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

Sears, Malcolm R.; Ottosson, Anders; Radner, Finn; Suissa, Samy

doi:10.1183/09031936.00145006

Cited by 101 publications

(71 citation statements)

References 40 publications

(41 reference statements)

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“…It is informative to compare our findings with those of the recent meta-analysis of the risk of formoterol, based on the AstraZeneca database [21]. As outlined in its accompanying editorial [22], when the analysis was restricted to trials with a non-LABA comparison group, the crude estimate of risk derived from the study by SEARS et al [21] was 2.5, similar to our point estimates of risk of between 2.0 and 3.2.…”

Section: Comparison With Previous Formoterol Meta-analysissupporting

confidence: 62%

“…This contrasted with the approach of the recent formoterol meta-analysis, in which clinical trials without a non-formoterol comparator treatment were included [21], which led to an underestimate of the risk of mortality associated with formoterol treatment, as outlined in its accompanying editorial [22].…”

Section: Methodological Issuesmentioning

confidence: 92%

“…Using this approach, a total of 62 studies of almost 50,000 subjects involving around 22,500 patient-yrs of treatment was included in the meta-analysis. This represented a modest increase in power compared with the recent formoterol metaanalysis which included almost 40,000 subjects involving around 20,000 patient-yrs of treatment from studies with a non-formoterol comparator group [21].…”

Section: Methodological Issuesmentioning

confidence: 99%

“…Recently, a meta-analysis of the risk of asthma mortality associated with formoterol treatment has been reported [21]. The key findings were that, owing to the very low asthma death rate, the analysis had insufficient power and, although the point estimates were consistent with an increased risk of death in patients taking formoterol, the confidence intervals were wide and the differences not statistically significant.…”

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confidence: 99%

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Risk of mortality associated with formoterol: a systematic review and meta-analysis

Wijesinghe¹,

Weatherall²,

Perrin³

et al. 2009

European Respiratory Journal

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There is concern long-acting b-agonist (LABA) drugs may increase the risk of asthma mortality.We undertook a systematic review which included the AstraZeneca Formoterol Clinical Trial Safety Database and Novartis Food and Drug Aministration Formoterol Briefing Document. Randomised controlled clinical trials of duration o4 weeks that compared formoterol with a non-LABA comparator treatment in asthma were included in a meta-analysis of the risk of all-cause mortality and asthma death. Simple contingency tables, Peto's one-step method and a Bayesian analysis were used.There were 42 deaths (nine from asthma) recorded in 62 studies with 49,327 subjects. The simple contingency table odds ratio for risk of all-cause mortality with formoterol was 1.1 (95% CI 0.6-2.2) and for asthma death was 2.7 (95% CI 0.5-26.7). Analyses by the other methods using both ''as randomised'' and ''as exposed'' classifications of treatment gave similar risk estimates with wide confidence and credible intervals.We conclude that there was insufficient power to determine whether formoterol increases the risk of mortality. However, the point estimates of a 2.0-to 3.2-fold increased risk of asthma death are not reassuring and add weight to evidence that LABA use in certain circumstances may increase the risk of asthma mortality.

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Section: Comparison With Previous Formoterol Meta-analysissupporting

confidence: 62%

Section: Methodological Issuesmentioning

confidence: 92%

Section: Methodological Issuesmentioning

confidence: 99%

mentioning

confidence: 99%

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Risk of mortality associated with formoterol: a systematic review and meta-analysis

Wijesinghe¹,

Weatherall²,

Perrin³

et al. 2009

European Respiratory Journal

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“…Introduction β 2 -adrenergic receptor (β 2 -AR) agonist is administered in a variety of clinical situations [1][2][3][4][5] mostly for its bronchodilating effects. Furthermore, the regulation of β 2 -AR agonist on the production of inflammatory cytokines has been recognized.…”

mentioning

confidence: 99%

Fenoterol, a β2-adrenoceptor agonist, inhibits LPS-induced membrane-bound CD14, TLR4/CD14 complex, and inflammatory cytokines production through β-arrestin-2 in THP-1 cell line

Wang

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim: To investigate the molecular mechanism and signaling pathway by which fenoterol, a β 2 -adrenergic receptor (β 2 -AR) agonist, produces anti-inflammatory effects. Methods: THP-1, a monocytic cell line, was used to explore the mechanism of β 2 -AR stimulation in LPS-induced secretion of inflammatory cytokines and changes of toll-like receptors (TLRs). We labeled TLR4 and CD14 using monoclonal anti-TLR4 PE-conjugated and anti-CD14 FITC-conjugated antibodies in THP-1 cells stimulated by β 2 -AR in the presence or absence of lipopolysaccharide (LPS) and small, interfering RNA (siRNA)-mediated knockdown of β-arrestin-2, and then analyzed their changes in distribution by flow cytometry, Western blotting and confocal analysis. Results: LPS-induced membrane-bound CD14, TLR4/CD14 complex levels and elevation of inflammatory cytokines were all significantly reduced by pre-incubation of fenoterol (P<0.05). However, the total level of CD14 and TLR4 was not significantly changed. Interestingly, confocal microscopy revealed redistribution of CD14 and TLR4/CD14 complex under β 2 -AR stimulation. Furthermore, siRNAmediated knockdown of β-arrestin-2 eliminated the anti-inflammatory effects and redistribution of CD14 and TLR4/CD14 complex stimulated by β 2 -AR. Conclusion: β 2 -AR agonist exerts its anti-inflammatory effects by down-regulating TLR signaling in THP-1 cells, potentially resulting from β-arrestin-2 mediated redistribution of CD14 and TLR14/CD14 complex.

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Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events

Cates

Jaeschke

Schmidt

et al. 2013

Cochrane Database of Systematic Reviews

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We found no statistically significant differences in fatal or non-fatal serious adverse events in trials in which regular salmeterol was randomly allocated with ICS, in comparison to ICS alone at the same dose. Although 13,447 adults and 1862 children have now been included in trials, the frequency of adverse events is too low and the results are too imprecise to confidently rule out a relative increase in all cause mortality or non-fatal adverse events with salmeterol used in conjunction with ICS. However, the absolute difference between groups in the risk of serious adverse events was very small. We could not determine whether the increase in all cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular ICS. We await the results of large ongoing surveillance studies mandated by the FDA to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.

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

Cited by 101 publications

References 40 publications

Risk of mortality associated with formoterol: a systematic review and meta-analysis

Risk of mortality associated with formoterol: a systematic review and meta-analysis

Fenoterol, a β2-adrenoceptor agonist, inhibits LPS-induced membrane-bound CD14, TLR4/CD14 complex, and inflammatory cytokines production through β-arrestin-2 in THP-1 cell line

Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events

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