ORIGINAL RESEARCH

SABINA: An Overview of Short-Acting b2-Agonist Usein Asthma in European Countries

Christer Janson . Andrew Menzies-Gow . Cassandra Nan .

Javier Nuevo . Alberto Papi . Jennifer K. Quint . Santiago Quirce .

Claus F. Vogelmeier

Received: December 20, 2019 / Published online: January 24, 2020� The Author(s) 2020

ABSTRACT

Introduction: Globally, individuals withasthma tend to overrely on short-acting b2-ag-onists (SABAs) and underuse inhaled corticos-teroids, thereby undertreating the underlyinginflammation. Such relief-seeking behavior hasbeen reinforced by long-standing treatmentguidelines, which until recently recommendedSABA-only use for immediate symptom relief.We aimed to describe the current burden of

SABA use among European individuals withasthma within the SABA use IN Asthma(SABINA) program.Methods: Prescription and/or dispensing dataduring 2006–2017 from electronic medicalrecords and/or national patient registries in theUnited Kingdom (UK), Germany, Italy, Spain,and Sweden were analyzed. Individuals aged atleast 12 years old with a current asthma diag-nosis and no other chronic respiratory condi-tions were included. Asthma treatment step andseverity were based on treatment guidelines inuse in each individual country. The proportionof individuals prescribed SABA was measuredduring a 12-month period. SABA overuse wasdefined as at least three SABA canisters per year.Results: More than one million individualswith asthma were included across five Europeancountries. Overall, the majority of individuals

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.11590857.

C. JansonDepartment of Medical Sciences: Respiratory,Allergy and Sleep Research, Uppsala University,Uppsala, Sweden

A. Menzies-GowLung Division, Royal Brompton Hospital, London,UK

C. NanBiopharmaceuticals Medical, AstraZeneca,Gothenburg, Sweden

J. Nuevo (&)Biopharmaceuticals Medical, AstraZeneca, SerranoGalvache 56, 28033 Madrid, Spaine-mail: Javier.Nuevo@astrazeneca.com

A. PapiDepartment of Medical Sciences, University ofFerrara, Ferrara, Italy

J. K. QuintRespiratory Epidemiology, Occupational Medicineand Public Health, National Heart and LungInstitute, Imperial College London, London, UK

S. QuirceDepartment of Allergy, La Paz University Hospital,and CIBER of Respiratory Diseases (CIBERES),Madrid, Spain

C. F. VogelmeierDepartment of Medicine, Pulmonary and CriticalCare Medicine, University Medical Center Giessenand Marburg, Philipps-University Marburg, Memberof the German Center for Lung Research (DZL),Marburg, Germany

Adv Ther (2020) 37:1124–1135

https://doi.org/10.1007/s12325-020-01233-0

were over 45 years of age, except in Sweden(mean age 27.6 years) where individuals agedover 45 years were excluded to avoid a potentialchronic obstructive pulmonary disease co-diag-nosis. The study population was predominantlyfemale (55–64%), except in the UK (46%). Theprevalence of SABA overuse was 9% in Italy,16% in Germany, 29% in Spain, 30% in Sweden,and 38% in the UK. In the UK, SABA overusewas greater in individuals with moderate-to-severe asthma versus individuals with mildasthma (58% versus 27%, respectively), whileSABA overuse was similar in individuals withboth mild (9–32%) and moderate-to-severe(8–31%) asthma in the other Europeancountries.Conclusions: The findings of this study fromthe SABINA program show that SABA overuse(at least three canisters per year) is commonacross Europe, despite the different healthcareand reimbursement policies of each country.

Keywords: Europe; Overreliance; Prescription;Public health; Short-acting b2-agonist

Key Summary Points

Why carry out this study?

Despite the availability of effective asthmatreatments, some individuals are poorlycontrolled because of overreliance onshort-acting b2-agonists (SABAs) andunderuse of inhaled corticosteroids.

As a result of growing evidence that SABAoverreliance is associated with anincreased risk of asthma-relatedexacerbations and mortality, a global viewof SABA prescriptions is needed to betterunderstand the public health burden ofSABA overuse in asthma management.

As part of the SABINA (SABA use INAsthma) program, this study aimed toprovide an overview of similarities anddifferences in SABA prescription trendsacross five European countries (UK,Germany, Italy, Spain, and Sweden) inover one million individuals.

What was learned from the study?

SABA overuse (C 3 canisters per year)occurred in approximately one-third ofmild, moderate, and severe individualswith asthma across Europe, despite thedifferent healthcare and reimbursementpolicies of each country.

These findings indicate that there is asignificant group of individuals who arenot optimally treated according to currentrecommendations.

