The safety of formoterol among patients with asthma using inhaled corticosteroids. Systematic review and meta‑analysis

Jaeschke, Roman; O’Byrne, Paul M.; Nair, Parameswaran; Mejza, Filip; Leśniak, Wiktoria; Brožek, Jan; Thabane, Lehana; Ji, Cheng; Bała, Małgorzata M; Sears, Malcolm R.; Guyatt, Gordon

doi:10.20452/pamw.508

Cited by 20 publications

(17 citation statements)

References 22 publications

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“…However, the absolute rate of asthma mortality is low (0.48 per 1,000 treatment-yrs). The significantly lower risk found for asthma SAEs for formoterol versus non-LABA added to ICS treatment is similar to the findings of a recent meta-analysis by JAESCHKE et al [31].…”

Section: Discussionsupporting

confidence: 88%

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Sears

Ottosson²,

Radner³

et al. 2009

European Respiratory Journal

101

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The safety of long-acting b 2 -agonist (LABA) treatment in asthma has been questioned following reported increased respiratory deaths when salmeterol was added to usual pharmacotherapy. The aim of this study was to examine whether asthma, cardiac or allcause mortality and morbidity were increased with formoterol use.The analysis included all AstraZeneca randomised controlled parallel-group asthma trials of 3-12-months duration involving formoterol. Risks associated with formoterol use compared with non-LABA treatment, overall and in combination with inhaled corticosteroids (ICS), were assessed using an intention-to-treat analysis of the rates and rate ratios of deaths and serious adverse events (SAEs). The main objective of this study was to compare asthma-related mortality in patients using formoterol and those not using formoterol.There were eight asthma-related deaths (0.34 per 1,000 person-yrs) among 49,906 formoterolrandomised patients (92% using ICS), and two (0.22 per 1,000 person-yrs) among 18,098 patients (83% using ICS) not randomised to formoterol, which was nonsignificant. Asthma-related SAEs (.90% of which were hospitalisations) were significantly fewer among formoterol-randomised patients (0.75 versus 1.10%). There was no increase in asthma-related SAEs with increased daily doses of formoterol (9, 18 or 36 mg). There was no significant difference in cardiac mortality or noncardiac nonasthma-related mortality in formoterol-randomised compared to non-LABAtreated patients. All-cause mortality was similar. In the data set in which all subjects were prescribed ICS at baseline, there were seven asthma-related deaths (0.32 per 1,000 person-yrs) among 46,003 formoterol-randomised patients and one (0.14 per 1,000 person-yrs) among 13,905 patients not randomised to formoterol, which was also nonsignificant.There were few asthma-related or cardiac-related deaths among patients randomised to formoterol, and all differences were nonsignificant compared with non-long-acting b 2 -agonistrandomised patients. However, despite data on .68,000 patients, the power was insufficient to conclude that there was no increased mortality with formoterol. Cardiac-related serious adverse events were not increased, and asthma-related serious adverse events were significantly reduced with formoterol.

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Section: Discussionsupporting

confidence: 88%

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Sears

Ottosson²,

Radner³

et al. 2009

European Respiratory Journal

101

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“…Several other meta-analyses have been performed to assess the safety of formoterol with or without concomitant ICS in adults and children (12)(13)(14) and the lower risk of asthma-related SAEs reported in the Cates review concur with the Jaeschke (12) and Sears meta-analyses (13). Jaeschke et al reviewed 18 trials in adolescents and adults, and found no evidence of harm associated with the use of formoterol in combination with ICS compared to ICS alone at the same or higher dose (12).…”

mentioning

confidence: 76%

“…Jaeschke et al reviewed 18 trials in adolescents and adults, and found no evidence of harm associated with the use of formoterol in combination with ICS compared to ICS alone at the same or higher dose (12). However, the frequency of asthmarelated deaths and asthma-related SAEs, reflected in the need for endotracheal intubation, was too small to draw firm conclusions (12). In the Sears review, SAEs were lower in those randomized to formoterol with or without concomitant ICS in comparison to non-LABA treatments.…”

mentioning

confidence: 99%

Commentary on ‘Regular treatment with formoterol and inhaled steroids for chronic persistent asthma: serious adverse events’

