Factors associated with health status and exacerbations in COPD maintenance therapy with dry powder inhalers.

The study aimed to determine the associations of Peak Inspiratory Flow (PIF), inhalation technique and adherence with health status and exacerbations in participants with COPD using DPI maintenance therapy. This cross-sectional multi-country observational real-world study included COPD participants aged ≥40 years using a DPI for maintenance therapy. PIF was measured three times with the In-Check DIAL G16: (1) typical PIF at resistance of participant's inhaler, (2) maximal PIF at resistance of participant's inhaler, (3) maximal PIF at low resistance. Suboptimal PIF (sPIF) was defined as PIF lower than required for the device. Participants completed questionnaires on health status (Clinical COPD Questionnaire (CCQ)), adherence (Test of Adherence to Inhalers (TAI)) and exacerbations. Inhalation technique was assessed by standardised evaluation of video recordings. Complete data were available from 1434 participants (50.1% female, mean age 69.2 years). GOLD stage was available for 801 participants: GOLD stage I (23.6%), II (54.9%), III (17.4%) and IV (4.1%)). Of all participants, 29% had a sPIF, and 16% were shown able to generate an optimal PIF but failed to do so. sPIF was significantly associated with worse health status (0.226 (95% CI 0.107-0.346), worse units on CCQ; p = 0.001). The errors 'teeth and lips sealed around mouthpiece', 'breathe in', and 'breathe out calmly after inhalation' were related to health status. Adherence was not associated with health status. After correcting for multiple testing, no significant association was found with moderate or severe exacerbations in the last 12 months. To conclude, sPIF is associated with poorer health status. This study demonstrates the importance of PIF assessment in DPI inhalation therapy. Healthcare professionals should consider selecting appropriate inhalers in cases of sPIF.

Introduction

COPD is a chronic and progressive lung disease, impacting the lives of ~384 million patients worldwide[1,2]. The main pharmacotherapeutic treatment for COPD is maintenance therapy with long-acting bronchodilators[3]. The most used devices for administration of long-acting bronchodilators are dry powder inhalers (DPIs)[4].

Despite the variety of available therapies, studies reveal that COPD tends to be undertreated[5]. This may be partially explained by the incorrect use of inhalers, which results in critical errors, a limitation of the dose of medication that is delivered into the airways and eventually, undertreatment. This means that even if the patient is adherent to prescribed treatment regimens, a clinical response may not be sufficiently achieved[6]. A successful treatment of COPD with maintenance therapy depends on a complex constellation of factors, among which all aspects regarding breathing manoeuvres.

Taking into consideration that DPIs are breath-actuated devices, it is crucial that patients can generate a sufficient peak inspiratory flow rate (PIF) to enable optimal drug delivery to the airways[7-9]. The relation between PIF and drug delivery is based on the fact that a minimum inspiratory flow is required to de-agglomerate the medication-containing powder from its lactose carrier within the DPI, so that particles of <5 μm in diameter are released from the inhaler device. Several independent predictors of patients being unable to generate an optimal PIF have been identified, such as female gender, shorter height, and older age[10,11].

Although patients might be able to generate sufficient flow for a given device with maximal effort and attention to technique, this flow is often not generated in daily life[12]. The typical PIF of a patient is defined as the PIF achieved with the inhaler device that the patient uses in everyday life. If the typical PIF is lower than the optimal PIF for a given device, it seems likely that the patient does not generate enough inspiratory flow to overcome the internal resistance of the device. In such cases, medication will not be optimally inhaled, potentially lowering the efficacy of the maintenance therapy. Therefore, it is recommended to select a device with lower internal resistance for patients with a limited ability to generate sufficient PIF. A reduced PIF with a mismatch in chosen inhaler device predicts all-cause and COPD readmissions in patients with COPD[9].

Another factor that is likely to reduce the efficacy of therapy, is having a poor inhalation technique[13-16]. Commonly made inhalation technique errors by patients with COPD include drug priming without inhalation, failure to exhale before inhalation, exhalation into the inhaler, an inadequate generation of inspiratory flow, lack of chin lift and making multiple inhalations with one actuation[12,17]. In addition to successful inhalation, medication adherence is an important prerequisite for the effectiveness of maintenance therapy[18]. Adherence to prescribed treatments is generally low in primary care patients with COPD[19]. Non-adherence can be categorized as sporadic (e.g. patient forgets to take the medication), deliberate (e.g. due to patient’s perception of medication necessity[20], but it can also be unconscious (e.g. due to inappropriate handling of the DPI)[21].

