REVIEW

Inhaler Devices for Delivery of LABA/LAMA Fixed-Dose Combinations in Patients with COPD

Anthony D’Urzo . Kenneth R. Chapman . James F. Donohue .

Peter Kardos . M. Reza Maleki-Yazdi . David Price

Received: December 13, 2018 / Published online: March 13, 2019� The Author(s) 2019

ABSTRACT

Inhaled fixed-dose combinations (FDCs) of along-acting b-agonist (LABA) and a long-actingmuscarinic antagonist (LAMA) have become thecornerstone for the maintenance treatment ofsymptomatic COPD patients. In this regard,global COPD treatment guidelines have recog-nized the importance of inhaler devices as inte-gral contributors to the effectiveness of LABA/LAMA FDCs and recommend regular assessmentof inhaler device use by the patients in order toimprove long-term clinical outcomes. Optimal

disease control is also highly dependent uponpatient preferences and adherence to inhalerdevices. This review objectively examines andcompares the major inhaler devices used todeliver different LABA/LAMA FDCs, discusses theinhaler device characteristics that determinedrug deposition in the airways, real-life prefer-ence for inhaler devices, and handling of inhalerdevices that impact the results of the long-termmanagement of COPD. The introduction of newLABA/LAMA FDCs, new inhaler devices, andmore clinical studies have created confusionamong physicians in choosing the optimalinhaled therapy for COPD patients; in this con-text, this review attempts to provide an evidence-based framework for informed decision-makingwith a particular focus on the inhaler devices.

Enhanced digital features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.7776272.

A. D’Urzo (&)Department of Family and Community Medicine,University of Toronto, Toronto, ON, Canadae-mail: tonydurzo@sympatico.ca

K. R. ChapmanAsthma and Airway Centre, University HealthNetwork, University of Toronto, Toronto, ON,Canada

J. F. DonohuePulmonary Diseases and Critical Care Medicine,Department of Medicine, University of NorthCarolina, Chapel Hill, NC, USA

P. KardosGroup Practice and Centre for Allergy, Respiratoryand Sleep Medicine, Red Cross Maingau Hospital,Frankfurt, Germany

M. R. Maleki-YazdiDivision of Respiratory Medicine, Women’s CollegeHospital, University of Toronto, Toronto, ON,Canada

D. PriceCentre of Academic Primary Care, University ofAberdeen, Aberdeen, UK

D. PriceObservational and Pragmatic Research Institute,Singapore, Singapore

Pulm Ther (2019) 5:23–41

https://doi.org/10.1007/s41030-019-0090-1

Funding. The preparation of this manuscriptwas funded by Novartis Pharma AG.

Keywords: Bronchodilation; Chronicobstructive pulmonary disease; Combinationbronchodilator agents; Inhalers; LABA; LAMA;Pharmacotherapy

INTRODUCTION

Chronic obstructive pulmonary disease (COPD)is an increasingly common respiratory diseasecaused by substantial long-term exposure tonoxious particles or gases and marked by per-sistent respiratory symptoms and airflow limi-tation [1]. COPD affects an estimated210 million people worldwide [2]. By 2030,COPD is projected to be the third leading causeof mortality globally [3]. The significant eco-nomic burden imposed by COPD continues toincrease both in terms of direct and indirecthealthcare costs [4, 5].

The Global Initiative for Chronic Obstruc-tive Lung Disease (GOLD) report provides astrategy for the assessment and management ofCOPD and suggests categorizing these patientsinto four groups, A–D, based on symptoms andexacerbation history [6]. Inhaled therapy isfundamental in all classes of COPD patients.GOLD recommends the combination of a long-acting b-agonist (LABA) and a long-actingmuscarinic antagonist (LAMA) as the first-linetreatment for patients in GOLD groups B andD, i.e., patients with high symptom burdenand those who are at a greater risk of exacer-bations, respectively. Starting with LABA/LAMAcombination therapy is recommended on thebasis of the greater efficacy of this therapy inimproving lung function, symptoms, quality oflife, and in reducing exacerbations when com-pared to monotherapy or to LABA/inhaledcorticosteroid (ICS) combinations in thesepatients [6–15].

The current GOLD strategy has explicitlyrecognized the importance of inhaler choiceand instructions in the context of COPD man-agement. Moreover, for the first time, GOLD

2019 has recommended to consider switchingmolecules and/or inhaler devices within classesto improve response/outcomes [6]. Followingcareful device selection tailored to individualpatient needs and abilities, the importance ofinitial education and training in inhaler devicetechnique is emphasized. Regular reassessmentof inhaler technique has been recommended toimprove long-term therapeutic outcomes.Finally, before concluding that the currenttreatment is insufficient, inhaler technique (andadherence to therapy) should be reviewed [6].The GOLD strategy has also recognized theimportance of delivering more than one drugvia a single inhaler device, especially in light ofthe evidence that use of multiple devicesrequiring different inhalation techniquesdiminishes the effectiveness of therapy [16].Long known to being a critical issue in asthmamanagement, ensuring adequate inhalationtechnique may be of even greater importance inolder COPD patients who are more likely tohave debilitating comorbidities such as arthritisof the hands and typically have far less venti-lator reserve [17, 18].

Fixed-dose combinations (FDCs) of LABA/LAMA have become the foundation of COPDtreatment and this article provides an overviewof the key aspects of inhaler devices that areused to deliver this therapy in FDCs to patientswith COPD. More importantly, this review isaimed to provide guidance to physicians onevaluating device characteristics and ensuringcorrect inhaler use by patients, in light of therenewed focus on patients’ ability to use thesedevices correctly for optimal treatment out-comes. We describe key inhaler device-relatedfactors that influence the patients’ and physi-cians’ perception of devices, ultimatelyimpacting the effectiveness of LABA/LAMAcombination therapy in COPD.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not contain any studies withhuman participants or animals performed byany of the authors.