Elkout

Helms

2010

Evid.‐Based Child Health

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This is a commentary on a Cochrane review, published in this issue of EBCH, first published as: Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. The balance of safety and efficacy of long term long acting beta agonists (LABAs) in combination with inhaled corticosteroids (ICS) in the management of persistent asthma continues to be a subject of intense interest and the recent systematic review and metaanalysis by Cates et al. provides reassurance while raising questions about this treatment option (1). The review includes studies that randomized symptomatic children and adults to either twice daily formoterol and ICS, or to the same dose of ICS. Four deaths were noted in the 8,028 included adults (1 asthmarelated), all in those randomized to formoterol and ICS; no deaths occurred in the 2788 included children aged 6-11 years. As might be expected with only one asthma-related death in a large exposed population, this difference was not statistically significant, a conclusion also supported by the lack of evidence of any increase in serious adverse events (SAEs) with even a decreased risk of asthma-related SAEs in adults randomized to formoterol and ICS. However, in children, a small non-significant increase in SAEs was observed in those randomized to formoterol and ICS.Concerns regarding LABA were raised soon after their introduction in 1990s and confirmed in two large prospective studies (2-3) which reported an increased risk of deaths associated with salmeterol. No such evidence was available at that time for formoterol (4). Although both available LABAs are potent long acting bronchodilators, the more rapid onset of action of formoterol has subsequently resulted in its license extension as an asthma reliever in addition to asthma prophylaxis (5-6). Asthma management guidelines *Correspondence to: Peter J. Helms, E-mail: p.j.helms@abdn.ac.uk recommend that LABAs should not be used without concomitant ICS (7-9), and previous studies and meta-analyses have confirmed increased risks associated with LABA monotherapy (10-11). However, it is unclear to what extent concomitant ICS protect against fatal and non fatal SAEs, as addressed in the Cochrane review.Several other meta-analyses have been performed to assess the safety of formoterol with or without concomitant ICS in adults and children (12-14) and the lower risk of asthma-related SAEs reported in the Cates review concur with the Jaeschke (12) and Sears meta-analyses (13). Jaeschke et al. reviewed 18 trials in adolescents and adults, and found no evidence of harm associated with the use of formoterol in combination with ICS compared to ICS alone at the same or higher dose (12). However, the frequency of asthmarelated deaths and asthma-related SAEs, reflected in the need for endotracheal intubation, was too small to draw firm conclusions (12). In the Sears review, SAEs were lower in those randomized to formoterol with or without concomitant ICS in comparison to non-LABA treatments....

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“…A previous case-control study observed no adverse impact of medium-to long-term use of LABAs on mortality (56). A meta-analysis including 18 doubleblind studies (17 of which were not included in the Salpeter meta-analysis) and 12 229 participants, where formoterol was used in combination with an ICS, reported a 29% reduction in hospital admissions and a 31% reduction in asthma-related serious adverse events with formoterol plus ICS compared with ICS alone (57). Another analysis of a large number of studies of formoterol reported that the use of this medication in Figure 4.…”

Section: Safety Of Budesonide/formoterol Maintenance and Reliever Thementioning

confidence: 97%

Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma

Humbert

Andersson

Buhl³

2008

Allergy

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The Global Initiative for Asthma (GINA) guidelines aim at improving asthma control and preventing future risk. For patients with moderate to severe asthma an inhaled corticosteroid (ICS) or an ICS/long‐acting β2‐agonist (LABA) combination with a short‐acting β2‐agonist (SABA) as reliever is recommended. Despite the availability of effective maintenance therapies, a large proportion of patients still fail to achieve guideline‐defined asthma control, and overuse of SABA reliever medication at the expense of ICS is commonly observed. New simplified treatment approaches may offer a solution and assist physicians to achieve overall asthma control. One such treatment approach, which is recommended in the GINA guidelines, is budesonide/formoterol for both maintenance and reliever therapy. This treatment strategy significantly reduces the rate of severe asthma exacerbations compared with ICS/LABA plus SABA and achieves equivalent daily symptom control compared with higher doses of ICS/LABA plus separate SABA for relief. These benefits are achieved at a lower overall steroid load, and budesonide/formoterol maintenance and reliever therapy is well tolerated in patients with moderate to severe asthma. This review discusses current asthma management in patients with moderate to severe disease and examines the evidence for alternative asthma management approaches.

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The safety of formoterol among patients with asthma using inhaled corticosteroids. Systematic review and meta‑analysis

Cited by 20 publications

References 22 publications

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Long-acting -agonists: a review of formoterol safety data from asthma clinical trials

Commentary on ‘Regular treatment with formoterol and inhaled steroids for chronic persistent asthma: serious adverse events’

Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma

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