Of particular concern to real-life practice is the fact that, although the majority of patients are treated in primary care in many countries, little is known about the prevalence of suboptimal PIF and/or inhalation technique errors in COPD patients in this healthcare setting. Also, the associations between a suboptimal PIF, inadequate inhalation technique and medication adherence with effectiveness of COPD maintenance therapy remain largely unexamined. PIF and inhalation technique errors are rarely assessed in primary care for the principle aim of evaluating and selecting an inhaler device. Moreover, in COPD, in contrast to asthma, it is unknown whether some inhalation technique errors are more critical than others for the effectiveness of treatment[15,16,22]. In this study, critical errors will be determined based on their association with health status.

Together, all these factors are likely to increase the risk of patients not optimally benefiting from maintenance therapy.

To understand how the interactions of these factors together may negatively affect health status of COPD patients and contribute to the risk of exacerbations, we evaluated this in the PIFotal COPD study. The aim of this study is to determine the association of PIF, inhalation technique errors and adherence with health status and exacerbations in COPD patients receiving maintenance therapy with a DPI.

Methods

Study design

The PIFotal COPD study was a cross-sectional observational real-world study in five European countries (Greece, the Netherlands, Poland, Portugal, Spain) and Australia[23]. Participants were recruited and included in the study between October 2020 and May 2021. PIFotal was registered in a public database prior to execution (clinicaltrials.gov identifier NCT04532853). Local medical ethics committees reviewed and approved the study protocol, and all subjects gave written informed consent. A flow chart of study procedures is illustrated in Fig. 1.

Fig. 1

Flow chart of PIFotal COPD study.

Participants were invited for clinical examination (Step 1) and eligibility was verified (Step 2). Prior to participation, participants provided written informed consent (Step 3). Subsequently, their PIF was assessed, namely typical PIF (Step 4), a patient’s maximal PIF against the resistance of their own device (Step 5) and a patient’s maximal PIF at low resistance (Step 6). Next, participants filled out questionnaires to assess health status, number of exacerbations, self-reported medication adherence, medication use, and demographic and clinical covariates (Step 7). Subsequently, participants inhaled their usual medication, which was video recorded for later assessment (Step 8). Lastly, participants received tailored inhalation instructions based on the inhalation errors they made (Step 9) after which the clinical assessment was finished (Step 10).

Study population

Inclusion/exclusion criteria were limited to ensure a real-world setting as much as possible. Participants with a clinical diagnosis of COPD, aged 40 years or older, who were treated with a DPI as maintenance therapy for their COPD in the previous 3 months or longer, were eligible for participation. Participants were excluded from participation if they were unable to give informed consent, were participating in other trials with COPD medication, if they had an exacerbation in the 6 weeks prior to participation or if they had a life-threatening disease with a life expectancy <6 months.

Peak inspiratory flow (PIF)

PIF (L/min) was assessed with the In-Check DIAL G16 (Clement Clarke, UK), a multi-patient device using disposable, single-patient mouthpieces with inspiratory one-way valves. The In-Check DIAL G16 can be set to resemble resistance of the participant’s inhaler. If a participant used multiple inhalers, the assessment priority determined the typical measurements with PIF and inhaler measurements. The priority assigned to the devices to determine the primary inhaler can be found in Supplementary Table 1.

With the In-Check DIAL G16, PIF was assessed in three ways: (1) typical PIF at the resistance of the own inhaler, (2) maximal PIF at the resistance of the own inhaler and (3) maximal PIF at low resistance[24,25]. For the typical PIF measurement participants were asked to inhale with the In-Check DIAL as they normally would with their DPI. For both maximal PIF measurements, participants were instructed to exhale fully and then inhale as hard and fast as possible. Maximal measurements were performed twice. The maximal of the two attempts was included in the data analysis. A suboptimal PIF was defined as typical PIF being lower than required for the device (Table S1), and optimal PIF as typical PIF equal to or higher than required for the device.

Participants with a typical PIF that was equal to or higher than the optimal PIF for their device were pragmatically named the ‘can and will do’ group. Participants with a typical PIF below the optimal PIF for their device, but able to perform a maximal PIF that is equal to or higher than the optimal PIF, were named the ‘can, but will not do’ group. Participants with both their typical and their maximal PIF below the optimal PIF for their device were named the ‘cannot do’ group.

Inhalation technique and adherence

Inhalation technique was observed and documented by video recording which was rated offline for errors by two independent observers. They used checklists on inhaler-specific and inhaler-independent commonly made errors, based on recommendations of the Netherlands Lung Alliance (www.inhalatorgebruik.nl) or, if unavailable for specific devices, the Aerosol Drug Management Improvement Team (www.inhalers4u.org). Inhalation technique was evaluated by grouping errors in steps together in 11 categories (Supplementary Table 2). To assess which errors could be regarded as critical in this analysis, all inhalation technique error groups (Supplementary Table 2) were tested for their association with moderate and severe exacerbations and health status (CCQ-score).

