Journal of Asthma, 48:839–847, 2011Copyright © 2011 Informa Healthcare USA, Inc.ISSN: 0277-0903 print / 1532-4303 onlineDOI: 10.3109/02770903.2011.611954

PHARMACOTHERAPY

A Comparison of Budesonide/Formoterol Maintenance and RelieverTherapy Versus Conventional Best Practice in Asthma Management

in Spain

SANTIAGO QUIRCE, M.D., PH.D.,1,2,∗ CARLOS BARCINA, M.D.,3 VICENTE PLAZA, M.D., PH.D.,4 EDUARDOCALVO, M.D.,5 MERCEDES MUÑOZ, M.D.,3 RUBÉN AMPUDIA, M.SC.,6 AND MARGARITA CAPEL, M.SC.7

1Department of Allergy, Hospital La Paz, IdiPAZ, Madrid, Spain.2CIBER de Enfermedades Respiratorias, CIBERES, Madrid, Spain.

3Medical Department, AstraZeneca, Madrid, Spain.4Department of Pneumology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

5University Health Centre Pozuelo Estación, Pozuelo de Alarcón, Madrid, Spain6Department of Biometrics, Quintiles, Madrid, Spain.

7Health Economics and Outcomes Research, AstraZeneca, Madrid, Spain.

Objective. To study the effectiveness and safety in a real-life setting of budesonide/formoterol (Symbicort) Maintenance And Reliever Therapy®

(Symbicort SMART®), a simplified management approach with one inhaler, compared with conventional best practice (CBP) with multipleinhalers in patients with persistent asthma. Design. Open-label randomized controlled parallel-group trial, 6-month treatment. Participants. Atotal of 654 adult patients, with persistent asthma receiving treatment with inhaled corticosteroids (ICS), either alone or in conjunction withlong-acting β2-agonist. Main outcome measures. Time to first severe asthma exacerbation and number of severe asthma exacerbations. Results.No difference between groups was seen in time to first severe exacerbation (p= .2974). Exacerbation rates were low in both groups. A total of 22patients in the Symbicort SMART group experienced a total of 24 severe asthma exacerbations, and 31 patients in the CBP group experienceda total of 34 severe asthma exacerbations (annual rate 0.16 vs. 0.22, p = .2869). The mean daily dose of ICS expressed in beclomethasonedipropionate equivalent was significantly lower in the Symbicort SMART group (including as-needed use) versus the CBP group (799 μgvs.1184 μg; p < .001). Mean scores in Asthma Control Questionnaire, five-question version, improved significantly in the SMART groupcompared with the CBP group (p = .0292). Symbicort SMART and CBP were equally well tolerated. The mean drug cost per patient per 6months was lower for the patients in the SMART group compared with patients receiving CBP (=C295.32 vs. =C387.98, p< .0001). Conclusions.A simplified regimen using budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) was at least as effective at improvingclinical control compared with CBP with a significantly lower ICS dose and lower drug costs.

Keywords cost analysis, asthma exacerbations, asthma treatment, budesonide/formoterol

INTRODUCTION

International [Global Initiative for Asthma (GINA)] (1)and national [Guía Española para el Manejo del Asma(GEMA)] (2) asthma management guidelines emphasizethe importance of effective asthma treatment to achieveand maintain asthma control. Overall asthma controlconsists of two domains: current or day-to-day asthmacontrol (absence of asthma symptoms, minimal relieveruse, normal activity levels, and lung function) and futurerisk (absence of asthma exacerbations, prevention ofdecline in lung function, and no side-effects from drugs)(3, 4).

Several randomized, double-blind, clinical trialshave shown that budesonide/formoterol (SymbicortTurbuhaler®) used as Maintenance And RelieverTherapy® (Symbicort SMART®) can improve asthmacontrol, particularly in reducing exacerbations, compared

∗Corresponding author: Dr. Santiago Quirce, Hospital La Paz, Servicio deAlergia, P. Castellana, 261, 28046 Madrid, Spain; Tel: +34 91 727 7080;Fax: +34 91 727 7050; E-mail: squirce.hulp@salud.madrid.org

with higher fixed doses of inhaled corticosteroids (ICS)delivered with alternative ICS/long-acting β2-agonist(LABA) therapies plus a short-acting β2-agonist (SABA)or formoterol as reliever therapy (reviewed in 5). Thistreatment strategy has been shown to cause a reductionin asthma exacerbations compared with higher doses ofbudesonide (6–8) or fluticasone (9). Better outcomeswith budesonide/formoterol maintenance and relievertherapy have also been demonstrated as comparedwith the same (10) or higher (11) maintenance dosesof budesonide/formoterol or salmeterol/fluticasone(11–13), using either a SABA (6–9) or formoterol(10) as reliever. In addition, budesonide/formoterolmaintenance and reliever therapy was well toleratedin randomized clinical trials versus fixed-dosealternatives and was not associated with an increasedrisk of death or asthma-related serious adverse events(SAEs) (14).