Following the recent 2019 GlobalInitiative for Asthma (GINA) update,which no longer recommends treatingadolescents and adults with as-neededSABA alone for symptom relief, changes inphysician and patient behaviors towardsSABA use, and updates to nationalhealthcare policies, are required to ensurethat individuals with asthma are notexposed to SABA alone in the treatment oftheir asthma.

INTRODUCTION

Asthma is a chronic, heterogeneous, fluctuat-ing, inflammatory disease of the airways that isestimated to affect 339 million people world-wide [1]. In Europe, over 8% of adults haveasthma, with the highest prevalence found inthe United Kingdom (UK) and Sweden [1–3].Anti-inflammatory maintenance treatmentwith low-dose inhaled corticosteroids (ICS) isthe cornerstone of asthma treatment [4]. As-needed short-acting b2-agonists (SABAs) havebeen traditionally prescribed for symptomrelief, with or without daily maintenancetreatment, depending on the level of asthmaseverity [5, 6]. However, evidence on the safetyrisks associated with high SABA use has grownsubstantially in the last few years [7–10]. Inparallel, clinical trials have reported the superi-ority of anti-inflammatory reliever therapy withas-needed ICS–formoterol versus as-needed

Adv Ther (2020) 37:1124–1135 1125

SABA in terms of symptom control and reduc-tion in exacerbation risk [11–15]. Consequently,the 2019 Global Initiative for Asthma (GINA)recommendations have eliminated SABAmonotherapy in step 1 and instead recommendas-needed low-dose ICS–formoterol as the pre-ferred reliever in steps 1–2. In addition, in GINAsteps 3–5, low-dose ICS–formoterol is the pre-ferred reliever for patients prescribed ICS–for-moterol maintenance and reliever therapy [16].

With this knowledge, SABA overreliance isnow an even greater concern. However, it willbe difficult to change this overreliance, linkedto decades of patient behavior and guidelinesrecommending, until very recently, SABA usefor immediate symptom relief and as the firsttreatment for newly diagnosed mild intermit-tent asthma [17, 18]. When symptoms worsen,most individuals with asthma overrely on theirSABA inhaler for symptomatic relief, often atthe expense of ICS maintenance therapy[19–21]. As SABAs have no anti-inflammatoryeffect [22, 23], they neither treat the underlyinginflammation nor protect against exacerba-tions. The continued reliance on SABA relieversleaves individuals across all asthma severities atrisk of preventable attacks whether adherent ornot to their maintenance controller [11, 14].Indeed, in the UK, SABA overuse and the rela-tive underuse of ICS was highlighted as one ofthe underlying reasons for preventable asthmaattacks and deaths [24].

There are limited data on SABA and ICSprescription trends in European countries, and apan-European view of potential SABA overuseand relative ICS underuse is lacking. The SABAuse IN Asthma (SABINA) program [25] wastherefore initiated to describe the global extentof SABA and ICS use in asthma and its clinicalconsequences. For the purpose of this analysis,which was to understand the current state ofasthma reliever prescriptions relative to recenttreatment recommendations, we aimed to pro-vide an overview of the similarities and differ-ences in SABA prescription trends only, forindividuals with asthma across Europeancountries.

METHODS

Study Design

The SABINA program encompasses three mainpillars: SABINA I (a retrospective, observationaldatabase study with expanded objectives in theUK), SABINA II (a distributed harmonized set ofmulticountry retrospective observational data-base studies in Europe and Canada), andSABINA III (a prospectively collected multi-country cross-sectional study in 25 countries).Full details of the SABINA program are describedelsewhere [25]. In this study, prescription datagenerated from the European arms of SABINA—SABINA I (UK) and SABINA II (Italy, Germany,Spain, and Sweden)—were analyzed. On thebasis of data availability, individual countrydata were obtained from electronic medicalrecords and/or national patient registries asshown in Table 1.

Patient Population

Individuals aged at least 12 years old with acurrent asthma diagnosis were included in thestudy. In Sweden, the study population inclu-ded all individuals with asthma who collectedat least two drugs for obstructive lung disease(ATC R03) from pharmacies in a 1-year period.In addition, the upper age limit of 45 years wasapplied in Sweden to ensure that individualswith chronic obstructive pulmonary disease(COPD) were excluded, a validated proxy forasthma [26]. The definition of current asthmavaried across studies (Table 1). For instance, inmost countries, current asthma was defined asan asthma diagnosis code within 1 or 3 yearsbefore the index date (date on which the indi-vidual first entered the study); however, inSweden, it was defined as at least two prescrip-tions for a chronic obstructive lung diseasemedication within 12 months of study entry.All studies required individuals with asthma tohave data for at least 12 months before and afterstudy entry. Study periods varied between 2006and 2018. However, all countries includedrecent data (2016–2018) on SABA use, while

1126 Adv Ther (2020) 37:1124–1135

some countries, such as Sweden and the UK,included data from as early as 2006.