Adherence was calculated based on the answers on the 12-item Test of Adherence to Inhalers (TAI-12). Because of the more precise testing of inhalation technique in the study, item 12, concerning physician-observed critical inhalation technique errors, was replaced with the objective assessment of inhalation technique video. Items 1 to 10 could be scored 1–5 points each. Item 11 and inhalation technique could be scored with 1 or 2 points. Only if participants scored the maximum number of points on all items (total 50 points), he or she was considered adherent. We further used three different representations of non-adherence as exploratory predictors: sporadic non-adherence (TAI-12 items 1 to 5 < 25), deliberate non-adherence (TAI-12 items 6 to 10 < 25) and unconscious non-adherence (TAI-12 item 11 and video assessment <4)[26].

Health status, exacerbations and healthcare resources

COPD-related health status was measured with the 10-item self-administered CCQ[27], 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. Exacerbations in the previous 12 months were counted from the medical records (32%) or reported by the participants (68%), and were evaluated as either moderate, severe or combined. 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.

The CAT was self-administered by the participant and consists of 8 items with 5-point Likert scales to rate symptoms (e.g. frequency of coughing), disability, quality of sleep and energy.

Statistical analysis

The primary objective was to determine the associations of PIF, inhalation technique errors, and overall medication adherence with health status. There were two secondary objectives to determine the associations of PIF, inhalation technique errors, and overall medication adherence with the number of exacerbations (A) and to determine the proportion of participants with suboptimal PIF and different inhalation technique errors for clusters of inhaler devices (according to internal inhaler resistance) (B).

Inhalation technique videos were scored via a list of potential observed technique errors, specified per inhaler. For this article, the relation between observed errors and health status was assessed. We first constructed univariate models, and, to prevent type I statistical errors, inhalation errors with p-values < 0.1 were further considered as critical errors in the multi-level models. Three inhalation errors from this list occurred related to CCQ scores with a p-value < 0.1 and were further considered as critical errors in the analyses.

For each outcome-predictor combination, a multi-level regression model was fitted, allowing for a random effect at the level of the participants’ general practitioner (n = 621). Multiple imputation was used to handle missing data. Each candidate confounder was tested separately for bias potential, defined as the change in coefficient of the fixed effect under study. All candidate confounders were added to the model one by one, sorted by bias potential in a descending order. Whenever the bias potential was ≥5%, the candidate confounder was retained in the model. A list of all candidate confounders can be found in Supplementary Table 3 and an overview of confounders included in the models can be found in Supplementary Table 4.

Since for each outcome measure associations were assessed for 5 variables (suboptimal PIF, overall adherence and 3 critical errors), we adjusted the p-values for multiple testing using the false discovery rate according to Simes[28]. All statistical analyses were done using Stata version 15/MP.

Sample size calculation

A sample size calculation was performed prior to study execution. A sample size of 1200 participants was estimated to be sufficient to achieve sufficient (≥80%) statistical power. It was assumed that the difference between optimal and suboptimal PIF would lead to a Clinical COPD Questionnaire (CCQ) score difference of 0.2 points[29]. This minimal detectable difference yielded a sample size of 1176 participants, with an α of 5% and a power of 80%.

Ethics approval

The PIFotal COPD study protocol received approvals from the following institutional ethics committees/institutional review boards: Australia: Human Research Ethics Committee (HREC 3) University of Sydney; Greece: Research Ethics Committee University of Crete; Poland: Komisja Bioetyczna przy Beskidziej Izble Lekarskiej – Bielsko Biala; Komisji Bioetycznej przy Śląskiej Izbie Lekarskiej; Silesian Medical Society (Śląska Izba Lekarska); Bioethics Committee at Lower Silesian Medical Association; Bioethics Committee at the Medical University of Biaystok; Portugal: North Health Regional Administration (ARS Norte); Matosinhos Local Health Unit (ULS Matosinhos); Guimarães Hospital; Center Health Regional Administration (ARS Centro); Regional Health Administration of Lisbon and Tagus Valley (ARS LVT); Spain: Comité de Ética de la Investigación (CEI) Islas Baleares; CEI Hospital Universitario de Gran Canaria; The Netherlands: Medisch Ethische Toetsingscommissie (METC) Assen exempted this study.

