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The Safety of Long-Acting b-Agonists among Patients with Asthma Using Inhaled Corticosteroids

Systematic Review and Metaanalysis
_ 2,3,4, ´ niak2,3, Jan Brozek Roman Jaeschke1,2, Paul M. O’Byrne1, Filip Mejza2,3, Parameswaran Nair1, Wiktoria Les 5,6 6 4,5,7 1 1,5,7 ¨ nemann Lehana Thabane , Ji Cheng , Holger J. Schu , Malcolm R. Sears , and Gordon Guyatt
Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 2Polish Institute of Evidence-Based Medicine, Krakow, ´ b Wewne Poland; 3II Katedra Choro ˛ trznych, Jagiellonian University School of Medicine, Krakow, Poland; 4Italian National Cancer Institute, Rome, Italy; 5Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 6Biostatistics Unit, Father Sean O’Sullivan Research Centre, St. Joseph’s Healthcare, Hamilton, Ontario, Canada; and 7CLARITY Research Group, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
1

Rationale: Inhaled long-acting b-agonists (LABAs), when used as monotherapy in asthma, may increase asthma-related hospitalizations, life threatening events requiring intubation/mechanical ventilation, and asthma-related deaths, but concomitant use of inhaled corticosteroids (ICS) may modify this effect. Objectives: To determine the safety of long-acting b-agonists among patients with asthma using corticosteroids. Methods: We conducted a systematic review and metaanalysis of parallel-group, blinded, randomized, controlled trials with at least 12 weeks of treatment addressing the impact of LABA on asthmarelated and total morbidity and mortality in patients concomitantly using ICS. We searched MEDLINE, EMBASE, ACPJC, and Cochrane (Central) databases, and contacted authors and sponsors. Measurements and Main Results: We used a random effects model to pool results from different studies as odds ratios (ORs) (95% confidence interval [CI]) (OR , 1.0 favors LABA). The search yielded 62 relevant studies included in this analysis. Among over 29,000 participants (15,710 taking LABA, with over 8,000 patient-years observed in the LABA groups), there were three asthma-related deaths and two asthma-related, nonfatal intubations (all in LABA groups; < one event per study). Differences in asthma-related hospitalizations (OR, 0.74; 95% CI, 0.53–1.03) and asthma-related serious adverse events (mostly hospitalizations; OR, 0.75; 95% CI, 0.54–1.03) failed to reach statistical significance. The OR for total mortality was 1.26 (95% CI, 0.58–2.74), reflecting 14 deaths in LABA groups and eight deaths in control groups, respectively. Conclusions: In patients with asthma using ICS, LABA did not increase the risk of asthma-related hospitalizations. There were very few asthma-related deaths and intubations, and events were too infrequent to establish LABA’s relative effect on these outcomes. Keywords: long-acting b-agonists; randomized trials; toxicity; adverse events; systematic review

AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject

There are data suggesting that long-acting b-agonists (LABAs) increase mortality in patients with asthma. However, this issue has not been optimally evaluated in patients receiving concomitant corticosteroids.
What This Study Adds to the Field

In patients with asthma using ICS, LABA did not increase the risk of asthma-related hospitalizations. There were very few asthma-related deaths and intubations, and events were too infrequent to establish LABA’s relative effect on these outcomes. Harmful effects have included severe asthma exacerbations requiring hospitalization, life-threatening exacerbations requiring intubations, and asthma-related death (4). These reports, however, largely reflect data from clinical settings in which inhaled steroids were not mandated as a background treatment. Asthma management guidelines have consistently recommended that LABAs should only be used in combination with inhaled corticosteroids (ICS) (5, 6). Systematic reviews have not yet comprehensively addressed the impact of LABAs on these most serious outcomes in the presence of mandated ICS in populations receiving, and not receiving, LABAs (7–10). We therefore conducted a systematic review to examine the safety of LABAs (both formoterol and salmeterol) when taken regularly by patients with asthma who are also taking ICS. Specifically, we address the relative and absolute rate of serious adverse events (SAEs) in randomized trials of patients treated with LABAs versus control populations not receiving LABAs. Outcomes of interest include death, life-threatening situations leading to intubation and ventilation, hospitalization, and SAEs (in each case, both asthma-related and total). Although the primary focus was LABA safety in studies in which the dose of ICS was similar among patients receiving and not receiving LABA, we also evaluated studies using higher doses of ICS among patients not receiving LABA. Some of the results of this study have been previously reported in abstracts (11, 12).