Results from randomized clinical trials cannot alwaysbe extrapolated into clinical settings where physicians canchoose and modify treatment according to their judgment.Although the maintenance and reliever therapy strategy

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840 S. QUIRCE ET AL.

has been included in the GINA (1) and GEMA guidelines(2) as a valid option for patients with persistent asthmanot well controlled with low-dose ICS, there is a relativepaucity of data showing the benefits of this strategy inreal-life asthma management.

Several recent studies have compared budesonide/formoterol maintenance and reliever therapy with clin-icians’ choice of conventional best practice (CBP)(15–19). A study conducted in Canada confirmed thatbudesonide/formoterol maintenance and reliever therapyachieved similar improvements in clinical control com-pared with CBP, with a significantly lower ICS doseand lower cost, while maintaining similar control ofeosinophilic airway inflammation (17).

This 6-month study performed in Spain in outpatientsaged ≥18 years was intended to further validatethe efficacy, safety, and cost of budesonide/formoterolmaintenance and reliever therapy compared with CBP ina real-life setting. The study compared the maintenanceand reliever therapy strategy with a conventional stepwisetreatment regimen in patients who presented symptoms onICS with or without other controller medications.

METHODS

Study Design

This was a 26-week, randomized, open-label, parallel-group multicenter study in patients with asthma(NCT 00385593). The patients were not pre-matchedbefore randomization. An open, randomized design wasselected since the maintenance and reliever therapystrategy is based on the use of only one inhaler andthe complexity of therapeutic options in the CBP arm,with multiple therapies allowed, made it unfeasible toblind the treatment options. The study design intendedto reproduce as close as possible the CBP in asthmamanagement, minimizing any interference in physicians’and patients’ attitudes, and avoiding any kind ofbias. The study consisted of a 2-week run-in periodfollowed by a 26-week randomized treatment period.The primary objective was to compare the efficacy ofbudesonide/formoterol maintenance and reliever therapywith the conventional best therapeutic practice in adultpatients with suboptimally controlled persistent asthma.The secondary objective was to collect safety data ofboth therapeutic strategies in the two treatment groupsby evaluating the incidence and type of SAEs anddropouts due to adverse events (AEs). In addition, acost analysis of both treatment arms was performed. Thetrial was performed in 69 centers across Spain underthe supervision of 69 investigators, 39 of whom werespecialists (23 allergologists and 16 chest physicians) and30 general practitioners, between June 2006 and October2008. Due to problems with the recruitment, particularlyenrolling patients with uncontrolled asthma in spite ofbeing treated regularly with ICS (with or without LABA),the study was closed before randomizing the number ofpatients aimed for in the sample size calculation.

Study Patients

Female and male outpatients at least 18 years of age withpersistent asthma currently treated with an ICS eitherwith or without a LABA were enrolled. The dose ofICS had to be at least 400 μg/day (320 μg releaseddose) of budesonide or equivalent. Patients had to havea history of suboptimal asthma control within 1 monthprior to enrollment, as judged by the investigator. To berandomized, patients had to have used a SABA on atleast three occasions during the previous week. Patientswho were treated with oral corticosteroids or who hadexperienced an asthma exacerbation requiring a changein asthma treatment during the preceding 2 weeks beforerandomization were excluded from the study.

A total of 791 patients were enrolled and finally 654patients were randomized (Figure 1). All participants gavewritten informed consent. The study was approved bythe ethics committee of the Madrid region. The estimatedsample size for this study was 1000 patients.

Interventions

During the run-in period all enrolled patients continuedwith their usual treatment for asthma. Overall, 654patients were randomized (1:1) to one of the followingtwo treatment groups:

– Budesonide/formoterol dry powder inhaler 160/4.5 μg,one inhalation twice daily plus as-needed additionaldosage if necessary (Symbicort SMART). After ran-domization, maintenance dose adjustment was allowedup to two inhalations twice daily or one inhalation twicedaily based on the investigator’s judgment. Duringthe treatment period, patients in the maintenance andreliever therapy group were not to use more than10 inhalations as needed during any single day. Theaddition of another class of anti-asthma medication waspermitted at the discretion of the investigator.

