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Meta-Analysis
. 2012 Apr 18;2012(4):CD006923.
doi: 10.1002/14651858.CD006923.pub3.

Regular treatment with formoterol for chronic asthma: serious adverse events

Christopher J Cates  1 , Matthew J Cates
Affiliations
Meta-Analysis

Regular treatment with formoterol for chronic asthma: serious adverse events

Christopher J Cates et al. Cochrane Database Syst Rev. .

Abstract

Background: Epidemiological evidence has suggested a link between beta(2)-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta(2)-agonists are safe.

Objectives: The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular formoterol versus placebo or regular short-acting beta(2)-agonists.

Search methods: We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and Food and Drug Administration (FDA) submissions in relation to formoterol. The date of the most recent search was January 2012.

Selection criteria: We included controlled, parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular formoterol and were of at least 12 weeks' duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.

Data collection and analysis: Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second author checked them. We sought unpublished data on mortality and serious adverse events.

Main results: The review includes 22 studies (8032 participants) comparing regular formoterol to placebo and salbutamol. Non-fatal serious adverse event data could be obtained for all participants from published studies comparing formoterol and placebo but only 80% of those comparing formoterol with salbutamol or terbutaline.Three deaths occurred on regular formoterol and none on placebo; this difference was not statistically significant. It was not possible to assess disease-specific mortality in view of the small number of deaths. Non-fatal serious adverse events were significantly increased when regular formoterol was compared with placebo (Peto odds ratio (OR) 1.57; 95% CI 1.06 to 2.31). One extra serious adverse event occurred over 16 weeks for every 149 people treated with regular formoterol (95% CI 66 to 1407 people). The increase was larger in children than in adults, but the impact of age was not statistically significant. Data submitted to the FDA indicate that the increase in asthma-related serious adverse events remained significant in patients taking regular formoterol who were also on inhaled corticosteroids.No significant increase in fatal or non-fatal serious adverse events was found when regular formoterol was compared with regular salbutamol or terbutaline.

Authors' conclusions: In comparison with placebo, we have found an increased risk of serious adverse events with regular formoterol, and this does not appear to be abolished in patients taking inhaled corticosteroids. The effect on serious adverse events of regular formoterol in children was greater than the effect in adults, but the difference between age groups was not significant.Data on all-cause serious adverse events should be more fully reported in journal articles, and not combined with all severities of adverse events or limited to those events that are thought by the investigator to be drug-related.

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Conflict of interest statement

None known.

Figures

1
1
Changes in asthma mortality (5 to 34 age group) in three countries in relation to the introduction of isoprenaline forte in the UK and New Zealand and of fenoterol in New Zealand. (From Blauw 1995. With permission from the Lancet).
2
2
Inhaled fenoterol market share and annual asthma mortality in New Zealand in persons aged 5 to 34
3
3
Study flow diagram.
4
4
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
5
5
Forest plot of comparison: 1 All‐cause mortality, outcome: 1.1 Overall results.
6
6
Forest plot of comparison: 2 Adults and children non‐fatal serious adverse events, outcome: 2.1 Formoterol versus placebo or salbutamol.
7
7
Serious adverse events with regular formoterol compared to placebo. In the control group 12 people out of 1000 had serious adverse events over 16 weeks, compared to 19 (95% CI 13 to 27) out of 1000 for the active treatment group.
1.1
1.1. Analysis
Comparison 1 All‐cause mortality, Outcome 1 Overall results.
2.1
2.1. Analysis
Comparison 2 Adults and children non‐fatal serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
3.1
3.1. Analysis
Comparison 3 Adults and children non‐fatal serious adverse events (without formoterol 24 µg arms), Outcome 1 Formoterol versus placebo or salbutamol.
4.1
4.1. Analysis
Comparison 4 Adults with non‐fatal serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
5.1
5.1. Analysis
Comparison 5 Children with non‐fatal serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
6.1
6.1. Analysis
Comparison 6 Children with non‐fatal serious adverse events (without formoterol 24 µg arms), Outcome 1 Formoterol versus placebo or salbutamol.
7.1
7.1. Analysis
Comparison 7 Dose comparison: formoterol 24 µg versus 12 µg twice daily, Outcome 1 Serious adverse events.
8.1
8.1. Analysis
Comparison 8 Adults and children fatal and non‐fatal serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
9.1
9.1. Analysis
Comparison 9 Asthma mortality, Outcome 1 Formoterol versus placebo or salbutamol.
10.1
10.1. Analysis
Comparison 10 Cardiovascular mortality, Outcome 1 Formoterol versus placebo or salbutamol.
11.1
11.1. Analysis
Comparison 11 Adults and children non‐fatal asthma‐related serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
12.1
12.1. Analysis
Comparison 12 Adults and children non‐fatal asthma‐related serious adverse events (Novartis data), Outcome 1 Formoterol versus placebo or salbutamol.
13.1
13.1. Analysis
Comparison 13 Hospitalisations for asthma, Outcome 1 Formoterol versus placebo or salbutamol.
14.1
14.1. Analysis
Comparison 14 Adults and children non‐fatal cardiovascular serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
15.1
15.1. Analysis
Comparison 15 Impact of inhaled corticosteroids on asthma‐related SAEs, Outcome 1 Patients with at least one asthma‐related SAE.
16.1
16.1. Analysis
Comparison 16 Adults and children published non‐fatal serious adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
17.1
17.1. Analysis
Comparison 17 Adults and children all adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
18.1
18.1. Analysis
Comparison 18 Adults and children published adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
19.1
19.1. Analysis
Comparison 19 Adults and children all published drug‐related adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
20.1
20.1. Analysis
Comparison 20 Adults and children serious drug‐related adverse events, Outcome 1 Formoterol versus placebo or salbutamol.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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References to studies excluded from this review

Adler 2006 {published data only}
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Cazzola 2002 {published data only}
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Ceylan 2004 {published data only}
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Chetta 1993 {published data only}
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Chuchalin 2002 {published data only}
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Dahl 2004 {published data only}
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    1. Kruse M, Rosenkranz B, Dobson C, Ayre G, Horowitz A. Safety and tolerability of high‐dose formoterol (Aerolizer) and salbutamol (pMDI) in patients with mild/moderate, persistent asthma. Pulmonary Pharmacology and Therapeutics 2005; Vol. 18, issue 3:229‐34. - PubMed
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