Harmful effects of long-acting b-agonists (LABAs) in patients with asthma have been suggested by a large, randomized trial of salmeterol versus salbutamol by Castle and colleagues (1); more recently by another trial of salmeterol versus placebo added to usual therapy by Nelson and colleagues (2); and finally by a systematic review of data for both salmeterol and formoterol performed by Salpeter and colleagues (3), but heavily influenced by the study by Nelson and colleagues.
(Received in original form April 1, 2008; accepted in final form September 4, 2008) Correspondence and requests for reprints should be addressed to Roman Jaeschke, M.D., 301 James Street South, Fontbonne Building, Room F506, Hamilton, ON, L8P 3B6 Canada. E-mail: jaeschke@mcmaster.ca This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 178. pp 1009–1016, 2008 Originally Published in Press as DOI: 10.1164/rccm.200804-494OC on September 5, 2008 Internet address: www.atsjournals.org

METHODS
Eligibility Criteria
We included studies with the following characteristics: treatment allocation by randomization; parallel control groups (crossover studies excluded) with at least 12 weeks of treatment; blinding of patients and

serevent.J. astrazenecaclinicaltrials. or requires inpatient hospitalization or prolongation of existing hospitalization. Two reviewers (R. and did not want to overlook possible explanations of heterogeneity that warranted serious consideration. in separate study devices. lack of blinding of patients or care-givers (seven articles). The contact with authors and sponsors was done independently and in parallel. and. In addition. asthma-related nonfatal hospitalization. F.) screened titles and abstract to identify articles for full review. The dose of ICS need not have been the same in the intervention and control groups. we explored heterogeneity by performing univariable and multivariable metaregressions to investigate the following a priori hypotheses of factors potentially influencing effect size: medication used (salmeterol vs. Screening of citations of all potentially eligible articles. The reasons for exclusions of studies from the analysis were in most cases multiple. We reviewed manufacturers’ Web sites listing their studies (http://www.M.2 (StataCorp LP. Final data on outcome measures were obtained from published reports. asthma-related nonfatal intubation and ventilation. or is life-threatening. 60–100% as large and worthy of understanding.any untoward medical occurrence that at any dose results in death. blinding of patients and care-givers.. and death from all causes (total death).1010 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008 care-givers. or is a congenital anomaly/birth defect. These analyses were performed using STATA version 9. authors. Eligible studies involved patients with asthma (excluding children younger than 12 yr).40% for >1 yr). Details about the occurrence of outcome of interests were not provided in the majority of the published reports. in each case. We also excluded studies in which the control group received another asthma study medication (leukotriene receptor antagonist. for 12 wk in 24-wk studies). Outcome Measures Prespecified outcomes included: asthma-related death. crossover design (18 articles). Control Group Eligibility required that all patients in the control group used ICS.10 as a threshold P value because we anticipated limited power to this analysis. .N. UK) using the DerSimonian and Laird random effect model (15).2 (Cochrane Review Manager. excessive missing data for . Discrepancies were resolved by contacting the study sponsor. etc. In addition. blinded assessment and classification of outcomes. P. These same reviewers then evaluated the full text of all articles deemed potentially eligible by either reviewer for final inclusion. dose of ICS used in the control group (similar dose of ICS to LABA group or increased dose). The secondary prespecified outcomes were: total nonfatal intubation and ventilation. and J. or W. we considered the following a priori rules for the interpretation of heterogeneity of results (measured by I2): 0–30% as low. We accepted the authors’ or manufacturers’ classifications of events as asthma-related or non–asthma-related. and total death or intubation. acceptable follow-up of patients receiving study medication (outcome data for the full duration of planned treatment missing for . and updated the search in April 2008. all patients had to be receiving at least some ICS (in studies having more than 2 treatment groups. we obtained the full manuscript of 234 publications (Figure 1).. theophylline) in addition to ICS. foradil. either as a part of study protocol (study medication) or as a required background therapy. review article/editorial/letter/ protocol rather than original article (26 articles). In