Therapeutic Advances in Respiratory Disease Review

Therapeutic Advances in
Differences in the pharmacodynamics Respiratory Disease
(2008) 2(5) 279–299

of budesonide/formoterol and DOI: 10.1177/

1753465808096135
ß SAGE Publications 2008
salmeterol/fluticasone reflect differences Los Angeles, London,
New Delhi and Singapore

in their therapeutic usefulness in asthma

Bertil Lindmark

Abstract: Although the available inhaled corticosteroid (ICS)/long-acting b2-agonist (LABA)

combinations principally work in a similar fashion, they differ in several important ways,
leading to different efficacy. The ICS/LABA combination product budesonide/formoterol can
be used as both maintenance and reliever therapy, providing a fixed maintenance dose,
which does not change, and replacing short-acting b2-agonists as relievers thereby
allowing intervention to address the underlying inflammation at the earliest sign of sympto-
matic worsening. This approach is not suitable for other combination products such as sal-
meterol/fluticasone. Here we review the pharmacological differences of budesonide/
formoterol and salmeterol/fluticasone that permit the use of budesonide/formoterol as both
maintenance and reliever therapy.

Keywords: budesonide/formoterol, salmeterol/fluticasone, asthma, maintenance and reliever

therapy, pharmacodynamics, clinical efficacy, exacerbations

Introduction Well-controlled asthma, according to the Global Correspondence to:

Asthma is a chronic inflammatory disease of the
airways [Global Initiative for Asthma, 2007]
that, if untreated or inadequately treated, can
dramatically impair quality of life and can be
life-threatening. More than 3 million people in
the UK alone suffer from asthma and the disease
places a significant personal, social and financial
burden on individuals, their families and the heal-
thcare systems that support them [Masoli et al.
2004]. The nature of the disease is characterised
by periodic symptomatic worsenings and
when additional controller treatment is needed
these are normally classified as exacerbations.
In patients with a history of multiple exacerba-
tions the risk for long-term progressive decline in
lung function has been established [Bai et al.
2007] although no association has been seen in
patients without exacerbations. This means
that patients require long-term support and
medication and prevention of exacerbations is
essential to reduce future risk for patients.
Bertil Lindmark
Initiative for Asthma (GINA) clinical guidelines AstraZeneca R&D,
[2007], is defined by no troublesome day- or Lund, Sweden.
Bertil.E.Lindmark@
night-time symptoms, little or no requirement astrazeneca.com
for reliever medication, near normal lung func-
tion and no exacerbations.
Pharmacotherapy for patients with mild to
moderate asthma generally consists of an inhaled
corticosteroid (ICS), with or without a long-
acting b2-agonist (LABA), taken daily to prevent
symptoms emerging along with a short-acting
b2-agonist (SABA) such as salbutamol or
terbutaline taken as needed to relieve any
emergent symptoms. Asthma medications are
usually administered via inhalation as this offers
the most direct route to their primary site of
action, the lungs. Despite the efficacy of available
medications, many patients remain confused
about when to use which inhaler and there is
still an over-reliance on SABAs, an approach
that treats symptoms but fails to address the

http://tar.sagepub.com 279
Therapeutic Advances in Respiratory Disease
underlying cause of the worsening symptoms –
airway inflammation. As b-agonists do not have
any substantial anti-inflammatory properties
they can, in the worst case, mask asthma dete-
rioration, placing patients at increased risk of a
severe, potentially life-threatening exacerbation.
Moreover, many asthma patients remain inade-
quately controlled according to clinical guideline
targets and continue to suffer a reduced quality of
life as a result of their disease [Adachi et al. 2008;
Desfougeres et al. 2007; Partridge et al. 2006;
Rabe et al. 2004, 2000].
Suboptimal asthma control can present many
challenges in the demanding primary care setting
where levels of poor control can often remain
hidden from the healthcare provider [Chapman
et al. 2008; Levy, 2008]. A survey of primary
care physicians and their asthma patients in
Canada revealed that 59% of the 10,428 patients
who took part met the criteria for uncontrolled
asthma according to current clinical guidelines
[Chapman et al. 2008]. Other surveys have
demonstrated similarly high levels of uncontrolled
asthma in real-world evaluations [van den
Nieuwenhof et al. 2008; Cazzoletti et al. 2007].
Given the prevalence and morbidity of asthma,
the clinical challenge is to find effective ways to
help patients with suboptimal asthma control.
These may include the development and imple-
mentation of individualised asthma plans and
asthma clinics. However, such approaches
require a significant time investment that is not
always achievable, particularly in the primary
care setting. Indeed, while primary care
physicians are generally aware of the recommen-
dations for the management of asthma patients,
implementation is often poor [Levy, 2008]. It is
important to emphasise that approaches that rely
on a significant deterioration in asthma symptoms
and action plans have been shown to be ineffective
at preventing exacerbations [Fitzgerald et al.
2004; Harrison et al. 2004]. Alternative medica-
tion strategies also offer an effective method to
control asthma symptoms, reduce the risk and/or
severity of exacerbations and can complement
other approaches to asthma management.
Combination inhalers, containing both an ICS
and a LABA, offer one such alternative medica-
tion strategy and are included in the current
GINA clinical guidelines for the management of
asthma [GINA, 2007]. For adults whose asthma is
not controlled on low/moderate dose ICS alone,
280
the GINA guidelines [2007] recommend an
ICS in combination with a LABA, at a dose
related to the severity of asthma. Combination
inhalers are preferred to two separate inhalers
as they probably improve compliance with the
ICS component [NICE Technology Appraisal
Guidance 138, 2008]. The two most commonly
used fixed-dose combinations are budesonide/
formoterol (SymbicortÕ , AstraZeneca, Lund,
Sweden) and salmeterol/fluticasone (SeretideTM,
GlaxoSmithKline, Uxbridge, UK), although
more recently another fixed-dose combination
product of beclomethasone/formoterol
(FosterTM, Chiesi Farmaceutica, Parma, Italy)
has become available in some European countries
as fixed-dose maintenance therapy only [Papi et al.
2007]. However, for the purposes of this review
the focus will be on the two most commonly used
combinations of budesonide/formoterol and sal-
meterol/fluticasone.
Despite both combination inhalers containing
an ICS and a LABA, there are important pharma-
cological and pharmacodynamic differences
between the respective components in each com-
bination, and these differences impact on the way
the products can be used clinically. Specifically,
the pharmacodynamic profile of budesonide/for-
moterol but not that of salmeterol/fluticasone
offers the possibility to use budesonide/formoterol
both as a daily maintenance treatment and as
a reliever therapy as needed – the SymbicortÕ
maintenance and reliever therapy (Symbicort
SMARTÕ ) approach. While there are clear
difference between the two ICS components,
budesonide and fluticasone, and between the
two LABA components, formoterol and
salmeterol, some investigators believe that it is
the difference in the LABA components that
allows budesonide/formoterol to be used as both
a maintenance and reliever therapy [Barnes,
2007; Cazzola and Curradi, 2007]. This approach
provides patients with an adequate maintenance
dose and in addition an increased dose of the
anti-inflammatory component of their medication
(the budesonide component of the combination)
when they have symptoms and addresses the
underlying cause of the symptomatic worsening
while avoiding confusion on which inhaler to
use. It should be noted that 80/4.5 mg and 160/
4.5 mg strength pMDIs are approved for use in
some markets (SymbicortÕ in the US, Australia
and South Africa; and VannairÕ in Venezuela,
New Zealand and Switzerland) as fixed-dose
therapy for asthma and not as maintenance and
http://tar.sagepub.com