24 Pulm Ther (2019) 5:23–41

DELIVERY OF LABA/LAMACOMBINATION THERAPY TO COPDPATIENTS

Several devices are available to deliver LABA/LAMA in a FDC to COPD patients and eachdevice has its own features that should be con-sidered when tailoring treatment to specificpatient needs. These devices include pressurizedmetered-dose inhalers (pMDIs), dry powderinhalers (DPIs), and soft-mist inhaler (SMI) [19]and are listed in Table 1.

The pMDIs are widely used because of theirsmall size and unobtrusive nature. Their use con-tinues despite evidence of frequent coordinationerrors and mishandling of these devices bypatients [20–23]. However, the CRITIKAL studyshowed that poor coordination between the startof an inhalation and actuation of the dose (i.e.,actuation coming before inhalation) was a criticalerror with MDIs that was associated with poordisease outcomes [24]. The CRITIKAL study resultsalso indicated that exhaling into the mouthpieceor not holding the inhaler upright was a criticalpMDI error; moreover, inspiratory effort was notslow and deep enough in the majority of asthmapatients using a pMDI [24]. Lack of deviceknowledge, incorrect second dose preparation,timing, or inhalation, exhaling into the mouth-piece, and not holding the inhaler upright havealso been identified as critical errors associatedwith pMDIs [24–26]. A notable development hasbeen breath-activated pMDIs, which incorporate atriggering mechanism that releases the dose whena patient’s inspiratory effort is detected [21, 22].The use of a valved holding chamber (a reservoirwith a one-way valve permitting airflow into thepatient’s mouth) to activate the pMDI beforeinhalation has been propagated to eliminatepotentially critical inhaler handling errors and toincrease lung deposition of drug particles [27, 28].

The DPIs are devices containing drugs inpowdered formulation consisting of micronizedparticles in a respirable range [29]. Most DPIsallow the particles to be deagglomerated usingenergy created by the patient’s own inspiratoryflow. These devices are available as single- andmultiple-dose configurations [29, 30]. DPIs arebreath-actuated and thus they do not have the

issue of coordinating actuation and inhalation[31]. DPIs offer increased stability of drug for-mulation, flexibility in inhaler design options,and ability to achieve a high fine particle fraction[32]. However, DPIs do have some inherent lim-itations, e.g., variable airflow resistance, andoften the inability of patients to achieve ade-quate inspiratory flow in order to mobilize thedry powder medication. However, some patientsfail to generate sufficient inspiratory effort even ifthey are capable of achieving it [33]. The CRITI-KAL study showed that insufficient inspiratoryeffort was a critical error associated with the useof DPIs [24]. Although DPIs obviate the issue ofcoordinating inhalation to an actuation, othererrors are seen such as incorrect loading andpreparation of the dose, blowing into the device,and exposing multi-dose reservoir devices toenvironmental moisture [24, 29, 33].

The SMI is a multiple-dose, propellant-free,hand-held, liquid inhaler device that generatesan inhalable aerosol from a drug solution usinga patient-independent and reproducible energysupply [34]. The aerosol plume generated bythis device is slower and lasts longer thanaerosol clouds from pMDIs [35]. Limitations ofthe SMI include potential issues in dose prepa-ration, the device being non-breath-actuated,unavailability in many countries, and relativelyhigher costs compared with other devices [36].

In the context of the limitations and advan-tages of different classes of devices (Table 1), theshift from pMDIs to DPIs and SMI signifies adevelopment in inhaled therapy. The newerinhaler devices exclude propellants, minimizepatient limitations (including cognitive and psy-chomotor impairment that may limit inhaler use)and errors in handling the device, and improvethe consistency of drug delivery to the lungs. Inthe subsequent sections, we describe representa-tive devices from these classes of inhalers.

INHALER DEVICES AVAILABLEFOR LABA/LAMA DELIVERY

Aerosphere�

The Aerosphere� (AstraZeneca Pharmaceuticals,Wilmington, DE, USA) is a hydrofluoroalkane-

Pulm Ther (2019) 5:23–41 25

Table1

Key

characteristicsof

theinhalerdevicesused

forLABA/LAMA

delivery

Inhaler

type

Form

ulation

Available

devices

LABA/L

AMA

medications

delivered

Advantages

Lim

itations

Pressurized

metered-

dose

inhaler

Drugsuspendedor

dissolvedin

apropellant

Aerosphere�

Form

oterol

and

glycopyrronium

Com

pact

andportable

Offer

consistent

dosing

andrapiddelivery

Can

beused

independ

ently

andun

obtrusively

FormanyCOPD

patients,itispossibleto

easilyachieve

theslo

winhalation

flowrequired

withapM

DIwith

training

Whenused

withavalved

holdingcham

ber,im

provem

ent

inlung

deposition

ofdrug

particlesandreductionin

hand

–breath(activation–

inhalation)coordination

problemsisseen

Patientswithpoor

dexterityor

weakgrip

may

finditdifficult

toactuatethedevice

Actuation

before

inhalation

iscommon

Failureof

properhand

–inh

alationcoordination

whileusinga

pMDIresults

ingreatly

reduceddosesof

drug

reaching

the

lungs

Lackfeedback

mechanism

sconfi

rmingdose

delivery

Contain

propellants(requiredto

generate

theaerosolcloud

andalso

forsuspension

ordissolutionof

active

ingredient)

Patientswould

notbreatheoutto

emptylungsbefore

inhalation

(due

tolack

ofproper

perception

ofairflow

resistance)

Patient’s

head

should

alwaysbe

tiltedback

forproper

inhalation

Drypowder

inhaler

Drugblendedin

lactose;drug

alone;drug/

excipient

particles

Breezhaler�

Neohaler�

Ellipta�

Genuair�

Indacateroland

glycopyrronium

;vilanterol

and

umeclidinium;

form

oterol

and

aclidinium

Com

pact

andportable

Breath-actuated:do

notrequirecoordination

ofinhalation

withactivation

anddo

notrequirehand

strength

SomeDPIshave

afeedback

mechanism

forthepatientto

ensure

they

have

inhaledthemedication

Donotcontainapropellant

Requiresaminim

uminspiratoryflow,w

hich

isrelatedto

the

device’sresistance

andvaries

from

onedevice

toanother

Geriatricand/or

patientswithvery

severe

COPD

may

lack

theability

togenerate

sufficiently

high

inspiratoryflows

throughsomeDPIs,thereforecomprom

ising,ifnot

preventing,d

osedelivery

Mostinhalersaremoisturesensitive

Patientswould

notbreatheoutto

emptylungsbefore

inhalation

(due

tolack

ofproper

perception

ofairflow

resistance)

