The b2-agonists are widely used in the. Improved lung function and symptom control with formoterol on demand in asthma

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1 Eur Respir J 2006; 27: DOI: / CopyrightßERS Jourals Ltd 2006 Improved lug fuctio ad symptom cotrol with formoterol o demad i asthma D. Cheug*, H.C.J. va Klik # ad R. Aalbers ", for the OZON study group ABSTRACT: May asthma patiets remai symptomatic despite maiteace therapy with ihaled corticosteroids (ICS) ad salbutamol as rescue medicatio. I the preset study the relative efficacy ad preferece for as-eeded formoterol compared with salbutamol was examied. I total, 211 patiets with a mea age of 45 yrs (mea forced expiratory volume i oe secod (FEV1) 77% predicted ormal), usig ICS, were radomised to 3 weeks double-blid treatmet with as-eeded formoterol 4.5 mg Turbuhaler1 ad with as-eeded salbutamol 100 mg Turbuhaler1 i a cross-over fashio. Overall, lug fuctio ad symptom cotrol were better with as-eeded formoterol tha with aseeded salbutamol. Durig as-eeded formoterol treatmet daytime ad ight-time symptom scores were lower, peak expiratory flow ad FEV1 were higher ad patiets experieced fewer disturbed ights (34%) compared with as-eeded salbutamol. Patiets preferred the formoterol treatmet to salbutamol. Of the 162 patiets expressig a preferece, formoterol was preferred by 68% (95% cofidece iterval: 60 75). Subjective assessmet of effectiveess also favoured formoterol, which was perceived as slightly faster actig tha salbutamol. I coclusio, as-eeded formoterol improved symptoms ad lug fuctio compared with salbutamol ad was perceived as more effective ad at least as fast actig for symptom relief. KEYWORDS: Asthma, formoterol turbuhaler, reliever, salbutamol The b2-agoists are widely used i the treatmet of asthma for relief of brochocostrictio. Due to their established efficacy ad safety profile they have reached a promiet place i the maagemet of asthma [1]. Rapid-actig b 2 -agoists, such as salbutamol (albuterol) ad terbutalie, are primarily used for as-eeded therapy, whilst b 2 -agoists with a log duratio of effect, such as salmeterol ad formoterol, are geerally reserved for maiteace treatmet i cojuctio with ihaled corticosteroids (ICS). However, formoterol, ulike salmeterol, has a rapid oset of brochodilatio, which allows it to be used both for maiteace ad as-eeded therapy [2 5]. Addig a log-actig b 2 -agoist to ICS therapy, as a maiteace treatmet, has bee show to reduce the frequecy of asthma exacerbatios [6, 7]. Aother study has show that as-eeded formoterol ca reduce the icidece of severe asthma exacerbatios compared with as-eeded terbutalie [8], with lower overall maagemet costs [9]. At the start of the preset study, o published studies were available examiig the relative efficacy of ihaled formoterol i compariso with ihaled salbutamol, with both treatmets used strictly as eeded. However, recetly, a ope compariso of formoterol ad salbutamol showed that the use of as-eeded formoterol was associated with improved asthma cotrol [10]. The primary aim of the preset study was to ivestigate relative efficacy ad patiet preferece for formoterol ad salbutamol whe used oly as reliever medicatio. Havig both b 2 - agoists available i idetical ihalers made it possible to assess the relative efficacy of the two drugs i a double-blid, cotrolled settig i a cross-over desig. It was aticipated that by allowig free as-eeded use of both drugs, the patiets would compesate for the shorter duratio of actio of salbutamol by takig more frequet ihalatios. If this theory reflected actual patiet behaviour durig the study, a likely outcome would be a similar efficacy betwee the two treatmets. Therefore, a AFFILIATIONS *Dept of Pulmoology, Vlietlad Hospital, Schiedam, # Dept of Pulmoology, Diacoessehuis, Leide, ad " Martii Hospital, Groige, The Netherlads. CORRESPONDENCE D. Cheug Dept of Pulmoology Vlietlad Hospital Burg. Kappertlaa 25 NL-3116 BA Schiedam The Netherlads Fax: dcheug@ssvz.l Received: Jauary Accepted after revisio: November SUPPORT STATEMENT The preset study was fiacially supported by AstraZeeca BV, Zoetermeer, The Netherlads (study umber BN-00D-0029). Europea Respiratory Joural Prit ISSN Olie ISSN VOLUME 27 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

