Safety concerns regarding inhaled adrenergic. Long-acting b-agonists: a review of formoterol safety data from asthma clinical trials

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1 Eur Respir J 2009; 33: DOI: / CopyrightßERS Jourals Ltd 2009 Log-actig b-agoists: a review of formoterol safety data from asthma cliical trials M.R. Sears*,#, A. Ottosso ", F. Rader " ad S. Suissa +,1 ABSTRACT: The safety of log-actig b 2 -agoist (LABA) treatmet i asthma has bee questioed followig reported icreased respiratory deaths whe salmeterol was added to usual pharmacotherapy. The aim of this study was to examie whether asthma, cardiac or allcause mortality ad morbidity were icreased with formoterol use. The aalysis icluded all AstraZeeca radomised cotrolled parallel-group asthma trials of 3 12-moths duratio ivolvig formoterol. Risks associated with formoterol use compared with o-laba treatmet, overall ad i combiatio with ihaled corticosteroids (ICS), were assessed usig a itetio-to-treat aalysis of the rates ad rate ratios of deaths ad serious adverse evets (SAEs). The mai objective of this study was to compare asthma-related mortality i patiets usig formoterol ad those ot usig formoterol. There were eight asthma-related deaths (0.34 per 1,000 perso-yrs) amog 49,906 formoterolradomised patiets (92% usig ICS), ad two (0.22 per 1,000 perso-yrs) amog 18,098 patiets (83% usig ICS) ot radomised to formoterol, which was osigificat. Asthma-related SAEs (.90% of which were hospitalisatios) were sigificatly fewer amog formoterol-radomised patiets (0.75 versus 1.10%). There was o icrease i asthma-related SAEs with icreased daily doses of formoterol (9, 18 or 36 mg). There was o sigificat differece i cardiac mortality or ocardiac oasthma-related mortality i formoterol-radomised compared to o-labatreated patiets. All-cause mortality was similar. I the data set i which all subjects were prescribed ICS at baselie, there were seve asthma-related deaths (0.32 per 1,000 perso-yrs) amog 46,003 formoterol-radomised patiets ad oe (0.14 per 1,000 perso-yrs) amog 13,905 patiets ot radomised to formoterol, which was also osigificat. There were few asthma-related or cardiac-related deaths amog patiets radomised to formoterol, ad all differeces were osigificat compared with o-log-actig b 2 -agoistradomised patiets. However, despite data o.68,000 patiets, the power was isufficiet to coclude that there was o icreased mortality with formoterol. Cardiac-related serious adverse evets were ot icreased, ad asthma-related serious adverse evets were sigificatly reduced with formoterol. KEYWORDS: Asthma, formoterol, log-actig b-agoist, morbidity, mortality, safety Safety cocers regardig ihaled adreergic compouds date back to the late 1940s. Up to five-fold icreases i mortality amog users of ihaled adreali [1] ad highdose isoprealie [2 4] were reported i 1948 ad the 1960s, respectively. A more recet mortality epidemic i New Zealad, begiig i 1976 [5], led to a series of case cotrol studies [6 8] that idicated a icreased risk of fatal asthma This article has supplemetary material accessible from For editorial commets see page 3. associated with prescriptio of feoterol. A study i Saskatchewa (Caada) foud a icreased risk of mortality with icreasig use of both feoterol ad salbutamol [9]. Although cardiac adverse evets were frequetly cosidered resposible for the icreased risk, a 1-yr cliical trial showed icreased airway resposiveess ad worseed asthma cotrol durig regular treatmet with feoterol added to usual therapy AFFILIATIONS *Firestoe Istitute for Respiratory Health, St Joseph s Healthcare, ad # McMaster Uiversity, Hamilto, ON, + Cetre for Cliical Epidemiology, Jewish Geeral Hospital, ad 1 Dept of Epidemiology ad Biostatistics, McGill Uiversity, Motreal, QC, Caada. " AstraZeeca R&D, Lud, Swede. CORRESPONDENCE M.R. Sears Firestoe Istitute for Respiratory Health St Joseph s Healthcare 50 Charlto Ave E Hamilto, ON L8N 4A6 Caada Fax: searsm@mcmaster.ca Received: November Accepted after revisio: August SUPPORT STATEMENT M.R. Sears reviewed the trial data, icludig details of all deaths, ad was primarily resposible for writig this article ad for the medical cotet. S. Suissa was resposible for the statistical ad pharmacoepidemiological cotet. A. Ottosso ad F. Rader were resposible for extractio, validatio ad aalysis of data from the AstraZeeca trials. All authors read ad approved the fial mauscript. STATEMENT OF INTEREST Statemets of iterest for all authors of this mauscript ca be foud at statemets.shtml Europea Respiratory Joural Prit ISSN Olie ISSN c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 1 21

2 SAFETY OF FORMOTEROL IN ASTHMA TRIALS M.R. SEARS ET AL. compared with b-agoist used oly as eeded for symptom relief [10, 11]. However, subsequet US ad UK trials of regular versus as eeded salbutamol did ot detect sustaied adverse effects o asthma cotrol [12, 13]. Nevertheless, durig the 1990s, cosesus guidelies icreasigly advocated use of short-actig b 2 -agoists (SABAs) oly as eeded for symptom relief [14 16]. The itroductio of the log-actig b 2 -agoists (LABAs) salmeterol ad formoterol prompted questios regardig the possibility of safety issues. Cliical trials showed substatial beefit from addig LABAs to ihaled corticosteroid (ICS) therapy, exceedig that of doublig or eve further icreasig the dose of ICS [17 19]. At the same time, the Serevet Natiowide Surveillace (SNS) trial i the UK reported a osigificat three-fold excess of asthma-related deaths i patiets usig regular salmeterol compared with regular salbutamol over 16 weeks [20]. Of the patiets studied, 69% were usig ICS at baselie. A cotrolled study that employed stepwise reductio of ICS to permit iflammatio to gradually icrease demostrated the potetial for LABAs to mask cliical evidece of progressive iflammatio [21]. I the USA, the Food ad Drug Admiistratio (FDA) approved salmeterol as mootherapy, as well as for use i combiatio with other therapies, but required a post-marketig cliical trial i order to address safety cocers raised by the SNS study. The US study was halted prematurely i 