Rationale: Inhaled long-acting β-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 β-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 asthma-related 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.
There are data suggesting that long-acting β-agonists (LABAs) increase mortality in patients with asthma. However, this issue has not been optimally evaluated in patients receiving concomitant corticosteroids.
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).
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 care-givers; acceptable follow-up of patients receiving study medication (outcome data for the full duration of planned treatment missing for <20% of patients taking LABA in trials ≤3 mo long, <30% for 3 mo to <1 yr long, <40% for ≥1 yr). Eligible studies involved patients with asthma (excluding children younger than 12 yr); all patients had to be receiving at least some ICS (in studies having more than 2 treatment groups, we included patients in groups mandated to receive some ICS).
The intervention group consisted of individuals using LABA regularly in addition to ICS. LABA and ICS could be delivered through single or through separate devices, and patients could be receiving ICS as part of study medication or as nonstudy treatment required by the study protocol.
Eligibility required that all patients in the control group used ICS, either as a part of study protocol (study medication) or as a required background therapy. The dose of ICS need not have been the same in the intervention and control groups. 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; in situations where data for both subgroups were to be used in one analysis, those studies were classified as using increased dose of ICS in order to avoid double counting of LABA-exposed patients. We excluded studies in which control patients received regular LABA or regular short-acting β agonist (SABA). We also excluded studies in which the control group received another asthma study medication (leukotriene receptor antagonist, theophylline) in addition to ICS. 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 μg fluticasone = 200 μg budesonide = 250 μg beclomethasone = 400 μg triamcinolone (5, 13).
Prespecified outcomes included: asthma-related death; asthma-related nonfatal intubation and ventilation; asthma-related nonfatal hospitalization; asthma-related nonfatal SAE; and death from all causes (total death). SAE was defined in the spirit of the International Conference of Harmonization of technical requirements for registration of pharmaceuticals for human use as “…any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires inpatient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.” (14).
The secondary prespecified outcomes were: total nonfatal intubation and ventilation; total nonfatal hospitalization; total nonfatal SAE; asthma-related death or intubation; and total death or intubation. We accepted the authors' or manufacturers' classifications of events as asthma-related or non–asthma-related.
We conducted two independent searches of MEDLINE, EMBASE, ACPJC, and Cochrane (Central) databases from 1966 to mid-2006, and updated the search in April 2008. The terms used included: asthma; bronchodilator agents/or adrenergic β-agonists/or β2-agonist; formoterol or salmeterol; foradil, serevent, oxis, glucocorticoids/or adrenal cortex hormones/or budesonide/or inhaled corticosteroid; drug therapy, combination/or drug interactions/or drug combinations. Screening of citations of all potentially eligible articles, including systematic reviews, provided another strategy for study identification. We reviewed manufacturers' Web sites listing their studies (http://www.astrazenecaclinicaltrials.com/article/511012.aspx under formoterol and budesonide/formoterol; http://ctr.gsk.co.uk/medicinelist.asp under salmeterol, fluticasone propionate, and fluticasone propionate/salmeterol xinafoate). In addition, we asked manufacturers of LABAs to indicate all primary studies fulfilling our criteria but not previously identified.
Two reviewers (R.J. and J.B., F.M., P.N. or W.L.) screened titles and abstract to identify articles for full review. These same reviewers then evaluated the full text of all articles deemed potentially eligible by either reviewer for final inclusion.
Two reviewers independently extracted data from the articles and manufacturers' documents, reconciling differences by consensus. The data available in published papers were in most cases sufficient to decide about inclusion or exclusion of primary studies in the analysis. Details about the occurrence of outcome of interests were not provided in the majority of the published reports. Therefore, after identification of studies fulfilling eligibility criteria, we asked corresponding authors to provide information regarding the outcomes of interest and clarification of selected methodological details (concealment of randomization, blinded assessment and classification of outcomes, blinding of patients and care-givers, funding source). Because we anticipated difficulties reaching some authors of older studies, we also asked study sponsors for the same information. The contact with authors and sponsors was done independently and in parallel. Final data on outcome measures were obtained from published reports, authors, and, in each case, sought from manufacturers. Discrepancies were resolved by contacting the study sponsor.
The data were analyzed using RevMan 4.2 (Cochrane Review Manager, Cochrane Collaboration, Oxford, UK) using the DerSimonian and Laird random effect model (15). Studies with no events were excluded in all analyses. In each case, we analyzed the number of patients with a given outcome, allowing only one outcome in a given category per patient. We decided, a priori, to restrict formal statistical analyses to variables in which six or more events occurred.
