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

Jaeschke, Roman; O'Byrne, Paul M.; Mejza, Filip; Nair, Parameswaran; Leśniak, Wiktoria; Brožek, Jan; Thabane, Lehana; Ji, Cheng; Schünemann, Holger J.; Sears, Malcolm R.; Guyatt, Gordon

doi:10.1164/rccm.200804-494oc

Cited by 100 publications

(60 citation statements)

References 22 publications

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“…However, when added to GC treatment compared with the same dose of GC plus placebo, only formoterol reduces asthma-related hospital admissions, as shown in a recent systematic review (Jaeschke et al, 2008). This finding is also in agreement with the largest double-blind study comparing fixed-dose combination therapy with budesonide-formoterol versus salmeterol-fluticasone at equivalent GC doses (Kuna et al, 2007), which found a lower rate of asthma-related hospitalizations/emergency room visits in formoterol-treated patients.…”

Section: Discussionsupporting

confidence: 83%

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

Adner

Larsson

Säfholm

et al. 2010

J Pharmacol Exp Ther

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During asthma exacerbations, increased airway inflammation may impair the effects of ␤ 2 -adrenoceptor (␤ 2 AR) agonists. It is unclear whether this impairment is prevented by inhaled glucocorticoids (GCs). We have investigated the relaxation of carbachol-contracted mouse tracheal segments to the ␤ 2 AR agonists formoterol, terbutaline, and salmeterol. The segments were pre-exposed for 4 days to the proinflammatory cytokines tumor necrosis factor ␣ (100 ng/ml) and interleukin-1␤ (10 ng/ml) with or without the GC, budesonide (1 M). Formoterol and terbutaline induced greater maximal relaxation (R max ) than salmeterol. The cytokines decreased R max of all ␤ 2 AR agonists, whereas budesonide had no effect. However, after concomitant treatment with cytokines and budesonide, the R max values of formoterol and terbutaline were not impaired, whereas budesonide did not prevent the decrease in the R max of salmeterol. A similar pattern was observed for cAMP production by the agonists. In tracheal smooth muscle, ␤ 2 AR mRNA was not affected by the cytokines but increased with budesonide. However, the cytokines markedly increased cyclooxygenase (COX)-2 mRNA expression, which may lead to heterologous desensitization of ␤ 2 AR. It is noteworthy that the cytokine-induced increase of COX-2 was blocked by concomitant budesonide suggesting that heterologous desensitization of ␤ 2 AR by the cytokines may be prevented by budesonide treatment. Budesonide prevented cytokine-induced impairment of the tracheal relaxation and ␤ 2 AR/cAMP signaling for formoterol but not for salmeterol. This suggests that differences exist between formoterol and salmeterol in ␤ 2 AR coupling/activation and/or signal transduction upstream of cAMP. These results imply that maximal bronchodilator effects of formoterol, but not of salmeterol, are maintained by budesonide treatment during periods with increased inflammation, such as asthma exacerbations.

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Section: Discussionsupporting

confidence: 83%

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

Adner

Larsson

Säfholm

et al. 2010

J Pharmacol Exp Ther

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“…Many questions were not readily answered because of the structure of those studies, particularly whether the outcomes related directly to adverse effects of LABA treatment or to undertreatment with anti-inflammatory medications such as inhaled corticosteroids (ICS) allowing asthma to be less well controlled despite symptomatic relief from the bronchodilator (''masking'') [4]. Numerous meta-analyses and reviews of clinical trials involving salmeterol and formoterol with and without ICS in patients with asthma have been published [5][6][7][8][9][10][11][12][13]. Although controversy has continued, there is growing consensus that use of LABAs with adequate ICS is both effective and safe [14,15].…”

Section: Introductionmentioning

confidence: 99%

Safety of formoterol in asthma clinical trials: an update

Sears

Radner

2013

European Respiratory Journal

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Use of long-acting b-agonists (LABAs) in asthma remains controversial, and large safety trials are in progress. We have previously reported safety outcomes with formoterol in 117 AstraZeneca asthma trials (78 339 patients, 92% using inhaled corticosteroids) completed by December 2006, and have now added 32 trials with formoterol (26 124 patients, 100% using inhaled corticosteroids) completed by December 2011.The primary dataset of 79 randomised controlled trials includes 94 684 patients, 67 380 of whom were exposed to formoterol, while the complete dataset comprises 149 trials and 104 463 patients. There were no new asthma-related deaths in the expanded primary dataset, with eight asthma-related deaths among formoterolrandomised patients and two among non-LABA-randomised patients (relative risk 1.13, 95% CI 0.23-10.9), and 15 versus nine cardiac-related deaths (relative risk 0.47, 95% CI 0.19-1.22). Nonfatal asthma-related serious adverse events were significantly reduced with formoterol (relative risk 0.63, 95% CI 0.53-0.75), as were discontinuations due to adverse events. Examining 40 trials with direct formoterol versus non-LABA comparisons, Mantel-Haenszel relative risk for asthma-related death was 2.75 (95% CI 0.52-14.4) and for serious adverse events 0.83 (95% CI 0.68-1.02).We conclude that this enlarged dataset indicates no increased risk of asthma-related deaths among patients exposed to formoterol compared with non-LABA treatments, although the wide confidence interval precludes certainty. @ERSpublications No increased risk of asthma-or cardiac-related deaths or serious adverse events associated with the use of formoterol http://ow.ly/qfShl For editorial comments see page 6.

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“…Although other large studies have failed to find any significant differences in mortality or morbidity (notably hospitalizations) in relation to LABA use (Jaeschke et al, 2008;Sears et al, 2009), in another meta-analysis conducted by the FDA (Levenson, 2008), it was concluded that any increased risk of asthma-related events was confined to patients taking salmeterol (and not formoterol) who were not simultaneously taking concomitant ICS. A recent study has examined the association between LABAs and severe asthma exacerbations in a large US Medicaid pop-484 ulation (940,449 patients aged Ͻ40 years) of newly diagnosed asthma and pre-existing asthma cohorts, controlling for disease severity to the greatest extent possible (Guo et al, 2011).…”

Section: Triple Combination Therapiesmentioning

confidence: 98%

Pharmacology and Therapeutics of Bronchodilators

et al. 2012

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

Abstract: 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.

Cited by 100 publications

References 22 publications

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

Budesonide Prevents Cytokine-Induced Decrease of the Relaxant Responses to Formoterol and Terbutaline, but Not to Salmeterol, in Mouse Trachea

Safety of formoterol in asthma clinical trials: an update

Pharmacology and Therapeutics of Bronchodilators

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