2003, whe a iterim aalysis idicated that additio of salmeterol to usual therapy was associated with a icrease i both severe exacerbatios ad mortality compared with placebo [22]. Post hoc subgroup aalyses suggested that the icreased mortality was cofied to patiets ot prescribed ICS at baselie (ie deaths with salmeterol ad oe with placebo, compared with four ad three deaths, respectively, amog patiets usig ICS at baselie). However the use of ICS was ot recorded durig the treatmet period. I three placebo-cotrolled trials (51,613) with formoterol (Foradil TM ; Novartis Pharmaceuticals, Basle, Switzerlad), a higher dose (24-mg metered dose twice daily) teded to be associated with more serious asthma exacerbatios tha a lower dose (12 mg twice daily) [23]. However, a large phase IV, radomised placebo-cotrolled trial (52,085) of Foradil TM foud all doses of formoterol to be associated with fewer exacerbatios tha placebo, with o idicatio of ay dose respose relatioship [24]. Followig a safety review of LABAs [25], the Pulmoary- Allergy Drugs Advisory Committee (PADAC) of the FDA recommeded additioal safety labellig iformatio for this class. I November 2005, the FDA directed US maufacturers of salmeterol- ad formoterol-cotaiig products to update existig product labels with ew warigs [26]. The PADAC review icluded formoterol data oly from Novartis trials, as oly that preparatio (Foradil TM ) was the marketed i the USA. However, the AstraZeeca cliical database for formoterol is much larger tha that available through Novartis trials. The formoterol Turbuhaler (Oxis1; AstraZeeca, Lud, Swede) is curretly licesed i 82 coutries ad the combied ICS/LABA budesoide/formoterol Turbuhaler (Symbicort1; AstraZeeca) i 101 coutries. The preset article reports a comprehesive review of safety data obtaied i completed AstraZeeca trials (up to December 2006) ivolvig formoterol with respect to the risks of asthma-related ad cardiac-related death ad serious adverse evets (SAEs), as well as all-cause mortality. Three questios were posed of the data. 1) What are the risks of exposure to formoterol compared to other treatmet regimes that do ot iclude a LABA (o-laba)? 2) What are the risks of exposure to formoterol whe give i combiatio with ICS compared to treatmet with o-laba plus ICS? 3) What are the risks of exposure to formoterol without ICS compared with formoterol i combiatio with ICS? The use of other treatmets (e.g. SABAs) was ot take ito accout. I order to achieve the largest possible data set, ad mimic a real-life situatio i which patiets may ot adhere to guidelies, the primary aalysis of the preset study focused o questio 1. However, give that all guidelies state that LABAs should be used i asthma maagemet i combiatio with ICS, ad as use of ICS may be regarded as a potetial cofouder i studies of LABA safety, questio 2 was added as a post hoc aalysis to determie risks associated with the additio of LABA to treatmet with ICS versus o-laba with ICS. METHODS Data source All AstraZeeca trials (completed by December 2006) i patiets with asthma ivolvig the use of formoterol either aloe as maiteace or reliever therapy or i combiatio with budesoide were idetified through the compay database. This cosisted of 78,339 patiets participatig i 117 trials (fig. 1). This large data set was the subjected to reductio i order to brig about more uiformity. The first step excluded trials i which treatmet was short. Sice a adverse effect of treatmet o asthma severity may require exposure over may moths, the mai aalysis icluded all radomised cotrolled trials with duratios of 3 12 moths, performed either as cetrally ru trials or trials ru by marketig compaies i differet coutries (locally ru). I order to focus o adverse effects associated with formoterol i compariso with those of o-laba regimes, treatmet arms ivolvig radomisatio to the other LABA, salmeterol, were excluded from the mai aalyses (fig. 1). The remaiig trials icluded those from the cetrally ru AstraZeeca cliical developmet programmes for formoterol Turbuhaler (14 trials), budesoide/formoterol Turbuhaler (19 trials) ad budesoide/formoterol pressurised metered-dose ihaler (pmdi; 11 trials), ad 20 trials coducted by local AstraZeeca marketig compaies with formoterol Turbuhaler or budesoide/formoterol Turbuhaler. Details of these 64 trials, ivolvig 72,174 radomised patiets, are provided i tables E-1 E-3 of the supplemetary material. After excludig the 4,170 patiets radomised to salmeterol, the resultig overall data set icluded 68,004 patiets, of whom 49,906 were radomised to formoterol-cotaiig products ad 18,098 to o-laba products (fig. 1). A supplemetary aalysis of all idetified AstraZeeca asthma trials, regardless of duratio or study desig, was also performed i order to esure that o importat safety sigals were missed by selectig oly trials of 3 12 moths duratio. These icluded all cetrally ru trials i asthmatic patiets, icludig log-term safety studies, emergecy departmet trials 22 VOLUME 33 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

3 M.R. SEARS ET AL. SAFETY OF FORMOTEROL IN ASTHMA TRIALS All AstraZeeca formoterol trials i asthmatic patiets (117 trials; =78339) 53 trials excluded for oparallel-group desig or duratio other tha 3 12 moths (=6165) Parallel-group formoterol trials of 3 12 moths' duratio i asthmatic patiets (64 trials; =72174) Patiets radomised to salmeterol excluded (=4170) Overall dataset (=68004): FORM radomised (=49906) No-LABA radomised (=18098) Trials without comparator o-laba groups excluded: FORM radomised (=28409) No-LABA radomised (=0) Trials comparig FORM with o-laba: FORM radomised (=21497) No-LABA radomised (=18098) RELIEF-trial excluded (use of ICS kow oly at baselie): FORM radomised (=8924) No-LABA radomised (=8938) FORM versus o-laba trials with documeted ICS maiteace doses (icludig o dose): FORM radomised (=12573) No-LABA radomised (=9160) Maiteace ICS-users i FORM versus o-laba trials: FORM radomised (=11773) No-LABA radomised (=8102) No-ICS users i FORM versus o-laba trials: FORM radomised (=800) No-LABA radomised (=1058) FIGURE 1. Flow chart showig all