Personalizing Selection of Inhaled Delivery Systems in Chronic Obstructive Pulmonary Disease

Abstract

It can be challenging for healthcare professionals (HCPs) to prescribe inhaled therapy for patients with chronic obstructive pulmonary disease (COPD) because of the multiple individual and combinations of inhaled medications available in numerous delivery systems. Guidance on the selection of an inhaled delivery system has received limited attention compared with the emphasis on prescribing the class of the inhaled molecule(s). Although numerous recommendations and algorithms have been proposed to guide the selection of an inhaled delivery system for patients with COPD, no specific approach has been endorsed in COPD guidelines/strategies or by professional organizations. To provide recommendations for an inhaler selection strategy at initial and follow-up appointments, we examined the impact of patient errors using handheld inhalers on clinical outcomes and performed a focused narrative review to consider patient factors (continuity of the inhaled delivery system, cognitive function, manual function/dexterity, and peak inspiratory flow) when selecting an inhaled delivery system. On the basis of these findings, five questions are proposed for HCPs to consider in the initial selection of an inhaler delivery system and three questions to consider at follow-up. We propose that HCPs consider the inhaled medication delivery system as a unit and to match appropriate medication(s) with the unique features of the delivery system to individual patient factors. Assessment of inhaler technique and adherence together with patient outcomes/satisfaction at each visit is essential to determine whether the inhaled medication delivery system is providing benefits. Continued and repeated education on device features and correct technique is warranted to optimize efficacy.

It can be challenging for healthcare professionals (HCPs) to prescribe inhaled therapy for patients with chronic obstructive pulmonary disease (COPD) because of the multiple individual and combinations of inhaled medication(s) available in numerous delivery systems. Generally, the medication class has been prioritized over the inhaled device. For example, 63–94% of pulmonologists indicated that the medication class was more important than the device type (1, 2). Furthermore, guidelines from professional organizations have emphasized the medication class for treating patients with COPD, with limited consideration for selecting among the four delivery systems (3–5). This prioritization of inhaled medication over delivery system may reflect, in part, the finding of Plaza and colleagues (6) that HCPs have “inadequate knowledge about the proper use of inhalers.”

The 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report enumerates “basic principles for appropriate inhalation device choice” (7). These include assessment of the patient’s cognition, dexterity, and strength, as well as the ability of the patient to perform the correct inhalation maneuver for a specific device (7). However, the GOLD 2023 report does not specify how to assess these patient attributes (7). Failure to address these considerations may explain why patients with COPD continue to make critical errors when using inhalation devices (8–10).

There continues to be an unmet need for simple, practical, and evidence-based guidance for HCPs on selecting appropriate inhaled medication delivery systems for patients with COPD. The objectives of this focused review are: 1) to review briefly unique features of the four inhaled delivery systems and the common errors made using each system, 2) to consider the impact of inhalation errors on clinical outcomes, 3) to provide recommendations on initial inhaler selection strategy, and 4) to provide recommendations on inhaler selection strategies at follow-up. Our goal is to provide practical information for HCPs on how to select the most appropriate inhaled medication delivery system for individual patients (i.e., precision medicine) to optimize patient outcomes.

Inhaled Delivery Systems and Reported Technique Errors

Each of the four delivery systems has unique features that have been well described (Table 1). Patients are more likely to make errors if they are prescribed more than one device type (11), and combination therapy is more effective and more convenient for patients if prescribed in a single device (7, 12). However, HCPs continue to prescribe multiple delivery systems, and patients continue to make errors with each type.

Table 1.