– CBP: active stepped and individualized treatmentin accordance with both international (GINA) andnational (GEMA) guidelines for asthma management.Patients in the CBP group could be treated withany asthma medication, except budesonide/formoterolmaintenance and reliever therapy and/or maintenancewith oral corticosteroids. Patients in this group hadto be treated with at least ICS as maintenancetreatment. Asthma medication could be modified afterrandomization at scheduled visits or any time duringthe study course.

The treatment period lasted for 26 weeks. After therandomization visit (visit 1), the patients were seen onscheduled visits at their study center at 4 (visit 2),13 (visit 3), and 26 weeks (visit 4) of the study.All study medication was picked up freely (defrayedby AstraZeneca) by the patients at a local pharmacy.Given that the study design closely resembled thestandard clinical practice, no formal compliance checkingwas performed. Patients recorded on a diary card anymodification of asthma therapy, either regarding dose or

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BUDESONIDE/FORMOTEROL MAINTENANCE AND RELIEVER 841

N = 791Enrolled

– Excluded (99)

N = 137Non-randomized

N = 326CBP

N = 289Completed

N = 37Did not complete

N = 654Randomized

N = 328SMART

N = 58Did not complete

N = 270Completed

– Adverse events (4)– Consent withdrawal (16)– Lost for follow-up (14)– Other causes (4)

– Excluded (0)

– Adverse events (2)– Protocol violation (4)

– Consent withdrawal (7)– Lost for follow-up (8)

– Other causes (15)– Randomization failure (1)

– Excluded (2)

– Adverse events (3)– Protocol violation (7)

– Consent withdrawal (17)

– Lost for follow-up (12)

– Other causes (17)– Randomization failure (0)

FIGURE 1.—Patients flow.

medication, as well as daily use of as-needed medicationfor the 14 days prior to next study visit. The investigatorchecked at each visit the patient’s diary and its contentwas transcribed into appropriated section of the CaseReport Forms.

Outcomes

The data collection process was designed to influenceboth the patient and the physician behavior as littleas possible during the study period to maintain areal-life setting. The primary variable was time to firstsevere asthma exacerbation (10–13). A severe asthmaexacerbation was defined as deterioration in asthmaleading to at least hospitalization or emergency roomtreatment for asthma or treatment with oral corticosteroidsfor at least three consecutive days (3).

Secondary efficacy variables included the number ofsevere asthma exacerbations, days on treatment withoral corticosteroids, mean use of as-needed medication,prescribed asthma medications, and mean daily use ofICS. Patients completed their daily use of as-neededmedication (total number of inhalations per day) in a diarycard during the past 14 days before each visit during thetreatment period.

To assess lung function, pre- and post-bronchodilatorpeak expiratory flow (PEF) measurements were per-formed in the office with a Mini Wright peak flow meter(Clement Clarke, Harlow, UK) at baseline (visit 1) and atthe 6-month visit (last visit).

The Asthma Control Questionnaire, five-questionversion (ACQ5) (20) was self-administered during thestudy visits. The change from baseline to the averageduring the treatment period (mean of visits 3, 4, and 5)was calculated for the ACQ5 score (10–13). In addition,a repeated measures analysis for ACQ5 at all study visitswas performed.

Health economic variables were collected: hospital-izations, emergency room visits for asthma, visits to thegeneral practitioner or specialist, medical consultationby telephone, ambulance use, maintenance and relievermedication use for asthma, patient’s employment status,and number of days off work.

Statistical Analysis

The power calculation was based on the primary outcomevariable “time to first severe asthma exacerbation” anda log-rank test of time to event in groups followed fora fixed time assuming constant hazard ratio. The timeto the first severe asthma exacerbation was describedusing Kaplan–Meier curves. The treatment groups were

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842 S. QUIRCE ET AL.

compared using a Cox proportional hazards model withtreatment as a factor. The total number of asthmaexacerbations per patient was compared using a Poissonregression model with treatment as a factor and the timein the study as an offset variable. Confidence intervals andp-values were adjusted for overdispersion. The changein ACQ5 from randomization to the average of visits2–4 score was compared between treatment arms usingan analysis of variance model with treatment as a factorand the score at randomization as a covariate. Moreover,repeated measures analysis of ACQ5 was performed. Theuse of as-needed medication was thoroughly described.The mean number of as-needed inhalations per day wascalculated for each patient (during the 14 days priorto every study visit), and this was compared betweentreatment groups using an analysis of variance modelwith treatment as a factor. The maintenance medicationprescribed for asthma was recorded, excluding treatmentfor asthma exacerbations. Daily use of ICS and treatmentwith oral corticosteroids for asthma exacerbations wasanalyzed. Safety data were analyzed using descriptivestatistics and a cost analysis was performed.