Patient’s

head

should

alwaysbe

tiltedback

forproper

inhalation

Soft-m

ist

inhaler

Aqueous

solution

Respimat�

Olodaterolandtiotropium

Portable

Multi-dosedevice

The

relativelylong

generation

timeof

theaerosolcould

facilitatecoordination

ofinhalation

andactuation

Doesnotcontainapropellant

The

dispensedmetered

volumeperdose

of15

lLlim

itsthe

dose-deliverycapacity

todrugswithadequate

solubility

withrespectto

therequired

dose

Requireshand

–breathcoordination

Allpatientsmay

notbe

ableto

independ

ently

load

the

cartridgein

thedevice

cham

berpriorto

initialuseor

toactivatethedevice

inbetweendoses(turning

lever-dexterity

issues)

Twoactuations

arerequired

toachievedeliveryof

thedaily

treatm

entdose

26 Pulm Ther (2019) 5:23–41

propelled pMDI containing 20–180 inhalations[37]. The canister has an attached dose indicatorand is supplied with an actuator body andmouthpiece with a cap. Aerosphere� containsporous particles that form a co-suspension withdrug crystals; the porous particles are comprisedof the phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride. Aftereach actuation, the device delivers glycopyrro-nium 7.2 lg and formoterol furoate 4.8 lg fromthe actuator. Priming the Aerosphere� beforethe first dose is essential to ensure appropriatedrug content in each actuation; priming beforefirst use requires four sprays (actuations) intothe air away from the face, shaking well prior toeach spray [37].

Breezhaler�

The Breezhaler� (Novartis Pharma AG, Basel,Switzerland) is a breath-actuated, single-dose,capsule-based DPI used to deliver a variety ofmedications, including indacaterol (a LABA),glycopyrronium (a LAMA), indacaterol/gly-copyrronium FDC and budesonide (an ICS)[38]. In case of Ultibro� Breezhaler�, eachdelivered dose contains 110 lg of indacaterolmaleate equivalent to 85 lg of indacaterol and54 lg of glycopyrronium bromide equivalent to43 lg of glycopyrronium [38]. The Breezhaler�

requires the loading of a drug-containing cap-sule prior to each inhalation. Generally, oneinhalation is enough to empty the capsule formost patients. Should the capsule not com-pletely empty upon a shallow and short inspi-ration, e.g., low inhaled volume, patients willsee powder remaining in the capsule and cantherefore repeat the inhalation manoeuver. TheBreezhaler� was designed to provide immediatesensory feedback to the patient that the dosehas been administered correctly: by hearing adistinctive ‘‘whirring’’ noise on correct inhala-tion, by visually checking that the transparentdrug capsule is empty, and by tasting the lactoseexcipient [38]. The Breezhaler� has a lowintrinsic resistance; most patients are able togenerate the minimum inspiratory flow rate of30 L/min with Breezhaler� and the device pro-vides consistent dose delivery using inspiratory

flow rates between 30 and 100 L/min [39–41].Low-resistance devices such as Breezhaler�

allow air to flow through them easily [41].Owing to its low resistance, Breezhaler� pro-vided consistent dose delivery with regards toboth the delivered dose and fine particle massacross the range of inhalation flow ratesachievable by COPD patients [42, 43]. Patientswith mild to very severe COPD have beenshown to use the Breezhaler� device success-fully, with a low device complaint rate(\0.03%) and no device failures from approxi-mately 90,000 recorded uses [38]. The Breezha-ler� was shown to deliver a higher fine particlefraction and greater drug deposition in thelungs (lower oropharyngeal drug deposition)compared with the high-resistance HandiHaler�

DPI [44]. Multiple steps are required for drugadministration with Breezhaler�, which mayinduce errors; regardless of this, the recentlarge-scale real-world INHALER study showedthat patients committed fewest errors withBreezhaler� versus any other studied inhaler,including pMDIs and SMIs [45].

Ellipta�

The Ellipta� DPI (GSK, Research Triangle Park,NC, USA) is single-step activation, multiple-dose inhaler that comes in a two-strip configu-ration for delivery of LABA/LAMA combination[46]. It was designed to deliver LABA/LAMAdual bronchodilator FDC such as vilanterol andumeclidinium [47]. Anoro� Ellipta� delivers55 lg of umeclidinium and 22 lg of vilanterolper dose. Compared with other DPIs, theEllipta� device requires fewer steps for actuationand use requiring only that the patient open themouthpiece cover fully, inhale the powder, andclose the mouthpiece [46, 47]. Ellipta� has amedium airflow resistance; in vitro data showedthat doses of drugs delivered via the Ellipta�

device were consistent at inspiratory flow ratesof at least 30 L/min [31, 48]. This suggests thatEllipta� can be used even by patients with sev-ere COPD notwithstanding that real-life usemay differ from that observed in randomizedcontrolled trials. A frequent error of insufficientinhalation effort observed with Diskus� in the

Pulm Ther (2019) 5:23–41 27

CRITIKAL study has also been observed withEllipta�. In an in vitro study that replicatedinhaler-specific patient inhalation profiles thatwere previously recorded in vivo using theElectronic Lung (eLungTM), drug dose deliveryvia the Ellipta� DPI was consistent across therange of patient representative inhalationparameters for all therapies such as formoterol/vilanterol, umeclidinium/vilanterol, and for-moterol [49]. A recent study showed thatpatients with mild to very severe COPD couldalso generate sufficient inspiratory flows foroptimum drug delivery via Ellipta� [50]; itshould be noted that this may not always betrue in real life.

