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

Abstract

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.

Randomized controlled trial of adherence with single or combination inhaled corticosteroid/long-acting β-agonist inhaler therapy in asthma

“…3,[9][10][11]14 These findings are of clinical relevance because monotherapy with LABAs in patients with poorly controlled asthma may be associated with an increased risk of mortality. [29][30][31][32] This finding would provide support for the recommendation that LABAs are prescribed only as ICS/LABA combination therapy, thereby ensuring that LABA monotherapy cannot occur. 33 Another observation from our study is that subjects were essentially taking their ICS therapy within the framework of variable dosing.…”

Prescribing practices and asthma control with hydrofluoroalkane-beclomethasone and fluticasone: A real-world observational study

“…4,24 However, there are concerns about the potential for increased asthmarelated mortality associated with the use of long-acting b-agonists, both as monotherapy and in conjunction with ICSs. 4,25,26 In this analysis 80.8% of patients receiving an increased dose of ICS as step-up therapy achieved asthma control, an increase from 66.6% at baseline; the rate of asthma exacerbations decreased, and only 12% to 19% of patients required a subsequent change to combination therapy or additional therapy, most commonly the addition of a long-acting b-agonist.…”

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

“…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).…”

“…However despite the largeincluded population (n = 68, 004 adults and children), there was insufficient power to confirm any association between formoterol use and asthma mortality (13). In the Wijesinghe review and metanalysis, asthma mortality was the only outcome assessed and was, as in previous reviews, inconclusive because of insufficient power to assess this outcome by LABA exposure (14).Despite the increasing number of studies, reviews and meta-analyses, little has changed regarding the controversy surrounding the risk: benefit ratio of LABAs. The findings from the recent Cates review (1) are not entirely reassuring, as analyses were…”