International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 No.

6/2015 (447-455)

Original
2015 Dustri-Verlag Dr. K. Feistle
ISSN 0946-1965
DOI 10.5414/CP202224
e-pub: April 24, 2015

Real-life use of budesonide/formoterol in

clinical practice: a 12-month follow-up
assessment in a multi-national study of
asthma patients established on single-inhaler
maintenance and reliever therapy
Bjrn Stllberg1, Ian Naya2, Jan Ekelund3, and Gran Eckerwall4
University, Uppsala, Sweden, 2AstraZeneca, Macclesfield, UK,
Surgical Outcomes Research Group, University of Gothenburg,
Gothenburg, and 4AstraZeneca R&D, Mlndal, Sweden

1Uppsala

3Scandinavian

Key words
inhaled corticosteroid/
long-acting 2-agonist
inhaler use observational study real-world
evidence treatment

Received
July 28, 2014;
accepted
January 13, 2015
Correspondence to
Bjrn Stllberg, MD,
PhD
Department of Public
Health and Caring
Sciences, Family
Medicine and Preventive
Medicine, Uppsala
University, Box 564, SE
75122 Uppsala, Sweden
[email protected]

Abstract. Objective: The efficacy and

safety of budesonide/formoterol maintenance and reliever therapy (MRT) has been
demonstrated in phase III clinical studies,
but limited data are available in a real-life
setting. We examined the pattern of maintenance and as-needed inhaler use in routine
clinical practice among patients with asthma receiving budesonide/formoterol MRT
(NCT00505388). Methods: This 12-month
European observational study enrolled patients prescribed budesonide/formoterol
MRT and grouped them based on regimen:
80/4.5g one inhalation twice daily (b.i.d.);
160/4.5g one inhalation b.i.d.; 160/4.5g
two inhalations b.i.d. (all plus as needed).
Patient data were collected daily using an
interactive voice- or web-response system.
The primary outcome measure was total
number of budesonide/formoterol inhalations/day. Results: Overall, 4,581 patients
were included (64% female; mean age 48.4
years; regimen: 80/4.5g, n = 119; 160/4.5
g, n = 3,106; 2 160/4.5 g, n = 1,355).
Mean (median) total numbers of budesonide/
formoterol inhalations/day were 2.48 (2.11),
2.53 (2.14), and 4.27 (4.05) for 80/4.5 g
b.i.d., 160/4.5 g b.i.d., and 2 160/4.5
g b.i.d., respectively; corresponding mean
(median) number of as-needed inhalations/
day were 0.68 (0.17), 0.73 (0.26), and 1.08
(0.45), respectively. As-needed budesonide/
formoterol use was generally low with a
mean of 6166% of reliever-free days; over
4 reliever inhalations/day occurred on a mean
of 0.4 2.5% of days for all budesonide/
formoterol MRT regimens. Conclusions: In
routine clinical practice, all budesonide/formoterol MRT regimens were associated with
a high proportion of reliever-free days and
low incidence of high reliever-use days, indicating acceptable levels of asthma control
with this symptom-adjusted controller regimen.

Introduction
Asthma is a chronic inflammatory airway disease that places a large burden both
on patients and society [1]. It is characterized
by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm,
which can lead to lung impairment, sleep disturbances, and limitations of daily activity [1].
The main goal of asthma management is
to control and prevent symptoms and exacerbations in order to achieve optimal lung function and quality of life [1, 2]. This is normally
achieved through the long-term use of both
maintenance (long-term anti-inflammatory)
and reliever (short-term symptom relief)
therapies. Current recommendations suggest
that patients with asthma of at least moderate severity are treated with maintenance
inhaled corticosteroid/long-acting 2-agonist
(ICS/LABA) therapy plus a rapid-acting
bronchodilator as reliever [1]. However, in
a large number of countries (and throughout
Europe) fixed-dose budesonide/formoterol is
available as a maintenance treatment with asneeded adjustments taken as reliever therapy
when symptoms occur.
A growing body of evidence from over
14,000 patients from double-blind phase
IIIa/IIIb studies indicates the improved efficacy and safety of budesonide/formoterol
maintenance and reliever therapy (MRT)
compared with traditional fixed-dose maintenance and traditional short-acting 2-agonist
(SABA) reliever therapy [3, 4, 5, 6, 7, 8].
Budesonide/formoterol MRT was shown to
provide effective asthma control and reduce
the number and risk of severe exacerbations