the univariable analysis.. quality of life data. including systematic reviews. LABA and ICS could be delivered through single or through separate devices. Therefore. and fluticasone propionate/salmeterol xinafoate).aspx under formoterol and budesonide/formoterol. combination/or drug interactions/or drug combinations. or as a nonstudy background medication. In choosing the appropriateness of combining data.) (24 articles). performed using a t test. Studies with no events were excluded in all analyses. College Station. use of data for multiple publication from one study (usually in the form of additional economic analysis.30% for 3 mo to . reconciling differences by consensus. Cochrane Collaboration. Of those. when explicit data were not available. use of LABA in both groups (10 articles).B. total nonfatal hospitalization. those studies were classified as using increased dose of ICS in order to avoid double counting of LABA-exposed patients. but included: not all participating patients received ICS (37 articles). In each case. TX). a priori. formoterol or salmeterol.20% of patients taking LABA in trials <3 mo long.1 yr long. sought from manufacturers. . we asked corresponding authors to provide information regarding the outcomes of interest and clarification of selected methodological details (concealment of randomization. asthma-related nonfatal SAE. allowing only one outcome in a given category per patient. glucocorticoids/or adrenal cortex hormones/or budesonide/or inhaled corticosteroid. The data available in published papers were in most cases sufficient to decide about inclusion or exclusion of primary studies in the analysis. we assumed that patients who did not complete the total duration of follow-up for a given study received medication assigned by randomization for 50% of the study duration (i. we analyzed the number of patients with a given outcome. formoterol). Data Extraction Two reviewers independently extracted data from the articles and manufacturers’ documents. SAE was defined in the spirit of the International Conference of Harmonization of technical requirements for registration of pharmaceuticals for human use as ‘‘. oxis. .’’ (14). we asked manufacturers of LABAs to indicate all primary studies fulfilling our criteria but not previously identified. Because we anticipated difficulties reaching some authors of older studies.uk/medicinelist.e. We chose 0.L.asp under salmeterol. For the estimation of number of patient-years on LABA treatment. .co. Statistical Analysis The data were analyzed using RevMan 4. asthma-related death or intubation. duration less than 12 weeks (16 articles). 13). after identification of studies fulfilling eligibility criteria. or results in persistent or significant disability/incapacity.10. We designated studies that used different ICS in LABA and control groups as ‘‘similar ICS dose’’ or ‘‘increased ICS dose’’ on the basis of the following: 125 mg fluticasone 5 200 mg budesonide 5 250 mg beclomethasone 5 400 mg triamcinolone (5. We decided. and use of ICS as part of study medications in single device with LABA.402 titles and abstracts identified during the primary search. Oxford. We excluded studies in which control patients received regular LABA or regular short-acting b agonist (SABA). Search Strategy—Identification of Studies We conducted two independent searches of MEDLINE. ACPJC. Intervention Group The intervention group consisted of individuals using LABA regularly in addition to ICS. fluticasone propionate.gsk. provided another strategy for study identification. we also asked study sponsors for the same information. we included patients in groups mandated to receive some ICS). 95–100% do not aggregate. pediatric population (16 articles). total nonfatal SAE. and an additional 17 identified by manufacturers of the drugs under investigation. and Cochrane (Central) databases from 1966 to mid-2006. the criterion for statistical significance for each of the above analyses. bronchodilator agents/or adrenergic b-agonists/or b2-agonist. EMBASE. funding source). http://ctr. to restrict formal statistical analyses to variables in which six or more events occurred. 30–80% as moderate and worthy of investigation. 63 publications describing 65 studies were eligible (20 publications involving formoterol and 43 publications describing 45 studies involving salmeterol). drug therapy. The terms used included: asthma. RESULTS Of 1.com/article/511012. and patients could be receiving ICS as part of study medication or as nonstudy treatment required by the study protocol. was set a priori at an a of 0. in situations where data for both subgroups were to be used in one analysis. Studies with two control groups taking different ICS doses were considered in principle as two studies when data in such subgroups of patients were available.

