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.
An overview of Cochrane reviews [Abstract] 1 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 T1). 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.
| 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 T2) 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).
| 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) |
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