Genuair�

Genuair� (AstraZeneca, Cambridge, UK) is amulti-dose DPI designed to deliver inhaledmedications such as FDC of formoterol andaclidinium to patients with COPD [51, 52]. Eachdelivered dose contains 396 lg of aclidiniumbromide (equivalent to 340 lg of aclidinium)and 11.8 lg of formoterol fumarate dihydrate.The device is relatively easy to use: the patientneed only remove the cap on the mouthpiece,press and release the green button at the back;with successful inhalation the color of thecontrol window turns from green to red with anaudible click [52]. Genuair� has a mediumresistance to inspiratory airflow and uses anoptimized dispersion system to ensure effectivedeagglomeration of the inhalation powder[52, 53]. Genuair� has been shown to deliver aconsistent fine particle dose at inspiratory flowrates of greater than 35 L/min [53, 54]. Thedevice provides a fine particle fraction averaging40% [55]. A limitation for Genuair� is the initialflow acceleration which needs high effort.

Respimat�

Respimat� (Boehringer Ingelheim, Ingelheim,Germany) is a multi-dose, propellant-free,hand-held SMI that delivers FDC of olodateroland tiotropium [56]. The delivered dose is 2.5 lgtiotropium (as bromide monohydrate) and2.5 lg olodaterol (as hydrochloride) per puff.

The device works by forcing a metered dose ofthe drug solution through a precisely engi-neered nozzle, producing two fine jets of liquidthat converge at a preset angle; this generates anaerosol cloud (the soft mist) [57]. The aerosolspray exits the Respimat� more slowly and for alonger duration than with the pMDIs, resultingin a higher fraction of fine particles than mostpMDIs and DPIs. This translates into loweroropharyngeal deposition and consequentlyhigher lung drug deposition, higher than with apMDI [34, 57]. In clinical trials in patients withCOPD, bronchodilator drugs delivered fromRespimat� were equally as effective in bron-chodilation at half the dose delivered from apMDI and 3.6 times more effective than theHandihaler� DPI [57]. Respimat� was consis-tently shown to be well accepted by COPDpatients, largely because of its inhalation andhandling characteristics [57]. As the meteredvolume is fixed at 15 lL, Respimat� is limited todrugs with adequate solubility in order to deli-ver the required dose [25, 56]. Additionally, thepatients need to have good dexterity to twistand open the cap.

CHARACTERISTICS OF LABA/LAMAINHALER DEVICES: DRUGDEPOSITION AND AIRFLOWRESISTANCE

The most important factors that determine drugdeposition in the airways through inhalationinclude device characteristics, type of drug for-mulation, deagglomeration, particle size, oraland bronchial deposition, aerosol physicalproperties (e.g., aerosol velocity), and patientcharacteristics (such as inspiratory flow, diseasestate, preparation of the device, coordination ofsteps) [20, 21]. These factors ultimately deter-mine patients’ functional and clinical responsesto the treatment. Key device attributes perti-nent to inhaler choice and patient adherenceinclude convenience, ease of use, simpleinstructions, minimal potential for errors, air-flow resistance, efficiency of delivery, and cost[58]. Consequent to the technological advancesin the design of inhaler devices, the newer

28 Pulm Ther (2019) 5:23–41

inhaler devices afford a pulmonary drug depo-sition fraction of 30–50% of the nominal dose(Table 2), substantially higher than the 10–15%with older devices [33].

The turbulent force generated by the patientis responsible for deaggregation of the powderinto smaller particles and hence for the avail-able amount of optimum-sized particles fordrug deposition. This energy is the product ofthe patient’s inspiratory flow and the device’sintrinsic resistance [32, 59]. As Table 2 shows,with the low-resistance Breezhaler� a muchhigher inspiratory flow is generated whileachieving adequate deposition than thatachieved with a higher intrinsic resistance. Inthis context, the intrinsic resistance of a DPIdevice refers to the inspiratory flow raterequired to release the correct amount of drug.Accordingly, within the DPI class, there are high(required inspiratory flow rate 90 L/min), med-ium (60–90 L/min), and low (\50 L/min)intrinsic resistance devices [30, 36]. The lowerthe device’s intrinsic resistance, the smaller theeffort required from the patient to generatesuch airflow, which may be especially

important in patients with severe airflow limi-tation. However, perturbations in expiratoryairflow are not necessarily predictive ofimpaired inspiratory flow rates [60]. Among theDPIs that deliver LABA/LAMA, Breezhaler� hasthe lowest airflow resistance, followed byEllipta� and Genuair� [61] (Table 2). Moreover,a recent study showed that patients with COPDwere able to inhale with the least inspiratoryeffort and generate the highest mean PIF via theBreezhaler� inhaler than with the Ellipta� andHandiHaler� inhalers, irrespective of patients’COPD severity, age, or gender [62]. Low resis-tance characteristics could explain patient-re-ported ‘‘comfort’’ inhaling through somedevices; the flow rate produced by a standardpressure drop of 4 kPa was greater using Breez-haler� than other DPI devices in vitro [63]. It isimportant to note that for DPIs, the speed ofparticles upon ejection from the mouthpiece,the disaggregation of the drug, the distributionof drug within the lungs, and the variability ofthe effective inhaled dose are optimal onlywhen the inhalation flow rate and the intrinsicresistance of the device are balanced [32]. For

Table 2 Device intrinsic airflow resistance influences the inspiratory flow rate that patients can achieve [59] and drugdeposition in lungs with different DPI inhaler devices

Device Measured mean

airflow resistance*

kPa0.5 L/min

Inspiratory flow

rate*

(L/min)

Drug deposition in

lungs# (% of

nominal dose)

Breezhaler® 0.017 111 43%

Ellipta® 0.027 74 33–49%

Genuair® 0.031 64 32%

Handihaler® 0.058 37 -

Low resistance

High resistance

Moderate resistance

*The pressure drop and corresponding flow rate were measured at a defined pressure point or a constant flow rate (0–100 L/min) using a test system with a mass flow meter, a differential pressure sensor connected to a sampling tube, a flow controlvalve, and vacuum pumps. Inspiratory flow resistance was calculated by linear regression using the method of least-squares# Combining in vitro mouth–throat deposition measurements, cascade impactor data, and computational fluid dynamicssimulations

Pulm Ther (2019) 5:23–41 29

example, a device such as Genuair� with lowvariability in the aerodynamic characteristicsand medium intrinsic resistance was shown tocombine the positive aspects of achievable flowrates, consistent and efficient fine particle gen-eration, and reduced impaction losses in theupper airways [59]. An in vitro comparison offour LABA/LAMA inhaler devices throughmodeling of the lung deposition showed thatthe Respimat�, an SMI device, provided thelowest amount of particles deposited in themouth–throat region and the highest amountreaching all regions of the simulation lungmodel, followed by the DPI devices Breezhaler�,Ellipta�, and Genuair� [63].