reliever therapy (Symbicort SMARTÕ ), which is
approved using the TurbuhalerÕ . At this time,
these pMDI strengths/devices have not been
studied for maintenance and reliever therapy
and require two actuations per delivered dose.
In addition, dosing with two actuations results
in a higher dose of formoterol per dose than is
currently received with Symbicort SMARTÕ.
For these reasons, the currently available pMDI
devices at these strengths are not appropriate for
use as single maintenance and reliever therapy.
SymbicortÕ maintenance and reliever therapy
has now been extensively studied both in com-
parison with ICS monotherapy (two- to four-fold
higher maintenance) and higher fixed-dose com-
bination therapy. This review will examine the
pharmacological and pharmacodynamic proper-
ties of the components of the budesonide/formo-
terol and salmeterol/fluticasone combinations
and evaluate the available clinical data as a basis
for informing clinical decision-making.
Pharmacological and pharmacodynamics of
combination therapies for asthma
management
LABA component
Formoterol is a b2-agonist of similar or higher
intrinsic efficacy than salbutamol and terbutaline.
Formoterol added to ICS has proven effective in
improving asthma control as maintenance therapy
in all types of asthma patients [O’Byrne et al.
2005; Pauwels et al. 1997] and also as a reliever
medication, significantly reducing the exacerba-
tion rate and improving symptoms [Cheung
et al. 2006; Rabe et al. 2006b; Pauwels et al.
2003; Tattersfield et al. 2001]. Formoterol is a
potent airway smooth muscle relaxant and shows
high affinity and selectivity for b2-adrenoceptors
[Anderson, 1993]. Like short-acting b-agonists
(SABAs), formoterol exhibits a dose–response
curve with increasing doses providing greater
bronchoprotective and bronchodilator effects
[Cheung et al. 2006; van der Woude et al. 2004;
Boonsawat et al. 2003; Seberova and Andersson,
2000; Anderson, 1993; Faulds et al. 1991].
Moreover, formoterol delivers this increased effi-
cacy as rapidly as salbutamol and terbutaline
[Anderson, 1993; Faulds et al. 1991], with a dura-
tion of action in excess of 12 hours [Lötvall et al.
2006]. Finally, adequate water solubility and
moderate lipophilicity of formoterol ensures
rapid diffusion to b2-adrenoceptors on the
http://tar.sagepub.com
Review
% increase
in FEV1 Budesonide/formoterol 160/4.5 µg 1 inhalation
Salmeterol/fluticasone 50/250 µg 1 inhalation
25
Placebo 1 inhalation
20
*
15 *p<0.001 vs salmeterol/fluticasone
10 *
5
0
−5
0 5 10 15
Time (minutes)
Figure 1. Onset of bronchodilator action (percentage increase in FEV1
from baseline) of single doses of salmeterol/fluticasone and
budesonide/formoterol at 3 and 15 minutes in patients with stable
asthma [Palmqvist et al. 2001].
airway smooth muscle cells and a rapid broncho-
dilator effect [Lötvall, 2001].
Like formoterol, salmeterol is a b2-agonist that
achieves bronchodilation via relaxation of the
airway smooth muscle. However, salmeterol
has lower intrinsic efficacy and slower onset of
effect than all other b-agonists that have been
developed for clinical use [Anderson, 2000].
The onset of action (measured as increase in
FEV1) of salmeterol/fluticasone and budesonide/
formoterol are shown in Fig. 1 [Palmqvist et al.
2001]. Salmeterol may diffuse more slowly to
the b2-adrenoceptors because of its high lipophi-
licity, and this may explain the slower onset of
action [Lötvall, 2001]. Salmeterol is administered
at its maximally effective dose in clinical practice
as there is no evidence of a dose–response rela-
tionship above 50 mg twice daily [Pohunek et al.
2004; Palmqvist et al. 2001, 1999]; indeed,
double-dose formoterol has greater additional
bronchoprotective effects, which may be impor-
tant in preventing exacerbations, than double-
dose salmeterol [van der Woude et al. 2004;
Currie et al. 2003]. Because of the slow onset of
action and the lack of dose–response, salmeterol is
not considered to be suitable for use as a reliever
medication.
The systemic activity of these two agents also
distinguishes between them, again supporting
the use of formoterol but not salmeterol as a
reliever medication. The systemic activity of
formoterol is short-lived, comparable with
281
Therapeutic Advances in Respiratory Disease
that reported for salbutamol or terbutaline
[Seberova and Andersson, 2000]. Consequently,
the risk of a longer duration of systemic side
effects with formoterol compared with
salbutamol or terbutaline is minimal. In contrast,
the systemic effect of salmeterol is long-lasting
and repeated dosing increases the risk for persis-
tence of b-agonist related adverse systemic
side-effects [Guhan et al. 2000; Bennett and
Tattersfield, 1997].
Corticosteroid component
The corticosteroid components of the formoterol/
budesonide and salmeterol/fluticasone combina-
tion products also have distinct pharmacological
and pharmacodynamic profiles that are of
relevance in terms of their clinical use. Inhaled
budesonide has been available for the manage-
ment of asthma since the early 1980s.
Budesonide exerts a pronounced and long-lasting
anti-inflammatory effect on airway tissues when
given via inhalation [Laitinen et al. 1992] achiev-
ing significant and sustained improvements in
both symptoms and lung function [Juniper et al.
1990]. Budesonide has a relatively high water
solubility and is readily dissolved in mucosal
fluids; as a consequence, budesonide is rapidly
absorbed into airway tissues. Importantly, the
absorption of budesonide into airways tissue
does not appear to be affected by lung function,
with comparable plasma concentrations achieved
following pulmonary delivery in healthy and
asthmatic individuals [Harrison and Tattersfield,
2003]. Once absorbed intracellularly, budesonide
undergoes reversible conjugation with intracellu-
lar fatty acids, which prolongs its retention within
the airways – its principle site of therapeutic action
– and its duration of action [Miller-Larsson et al.
1998; Wieslander et al. 1998]. A dose–response
relationship has been demonstrated for budeso-
nide [Miyamoto et al. 2000; Busse et al. 1998]
and an increase in the dose and frequency of
budesonide administration has been shown to be
beneficial in quickly reducing inflammation and
bronchoconstriction in patients with unstable
asthma [Toogood et al. 1982]. Moreover, increas-
ing the dose and frequency of dosing of budeso-
nide at the first sign of worsening asthma has been
shown to effectively manage an exacerbation as
well as a regular four-fold higher maintenance
dose of budesonide [Foresi et al. 2000].
Like budesonide, fluticasone also has an anti-
inflammatory effect on airway tissues when given
via inhalation and has an approximately 2:1
282
potency vs budesonide in vitro [GINA, 2007].
However, in contrast to budesonide, fluticasone
does not undergo the intracellular esterification
process and consequently is not as well retained
within the airway tissue [Tunek et al. 1997].
Unlike budesonide, the absorption of fluticasone
is affected by lung function with markedly lower
plasma concentrations achieved in asthmatic
individuals compared with non-asthmatics
[Harrison and Tattersfield, 2003]. Moreover,
fluticasone is highly lipophilic and while this
results in a long plasma elimination half-life it is
also suggestive of greater systemic accumulation
of the steroid upon repeat dosing [Thorsson et al.
2001]. Importantly, highly lipophilic drugs such
as fluticasone are more likely to be retained in the
lumen of the airways for longer than less lipophilic
drugs and as a result can be more affected by
airway (mucociliary) clearance and coughing,
suggesting that a reduced dosage remains in the
lungs [Edsbäcker et al. 2008].
The pharmacodynamic differences described
above between formoterol/salmeterol and bude-
sonide/fluticasone impact on the clinical use of
the two products, with the pharmacological and
pharmacodynamic properties of budesonide/for-
moterol allowing for the use of the combination
as both maintenance and reliever therapy.
Clinical effectiveness
Clinical effectiveness of combination therapy
For both the budesonide/formoterol and salme-
terol/fluticasone combinations, the addition of a
LABA to the ICS component for patients not
adequately controlled on ICS alone has been
shown to produce greater improvements in pul-
monary function and symptomatology and
reduction in the exacerbation rate than higher
doses of ICS alone [Barnes, 2007; Heyneman
et al. 2002; O’Byrne et al. 2001; Shrewsbury
et al. 2000; Pauwels et al. 1997; Woolcock et al.
1996; Greening et al. 1994].
O’Byrne and colleagues [2001] reported the
results of a one-year trial in which patients with
mild persistent asthma were stratified according
to whether they were currently receiving an ICS
or not. Among 698 patients who were initially
corticosteroid-free, treatment with budesonide
plus formoterol resulted in comparable reduc-
tions in the risk of severe exacerbations
and symptom-free days as budesonide alone
http://tar.sagepub.com