Features of inhaled delivery systems

Delivery System	Features
pMDI	HFA is the propellant in pMDIs, releasing a slower velocity and warmer plume compared with the propellant chlorofluorocarbon.
	The patient needs to coordinate actuation of the pMDI with a slow and steady inhalation of 30–60 L/min for optimal deposition into the lower respiratory tract.
	Breath-actuated pMDIs are available.
	HFA has a higher carbon footprint compared with other inhaled delivery systems.
SMI	The SMI incorporates a spring that when tightened and then released forces the liquid medication through fine nozzle outlets to generate a slow-moving mist over 1.5 s.
	The patient needs to coordinate actuation of the SMI with a slow and steady inhalation of 15–30 L/min.
	The carbon footprint of the SMI is considered to be about 5% that of the pMDI.
DPI	Most dry powder formulations attach to larger carrier particles (usually lactose), which act as a bulking agent and improve the flowability of the powder.
	Two key features of all DPIs are a unique internal resistance and breath actuation. The patient must inhale hard and fast to create turbulent energy within the device to disaggregate and then break the powder formulation into respirable particles.
	Turbulent energy within the DPI is the product of the individual’s PIF and the internal resistance of the DPI. In vitro studies using lung models have established both minimal and optimal PIFr values that have been extrapolated for clinical application.
	Suboptimal PIFr results in a reduced fine-particle dose emitted from the device with limited therapeutic benefit.
	The carbon footprint of DPIs is minimal and dependent on raw materials and manufacturing.
Nebulizer	The jet nebulizer is the most commonly used type for outpatients with COPD, in which compressed air forces the medication solution onto the surface of a baffle that breaks the liquid into small droplets.
	As the patient uses tidal breathing, no coordination between actuation and inhalation is required.
	A jet nebulizer may be breath enhanced or breath actuated such that drug delivery occurs only during inhalation.

Definition of abbreviations: COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; HFA = hydrofluoroalkane; PIF = peak inspiratory flow; PIFr = peak inspiratory flow against the simulated resistance of a dry powder inhaler; pMDI = pressurized metered-dose inhaler; SMI = slow mist inhaler.

Information is derived from References 37, 41, 47, and 58.

Pressurized Metered-Dose Inhaler

Sanchis and colleagues (9) found that the most frequent errors with pressurized metered-dose inhalers (pMDIs) involved coordination (45%), speed and/or depth of inspiration (44%), and no breath hold after inhalation (46%). In a review of 10 studies involving patients with COPD, Cho-Reyes and colleagues (13) reported that the most prevalent errors with pMDIs were failure to exhale fully and away from the inhaler before inhalation (66%), hold breathing for 5–10 seconds (42%), inhale slowly and deeply (39%), and shake the inhaler before use (34%).

Slow Mist Inhaler

Navaie and colleagues (14) examined user errors among 1,288 patients reported in 12 studies. The aggregate results showed that 59% of patients had errors with slow mist inhalers (SMIs), with the most common being failure to exhale completely and away from the device (48%); hold breathing for up to 10 seconds (31%); take a slow, deep breath while pressing the dose release button (28%); hold the inhaler upright (23%); and turn the base until it clicked (18%).

Dry Powder Inhaler

Melani and colleagues (15) reported that failure of patients to perform a forceful, quick, and deep inhalation was the most common critical error, occurring in 22–28% of patients using one of three different dry powder inhalers (DPIs). Sanchis and colleagues (9) reported that the most frequent errors with DPIs were incorrect preparation in (29%), no full expiration before inhalation (46%), and no breath hold after inhalation (37%).

Nebulizers

To our knowledge, there are no published studies describing errors among outpatients with COPD using nebulizer therapy.

The Relationship between Patient Errors and Clinical Outcomes

The relationship between patient errors and clinical outcomes was reviewed in 2018 in patients with asthma and COPD. At the time, much of the evidence was available only as meeting abstracts, and there were few peer-reviewed publications (10). Although additional reports have been published, recent evidence remains problematic. For example, prospective cohort studies have not specifically assessed changes in outcomes in patients whose error rates reduced, nor have they accounted for confounding factors such as poor adherence. Furthermore, in cross-sectional studies, it is impossible to separate cause and effect.