Patient demographics and clinical character-istics may also influence drug delivery; anassessment of inhalation characteristics showedthat adults with asthma had greater inspiratorycapacity than patients with COPD but childrenwith asthma had the least capacity [64]. There isstill ambiguity with regards to the effect ofintrinsic resistance on drug deposition. A higherinspiratory rate with a high intrinsic resistancedevice would result in a higher particle deag-glomeration, but a higher airflow rate would alsolead to increased drug particle velocity, which isexpected to result in higher oropharyngeal drugdeposition. The behavior of the upper airwaymay have an impact on drug deposition; in thisregard, studies have assessed how the humanupper airway behaves with different resistancesand geometries of the inhalers and in turnaffects drug deposition [65]. For high-resistanceinhalers, a correlation between maximuminspiratory pressure (MIP) and change in airwayvolume was shown with those exhibitingexpansion in the upper airway having generallylow MIP [66]; a linear relationship was observedbetween airway volume changes and maximumcalculated volumetric airflow [66]; evaluation ofthe impact of inhalation maneuvers, inhalermouthpiece geometries, and a stepped mouth-piece on the size of the upper airway showedthat enlarged size of the upper airway mightdecrease aerosol deposition in the upper airwayand increase lung deposition [67]. Additionally,a high inspiratory flow rate may be difficult toattain in children, elderly, and in patients withsevere airflow obstruction in COPD. Lower peak

inspiratory flow rates generated from a DPI,measured using an In-Check DIAL device, wereobserved in patients with COPD or asthma whowere older than 60 years, compared withyounger patients [68]. That said, clinical studieshave shown that most patients were able to use ahigh-resistance DPI effectively, even duringexacerbations [55, 60]. Consequently, it hasbeen suggested that peak inspiratory flow ratesshould be measured prior to discharge ofpatients admitted for acute COPD exacerbationand during clinic visits to ensure optimumdevice selection and drug delivery of COPDpatients, especially in the elderly, femalepatients, and those with short stature [69].However, we should also consider that achiev-ing a specific flow rate is also dependent on theresistance of the device; in this context, highinspiratory flow rate alone may not be enoughto test the patient’s ability to use a distinctdevice. Hence, we suggest that the patientshould be tested on his prescribed device.Despite the lack of complete understanding ofthe relationship between drug deposition andairflow resistance, DPIs appear to be suitable de-vices to deliver inhaled medications to patientswith COPD of varying severity. Nevertheless, itis important to consider that patients with verysevere COPD were not systematically includedin all clinical studies, and as an example patientswho are undergoing acute exacerbations ofCOPD, i.e., a hospitalization, are typically notenrolled in any study, therefore making it diffi-cult to evaluate the appropriateness of differenttypes of inhalers.

Ultimately, healthcare professionals andcaregivers should appreciate that on the basis ofthe clinical data showing significant efficacythroughout a wide spectrum of disease severity,all devices appear to be adequate for useregardless of their different physical properties.Thus, it is worthy to consider that clinical out-comes throughout randomized controlledstudies or in real-life settings may not always beaffected by physical characteristics or theoreti-cal issues. In other words, one cannot dissociatethe overall clinical efficacy of inhaled medica-tions for COPD from inhaler specificities andhandling aspects within the context where evi-dence was generated.

30 Pulm Ther (2019) 5:23–41

PREFERENCE FOR LABA/LAMAINHALER DEVICES

Patients’ and physicians’ preference for a par-ticular inhaler device influences treatmentadherence in the long-term management ofCOPD that in turn affects the treatmentoutcomes.

In a large real-word study that assessedinhaler preference in patients with COPD, theease of use, dose delivery recording (deliveryfeedback), and dose capacity (single- or multi-dose) were cited by patients as the mostimportant device attributes while choosing adevice. Moreover, key factors that patientsconsidered made the device easier to use werefewer steps to operate the inhaler, easier coor-dination of breathing manoeuver, and leastresistance while inhaling [58]. For healthcareproviders, patient satisfaction and ease of usewere considered as the most important attri-butes when selecting an inhaler device forpatients [58]. Another real-life study assessedand compared the patients’ preference forBreezhaler�, Genuair�, and Respimat� inasthma and COPD outpatients by means of adevice handling questionnaire [70]. In thisstudy, Genuair� and Respimat� were the mostliked and were perceived by patients as theeasiest to use. Patients and nurses also perceivedthese two devices as the least problematic; itshould be noted that in this study, patients werenot asked to insert the cartridge into theRespimat� device, which remains a vital stepprior to prepare the actuations [70]. Meannumber of attempts required to achieve the firsteffective actuation was the highest with theBreezhaler� device, therefore reinforcing theimportance of patient education with a newdevice. Respimat� proved to be the most pre-ferred in COPD patients since it was the mostliked and its success rate at first attempt was thehighest. Furthermore, previous experience withDPIs and/or MDIs did not affect preference foran individual device in patients with COPD orasthma [71]. Respimat� was preferred over thepMDI by patients with COPD and otherobstructive lung diseases [71]. In comparativestudies with pMDIs, the patient total

satisfaction score with Respimat� was statisti-cally and clinically significantly higher thanwith the comparator pMDI [71]. In a cross-sec-tional study among patients with COPD inSpain using the validated Patient Satisfactionand Preference Questionnaire (PASAPQ),patients reported satisfaction with both Respi-mat� and Breezhaler� devices [72].