Cost variables were collected by self-reporting andanalyzed from the social perspective, including direct andindirect health-related costs in both treatment groups. Thehealth resource use included hospitalizations, emergencyroom visits for asthma, and visits to the general practi-tioner or specialist, medical consultation by telephone,and ambulance use, as well as cost of maintenance andreliever medication for asthma. Loss of work productivitywas assessed considering the number of days off workfor sick leave. A unit cost was applied to the resourceuse data (21, 22). The direct cost per patient includedhealthcare cost and drug cost. Anti-asthma medicationwas calculated as the mean number of inhalations perday per patient during the 6-month study period. The costof indirect health resources related to productivity losswas calculated using the average national salary (23). Thesum of direct and indirect costs provided the total cost oftreatment in both treatment strategies.

RESULTS

Demographic and Clinical Characteristics

A total of 791 patients were enrolled in the study and654 patients were included in the full analysis set (328randomized in SMART group and 326 in the CBP group).Overall, 559 patients (85.5%) completed the study. Allpatients except for two (who did not take their asthmamedication) were included in the safety analysis. Ahigher number of discontinuations were reported in theSMART group compared to CBP (Figure 1). Reasonsfor the higher discontinuation rate in the SMART groupmay be explained by the study design. If the patientsin the SMART group did not like the allocated studytreatment and hence asked for a different treatment ordose, most commonly their usual treatment, they had to bediscontinued from the study. On the contrary, in the CBPgroup treatment adjustments were possible according tothe patient’s preference.

TABLE 1.—Demographic and clinical characteristics of randomizedpatients.

CBP SMART

N 326 328Male (%) 38 33.5Age [years (range)] 44.3 (8–82) 43.7 (18–89)Median time since diagnosis

[years (range)]11.2 (0.3–60.6) 9.7 (0.3–57.4)

ICS [μg/day (as BDP equivalent)(SD)]

1040 (592) 1028 (590)

LABA use (%) 81 80Number of as-neededinhalations/day (SD)

1.6 (1.2) 1.6 (1.2)

As-needed reliever-free days (%) 26.4 26.7ACQ5 score (%)≤0.75 (well controlled) 20.6 13.3>0.75–<1.50 35.9 36.9≥1.50 (not well controlled) 43.5 49.8PEF (L/min)Pre-BD (SD) 355.4 (117.4) 356.3 (129.8)Post-BD (SD) 384.4 (116.2) 385.8 (128.4)

Note: CBP, conventional best practice; BDP, beclomethasone dipropionate; LABA,long-acting β2-agonist; SMART, budesonide/formoterol maintenance and relievertherapy.

Clinical and demographic data of study patients atbaseline are shown in Table 1. The baseline data weresimilar in both treatment groups, allowing for furthercomparisons between them. The mean age of randomizedpatients was 44 years (range 17–89), with a predominanceof women (64.2%).

Their mean daily dose of ICS during the run-in periodwas 1034 μg [expressed as beclomethasone dipropionate(BDP) equivalent]. The median time since diagnosis was10.5 years (0.3–60.6). Overall, 80.4% of patients werereceiving treatment with a LABA. The mean number ofas-needed inhalations of SABA per day was 1.6. Theinvestigators classified asthma severity at study entry asmild persistent in 26%, moderate persistent in 32%, andsevere in 42% of the study patients.

Efficacy

Severe Exacerbations. There was numerically a trendfavoring the SMART group although no difference couldbe shown on the time to first severe asthma exacerbationbetween the study groups (Figure 2) (hazard ratio:

Days since randomisation30 60 90 120 150 180

0

p = 0.2974

4 -

8 -

10 -

12 -

14 -

Patie

nts

with

a s

ever

eex

acer

batio

n (%

)

CBPSMART

2 -

6 -

n = 326

n = 328

FIGURE 2.—Time to first severe asthma exacerbation (Kaplan–Meier plot).