In choosing the appropriateness of combining data, we considered the following a priori rules for the interpretation of heterogeneity of results (measured by I2): 0–30% as low; 30–80% as moderate and worthy of investigation; 60–100% as large and worthy of understanding; 95–100% do not aggregate. In addition, 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. formoterol); dose of ICS used in the control group (similar dose of ICS to LABA group or increased dose); and use of ICS as part of study medications in single device with LABA, in separate study devices, or as a nonstudy background medication. These analyses were performed using STATA version 9.2 (StataCorp LP, College Station, TX).
In the univariable analysis, the criterion for statistical significance for each of the above analyses, performed using a t test, was set a priori at an α of 0.10. We chose 0.10 as a threshold P value because we anticipated limited power to this analysis, and did not want to overlook possible explanations of heterogeneity that warranted serious consideration.
For the estimation of number of patient-years on LABA treatment, when explicit data were not available, 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.e., for 12 wk in 24-wk studies).
Of 1,402 titles and abstracts identified during the primary search, and an additional 17 identified by manufacturers of the drugs under investigation, we obtained the full manuscript of 234 publications (Figure 1). Of those, 63 publications describing 65 studies were eligible (20 publications involving formoterol and 43 publications describing 45 studies involving salmeterol).
The reasons for exclusions of studies from the analysis were in most cases multiple, but included: not all participating patients received ICS (37 articles); review article/editorial/letter/protocol rather than original article (26 articles); use of data for multiple publication from one study (usually in the form of additional economic analysis, quality of life data, etc.) (24 articles); crossover design (18 articles); duration less than 12 weeks (16 articles); pediatric population (16 articles); use of LABA in both groups (10 articles); lack of blinding of patients or care-givers (seven articles); excessive missing data for patients receiving study medication (six articles); inclusion of patients with chronic obstructive pulmonary disease (three articles); not using LABA in all patients in one group (three articles); and comparison of LABA with SABA (one article). In addition, 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); one study finished, but not yet published, either in a peer-reviewed journal or on the Clinical Trial Register maintained by the manufacturer; in two cases, we were unable to obtain full sets of data from groups of patients using 100 μg of salmeterol twice a day (19, 20). Of note, in the primary articles describing the results of those studies (16–20), there was no record of deaths or intubations.
Only one additional publication was identified during an update of the manuscript in April 2008 (2007 Corren, see online supplement). Thus, we have analyzed data from 62 studies described in 60 publications. These publications are listed in the online supplement, as are the details about included studies.
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. 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.
We included 19 studies using formoterol that were sponsored by AstraZeneca. Among those, 12 used similar doses of ICS in both groups, and seven used higher doses of ICS in the control group than in those taking formoterol. For one study, we excluded children below 12 years of age (stratified at randomization, study label “2005 O'Byrne”). All these studies used concealed randomization procedures, and, in all cases, assignment of “asthma-related” to an event was done without knowledge of treatment used. This group of studies included 12,473 participants (7,111 taking formoterol) and provided observation of over 4,100 patient-years in formoterol groups.
Two studies using formoterol fumarate (Foradil) were sponsored by Novartis or its predecessor (Ciba-Geigy). In one of those studies, the dose of ICS in the control group was increased (16); in the second, the dose was unchanged in comparison to formoterol group (17). As we were not able to obtain complete data, those studies were not included in the analyses. However, the authors of primary reports of those studies, when reviewing safety, did not indicate either death or intubation as events in the study.
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; in 24, ICS doses were similar (five studies were counted in both categories, as those studies had two control groups). These studies included 16,928 participants (8,599 taking salmeterol) and provided observations of over 4,100 patient-years in the salmeterol groups. Authors and sponsors reported all studies as randomized with concealment of allocation and double blinding. In 2007, a group of external reviewers, without knowledge of patients' group assignment, adjudicated all events (death, nonfatal intubation, hospitalization, and SAE).
We included 62 randomized, controlled trials, including 29,401 patients and providing over 8,200 patient-years of observation among patients receiving LABA. Intervention and control groups received similar doses of ICS in 36 studies (15,372 patients, >4,200 patient-years on LABA). In 31 studies, the dose of ICS in the ICS-only group was higher than in the LABA group (14,409 patients, >4,000 patient-years on LABA). Five studies had two control groups, one with similar and the other with increased dose of ICS. We present analyses of data from all 62 studies (Table 1), and from 36 studies using similar doses of ICS in both groups (Table 2). Considering all 62 studies, there were three asthma-related deaths and two asthma-related nonfatal intubations (all in LABA groups, no more than one event per study). There were no statistically significant differences between groups in asthma-related hospitalizations (Figure 2) (odds ratio [OR], 0.74; 95% confidence [CI], 0.53–1.03) and asthma-related SAEs (mostly hospitalizations; OR, 0.75; 95% CI, 0.54–1.03). The OR for total mortality was 1.26 (95% CI, 0.58–2.74), based on 14 deaths in LABA groups and eight deaths in control groups (Figure 3). Data from 36 studies in which all patients received a similar dose of ICS (Table 2) showed a similar pattern.
