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Meta-Analysis
. 2018 Dec 3;12(12):CD006922.
doi: 10.1002/14651858.CD006922.pub4.

Inhaled steroids with and without regular salmeterol for asthma: serious adverse events

Christopher J Cates  1 , Stefanie Schmidt, Montse Ferrer, Ben Sayer, Samuel Waterson
Affiliations
Meta-Analysis

Inhaled steroids with and without regular salmeterol for asthma: serious adverse events

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

Abstract

Background: Epidemiological evidence has suggested a link between use of beta₂-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta₂-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS.

Search methods: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018.

Selection criteria: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration.

Data collection and analysis: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations.

Main results: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12).

Authors' conclusions: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment.However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.

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Conflict of interest statement

Previous versions

Roman Jaeschke received honoraria for lectures from Boehringer Ingelheim (2006; USD4000) and GlaxoSmithKline (2007; EUR2000), as well as travel support from Boehringer Ingelheim and GlaxoSmithKline (2006 and 2007; up to USD1000). This occurred more than five years before publication of the review.

Mattthew Cates and Toby Lasserson: none known.

Figures

Figure 1
Figure 1
Study flow diagram: review update.
Figure 2
Figure 2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figure 3
Figure 3
Forest plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.1 All‐cause mortality.
Figure 4
Figure 4
Forest plot of comparison: 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, outcome: 2.1 All‐cause mortality.
Figure 5
Figure 5
Forest plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.2 All‐cause non‐fatal SAE.
Figure 6
Figure 6
Forest plot of comparison: 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, outcome: 2.5 Asthma‐related mortality.
Figure 7
Figure 7
Forest plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.3 Asthma‐related SAE.
Figure 8
Figure 8
Funnel plot of comparison: 1 Regular salmeterol in addition to regular inhaled corticosteroids, outcome: 1.2 All‐cause non‐fatal SAE.
Figure 9
Figure 9
Forest plot of comparison: 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, outcome: 2.2 All‐cause non‐fatal SAE.
Figure 10
Figure 10
Forest plot of comparison: 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, outcome: 2.4 Asthma‐related SAE.
Analysis 1.1
Analysis 1.1
Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 1 All‐cause mortality.
Analysis 1.2
Analysis 1.2
Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 2 All‐cause non‐fatal SAE.
Analysis 1.3
Analysis 1.3
Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 3 All‐cause SAE (fatal and non‐fatal).
Analysis 1.4
Analysis 1.4
Comparison 1 Regular salmeterol in addition to regular inhaled corticosteroids, Outcome 4 Asthma‐related SAE.
Analysis 2.1
Analysis 2.1
Comparison 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, Outcome 1 All‐cause mortality.
Analysis 2.2
Analysis 2.2
Comparison 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, Outcome 2 All‐cause non‐fatal SAE.
Analysis 2.3
Analysis 2.3
Comparison 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, Outcome 3 All‐cause SAE (fatal and non‐fatal).
Analysis 2.4
Analysis 2.4
Comparison 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, Outcome 4 Asthma‐related SAE.
Analysis 2.5
Analysis 2.5
Comparison 2 Risk difference meta‐analysis: regular salmeterol in addition to regular ICS, Outcome 5 Asthma‐related mortality.
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Update of

References

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References to other published versions of this review

    1. Cates CJ, Cates MJ, Lasserson TJ. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD006922] - DOI - PubMed
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