The studies performed as part of the SABINAprogram were each approved by the institu-tional review board of the ethics committee intheir individual country and were conducted inaccordance with the Declaration of Helsinki of1964 and its later amendments, the Interna-tional Council for Harmonisation of TechnicalRequirements for Pharmaceuticals for HumanUse (ICH), Good Clinical Practice (GCP), andthe applicable legislation on non-interventionalstudies and/or observational studies.

Study Measures

SABA UseThe percentage of individuals with asthma whowere prescribed SABA was recorded during a12-month period. SABA use was categorized bythe number of canister prescriptions per year(0–2, 3–6, 7–12, or 13 and more). According tothe guidelines, appropriate use of SABA is con-sidered as fewer than three puffs per week,which is equivalent to fewer than 150 puffs/actuations per year or at most two prescribedcanisters per year. For consistency across allcountries in the SABINA program, one SABAcanister was assumed to contain 150

Table 1 Study design features in SABINA I and II

SABINA I (UK) SABINA II

Germany Italy Sweden Spain

Data source Primary care

records

(CPRD

GOLD),

linked with

secondary care

(HES) and

mortality

(ONS) data

IMS� Disease

Analyzer:

electronic

medical records

from general

practitioner and

pulmonologist

panels

IQVIA� databases:

electronic medical

records from

primary care

(Longitudinal

Patient Database)

and secondary

care (Patient

Analyzer)

physicians

Nationwide

longitudinal

cohort study

(HERA): linked

data from national

patient, pharmacy

dispensing, and

mortality registries

BIG-PAC�

database:

electronic

medical records

from primary and

specialized

healthcare

Study period 2007–2017 2013–2018 2015–2018 2006–2016 2017–2018

Age C 12 years C 12 years C 12 years 12–45 years C 12 years

Asthma

definition

Asthma diagnosis

code within

3 years of index

date

Asthma diagnosis

code during study

period

Asthma diagnosis

code 1 year prior

to index date

C 2 collections for a

chronic

obstructive

pulmonary disease

medication within

12 months

Asthma diagnosis

code and C 2

healthcare uses

within study

period

Asthma

treatment

steps

2016 BTS

guidelines

2018 GINA

recommendations

2018 GINA

recommendations

2018 GINA

recommendations

2018 GINA

recommendations

BTS British Thoracic Society, CPRD Clinical Practice Research Datalink, GINA Global Initiative for Asthma, HERA HighEfficiency Reliable Access (to data stores), HES Hospital Episode Statistics, ONS Office for National Statistics, SABINASABA use IN Asthma

Adv Ther (2020) 37:1124–1135 1127

inhalations [25]. However, in Germany andSpain, one canister was defined as containing200 inhalations based on a preliminary analysisof the data, which showed that nearly all pre-scribed SABA canisters contained 200 doses. Onthe basis of this assumption and allowing forindividuals to have multiple SABA inhalers atthe same time, SABA overuse was defined asprescription/dispensing of at least three canis-ters per year.

Treatment Step and Asthma SeverityIndividuals with asthma were categorized intotreatment steps (1–5) and severity (mild,steps 1–2; moderate–severe, steps 3–5) by theirICS prescriptions (low, medium, or high) in theyear prior to their index date on the basis of the2016 British Thoracic Society (BTS) guidelines

[6] (low-dose ICS, 400–799 lg beclometasonedipropionate [BDP] equivalent; medium-doseICS, 800–1599 lg; high-dose ICS, at least1600 lg) for the UK or 2018 GINA recommen-dations [5] (low-dose ICS, 200–500 lg BDPequivalent; medium-dose ICS, 500–1000 lg BDPequivalent; high-dose ICS, more than 1000 lgBDP equivalent) for the remaining countries.

Statistical Analysis

Baseline characteristics were described as mean(standard deviation, SD) for continuous vari-ables and absolute and relative frequencies forcategorical variables. Descriptive statistics wereprovided for the SABA prescription data.