Patient and public involvement

No patients were directly involved in the conceptualization 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, data to be collected, 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. For the contributing sites, the data collection raised awareness of the importance of a suboptimal PIF and/or inhalation technique errors in COPD patients and their medication adherence rates. Likewise, the participants could receive inhalation technique instructions during the visit. We plan on sharing our findings with clinicians, patients, and the public.

Table 1

Overview of participant characteristics.

		PIF optimal (n = 987)	PIF suboptimal (n = 402)	Total (n = 1434)	P value
Female	n (%)	493 (49.9)	212 (52.7)	718 (50.1)	0.346
Age (years)	Mean (SD)	68.6 (9.2)	70.9 (9.3)	69.2 (9.3)	<0.001
GOLD stage	n (% non-missing)	551 (55.8)	209 (52.0)	801 (55.9)	0.959
	I, n (%)	131 (23.8)	49 (23.4)	189 (23.6)
	II, n (%)	308 (55.9)	114 (54.5)	440 (54.9)
	III, n (%)	91 (16.5)	38 (18.2)	139 (17.4)
	IV, n (%)	21 (3.8)	8 (3.8)	33 (4.1)
Years since COPD diagnosis	n (% non-missing)	974 (98.7)	398 (99.0)	1417 (98.8)	0.481
	Median (IQR)	8.0 (5.0;14.0)	7.0 (4.0;14.0)	8.0 (5.0;14.0)
Body mass index (kg/m2)	n (% non-missing)	986 (99.9)	402 (100.0)	1433 (99.9)	0.016
	<18.5, n (%)	15 (1.5)	7 (1.7)	22 (1.5)
	18.5–<25, n (%)	279 (28.3)	145 (36.1)	432 (30.1)
	≥25–<30, n (%)	388 (39.4)	148 (36.8)	562 (39.2)
	≥30–<40, n (%)	283 (28.7)	89 (22.1)	382 (26.7)
	≥40, n (%)	21 (2.1)	13 (3.2)	35 (2.4)
Smoking status	Current, n (%)	307 (31.1)	119 (29.6)	436 (30.4)	<0.001
	Former, n (%)	583 (59.1)	213 (53.0)	824 (57.5)
	Never, n (%)	97 (9.8)	70 (17.4)	174 (12.1)
Medication class in the primary inhaler	LABA, n (%)	84 (8.5)	25 (6.2)	112 (7.8)	<0.001
	LAMA, n (%)	265 (26.8)	112 (27.9)	385 (26.8)
	LABA/LAMA, n (%)	270 (27.4)	71 (17.7)	357 (24.9)
	LABA/LAMA/ICS, n (%)	31 (3.1)	26 (6.5)	63 (4.4)
	ICS, n (%)	6 (0.6)	3 (0.7)	9 (0.6)
	ICS/LABA, n (%)	331 (33.5)	163 (40.5)	506 (35.3)
	Short-acting, n (%)	0 (0.0)	2 (0.5)	2 (0.1)
Complete medication regimen	LAMA or LABA or ICS mono, n (%)	234 (23.7)	86 (21.4)	325 (22.7)	0.002
	LAMA + LABA, n (%)	264 (26.7)	78 (19.4)	359 (25.0)
	ICS + (LAMA or LABA), n (%)	284 (28.8)	123 (30.6)	419 (29.2)
	Triple therapy, n (%)	205 (20.8)	115 (28.6)	331 (23.1)
Cardiovascular comorbidity	n (% non-missing)	982 (99.5)	399 (99.3)	1426 (99.4)	0.022
	n (%)	426 (43.4)	200 (50.1)	642 (45.0)
Comorbid asthma	n (%)	165 (16.7)	71 (17.7)	246 (17.2)	0.671
Clinical COPD Questionnaire (CCQ)	Mean (SD)	1.7 (1.0)	1.9 (1.1)	1.7 (1.1)	<0.001
Exacerbations, moderate (n, %)	0, n (%)	785 (79.5)	299 (74.4)	1113 (77.6)	0.115
	1, n (%)	111 (11.2)	48 (11.9)	167 (11.6)
	2, n (%)	41 (4.2)	29 (7.2)	72 (5.0)
	3, n (%)	23 (2.3)	12 (3.0)	37 (2.6)
	≥4, n (%)	27 (2.7)	14 (3.5)	45 (3.1)
Exacerbations, severe (n, %)	0, n (%)	962 (97.5)	381 (94.8)	1386 (96.7)	0.047
	1, n (%)	20 (2.0)	16 (4.0)	38 (2.6)
	2, n (%)	2 (0.2)	3 (0.7)	5 (0.3)
	3, n (%)	2 (0.2)	0 (0.0)	2 (0.1)
	≥4, n (%)	1 (0.1)	2 (0.5)	3 (0.2)