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BUDESONIDE/FORMOTEROL MAINTENANCE AND RELIEVER 843

0.748; 95%CI: 0.433–1.292; p = .2974). This differencenumerically corresponded to a 25% lower risk in theSMART group. The SMART group had a numericallylower mean number of estimated severe exacerbationper year (0.16) compared with the CBP group (0.22)(Poisson regression rate ratio= 0.753; 95%CI: 0.44–1.26;p = .2869). Table 2 shows the number of severe asthmaexacerbations during the study expressed as total numberand according to the different subcriteria of severe asthmaexacerbations. The number of days on treatment with oralcorticosteroids because of severe asthma exacerbationswas 177 in the SMART group and 229 in the CBP group(22.7% reduction, p < .001) (Figure 3).

As-Needed Reliever Use. Most patients in both treatmentarms had at least 1 day during which one or more inhala-tions of reliever medication was required (86% vs. 90%patients in the SMART and CBP groups, respectively).Eight patients in the SMART group and 13 in the CBPgroup used more than 7 as-needed inhalations in a singleday.

Overall, the mean number of as-needed inhalations perday decreased in both groups at 6 months as comparedwith baseline. The mean number of as-needed inhalationsat the end of the study was 1.03 and 1.02 in the SMARTand CBP arms, respectively, and the differences were notstatistically significant. The percentage of symptom-freedays (without reliever use) was similar in the SMARTgroup (52%) and in the CBP group (50%).

Lung Function. After 6 months of treatment the meanpre-bronchodilator PEF increased from baseline by 24.4L/min in the SMART group and by 20.2 L/min inthe CBP group. The increase from baseline in thepost-bronchodilator PEF was 20.1 L/min and 16.2 L/minin the SMART and CBP groups, respectively. Theobserved differences in pre- and post-bronchodilator PEFmeasurements were not statistically significant.

22.7% reductionp < 0.001

300 299

177

250

200

150

Day

s

100

50

0Use of oral

glucocorticosteroidsdue to exacerbations

SMART

CBP

FIGURE 3.—Total number of days with oral glucocorticosteroids.

TABLE 2.—Number of patients with severe asthma exacerbations (total andby subcriteria).

Event SMART CBP

Severe asthma Number of patients 22 (6.7%) 31 (9.5%)exacerbations (total∗) Number of events 24 34

Number with 1 event 20 28Number with 2 events 2 3Number with >2events

0 0

Total number of days 216 254Treatment with oral GCS

Number of patients 15 (4.6%) 24 (7.4%)Number of events 17 26Number with 1 event 13 23Number with 2 events 2 1

Emergency room treatmentNumber of patients 13 (4.0%) 13 (4.0%)Number of events 14 15Number with 1 event 12 11Number with 2 events 1 2

HospitalizationNumber of patients 1 (0.3%) 0 (0%)Number of events 1 0Number with 1 event 1 0Number with 2 events 0 0

Notes: aSome patients fulfilled more than one subcriteria of severe asthmaexacerbation.GCS, glucocorticosteroids; CBP, conventional best practice; SMART, budes-onide/formoterol maintenance and reliever therapy.

Asthma Control Questionnaire. Asthma control assessedby ACQ5 improved in both treatment groups com-pared with baseline values. At the end of the study,there were more patients with well-controlled asthma(ACQ5 < 0.75) in the SMART group (47.8%) than inthe CBP group (41.5%). Overall, 47% of the patients inthe SMART group and 43% in the CBP group achieveda clinically relevant improvement in asthma control(reduction in ACQ5 score ≥0.5). The mean change frombaseline in ACQ5 was shown to be higher in the SMARTgroup compared with the CBP group (mean differencebetween groups−0.12; 95%CI:−0.23,−0.01; p= .0292,Figure 4). In addition, repeated measures analysis showedstatistically significant differences between ACQ5 at visit

p = 0.0292

n = 301

n = 306

1.8

1.7

1.6

1.5

1.4

1.3

1.2

1.1AC

Q o

vera

ll sc

ore

1.0

0.9

0.8V1 V2 V3

Visit numberV4

SMART CBP

FIGURE 4.—Mean Asthma Control Questionnaire five-question version(ACQ5) score over the study period.

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844 S. QUIRCE ET AL.

1 and visit 2 (p < .05), and between visit 1 and visit 3(p < .05), but not between visit 1 and visit 4. The globalp-value using repeated measures showed a significantchange in ACQ5 in the SMART group versus the CPBgroup (p = .0171).