patiets ivolved i AstraZeeca trials with formoterol (FORM). LABA: log-actig b 2 -agoist; RELIEF: Real life effectiveess of Oxis Turbuhaler as eeded i asthmatic patiets durig six moths; ICS: ihaled corticosteroid. i acute severe asthma, pharmacokietic ad high-dose tolerace studies, methacholie-iduced brochocostrictio studies ad trials i a prematurely termiated (due to device malfuctio) formoterol pmdi programme. All idetified locally ru parallel-group trials i asthmatic patiets were also icluded. There were o exclusios of salmeterol-radomised patiets i the supplemetary aalysis. Results from this supplemetary aalysis are summarised i the preset article ad further described i the supplemetary material. Outcome evets All deaths ad ofatal SAEs were evaluated at the time by the origial ivestigators ivolved i each study, ad prior to ublidig i blided trials. All fatalities i all trials were reassessed by the preset authors, ad categorised as asthmarelated, cardiac-related or due to other reasos. Asthmarelated evets were defied as ay evet coded to the preferred terms asthma, status asthmaticus or brochospasm accordig to the Medical Dictioary for Regulatory Activities (MedDRA) Versio 8.0 [27]. I additio, two deaths origially coded to respiratory failure were cosidered asthma-related. Cardiac-related evets were defied as ay evet coded usig MedDRA accordig to the terms i table E-4 of the supplemetary material. SAEs (asthma-related ad cardiac-related) were defied usig the Iteratioal Coferece o Harmoisatio recommedatios, i.e. ay adverse evet that was immediately lifethreateig, required ipatiet hospitalisatio or prologatio of existig hospitalisatio, resulted i persistet or sigificat disability or icapacity, was a cogeital abormality/birth defect or was a importat medical evet that may jeopardise the subject or require medical itervetio to prevet oe of the outcomes listed above. Data aalyses For each patiet, the perso-time of follow-up i the trial was measured ad cumulated to obtai exposure i perso-yrs ad the rate of fatal outcome evets, expressed per 1,000 persoyrs, for each treatmet group was computed. The crude rate ratio (RR) associated with formoterol use ad its cofidece iterval (CI) were computed usig the exact method as described i the maual for StatXact1 [28]. For ofatal evets, the crude RR was approximated by the odds ratio (OR) usig the umber of radomised patiets ad the umber of patiets experiecig at least oe evet. The adjusted RR, to cotrol for variatios i properties of the idividual trials, was estimated from the OR computed by coditioal logistic regressio, adjustig for trial as a covariate. This approach was supplemeted with a meta-aalysis at the trial level as described by MARTIN ad AUSTIN [29]. For RRs ad ORs, differeces were cosidered sigificat whe the 95% CI excluded Formoterol doses were expressed as delivered doses. Formoterol delivered doses of 9, 18 ad 36 mg correspod to metered doses of 12, 24 ad 48 mg, respectively. Ethicity was classified as Caucasia, Orietal, Black (icludig Africa America) ad other. Aalysis of risks of exposure to formoterol versus o-laba (questio 1) This costituted the primary aalysis, with asthma mortality beig chose as the primary outcome. The itet-to-treat approach for all trials of 3 12 moths duratio was used to classify patiets radomised to: 1) formoterol-cotaiig products, i.e. formoterol aloe or formoterol combied with budesoide (two ihalers or i a sigle device); or 2) o- LABA products, icludig ICS (budesoide/fluticasoe), SABA (terbutalie/salbutamol) ad placebo. c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 1 23

4 SAFETY OF FORMOTEROL IN ASTHMA TRIALS M.R. SEARS ET AL. Additioal stratified aalyses were performed by age, sex ad ethicity. The formoterol dose respose effect o the risk of asthma-related SAEs was also assessed. Aalysis of risks of exposure to formoterol plus ICS versus o-laba plus ICS (questio 2) Risks were aalysed by comparig outcomes amog all patiets usig or ot usig ICS at baselie (global ICS aalysis). A further aalysis excluded patiets i trials without a o-laba comparator ad patiets i the Real life effectiveess of Oxis Turbuhaler as eeded i asthmatic patiets durig six moths (RELIEF; SD ) trial [30] sice ICS use durig this trial was ot documeted after the baselie visit. This leaves a subset of trials ivolvig a direct compariso betwee formoterol ad o-laba treatmet i patiets with documeted maiteace treatmet with ICS durig the trial, icludig o dose (fig. 1). The ICS-exposed patiets i this subset of trials are referred to as the radomised ICS data set. Aalysis of risks of exposure to formoterol without ICS versus formoterol with ICS (questio 3) Oly trials with at least oe treatmet arm with formoterol combied with ICS ad oe treatmet arm with formoterol without ICS could be utilised for this aalysis. RESULTS Asthma-related deaths ad SAEs Comparig asthma-related mortality with formoterol versus o-laba i the overall dataset, the aprioriprimary outcome of the preset study, there were eight deaths amog 49,906 formoterol-radomised patiets ad two amog 18,098 o- LABA-radomised patiets (0.34 versus 0.22 per 1,000 treatmet-yrs; RR 1.57; 95% CI ; table 1). For asthmarelated ofatal SAEs withi the same overall dataset, a sigificatly lower risk was observed amog the formoterolradomised patiets (374 (0.75%) patiets with asthma-related SAEs versus 199 (1.10%); RR 0.68; 95% CI ; table 2). Comparig asthma-related mortality with formoterol versus o-laba amog patiets prescribed ICS at baselie i the overall data set (global ICS aalysis), seve versus oe asthma death yielded a RR of 2.32 (95% CI ; table 1). Withi this data set, aalysis of asthma-related ofatal SAEs showed a sigificatly lower risk amog formoterol patiets prescribed ICS at baselie compared to those prescribed o-laba plus ICS (RR 0.63; 95% CI ; table 2). Comparig asthma-related mortality with formoterol versus o-laba amog patiets all o maiteace treatmet with ICS i the radomised ICS data set, there were three versus o asthma deaths, yieldig a RR of (95% CI 0.29 ; table 3). For asthma-related ofatal SAEs, there