(60% and 48%, respectively) but an improve-
ment in lung function. For patients already
receiving an ICS (n ¼ 1272), addition of formo-
terol proved more effective than doubling the
ICS dose alone, reducing the risk for severe
exacerbations by 43% and reducing the number
of poorly controlled days by 30%. In a separate
study, the addition of formoterol to ongoing
budesonide therapy reduced the rates of severe
and mild asthma exacerbations by 63% and
62%, respectively, compared with a reduction of
49% and 37% for the same dose of budesonide
alone [Pauwels et al. 1997].
Similar beneficial effects have been reported
when salmeterol was added to ICS therapy.
The addition of salmeterol to beclomethasone
achieved greater improvements in lung function
than increasing the dose of beclomethasone alone
among patients poorly controlled with ICS alone
[Greening et al. 1994]. Consistent with this,
Woolcock and coworkers [1996] found that the
addition of salmeterol to beclomethasone among
patients not controlled with beclomethasone
alone achieved greater improvements in lung
function and significantly greater symptom
control compared with doubling the beclometha-
sone dose alone. In this study, doubling the dose
of salmeterol from 50 to 100 mg twice daily in
combination with beclomethasone had no
added benefit on efficacy but increased the
reporting of b-agonist-related adverse events
[Woolcock et al. 1996]. The beneficial effect of
adding salmeterol to fluticasone has also been
compared with an increased dose of fluticasone
alone in patients with moderate to severe asthma,
with marked improvements in lung function and
symptom control [Heyneman et al. 2002].
However, in a non-specialist practice setting
the addition of salmeterol to ongoing anti-
inflammatory therapy (beclomethasone) was no
more effective that placebo in preventing
exacerbations, although it did significantly
improve peak expiratory flow and reduce
salbutamol use [D’Urzo et al. 2001].
Having established the efficacy of the fixed-dose
budesonide/formoterol and salmeterol/
fluticasone combination therapies in the treat-
ment of uncontrolled asthma, several studies
have performed direct comparisons between the
two as part of their design. The 6-month
COMPASS study recruited adults and adoles-
cents who were symptomatic on their existing
ICS dose alone during a two-week run-in
http://tar.sagepub.com
Review
and randomised 1105 patients to fixed-dose bude-
sonide/formoterol (640 mg/day; BDP equivalent
1000 mg/day) and 1123 patients to fixed-dose sal-
meterol/fluticasone (500 mg/day; BDP equivalent
1000 mg/day). The effects of both fixed-dose regi-
mens were similar for all of the efficacy
parameters except for a statistically significant
increase in asthma-related hospital admissions/
emergency room treatments with salmeterol/
fluticasone [Kuna et al. 2007]. The much smaller
comparator study by Aalbers et al. [2004]
also found similar efficacy and levels of well-
controlled asthma (primary endpoint) with the
same fixed-doses of budesonide/formoterol and
salmeterol/fluticasone combination therapies.
In a third study, a large 24-week double-blind
study (EXCEL) comparing the same fixed-dose
of budesonide/formoterol (400/12 mg twice daily
[metered dose]; BDP equivalent 1000 mg/day)
and fixed-dose salmeterol/fluticasone (50/250 mg
twice daily; BDP equivalent 1000 mg/day)
in adults with asthma, Dahl and colleagues
reported that both regimens produced equal
improvements in well-controlled asthma and
lung function, and similar reductions in the
overall asthma exacerbation rate, which was the
primary variable [Dahl et al. 2006]. The published
study attempted to suggest that fixed-dose salme-
terol/fluticasone was superior to budesonide/for-
moterol in reducing the rate of moderate/severe
exacerbations using post hoc analyses on the last
8 weeks of the study but the weaknesses in this
post hoc analysis and failure to fully report the
most severe exacerbations by treatment group,
which were reduced in the budesonide/formoterol
group, have been highlighted in the literature
[Naya and Andersson, 2007].
In a meta-analysis of the effectiveness of fixed-
dose maintenance therapy including all of the
above studies with either budesonide/formoterol
or salmeterol/fluticasone [Edwards et al. 2007]
there were no differences between the fixed-
dose ICS/LABA combinations apart from one,
namely the increased risk of severe exacerbations
resulting in emergency treatment, which were
consistently higher in all three studies in patients
receiving salmeterol/fluticasone with an overall
49% increase that was statistically significant
[Edwards et al. 2007].
Meta-analyses focusing on hospital admissions
due to exacerbations
The reported reduction in the risk of
asthma-related hospitalisations/ER visits with
283
Therapeutic Advances in Respiratory Disease
budesonide/formoterol versus salmeterol/flutica-
sone is supported by other independent
meta-analyses of fixed-dose combinations versus
ICS alone that have excluded studies with the
potential for LABA monotherapy. Jaeschke
and coworkers [2007] analysed data from 18
clinical studies including formoterol with ICS
in patients with asthma and found that the
addition of formoterol resulted in a 41% reduc-
tion in asthma-related hospitalisation admissions
versus a similar or higher dose of ICS alone
[Jaeschke et al. 2007], whereas a separate
meta-analysis of 52 studies in which salmeterol
was added to ICS therapy found no change
in the risk of hospitalisation admissions
[Nelson et al. 2007].
The greater reduction in the risk of asthma-
related hospitalisation/emergency room visits
seen with fixed-dose budesonide/formoterol
compared with fixed-dose salmeterol/fluticasone
is most likely due to the different pharmacology
of the LABAs as discussed above; that is, the
greater intrinsic activity and bronchoprotective
effect of formoterol compared with salmeterol
during periods with severe exacerbations ensures
that this LABA provides greater protection from
severe exacerbations.
Responding to changing symptoms
Asthma exacerbations have considerable impact
on patients’ quality of life together with health-
care resource use and costs. Thus, responding
promptly to worsening symptoms with the aim
of preventing or ameliorating an exacerbation is
a key clinical aim of asthma management.
100
Window of opportunity
% Change from day –14
80 to increase
anti-inflammatory?
60
40
20
–15 –10 –5
Days before and after an exacerbation
Figure 2. Asthma exacerbations: a descriptive study of 425 severe exacerbations showing change in SABA
reliever use and night-time symptoms in the 14 days prior to and after an exacerbation, adapted from
Tattersfield et al. [1999], and a hypothetical window of opportunity to ameliorate or abort these events
through early intervention with as needed budesonide/formoterol.
284
Although it is not possible to predict with any
accuracy when an exacerbation might occur or
how severe such an event might be, reliever use
with SABA increases, on average, 5–7 days prior
to an exacerbation [Tattersfield et al. 1999]. This
presents a window of opportunity to intervene
early with a higher efficacy b-agonist for
increased bronchoprotection and additional ICS
anti-inflammatory therapy at the time of increas-
ing symptoms with the aim of preventing the
development of a full exacerbation (Fig. 2).
As mentioned previously, SABAs do not have sig-
nificant anti-inflammatory properties and can, in
the worst case scenario, mask underlying asthma
deterioration by achieving acute but temporary
symptomatic relief but failing to address the
underlying inflammatory process. Studies have
shown that as a result of the pharmacological
and pharmacodynamic properties of the compo-
nents, the budesonide/formoterol combination is
suitable for as needed treatment of worsening
symptoms in addition to its proven use as a main-
tenance medication. Formoterol, when used as
needed, is the only b-agonist shown to reduce
asthma exacerbations [Pauwels et al. 2003;
Rabe et al. 2006b; Tattersfield et al. 2001]. This
benefit is also seen irrespective of background
maintenance therapy. Moreover, budesonide is
also the only ICS that when used as needed has
been shown to reduce asthma exacerbations
[Rabe et al. 2006b].
Maintenance and as-needed reliever therapy
Budesonide/formoterol maintenance and reliever
therapy (Symbicort SMARTÕ ) is a new concept
Night-time symptoms
SABA rescue use
…… Hypothetical outcome
0 5 10 15
http://tar.sagepub.com

