patients have been shown to make more errors in the handling and inhaling when using pMDI instead of DPI [16, 17]. In this study, the subjects were trained, and the device use was monitored by the study personnel. This limits the study’s generalizability to real-life situations. However, the results show that pulmonary function is not a limiting factor and more emphasis should be put on training the patients and health care professionals in the correct use of the devices.

In the present study, a low PIF was associated with female gender and a low FEV1. These association were, however, too weak to be useful in clinical practice. There have been efforts to determine suitable predictors for PIF in COPD already previously. Tsuburai et al. studied the correlation of hand grip strength to PIF and found it to correlate better with PIF than age, FVC, or 6-min walking test. However, this was only observed in men and none of the subjects failed to achieve sufficient PIF [18]. Ghosh et al. concluded that female sex was the only factor associated with reduced PIF [19]. There have also been attempts to model the actual deposition of the inhaled drug particles. Horváth et al. modeled drug deposition with dry powder inhalers and concluded that age or disease severity had no statistically significant effect on the deposition patterns [20]. There is a concern among clinicians that due to their impaired expiratory lung function, patients with COPD would have difficulties in using dry powder inhalers (DPIs). It is noteworthy that expiratory parameters in spirometry tests are poorly associated with the inspiratory performance. Terzano and Oriolo found that PIF mildly correlated with mouth inspiratory pressure, inspiratory capacity, and vital capacity, but not with any other lung function parameters [21]. Anderson et al. found no correlation between spirometric PIF and FEV1 in patients with COPD [22]. The results highlight that the inspiratory and expiratory maneuvers are physiologically distinct and cannot be used to predict each other. Therefore, the ability of the patient to use the DPI device is not affected by the severity of the disease in COPD, and low FEV1 should not be used to refuse patients from using DPIs.

A potential limitation for this work is that even though the diagnosis was documented, it was not confirmed by the study group at the recruitment to the clinical studies. However, the FEV1/FVC was measured for each patient and from Fig. 2D we see that the vast majority of the subjects fall below 0.72 cut-off and there was a wide range of disease severities included in the population. Also, a wider range in the variable may be beneficial for the building of the PIF prediction model.

While choosing the correct inhaler for each patient is important, in the end it is the disease control, and therefore the clinical end points, that matter. A Cochrane review in 2016 compared delivery methods of bronchodilators during acute exacerbation of COPD but found the evidence lacking to make conclusions [23]. In studies with clinical endpoints, the results have been similar. In the KRONOS study, no significant difference in FEV1 was seen between the pMDI and DPI delivery of budesonide/formoterol fumarate fixed-dose combination in a population of 635 patients with COPD [24]. Maltais et al. compared two long-acting β agonist/long-acting muscarinic agonist fixed-combination products administered from either pMDI or DPI. They concluded that while the products were similar in terms of peak FEV1, the pMDI product failed to achieve non-inferiority for morning pre-dose FEV1 [25]. The Easyhaler has been studied in children for the treatment of acute exacerbation of asthma and no significant difference was found when compared to pMDI with spacer or nebulizer [26].

Conclusions

Based on our data, obesity, age, or severity of airflow limitation are not limiting factors on use of DPIs, and for example, FEV1 should not be used as a decisive factor when selecting an inhaler device with the patient. On the other hand, 99% of the patients in this study were able to use the Easyhaler successfully. Hence, failing to achieve sufficient inspiratory flow rate with the Easyhaler is rare and the required inspiratory flow rate does not limit the use of the Easyhaler among patients with COPD.