Several studies were previously carried out tocompare ease of use and patient satisfactionwith commercially available inhalers. While alldevices tested in a non-interventional settingwere deemed acceptable to patients, statisticallysignificant differences were neverthelessobserved in the questionnaire ratings from dif-ferent inhalers [73]. Notably, patients with sev-ere COPD expressed a higher feeling ofsatisfaction with their devices than those withmoderate or mild disease, independent of thedevice used; this may have been due to thelonger use, familiarity with the device, andprobably better adherence (because of theirsevere symptoms) of patients with severe COPD[73]. In DPI-naıve patients with COPD, Breez-haler� was preferred over HandiHaler� and wasmore likely to be used correctly [74]. A real-lifestudy evaluated inhaler preference and han-dling errors with the Ellipta� and Breezhaler�

DPIs in device-naıve Japanese volunteers aged40 years or older [75]. It was observed thatEllipta� DPI was preferred over Breezhaler� onthe basis of its ease-of-use features and wasassociated with fewer handling errors [75]. Incontrast, in the ADVANTAGE study, device-naıve patients with COPD reported greaterpreference for the Breezhaler� than for theEllipta� device for confidence of dose deliveryand comfort of the mouthpiece [76]. Such dif-ferences may be linked to the larger mouthpieceof the Breezhaler� as well as to the ability forpatients to visually confirm if any powder is leftin the capsule after each actuation. These resultswere confirmed in the recent Real life Experi-ence and Accuracy of inhaLer use (REAL) surveyconducted in patients with COPD, which gath-ered insights into real-life inhaler use bypatients and healthcare providers, device attri-butes, and training [77]. The majority ofpatients using Breezhaler� reported either beingvery confident or confident of having taken a

Pulm Ther (2019) 5:23–41 31

full dose, which was higher than those usingGenuair�, Ellipta�, and Respimat�. However,this study also identified a low incidence ofpatient training and monitoring by healthcareproviders for correct inhaler use [77]. In therecently reported INHALATOR study, a signifi-cantly greater proportion of patients expressedpreference for Breezhaler� than for Respimat�

(57.1% versus 30.1%) [78]. It should be notedthat good clinical practice implies that patientsare educated on how to use a new device uponfirst encounter, while the INHALATOR studydesign was apparently relying on patientsfamiliarizing themselves with the new devicevia product leaflets; also, the study was meant toevaluate the correct use and satisfaction ratherthan the efficacy between devices [78]. It isimportant to note that differences in activedrug in each of the devices evaluated, amongother limitations in the INHALATOR study,may have influenced the overall results.

It is noteworthy that in the inhaler devicepreference studies that were sponsored by thepharmaceutical companies, the sponsor’s deviceseemed favored by the type of questions askedto participants and typically came out as a pre-ferred choice in most of the studies. Unsurpris-ingly, these observations suggest an intent tohighlight differential device specificities.Patients with unstable disease or who wereunable to use inhalers were usually excludedand the extent of instruction and coachinggiven in the studies was highly variable. Inter-estingly, some studies sponsored by pharma-ceutical companies found no significantdifferences in terms of patient satisfactionbetween different types of devices (includingDPIs and SMI) [58, 70, 79]. On the other hand,and as discussed in the following section of thisreview, studies including CRITIKAL [24] andINHALER [45] showed different specific errorsassociated with different inhaler devices. Thesestudies, along with a recent systematic review,demonstrated the impact of critical errors inhandling inhaler devices on health outcomes inpatients with COPD and asthma [80].

There have been no well-designed studiesthat attempted to evaluate how differencesamong the devices would translate in terms ofrelevant patient outcomes. Moreover, patient

preference is as important as clinical evidencewhen selecting an appropriate device and ulti-mately in realizing optimal clinical outcomes;therefore, improved patient education,patient–physician interaction, and affordabilityalong with greater ease of using inhaler deviceswould lead to correct inhaler choice.

HANDLING OF INHALER DEVICES

In randomized clinical studies that compareinhaled treatments in COPD, the correct use ofinhaler devices is an inclusion criterion. How-ever, in real life, patients continue to makeerrors with their usual inhaler device [81],which may negate the treatment benefitsobserved in clinical studies. In this regard, var-ious studies have assessed inhaler handling inreal life. It has been shown that most inhalerusers not only make errors but also thosepatients who did not get proper education oninhaler technique are more inclined to misusetheir device [82]. A recent Japanese study hasalso suggested that patients, regardless of hav-ing asthma or COPD, require to be instructed atleast three times, i.e., given demonstrations bytrained personnel in order to limit inhalerhandling errors [83]. Notably, while about 65%of patients made at least one handling error thatcould affect the efficacy after an initial guidanceon how to use the Breezhaler�, the Ellipta� orRespimat�, more than 90% of patients usingany device could successfully learn the correctuse after receiving guidance from pharmaciststhree times successively [83]. Whether inhalerhandling errors remain frequent among long-term inhaler users or are associated with worseclinical outcomes in COPD is discussed below.

The real-life INHALER study assessed inhalerdevice handling in approximately 3000 COPDpatients who were using inhaler devices for atleast 1 month [45]. Physicians assessed patients’inhaler technique and documented device-de-pendent (i.e., specific) or device-independenthandling errors. Handling errors were observedin over 50% of inhalations regardless of thedevice used. However, the number of errorsdeemed critical (i.e., those which significantlyreduced drug delivery) differed amongst the

32 Pulm Ther (2019) 5:23–41

devices. Device-independent errors (e.g., patientdid not exhale fully prior to inhalation) wereequally frequent across all devices. Fewerpatients made critical errors using Breezhaler�

versus other devices; Breezhaler� also had fewerdevice-specific errors. Overall, fewer criticalerrors were made with DPIs than with pMDIs orSMIs. Moreover, the recent INHALATOR studyshowed that the rate of correct device use, i.e.,no critical errors during inhalation technique,was similar between Breezhaler� and Respi-mat�. The evaluation of the patients’ inhalationtechnique was based on the investigator’sobservation [78].

An important finding of the aforementionedINHALER study was that the handling errorswere significantly associated with more fre-quent COPD exacerbations (Fig. 1) [45].