focusing on maintenance and as-needed therapy
using the same controller/anti-inflammatory
inhaler. This new treatment approach is
endorsed in the GINA guidelines [2007]. The
budesonide/formoterol maintenance and reliever
therapy approach increases controller therapy
on demand when control deteriorates; when sta-
bility is regained (symptoms abate) patients
default to fixed-dose maintenance therapy that
is usually at a lower dose than is possible with a
standard fixed-dose ICS/LABA regimen. Thus,
the greatest benefits are seen when control is
lost but during periods of stable control patients
default to a lower maintenance dose without any
increase in as-needed doses. This is feasible with
budesonide/formoterol but not salmeterol/fluti-
casone because of the pharmacodynamic proper-
ties of formoterol and budesonide, as discussed
earlier.
In the budesonide/formoterol clinical trial
programme, studies were conducted to address
how budesonide/formoterol maintenance and
reliever therapy compared with: higher-dose
ICS [Rabe et al. 2006a; O’Byrne et al. 2005;
Scicchitano et al. 2004]; alternative reliever
therapy and the same maintenance dose of ICS/
LABA [Rabe et al. 2006b; O’Byrne et al. 2005];
and higher doses of maintenance ICS/LABA
therapy [Bousquet et al. 2007; Kuna et al. 2007;
Vogelmeier et al. 2005]. The studies were per-
formed in patients with uncontrolled
asthma assessed on maintenance ICS alone in
the majority of studies; the main differences
between them lay in the types of treatment
patients were on when their asthma control was
assessed (see Table 1). These studies included
over 15,000 asthma patients aged
12 years
and have confirmed the efficacy and safety
of the budesonide/formoterol maintenance and
reliever therapy approach compared with
two- four-fold higher doses of ICS plus a SABA
as reliever therapy as well as with similar or
higher doses of ICS/LABA combinations
(Tables 2 and 3). In all of these studies a
severe exacerbation was defined as hospitalisa-
tion/emergency department (ED) treatment due
to asthma worsening, the need for oral steroid
therapy for
3 days because of asthma
(as judged by investigator), while for the STAY,
STEAM and STEP studies [Rabe et al. 2006a;
O’Byrne et al. 2005; Scicchitano et al. 2004];
the definition of a severe exacerbation was as
above but also included a decrease in peak
expiratory flow (PEF).
http://tar.sagepub.com
Review
Budesonide/formoterol maintenance and relie-
ver therapy vs higher-dose ICS
The efficacy of the budesonide/formoterol
maintenance and reliever approach has been
compared with higher doses of ICS alone in
three double-blind studies: STEAM [Rabe et al.
2006a], STEP [Scicchitano et al. 2004], and
STAY [O’Byrne et al. 2005].
The STAY study [O’Byrne et al. 2005] was a
12-month, double-blind, randomised, parallel-
group study in patients aged 4–80 years with
asthma treated with 400–1000 mg/day of ICS
(adults; 200–500 mg/day children). The study
was primarily conducted to examine the efficacy
of adding budesonide/formoterol as reliever
therapy for patients already receiving budeso-
nide/formoterol as maintenance therapy with
SABA as reliever medication. In total, 2760
patients were randomised to either budesonide/
formoterol maintenance and reliever regimen,
budesonide/formoterol maintenance therapy
(80/4.5 mg twice daily; 250 mg/day BDP equiva-
lent) plus terbutaline (0.4 mg) as needed, or
higher-dose budesonide (320 mg twice daily;
1000 mg/day BDP equivalent) plus terbutaline
(0.4 mg) as needed. Children received half the
maintenance dose given at night. Budesonide/for-
moterol maintenance and reliever therapy
significantly prolonged the time to first severe
exacerbation (defined as hospitalisation/ED
treatment due to asthma worsening, the need
for oral steroid therapy for
3 days or a PEF
less than 70% of baseline on two consecutive
days) compared with budesonide/formoterol
maintenance therapy plus SABA and higher-
dose budesonide plus SABA (p50.001 for
both), resulting in a 45–47% lower exacerbation
risk vs the other two treatment groups.
Budesonide/formoterol maintenance and reliever
therapy also prolonged the time to the first,
second and third exacerbation requiring medical
intervention (p50.001) compared with the
alternative regimens. Patients treated with the
budesonide/formoterol maintenance and reliever
therapy regimen experienced significantly fewer
severe exacerbations overall and fewer severe
exacerbations that required hospital or emer-
gency room treatment. Similarly, lung function
and asthma symptoms were significantly
improved among patients receiving the budeso-
nide/formoterol maintenance and reliever
regimen compared with those treated with the
higher-dose budesonide plus terbutaline regimen
(Tables 2 and 3) [O’Byrne et al. 2005].
285
286
Table 1. Budesonide/formoterol maintenance and reliever therapy clinical study program: treatment step when asthma control was assessed as insufficient prior to
randomisation