Prescribed Asthma Controller Medication. In the CBPgroup, 91% of patients were treated with an ICS plusLABA combination, either in the same inhaler (60%) orusing separate inhalers (31%). Moreover, 27% of patientswere treated with a leukotriene receptor antagonist(LTRA), 2% with inhaled anticholinergics, and 2.5% withmucolytic drugs.

Maintenance medication in the SMART group wasmodified as permitted in the study protocol. Themajority of patients in this group (85%) used theminimummaintenance dose of the budesonide/formoterolcombination (one inhalation twice daily). In additionto budesonide/formoterol, 0.9% of the patients in theSMART group were treated with xanthines, 1.8% withmucolytic drugs, and 14.9% with LTRA.

In the CBP arm, the average daily dose of ICS was1184 μg (expressed as BDP equivalent). In the SMARTgroup, the average maintenance daily dose of ICS was593 μg. Since in this group the patients could alsouse budesonide/formoterol as a reliever, the mean dailydose of ICS administered as needed was 206 μg and,in total, the average daily dose of ICS was 799 μg(BDP equivalent). Thus, a 33% reduction in the meandaily dose of ICS was observed in the SMART groupversus the CBP group (799 μg vs. 1184 μg, p < .001,Figure 5).

Safety. A total of 652 randomized patients were includedin the safety analysis dataset. There were no fatal SAEsin the study. No clinically relevant differences wereobserved between the treatment groups with regard to thenumber of SAEs and dropouts due to AEs.

Asthma treatments prescribed in the budesonide/formoterol maintenance and reliever therapy group andin the CBP group were well tolerated and no new orunexpected safety problems occurred. The number of

1200 1184

799

33% reduction,p < 0.001

1000

800 SMART

CBP600

DP

B e

quiv

alen

ts (

µg/d

ay)

400

200

0Dose/day (µg)

Inhaledglucocorticosteroids

FIGURE 5.—Average ICS daily dose over the study period.

TABLE 3.—List of most common adverse events (more than 2%).

Number (N, %) of patients who had an adverse event in each category

SMART (n = 326) CBP (n = 326)

n % n %

Nasopharyngitis 23 7.1 24 7.4Pharyngitis 7 2.1 13 4.0Asthma 10 3.1 7 2.1Back pain 11 3.4 5 1.5Rhinitis 10 3.1 5 1.5Bronchitis 6 1.8 9 2.8Gastroenteritis 9 2.8 6 1.8Headache 6 1.8 7 2.1

Note: CBP, conventional best practice; SMART, budesonide/formoterol maintenanceand reliever therapy,

patients with any AEs was 157 (48.2%) in the CBPgroup and 165 (50.6%) in the SMART group. The mostcommon AEs (more than 2%) are shown in Table 3.There were a total of 14 patients with SAEs, of whom9 (2.8%) were in the SMART group and 5 (1.5%) inthe CBP group. The SAEs observed in the CBP groupwere cerebral hemorrhage, pyrexia, bursitis infective,pneumonia, and breast cancer; and the SAEs observedin the SMART group were gastroenteritis, uterineleiomyoma, epicondylitis, melanocytic nevus, medullarythyroid cancer, gene mutation, irritable bowel syndrome,pneumonia, respiratory tract infection, diarrhea, andcataract (two patients had two SAEs). There were nofatalities during the study. In terms of the number ofpatients with AEs that led to discontinuation of the study,the number was 3 (0.9%) versus 2 (0.6%) for SMART andCBP arms, respectively.

Cost Analysis

The estimated drug cost used for asthma treatmentper patient in 6 months was =C295.32 in the SMARTgroup and =C387.98 in the CBP group (−=C92.66;95%CI: −115.00, −70.31; p < .0001). The cost of thecombination ICS/LABA was higher in the CBP group ascompared to the SMART group (=C34.87 difference), andalso the costs of montelukast (=C35.49) and other drugs(mainly SABA) (=C22.30) were higher in the CBP group

353.62

Total cost Drug cost

486.78

295.32

387.98

SMART CBP

FIGURE 6.—Mean asthma drug cost and mean total cost (euros) per patientover 6 months.

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BUDESONIDE/FORMOTEROL MAINTENANCE AND RELIEVER 845

compared to the SMART group. The total cost per patientover 6 months was =C353.62 in the SMART group and=C486.78 in the CBP group. Hence, in the SMART groupthe drug cost was reduced by 23.8% and the total costreduced by 27.3% compared with CBP (Figure 6).