2 D. CHEUNG ET AL. AS-NEEDED FORMOTEROL IN ASTHMA additioal aim of the curret study was to ivestigate patiets preferece for the study drugs, which was made possible by the double-blid ad cross-over desig of the study. METHODS Patiet characteristics Adult patiets (o18 yrs) with a diagosis of asthma accordig to the America Thoracic Society (ATS) [11] were studied. Erolled patiets were o ICS treatmet for.4 weeks. This treatmet was maitaied throughout the study. All patiets icluded had a baselie forced expiratory volume i oe secod (FEV1) o50% of predicted ormal value [12] ad FEV1 reversibility o12% after ihalig terbutalie 1.0 mg or salbutamol 0.4 mg. Patiets were excluded from the study if they: 1) used systemic glucocorticosteroids; 2) experieced a cliically relevat airway ifectio i the 4 weeks before the study; 3) had a cliically relevat cocomitat disease; ad 4) used b-blocker therapy or were pregat or breastfeedig. Systemic brochodilators were ot allowed ad all ihaled brochodilators were stopped at erolmet ad exchaged for the study drugs. Study desig The radomised, double-blid, cross-over study was performed i 27 cetres i the Netherlads. Eligible patiets etered a ru-i period (14 days) i which they cotiued their ICS at a costat dose ad all reliever ad maiteace brochodilators were exchaged for terbutalie (Bricayl1 Turbuhaler mg; AstraZeeca, Zoetermeer, the Netherlads) to be used oly as eeded. Reliever use was recorded usig a daily diary card. Patiets requirig o10 ihalatios of terbutalie over the ru-i period, but f8 ihalatios o ay sigle day were radomised. At radomisatio, the reliever medicatio was exchaged for blided study ihalers, cosistig of formoterol 4.5 mg (delivered dose, equivalet to 6 mg metered dose; Oxis1 Turbuhaler1, AstraZeeca) or salbutamol 100 mg (albuterol; salbutamol Turbuhaler1, AstraZeeca). After 3 weeks of treatmet patiets were switched to the alterative ihaler for aother 3 weeks. The curret study was performed accordig to Good Cliical Practice guidelies ad was subjected to approval by Medical Ethics Committees at all cetres. All patiets gave writte iformed coset before beig erolled. Efficacy measuremets Lug fuctio Peak expiratory flow (PEF) was recorded twice daily (mii- Vitalograph Absolute Scale; Vitalograph, Buckigham, UK) o daily diary cards throughout the study. FEV1 ad forced vital capacity (FVC) were measured at the cliic visits ad the highest values of both parameters recorded. All apparatus fulfilled the ATS specificatios for accuracy. Preferece After the secod treatmet period, patiets were give a questioaire i Dutch that assessed their overall preferece for either the first or secod treatmet, or if they had o preferece for either of the test treatmet periods. The two questios were as follows. 1) Which treatmet period out of the last 6 weeks do you prefer i geeral for use of your rescue medicatio for your asthma, treatmet period 1 or treatmet period 2? 2) You have bee requested to express a preferece, but if you have o preferece at all for either treatmet period you may choose o preferece. Symptoms Daytime ad ight-time asthma symptoms were recorded o a scale of 0 3 (05oe; 15mild; 25moderate; ad 35severe symptoms). Awakeigs due to asthma ad daily brochodilator use were also recorded. Subjective efficacy After the first ad secod treatmet period, patiets completed a questioaire with four questios usig a 100-mm visual aalogue scale (VAS). This questioaire assessed the patiet s perceptio of: 1) speed of oset of relief, i.e. How fast did you have