Individual double-blind SMART studies COSMOS

Open-label
study n ¼ 2143
GINA STEAM STEP STAY SMILE COMPASS AHEAD n ¼ 2309 [Vogelmeier
Treatment n ¼ 697 n ¼ 1890 n ¼ 2760 n ¼ 3394 [Rabe n ¼ 3335 [Bousquet et al. 2005]
step [Rabe [Scicchitano [O’Byrne et al. 2006b] [Kuna et al. et al. 2007]
et al. 2006a] et al. 2004] et al. 2005] 2007]
Therapeutic Advances in Respiratory Disease

Step II 100 77 93 0 84 41 51
(% patients)
Step III 0 23 7 100 # 16 53 36
(% patients)
Step IV 0 0 0 0 0 6 13
(% patients)
Test treatments
SMART 2
80/4.5 mg 2
160/ 80/4.5 mg bid 160/4.5 mg bid 160/4.5 mg 2
160/4.5 mg 1 or 2
160/
regimen once daily 4.5 mg plus as plus as bid plus as bid plus as 4.5 mg bid plus
plus as once daily needed* needed needed needed as needed
needed plus as
needed
Comparator Bud 400 mg Bud 400 mg Bud 400 mg Bud/form 160/ Bud/form SFC 50/500 mg SFC 250/50 mg
regimen once daily bid plus bid plus 4.5 mg bid 320/9 mg bid plus SABA bid plus SABA
plus SABA SABA as SABA as plus SABA as bid plus as needed as needed
as needed needed needed needed and SABA as although SFC
and bud/ bud/form needed titration
form 80/ 160/4.5 mg bid and SFC allowed the
4.5 mg bid plus formo- 250/50 mg dose to
plus SABA terol as bid plus increase to
as needed needed SABA as 500/50 mg bid
needed or decrease to
100/50 mg bid

Step II ¼ low to moderate dose ICS alone (1000 mg/day BDP equivalent).
Step III ¼ high-dose ICS (41000mg/day BDP equivalent) or low to moderate dose ICS (1000 mg/day BDP equivalent) þ LABA.
Step IV ¼ high-dose ICS þ LABA (41000 mg/day BDP equivalent).
*All patients on high-dose ICS (4800 mg budesonide equivalent) without LABA.
#All patients on low-dose ICS/LABA at 50% of the recommended upper limit for step III (400 mg budesonide equivalent per day). This study was to assess if add-on efficacy could
be detected with both as needed budesonide and as needed formoterol in patients on low dose combination therapy.
Bud: budesonide; bud/form: budesonide/formoterol; SFC: salmeterol/fluticasone.

http://tar.sagepub.com
 Table 2. Budesonide/formoterol maintenance and reliever therapy clinical study program: exacerbations requiring at least oral steroids and improvements in lung
function