ICS doses were similar (five studies were counted in both categories. one study finished. Mejza. not using LABA in all patients in one group (three articles).111 taking formoterol) and provided observation of over 4. Authors and sponsors reported all studies as randomized with concealment of allocation and double blinding. but not yet published. as those studies had two control groups). Studies Using Formoterol control group than in those taking formoterol. For one study. see online supplement).: The Safety of Long-Acting b-Agonists 1011 Figure 1. We found no case of discrepancy in number of deaths or intubations reported among the published data compared with information from sponsors or information from authors. In one of those studies. in 24. SABA 5 short-acting b-agonists.100 patient-years in the salmeterol groups. ICS 5 inhaled corticosteroid. we were unable to obtain full sets of data from groups of patients using 100 mg of salmeterol twice a day (19. Only one additional publication was identified during an update of the manuscript in April 2008 (2007 Corren. in two cases. see online supplement). as are the details about included studies. in the primary articles describing the results of those studies (16–20). COPD 5 chronic obstructive pulmonary disease. and seven used higher doses of ICS in the Of the 43 studies dealing with salmeterol—all sponsored by Glaxo Wellcome or GlaxoSmithKline or its subsidiary (Allen and Hanbury’s Ltd)—24 used higher doses of ICS in the control group than in the LABA group. inclusion of patients with chronic obstructive pulmonary disease (three articles). These publications are listed in the online supplement. . either in a peer-reviewed journal or on the Clinical Trial Register maintained by the manufacturer. when reviewing safety. As we were not able to obtain complete data. in all cases. LABA 5 long-acting b-agonist.Jaeschke. All these studies used concealed randomization procedures. there was no record of deaths or intubations. Thus. we were unable to obtain full data from five sources and data dealing with one subgroup from one source: no final response to the request for full data (16–18). 20). These studies included 16. All discrepancies concerning frequency of hospitalizations or SAE involved no more than one event per study group and/or one patient in the denominator for a given group. Of note. et al. and comparison of LABA with SABA (one article). we excluded children below 12 years of age (stratified at randomization. However. study label ‘‘2005 O’Byrne’’). patients receiving study medication (six articles). the authors of primary reports of those studies. a group of external reviewers. those studies were not included in the analyses. O’Byrne. without knowledge of patients’ group assignment.928 participants (8.599 taking salmeterol) and provided observations of over 4. The data in this figure refer to the original search completed in 2006. We included 19 studies using formoterol that were sponsored by AstraZeneca. and. Studies Using Salmeterol Formoterol (AstraZeneca-sponsored studies. Study selection. In addition. we have analyzed data from 62 studies described in 60 publications. did not indicate either death or intubation as events in the study. the dose was unchanged in comparison to formoterol group (17). In 2007. The updated search in April 2008 yielded one additional eligible study. Among those. the dose of ICS in the control group was increased (16). in the second.473 participants (7. This group of studies included 12. Formoterol (other sponsors and manufacturers).100 patient-years in formoterol groups. assignment of ‘‘asthma-related’’ to an event was done without knowledge of treatment used. Two studies using formoterol fumarate (Foradil) were sponsored by Novartis or its predecessor (Ciba-Geigy). 12 used similar doses of ICS in both groups.

