Safety of regular formoterol or salmeterol in adults with asthma

Long-acting beta₂-agonists (LABA) appear to be associated with more serious adverse events than placebo in adults with asthma. Combination of corticosteroids to LABA appears to reduce adverse events.

Comment: The quality of evidence is downgraded by inconsistency (variability in results).

A combination of LABA and corticosteroids (by using a combination inhaler containing both products) is recommended over LABA alone for adults whose asthma is not controlled by corticosteroids alone.

Summary

An overview of Cochrane reviews included 6 reviews. Of these, 4 reviews (89 studies, n=61 366 adults) related to the safety of regular formoterol or salmeterol as monotherapy or combination therapy. Two reviews assessed safety from studies in which adults were randomly assigned to formoterol versus salmeterol; these included 3 studies with 1 116 participants given monotherapy (all prescribed background inhaled corticosteroids, ICS) and 10 studies with 8 498 adults receiving combination therapy. An additional search for trials in September 2013 identified 5 new included studies; 693 adults with asthma treated with combination formoterol/fluticasone in comparison with the same dose of inhaled fluticasone, and 447 adults for whom formoterol monotherapy was compared with placebo. No studies reported separate results in adolescents.

None of the reviews found a significant increase in death of any cause from direct comparisons; however, none of the reviews could exclude the possibility of a two-fold increase in mortality on regular formoterol or salmeterol (as monotherapy versus placebo or as combination therapy versus ICS) in adults with asthma (table ). Absolute differences in mortality were very small, translating into an increase of 7 per 10 000 over 26 weeks on any monotherapy (95% CI 2 less to 23 more) and 3 per 10 000 over 32 weeks on any combination therapy (95% CI 3 less to 17 more). Very few deaths were reported in the combination therapy trials, and combination therapy trial designs were different from those of monotherapy trials. Therefore it was not possible to use indirect evidence to assess whether regular combination therapy was safer than regular monotherapy. Only one death occurred in the monotherapy trials comparing formoterol versus salmeterol, so evidence was insufficient to compare mortality.

Effect of LABAs on death of any cause

Comparison	OR (95% CI)	Participants (studies)
*with variable background ICS use; LABA = long-acting beta2-agonist; ICS = inhaled corticosteroid
Formoterol monotherapy versus placebo*	4.49 (0.24 to 84.80)	4 824 (13 studies)
Salmeterol monotherapy versus placebo*	1.33 (0.85 to 2.08)	29 128 (10 studies)
LABA monotherapy versus placebo*	1.37 (0.88 to 2.13)	33 952 (23 studies)
Formoterol combination therapy versus ICS	3.56 (0.79 to 16.03)	11 271 (25 studies)
Salmeterol combination therapy versus ICS	0.90 (0.31 to 2.60)	13 447 (35 studies)
LABA combination therapy versus ICS	1.42 (0.60 to 3.38)	24 718 (60 studies)

Direct evidence showed that non-fatal serious adverse events were increased in adults receiving salmeterol monotherapy (table ) but were not significantly increased in any of the other comparisons. This represents an absolute increase on any monotherapy of 43 per 10 000 over 26 weeks (95% CI 6 more to 85 more) and 16 per 10 000 over 32 weeks (95% CI 22 less to 60 more) on any combination therapy. Direct comparisons of formoterol and salmeterol detected no significant differences between risks of all non-fatal events in adults (as monotherapy or as combination therapy).

Effect of LABAs on non-fatal serious adverse events of any cause

Comparison	OR (95% CI)	Participants (studies)
*with variable background ICS use; LABA = long-acting beta2-agonist; ICS = inhaled corticosteroid
Formoterol monotherapy versus placebo*	1.26 (0.78 to 2.04)	5 758 (17 studies)
Salmeterol monotherapy versus placebo*	1.14 (1.01 to 1.28)	30 196 (13 studies)
LABA monotherapy versus placebo*	1.14 (1.02 to 1.29)	35 954 (30 studies)
Formoterol combination therapy versus ICS	0.99 (0.77 to 1.27)	11 271 (25 studies)
Salmeterol combination therapy versus ICS	1.15 (0.91 to 1.44)	13 447 (35 studies)
LABA combination therapy versus ICS	1.07 (0.90 to 1.27)	24 718 (60 studies)