beefit after usig a ihalatio from your study medicatio? ; 2) duratio of effect, i.e. How log did you have beefit after usig a ihalatio of your study medicatio? ; 3) overall effectiveess of the relief ihaler, i.e. How do you thik the study medicatio has worked for you? ; ad 4) their asthma i geeral, i.e. How did you feel i geeral about your asthma durig the past 3 weeks? A score of zero represeted the worst possible opiio ad a score of 100 represeted the best possible. Aalysis The preset study was desiged to be of sufficiet size to detect a cliically relevat preferece for formoterol or for salbutamol. It was aticipated that a differece i efficacy parameters might ot be detectable due to patiets titratig each study drug to get miimal symptoms; therefore, preferece was chose as a primary parameter. A statistically sigificat preferece was defied as oe of the two study drugs preferred by sigificatly.50% of all treated patiets. The miimal cliically relevat preferece was estimated to be 60%. Therefore, with 80% power ad a two-sided sigificace level of 5%, 200 patiets were required to be radomised ad 120 patiets were required to prefer oe treatmet i order to show a statistically sigificat preferece. Preferece was calculated both for all radomised patiets ad for the group that expressed a preferece. Spirometry ad VAS were aalysed by aalysis of variace (itet-to-treat aalysis), with patiet, period ad treatmet as factors. For FEV1 a additioal exploratory aalysis was performed, icludig oly the patiets who did ot use a dose of their brochodilator i the previous 6 h. PEF values, day ad ight symptom scores, ad as-eeded reliever medicatio use were averaged over the etire treatmet periods. PEF variability was calculated as the quotiet of the absolute differece betwee morig ad eveig PEF (PEFam ad PEFpm, respectively) ad the mea PEF over that day. Symptom-free days (SFD) were defied as a day with both morig ad eveig symptom score equal to zero ad o awakeigs due to asthma. All hypotheses were made usig two-sided alteratives. A p-value,5% was cosidered statistically sigificat. A exploratory aalysis was performed post hoc to ivestigate differeces i preferece ad VAS outcomes assessed by a questioaire i patiets who used frequet or less frequet as-eeded doses of terbutalie i the ru-i period. The study populatio was divided ito three tertiles of approximately c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 3 505

3 AS-NEEDED FORMOTEROL IN ASTHMA D. CHEUNG ET AL. equal size, depedig o the mea umber of daily doses of terbutalie i the ru-i: low,1.58 doses?day -1 (569); itermediate doses?day -1 (570); ad high.2.80 doses?day -1 (572). RESULTS Of the 251 patiets erolled, 211 were radomised (first treatmet: formoterol 5106, salbutamol 5105). Durig the ru-i period 40 patiets were excluded, maily due to deviatios from the terbutalie-use criteria. Patiets had moderate-to-severe asthma (mea FEV1 77% pred ormal) ad displayed 18% reversibility i FEV1 (table 1). Accordig to the Global Iitiative for Asthma (GINA) classificatio of asthma severity [1], 79 patiets had itermittet asthma (step 1), eight had mild persistet asthma (step 2), 90 had moderate persistet asthma (step 3) ad 34 had severe persistet asthma TABLE 1 Demographic data All radomised patiets Subjects 211 Males 105 (50) Mea age yrs Smokig habit (o/ex/curret) 94/88/29 Mea FEV1 L Mea FEV1 % pred Mea reversibility L Mea % reversibility Mea reversibility % pred Mea FVC L Mea ICS dose mg?day Data are preseted as (%) or mea SD, uless otherwise stated. FEV1: forced expiratory volume i oe secod; % pred: percetage predicted; FVC: forced vital capacity; ICS: ihaled corticosteroids. (step 4). The mea dose of ICS was 797 mg?day -1 (19 patiets took beclomethasoe, 103 budesoide ad 87 fluticasoe), idicatig that patiets had predomiatly moderate-to-severe asthma. Of the radomised patiets, 14 (7%) did ot complete both treatmet periods (formoterol 56, salbutamol 58), ie were withdraw due to adverse evets (AEs; formoterol 54, salbutamol 55) ad five due to withdrawal of coset or the use of prohibited medicatio. Efficacy There were large differeces i both objective ad subjective efficacy assessmets (table 2). FEV1 after formoterol treatmet was 5% higher tha after salbutamol treatmet (mea differece 0.12 L; 95% cofidece iterval (CI) ; p,0.0001). Similar differeces were observed i the exploratory aalysis of the 174 patiets who did ot use a dose of their study drug, i at least the last 6 h, prior to spirometry o both occasios (mea differece 0.11 L; 95% CI ; p,0.001). Other sigificat differeces i lug fuctio measures i favour of formoterol were: FVC (mea differece of 0.07 L; 95% CI ; p,0.01); PEFam (13.8 L?mi -1 ; 95% CI ; p,0.0001); ad PEFpm (13.7 L?mi -1 ; 95% CI ; p,0.0001). PEF variability did ot differ. After formoterol treatmet FEV1 was 80.5% pred, ad 77.1% pred after salbutamol treatmet (mea differece 3.5%; 95% CI %). Withi the study populatio of 211 patiets, the preferece for formoterol did ot differ sigificatly from the predefied 50% level (p50.58), but the preferece for salbutamol was sigificatly,50% (p,0.0001). I total, 110 patiets (52.1%) preferred formoterol (95% CI ), 52 patiets (24.6%) preferred salbutamol (95% CI ), 37 patiets had o preferece for either treatmet period ad 12 patiets were withdraw prior to beig able to express their preferece (fig. 1). Withi the populatio of 162 patiets expressig ay preferece, there was a 2.1-fold preferece for formoterol with formoterol preferred by 67.9% (95% CI ; p,0.001) ad salbutamol by the remaiig 32.1% (95% CI ; TABLE 2 Lug fuctio ad subjective efficacy measures Terbutalie ru-i Formoterol period Salbutamol period Treatmet differece p-value FEV1 L ( ), FVC L ( ),0.01 Morig PEF L?mi ( ), Eveig PEF L?mi ( ), Night-time symptoms ( ),0.001 Daytime symptoms ( ), Noctural awakeigs due to asthma?week ( ), Ihalatios?24 h ( ),0.001 Symptom-free days per period ( ),0.001 VAS: How fast beefit ( ) VAS: How log beefit ( ) VAS: How well did it work ( ), VAS: Asthma i geeral ( ),0.001 Data are preseted as mea SD or mea (95% cofidece iterval). FEV1: forced expiratory volume i oe secod; FVC: forced vital capacity; PEF: peak expiratory flow; VAS: visual aalogue scale (0 100 mm). 506 VOLUME 27 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

4 D. CHEUNG ET AL. AS-NEEDED FORMOTEROL IN ASTHMA 17.5% 5.7% 52.1% A aalysis performed post hoc o the data with the patiet populatio split ito three tertiles idicated that all tertiles gaied icreased beefit with formoterol compared with salbutamol (fig. 2). The differece i the umber of as-eeded ihalatios was largest i the itermediate- ad high-use tertiles (o1.58 doses terbutalie?day -1 ). These two groups also had the largest differece i favour of formoterol for treatmet preferece (o2.3-fold versus salbutamol, data ot show). The most marked differece i perceived effectiveess ad duratio of effect was observed i these two groups usig a itermediate or high umber of terbutalie ihalatios i the ru-i. I cotrast, the differece i perceived speed of oset of effect i favour of formoterol was greatest i the group who used a low umber of terbutalie ihalatios i the ru-i. 24.6% FIGURE 1. Proportio of all radomised patiets expressig a preferece for as-eeded medicatio. h: withdraw; &: formoterol; &: salbutamol; &: o preferece. p,0.0001). There was a small ad osigificat 1.3-fold preferece for the secod period, which had o ifluece o the mai outcome, as a equal umber of patiets started with either treatmet. Daytime ad ight-time asthma symptoms differed betwee the two treatmets i favour of formoterol. Mea ight-time asthma symptom score was 13% lower durig formoterol treatmet (mea differece 0.07; 95% CI ; p,0.001) ad daytime symptoms were 11% lower (mea differece 0.11; 95% CI ; p,0.0001). I additio, durig formoterol treatmet