DISCUSSION

Budesonide/formoterol dry powder inhaler used as bothmaintenance and reliever therapy (SMART) means thatthe patients receive a maintenance dose to achieveday-to-day asthma control, and additional inhalations areused for quick symptom relief. This therapeutic approachallows treatment of the underlying airway inflammationwhile providing rapid relief of symptoms. The additionaldoses of budesonide/formoterol administered as neededpermit the titration of doses according to patient’sneeds, providing timely adjustments in both ICS andbronchodilator (5, 6).

This study conducted in Spain confirmed that SMARTis an effective therapy for asthma compared with physi-cian’s choice of guideline-based conventional best thera-peutic practice in a real-life setting. The study protocoland interventions were designed to minimize any possibleinterference with patients’ and physicians’ behavior andattitudes on asthma management, resembling as closeas possible everyday clinical practice. In the CBP arm,changes in the maintenance dose and other treatment wereallowed at any scheduled or unscheduled consultationwith the physician. In the SMART arm, althoughthe budesonide/formoterol maintenance dose could betitrated (1 or 2 inhalations twice daily) according tothe physician’s judgment, the majority of patients (85%)were treated with the lower maintenance dose, and thiswas not associated with any evidence of deterioration ofasthma control. Although no formal compliance checkingwas performed, it was verified whether the patients hadwithdrawn the study medication from the local pharmacy.Moreover, the patient should record in a diary card thestudy medication he or she had taken during the 14 daysprevious to every study visit, and they should carry themedication canisters or packets used since the last visit.

There was no statistically significant differencebetween treatment groups in the primary efficacy variable(time to first exacerbation), and the percentage reductionin the rate of exacerbations with SMART did not reachstatistical significance compared with CBP. The estimatedsample size for this study was 1000 patients, but due toproblems with recruitment, the number of patients in theanalysis was smaller than planned, which implies lowerstatistical power. Although there was a trend favoring theSMART group versus CBP group, it was not possible,partly due to smaller sample size than expected, to showa difference between treatment arms. However, the totalnumber of severe exacerbations (24 vs. 34), and the totalnumber of days with severe asthma exacerbations (216vs. 254), was lower in the SMART group compared withthe CBP group. In addition, ACQ5 was improved to agreater extent over the study period with SMART than

with CBP. Therefore, patients in the SMART group hadbetter overall asthma control (numerically less asthmaexacerbations and improved current control).

In clinical trials, the SMART approach has beenshown to reduce severe exacerbations and to increase thelikelihood of controlling asthma more often, more rapidly,and a lower dose of ICS (6–11). A recent meta-analysisof randomized controlled trials of budesonide/formoterolmaintenance and reliever therapy showed that thistreatment strategy is well tolerated and is significantlymore effective at reducing severe exacerbations thanhigher fixed-dose ICS alone or higher dose combinationtherapy with LABA plus traditional SABA (24).

In an open study comparing budesonide/formoterolmaintenance and reliever therapy with salmeterol/fluti-casone, in which maintenance doses could be titrated byphysicians in accordance with normal clinical practice,SMART significantly prolonged the time to first severeexacerbation versus salmeterol/fluticasone and reducedthe total number of severe exacerbations (12), butthe overall incidence of exacerbations in both armswas higher than in this study. The low incidence ofexacerbations in the CBP arm in our study might be dueto the fact that patients with no history of exacerbationscould be included, and maintenance treatment dosagesand options in the CBP group could be freely modified.Thus, the lack of significant differences between SMARTand CBP with regard to time to first severe asthmaexacerbation and rate of exacerbations in this and in otherreal-life studies is likely to reflect lack of statistical power(17, 18).

Overall, in this study SMART was as well tolerated asCBP and resulted in better asthma control with less ICSload compared with CBP. Thus, this study has confirmedprevious results from a large pooled analysis of sixstudies performed in a setting reflecting normal clinicalpractice (16). Similar to our study, benefits were alsoseen in terms of both current asthma control (ACQ5) andexacerbation rates (16). The most commonly prescribedasthma medications in the CBP group were an ICS plusLABA combination (91%), either in the same inhaler(60%) or in separate inhalers (31%), and 27% of thepatients were also treated with LTRAs. Mean as-neededinhalation was similar in both treatment groups. However,the mean daily ICS dose was reduced significantly inthe SMART group versus the CBP group by around385 μg/day (BDP equivalent), which represents a 33%reduction. In addition, the number of days on treatmentwith oral glucocorticosteroids was also significantlyreduced by 22.7% in the SMART group compared withthe CBP group. As a result, improvements in overallasthma control achieved with SMART also occurred at alower corticosteroid load.