Effect of Errors on Lung Function

Maricoto and colleagues (16) showed that forced expiratory volume in 1 second improved significantly after training in inhaler use (mean change, 145.7 mL [95% confidence interval (CI), 11.7–279.8]; P = 0.0350). A cross-sectional study showed that patients making no errors had significantly better mean forced expiratory volume in 1 second compared with those making errors (P = 0.04) (17), but another showed no correlation (18).

Effect of Errors on Symptoms and Health Status

Göriş and colleagues (19) reported a significant improvement in mean modified Medical Research Council (mMRC) breathlessness scale score after training in inhaler use, with no change in the control group, but this was not confirmed in a later study (16). Two cross-sectional studies showed a nonsignificant trend for worse scores in patients making errors (20, 21), but other studies have shown no correlation (15, 18, 19).

Göriş and colleagues (19) showed that health status improved after training, with no change in the control group, but other studies have shown no effect (20, 22, 23). Cross-sectional studies have shown an inconsistent relationship between errors and health status (18, 20, 21, 24).

Effect of Errors on Exacerbations and Healthcare Resources Use

Cushen and colleagues (25) used electronic monitoring of adherence and inhalation technique and showed that patients who were adherent but made critical errors experienced more exacerbations during the 12-month follow-up period than those who were adherent and did not make errors (4.62 [standard deviation, 4.69] vs. 4.26 [standard deviation, 4.46] per person per year), but the difference was not statistically significant. Göriş and colleagues (19) reported a reduction in exacerbations after training, but the duration of follow-up was only three months, and another study with longer follow-up showed no change (22). Additional cross-sectional studies have shown an inconsistent relationship between error rates and exacerbations or healthcare use (15, 18, 21, 24, 26–29).

Before adjusting for adherence, Leving and colleagues (30) found that errors in the specific inhalation steps “breathe in” and “hold breath,” as well as the overall total number of errors made, were associated with higher COPD-related healthcare costs. However, when adjusted for adherence, no significant associations were observed between the number of errors and specific cost components.

Patient Factors to Consider When Selecting an Inhaled Delivery System

Continuity of Inhaled Delivery System

Evidence demonstrates that prescribing the same type of handheld device is beneficial for patients with COPD compared with prescribing different delivery systems. For example, Bosnic-Anticevich and colleagues (11) showed that patients using similar devices had a lower rate of exacerbations compared with the use of a mixed-devices cohort (adjusted incidence ratio, 0.82 [95% CI, 0.80–0.84]). In addition, Halpin and colleagues (31) found that patients with COPD using single-inhaler triple therapy had significantly higher adherence than those using multiple-inhaler triple therapy at 6, 12, and 18 months (P < 0.001).

Changing inhaled delivery systems for nonclinical reasons, such as cost, contracts, or environmental impact, is not recommended and can lead to worse outcomes (7, 32). Healthcare insurance companies and/or governments often contract with pharmaceutical companies to provide medications at specific costs. This approach has generally focused on the class of the inhaled medication to treat patients with COPD, with little consideration given to the unique features of the different delivery system. As a consequence, one or more inhaled medication delivery systems may be designated as the “preferred” treatment. Prescription of a “nonpreferred” medication delivery system may not be allowed or may lead to excessive costs for patients. By restricting the availability of different delivery systems, these arrangements limit the ability of HCPs to personalize inhaled therapy and prescribe the most appropriate delivery systems for patients. Contracts between healthcare insurance companies and/or governments and pharmaceutical companies may be for a fixed time (e.g., one year). Thus, a new contract could result in changes of preferred status of the particular delivery system and necessitate a different prescription despite good efficacy and adherence to the previous inhaled medication delivery system by the patient.

Cognitive Function

The prevalence of cognitive impairment in patients with COPD is reported to range from 10% to 61% (33). Impaired cognition can include memory loss, trouble completing tasks, and/or difficulty following instructions. Thus, affected patients may be challenged and unable to perform the different steps required for correct handheld inhaler use. In an observational cohort study, O’Conor and colleagues (34) found that among 388 adults with COPD, those who had deficits in fluid cognitive abilities (which involve active information processing) made more errors using their inhaler.