Table 2 Baseline characteristics of individuals with asthma

Italy Germany Spain Sweden UK

Total number of included individuals with asthma 22,102 53,866 39,555 365,324 574,913

Mean age in years at study entry (SD) 50.8

(19.1)

51.0

(18.0)

49.8

(20.7)

27.6

(11.0)

50.0

(20.6)

Male gender (%) 42 40 36 45 54

Individuals with mild asthma (treatment stepa 1–2) (%) 37 60 27 48b 65

Individuals with moderate-to-severe asthma (treatment stepa 3–5) (%) 63 40 73 50 35

BTS British Thoracic Society, GINA Global Initiative for Asthma, SD standard deviationa Treatment steps were based on GINA 2018 for all countries, except the UK (BTS 2016)b Approximately 2% of individuals could not be classified into a GINA therapy step in Sweden

Table 3 Treatment characteristics: overall SABA use

Italy Germanya Spain Sweden UK

Mean (SD) number of annual SABA canisters 3.1 (4.0) 1.6 (3.9) 3.3 (3.6) 1.9 (2.9) 4.2 (5.1)

Individuals with 0–2 SABA canisters/year (%) 91 84 71 70 62

Individuals with C 3 SABA canisters/year (%) 9 16 29 30 38

Individuals with 3–6 SABA canisters/year (%) 6 10 19 25 24

Individuals with 7–12 SABA canisters/year (%) 2 3 6 5 11

Individuals with C 13 SABA canisters/year (%) 1 2 4 1 4

GP general practitioner, SABA short acting b2-agonist, SD standard deviationa This analysis was based on GP-treated individuals only (n = 29,636)

1128 Adv Ther (2020) 37:1124–1135

RESULTS

Patient Baseline Demographicsand Clinical Characteristics

Overall, 1.06 million individuals with asthmawere included across the countries. On average,most individuals were at least 45 years of age,except in Sweden where the mean age of indi-viduals was 27.6 years (Table 2). Most individu-als with asthma were female, except in the UK,where male individuals constituted the majority(54%). The severity of asthma (as determined bytreatment step) varied across countries. In Ger-many and the UK, most of the study populationincluded were treated as having mild asthma(60% and 65%, respectively). In Italy and Spain,most individuals had moderate-to-severeasthma (63% and 73%, respectively), while inSweden, they were distributed almost equallyacross severities.

SABA Use

The characteristics of SABA use are summarizedin Table 3 and Fig. 1. The mean number ofannual SABA canisters used varied across coun-tries. Overall, the prevalence of SABA overuse

was 9% in Italy, 16% in Germany, 29% in Spain,30% in Sweden, and 38% in the UK. In the UK,SABA overuse was greater in individuals withmoderate-to-severe asthma versus mild asthma(58% versus 27%). Overall, SABA overuse wassimilar in individuals with mild (9–32%) andmoderate-to-severe (8–31%) asthma in theother European countries.

DISCUSSION

SABINA I and II assessed SABA prescriptiontrends across European countries in over a mil-lion individuals with asthma. Overall, with theexception of Italy, SABA use was commonacross all asthma severities, and our data suggestthat approximately one-third of individuals areoverusing SABA.

Our findings are generally consistent withthose of other studies in a European populationusing the same SABA canister cutoff, but dif-ferent study designs. In the cross-sectionalASTHMAPOP survey among 15,587 adults inFrance, 28.3% of patients reported using at leastthree SABA canisters per year [27]. Similarly, aPolish study of pharmacy prescription recordsof 91,673 adult patients observed that 29–37%of patients with asthma were prescribed at least

Fig. 1 SABA use in individuals with mild and moderate-to-severe asthma across European countries. In Germany,analysis was based on GP-treated individuals only(n = 29,636). Treatment steps were based on GINA

2018 for all countries, except the UK (BTS 2016). BTSBritish Thoracic Society, GINA Global Initiative forAsthma, GP general practitioner, SABA short-acting b2-agonist

Adv Ther (2020) 37:1124–1135 1129

three SABA canisters per year [28]. Differencesin national healthcare and medication reim-bursement policies may impact medicationprescribing practices and related clinical out-comes, and this needs to be taken into consid-eration for the present study findings. Forinstance, SABA is available without a prescrip-tion in Italy, Spain, and the UK (emergencyaccess only), but not in Germany and Sweden.Notably, availability of SABA without a pre-scription has been linked to undertreatment ofasthma (relative to the relevant guidelines rec-ommendations) and infrequent consultationswith physicians [29]. Moreover, it has beenshown that without regular medical supervi-sion, patients are more likely to overuse SABA[30]. Although SABA medication is not availablewithout a prescription in many countries in theSABINA program, such findings have far-reach-ing global implications. Consequently, animproved understanding of this population ofindividuals with asthma who purchase SABA,especially their attitudes and beliefs aboutasthma and its treatment, is essential. A recentreal-world, cross-sectional observational studyin Australia, where SABA medication can bepurchased from the community pharmacistwithout a prescription, identified a cohort ofindividuals with suboptimal asthma control, co-existing allergic rhinitis, and poor ICS adher-ence who were SABA overusers (used SABA morethan twice a week in the past 4 weeks) [31].Addressing such findings in primary care iscritical to address the issue of SABA overuse.Because the availability of SABA without pre-scription was not taken into account in ouranalysis, actual SABA use may be even higher incountries that do not require a prescription topurchase SABA medication. This finding is par-ticularly apparent in the assessment of SABAprescriptions in Italy in our study, where SABAoveruse was less evident compared with otherEuropean countries. From initial marketresearch, it is understood that a relatively largeproportion of individuals with asthma obtainSABA inhalers without prescription, whichcould explain the low prevalence of SABAoveruse in prescription databases. Further anal-yses are now planned to investigate this possi-bility in Italy.