patiets had 34% fewer ights i which sleep was disturbed by asthma symptoms (mea differece 0.36 ights? week -1 ; 95% CI ; p,0.0001). Durig formoterol treatmet, patiets had 23% more SFD (5.8 versus 4.8 days? period -1, mea differece 1.1 days; 95% CI ; p,0.001). O 14% of the days i both treatmet periods o as-eeded ihalatios were used. Patiets required 9% fewer ihalatios of formoterol compared with salbutamol (mea differece 0.22 ihalatios?day -1 ; 95% CI ; p,0.001). The cumulative frequecy distributio of the umber of days with a specific umber of doses idicated a turig poit betwee 3 4 doses?day -1. Days with less tha three doses were more commo durig formoterol treatmet, while days with more tha four doses were more commo durig salbutamol treatmet. Patiets perceptio of the effectiveess of relief medicatio o the VAS showed that they rated formoterol to be more effective tha salbutamol treatmet o all attributes assessed (table 2). Two questios resulted i sigificat differeces: 1) How well did the study drug work for you? ; ad 2) How did you feel i geeral about your asthma? (Both p,0.001). Perceived duratio of effect did ot reach the formal sigificace level betwee the two groups (p50.067). Surprisigly, there was a differece i perceived oset of actio i favour of formoterol, although this was ot sigificatly differet (p50.051). Safety There was o differece i the icidece of AEs i the two treatmet periods (formoterol treatmet: 47 evets; salbutamol treatmet: 50 evets). The most frequetly reported AEs (.2% of the study populatio) were respiratory tract ifectios (ie i the formoterol group ad 18 i the salbutamol group); headache (five formoterol, four salbutamol); ad asthma deterioratio (four formoterol, five salbutamol). Nie patiets were withdraw due to AEs; four patiets i the formoterol group (three due to asthma exacerbatio ad oe due to palpitatios) ad five patiets i the salbutamol group (two due to asthma exacerbatio, oe due to headache, oe due to respiratory tract ifectio ad oe due to worseig of cholelithiasis). There were few asthma exacerbatios durig the study requirig a predisoloe course ad oe patiet o salbutamol treatmet was hospitalised for a exacerbatio. DISCUSSION The preset study showed that durig salbutamol treatmet asthma patiets did ot titrate their as-eeded use to a optimal level. Durig treatmet with formoterol a higher level of asthma cotrol was obtaied, defied as better symptom cotrol ad superior lug fuctio, tha durig salbutamol treatmet whe both were used as eeded by patiets with moderate-to-severe asthma. Statistically sigificat ad cliically relevat differeces were observed i FEV1, PEF, daytime ad ight-time asthma symptoms i favour of formoterol. This improved cliical efficacy was accompaied by a 2.1-fold greater preferece for formoterol ad by a differece i patiets perceptio of the overall effectiveess of treatmet. As expected, the umber of daily as-eeded ihalatios was sigificatly lower durig formoterol treatmet, a cosequece of the drugs log duratio of actio [2]. The relatively small differece (9%) may be partly explaied by icludig patiets with low or ifrequet as-eeded use, i.e. those maily usig a sigle daily dose upo risig or before goig to sleep. These patiets were likely to record a similar umber of ihalatios while beig treated with a short-actig or a log-actig brochodilator. The curret study also shows that while usig salbutamol as eeded, the patiets i the preset study did ot icrease the frequecy of reliever use to gai maximal attaiable brochodilatig effect ad miimal symptoms. I theory, by icreasig the frequecy of ihalatios of the shortactig brochodilator, a similar brochodilatig effect should be attaiable as whe usig the log-actig brochodilator at a c EUROPEAN RESPIRATORY JOURNAL VOLUME 27 NUMBER 3 507