No. of Studies with Events
No. of Patients with Events (LABA + ICS/ICS Alone)
OR (95% CI)
|Asthma-related nonfatal intubation||2||2/0||—|
|Asthma-related nonfatal intubation or death||5||5/0||—|
|Asthma-related nonfatal hospitalization||34||66/77||0.74 (0 0.53–1.03)|
|Asthma-related nonfatal SAE||37||73/83||0.75 (0.54–1.03)|
|Total mortality||13||14/8||1.26 (0.58–2.74)|
|Total nonfatal intubation and ventilation||4||3/2||—|
|Total nonfatal intubation or death||15||17/10||1.27 (0.62–2.61)|
|Total nonfatal hospitalization||54||385/315||1.06 (0.91–1.24)|
|Total nonfatal SAE||54||433/353||1.05 (0.91–1.22)|
No. of Studies with Events
No. of Patients with Events (LABA + ICS/ICS Alone)
OR (95% CI)
|Asthma-related nonfatal intubation||1||1/0||—|
|Asthma-related nonfatal intubation or death||3||3/0||—|
|Asthma-related nonfatal hospitalization||18||32/42||0.66 (0.41–1.05)|
|Asthma-related nonfatal SAE||19||37/45||0.68 (0.44–1.06)|
|Total mortality||10||10/4||1.34 (0.53–3.35)|
|Total nonfatal intubation and ventilation||2||1/1||—|
|Total nonfatal intubation or death||11||11/5||1.30 (0.54–3.11)|
|Total nonfatal hospitalization||29||191/161||1.05 (0.85–1.31)|
|Total nonfatal SAE||29||213/180||1.04 (0.85–1.27)|
Individual study results were largely consistent for all outcomes (tests for heterogeneity while using RevMan had P values not lower than 0.30; I2 < 10%).
Examination of the a priori hypotheses to explore the heterogeneity that was present (type of drug, similarity of ICS dose in the LABA and control groups, and the mode of drug delivery investigated, each for several outcomes) failed, in almost all cases, to explain the small degree of heterogeneity that existed. In only two cases did we find P values close to the prespecified threshold of 0.1. First, for asthma-related hospitalization (Figure 2), the univariable analysis for the test of interaction related to the two formulations (i.e., testing the hypothesis that the effect of formoterol differs from the effect of salmeterol) resulted in a P value of 0.13. This result raises the possibility that formoterol may yield more favorable effects than salmeterol on asthma-related hospitalization. Second, for asthma-related SAEs, the univariable analysis for the test of interaction related to the two formulations resulted in a P value of 0.06, again raising the possibility of a more favorable effect of formoterol than salmeterol. In multivariable analyses, the P value for the effect of drug was 0.07 for asthma-related SAE and 0.12 for asthma-related hospitalizations. Asthma-related deaths (two deaths in studies using formoterol and one in studies using salmeterol) and asthma-related intubation and ventilation (none and two, respectively) were too infrequent to analyze. For total mortality, the P value for the test of interaction related to formulation was 0.82.
This metaanalysis of the effect of LABAs in combination with ICS on serious, harmful effects in clinical trials of asthma did not show an increased risk for hospitalizations or SAEs, whereas the relative effect on asthma-related mortality and asthma-related intubation and ventilation could not be assessed, because of the very low frequency of these events. This contrasts with the report of Nelson and colleagues (2), who reported increased risk of respiratory-related death (relative risk [RR], 2.16; 95% CI, 1.06–4.41), asthma-related deaths (RR, 4.37; 95% CI, 1.25–15.34), and of combined asthma-related deaths and life-threatening experiences (RR, 1.71; 95% CI, 1.01–2.89) associated with the use of salmeterol. A subsequent systematic review and metaanalysis largely replicated those findings, and also recorded significant increase in the risk of asthma-related hospitalization (OR, 2.6; 95% CI, 1.6–4.3) (3). Considerations regarding the potential mechanisms of these adverse effects included masking of increasing inflammation, delaying awareness of worsening asthma (21), and induction of bronchodilator subsensitivity (22, 23). Our study did not confirm those findings in a setting mandating use of ICS.
The studies that found increased deaths and hospitalizations with use of LABAs did not mandate ICS use, and included many patients who were not taking ICSs. Although they are effective and long-lasting bronchodilators, LABAs are not known to have clinically significant antiinflammatory effects in the airways. No recently published asthma treatment guidelines recommend LABA use without ICS (5, 6). Hence, we have considered a different population: patients who were receiving ICS concomitantly with LABAs. Indeed, there is only a single study (2002 Price, see online supplement) common to the 19 studies in the previous publication by Salpeter (3) and the 62 studies in the current metaanalysis. The differences in the results from previous metaanalysis are thus not entirely unexpected, but nevertheless require exploration.