Although similar SABA use trends wereobserved despite differences across nationalpolicies, data sources, and study designs, therewere some differences in relation to SABA useand asthma severity. Among the five countriesanalyzed, the UK had the lowest percentage ofindividuals receiving treatment for moderate-to-severe asthma, and the highest averagenumber of annual SABA prescriptions. Thiscould indicate that individuals with uncon-trolled asthma in the UK are more likely to beprescribed SABA rather than being reviewed andprescribed an increased dose of their mainte-nance therapy as recommended by guidelines[6]. Indeed, according to a recent survey amongindividuals with asthma in the UK, over 60% ofrespondents indicated that they did not receivebasic asthma care, and approximately 20% ofrespondents did not receive an annual asthmareview [32].

Exposure and adherence to maintenance ICSwill likely impact SABA use, and it is, therefore,important to put these findings into the contextof ICS exposure. SABA overuse was greater inindividuals with moderate-to-severe asthma (upto 58%) compared with individuals with mildasthma, suggesting a greater degree of poorasthma control in these individuals despitereceiving maintenance ICS to treat the under-lying inflammation. Similar results were repor-ted from the recent Polish pharmacyprescription study, in which patients on ahigher treatment step received more SABA pre-scriptions compared with patients on lowertreatment steps [28]. It is possible that low ICSadherence is a driving factor or that mainte-nance therapy exposure is simply an indicationof disease severity and of an increased likeli-hood of the presence of symptoms that requireSABA. More detailed analyses in the individualSABINA studies are underway to investigate thepotential association of ICS and SABA use.

Overall, our findings indicate that there isconsiderable SABA use—and indeed SABAoveruse—among individuals across Europe,which puts them at risk of adverse outcomes.Changes in physician and patient behaviorstowards SABA use, active engagement inadapting 2019 GINA recommendations to localguidelines, and updates to national healthcare

1130 Adv Ther (2020) 37:1124–1135

policies will be needed to ensure that individu-als with asthma are not unnecessarily exposedto SABA alone in the treatment of theirinflammatory disease. Physicians shouldencourage the appropriate use of ICS, eliminateSABA monotherapy as per evidence-based rec-ommendations, challenge patient attitudes andpractices around SABA use, and ensure thatindividuals understand that asthma is aninflammatory condition. Importantly, individ-uals should be trained on the appropriate use oftherapy [33] and the technical use of inhalers[34]. Asthma education programs discouragingunregulated SABA use should be given dueconsideration. Education, together with regularmedical reviews and written personal asthmaaction plans, is advocated in guidelines and hasbeen shown to improve health outcomes forindividuals with asthma [35]. Therefore, a driveto implement personal actions plans, describinghow patients may recognize a deterioration inasthma control and what steps should be takento re-establish control [36], could further assistin curbing SABA overuse. Other healthcareprofessionals, such as nurses and pharmacists,could also provide training and support topatients. Pharmacists can also play an integralrole as they are in the unique position of beingable to initiate conversations about SABA over-use and can spend time educating patients andanswering any questions [31].

Potential limitations of this analysis relate tothe observational nature of the included studiesand the use of medical databases that were notnecessarily designed for research purposes.However, the results were comparable to thosefrom the UK arm of SABINA, which usedresearch-quality data from the Clinical PracticeResearch Datalink [37]. This increases confi-dence in the robustness of the data across therest of the countries. Additionally, the upperage limit of 45 years in Sweden may have led tomore individuals with severe asthma beingexcluded from the analysis. However, the algo-rithm that was used to identify individuals withasthma based on pharmacy collection of drugs(ATC R03) for obstructive lung disease wasshown to be a suitable proxy for asthma diag-nosis in this age group in validation studiesfrom Sweden [26]. This restriction was not

