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Asthma
An open-label randomised study by Aalbers et al. was not only a worsened and who required an increased dose, 67% regained
head-to-head comparison of fluticasone plus salmeterol and control of their asthma within seven days. Over half (57% of
budesonide plus formoterol at fixed doses, but also included a third patients [120/211]) did not require an increase in treatment. On
treatment arm in which patients received budesonide plus average, patients adjusting their dosages used significantly fewer
formoterol adjustable maintenance dosing in the six-month open- inhalations than those receiving fixed-dose budesonide plus
extension phase of the study.
20
In the adjustable dosing group, formoterol (3.4 versus 4.0 inhalations per day, adjusted mean
patients received either one or two inhalations of budesonide plus difference 0.51 inhalations, 95% CI 0.36–0.66; p<0.001), as well as
formoterol 160/4.5µg twice daily depending on their level of asthma less ICS plus LABA (544/15 versus 640/18µg per day).
control. They were also allowed to increase the frequency to four
inhalations twice daily if required. Patients in the adjustable- A 12-month dose-titration open-label study conducted by
regimen arm were also given oral and written instructions regarding Vogelmeier et al. randomised adolescents and adults to budesonide
plus formoterol 160/4.5µg two inhalations twice daily plus
Within one month of adjustable
additional inhalations as needed, or fluticasone plus salmeterol
250/50µg one inhalation twice daily plus salbutamol as relief
maintenance dosing, 45% of patients medication.
40
Both regimens provided sustained improvements in
(95/211) had gained sufficient control to
symptoms and lung function. The adjustable dosing regimen was
associated with an increased time to first severe exacerbation
merit a reduction from two to one compared with fluticasone plus salmeterol (95% CI 7–39; p=0.0076).
inhalation twice daily during the open
Furthermore, the total number of severe exacerbations was
significantly reduced in the adjustable-dosing group (255 versus
extension period. 329; p<0.01). From week four of the study, the mean total dose of
ICS decreased in the budesonide plus formoterol adjustable dosing
self-management and actions to be undertaken should their group. In contrast, there was an increase in the fluticasone plus
asthma worsen. Although the OR for one week of well-controlled salmeterol group. Both treatment regimens were well tolerated and
asthma was similar between the fixed-dose regimens, the six- no differences were reported between the groups in the number or
month open-extension phase revealed an increase in the OR for severity of adverse events.
adjustable-dose budesonide plus formoterol compared with fixed-
dose budesonide plus formoterol (OR 1.335, 95% CI 1.001–1.783; More recently, Busse et al. compared budesonide plus formoterol
p=0.049), but no significant increase compared with fixed-dose pressurised metered-dose inhaler (pMDI) 160/4.5µg two inhalations
fluticasone plus salmeterol (OR 1.048, 95% CI 0.791–1.391). The twice daily in adjustable and fixed doses against fixed-dose
adjustable-dose budesonide plus formoterol group experienced fluticasone plus salmeterol DPI 250/50µg one inhalation twice daily
fewer asthma exacerbations requiring oral steroid treatment, in 1,225 patients with persistent asthma.
25
Fixed-dose budesonide
emergency room visits or hospitalisation than the fixed-dose plus formoterol DPI and pMDI have been shown to have similar
budesonide plus formoterol or fluticasone plus salmeterol groups safety and efficacy.
41
This randomised, open-label phase III study
(35, 50 and 59 exacerbations, respectively). The total rate of compared the efficacy and tolerability of adjustable dosing with
exacerbations of 0.024 per month with adjustable-dose budesonide budesonide plus formoterol pMDI versus fixed-dose budesonide
plus formoterol translates into a non-significant 32.0% rate plus formoterol pMDI and fixed-dose fluticasone plus salmeterol
reduction compared with its fixed-dose counterpart (95% CI PDI.
25
No significant difference was apparent between the
-4.8–55.9), and a statistically significant rate reduction of 39.7% treatment groups in time to the first exacerbation over the study
compared with fixed doses of fluticasone plus salmeterol (95% CI duration of seven months or the percentage of patients in each
8.3–60.3; p=0.018). Patients in the adjustable-dose budesonide plus group who experienced at least one exacerbation over the
formoterol group also used their reliever medication less frequently treatment period. There also appeared to be no significant
than those in the fixed-dose groups, with a mean difference of 0.23 difference between the treatment groups in the change in FEV
1
or
occasions compared with the fluticasone plus salmeterol group PEF from baseline, or the number of symptom-free days, rescue-
(95% CI 0.05–0.41; p<0.05) and 0.30 occasions compared with the medication-free days or days with well-controlled asthma. From the
budesonide plus formoterol group (95% CI 0.12–0.48; p<0.01). initial dosage regimen of 160/4.5µg two inhalations twice daily, 77%
of patients (298/389) randomised to adjustable-dose budesonide
The incidence of adverse events was similar in each treatment plus formoterol were able to step their dosing down to two
group, with 57% (124/219) in the adjustable-dose budesonide plus inhalations once daily; 22% (86/389) stepped up to four inhalations
formoterol group, 58% (124/215) in the fixed-dose budesonide twice daily. The adjustable-dose budesonide plus formoterol group
plus formoterol group and 66% (147/224) in the fixed-dose required significantly less study medication compared with the
fluticasone plus salmeterol group experiencing at least one adverse fixed-dose budesonide plus formoterol group (mean 3.0 versus 4.0
event. Both regimens of budesonide plus formoterol were inhalations per day, respectively; p<0.001). Treatments were well-
associated with a lower incidence of dysphonia. Furthermore, tolerated, with any adverse events being mild or moderate in
candidiasis occurred in only 1% of adjustable-dose budesonide plus intensity and no serious study-related adverse events.
formoterol patients compared with 3% of fixed-dose fluticasone
plus salmeterol patients. Within one month of adjustable The efficacy of adjustable dosing regimens of combined ICS plus
maintenance dosing, 45% of patients (95/211) had gained sufficient LABA therapy versus fixed-dose ICS plus LABA combination
control to merit a reduction from two to one inhalation twice daily therapy has also been evaluated in randomised, double-blind,
during the open extension period. Of those patients whose asthma double-dummy trials. The CONCEPT trial was a multicentre,
12 EUROPEAN RESPIRATORY DISEASE
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