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Stllberg, Naya, Ekelund, and Eckerwall

compared with other ICS/LABA combinations at similar or higher maintenance doses

[3, 4, 5, 6]. This novel regimen has also improved overall asthma control at a lower corticosteroid load compared with conventional
best practice (including ICS/LABA plus
SABA therapy at the physicians discretion,
as well as any additional controller medications at Global Initiative for Asthma [GINA]
steps 3 and 4) [9, 10, 11].
As-needed reliever use is recorded solely
as median SABA use in many randomized
clinical trials with fixed-dose regimens, giving little information for the 50% of patients
with asthma that is not well controlled [12,
13, 14]. Clinical trials of budesonide/formoterol MRT have shown mean use of asneeded medication to be approximately one
inhalation/day in patients with uncontrolled
asthma on conventional GINA step 2 4
therapy [3, 4, 5, 6, 7, 8], but it is not known
how usage patterns of MRT translate to clinical practice in a typical asthma population.
Therefore, detailed knowledge on the levels of as-needed budesonide/formoterol use
in real life is needed to accurately indicate
the degree of asthma control and potential
for over-use of this regimen [15]. These data
will also be of use in gauging the true costs
of implementing budesonide/formoterol
MRT use in routine clinical practice.
To examine the use of budesonide/formoterol MRT in real-life clinical practice
amongst patients who had been prescribed
the regimen, this observational study investigated the usage profile of budesonide/formoterol MRT in European clinical practice
to establish if actual use was consistent with
1) the label, 2) target levels of as-needed
medication use indicating good asthma control, and 3) published randomized prospective trial data on the product. Therefore, no
efficacy outcome measures were examined
or reported in this study.

Methods
The pattern of maintenance and asneeded inhaler use among patients with
asthma receiving an existing regimen of
budesonide/formoterol MRT was examined
during a 12-month, observational study in
twelve European countries (Belgium, Bul-

garia, Czech Republic, Denmark, Germany,

Greece, Hungary, the Netherlands, Norway,
Portugal, Sweden, and the United Kingdom;
NCT00505388). This observational study
was undertaken to fulfil regulatory commitments and examine budesonide/formoterol
MRT in real-life clinical practice following
the approval and introduction of budesonide/
formoterol MRT in Europe.

Study design
The study involved two planned visits to
the clinic: one at baseline (inclusion) and one
after 12 months. Between the two planned
study visits, patients were treated and assessed in accordance with normal clinical
practice (participation in the study did not
change the asthma treatment they received).
A 12-month study design/duration of assessment was planned to minimize the influence
of seasonal inhaler use.
Patient data were collected on a daily basis using an interactive voice-response system (IVRS) and/or interactive web-response
system (IWRS; ICON Clinical Research,
Dublin, Ireland). At inclusion, patients were
instructed how to use IVRS/IWRS to record
and report their medication usage daily during the study period. The frequency at which
patients reported data was monitored (but
actual data on adherence were not monitored
on a regular basis), and patients were sent
reminders if they did not use the system frequently or had poor adherence.

Patient population
To be eligible for the study, patients were
required to have received an asthma diagnosis and to have been prescribed budesonide/
formoterol MRT prior to entry (so as to reflect
actual real-world patient usage and not protocoled use of the regimen). Patients were also
required to provide signed and dated informed
consent. There were no exclusion criteria to
limit patient characteristics. Patients with
asthma were treated according to normal clinical practice and followed instruction according to the drug label. At inclusion, patients
were segmented into one of three groups by
their prescribed daily maintenance dose of

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Real-life use of budesonide/formoterol in asthma

Table 1. Patients baseline demographics.