necessary in other countries, where other vali-dated algorithms were used (e.g., the UK) [38],and where sensitivity analyses were conductedto exclude individuals with a COPD co-diagno-sis. Despite these differences, similar overalltrends were seen across the countries, indicatingthat the age restriction applied to Sweden mayhave had limited impact on the results. Of note,dispensed or prescribed SABA may not alwaysequal the medication taken and may lead to anoverestimation of actual SABA overuse. Auto-matic repeat prescriptions, or simultaneousprescriptions of multiple SABA canisters, mayresult in individuals having more SABA inhalersin their possession, which they may not neces-sarily use. From clinical experience, we knowthat individuals with asthma typically havemultiple SABA inhalers such that there is at leastone inhaler in each of their surroundings (e.g.,home, office, car). This is done so that individ-uals with asthma have immediate access to theirreliever in the event of a sudden worsening insymptoms. Despite these limitations, the cur-rent manuscript assessed a large asthma popu-lation across five countries and providesimportant insights regarding SABA use and theextent of SABA overuse. The use of standardizedthresholds for SABA overuse in the SABINAprogram enabled comparisons across countries,which were previously limited by the varyingSABA overuse thresholds used across publishedstudies [39–41]. The next steps for the programare to describe SABA use across additionalcountries, and to investigate the association ofSABA use, maintenance ICS therapy, and clini-cal outcomes with healthcare resource use.Additionally, further context around patient’squality of life and patient’s adherence behaviorswill provide important insights into how tobetter interpret the program findings and howto potentially decrease SABA use in the future.More in-depth analyses should be performed inthose countries that are involved in the SABINAprogram.

CONCLUSIONS

There is a growing body of evidence that highSABA use is associated with increased risk of

Adv Ther (2020) 37:1124–1135 1131

adverse asthma-related outcomes. Individualsacross all asthma severities remain at risk ofexacerbations when they continue to overrely onSABA at the expense of ICS, leaving the underly-ing inflammation undertreated. Data from theSABINA program demonstrated that a consider-able proportion of individuals with asthma acrossEurope are using at least three SABA canisters peryear, indicating that there is a significant group ofindividuals who are currently not optimally trea-ted according to the 2019 GINA recommenda-tions. The combination of an ICS/fast-onset butlong-acting b2-agonist will be an effective patient-friendly strategy for improving adherence to evi-dence-based guidelines. Further work to supportchanges to national treatment guidelines and,therefore, ensure successful implementation ofthe latest GINA recommendations is currentlyunderway.

ACKNOWLEDGEMENTS

We would like to acknowledge all theresearchers involved in the SABINA program.

Funding. The SABINA program is funded byAstraZeneca. AstraZeneca also funded the jour-nal’s Rapid Service Fees for publication of thismanuscript and the open access fees.

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.

Medical Writing, Editorial, and OtherAssistance. Medical writing and editorial sup-port were provided by Urvashi Nikte, MDS andMichelle Rebello, PhD, of Cactus Communica-tions (Mumbai, India), which was funded byAstraZeneca and conducted in accordance withthe GPP3 guidelines (http://www.ismpp.org/gpp3).

Disclosures. Christer Janson has receivedpayments for educational activities from

AstraZeneca, Boehringer Ingelheim, Chiesi,GlaxoSmithKline, Novartis, and Teva, and hasserved on advisory boards arranged by AstraZe-neca, Boehringer Ingelheim, Chiesi,GlaxoSmithKline, Novartis, and Teva. AndrewMenzies-Gow has attended advisory boards forAstraZeneca, GlaxoSmithKline, Novartis,Sanofi, and Teva. He has received speaker feesfrom AstraZeneca, Novartis, Roche, and Teva.He has participated in research with AstraZe-neca for which his institution has been remu-nerated and has attended internationalconferences with Teva. He has had consultancyagreements with AstraZeneca, Sanofi, and Vec-tura. Cassandra Nan is an employee of Astra-Zeneca and holds shares in AstraZeneca andGSK. Javier Nuevo is an employee of AstraZe-neca. Alberto Papi reports grants, personal fees,non-financial support, and other from AstraZe-neca, Boehringer Ingelheim, Chiesi Farmaceu-tici, and GlaxoSmithKline; personal fees fromSanofi/Regeneron; personal fees and non-fi-nancial support from Zambon; grants, personalfees, non-financial support, and other fromTeva; personal fees and non-financial supportfrom Novartis; personal fees, non-financialsupport, and other from Mundipharma; per-sonal fees and non-financial support fromAlmirall; grants, personal fees, and non-finan-cial support from Menarini; and grants fromMaugeri and Fondazione Chiesi Farmaceutici,outside the submitted work. Jennifer K Quint’sresearch group has received funds from TheHealth Foundation, MRC, British Lung Foun-dation, IQVIA, Chiesi, and Asthma UK outsidethe submitted work; grants and personal feesfrom GlaxoSmithKline, Boehringer Ingelheim,AstraZeneca, Bayer, and Insmed. SantiagoQuirce has been a consultant for ALK, AstraZe-neca, GSK, Mundipharma, Novartis, Sanofi, andTEVA and received lecture fees from AstraZe-neca, Chiesi, GSK, Leti, Mundipharma, andNovartis. Claus F Vogelmeier reports grants andpersonal fees from AstraZeneca, Grifols,GlaxoSmithKline, Novartis, and BoehringerIngelheim and personal fees from CSL Behring,Chiesi Farmaceutici, MedUpdate, Menarini, andNuvaira, outside the submitted work.