OR 5 odds ratio. In 31 studies. 1.24) 1. to explain the small degree of heterogeneity that existed. for asthma-related hospitalization (Figure 2).06–4. for asthma-related SAEs.26 (0. Considering all 62 studies.85–1.. and of combined asthma-related deaths and life-threatening experiences (RR.31) 1. In only two cases did we find P values close to the prespecified threshold of 0. including 8.6. controlled trials. the univariable analysis for the test of interaction related to the two formulations (i.41). similarity of ICS dose in the LABA and control groups.30 (0.431 patients taking long-acting b-agonist and ICS (over 4.372 patients.62–2. in almost all cases.401 patients and providing over 8.4. 1. the univariable analysis for the test of interaction related to the two formulations resulted in a P value of 0. In multivariable analyses.1.35) — 1. of Patients with Events No. 0. who reported increased risk of respiratory-related death (relative risk [RR]. 10%).75. .03) 0.26 (95% CI. Considerations regarding the potential mechanisms of these TABLE 2.03) and asthma-related SAEs (mostly hospitalizations. no more than one event per study). 1. and SAE).58–2. Individual study results were largely consistent for all outcomes (tests for heterogeneity while using RevMan had P values not lower than 0.41–1.53–1. one with similar and the other with increased dose of ICS.34). asthma-related deaths (RR.3) (3).54–1. 0. including 15.000 patient-years) and 13. 4.05) 0. We present analyses of data from all 62 studies (Table 1). 0. A subsequent systematic review and metaanalysis largely replicated those findings.06 (0.01–2.37.58–2.11) 1. Effects of Treatment—Salmeterol and Formoterol Studies Combined TABLE 1. each for several outcomes) failed. there were three asthma-related deaths and two asthma-related nonfatal intubations (all in LABA groups.54–3. For total mortality. 95% CI. the P value for the test of interaction related to formulation was 0. 95% CI. Intervention and control groups received similar doses of ICS in 36 studies (15. Second. . 0.74).75 (0. 0.91–1.941 patients taking ICS without LABA.74. 2. This con- For definition of abbreviations.07 for asthma-related SAE and 0. 95% CI.16.1012 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008 adjudicated all events (death. of Patients with Events No. including 29.71. see Table 1. This result raises the possibility that formoterol may yield more favorable effects than salmeterol on asthma-related hospitalization. SAFETY OF LONG-ACTING b-AGONIST WITH INHALED CORTICOSTEROIDS VERSUS INHALED CORTICOSTEROIDS ALONE No. Data from 36 studies in which all patients received a similar dose of ICS (Table 2) showed a similar pattern.89) associated with the use of salmeterol. of Studies (LABA 1 ICS/ with Events ICS Alone) 3 2 5 34 37 13 4 15 54 54 3/0 2/0 5/0 66/77 73/83 14/8 3/2 17/10 385/315 433/353 We included 62 randomized.54–1.61) 1.74 (0 0. and from 36 studies using similar doses of ICS in both groups (Table 2).05 (0.000 patient-years on LABA). again raising the possibility of a more favorable effect of formoterol than salmeterol. .6–4.13.04 (0. 2.30. 95% CI.25–15. 95% confidence [CI]. nonfatal intubation.66 (0. Exploration of Heterogeneity Outcome Asthma-related mortality Asthma-related nonfatal intubation Asthma-related nonfatal intubation or death Asthma-related nonfatal hospitalization Asthma-related nonfatal SAE Total mortality Total nonfatal intubation and ventilation Total nonfatal intubation or death Total nonfatal hospitalization Total nonfatal SAE OR (95% CI) — — — 0.06) 1. LABA 5 long-acting b-agonist. and also recorded significant increase in the risk of asthma-related hospitalization (OR. SAFETY OF LONG-ACTING b-AGONIST WITH INHALED CORTICOSTEROIDS VERSUS INHALED CORTICOSTEROIDS ALONE IN PATIENTS ON SIMILAR DOSES OF INHALED CORTICOSTEROIDS No. harmful effects in clinical trials of asthma did not show an increased risk for hospitalizations or SAEs.03).05 (0. hospitalization.74) — 1.06. First. based on 14 deaths in LABA groups and eight deaths in control groups (Figure 3).27 (0.53–1. The OR for total mortality was 1. because of the very low frequency of these events. respectively) were too infrequent to analyze. Data are from 62 studies.82.44–1. 