Characteristic

Sex, no. (%)

Male
Female
Age, years
Mean
Range

Budesonide/formoterol
All patients
80/4.5 g b.i.d. 160/4.5 g b.i.d. 2 160/4.5 g b.i.d. (n = 4,581)
(n = 119)
(n = 3,106)
(n = 1,355)
42 (35)
77 (65)

1,099 (35)
2,007 (65)

490 (36)
865 (64)

1,631 (36)
2,950 (64)a

46.0
1786

47.8
1889

50.1
1888

48.4
1789

b.i.d. = twice daily. aIncludes 1 patient wrongly prescribed 320/18 g who was
only included in the all patients group.

budesonide/formoterol: 80/4.5g, one inhalation twice daily (b.i.d.); 160/4.5g, one inhalation b.i.d.; 160/4.5g, two inhalations b.i.d.
(all plus budesonide/formoterol as-needed).
Discontinuations were permitted at the discretion of the investigator. Minimal baseline data
were collected using the IVRS system, which
included gender, age, and race.

Outcome measures
The primary outcome measure was
the total number of IVRS/IWRS-reported

budesonide/formoterol
inhalations/day;
secondary outcomes included the number
of as-needed (reliever) inhalations with
budesonide/formoterol. The number of
maintenance inhalations was calculated as
the difference between total and as-needed
inhalations.

Statistical analyses
Descriptive statistical analyses (number
of observations, median, mean, standard
deviation, minimum and maximum) were
performed, and plots illustrating different
aspects of the daily use of budesonide/formoterol were prepared. Since no statistical
hypothesis test was planned, the sample size
was not based on any formal power calculation but was based on the intention to describe budesonide/formoterol MRT as accurately as possible. Initially the study aimed to
recruit 8,000 patients, but two interim analyses showed there was no evidence of misuse
of the budesonide/formoterol MRT concept.
Therefore, the target number was reduced
to 4,400. The full analysis set was used in

Figure 1. Patient disposition throughout the study. aIncludes 1 patient wrongly prescribed 320/18g who
was only included in the all patients group; breasons for discontinuation include: incorrect enrolment
(n=34); terminated study treatment (n=106); voluntary discontinuation by patient (n=453); lost to followup (n=134); and severe non-adherence to protocol (n=91). b.i.d. = twice daily.

450

Stllberg, Naya, Ekelund, and Eckerwall

tients in the 80/4.5g group, 2,542 patients

in the 160/4.5 g group and 1,119 patients
in the 160/4.5g group (Figure 1). One patient was treated with an alternative regimen
than recommended (two inhalations b.i.d. of
80/4.5g (320/18g maintenance)) and was
only included in an all patients group.
Patients baseline characteristics are described in Table 1. The mean age was 48.4
years (range 1789), 64% were female, and
the population was predominantly Caucasian.

Medication exposure
Figure 2. Median and mean number of inhalations/day (maintenance, as-needed, and total use)
by treatment group. b.i.d. = twice daily.

all descriptions of data and comprised all

included patients with diary data after inclusion in the study.

Results
Patients
The first patient was enrolled in July
2007 and the last patient finished the study in
April 2010. Of 5,124 patients enrolled from
twelve European countries, diary data were
available for 4,581 patients (89.4%; the full
analysis set); 41 patients were excluded because one study site was regarded as unreliable and 502 were not included due to the
absence of IVRS/IWRS diary data. From
4,581 included patients, 119 (3.0%), 3,106
(67.8%), and 1,355 (29.6%) were initiated
on the budesonide/formoterol MRT regimen
using a target maintenance level of 80/4.5g
b.i.d., 160/4.5g b.i.d., and 2 160/4.5g
b.i.d., respectively. In total, 818 patients discontinued treatment; reasons for discontinuation included voluntary discontinuation by
subject (453 patients), patient unavailability
(134 patients), termination of study treatment
(106 patients), severe non-compliance with
protocol (91 patients) or incorrect enrolment
(34 patients). A further 7 patients were either
untreated or had no data on treatment available. A total of 3,756 patients (73.3% of patients enrolled) completed the study; 94 pa-