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, as the total number of patient-years exposure to LABA was similar (∼8,000 patient-years in both data sets). Table 3 illustrates some differences in the results of this and the previous systematic review. Caution in interpretation is required because of indirect comparisons.
No. of Patients among Included Studies (Reference)
|Outcome||Salpeter and Colleagues (3)|
|Asthma-related deaths||15 (13 in Reference 2)||3|
|Nonfatal asthma-related intubation||35 (24 in Reference 2)||2|
|Asthma-related mortality||3 (3 in Reference 2)||0|
| Nonfatal asthma-related intubation||22 (19 in Reference 2)||0|
In our analysis of trials in which all patients used ICS, we did not find a significant increase in deaths or life-threatening events. Our results do not, however, exclude a relative increase in deaths—in particular, asthma-related deaths—and asthma-related intubations associated with LABA use, because patients receiving LABAs experienced the few asthma-related deaths and intubations that did occur. Our results show that the absolute increase in LABA-associated deaths or intubations from asthma in populations, such as those participating in these trials, is small, if it exists at all (3 deaths and 2 nonfatal intubations in 15,710 patients receiving LABA). 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). Furthermore, our results exclude an important increase in asthma-related hospitalizations or SAEs, and suggest the possibility of benefit of LABA used with ICS on these outcomes.
Our findings contrast with the recent Cochrane Review of 62,630 patients in trials comparing salmeterol with placebo or salbutamol, in which ICS use was not required in all patients (10). In those studies, there was a significant increase in nonfatal SAEs related to use of salmeterol (OR, 1.14; 95% CI, 1.01–1.28).
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. Nevertheless, such an explanation seems unlikely: The mean age of patients enrolled in the study by Nelson and colleagues (2) was 39.1 years (in the midrange for the studies included in our metaanalysis), and the mean PEF was 83.9% of predicted; the main inclusion criteria of Nelson and colleagues were clinical diagnosis of asthma and receiving asthma prescription medication, whereas the majority of studies in our metaanalysis required patients to be symptomatic despite treatment with ICS. All these factors make it unlikely that underlying asthma severity was markedly higher in the study population of Nelson and colleagues, and was thus a cause of different results.
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. Such factors might include less careful management and more overuse of LABA and SABA in the less rigorously controlled trials. One cannot disprove this hypothesis with certainty, although the accompanying observation of lower number of asthma-related hospitalizations speaks against it.
Finally, 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. This hypothesis suggests that ICS provides both protection against severe asthma deterioration and protection against the potential harmful actions of LABA.
Our analysis, however, had too few of the most severe events to make definitive statements about the relative effects on deaths and intubations. The effect, if it exists at all, is smaller than can be inferred from the analysis of Salpeter and colleagues (3). On the other hand, given the number of patients using LABA worldwide, any true underlying increase in mortality would be important. Thus, among patients with asthma that is not well controlled with low doses of ICS, those concerned about the remaining uncertainty (and their physicians) may well prefer increasing the dose of ICS instead of adding LABA.
Our exploration of heterogeneity suggests that formoterol may result in fewer asthma-related hospitalizations and asthma-related SAEs than salmeterol. The hypothesis was one of only three a priori hypotheses that we examined, and the magnitude of the difference was relatively large (Figure 2). These factors support an inference of a real difference between drugs. On the other hand, the studies represent indirect rather than head-to-head comparison, and were conducted in different time periods and locations. In addition, patients did not experience hospitalizations in different proportion of studies (in over 50% of studies using salmeterol, and under 25% of studies using formoterol). Furthermore, the P value of the test for interaction is unimpressive (0.12 for asthma-related hospitalizations). Thus, the inference that the drugs have different effects on hospitalization is weak, and only a direct head-to-head comparison may establish whether there is a true difference (24, 25). Similar reasoning applies to the indirect comparisons of SAEs.
The added value of our analysis in comparison with related clinical questions examined by others (8–10, 26, 27) relates to: focusing on specific questions not examined before in detail; 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); obtaining and including complete data on mortality and respiratory failure requiring intubation, both asthma-related and total; and cooperation of the main manufacturers of LABA (AstraZeneca and GlaxoSmithKline) with disclosure of their data.
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. 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. Additional limitations are our exclusion of children less than 12 years of age, and our failure to explore similarities or differences in effect in this subpopulation.
In summary, our systematic review evaluated the safety of adding LABA to ICS, and did not reveal convincing evidence of harm. We have extended previous reports that addition of LABA has no detrimental effect on the number of asthma-related hospitalizations and SAEs in patients receiving ICS (8, 9). We have not, however, excluded the possibility of a relative increase in deaths in patients receiving LABA who are also using ICS, a possible increase that may be important at a population level or to individual patients. 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, patient, and policy maker.
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