was, agai, a sigificatly lower risk amog patiets treated with formoterol plus ICS compared to o-laba plus ICS (OR 0.69; 95% CI ; table 3). Asthma-related deaths ad SAEs by age, sex ad ethicity The patiets ages at death were 13, 35, 43, 44, 55, 56, 65 ad 67 yrs for formoterol ad 18 ad 45 yrs for o-laba regimes. Review of the asthma-related deaths, icludig age, sex, race, cocomitat medicatio, duratio of trial, duratio of formoterol exposure before death, daily formoterol dose ad certified cause of death, revealed o cosistet patters amog ay of these variables (table 4). There were o deaths amog the small umber (51,189) of Black subjects. There was o evidece of icreased risk of asthma-related SAEs associated with formoterol i ay subgroup of patiets by age, sex or ethicity i the overall data set (table 5). Nofatal asthma-related SAEs amog Black subjects were reported i eight out of 861 (0.9%) formoterol-radomised ad three out of 328 (0.9%) o-laba-radomised patiets. These rates are similar to those i the other small subgroups (Orietal ad other), ad are ot otably differet from those i Caucasias, i whom ofatal asthma-related SAEs were reported by 268 out of 39,868 (0.7%) formoterol-exposed ad 123 out of 14,818 (0.8%) o-laba patiets. Asthma-related SAEs by daily dose of formoterol There was o icreased risk of ofatal asthma-related SAEs related to icreased doses of formoterol by radomised treatmet (overall data set; table 6). Cardiac-related deaths ad SAEs Although cardiac-related death may have a respiratory-related compoet, all cases of cardiac death had terms reported that motivated their assigmet as cardiac-related rather tha asthma-related (table E-5 of supplemetary material). There were eight cardiac-related deaths amog 49,906 formoterolradomised patiets (oe ot usig ICS at baselie) ad ie amog 18,098 patiets radomised to o-laba regimes (three ot usig ICS at baselie). Rates of cardiac-related death by radomisatio (deaths per 1,000 treatmet-yrs) are icluded i table 1. Ages at death raged yrs for formoterolradomised patiets ad yrs for o-laba-radomised patiets. Deaths amog the formoterol-radomised patiets were reported as due to cardiac arrest (52), cardiac failure/ myocardial ifarctio (52), myocardial ifarctio (52), cardiorespiratory failure ad myocardial ischaemia. Deaths amog the o-laba-radomised patiets were reported as due to myocardial ifarctio (54), cardiac failure, cardiac arrest, sudde cardiac death, aortic steosis ad cardiomyopathy. The percetage of patiets reportig at least oe cardiacrelated SAE was similar for formoterol-radomised (0.21%) compared with o-laba-radomised (0.25%) patiets (OR 0.83; 95% CI ; table 2). Aalysis of cardiac-related deaths ad SAEs i the overall data set, amog patiets prescribed ICS at baselie (global ICS aalysis) ad i the radomised ICS data set showed o sigificat differeces betwee treatmets (tables 1 3). Deaths due to other causes Deaths due to causes other tha asthma-related or cardiacrelated causes were umerically more frequet amog the formoterol-radomised patiets tha amog the o-labaradomised (18 deaths amog 49,906 patiets versus three deaths amog 18,098 patiets; RR 2.35; 95% CI ; table 1). The deaths were reported as stroke, liver cirrhosis ad a udefied cause for the three o-laba-exposed patiets, ad as lug cacer (52), brai tumour (52), stroke (52), suicide (52), pulmoary embolism, hepatic carcioma, 24 VOLUME 33 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

5 M.R. SEARS ET AL. SAFETY OF FORMOTEROL IN ASTHMA TRIALS TABLE 1 Rates ad rate ratios (RRs) of cause-specific death across radomised cotrolled trials stratified by ay ihaled corticosteroid (ICS) use at baselie Formoterol No Formoterol RR (95% CI) # Patiets Deaths Rate per TTY Patiets Deaths Rate per TTY Asthma-related death All subjects ( ) With ICS ( ) No ICS ( ) Cardiac-related death All subjects " ( ) With ICS ( ) No ICS ( ) Other deaths All subjects ( ) With ICS ( ) No ICS ( ) Total deaths All subjects ( ) With ICS ( ) No ICS ( ) CI: cofidece iterval; : 1,000 perso-yrs; TTY: 1,000 treatmet-yrs. # : for asthma, cardiac, other or ay death for formoterol versus o-log-actig b 2 -agoist (o- LABA) [28]. " : two salbutamol as eeded radomised patiets i the Real life effectiveess of Oxis Turbuhaler as eeded i asthmatic patiets durig 6 moths (SD ) trial who suffered a cardiac-related death actually were exposed to formoterol as eeded: oe erroeously received formoterol istead of salbutamol at start of treatmet, ad oe used salbutamol for 5 weeks ad the exchaged medicatio with a formoterol-radomised patiet ad died 2 days later; the physicia could ot determie which drug was used before death. Whe applyig a worst-case approach ad reassigig these two deaths to formoterol, the resultig 10 versus seve cardiac deaths give rates of 0.43 versus 0.76perTTYad arr (95% CI) for cardiacdeath of0.56 ( ) for formoterolversus o-laba, as calculated usig StatXact (Cytel1 Ic.,Cambridge, MA, USA) [27]. peritoeal metastases, ovaria cacer, road accidet, carbo mooxide itoxicatio, typhoid fever ad udefied cause (53) for the 18 formoterol-exposed patiets (table E-6 of supplemetary material). No additioal iformatio is available for the four patiets who died due to a udefied cause (three formoterol-radomised ad oe o-laba-radomised patiet, i.e. the same icidece of 0.006%). All-cause mortality All-cause mortality was similar betwee treatmets, with 48 deaths reported i total, 34 (0.07%) amog formoterol-radomised patiets ad 14 (0.08%) amog o-laba-radomised patiets (table 1). Evet rates i the other subsets of trials Two subsets of trials were ot utilised i the aalyses of effects of formoterol o patiets receivig maiteace treatmet with ICS (the radomised ICS data set; fig. 1). The first subset, trials without a o-laba comparator group, comprised 28,409 patiets, all radomised to differet treatmet regimes of LABA plus ICS, maily i Symbicort versus Symbicort trials. Table 7 summarises the evet rates from these trials, with two asthma-related deaths (rate 0.16 per 1,000 treatmet-yrs) ad a low rate of asthma-related SAEs (icidece 0.67%). The secod subset cosisted