Manual Function/Dexterity

Adequate manual dexterity as well as finger/hand strength are required for patients with COPD to prepare and operate handheld devices (35–37). In response to an online survey, patients with COPD reported various comorbidities, such as arthritis (44%), difficulty with fine motor activities (36%), and tremor (15%), that may affect their ability to use a handheld device (1). In addition, Soysal Tomruk and colleagues (38) found that 35 hypoxemic patients with COPD had significantly worse hand dexterity (as measured on the Minnesota Manual Dexterity Test, which assesses placement and turning) compared with an age-matched healthy group.

Martinez and colleagues (39) observed that reduced handgrip strength was associated with an increased risk of an exacerbation in a cross-sectional analysis of 272 patients with COPD (risk ratio, 1.05 [95% CI, 1.01–1.08]). It is possible that those with suboptimal handgrip strength may be less likely to adhere to their inhaler regimens. However, to our knowledge, there are no reports of the prevalence of impaired manual function/dexterity in patients with COPD nor any possible relationship between manual ability and errors with inhalation technique.

Peak Inspiratory Flow

Peak inspiratory flow is the maximal airflow generated during inhalation and is typically measured using an inspiratory flow meter against the simulated resistance of a specific DPI. As all of the different DPIs available worldwide are breath actuated, the patient needs to inhale “forcefully” or “hard and fast” to create turbulent energy within the device to disaggregate, aerosolize, and disperse the powder formulation into respirable particles (40, 41). Turbulent energy within the DPI is determined by the product of its internal resistance and the patient’s peak inspiratory flow against the simulated resistance of a DPI (PIFr).

An optimal PIFr has been established by in vitro studies on the basis of a plateau in the emitted and fine-particle doses despite higher inspiratory flows (40). For clinical applications, an optimal PIFr ⩾60 L/min has been proposed for DPIs with low to medium-high resistance and ⩾30 L/min for high-resistance DPIs (40, 42, 43). Patients with suboptimal PIFr may be unable to completely inhale the powder medication out of the DPI, thereby leading to reduced delivery of the fine-particle dose to the lower respiratory tract, adversely affecting outcomes (44–46).

Moreover, patients with suboptimal PIFr have greater symptom burden (as measured using the mMRC scale [P = 0.003] and the COPD Assessment Test [P < 0.01]) and a shorter time to first exacerbation compared with patients with optimal PIFr (P = 0.048) (46). In addition, in a cross-sectional, multicountry study of 1,434 patients with COPD using DPIs for maintenance therapy, Leving and colleagues (30) showed that patients with suboptimal PIFr had higher medication costs compared with those with optimal PIFr (cost ratio, 1.07 [95% CI, 1.01–1.14]). These overall data, together with evidence from other studies, support the concept that PIFr is a predictive therapeutic biomarker in COPD (47).

Initial Selection of an Inhaled Delivery System

With one exception (i.e., inhaled corticosteroids are not available in SMIs), all three classes of inhaled medications are available in the four different delivery systems. Ideally, an HCP selects an inhaled delivery system for treatment of a patient with COPD by matching device attributes with individual patient factors to achieve the goals of therapy. Although numerous recommendations and algorithms have been proposed to guide the selection of inhaled delivery systems for patients with COPD (37, 48–50), no specific approach has been endorsed in COPD guidelines/strategies or by professional organizations.

Algorithms

On the basis of three domains—device attributes, patient factors, and HCP factors—identified in algorithms for the selection of inhaled delivery systems in patients with COPD, five questions have been proposed for HCPs to consider (Table 2) (37). Although the order of these questions as presented in Table 2 was based on the rank order (priorities) proposed by the authors of the nine algorithms for inhaler selection (37), HCPs can modify the approach.

Table 2.