1132 Adv Ther (2020) 37:1124–1135

Compliance with Ethics Guidelines. Thestudies carried out under the SABINA programconformed with ethical principles that areconsistent with the Declaration of Helsinki of1964 and its later amendments, ICH GCP,GPP3, and the applicable legislation on non-interventional studies and/or observationalstudies.

Data Availability. Data underlying thefindings described in this manuscript may beobtained in accordance with AstraZeneca’s datasharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1. Global Asthma Report 2018. http://www.globalasthmareport.org. Accessed 27 Sept 2019.

2. Selroos O, Kupczyk M, Kuna P, et al. National andregional asthma programmes in Europe. Eur RespirRev. 2015;24(137):474–83.

3. Gibson GJ, Loddenkemper R, Lundback B, Sibille Y.Respiratory health and disease in Europe: the newEuropean Lung White Book. Eur Respir J.2013;42(3):559–63.

4. Global Initiative for Asthma. Global Strategy forAsthma Management and Prevention 2019. https://ginasthma.org/gina-reports/. Accessed 27 Sept2019.

5. Global Initiative for Asthma. Global Strategy forAsthma Management and Prevention, 2018.https://ginasthma.org/gina-reports/. Accessed 11July 2019.

6. British Thoracic Society. Scottish IntercollegiateGuidelines Network: British guideline on the man-agement of asthma. https://www.brit-thoracic.org.uk/document-library/guidelines/asthma/btssign-asthma-guideline-2016/. Accessed 21 July 2019.

7. Stanford RH, Shah MB, D’Souza AO, Dhamane AD,Schatz M. Short-acting b-agonist use and its abilityto predict future asthma-related outcomes. AnnAllergy Asthma Immunol. 2012;109(6):403–7.

8. Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near-fatalasthma. Eur Respir J. 1994;7(9):1602–9.

9. Suissa S, Ernst P, Boivin JF, et al. A cohort analysis ofexcess mortality in asthma and the use of inhaledbeta-agonists. Am J Respir Crit Care. 1994;149(3):604–10.

10. Nwaru BI, Ekstrom M, Hasvold P, Wiklund F, TelgG, Janson C. Overuse of short-acting b2-agonists inasthma is associated with increased risk of exacer-bation and mortality: a nationwide cohort study ofthe global SABINA programme. Eur Respir J. 2020.https://doi.org/10.1183/13993003.01872-2019.

11. Beasley R, Holliday M, Reddel HK, et al. Controlledtrial of budesonide–formoterol as needed for mildasthma. N Engl J Med. 2019;380(21):2020–30.

12. O’Byrne PM, Bisgaard H, Godard PP, et al. Budes-onide/formoterol combination therapy as bothmaintenance and reliever medication in asthma.Am J Respir Crit Care. 2005;171(2):129–36.

13. Kuna P, Peters MJ, Manjra AI, et al. Effect ofbudesonide/formoterol maintenance and relievertherapy on asthma exacerbations. Int J Clin Pract.2007;61(5):725–36.

14. O’Byrne PM, FitzGerald JM, Bateman ED, et al.Inhaled combined budesonide–formoterol as nee-ded in mild asthma. N Engl J Med. 2018;378(20):1865–76.

15. Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide–formoterol versus maintenancebudesonide in mild asthma. N Engl J Med.2018;378(20):1877–87.

Adv Ther (2020) 37:1124–1135 1133

16. Reddel HK, FitzGerald JM, Bateman ED, et al. GINA2019: a fundamental change in asthma manage-ment: treatment of asthma with short-actingbronchodilators alone is no longer recommendedfor adults and adolescents. Eur Respir J. 2019;53(6):1901046.

17. Beasley R, Bird G, Harper J, Weatherall M. The fur-ther paradoxes of asthma management: time for anew approach across the spectrum of asthmaseverity. Eur Respir J. 2018;52:1800694.

18. O’Byrne PM, Jenkins C, Bateman ED. The paradoxesof asthma management: time for a new approach?Eur Respir J. 2017;50(3):1701103.

19. FitzGerald JM, Tavakoli H, Lynd LD, Al Efraij K,Sadatsafavi M. The impact of inappropriate use ofshort acting beta agonists in asthma. Respir Med.2017;131:135–40.

20. Partridge MR, van der Molen T, Myrseth SE, BusseWW. Attitudes and actions of asthma patients onregular maintenance therapy: the INSPIRE study.BMC Pulm Med. 2006;6:13.