of a sigle large ope-label trial, RELIEF, which compared as eeded use of formoterol with as eeded salbutamol, both give i additio to regular asthma treatmet [30]. I this trial, ICS could be iitiated or withdraw at ay time poit, ad data o ICS use were collected oly at baselie ad ot durig the treatmet period, meaig that treatmet with ICS could ot be cotrolled for. Evet rates i the RELIEF trial populatio are also preseted i table 7, together with rates by ICS prescriptio at baselie. The icidece of asthma-related SAEs for o-laba with ICS at baselie was sigificatly higher tha for o-laba without ICS prescriptio at baselie (1.55 versus 0.96%; RR 1.63; 95% CI ). For formoterol, similar results were obtaied (1.39 versus 0.81%; RR 1.74; 95% CI ), suggestig that ICS prescriptio at baselie i the RELIEF trial reflected asthma severity. Adjusted RRs Adjusted RRs cotrollig for trial effect were also calculated. The adjusted RRs were somewhat higher tha the crude RRs for the most rare evets, e.g. asthma death (RR 2.68; 95% CI ), cardiac death (RR 0.75; 95% CI ) ad allcause mortality (RR 1.39; 95% CI ), whereas the results were similar for the more frequet evets, such as SAEs. Noe of the adjusted comparisos showed ay sigificat differeces betwee treatmets. The calculatio of adjusted RRs for asthma mortality utilised data from oly four of the 64 trials (the RELIEF trial, with three versus two asthma-related deaths i formoterol-exposed versus o-laba-exposed patiets, ad SD , SD ad SD , with oe asthma-related death per trial c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 1 25

6 SAFETY OF FORMOTEROL IN ASTHMA TRIALS M.R. SEARS ET AL. TABLE 2 Asthma-related ad cardiac-related serious adverse evets (SAEs) across radomised cotrolled trials stratified by ay ihaled corticosteroid (ICS) use at baselie Formoterol No Formoterol RR (95% CI) # Patiets Patiets with SAEs " (%) Patiets Patiets with SAEs (%) Asthma-related SAEs All subjects (0.75) (1.10) 0.68 ( ) With ICS (0.75) (1.19) 0.63 ( ) No ICS (0.72) (0.79) 0.91 ( ) Cardiac-related SAEs All subjects (0.21) (0.25) 0.83 ( ) With ICS (0.21) (0.27) 0.76 ( ) No ICS (0.20) (0.17) 1.23 ( ) SAEs defied usig Iteratioal Coferece o Harmoisatio recommedatios. RR: rate ratio; CI: cofidece iterval; : 1,000 perso-yrs. # : for the odds ratio for asthma-related ad cardiac-related SAEs (for formoterol versus o-log-actig b 2 -agoist) [28], as calculated usig StatXact (Cytel1 Ic., Cambridge, MA, USA) [27]; " : at least oe ofatal SAE per patiet. amog the formoterol-exposed patiets). The remaiig 60 trials were ot used sice the coditioal aalysis was based oly o trials with at least oe outcome evet ad at least oe patiet i a treatmet group (meaig that the two deaths i trials with o comparator o-laba group were excluded from this aalysis). No other trials cotributed iformatio to the estimatio of the adjusted RR. Likewise, oly a small umber of trials provided data for cardiac deaths (three trials), other deaths (six trials; RR 2.41; 95% CI ) ad all-cause mortality (ie trials; RR 1.39; 95% CI ), whereas, for SAEs, more trials cotributed iformatio (30 trials for asthma-related SAEs; RR 0.84; 95% CI , ad 13 for cardiac-related SAEs; RR 0.81; 95% CI ). Meta-aalyses accordig to MARTIN ad AUSTIN [29] gave almost idetical results (data ot show). TABLE 3 Rates ad rate ratios (RRs) of cause-specific deaths ad serious adverse evets (SAEs) across radomised cotrolled trials comparig formoterol with o-log-actig b 2 -agoist (o-laba) stratified by kow maiteace ihaled corticosteroid (ICS) use # Formoterol No Formoterol RR (95%CI) + Patiets Deaths/ SAEs " Death rate per TTY SAEs % Patiets Deaths/ SAEs " Death rate per TTY SAEs % Asthma-related death Maiteace ICS (0.29 ) No ICS Cardiac-related death Maiteace ICS ( ) No ICS Asthma-related SAEs Maiteace ICS ( ) No ICS ( ) Cardiac-related SAEs Maiteace ICS ( ) No ICS NC CI: cofidece iterval; : 1,000 perso-yrs; TTY: 1,000 treatmet-yrs; NC: ot computable. # : all trials except Real life effectiveess of Oxis Turbuhaler as eeded i asthmatic patiets durig 6 moths trial (ICS treatmet durig the trial ot recorded) ad trials without a o-laba comparator; " : at least oe ofatal SAE per patiet; + : as calculated usig StatXact (Cytel1 Ic., Cambridge, MA, USA) [27]. 26 VOLUME 33 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

7 M.R. SEARS ET AL. SAFETY OF FORMOTEROL IN ASTHMA TRIALS TABLE 4 Details of all asthma-related deaths Patiet Cause of death cosidered ICS-exposed Baselie drug other tha radomised treatmet + Time i study util oset/death " days Duratio of radomised treatmet days Age/sex/ race Daily radomised treatmet dose Study ref. Duratio # days Radomised treatmet Case o. LABA ICS 35/F/X /247 NP NP Yes Status asthmaticus; septic shock mg Form mg Bud 1 Form SD / 181/ /160 mg 65/F/O /300 NP NP Yes Asthma Form/Bud + Terb p.r.. 2 Form SD / 448/ /M/C 159 e 166/198 NP NP Yes Respiratory failure 180 9/320 mg Form/Bud + Form/Bud p.r.. 3 Form SD / 110/ Form p.r.. 56/F/C 2 ## 2/2 Salm Flut Yes Asthma 4 Form SD / 26069/ Form p.r.. 43/F/O 69 69/69 NR BDP Yes Asthma 5 Form SD / 45304/ Form p.r.. 44/M/O 15 15/15 NR NR No Asthma 6 Form SD / 45218/ Salb p.r.. 45/F/O 92 92/92 NR NR No Asthma 7 No-LABA SD / 45224/ Salb p.r.. 18/M/C 91 91/91 NR BDP Yes Asthma 8 No-LABA SD / 71029/ mg Form 13/M/C 26 27/28 NP BDP Yes Respiratory failure 9 Form SD / 34/ /160 mg 67/F/C 28 28/31 NP NP Yes Asthma Form/Bud 10 Form AD / 9199/ ICS: ihaled corticosteroids; LABA: log-actig b 2 -agoist; Form: formoterol; Bud: budesoide; F: female; X: other (i.e. other tha Caucasia, Orietal or Black); Terb: terbutalie; O: Orietal; M: male; C: Caucasia; Salm: salmeterol; Flut: fluticasoe; BDP: beclomethasoe dipropioate; Salb: salbutamol; NR: oe reported; NP: oe permitted; p.r..: as eeded. # : from cliical study protocol; " : first day of radomised treatmet to day of oset of evet leadig to death/day of death; + : take i additio to study drug as maiteace therapy; 1 : patiet developed peumoia ad septic shock durig a hospital admissio for asthma, the probable immediate cause of death was septic shock; e : patiet hospitalised for asthma, discotiued trial o day 159, remaied at hospital ad developed respiratory isufficiecy that progressed ito respiratory failure with fatal outcome; ## : patiet radomised o day of severe asthma attack ad took oe dose of formoterol i the eveig, death was proouced the followig eveig. c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 1 27