Questions for healthcare professionals to consider in the initial selection of an inhaler delivery system and questions to ask at follow-up appointments

At Initial Selection
1. Can the patient perform correct inhaler technique? The HCP should observe directly whether the patient can perform correct inhaler technique: slow and steady for pMDIs and SMIs and forcefully or hard and fast for DPIs (7, 37). However, Leving and colleagues (56) reported that when the patient’s inspiratory maneuver—“forcefully and fast as possible”—was assessed as being correct by two independent observers, 24% of 817 patients had suboptimal PIFr (see question 3).
2. Can the patient handle the device? The HCP can inquire about and observe for hand weakness, tremor, and/or manual dexterity problems that might affect the patient’s ability to prepare and operate the different devices.
3. Can the patient generate optimal PIFr if a DPI is being considered? Measurement of the patient’s PIFr evaluates the ability of the patient to generate the optimal turbulent energy within the DPI.
4. Is the molecule(s) available in the device? Availability may depend on contracts between insurance companies and healthcare systems/governments.
5. Can the therapy be prescribed in the same device the patient is currently using?

At Follow-Up
1. Does the patient report “persistence of dyspnea and occurrence of exacerbations” (7)? or 2. Does the patient report any change in dyspnea (i.e., better, worse, or the same), and/or has the patient had an exacerbation? If the patient reports improvement and/or satisfaction with the treatment, it is reasonable to continue the inhaled medication delivery system (59).
3. Does the patient use correct inhaler technique? If the patient has poor inhaler technique, retraining is appropriate, continuing the treatment with reassessment at a subsequent follow-up appointment. On the other hand, if the patient has good technique and reports no reduction in dyspnea, a different inhaled medication delivery system should be considered, and/or the HCP should evaluate for other causes of dyspnea, such as anemia, anxiety, cardiovascular disease, deconditioning, depression, obesity, and pulmonary hypertension.

Definition of abbreviations: DPI = dry powder inhaler; HCP = healthcare professional; PIFr = peak inspiratory flow against the simulated resistance of a dry powder inhaler; pMDI = pressurized metered-dose inhaler; SMI = slow mist inhaler.

Recommendations for initial selection are adopted from Halpin and Mahler (37).

Shared Decision Making

Shared decision making is a communication process in which patients and HCPs work together to make healthcare decisions. Hsiao and colleagues (51) conducted a prospective, observational, multicenter study among patients with new diagnoses of COPD who were treatment naive and were prescribed long-acting β₂-agonists/long-acting muscarinic antagonists in a single inhaler (Breezhaler; Novartis Pharmaceuticals UK Ltd, Ellipta; GlaxoSmithKline, or Respimat; BoehrInger Ingelheim Pharmaceuticals, Inc). A COPD educator introduced the three inhalers to patients and demonstrated the various preparation and delivery steps in randomized order. The investigators found that shared decision making facilitated inhaler choice, with fewer errors, good adherence, patient satisfaction, and willingness to keep the initial inhaler in patients with new diagnoses of COPD (51). This process is endorsed for inhaled device selection in the 2023 GOLD report (7).

Selection of an Inhaled Delivery System at Follow-Up

At a follow-up appointment, the HCP should assess inhaler technique, efficacy, and any side effects of an inhaled medication delivery system. The 2023 GOLD report recommends that the patient’s inhaler technique should be evaluated at each follow-up visit and that the inhaler device and/or molecule be switched to target the predominant treatable trait—dyspnea or exacerbations—if the response to initial treatment is not appropriate (7). Although the mMRC scale and the COPD Assessment Test are proposed for the initial assessment of patients’ symptoms, the 2023 GOLD report does not recommend any scale or instrument to quantify symptoms at follow-up appointments (7). The report suggests that HCPs ask patients whether they continue to experience persistent symptoms (e.g., dyspnea) and/or have experienced exacerbations since the previous visit (Table 2).