Total medication use

The median exposure to budesonide/formoterol was 344 days, which was consistent
across the three cohorts. Mean (median) days
of exposure for the budesonide/formoterol
80/4.5 g b.i.d., 160/4.5 g b.i.d., and 2
160/4.5g b.i.d. groups were 267 (337), 269
(345), and 268 (342) days, respectively.
Overall, the mean (median) numbers of
budesonide/formoterol inhalations/day, including maintenance and as-needed use for
the 80/4.5g b.i.d., 160/4.5g b.i.d., and 2
160/4.5g b.i.d. groups, were 2.48 (2.11),
2.53 (2.14), and 4.27 (4.05), respectively.
Mean (median) inhalations/day for maintenance, as-needed, and total use are shown
in Figure2. The mean and median numbers
of inhalations for each dose cohort by country are described in Table 2. In general, the
median and mean numbers in the lower-dose
groups were around 2.1 and 2.5 inhalations/
day, but almost doubled in the higher-dose
group due to the higher maintenance dose.
Across all twelve countries, the level of
total budesonide/formoterol inhalations/
day for the most commonly used regimen
(160/4.5 g b.i.d. plus as-needed) showed
a reduced variability for the median versus
mean estimates of use by country; these values ranged between 2.02.2 and 2.12.9,
respectively.
There were only small proportions of patients with very low or very high budesonide
use (Figure 3). The proportion of patients
with potential over-use was very small and
<1% of patients were exposed to budesonide
doses > 1,600 g/day. Under-use was uncommon with all three regimens: <5% of pa-

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Real-life use of budesonide/formoterol in asthma

Table 2. As-needed and total budesonide/formoterol use by country.

Country

Belgium

Bulgaria

Czech
Republic
Denmark

Germany

Greece

Hungary

Netherlands
Norway

Portugal

Sweden

United
Kingdom
All

No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean
No.
Median
Mean

As-needed doses
inh/
inh/week
day
621
0.27
1.89
0.86
6.02
125
0.25
1.75
0.57
3.99
349
0.22
1.54
0.80
5.60
68
0.20
1.40
0.86
6.02
465
0.35
2.45
0.87
6.09
562
0.27
1.89
0.83
5.81
475
0.29
2.03
0.81
5.67
335
0.32
2.24
0.77
5.36
418
0.61
4.27
1.11
7.77
282
0.04
0.28
0.30
2.10
417
0.30
2.10
0.67
4.69
464
0.58
4.06
1.38
9.66
4,581
0.30
2.10
0.83
5.81

Maintenance + as-needed inh/day

80/4.5 g
160/4.5 2 x 160/4.5
b.i.d.
g b.i.d.
g b.i.d.
5
482
134
2.15
2.20
4.03
2.27
2.56
4.17
2
96
27
2.07
2.14
3.32
2.08
2.34
3.45
2
286
61
1.66
2.14
4.04
1.66
2.54
4.15
5
45
18
2.09
2.12
4.03
2.01
2.32
4.00
18
370
77
2.07
2.10
4.00
3.15
2.43
3.91
7
258
297
2.08
2.20
4.00
2.08
2.86
4.08
3
302
170
2.00
2.12
4.16
1.94
2.45
4.48
8
250
77
2.03
2.07
4.00
2.09
2.49
3.95
6
281
131
2.08
2.25
4.45
2.36
2.72
4.78
3
254
25
1.76
2.00
3.81
1.52
2.13
3.56
24
278
115
2.11
2.23
4.18
2.40
2.53
4.37
36
204
223
2.43
2.20
4.18
2.69
2.67
4.50
119
3,106
1,355
2.11
2.14
4.05
2.48
2.53
4.27

b.i.d. = twice daily; inh = inhalation.

tients in each treatment group used less than

one-half of the prescribed maintenance dose.

As-needed medication use

As-needed use of budesonide/formoterol was generally low but higher in patients
who received the higher maintenance dose
(Figure 2). The mean (median) numbers of
as-needed inhalations/day were 0.68 (0.17),

0.73 (0.26), and 1.08 (0.45) for 80/4.5 g

b.i.d., 160/4.5 g b.i.d., and 2 160/4.5 g
b.i.d. groups, respectively. Median as-needed
use was below two inhalations/week for 50%
of patients taking two maintenance inhalations of budesonide/formoterol, and 50% of
patients taking the highest recommended dosage (2 160/4.5 g b.i.d. plus as needed) used
a maximum of 3.1 inhalations/week. When
pooling all data it was apparent that, overall,
59% of patients had a mean as-needed use
of 0.5 inhalations/day (< 3.5 inhalations/
week).
For ~2/3 of the study days, patients did
not require any as-needed inhalations of
budesonide/formoterol (Figure 4). Patients in
the two lower-dose groups had slightly more
reliever-free days and fewer high relieveruse days. Across all three treatment groups,
high as-needed use (over four inhalations/
day) was observed on 1.5 (0.4%), 4.3 (1.2%),
and 9.0 (2.5%) days of the study period for
the 80/4.5 g b.i.d., 160/4.5 g b.i.d., and 2
160/4.5 g b.i.d. groups, respectively.