95% CI. ICS 5 inhaled corticosteroid.691 patients taking ICS without LABA. Data are from 36 studies in which all patients were on similar doses of ICS. There were no statistically significant differences between groups in asthma-related hospitalizations (Figure 2) (odds ratio [OR]. 1.53–3.91–1. I2 . and the mode of drug delivery investigated.000 patient-years) and 6. Asthmarelated deaths (two deaths in studies using formoterol and one in studies using salmeterol) and asthma-related intubation and ventilation (none and two. the dose of ICS in the ICS-only group was higher than in the LABA group (14.22) Definition of abbreviations: CI 5 confidence interval.710 patients taking LABA and ICS (over 8.34 (0. the P value for the effect of drug was 0.200 patient-years of observation among patients receiving LABA. testing the hypothesis that the effect of formoterol differs from the effect of salmeterol) resulted in a P value of 0. Five studies had two control groups. SAE 5 serious adverse event. whereas the relative effect on asthma-related mortality and asthma-related intubation and ventilation could not be assessed. 1.27) DISCUSSION This metaanalysis of the effect of LABAs in combination with ICS on serious. trasts with the report of Nelson and colleagues (2). OR. Examination of the a priori hypotheses to explore the heterogeneity that was present (type of drug.200 patient-years on LABA).68 (0.e. of Studies (LABA 1 ICS/ with Events ICS Alone) 2 1 3 18 19 10 2 11 29 29 2/0 1/0 3/0 32/42 37/45 10/4 1/1 11/5 191/161 213/180 Outcome Asthma-related mortality Asthma-related nonfatal intubation Asthma-related nonfatal intubation or death Asthma-related nonfatal hospitalization Asthma-related nonfatal SAE Total mortality Total nonfatal intubation and ventilation Total nonfatal intubation or death Total nonfatal hospitalization Total nonfatal SAE OR (95% CI) — — — 0.85–1.03) 1.4.409 patients.12 for asthma-related hospitalizations.

Our study did not confirm those findings in a setting mandating use of ICS. and induction of bronchodilator subsensitivity (22. we did not find a significant increase in deaths or life-threatening events. Effects of LABA on asthmarelated hospitalizations among patients using ICS (only studies with at least one event are presented). but nevertheless require exploration. Mejza. 23). we have considered a different population: patients who were receiving ICS concomitantly with LABAs. see online supplement) common to the 19 studies in the previous publication by Salpeter (3) and the 62 studies in the current metaanalysis. as the total number of patientyears exposure to LABA was similar (z8. Caution in interpretation is required because of indirect comparisons.Jaeschke.: The Safety of Long-Acting b-Agonists 1013 Figure 2. Table 3 illustrates some differences in the results of this and the previous systematic review. because patients receiving LABAs experienced the few asthma-related deaths . delaying awareness of worsening asthma (21). Our results do not. Indeed. O’Byrne. asthma-related deaths—and asthmarelated intubations associated with LABA use. The differences in the results from previous metaanalysis are thus not entirely unexpected. No recently published asthma treatment guidelines recommend LABA use without ICS (5.000 patient-years in both data sets). et al. 6). and included many patients who were not taking ICSs. there is only a single study (2002 Price. Although they are effective and long-lasting bronchodilators. The studies that found increased deaths and hospitalizations with use of LABAs did not mandate ICS use. LABAs are not known to have clinically significant antiinflammatory effects in the airways. Hence. however. Decreased LABA exposure cannot explain the substantially smaller number of asthma-related deaths and intubations experienced by patients in the studies that we examined compared with the previous metaanalyses. adverse effects included masking of increasing inflammation. In our analysis of trials in which all patients used ICS. exclude a relative increase in deaths—in particular.