8 SAFETY OF FORMOTEROL IN ASTHMA TRIALS M.R. SEARS ET AL. TABLE 5 Nofatal asthma-related serious adverse evets (SAEs) by age, sex ad ethicity (overall data set) Formoterol-cotaiig products No-LABAcotaiig products Total Age group 4 11 yrs 39/3264 (1.2) 25/2165 (1.2) 64/5429 (1.2) yrs 24/4556 (0.5) 17/1889 (0.9) 41/6445 (0.6) yrs 270/37882 (0.7) 136/12596 (1.1) 404/50478 (0.8) o65 yrs 43/4162 (1.0) 21/1448 (1.5) 64/5610 (1.1) Ukow 0/42 (0) 0/0 (0) 0/42 (0) Sex Male 146/22057 (0.7) 72/8068 (0.9) 218/30125 (0.7) Female 228/27800 (0.8) 127/10030 (1.3) 355/37830 (0.9) Ukow 0/49 (0) 0/0 (0) 0/49 (0) Ethicity Caucasia 268/39868 (0.7) 123/14818 (0.8) 391/54686 (0.7) Black 8/861 (0.9) 3/328 (0.9) 11/1189 (0.9) Orietal 70/4065 (1.7) 53/1916 (2.8) 123/5981 (2.1) Other 25/2170 (1.2) 20/1036 (1.9) 45/3206 (1.4) Ukow 3/2942 (0.1) 0/0 (0) 3/2942 (0.1) Total 374/49906 (0.7) 199/18098 (1.1) 573/68004 (0.8) Data are preseted as /N (%) of patiets reportig at least oe asthma-related ofatal SAE (defied usig Iteratioal Coferece o Harmoisatio recommedatios). LABA: log-actig b 2 -agoist. Overall aalysis ad actual treatmet exposure The desig of the RELIEF study [30] meas that the overall aalysis did ot completely reflect actual exposure to LABAs. I the RELIEF trial, patiets could be o baselie maiteace LABA treatmet whe radomised to formoterol or salbutamol as eeded. A separate aalysis examied treatmetrelated differeces for asthma-related ad cardiac-related evets accordig to baselie treatmet, amely o ICS, ICS without LABA, ad ICS plus LABA (tables E-7 ad E-8 of supplemetary material). There was o apparet differece i asthma-related mortality betwee formoterol as eeded ad salbutamol as eeded, or betwee differet baselie treatmets. Likewise, for cardiac ad other deaths ad for all-cause mortality, o clear treatmet-related patter was apparet. Examiig asthma-related ad cardiac-related SAEs from the RELIEF trial by baselie ICS ad LABA use, for all withibaselie-medicatio-group safety comparisos, formoterol as eeded was associated with a similar or lower risk tha salbutamol as eeded. There was a relatioship betwee the overall frequecy of asthma-related SAEs ad baselie medicatio i the RELIEF trial [30]. For the combied formoterol plus salbutamol groups, SAEs were of lowest frequecy amog those receivig o ICS at baselie (0.88%), itermediate i those receivig ICS but o LABA (1.25%) ad of highest frequecy i those receivig both ICS ad a LABA (1.80%). This apparet paradox probably reflects physicia-determied baselie treatmet accordig to perceived severity, with ICS ad LABA prescribed for those with more severe asthma (ad hece more susceptible to SAEs), a example of cofoudig by severity. Supplemetary aalysis Numbers of trials ad patiets The supplemetary aalyses, which icluded all available trials i asthmatic patiets irrespective of duratio ad desig, added 53 trials to those i the primary aalyses, givig 117 trials ad 78,339 patiets i total. Amog these, 54,559 were radomised to formoterol, 4,474 to salmeterol ad 20,477 to a o-laba regime. Patiets i crossover trials were couted oce for each treatmet to which they were exposed, but oly oce i the totals colum. The umber of patiets per treatmet regime for each of the available trials is preseted i table E-3 of the supplemetary material. Asthma-related, cardiac-related ad all-cause mortality Across all of the available trials, there were 56 deaths, of which 10 were asthma-related (all i trials icluded i the overall data set). I additio to the 17 cardiac-related deaths i the overall data set, aother three were reported i the additioal trials (table E-5 of the supplemetary material), two i formoterolexposed patiets i a log-term safety trial ad oe i a salmeterol-exposed patiet. Five additioal deaths from other causes were added to the 21 deaths icluded i the overall data set (table E-6 of the supplemetary material), two i formoterol-exposed patiets, oe i a o-laba-exposed patiet ad two i salmeterol-exposed patiets. All-cause mortality across all available trials was 0.07% for formoterolradomised, 0.07% for o-laba-radomised ad 0.07% for salmeterol-radomised patiets. TABLE 6 Nofatal asthma-related serious adverse evets (SAEs) # by daily dose of formoterol (overall data set) Daily dose of formoterol Patiets Mea duratio days Patiets reportig SAEs " (%) 9 mg (1.07) 18 mg (0.58) 36 mg (0.44) As-eeded use/adjustable dosig (0.80) Total (0.75) # : defied usig Iteratioal Coferece o Harmoisatio recommedatios; " : at least oe asthma-related ofatal SAE per patiet; + : icludes childre who received 80/4.5 mg budesoide/formoterol oce daily plus terbutalie as eeded i trial SD ; 1 : all trials combied. 28 VOLUME 33 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

9 M.R. SEARS ET AL. SAFETY OF FORMOTEROL IN ASTHMA TRIALS TABLE 7 Evet rates i additioal subgroups Trial Formoterol No Formoterol Patiets Deaths Death rate per TTY Patiets with SAEs # (%) Patiets Deaths Death rate per TTY Patiets with SAEs # (%) No LABA comparator groups Asthma-related evets (0.67) Cardiac-related evets (0.21) Other deaths Total deaths RELIEF: overall results Asthma-related evets (1.19) (1.34) Cardiac-related evets (0.22) (0.38) Other deaths Total deaths RELIEF: BL ICS use Asthma-related evets (1.39) (1.55) Cardiac-related evets (0.22) (0.40) Other deaths Total deaths RELIEF: o BL ICS use Asthma-related evets (0.81) (0.96) Cardiac-related evets (0.23) (0.22) Other deaths Total deaths : 1,000 perso-yrs; TTY: 1,000 treatmet-yrs; SAEs: serious adverse evets; LABA: log-actig b 2 -agoist; RELIEF: Real life effectiveess of Oxis Turbuhaler as eeded i asthmatic patiets durig 6-moth trial; BL: baselie; ICS: ihaled corticosteroid. # : at least oe ofatal SAE per patiet (defied usig Iteratioal Coferece o Harmoisatio