5 AS-NEEDED FORMOTEROL IN ASTHMA D. CHEUNG ET AL. a) 20 b) 16 Differece i VAS score c) d) Differece i VAS score Low Itermediate High Level of reliever use at baselie Low Itermediate High Level of reliever use at baselie FIGURE 2. Differece i subjective effectiveess, assessed via visual aalogue scales (VAS (0 100 mm); mea 95% cofidece iterval formoterol mius salbutamol) i three subgroups, based o their as-eeded terbutalie use i the ru-i period. a) How fast did you feel a beefit? ; b) How log did you feel a beefit? ; c) How well did the study drug work for you? ; ad d) How i geeral did you feel about your asthma? Low:,1.58 doses?day -1 ; itermediate: doses?day -1 ; ad high:.2.80 doses?day -1. lower frequecy. I real life, patiets seem to settle for worse symptom cotrol while beig treated with salbutamol tha whe treated with formoterol. A exploratory aalysis was performed post hoc, splittig the study populatio ito three equal groups with a higher, medium or lower use of as-eeded medicatio durig the rui. Efficacy differeces betwee formoterol ad salbutamol existed i all three groups, but the patiets i the two groups with the highest use of reliever medicatio durig ru-i (o1.58 doses?day -1 ) showed the largest differeces i aseeded medicatio use, overall preferece towards formoterol ad subjective effectiveess i favour of formoterol. This suggests that more frequet users of as-eeded treatmet will beefit the most from the loger duratio of actio of formoterol. I cotrast, the subgroup with the lowest use of reliever medicatio reported formoterol to work faster tha salbutamol, which may idicate that frequet users may have a poorer perceptio of a brochodilatig effect. There were o differeces i the icidece (or profile) of AEs or asthma exacerbatios betwee the two study drugs. I total there were 24 patiet-yrs of observatio i the preset study i which oly oe hospitalisatio due to a asthma exacerbatio occurred ad oly five patiets (2%) required systemic corticosteroid therapy. The short assessmet period per patiet i the preset study limited the ability to detect a small differece i AE profile, but a favourable safety profile for aseeded formoterol was show i two other large, blided, log-term studies i compariso with as-eeded terbutalie [8, 13] ad i a recetly published study versus ope label aseeded salbutamol [10]. Nevertheless, all symptom, lug fuctio ad preferece measures appropriate for a 3-week assessmet period sigificatly favoured treatmet with aseeded formoterol. Ideed, the curret study is oe of the first to demostrate improved symptom cotrol with as-eeded formoterol versus as-eeded salbutamol. I the preset study, each treatmet was admiistered for 3 weeks. This allowed patiets to recall their asthma status i the first period whe aswerig questios o treatmet preferece o completio of the secod treatmet period. As patiets were istructed to use each treatmet strictly as eeded ad ot regularly, it was aticipated that steady state would be reached fairly quickly ad carry-over effects would be miimal. May aspects of reliever medicatio will have a impact o preferece. The preset study was performed with idetical ad blided ihalers, so the ease of use of ihaler could have 508 VOLUME 27 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL

6 D. CHEUNG ET AL. AS-NEEDED FORMOTEROL IN ASTHMA o ifluece o the outcome. The higher preferece for formoterol was more likely to be related to other factors, such as the observed differece i cliical effect. Patiets were asked to rate four subjective aspects of the study treatmets usig the VAS. All four showed formoterol to be rated as more effective tha salbutamol, although oly two of these were statistically sigificat. Patiets also perceived formoterol to have at least as fast a oset of effect as salbutamol. The beefits of as-eeded formoterol were further corroborated by traditioal efficacy parameters, such as a 5% icrease i FEV1, a 23% icrease i the umber of SFD ad a 34% lower icidece of awakeigs due to asthma. It remais uclear whether the observed differece