Maintenance use
Maintenance use varied across all three
regimens but was considered to be closer to
physicians prescription targets in the two
lower-dose budesonide/formoterol cohorts:
patients in the 80/4.5 g and 160/4.5 g
b.i.d. groups had a reported mean of 1.8 inhalations/day (versus a prescribed number
of two), compared with 3.2 inhalations/day
(versus a prescribed number of 4) for the 2
160/4.5 g b.i.d. group (Figure 2).

Discussion
Adherence to asthma medication is an
important consideration during treatment as
it is low irrespective of patient age [16, 17,
18], decreases further amongst those patients
who present with difficult-to-control asthma
[17, 19], and is correlated with negative outcomes [17, 18, 20]. Following the approval
and introduction of the budesonide/formoterol MRT in Europe, this observational study
was undertaken to fulfil regulatory commitments and examine this new treatment regimen in real-life clinical practice.

Stllberg, Naya, Ekelund, and Eckerwall

Figure 3. Cumulative range of total budesonide

exposure (both maintenance and reliever use).
b.i.d. = twice daily; ICS = inhaled corticosteroid.

452
similar in terms of as-needed reliever use,
but higher prescribed maintenance doses of
budesonide/formoterol were associated with
incremental increases in as-needed medication use. Thus, these data suggest that higher
maintenance doses were not associated with
greater levels of asthma control but likely
reflect a marker of disease severity and/or
worse compliance with regular ICS/LABA
maintenance therapy.
While the budesonide/formoterol MRT
regimen could be perceived to increase the
risk of ICS over-use, no signs of apparent
misuse were evident in this large real-life
study. Under- and over-use were low and,
based on the present results, ~ 90% of patients were likely to have received a dose of
ICS (~320 g/day of budesonide) that is reported to provide 80% of the clinical benefit
on current control during periods of stable
asthma [21]. The absence of need for reliever therapy reported on all regimens in close
to 2/3 of treatment days further corroborates
these findings. These results are in agreement with those of Patel et al., who recently showed that the efficacy of budesonide/
formoterol MRT was superior to fixed-dose
budesonide/formoterol plus SABA when using electronic adherence trackers [15].

Strengths and limitations of this

study

Figure 4. Mean percentage of days with different

budesonide/formoterol as-needed inhalation use.
b.i.d. = twice daily.

Main findings
As-needed (reliever) use of budesonide/
formoterol was low across all three regimens of budesonide/formoterol MRT. Furthermore, the high number of reliever-free
days combined with the low incidence of
high reliever-use days in all regimens suggests that all budesonide/formoterol MRT
regimens were associated with appropriate
levels of asthma control in the vast majority of patients when used in normal clinical
practice. Overall, the three regimens were

The strengths of this study include the

large size of the study population and the geographic spread of included countries (twelve
representative European countries where the
regimen was first launched). The use of the
IVRS/IWRS provided a patient-friendly and
reliable means of collecting data, but, importantly, also provided a means of reminding
patients who were not frequently reporting
data, thereby ensuring consistency and thoroughness of the dataset. Additionally, the
observational nature of the design combined
with the absence of exclusion criteria relating to patient characteristics/comorbidities
and freedom to co-prescribe other medications yielded a population of patients that can
be considered to represent real-life clinical
practice. This is an important consideration
as patients in randomized controlled trials are
not usually representative of clinical practice

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Real-life use of budesonide/formoterol in asthma