Study and Study Study treatments N Mean ICS dose, Rate reduction for Reduction in hospitali- Effects on lung function
citation duration mg/day (BDP first exacerbation sations and emergency
(months) equivalent) room visits

http://tar.sagepub.com
STEAM – mild- 6 Budesonide/ 354 240 (375) 76% fewer severe 90% fewer asthma- Significant improvements in
to-moderate formoterol (2
80/ exacerbations required related hospital and favour of bud/form SMART.
asthma 4.5 mg qd) SMART hospital/emergency emergency visits with Between-treatment
room visits and oral SMART (p50.001) differences:
[Rabe et al. Budesonide 342 320 (500) steroid courses with  Morning PEF: 25 L/min
2006a] (2
160 mg qd) plus SMART (p50.001) (p50.001)
SABA  Evening PEF: 18.8 L/min
(p50.001)
 FEV1: 0.148 L (p50.001)
STEP – 12 Budesonide/ 947 466 (728) 45% fewer severe Fewer asthma-related Significant improvements in
moderate-to- formoterol (2
160/ exacerbations required hospital/emergency favour of bud/form SMART.
severe asthma 4.5 mg qd) SMART hospital/emergency room visits with Between-treatment
room visits or oral SMART: 15 vs 25 differences:
[Scicchitano Budesonide 943 640 (1000) corticosteroid use with events (not significant)  Morning PEF: 20.3 L/min
et al. 2004] (2
160 mg bid) plus SMART (p50.001) (p50.001)
SABA  Evening PEF: 14.0 L/min
(p50.001)
 FEV1: 0.10 L (p50.001)
STAY 12 Budesonide/ 925 160 (250) 50% fewer severe Fewer asthma-related Significant improvements in
[O’Byrne et al. formoterol (80/ exacerbations required hospital/emergency favour of bud/form SMART
2005] 4.5 mg bid) SMART hospital/emergency room visits with SMART vs both bud/form þ SABA
room visits or oral vs bud/Form þ SABA: and bud þ SABA for:
Budesonide/ 926 160 (250) steroid use with SMART 25 vs 32 events (not Morning and evening
formoterol (80/ vs bud/form þ SABA significant) PEF (p50.001 both
4.5 mg bid) plus comparisons)
SABA
Budesonide 909 640 (1000) 45% fewer severe Fewer asthma-related
(320 mg bid) plus SABA exacerbations required hospital/emergency  SMART: 355/360 L/min
hospital/emergency room visits with SMART  Bud/form þ SABA: 346/
room visits or oral vs bud þ SABA: 25 vs 29 349 L/min
steroid use with SMART events (not significant)  Bud/form þ SABA: 346/
vs bud þ SABA 349 L/min
 Bud þ SABA: 339/345 L/min
FEV1 (p50.001 both com-
parisons)
 SMART: 2.51 L
 Bud/form þ SABA: 2.43 L
 Bud þ SABA: 2.41 L

(Continued)
Review

287
288
Table 2. Continued.

Study and Study Study treatments N Mean ICS Rate reduction for Reduction in hospitali- Effects on lung function
citation duration dose, mg/day first sations and emergency
(months) (BDP exacerbation room visits
equivalent)
Therapeutic Advances in Respiratory Disease

SMILE 12 Budesonide/formoterol 1107 803 (514) 27% lower risk with 27% fewer overall with Significant improvements in
[Rabe et al. (160/4.5 mg bid) SMART SMART vs formoterol SMART vs formoterol favour of bud/form SMART
2006b] Budesonide/formoterol 1137 640 (1000) as-needed (HR: 0.73 as-needed (98 vs 70 vs both formoterol and
(2
160/4.5 mg bid) plus [95% CI: 0.59–0.90]) events; p ¼ 0.046) terbutaline as needed for:
formoterol (4.5 mg)
Budesonide/formoterol 1138 640 (1000)
(2
160/4.5 mg bid) plus
SABA
45% lower risk with 39% fewer overall with Morning and evening PEF
SMART vs terbutaline SMART vs terbutaline change from baseline
as-needed (HR: 0.55 as-needed (70 vs 115 (p50.001 both comparisons)
[95% CI: 0.45–0.68]) events; p ¼ 0.001)
 SMART: 15.3/13.8 L/min
 Form as-needed: 10.6/
8.5 L/min
 Terb as-needed: 7.9/
7.5 L/min
FEV1 change from baseline
(p50.001 both comparisons)
 SMART: 0.06 l
 Form as-needed: 0.01 l
 Bud as-needed: 0.02 l
COSMOS 12 Budesonide/formoterol 1067 Flexible 25% lower risk with Fewer asthma-related Early, sustained and com-
[Vogelmeier SMART (320/9 to 640/ SMART vs SFC hospital/emergency parable improvement in
et al. 2005] 18 mg) (p ¼ 0.0076) room visits with FEV1 between the treatment
Salmeterol/fluticasone 1076 SMART vs SFC: 44 vs arms
(100/200 to 100/ 50 events (not
1000 mg) plus SABA significant)

http://tar.sagepub.com
 COMPASS 6 Budesonide/formoterol 1107 483 (755) 26% lower risk with 3% fewer asthma- Comparable improvements
[Kuna et al. (160/4.5 mg bid) SMART SMART vs fixed-dose related hospital/emer- in all three treatment arms
2007] Fixed-dose budesonide/ 1105 640 (1000) bud/form þ SABA gency room visits with Morning and evening PEF
formoterol (320/9 mg (p ¼ 0.026) SMART vs fixed-dose  SMART: 363/368 L/min

http://tar.sagepub.com
bid plus SABA bud/form plus SABA (5  Bud/form þ SABA: 362/
Fixed-dose salmeterol/ 1123 500 (1000) 33% lower risk with vs 5 events/100 366 L/min
fluticasone (2
25/ SMART vs SFC patients/6 months;  SFC: 367/370 L/min
125 mg bid) plus SABA (p ¼ 0.003) p ¼ 0.87) FEV1 (p50.001 both
comparisons)
39% fewer asthma-  SMART: 2.69 l
related hospital/emer-  Bud/Form þ SABA: 2.66 l
gency room visits with  SFC: 2.67 l
SMART vs SFC (5 vs 8
events/100 patients/6
months; p ¼ 0.0015)

AHEAD 6 Budesonide/formoterol 1154 792 (1238) Time to first exacer- 31% reduction in Comparable improvements
[Bousquet (2
160/4.5 mg bid) bation not significantly asthma-related hospi- in lung function
et al. 2007] SMART different between tal/emergency room Morning PEF:
High-dose salmeterol/ 1155 1000 (2000) treatment groups visits with SMART vs  SMART: 359.5 L/min
fluticasone (50/500 mg (hazard ratio 0.82; SFC (9 vs 13 events/100  SFC: 359.4 L/min
bid) plus SABA p ¼ 0.12). patients/year; Evening PEF
p ¼ 0.046)  SMART: 362.3 L/min
21% reduction in  SFC: 361.7 L/min
overall exacerbation
rate with SMART vs
high-dose SFC (25 vs
31 events/100
patients/year;
p ¼ 0.039)

Bud: budesonide; bud/form: budesonide/formoterol; SFC: salmeterol/fluticasone.