A meta-analysis included 12 studies with a total of 36 588 subjects with asthma. Studies were included if they were RCTs of long-acting beta-agonists (LABAs) compared with placebo or LABAs with inhaled corticosteroids (ICS) compared with an equal or higher dose of ICS alone of at least 3 months duration that reported at least 1 asthma-related intubation or death. The mean age of participants was 38 years. 5 studies evaluated LABAs with variable ICS use (n=29 335); ICS were used by 47.9% of the participants. Seven studies evaluated LABAs with concomitant ICS (n=7 253); all participants received ICS, either as uncontrolled background use or controlled as part of the study intervention. LABA+ICS was compared with an equal dose of ICS in 4 studies, an equal or higher dose of ICS in 1 study, and a higher dose of ICS in 2 studies. The use of LABAs with and without concomitant ICSs was associated with a significant increase in risk of asthma-related intubations and deaths (table ).

Effect of LABAs on asthma-related intubation and deaths

Subgroup	Peto OR (95% CI)	LABA n/N	Control n/N	Participants (studies)
LABA = long-acting beta2-agonist; ICS = inhaled corticosteroid ; n = number of participants with at least one asthma intubation or death; N = number of participants
LABA with variable ICS compared with placebo	1.83 (1.14 to 2.95)	45/15 068	23/14 267	29 335 (5 studies)
LABA with concomitant ICS compared with ICS alone	3.65 (1.39 to 9.55)	14/4 039	3/3 214	7 253 (7 studies)
Total (all studies)	2.10 (1.37 to 3.22)	59/19 107	26/17 481	36 588 (12 studies)

Another meta-analyses was conducted of asthma deaths in RCTs from the GlaxoSmithKline database that compared salmeterol with a non-LABA comparator treatment in asthma. A total of 215 studies with 106 575 subjects were included in the full dataset. 54 studies (n=13 145) evaluated salmeterol monotherapy (placebo controlled, no ICS use); 127 studies examined salmeterol with ICS use (randomised or baseline, n=48 715), of them 63 studies examined salmeterol/fluticasone combination versus ICS (n=22 600); and in 59 studies data on ICS use was not available. Salmeterol monotherapy increased the risk of asthma mortality and this risk was reduced with concomitant ICS therapy (table ). There was an increased risk of hospital admissions with salmeterol monotherapy and salmeterol with ICS therapy but not with salmeterol as combination salmeterol/fluticasone propionate therapy (table ).

Risk of death associated with salmeterol treatment

Comparison	Peto OR (95% CI)	Number of studies with data
Salmeterol monotherapy versus placebo*	7.3 (1.8 to 29.4)	1
Salmeterol with ICS (randomised or background) versus ICS**	2.1 (0.6 to 7.9)	2
Salmeterol as combination salmeterol/fluticasone propionate therapy versus ICS***	NA	0
All studies (any salmeterol versus non-LABA)****	2.7 (1.4 to 5.3)	7
*there were 8 asthma deaths, all in the SMART study; ** there were 9 deaths from asthma, 8 of which came from the SMART study; *** no studies with asthma deaths (63 studies with 22 600 subjects in whom the combination salmeterol/fluticasone propionate inhaler was compared with ICS therapy); **** 28/57 607 asthma deaths in subjects taking salmeterol and 7/48 968 in a non-LABA group

Risk of hospitalisation associated with salmeterol treatment ComparisonPeto OR (95% CI) Number of studies with data ICS = inhaled corticosteroid; LABA = long-acting beta₂-agonist Salmeterol monotherapy versus placebo 1.4 (1.0 to 2.0) 23 Salmeterol with ICS (randomised or background) versus ICS 1.3 (1.1 to 1.5) 55 Salmeterol as combination salmeterol/fluticasone propionate therapy versus ICS 1.0 (0.6 to 1.7) 20 All studies (any salmeterol versus non-LABA) 1.2 (1.1 to 1.4) 104

Clinical comments

Note

Date of latest search:

Ədəbiyyat

1. Cates CJ, Wieland LS, Oleszczuk M et al. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev 2014;(2):CD010314. Salpeter SR, Wall AJ, Buckley NS. Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events. Am J Med 2010;123(4):322-8.e2. Weatherall M, Wijesinghe M, Perrin K et al. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy. Thorax 2010;65(1):39-43.