[22], and so observational studies such as

this one are invaluable for informing policy
makers and improving guidelines [23].
Potential weaknesses of the study include
the lack of use of any objective measurements to determine exacerbation rates and
asthma control or airway inflammation, as
well as the absence of documentation of allergic status and concomitant asthma medication use. Such data would have enabled
further conclusions to be drawn between
treatment use and asthma symptoms and
control. It should also be noted that asthma
is a disease that may change in severity over
time and, therefore, a study of longer duration would be required to more closely assess disease changes. The high degree of adherence observed in this study also needs to
be considered. It is possible that the rate of
adherence may have been influenced by use
of the IVRS/IWRS system and its associated
automatic reminder service, thus giving an
inaccurate representation of real-life medication use.
The overall discontinuation rate for this
study was 17.9% (818 patients); of this number, 453 patients voluntarily discontinued
treatment. The reasons for this are not clear
as investigators were not asked to record
why patients discontinued.
Data for confounding factors such as
concomitant medications (including reliever medication), level of patient education,
smoking behavior and motivation for seeking treatment were not collected during this
study. It is possible that collection of such
data would enhance the findings of future
studies and so we recommend that this information be gathered where possible.
Patient age in this study ranged from
17 to 89 years, with a median age of 48.4
years. Given the expanded upper age range
of this population, clinical diagnosis becomes more complex; it is possible that patients near the top of this range may have a
mixed diagnosis of asthma and/or chronic
obstructive pulmonary disease. Therefore,
these patients may not provide results which
accurately represent an asthmatic-only population. Future sub-analyses of treatment results by age might serve to clarify this point.

Interpretation of findings in
relation to previously
publishedwork
As-needed use of budesonide/formoterol
was reduced in this study compared with randomized clinical trials, and the proportion of
days with increased as-needed medication
use was lower. The mean number of as-needed inhalations/day was ~ 1 in randomized
clinical trials of uncontrolled patients on existing standard of care therapy [3, 4, 5, 6, 7,
8], compared with a mean of 0.7 inhalations/
day in this study (on the most commonly
used 160/4.5 b.i.d. regimen). The difference
observed between randomized clinical trials
and this study is likely to be a result of differences in the inclusion criteria and resulting patient population. For example, in the
randomized trials, patients were required
to have used a SABA on 4 out of 7 days of
the baseline run-in period, thereby enriching
the population to be high users of reliever
therapy and potentially those with more severe disease. In contrast, no inclusion criteria
were used in the present study. The results
from this study are consistent with other prospective studies that employed less stringent
inclusion criteria (with respect to baseline
as-needed medication use) where mean asneeded reliever medication use was 0.60.9
inhalations/day [9, 24]. However, mean use
alone fails to capture an accurate picture of
reliever use and proportion of patients likely
to achieve adequate control. Median values
are more informative and were found to be
substantially lower for all three regimens
in this study. For the most commonly used
budesonide/formoterol 160/4.5 g b.i.d.
MRT regimen, at least 50% of patients used
less than two inhalations/week of reliever
therapy and ~2/3 of days were reliever free.
The current observational study indicates
that the total use of budesonide/formoterol
is lower in actual clinical practice than that
seen in randomized clinical trials, suggesting that the MRT concept may be associated
with lower treatment costs than expected.
The average patient on the most commonly
used 160/4.5 g b.i.d. plus as-needed regimen had a mean of 2.1 2.9 total inhalations/day across all twelve countries. Based
on clinical trial data, it is often assumed
this regimen will require two inhalations

454

Stllberg, Naya, Ekelund, and Eckerwall

of maintenance plus roughly one inhalation

of as-needed medication (three inhalations/
day) for all patients [3, 4, 6, 8], representing
a 343% increase in mean medication cost
relative to the findings reported here (for an
average patient across the twelve different
European countries). This discrepancy may
be explained by higher levels of control and
less as-needed use in the real-world setting
compared with previous randomized clinical trials. Additionally, it may be due to the
potential use of other controller medication,
which is not allowed in randomized studies,
or simply the presence of patients with less
severe asthma. It also factors in the result of
lower adherence to maintenance therapy.