21. Sadatsafavi M, Tavakoli H, Lynd L, FitzGerald JM.Has asthma medication use caught up with theevidence? A 12-year population-based study oftrends. Chest. 2017;151(3):612–8.

22. Hancox R, Aldridge R, Cowan J, et al. Tolerance tobeta-agonists during acute bronchoconstriction.Eur Respir J. 1999;14(2):283–7.

23. Zhao H, Li R, Lv Y, et al. Albuterol inhalationincreases FeNO level in steroid-naive asthmatics butnot COPD patients with reversibility. Clin Respir J.2017;11(3):328–36.

24. Levy ML. The national review of asthma deaths:what did we learn and what needs to change?Breathe. 2015;11(1):14–24.

25. Cabrera CS, Nan C, Lindarck N, Beekman M,Arnetorp S, van der Valk RJP. SABINA: global pro-gramme to evaluate prescriptions and clinical out-comes related to short-acting beta2-agonist use inasthma. Eur Respir J. 2019. https://doi.org/10.1183/13993003.01858-2019.

26. Ortqvist AK, Lundholm C, Wettermark B, Lud-vigsson JF, Ye W, Almqvist C. Validation of asthmaand eczema in population-based Swedish drug andpatient registers. Pharmacoepidemiol Drug Saf.2013;22(8):850–60.

27. Raherison-Semjen C, Izadifar A, Russier M, et al.Late breaking abstract—asthma prevalence andmanagement in adults in France in 2018: ASTH-MAPOP survey. Eur Respir J. 2018;52(suppl 62):OA292.

28. Kupczyk M, Barg W, Bochenek G, et al. Latebreaking abstract—overprescription of short-actingbeta2-agonists in asthma management? Pharmacyreports from 91,673 patients in Poland. Eur Respir J.2019;54(suppl 63):OA2107.

29. Gibson P, Henry D, Francis L, et al. Associationbetween availability of non-prescription beta 2agonist inhalers and undertreatment of asthma.BMJ. 1993;306(6891):1514–8.

30. Kuschner WG, Hankinson TC, Wong HH, Blanc PD.Nonprescription bronchodilator medication use inasthma. Chest. 1997;112(4):987–93.

31. Azzi EA, Kritikos V, Peters MJ, et al. Understandingreliever overuse in patients purchasing over-the-counter short-acting beta2 agonists: an Australiancommunity pharmacy-based survey. BMJ Open.2019;9(8):e028995.

32. AsthmaUK. Falling through the gaps: why morepeople need basic asthma care. Annual AsthmaSurvey report 2017. https://www.asthma.org.uk/share/?rid=7044. Accessed 27 Sept 2019.

33. Breekveldt-Postma NS, Koerselman J, Erkens JA, vander Molen T, Lammers JW, Herings RM. Treatmentwith inhaled corticosteroids in asthma is too oftendiscontinued. Pharmacoepidemiol Drug Saf.2008;17(4):411–22.

34. Crompton GK, Barnes PJ, Broeders M, et al. Theneed to improve inhalation technique in Europe: areport from the aerosol drug managementimprovement team. Respir Med. 2006;100(9):1479–94.

35. Gibson PG, Powell H, Coughlan J, et al. Self-man-agement education and regular practitioner reviewfor adults with asthma. Cochrane Database SystRev. 2003;1:Cd001117.

36. Reddel HK, Bateman ED, Becker A, et al. A summaryof the new GINA strategy: a roadmap to asthmacontrol. Eur Respir J. 2015;46(3):622–39.

37. Clinical Practice Research DataLink (CPRD).https://www.cprd.com/home. Accessed 17 Oct2019.

38. Nissen F, Morales DR, Mullerova H, Smeeth L,Douglas IJ, Quint JK. Validation of asthma record-ing in the Clinical Practice Research Datalink(CPRD). BMJ Open. 2017;7(8):e017474.

39. Belhassen M, Nibber A, Van Ganse E, et al. Inap-propriate asthma therapy—a tale of two countries: aparallel population-based cohort study. NPJ PrimCare Respir Med. 2016;26:16076.

1134 Adv Ther (2020) 37:1124–1135

40. Elkout H, Helms PJ, Simpson CR, McLay JS. Chan-ges in primary care prescribing patterns for paedi-atric asthma: a prescribing database analysis. ArchDis Child. 2012;97(6):521–5.

41. Tavakoli H, Mark FitzGerald J, Lynd LD, SadatsafaviM. Predictors of inappropriate and excessive use ofreliever medications in asthma: a 16-year popula-tion-based study. BMC Pulm Med. 2018;18(1):33.

Adv Ther (2020) 37:1124–1135 1135