The optimal maintenance dose with SMART is amatter of debate and probably needs to be individualized.In a recent real-life setting study, budesonide/formoterolmaintenance, and reliever therapy two inhalations bidas maintenance dose prolonged the time to first severeexacerbation, and it was found that patients with lowlung function benefited most from the higher maintenance

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846 S. QUIRCE ET AL.

dose (25). In our study, most patients remained in thelower maintenance dose of budesonide/formoterol andonly 15% were treated with two inhalations twice daily,which made it unfeasible to perform a separate analysis.

The cost of implementing SMART significantlyreduced direct and indirect costs versus CBP. Anotherreal-life study performed in Canada (17) showed that theasthma medication cost and the total cost per patient peryear were 28 and 23% lower with SMART as comparedto CBP, respectively. A Belgium and Luxembourg (18)study has also reported a reduction in drug costs whenusing SMART by =C15.26 per patient per month. Thedata obtained from both studies were very similar to ours.SMART has been shown to be cost-effective in moderateto severe asthma patients versus salmeterol/fluticasoneor fixed-dose budesonide/formoterol in several countries(26–30).

Despite the fact that all possible combinations ofcontroller therapy could be used in CBP, they wereassociated with less satisfactory asthma control thanthat achieved in the SMART arm. To explain theseresults, it might be argued that delivering as-needed anti-inflammatory therapy in line with increases in diseaseactivity is a rational approach to prevent exacerbationsand improve asthma control. In this regard, Foresi et al.(31) reported that in patients with a low-maintenancedose of ICS, a temporary increase in ICS dose atthe time of asthma deterioration is as effective atmaintaining asthma control and preventing exacerbationsas a higher maintenance dose of ICS. A recent trialsuggested that providing patients with asthma with aself-management plan incorporating a fourfold increase indose of ICS when asthma control starts to deteriorate maybe effective at preventing exacerbations (32). In patientswith uncontrolled asthma, treatment with ICS may bemore effective if the total daily dose is split into severaldoses administered over the course of the day (33). In alarge survey of asthma patients (34), it was found that74% of patients used SABA daily and, when symptomsdeteriorated, patients had a fourfold or greater increase inthe mean number of SABA inhalations per day, regardlessof maintenance therapy. It was reported that the increasein SABA use occurred earlier and to a greater extentcompared with ICS during periods of worsening asthma.This means that with conventional asthma management,patients use ICS too late and possibly at too low dose inresponse to asthma symptoms.

CONCLUSIONS

This study evaluated SMART strategy as a treatmentalternative to physicians’ free choice of guideline-basedCBP. Although this analysis failed to show thatSMART prolonged the time to first severe exacer-bation (primary variable) compared with CBP, therewere numerically fewer exacerbations, fewer days withexacerbation treatment, fewer doses of oral and ICS,lower costs, and improved asthma control comparedwith physicians’ choice of CBP. In this study, overall

budesonide/formoterol maintenance and reliever therapywas as well tolerated as CBP and no new or unexpectedsafety concerns were identified.

ACKNOWLEDGEMENTS

S. Quirce has been on advisory boards and has receivedspeaker’s honoraria from AstraZeneca, GlaxoSmithKline,MSD, Novartis, Almirall, Altana, Chiesi, and Pfizer. V.Plaza has received speaker’s honoraria from AstraZeneca,GlaxoSmithKline, MSD, Novartis, Almirall, and Chiesi.E. Calvo has participated in advisory committees forGlaxoSmithKline, Nycomed, and Novartis. He hascoordinated international clinical trials in primary caresponsored by AstraZeneca and has received speaker’shonoraria from Boehringher, Pfizer, AstraZeneca, Glaxo-SmithKline, Chiesi, MSD, and Almirall. Ruben Ampudiawas full-time employee of Quintiles Iberia SAU at thetime of the study. C. Barcina, M. Muñoz, and M. Capelwere full-time employees of AstraZeneca FarmacéuticaSpain S.A. at the time of the study.

DECLARATION OF INTERESTS

The authors report no conflicts of interest. The authorsalone are responsible for the writing and content of thispaper.

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