Review

289
290
Table 3. Budesonide/formoterol maintenance and reliever therapy clinical study program: adjusted mean changes in secondary endpoints
Study and citation Study treatments
STEAM Budesonide/formoterol
[Rabe et al. (2
80/4.5 mg qd) SMART
2006a] Budesonide (2
160 mg qd) plus
SABA
STEP Budesonide/formoterol
[Scicchitano et al. (2
160/4.5 mg qd) SMART
2004] Budesonide (2
160 mg qd) plus
SABA
STAY Budesonide/formoterol
[O’Byrne et al. (2
80/4.5 mg qd) SMART
2005] Budesonide/formoterol
(2
80/4.5 mg qd) plus SABA
Budesonide (320 mg bid) plus SABA
SMILE Budesonide/formoterol
[Rabe et al. (2
160/4.5 mg qd) SMART
2006b] Budesonide/formoterol
(2
160/4.5 mg qd) plus
formoterol (4.5 mg)
Budesonide/formoterol
(2
160/4.5 mg qd) plus SABA
COSMOS Budesonide/formoterol SMART
[Vogelmeier et al. (640/18 to 320/9 mg)
2005] Salmeterol/fluticasone (10/200 to
100/1000 mg) plus SABA
COMPASS Budesonide/formoterol
[Kuna et al. 2007] (2
160/4.5 mg qd) SMART
Fixed-dose budesonide/formo-
terol (320/9 mg bid plus SABA
Fixed-dose salmeterol/fluticasone
(2
25/125 mg bid) plus SABA
AHEAD Budesonide/formoterol
[Bousquet et al. (2
160/4.5 mg qd) SMART
2007] High-dose salmeterol/fluticasone
(50/500 mg bid) plus SABA
Bud: budesonide; bud/form: budesonide/formoterol; SFC: salmeterol/fluticasone.
http://tar.sagepub.com
N Symptom-free days Night-time awakenings Reliever inhalations/day
354 Significantly more with Significantly fewer with Significantly fewer with
SMART (between-treatment budesonide/formoterol budesonide/formoterol
342 difference): SMART (between- SMART (between-treatment
 6.5% (p ¼ 0.0043) treatment difference): difference):
 2.2% (p ¼ 0.065)  0.34 (p50.001)
947 Significantly more with Significantly fewer with Significantly fewer with
SMART (between-treatment budesonide/formoterol budesonide/formoterol
943 difference): SMART (between- SMART (between-treatment
 7.5% (p50.001) treatment difference): difference):
 3.3% (p50.001)  0.52 (p50.001)
925 Significantly improved vs Significantly fewer (% of Significantly improved vs
bud þ SABA and comparable nights) vs bud þ SABA and bud þ SABA and bud/form þ
926 with bud/form þ SABA (% of bud/form þ SABA SABA
Therapeutic Advances in Respiratory Disease
days)  9% (p50.001 both com-  0.73/day (p50.001 both
909  54% (p50.001 vs parisons) comparisons)
bud þ SABA)  12%  0.84/day
 53%  12%  1.03/day
 46%
1107  2% reduction vs formoterol Significantly fewer with Significantly greater reduc-
as-needed (p ¼ 0.079) SMART vs formoterol or tion with SMART vs formo-
1137  2% reduction vs terbutaline terbutaline as-needed terol or terbutaline as-
as-needed (p ¼ 0.16)  2% reduction vs formoterol needed:
as-needed (p ¼ 0.018)  0.17/day reduction vs formo-
1138  3% reduction vs terbutaline terol as-needed (p50.001)
as-needed (p ¼ 0.0025)  0.20/day reduction vs ter-
butaline as-needed (p50.001)
1067 Not reported Not reported Significantly fewer with
SMART:
1076  0.35/day (p50.001)
1107 Comparable between treat- Comparable between treat- Comparable between treat-
ments: ments: ments:
1105  2% reduction vs SFC (not  1% reduction vs SFC (not  0.07 additional inhalations/
significant) significant) day vs SFC (not significant)
1123  1% reduction vs bud/form  1% reduction vs bud/form  0.03 fewer inhalations/day
(not significant) (not significant) vs bud/form (not significant)
1154 Comparable: Comparable: Comparable:
 0.5% reduction vs SFC  1% increase vs SFC  0.04 fewer inhalations/day
1155 (p ¼ 0.73) (p ¼ 0.73) vs SFC (p ¼ 0.36)

The STAY study included patients from 4 to 80
years of age and confirmed the efficacy and safety
of the SMART approach in children as well as
adults [O’Byrne et al. 2005].
The STEAM study was a 6-month, randomised,
double-blind, parallel-group study in patients
with mild-to-moderate asthma (mean baseline
forced expiratory volume over 1 min [FEV1]
75% expected, mean ICS 348 mg/day; n ¼ 697)
[Rabe et al. 2006a]. Patients received either
budesonide/formoterol 80/4.5 mg two inhalations
once daily plus additional inhalations as needed
for symptom relief (mean ICS dose 375 mg/day
BDP equivalent) or budesonide only (160 mg
two inhalations once daily; 500 mg/day BDP
equivalent) plus terbutaline (0.4 mg) as needed.
Patients who received budesonide/formoterol
maintenance and reliever experienced 90%
fewer asthma-related hospitalisations or emer-
gency room visits than those randomised to
higher dose budesonide plus terbutaline. The
risk of having a severe exacerbation (hospitalisa-
tion/ED treatment, oral steroid therapy for
3
days, or
30% decrease from baseline in morn-
ing PEF on two consecutive days) was 54% lower
for those patients who received budesonide/for-
moterol maintenance and reliever than for those
receiving higher dose budesonide plus terbutaline
(p50.01) (Table 2). Lung function was also
significantly improved among those receiving
budesonide/formoterol maintenance and reliever
in terms of both PEF (34.5 l/min vs 9.5 l/min;
p50.001) and FEV1 (0.210 l vs 0.062 l, respec-
tively; p50.001). Patients on the budesonide/for-
moterol maintenance and reliever regimen also
needed required fewer as-needed inhalations
each day (treatment difference: 0.34 [95% CI:
0.51 to 0.17]; p50.001), had more symptom-
free days (treatment difference: 6.5 [95% CI: 2.0
to 11.0]; p ¼ 0.0043) and more asthma control
days (treatment difference: 7.6 [95% CI: 3.0 to
12.3]; p ¼ 0.0012) than those on higher dose
budesonide plus terbutaline (Table 3). The over-
all frequency of adverse events was comparable
in the two treatment arms; 38% of patients in
the budesonide/formoterol maintenance and
reliever arm reported at least one adverse event
compared with 41% of patients in the higher dose
budesonide plus terbutaline arm. Respiratory
infection was the most common adverse event
in both treatment groups and while aggravated
asthma was reported by five patients receiving
higher-dose budesonide plus terbutaline, this
event was reported by only one patient in the
http://tar.sagepub.com
Review
budesonide/formoterol maintenance and reliever
therapy group.
The STEP study compared the budesonide/for-
moterol maintenance and reliever regimen 160/
4.5 mg two inhalations once daily plus additional
inhalations as needed (mean ICS dose 728 mg/day
BDP equivalent) for symptom relief with a
higher-dose budesonide regimen (320 mg twice
daily; 1000 mg/day BDP equivalent) in patients
with moderate to severe asthma (mean baseline
FEV1 70% predicted, mean ICS 746 mg/day).
STEP was a 12-month study and recruited
1890 patients the majority of whom (83%) were
classed as having severe asthma. Among this
group of patients the budesonide/formoterol
maintenance and reliever regimen reduced the
risk of a severe exacerbation (hospitalisation/ED
treatment, oral steroid therapy for
3 days, or
morning PEF
70% of baseline on two conse-
cutive days) by 39% compared with higher-dose
budesonide plus terbutaline (p50.001).
Moreover, 45% fewer severe exacerbations per
patient required medical intervention with the
budesonide/formoterol maintenance and reliever
regimen (p50.001 vs higher-dose budesonide
plus terbutaline) (Table 2). As observed in the
STEAM study in patients with mild-to-moderate
asthma, a significantly greater improvement in
lung function was achieved by patients treated
with budesonide/formoterol maintenance and
reliever regimen than among those who received
higher-dose budesonide plus terbutaline
(morning PEF: mean treatment difference
20.3 l/min, p50.001; FEV1 mean treatment
difference: 0.10 l, p50.001) (Table 2). The
budesonide/formoterol maintenance and reliever
regimen resulted in more symptom-free and
asthma-control days (between-treatment differ-
ence: 7.5% and 8.6%, respectively) and signifi-
cantly fewer as-needed inhalations per day (0.9 vs
1.42, respectively; p50.001) (Table 3). Again, a
similar proportion of patients reported at least
one adverse event in each treatment arm (56%
vs 57%, respectively) with the most common
adverse event being respiratory infection.
The improved efficacy observed in the STEAM,
STEP and STAY studies with the budesonide/
formoterol maintenance and reliever approach
compared with higher-dose ICS plus SABA
was achieved at a lower overall steroid load
(total ICS and oral steroid treatment days)
(Fig. 3). This is particularly relevant for the treat-
ment of asthmatic children because of the
291
Therapeutic Advances in Respiratory Disease