recommedatios). Nofatal asthma-related ad cardiac-related serious adverse evets Across all trials i the supplemetary aalyses, there were 402 (0.7%) patiets amog the 54,559 formoterol-radomised patiets with at least oe asthma-related SAE ad 113 (0.2%) with at least oe cardiac-related SAE. Amog the 20,477 o- LABA-radomised patiets, the correspodig umbers were 207 (1.0%) ad 46 (0.2%). These results do ot differ from those of the primary aalysis. The results are preseted i table E-3 of the supplemetary material. DISCUSSION The primary purpose of the preset aalysis was to determie whether or ot use of formoterol was associated with a icreased risk of asthma mortality i the largest possible data set from cliical trials, icludig some patiets ot o regular treatmet with ICS. The preset aalysis ivolved 68,004 patiets from the AstraZeeca cliical trial programme for formoterol ad budesoide/formoterol, providig,23,600 perso-yrs of exposure to formoterol. Although a RR of 1.57 did ot show a sigificatly icreased risk of death, mortality is a rare evet i such trials ad estimates of risk should be iterpreted with cautio give that the trials were ot powered o these evets. More cofidece ca be placed i the rates for SAEs, for which the umbers of evets were substatially greater. The use of formoterol was associated with a sigificat reductio i asthma-related ofatal SAEs amog both patiets i the whole data set ad those prescribed ICS at baselie (global ICS aalysis), with the RRs beig 0.68 ad 0.63, respectively. Whe aalysig the safety of LABAs, two questios are importat. What is the overall risk of death if patiets are give a LABA regardless of other therapy? What is the relative risk whe a LABA, such as formoterol, is added to stadard treatmet with ICS? Eight asthma-related deaths i 23,600 perso-yrs of formoterol exposure i the overall data set yielded a mortality rate of 0.34 per 1,000 perso-yrs. The risk of asthma-related death comparig all formoterol-exposed patiets with all o-laba-exposed patiets i the overall aalysis was 1.57 (95% CI ). The other questio posed i the preset aalysis regarded the risk of formoterol compared with o-laba whe both were used with cocomitat ICS, as per iteratioal asthma guidelies. The global ICS aalysis (tables 1 ad 2) showed a RR of 2.32, but this was also ot sigificat ad was associated with wide CIs. This icluded all patiets usig ICS at least at baselie, but it also icluded both the RELIEF trial [30], i which use of ICS after trial etry was ot documeted (ICS could be discotiued or started), ad trials comparig differet strategies of usig combiatio ICS/LABA therapies i which there were o o-laba-radomised patiets. Hece the global aalysis could be viewed as less appropriate despite the larger umber of patiets. The aalysis based o the smaller radomised ICS c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 1 29

10 SAFETY OF FORMOTEROL IN ASTHMA TRIALS M.R. SEARS ET AL. data set (table 3), which retaied all patiets with kow ICS exposure durig treatmet ad a o-laba comparator arm, had three asthma-related deaths i 11,773 formoterol-radomised patiets compared to oe amog the o-labaradomised patiets. Mortality risk caot be accurately estimated with oly three deaths, albeit all i the formoterol arm, ad the calculated RR becomes ifiite. However, the absolute rate of asthma mortality is low (0.48 per 1,000 treatmet-yrs). The sigificatly lower risk foud for asthma SAEs for formoterol versus o-laba added to ICS treatmet is similar to the fidigs of a recet meta-aalysis by JAESCHKE et al. [31]. The data set was explored to assess the relative risk of usig formoterol aloe. However, the data were isufficiet to address this, the third, questio. Ideally, this questio would be addressed by examiig trials i which patiets were radomised to formoterol with ICS versus formoterol without ICS. The oly AstraZeeca trials usig this desig were those performed i the USA, where mootherapy with idividual compoets of combiatio therapy is required by the FDA. However, the 384 patiets radomised to formoterol without ICS i these trials were too few to aalyse with ay meaig. Overall,,8% of all formoterol-treated patiets i AstraZeeca asthma trials were ot exposed to ICS. Whe comparig all formoterol-exposed patiets to all o- LABA-exposed patiets i the overall data set, o icreased risks of cardiac-related deaths (table 1) or cardiac-related ofatal SAEs (table 2) were observed. Similarly, whe examied by ICS use by either the global ICS or radomised ICS method, there was o icreased risk of cardiac SAEs with regimes of formoterol with ICS versus o-laba with ICS (tables 2 ad 3). Hospital admissio is a recogised marker of risk of asthma mortality [32, 33]. Although these were ot aalysed separately, the sigificat reductio i asthma-related SAEs with formoterol,.90% of which were hospitalisatios, speaks agaist a relatioship betwee formoterol ad icreased asthma mortality. The mai limitatio of the preset study was the lack of sufficiet power to form a defiitive coclusio regardig the risk of death for patiets treated with formoterol. Although use of formoterol, largely with ICS, was ot associated with a sigificatly icreased risk of asthma-related deaths, the power was too low to coclude that there was o associatio with formoterol, eve with data o.68,000 patiets. Give the observed asthma mortality rate of,0.3 per 1,000 perso-yrs ad the overall sample sizes i the preset study of formoterol-exposed (49,906) ad o-exposed patiets (18,098), correspodig to 23,600 ad 9,200 treatmetyrs, respectively, the preset study had a 42, 70 ad 88% power for detectig three-, four- ad five-fold icreases i the risk. The study was also uable to adequately address the issue of age, sex ad ethicity factors, which could be importat i modifyig the risk of death. The AstraZeeca database lacks sufficiet umbers to specifically address the risk i the formoterol-exposed Black populatio, but o icrease i mortality or icidece of asthmarelated SAEs was see i the small umbers of Black subjects. The preset report also does ot provide the same weight of evidece as would a large