Use of Genuair� was associated with fewererrors compared with HandiHaler�, includingcritical errors that may impede the delivery ofsufficient doses or drug deposition to the lungs[52, 54]. In an assessment of critical inhalertechnique errors with Genuair� and Breezhaler�

after 2 weeks of daily use, the proportion ofpatients making these errors was low with bothGenuair� and Breezhaler� [84]. When com-pared with other inhalers, fewer COPD patients

had at least one overall error using the Ellipta�

inhaler compared with the Handihaler� orBreezhaler�; a larger proportion of patientsrated the Ellipta� inhaler very easy or easy touse compared with the Handihaler� or theBreezhaler� [85]. A cross-sectional study exam-ined specific patient characteristics and deviceattributes that are associated with poor han-dling technique among patients with COPDwho used at least one of the following devices:MDI, Diskus�, and Handihaler� [86]. It wasfound that poor inhaler technique was commonamong individuals with COPD, varied amongstdevices, and was even associated with race andlevel of education [86]. A real-life study com-pared handling of different inhaler devices(Aerolizer�, Autohaler�, Diskus�, or Tur-buhaler�) in primary care practice in France andobserved differences in device handling in pri-mary care that were not considered in con-trolled studies [87]. Although this study did notcompare devices that deliver LABA/LAMA FDCs,a comparison of findings from this study andthose from the INHALER study [45] indicatesthat device handling has not improved signifi-cantly over the several decades that handlingstudies have been performed.

#exacerbation with antibiotic therapy, corticosteroid therapy, emergency room visit or hospitalization.*exacerbation with emergency room visits or hospitalization.†restricted to patients treated for at least 3 months with the device.

Fig. 1 Association of critical device handling errors with COPD exacerbations

Pulm Ther (2019) 5:23–41 33

EFFECTIVE TREATMENT THROUGHAPPROPRIATE APPLICATIONOF INHALER DEVICES

The inhaled route of administration is consid-ered as the best way to deliver medications topatients with COPD. The availability of an arrayof medication classes and associated inhalerdevices with different degrees of efficacy hasactually made the selection of optimal inhaledtreatment complicated.

Ideally, inhalers should be easy to use andshould have multiple feedback and controlmechanisms that would reduce physician over-estimation and ignorance of correct inhalation,allow compliance to be monitored, facilitatepatient self-education, and give reassurance topatients in routine care. Treatment compliancein long-term disease management may beimproved by educating patients and physicianson the correct use of inhaler devices. In thisregard, studies such as the REAL survey haveattempted to assess the effectiveness of patient/healthcare provider training on correct inhaleruse [77]. Poor inhalation technique, number ofinhalation steps, clinical setting, and timeelapsed since training were shown to have an

impact on the effectiveness of the educa-tional/training intervention [77]. Educationalinterventions to improve inhaler technique inpatients were found to be effective in the shortterm [77]. To improve application of inhalerdevices in real life, the German Airway Leaguedeveloped a checklist for inhaler devices tocheck for inhaler errors. Moreover, they pre-pared free internet-based short videos for allavailable inhaler devices. It was shown that asingle session of patient information through ashort video sequence improved device use, andthe effect lasted for 4–8 weeks [88–90]. Videoinformation seemed to be very important inimproving inhalation technique, since health-care personnel in primary care and hospitals areoften not qualified for use of different inhalerdevices [91, 92].

A number of factors influence treatmentoutcomes with inhalation therapy (Fig. 2). Inparticular, characteristics of the drug and of thedelivery device, patient’s ability to use a deviceproperly, education/training, and patient’s per-sonal preference should be considered in orderto maximize treatment outcome throughinhalation therapy [6, 93]. However, one shouldinterpret device preference studies cautiously as

Fig. 2 Factors influencing treatment outcomes from inhaler devices

34 Pulm Ther (2019) 5:23–41

they often focus on handling-related preferencesand are frequently conducted with patientsusing placebo devices, therefore discarding someimportant aspects of inhaled medications. Theseinclude the patient’s ability to self-monitoradequate use of the device and uptake inhaledmedication, as well as the clinical benefits of theinhaled therapy as perceived by the patients[94]. These factors have the potential to supportpatients’ adherence and satisfaction and deservephysicians’ consideration. Highlighting theassociation of inhaler device application withclinical outcomes, Molimard et al. showed forthe first time that, despite limitations of theirstudy (e.g., short follow-up period), inhalermisuse may be linked to increased rates of severeexacerbations in COPD patients [45].

As inhaled medications are essentially ‘‘inte-grated’’ with their respective devices, the chal-lenge in ensuring the best possible application ofinhaled treatment is in identifying whether theempirical clinical efficacy of the delivered mole-cules or the differential inhaler use (more/lessclinical errors, or variable patient behaviorsusing different devices) determines the observedtreatment efficacy. Even a randomized head-to-head comparison of different LABA/LAMA FDCswould be limited as the comparison is oftenmade between different medications (eventhough of the same class) in different devices. Apossible solution could be more head-to-headstudies of different inhalers (e.g., administeringplacebo to remove medication bias or using adouble-dummy design wherein all patients useall inhalers, but some will be placebo).

CONCLUSIONS

Inhaler devices that offer consistent and effi-cient dosing, ease of use, and patient preferencelead to enhanced patient adherence and there-fore better treatment efficacy. Nonetheless,handling errors are common and numerouspatient factors still limit the use of contempo-rary devices. Such suboptimal inhaler use has anadverse effect on clinical outcomes. The GOLD2019 strategy has re-emphasized considerationof inhaler device attributes and handling whileprescribing treatment to COPD patients. In this

context, GOLD has explicitly stated that theimportance of education and training in inhalerdevice technique cannot be overemphasized.

It is important that a patient’s ability to usean inhaler device is checked by the healthcareprovider at the first visit and monitored at eachsubsequent visit, ideally every 3 months for aminimum of 1 year. Assessment of inhalertechnique and adherence has been recognizedby GOLD as an essential component of themanagement of stable COPD. Therefore, patienteducation and patient–healthcare providerinteractions are key to ensuring the correct useof inhaler devices. Technologic advances maysoon offer assistance. New electronic andinternet-connected inhaler devices, also calledsmart inhalers, e.g., eBreezhaler�, are in late-phase development to help with real-timemonitoring of treatment adherence and appro-priate device use, and even to train patients.The widespread adoption of smart inhalersmight be limited by concerns over cost-effec-tiveness, lack of evidence that they improvequality of life, and increased burden onhealthcare providers to monitor the data [95].