in which ICS use was not required in all patients (10). is small. Nevertheless. whereas the majority of studies in our metaanalysis required patients to be symptomatic despite treatment with ICS. Our findings contrast with the recent Cochrane Review of 62.710 patients receiving LABA).14.630 patients in trials comparing salmeterol with placebo or salbutamol. 1. and suggest the possibility of benefit of LABA used with ICS on these outcomes. and the mean PEF was 83. Furthermore. there was a significant increase in nonfatal SAEs related to use of salmeterol (OR. All these factors make it unlikely that underlying asthma severity was markedly higher in the study population of Nelson and colleagues. OR 5 odds ratio. such as those participating in these trials. Less severe underlying asthma in patients enrolled in LABA comparison studies in which ICS was mandated when compared with those in which ICS was not mandated could explain the difference in results. The frequency of asthma-related intubations appears approximately 10-fold lower among patients included in the current metaanalysis when compared with that of Salpeter and colleagues (3). such an explanation seems unlikely: The mean age of patients enrolled in the study by Nelson and colleagues (2) was 39.1014 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 178 2008 Figure 3. Such factors might include less careful management and more overuse of LABA and SABA in the less rigorously controlled .1 years (in the midrange for the studies included in our metaanalysis). the main inclusion criteria of Nelson and colleagues were clinical diagnosis of asthma and receiving asthma prescription medication. and was thus a cause of different results. Effects of LABA on total mortality among patients using ICS (only studies with at least one event are presented). Our results show that the absolute increase in LABA-associated deaths or intubations from asthma in populations.28). and intubations that did occur. if it exists at all (3 deaths and 2 nonfatal intubations in 15. CI 5 confidence interval. A third possibility is that other differences between the randomized trials that we examined (phase-3 studies) and the studies suggesting an increased mortality with LABA (postmarketing or phase-4 studies) may explain the varying results. 95% CI.01– 1. 1.9% of predicted. In those studies. our results exclude an important increase in asthmarelated hospitalizations or SAEs.

Nelson HS. He received honoraria from Merck Frosst. our systematic review evaluated the safety of adding LABA to ICS.com/ 6. one may postulate that the prognosis of asthma and the potential effects of LABA taken regularly are different among patients taking and those not taking concomitant ICS. O’Byrne. 27) relates to: focusing on specific questions not examined before in detail.306:1034– 1037. Boehringer Ingelheim.R. 2007]. Salpeter EE. and holds industrysponsored grants from AstraZeneca. and the magnitude of the difference was relatively large (Figure 2). received honoraria for lectures from AstraZeneca. and cooperation of the main manufacturers of LABA (AstraZeneca and GlaxoSmithKline) with disclosure of their data. those concerned about the remaining uncertainty (and their physicians) may well prefer increasing the dose of ICS instead of adding LABA. Mejza. GSK. GSK.T. and Schering Plough.J. however. Boehringer. Meta-analysis: effect of long-acting b-agonists on severe asthma exacerbations and asthma-related deaths. J. The added value of our analysis in comparison with related clinical questions examined by others (8–10. SMART Study Group. Our analysis. Martinez FD. and is currently acting as a consultant and received honoraria from Eli Lilly Canada Inc. Global Initiative for Asthma Web site [accessed December 13. however. a larger set of high-quality studies for which data were sought and obtained through contact with both authors (some studies) and manufacturers (all studies). Thus. Buckley NS. Lily. and GlaxoSmithKline (GSK). Chiesi Foundation. Additional limitations are our exclusion of children less than 12 years of age. and were conducted in different time periods and locations. AstraZeneca. J. We have not.ginasthma. Finally. P. Ono Pharma. received an honorarium from GSK. and Pfizer Inc. and our failure to explore similarities or differences in effect in this subpopulation. Furthermore. Roche. the P value of the test for interaction is unimpressive (0. N Engl J Med 2005. received funding from the following pharmaceutical companies to carry out research projects: Lotte and John Hecht Foundation. Conflict of Interest Statement: R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F. Hall J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.L.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Available from: http://www.S. GSK. H.. 2. Bristol-Myers Squibb. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. patients did not experience hospitalizations in different proportion of studies (in over 50% of studies using salmeterol. The main limitation of our study is that we were unable to fully explore alternative explanations of the difference in death and intubation rates in studies mandating concomitant ICS use and those that did not. Thus. The extent to which our results are reassuring regarding the use of LABA in patients receiving ICS may differ according to the perspective of physician. Biolipox. Boehringer Ingelheim. and Blood Institute. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Similar reasoning applies to the indirect comparisons of SAEs. Chiesi. excluded the possibility of a relative increase in deaths in patients receiving LABA who are also using ICS.B. Palmer J. has received research funding and/or an honorarium for lectures and consultations from AstraZeneca. and under 25% of studies using formoterol). We have extended previous reports that addition of LABA has no detrimental effect on the number of asthmarelated hospitalizations and SAEs in patients receiving ICS (8. COMPARISON OF NUMBER OF EVENTS OBSERVED IN THE METAANALYSIS BY SALPETER AND COLLEAGUES (3) AND IN THE CURRENT ARTICLE* No. The effect. and Topigen Inc. Chest 2006. a possible increase that may be important at a population level or to individual patients. any true underlying increase in mortality would be important. patient. and holds a chair in respiratory epidemiology jointly endowed by AstraZeneca and McMaster University.N. On the other hand. has been on advisory boards for AstraZeneca. Pfizer. Dorinsky PM. M. Salpeter SR. References 1. 2007]. Available from: http://www. Ann Intern Med 2006.nih. Pfizer.C. among patients with asthma that is not well controlled with low doses of ICS. One cannot disprove this hypothesis with certainty. Weiss ST. Topingen. if it exists at all. and his research group has a patent on a sputum filtration device. Guidelines for the diagnosis and management of asthma (EPR-3).353:2637–2639. 4. Bleecker ER. Medimmune. BMJ 1993. received grants over the last 5 years from AstraZeneca. Sepracor Inc...: The Safety of Long-Acting b-Agonists TABLE 3.B.12 for asthma-related hospitalizations). G. Exploration of factors such as socioeconomic status or race would require both measurement of those variables and access to individual patient data in studies mandating and not mandating concomitant ICS use. W. had too few of the most severe events to make definitive statements about the relative effects on deaths and intubations. Merck. 9). Merck.M. and has received lecture fees from these pharmaceutical companies.144:904–912. Altana. P. given the number of patients using LABA worldwide. and UnitedBioSource for development or consulting regarding quality-of-life instruments for chronic respiratory diseases. 2007 [accessed December 13. 5. Our exploration of heterogeneity suggests that formoterol may result in fewer asthma-related hospitalizations and asthmarelated SAEs than salmeterol. and two investigator-initiated grants from a FirestonePharmaceutical Industry Strategic Collaboration. although the accompanying observation of lower number of asthma-related hospitalizations speaks against it.O.gov/guidelines/asthma/ . 26. * Similar number of patient-year observations on LABA (z8. Ormiston TM. holds investigator-initiated grants from GSK Canada.129:15–26. Yancey SW.G. including those that are the subject of this systematic review. and policy maker. In summary. and Resistencia. 25). both asthma-related and total. These factors support an inference of a real difference between drugs. The hypothesis was one of only three a priori hypotheses that we examined.J. and travel support from Boehringer Ingelheim and GSK. and Altana Pharma. On the other hand. Fuller R. Nycomed. National Heart. will be conducting consulting work for GSK in the near future. This hypothesis suggests that ICS provides both protection against severe asthma deterioration and protection against the potential harmful actions of LABA. the studies represent indirect rather than head-tohead comparison. 3. is a journal editor and receives a salary from a clinical journal (Medycyna Praktyczna) in which various drugs are advertised. GSK. the inference that the drugs have different effects on hospitalization is weak. and Wyeth. and is a deputy editor of a medical journal (Medcyna Praktyczna) funded in part by industry advertisement. Nycomed. obtaining and including complete data on mortality and respiratory failure requiring intubation. or as lecture fees related to the methodology of evidencebased practice guideline development and/or research methodology. J. Castle W. trials. is smaller than can be inferred from the analysis of Salpeter and colleagues (3). et al.000). Merck Sharp & Dohme. GSK. Safety of long-acting b-agonists—an urgent need to clear the air.M. Lung. as well as from Chiesi. and did not reveal convincing evidence of harm. Biolipox. and only a direct head-to-head comparison may establish whether there is a true difference (24.nhlbi. L. of Patients among Included Studies (Reference) Outcome LABA groups Asthma-related deaths Nonfatal asthma-related intubation Control groups Asthma-related mortality Nonfatal asthma-related intubation Salpeter and Colleagues (3) 15 (13 in Reference 2) 35 (24 in Reference 2) 3 (3 in Reference 2) 22 (19 in Reference 2) 1015 Current Study 3 2 0 0 Definition of abbreviation: LABA 5 long-acting b-agonist. including manufacturers of the drugs that are the subject of this review. received research grants and fees and/or honoraria from AstraZeneca. and Merck Frosst Canada. In addition.Jaeschke.

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