Implications for future research,

policy and practice
The use of budesonide/formoterol MRT
has been shown to be highly successful in
asthma management in clinical trials compared with the current standard of care of a
fixed-dose regimen. Furthermore, data from
this observational study have demonstrated
that this treatment regimen is employed
successfully in everyday clinical practice
outside the confines of a structured clinical
study design, although in real-life reminders
are not generally used and this may have positively influenced patient adherence. In order
to ensure that patients received appropriate
assessment and care throughout the study,
two clinic visits were scheduled (at inclusion
and 12 months later) and patients were treated and assessed according to normal clinical
practice during the intervening period. This
arrangement allowed any deterioration in
asthma control to be identified and treated
appropriately. Patients use of budesonide/
formoterol MRT in routine clinical practice
was consistent with the recommendations in
the product label.

high reliever-use days indicate that acceptable levels of asthma control were achieved
for most patients across all budesonide/formoterol MRT regimens in routine clinical
practice.

Acknowledgments
This study was funded by AstraZeneca.
The sponsors were involved in the study design and interpretation of the data, always
in conjunction with the study investigators. The authors would like to thank Matt
Weitz, inScience Communications, Springer
Healthcare for medical writing assistance in
the preparation of this manuscript. This assistance was funded by AstraZeneca. Matt
Weitz does not qualify as an author because
he did not contribute to the conception or
design of the study, the acquisition, analysis,
or interpretation of data, nor did he provide
final approval of the manuscript.

Conflicts of interest
BS has received honoraria for educational activities from AstraZeneca, GlaxoSmithKline, Meda, Merck Sharp and Dohme, and
has served on an advisory board arranged by
AstraZeneca, Novartis, and Boehringer Ingelheim.
GE is a full-time employee of AstraZeneca and holds stock in the company.
IN was an employee of AstraZeneca at
the time the analysis was conducted.
JE is an ex-employee of AstraZeneca, but
has no current conflicts to declare.

References
[1]

[2]

Conclusions
In this real-life follow-up program
across twelve countries, as-needed use of
budesonide/formoterol as part of an MRT
regimen was low. The high percentages
of reliever-free days and low incidence of

[3]

GINA. Global strategy for asthma management

and prevention. 2014. p. Updated 2014. http://
www.ginasthma.org
British Thoracic Society Scottish Intercollegiate
Guidelines Network. British Guideline on the
Management of Asthma. Thorax. 2008; 63 (Suppl
4): iv1-iv121. CrossRef PubMed
Bousquet J, Boulet LP, Peters MJ, Magnussen H,
Quiralte J, Martinez-Aguilar NE, Carlsheimer A.
Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. 2007; 101: 24372446. CrossRef PubMed

455

Real-life use of budesonide/formoterol in asthma

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP,

Martnez-Jimenez NE, Buhl R. Effect of
budesonide/formoterol maintenance and reliever
therapy on asthma exacerbations. Int J Clin Pract.
2007; 61: 725-736. CrossRef PubMed
OByrne PM, Bisgaard H, Godard PP, Pistolesi M,
Palmqvist M, Zhu Y, Ekstrm T, Bateman ED.
Budesonide/formoterol combination therapy as both
maintenance and reliever medication in asthma. Am
J Respir Crit Care Med. 2005; 171: 129-136. CrossRef PubMed
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup
C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma
exacerbations: a randomised controlled, doubleblind study. Lancet. 2006; 368: 744-753. CrossRef PubMed
Rabe KF, Pizzichini E, Stllberg B, Romero S,
Balanzat AM, Atienza T, Lier PA, Jorup C.
Budesonide/formoterol in a single inhaler for
maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest.
2006; 129: 246-256. CrossRef PubMed
Scicchitano R, Aalbers R, Ukena D, Manjra A,
Fouquert L, Centanni S, Boulet LP, Naya IP,
Hultquist C. Efficacy and safety of budesonide/
formoterol single inhaler therapy versus a higher
dose of budesonide in moderate to severe asthma.
Curr Med Res Opin. 2004; 20: 1403-1418. CrossRef PubMed
Demoly P, Louis R, Ses-Petersen U, Naya I,
Carlsheimer A, Worth H, Almeida J, Sears MR.
Budesonide/formoterol maintenance and reliever
therapy versus conventional best practice. Respir
Med. 2009; 103: 1623-1632. CrossRef PubMed
Quirce S, Barcina C, Plaza V, Calvo E, Munoz M,
Ampudia R, Capel M. A comparison of
budesonide/formoterol maintenance and reliever
therapy versus conventional best practice in asthma management in Spain. J Asthma. 2011; 48:
839-847. PubMed
Soes-Petersen U, Kava T, Dahle R, Lei Y, Dam N.
Budesonide/formoterol maintenance and reliever
therapy versus conventional best standard treatment in asthma in an attempted real life setting.
Clin Respir J. 2011; 5: 173-182. PubMed
Dahl R, Chuchalin A, Gor D, Yoxall S, Sharma R.
EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/
budesonide combinations in adults with persistent
asthma. Respir Med. 2006; 100: 1152-1162.
CrossRef PubMed
Ind PW, Dal Negro R, Colman NC, Fletcher CP,
Browning D, James MH. Addition of salmeterol
to fluticasone propionate treatment in moderateto-severe asthma. Respir Med. 2003; 97: 555-562.
CrossRef PubMed
Woodcock AA, Bagdonas A, Boonsawat W, Gibbs
MR, Bousquet J, Bateman ED. Improvement in
asthma endpoints when aiming for total control:
salmeterol/fluticasone propionate versus fluticasone propionate alone. Prim Care Respir J. 2007;
16: 155-161. PubMed
Patel M, Pilcher J, Pritchard A, Perrin K, Travers
J, Shaw D, Holt S, Harwood M, Black P, Weatherall M, Beasley R. Efficacy and safety of maintenance and reliever combination budesonideformoterol inhaler in patients with asthma at risk of

