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Efficacy and Safety of Combination ICS/LABAs in Single Inhaler Devices for Asthma
randomised, double-blind, double-dummy study comparing fixed- SABA. In the study, 2,309 patients with symptomatic asthma (12
dose fluticasone plus salmeterol with budesonide plus formoterol years of age, FEV
1
>50% predicted) who had experienced an asthma
adjustable maintenance dosing in 688 adult patients with exacerbation in the previous year were randomised to receive
persistent asthma over a study duration of one year.
42
Data from budesonide plus formoterol 160/4.5µg two inhalations twice daily
the CONCEPT study showed an advantage for fluticasone plus and as needed, or one inhalation of fluticasone plus salmeterol
salmeterol, with a significantly greater percentage of symptom- 500/50µg twice daily plus terbutaline as needed for six months. The
free days for patients treated with fluticasone plus salmeterol DPI study showed that the time to first severe exacerbation (the pre-
250/50µg one inhalation twice daily compared with patients specified primary outcome) was not significantly prolonged (RR
receiving adjustable-dose budesonide plus formoterol DPI 0.82, 95% CI 0.63–1.05). Budesonide plus formoterol maintenance
160/4.5µg (58.8 versus 52.1%, respectively; p=0.034), in which and reliever therapy reduced total exacerbations from 31 to 25
patients modified their dosage in consideration of nocturnal events per 100 patients per year (p=0.039), and exacerbations
awakenings, frequency of rescue medication usage and changes in requiring hospitalisation/emergency room treatment were reduced
morning PEF. Patients receiving fixed-dose fluticasone plus from 13 to nine events per 100 patients per year (p=0.046). The
salmeterol demonstrated a 47% reduction in the annual mean treatments showed no difference in measures of lung function or
exacerbation rate compared with adjustable-dose formoterol (0.18 asthma symptoms. The mean dose of ICS received was lower using
versus 0.33, adjusted treatment rate ratio 0.53, 95% CI 0.34–0.85; budesonide plus formoterol maintenance and reliever therapy
p=0.008), as well as significantly higher mean morning PEF (400.1 792µg/day budesonide (1,238µg/day beclomethasone dipropionate
versus 390.6l/minute, adjusted mean difference 9.5l/minute, 95% [BDP] equivalent) versus 1,000µrog/day fluticasone (2,000µg/day
CI 2.7–16.3; p=0.006) and a significantly higher percentage of days BDP equivalent) with fluticasone plus salmeterol therapy;
free of rescue medication (94.5 versus 90.7%; p=0.008). Patients p<0.0001). Both treatments were well tolerated.
38
randomised to adjustable-dose budesonide plus formoterol used a
mean of 1.8 inhalations per day, equivalent to 360µg budesonide/ With different studies demonstrating different outcomes, the
day, and 235 patients (82.2%) reduced their dosing to one question arises as to the clinical implications of the studies.
inhalation per day. Taking into account the advantages reported in Although total exacerbation rates were not significantly different
association with fixed-dose fluticasone plus salmeterol over between the adjustable and fixed doses of budesonide plus
adjustable-dose budesonide plus formoterol, the authors of the formoterol in the studies by Aalbers et al.
20
and Busse et al.,
25
study suggest that patients with asthma may have a minimum all other studies demonstrated clearly that adjustable-dose
daily threshold of maintenance therapy that needs to be surpassed budesonide plus formoterol therapy resulted in fewer asthma
in order to prevent exacerbations. exacerbations requiring oral steroid treatment, emergency room
visits and hospitalisations, and both studies reported a reduction in
The COMPASS trial was a six-month randomised, double-blind, medication load. Fitzgerald et al. reported a lower rate of
double-dummy study that compared budesonide plus formoterol exacerbations with fixed-dose fluticasone plus salmeterol;
42
160/4.5µg one inhalation twice daily plus additional inhalations as however, this study had a lower step-down dose for budesonide
needed with fluticasone plus salmeterol 125/25µg one inhalation plus formoterol 200/6µg one inhalation daily. This step-down dose
twice daily or budesonide plus formoterol 320/9µg one inhalation.
23
is also lower compared with other studies that have investigated
Both fixed-dose regimen groups received terbutaline for relief the efficacy of adjustable-dose budesonide plus formoterol. The
medication. All three treatment regimens provided similar marked
improvements in lung function, asthma control days and asthma-
related quality of life. However, the adjustable dosing regimen
Adjustable dosing may provide greater
prolonged the time to first severe exacerbation requiring
hospitalisation, emergency room treatment or oral steroids
cost-effectiveness, and some patients
compared with both fixed-dose regimens (p=0.0034 and p=0.023,
may benefit from facing less exposure
respectively; log-rank test). While there was no significant
difference in total number of hospitalisations/emergency room
to the medication through less use
treatments between the adjustable and fixed-dose budesonide plus
compared with a fixed-dose regimen.
formoterol groups, there was a 39% rate reduction in the
adjustable-dose budesonide plus formoterol group compared with
fixed-dose fluticasone plus salmeterol therapy (relative risk [RR] inconsistencies could also be attributed to differences in
0.61, 95% CI 0.44–0.83; p=0.0015). There was also a 32% reduction methodology when carrying out the studies. The study conducted
in the fixed-dose budesonide plus formoterol group versus fixed- by Aalbers et al. allowed step-down therapy only when patients had
dose fluticasone plus salmeterol therapy (RR 0.68, 95% CI completed the initial four-week double-blind treatment, and in
0.51–0.92; p=0.013). As in previous head-to-head comparisons, consultation with a study investigator.
20
Conversely, the criteria for
adjustable- and fixed-dose budesonide plus formoterol and fixed- step-down therapy were more lenient with the open-label study by
dose fluticasone plus salmeterol were well tolerated, with notable Busse et al., and stricter criteria had to be met before step-up
between-group differences reported in the number or severity therapy could be approved.
25
Where Aalbers et al.
20
and Busse et
of adverse events. al.
25
used the recommended dosing regimens for patients with
moderate to severe asthma (budesonide plus formoterol 160/4.5µg
The efficacy of budesonide plus formoterol maintenance and two inhalations twice daily; fluticasone plus salmeterol DPI
reliever therapy has been assessed in comparison with sustained 250/50µg one inhalation twice daily),
43,44
in the study by Fitzgerald et
high-dose fluticasone plus salmeterol 500/50µg twice daily plus a al.
42
the step-down dose was lower.
EUROPEAN RESPIRATORY DISEASE 13
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