The 2023 GOLD recommendations do not take account of the fact that most patients continue to experience dyspnea. An alternative approach is to ask the patient if there has been any alleviation or worsening of symptoms with the prescribed pharmacotherapy. A focus on dyspnea relief is appropriate for three main reasons. First, dyspnea is the most frequent symptom for which patients with COPD seek medical attention, and its alleviation is a major goal of treatment (52, 53). Second, the successful inhalation of one or more bronchodilator molecules would be expected to increase expiratory airflow and/or deflate the lungs, leading to reductions in dyspnea (54). Finally, amelioration of dyspnea with pharmacotherapy can occur in days to weeks, whereas changes in exacerbation rates may not be observed for 6–12 months (55). Moreover, it may be difficult to determine whether a particular therapy has prevented an exacerbation in an individual patient.

We propose that HCPs ask patients if breathlessness with daily activities is “better, worse, or the same” (i.e., the thumb test) since inhaled medication delivery systems were prescribed. If a patient reports improvement, it is reasonable to continue current therapy. Conversely, if a patient indicates no change or worsening, it is important for the HCP to ascertain whether the patient is using the inhaled medication delivery system correctly and is adherent to the therapy. If the patient exhibits poor inhaler technique, retraining on correct technique is appropriate, continuing the treatment until reassessment at a subsequent follow-up appointment. On the other hand, if the patient has good technique and reports no benefit, then a different inhaled medication delivery system should be considered.

Discussion

Patients with COPD commonly make errors when using handheld devices. Unlike previous publications, we provide guidance on the assessment of the inhaled medication delivery system at follow-up (Table 2) as well as initial prescription. Although the 2023 GOLD report (7) recommends the evaluation of “persistence of dyspnea and occurrence of exacerbations,” many, if not most, patients continue to experience breathlessness during activities despite initial therapy because of nonreversible airflow limitation together with possible comorbidities, such as anemia, anxiety, cardiovascular disease, deconditioning, depression, obesity, and pulmonary hypertension. As an alternative, we propose that HCPs query patients about any changes in dyspnea to evaluate initial or recently prescribed inhaled therapy (Table 2). This recommendation focuses on the patient experience and, to our knowledge, has not been proposed previously in COPD guidelines/strategies.

Ideally, HCPs should match device attributes with individual patient factors for the personalized selection of an inhaled medication delivery system. This evaluation should include the ability of the patient to perform the required inhalation technique: “slow and steady” for pMDIs and SMIs, forcefully or hard and fast for DPIs, and normal tidal breathing for nebulizers (Figure 1). Other considerations include the continuity of the inhaled delivery system, if possible, as provided by health insurance or an approved formulary as well as the patient’s cognitive function, manual function/dexterity, and PIFr (Figure 1) (37, 56). It is important that HCPs prescribe inhaled delivery systems they are familiar with, know how to use, and are able to demonstrate and teach correct technique to patients. This may require that HCPs review any gaps in their inhaler knowledge and/or provide reference materials, such as handouts and/or links to videos, appropriate to learning style and the health literacy of their patients. Algorithms and shared decision making tools are available to help HCPs personalize the selection of an inhaled medication delivery system (37).

Figure 1.

Device attributes and patient factors to consider when personalizing the selection of an inhaled delivery system. DPI = dry powder inhaler; PIFr = peak inspiratory flow against the simulated resistance of a dry powder inhaler; pMDI = pressurized metered-dose inhaler; SMI = slow mist inhaler.

Conclusions

Guidance on the selection of an inhaled delivery system has received limited attention compared with the emphasis on prescribing the class of inhaled molecule(s). HCPs should personalize the selection of inhaled medication delivery systems by matching appropriate medication(s) with the unique features of the delivery system to individual patient factors. Assessment of inhaler technique and adherence together with patient outcomes/satisfaction at each visit is essential to determine whether the inhaled medication delivery system is providing benefits. Although digital inhalers can provide information about patient adherence and technique, this technology is not widely used in clinical practice at the present time (57). Continued and repeated education on device features and correct technique is warranted for both patients and HCPs to optimize treatment outcomes (7, 40).