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

severe exacerbations: a randomised controlled

trial. Lancet Respir Med. 2013; 1: 32-42. PubMed
CrossRef
Bender BG, Rankin A, Tran ZV, Wamboldt FS.
Brief-interval telephone surveys of medication
adherence and asthma symptoms in the Childhood Asthma Management Program Continuation
Study. Annals of allergy, asthma & immunology:
official publication of the American College of
Allergy, Asthma, &. Immunology. 2008; 101:
382-386.
Murphy AC, Proeschal A, Brightling CE, Wardlaw AJ, Pavord I, Bradding P, Green RH. The relationship between clinical outcomes and medication adherence in difficult-to-control asthma.
Thorax. 2012; 67: 751-753. CrossRef PubMed
Williams LK, Pladevall M, Xi H, Peterson EL, Joseph C, Lafata JE, Ownby DR, Johnson CC. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with
asthma. J Allergy Clin Immunol. 2004; 114:
1288-1293. CrossRef PubMed
Gamble J, Stevenson M, McClean E, Heaney LG.
The prevalence of nonadherence in difficult asthma.
Am J Respir Crit Care Med. 2009; 180: 817-822.
CrossRef PubMed
Williams LK, Peterson EL, Wells K, Ahmedani
BK, Kumar R, Burchard EG, Chowdhry VK, Favro D, Lanfear DE, Pladevall M. Quantifying the
proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J
Allergy Clin Immunol. 2011; 128: 1185-1191.
PubMed
Masoli M, Holt S, Weatherall M, Beasley R. Doseresponse relationship of inhaled budesonide in
adult asthma: a meta-analysis. Eur Respir J. 2004;
23: 552-558. CrossRef PubMed
Herland K, Akselsen JP, Skjnsberg OH, Bjermer
L. How representative are clinical study patients
with asthma or COPD for a larger real life population of patients with obstructive lung disease?
Respir Med. 2005; 99: 11-19. CrossRef PubMed
Holgate S, Bisgaard H, Bjermer L, Haahtela T,
Haughney J, Horne R, McIvor A, Palkonen S, Price
DB, Thomas M, Valovirta E, Wahn U. The Brussels
Declaration: the need for change in asthma management. Eur Respir J. 2008; 32: 1433-1442. CrossRef
PubMed
Vogelmeier C, DUrzo A, Pauwels R, Merino JM,
Jaspal M, Boutet S, Naya I, Price D. Budesonide/
formoterol maintenance and reliever therapy: an
effective asthma treatment option? Eur Respir J.
2005; 26: 819-828. CrossRef PubMed