Finally, in view of the gap that still remainsin the selection and application of appropriateinhaler devices for delivery of optimal COPDtreatment, this review indicates that both theefficacy of the drug and appropriate applicationof inhaler devices cannot be dissociated in thecontext of evolving COPD management thathas placed an increasing emphasis on the use ofLABA/LAMA fixed-dose bronchodilator combi-nations. Although influenced by physician andpatient preferences, the choice of an appropri-ate inhaler and continuous educational effortsto reinforce appropriate device handling are ofequal importance to ensure therapies optimallycontribute to the management of COPD.

ACKNOWLEDGEMENTS

Funding. The preparation of this manuscriptwas funded by Novartis Pharma AG. No fundingor sponsorship was recieved for the publicationof this article.

Pulm Ther (2019) 5:23–41 35

Medical Writing and Editorial Assis-tance. The authors thank David Prefontaine,PhD and Rahul Lad, PhD (Novartis), and Prav-een Kaul, PhD for providing medical writingand editorial support, which was funded byNovartis Pharma AG in accordance with GoodPublication Practice (GPP3) guidelines.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Anthony D’Urzo has receivedresearch, consulting and lecturing fees fromGlaxoSmithkline, Sepracor, Schering Plough,Altana, Methapharma, AstraZeneca, ONOpharma, Merck Canada, Forest Laboratories,Novartis Canada/USA, Boehringer Ingelheim(Canada) Ltd, Pfizer Canada, SkyePharma, andKOS Pharmaceuticals and Almirall. M. RezaMaleki-Yazdi has received grants/research sup-port from Novartis, Boehringer Ingelheim, GSK,Pfizer, Nycomed, AstraZeneca, Ono Pharma-ceuticals, Merck and Forest Pharmaceuticals;speaker’s bureau/honoraria from Novartis,Boehringer Ingelheim, GSK, Pfizer, Nycomed,AstraZeneca, Merck; consulting fees fromNovartis, Boehringer Ingelheim, GSK, Pfizer,Nycomed, AstraZeneca and Merck. James F.Donohue serves on DMSB for AstraZeneca,Teva, Gilead, and has been on advisory boardsfor AstraZeneca, Boehringer-Ingelheim,GlaxoSmithKline, Novartis, Sunovion, Thera-vance, and Innoviva. In the past three years,Kenneth R. Chapman has received compensa-tion for consulting with Almirall, CSL Behring,Forest, GlaxoSmithKline, Grifols, Merck Frosst,Novartis, Regeneron, Roche, Sanofi, Takeda; hasundertaken research funded by AstraZeneca,Boehringer-Ingelheim, CSL Behring, ForestLabs, Genentech, GlaxoSmithKline, Grifols,Novartis, Regeneron, Roche and Sanofi; and hasparticipated in continuing medical educationactivities sponsored in whole or in part byAstraZeneca, Boehringer-Ingelheim, CSL Behr-ing, GlaxoSmithKline, Grifols, Merck Frosst andNovartis. David Price has board membership

with Aerocrine, Amgen, AstraZeneca, Boehrin-ger Ingelheim, Chiesi, Mylan, Mundipharma,Napp, Novartis, and Teva Pharmaceuticals;consultancy agreements with Almirall, Amgen,AstraZeneca, Boehringer Ingelheim, Chiesi,GlaxoSmithKline, Mylan, Mundipharma, Napp,Novartis, Pfizer, Teva Pharmaceuticals, andTheravance; grants and unrestricted funding forinvestigator-initiated studies (conductedthrough Observational and Pragmatic ResearchInstitute Pte Ltd) from Aerocrine, AKL Researchand Development Ltd, AstraZeneca, BoehringerIngelheim, British Lung Foundation, Chiesi,Mylan, Mundipharma, Napp, Novartis, Pfizer,Respiratory Effectiveness Group, Teva Pharma-ceuticals, Theravance, UK National Health Ser-vice, Zentiva; payment for lectures/speakingengagements from Almirall, AstraZeneca,Boehringer Ingelheim, Chiesi, Cipla,GlaxoSmithKline, Kyorin, Mylan, Merck, Mun-dipharma, Novartis, Pfizer, Skyepharma, andTeva Pharmaceuticals; payment for manuscriptpreparation from Mundipharma and TevaPharmaceuticals; payment for the developmentof educational materials from Mundipharmaand Novartis; payment for travel/accommoda-tion/meeting expenses from Aerocrine, Astra-Zeneca, Boehringer Ingelheim, Mundipharma,Napp, Novartis, and Teva Pharmaceuticals;funding for patient enrolment or completion ofresearch from Chiesi, Novartis, Teva Pharma-ceuticals, and Zentiva; stock/stock options fromAKL Research and Development Ltd whichproduces phytopharmaceuticals; owns 74% ofthe social enterprise Optimum Patient Care Ltd(Australia, Singapore, and UK) and 74% ofObservational and Pragmatic Research InstitutePte Ltd (Singapore); and is peer reviewer forgrant committees of the Efficacy and Mecha-nism Evaluation programme, and Health Tech-nology Assessment. In the past 3 years, PeterKardos received compensation for scientificadvisory boards, steering committee and pre-sentations from following companies: AstraZe-neca, Boehringer Ingelheim, Chiesi,GlaxoSmithKline, Menarini, Novartis and Teva.He was also reimbursed for attending confer-ences from AstraZeneca and Novartis. No otherconflict of interests exists.

36 Pulm Ther (2019) 5:23–41

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing not appli-cable to this article as no datasets were gener-ated or analyzed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), whichpermits unrestricted use, distribution, andreproduction in any medium, provided you giveappropriate credit to the original author(s) andthe source, provide a link to the CreativeCommons license, and indicate if changes weremade.

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