radomised cotrolled trial of formoterol safety. The report was compiled as a observatioal study, usig data from radomised cotrolled trials. Several factors eed to be cosidered with respect to their potetial for itroducig bias ito these fidigs. Data were derived from formoterol arms of umerous trials, ad comparator data from arms i the same or differet trials. May trials did ot have o-laba arms or o-ics arms. There may have bee differeces i asthma severity ad idicatios for ICS treatmet i the differet trials, impactig outcomes. Patiets etered ito most of these trials were required to be i a relatively stable coditio with o recet exacerbatio or requiremet for oral corticosteroid; it is ot possible to kow to what extet these etry criteria may have selected a populatio at lower risk of SAEs from treatmet. Some deaths ad SAEs were assessed ad coded as asthma-related or cardiac-related i ope trials i which the assiged treatmet was kow. Aalyses of multiple trial data sets are difficult because of differeces i study desig ad selectio criteria, icludig severity of disease ad treatmet. A further criticism of the preset study is that it did ot iclude all trials ivolvig formoterol. Novartis formoterol trials were ot icluded i the preset review as the primary data from their published ad upublished trials were ot available to the preset authors. Furthermore, possible differeces i the formulatio ad delivery of the two preparatios of formoterol could cofoud or ivalidate the aalyses. The dose-related icrease i ofatal asthma-related SAEs observed i the Novartis phase III formoterol programme [23] was ot cofirmed i their phase IV trial comprisig 2,085 patiets [24], or i the preset review of almost 50,000 formoterol-treated patiets. O the cotrary, the risk of SAEs i the AstraZeeca trials decreased with higher formoterol doses, a effect that may also be attributable to the higher dose of cocomitat ICS geerally used with higher doses of formoterol. Coversely, the data from the preset study reflect the full breadth of experiece with formoterol i AstraZeeca trials i may differet populatios ad situatios, icludig oe very large trial (RELIEF), i which formoterol could be used freely as reliever medicatio ad also i additio to maiteace formoterol i some patiets [30]. The fidigs reported here cotrast with the report of SALPETER et al. [34], who udertook a meta-aalysis of LABA trials with duratios of o3 moths i which LABA was compared with placebo therapy. They cocluded that sigificatly icreased mortality ad morbidity were associated with both LABAs. However, their aalyses icluded oly oe of the trials [35] icluded i the preset primary aalysis ad oe additioal trial [36] icluded i the preset supplemetary aalysis, out of a total of 117 AstraZeeca trials i the preset review, ad specifically excluded may relevat trials, as oted i several resposes [37] to the origial report of SALPETER et al. [34]. Oe sigle trial, the Salmeterol Multiceter Asthma Research Trial (SMART), accouted for.26,000 (78%) patiets icluded i their meta-aalysis, whereas the two AstraZeeca trials that were icluded cotributed oly 753 (2%) patiets. I a critique of the paper, CHINCHILLI [38] made the followig commet: Give the domiatio by the SMART trial, however, it may be icorrect to claim that this costitutes a systematic overview to ivestigate the risks of LABAs o asthma-related deaths. The coclusio of SALPETER et al. [34] also differs markedly from that of two recet Cochrae aalyses o this topic [39, 40]. 30 VOLUME 33 NUMBER 1 EUROPEAN RESPIRATORY JOURNAL

11 M.R. SEARS ET AL. SAFETY OF FORMOTEROL IN ASTHMA TRIALS These aalyses icluded trials i which ICS was uiformly used by all patiets, ad cocluded that add-o LABA was both effective ad safe. A more recet Cochrae aalysis [41] examied trials of LABAs for chroic asthma i adults ad childre i which the backgroud therapy cotaied varied or o ICS, ad excluded those i which patiets were uiformly takig ICS. I this latter review of 67 trials, a media of oly 62% were takig ICS. The beefits of add-o LABA o asthma cotrol were see both with ad without ICS therapy, but the authors idetified potetial safety issues with LABA without ICS, agai based almost exclusively o the trial of NELSON et al. [22], i which excess mortality was see amog patiets without ICS at baselie. The Asthma Guidelies Committee of the Caadia Thoracic Society carefully reviewed the metaaalysis of SALPETER et al. [34], ad affirmed the safety of LABA used i cojuctio with ICS [42]. I summary, the preset study is the largest aalysis to date of trials ivolvig the log-actig b 2 -agoist formoterol. Numerous studies have show the beefit of addig a logactig b 2 -agoist compared with doublig or further icreasig the dose of ihaled corticosteroid [18, 19, 36] ad the greater beefits to most outcomes of addig a log-actig b 2 -agoist compared with addig a leukotriee atagoist [43]. Iteratioal asthma treatmet guidelies ad the US Food ad Drug Admiistratio ow emphasise that log-actig b 2 - agoist should ot be used as mootherapy i asthma but always together with a ihaled corticosteroid [44]. The reductio i asthma-related serious adverse evets associated with use of formoterol compared with o-log-actig b 2 - agoist, ad the lack of ay dose respose relatio with serious adverse evets, provides some reassurace regardig the safety of formoterol used largely with ihaled corticosteroid, but, give the ifrequecy of deaths, the power of the preset study is isufficiet to coclude with cofidece that there is o associatio betwee formoterol ad mortality. Further studies of mortality i asthma are required i order to permit better assessmet of risks so that these ca be compared agaist the widely accepted beefits that log-actig b 2 -agoists have brought to the maagemet of patiets with asthma. ACKNOWLEDGEMENTS The authors are grateful to the reviewers of this article for their detailed cosideratio of the complex issues ivolved ad their helpful suggestios regardig data presetatio. REFERENCES 1 Beso RL, Perlma F. Cliical effects of epiephrie by ihalatio. 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