i overall cliical effect with formoterol relates solely to its loger duratio of actio or to other specific properties. I oe comparative study, as-eeded formoterol compared with aseeded terbutalie reduced the icidece of severe asthma exacerbatios by 45% [8]. Furthermore, other studies have show that regular formoterol treatmet leads to a decrease i severe exacerbatios [6, 7]. Possible explaatios for the beefits of formoterol i asthma may be foud i the observatio that formoterol ehaces the ati-iflammatory effects of corticosteroids i vitro [14]. Iterestigly, formoterol has bee show to decrease the presece of eosiophils i the airway mucosa ad sputum of asthmatics [15 17], while i other recetly published studies other b 2 -agoists, such as terbutalie ad salmeterol, did ot sigificatly ifluece sputum or airway mucosa eosiophil cotet [18 20]. With the advet of combiatio therapy (ICS plus a logactig b-agoist) for maiteace treatmet of more severe asthma, the possibility of usig formoterol both as maiteace ad as eeded should be cosidered. IND et al. [13] showed that as-eeded formoterol, i additio to regular doses as part of a combiatio regime, was as well tolerated ad as effective as terbutalie. Therefore, if formoterol ca be easily substituted for other, short-actig rescue medicatios, this ew practice tred should ot affect the usefuless of as-eeded formoterol. Ideed, there may be some iheret advatages to usig formoterol as both maiteace ad as-eeded therapy, icludig a eed for fewer ihalers, leadig to improved adherece to treatmet. Furthermore, the REal LIfe EFfectiveess of Oxis1 Turbuhaler1 as-eeded i asthmatic patiets (RELIEF) study [10] demostrated that patiets receivig maiteace log-actig b-agoists used a similar umber of rescue ihalatios of either formoterol or salbutamol, but that those without maiteace log-actig b-agoists used sigificatly more ihalatios of salbutamol compared with formoterol. I coclusio, i patiets usig ihaled corticosteroids as maiteace therapy, as-eeded treatmet with formoterol results i improved lug fuctio ad symptom cotrol compared with as-eeded salbutamol. Formoterol treatmet was perceived to be at least as fast actig as salbutamol treatmet ad formoterol treatmet was sigificatly preferred over salbutamol by asthma patiets. ACKNOWLEDGEMENTS The followig icluded patiets i the preset study: J. Asi, T.A. Batje, W.G. Boersma, H.E.J. Siighe Damsté, J.J.P. de Hertog, H. Dik, W.B.M. Evers, A.H.M. va der Heijde, A.F. Kuipers, J.L. va der Lichte, P.B. Luursema, B.J.M. Paekoek, H.R. Pasma, W.R. Pieters, J.H.E.M. Schije, A.P. Sips, R. Slotema, P.I. va Spiegel, I. Utama, G.T. Verhoeve, J. Westbroek, M. Westeed, F.A. Wilschut, G.J.M. va Doesburg, I.C. Spelt, J.M.M. va der Weerde, A. Veerma, W. Stevers, ad I.G.C.M. Bieres. The authors would like to thak the AstraZeeca study team for their help i moitorig the study ad performig the statistical aalysis: I. Stobbe { ; M. Tielema; P. Gobbes; M. Plaisier; D. Neppelebroek; H. Vliegethart-de Gouw; R. Kalpoe ad M. Boorsma. They would also like to thak C. McCa for editorial help with the mauscript. REFERENCES 1 GINA Workshop Report: Global Strategy for Asthma Maagemet ad Prevetio, available from Date last accessed: Nov Date last updated: va Noord JA, Smeets JJ, Raaijmakers JA, Bommer AM, Maese FP. Salmeterol versus formoterol i patiets with moderately severe asthma: oset ad duratio of actio. Eur Respir J 1996; 9: va Noord JA, Smeets JJ, Maese FPV. A compariso of the oset of actio of salbutamol ad formoterol i reversig methacholie-iduced brochocostrictio. Respir Med 1998; 92: Politiek MJ, Boorsma M, Aalbers R. Compariso of formoterol, salbutamol ad salmeterol i methacholieiduced severe brochocostrictio. Eur Respir J 1999; 13: Seberová E, Adersso A. Oxis (formoterol give by Turbuhaler) showed as rapid a oset of actio as salbutamol give by a pmdi. 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