Budesonide/formoterol + SABA
50 Budesonide/formoterol + formoterol

Asthma exacerbations/100 patients/year

Salmeterol/fluticasone + SABA
A Symbicort SMART
40
C
B
B D&E
30 C
C D& E
20
A B
A=O’Byrne et al (2005)
10 B=Rabe et al (2006b)
C=Kuna et al (2007)
D=Vogelmeier et al (2005)
E=Bousquet et al (2007)
0
Low Medium High
250 to 500 501 to 1000 >1000 (BDP equiv. µg/d)

Maintenance plus as needed ICS dose

Figure 3. Asthma exacerbation rate (events/100 patients/year) in moderate-to-severe asthma patients

receiving either budesonide/formoterol maintenance and reliever therapy (Symbicort SMARTÕ ) or fixed-dose
budesonide/formoterol or salmeterol/fluticasone þ separate reliever in five clinical studies stratified by mean
daily ICS dose (BDP equivalents). All individual points represent the mean ICS dose range and exacerbation
rate from over 900 patients receiving each ICS/LABA combination. For simplicity, all ICS doses have been
summarised as low, medium or high dose in accordance with GINA guidelines. For budesonide maintenance
and reliever therapy (Symbicort SMARTÕ ) the overall ICS dose includes both maintenance and as needed
therapy. Note that within studies (A–E) the exacerbation rate was significantly lower with Symbicort SMARTÕ
compared with all other comparators (all p50.05). The dotted lines represent a trend analysis highlighting
the likelihood of dose-related increases in efficacy in preventing exacerbations with fixed-dose ICS/LABA and
with Symbicort SMARTÕ .

potential impact of high doses of steroids on Rates of exacerbation requiring medical interven-
growth. The STAY study showed that children tion were reduced by 70–79% with budesonide/
who were treated using the budesonide/formo- formoterol maintenance and reliever therapy
terol fixed dose or maintenance and reliever vs fixed-dose budesonide and fixed-dose combi-
regimens grew significantly more than those nation (0.08/patient vs 0.28/patient and 0.40/
treated with higher-dose budesonide plus terbu- patient, respectively; both p50.001). As reported
taline [O’Byrne et al. 2005]. in the primary publication of the STAY study by
O’Byrne et al. (2005), yearly growth improved by
The results from STAY for children aged 4–11 1.0 cm vs fixed-dose budesonide (p50.01).
years have been published in further detail
[Bisgaard et al. 2006]. Budesonide/formoterol Budesonide/formoterol maintenance
maintenance and reliever therapy was comp- and reliever therapy vs alternative reliever
ared with fixed-dose budesonide/formoterol plus maintenance ICS/LABA
(80/4.5 mg/day; 250 mg/day BDP equivalent) plus Two studies have directly compared with
as-needed terbutaline (0.4 mg) or higher-dose budesonide/formoterol maintenance and reliever
budesonide (320 mg/day; 500 mg/day BDP approach with budesonide/formoterol plus
equivalent) plus as-needed terbutaline (0.4 mg) an alternative as-needed SABA regimen:
[Bisgaard et al. 2006]. Budesonide/formoterol STAY [O’Byrne et al. 2005] and SMILE
maintenance and reliever therapy prolonged the [Rabe et al. 2006b].
time to first exacerbation (hospitalisation/ED
treatment, oral steroid therapy for
3 days, As noted earlier, the STAY study was primarily
increase in ICS or additional treatment, or morn- conducted to compare the efficacy of the bude-
ing PEF
70% of baseline on two consecutive sonide/formoterol maintenance and reliever
days) vs fixed-dose budesonide (p ¼ 0.02) and approach with that of budesonide/formoterol
fixed-dose budesonide/formoterol (p50.001). maintenance plus as-needed SABA [O’Byrne

292 http://tar.sagepub.com

et al. 2005]. In this study, the maintenance and
reliever regimen reduced the risk of experiencing
a severe exacerbation (hospitalisation/ED treat-
ment, oral steroid therapy for
3 days, or morn-
ing PEF
70% of baseline on two consecutive
days) by 45% and the risk of a severe exacerba-
tion requiring hospitalisation/ED treatment by
50% compared with the budesonide/formoterol
plus SABA regimen (Table 2). Lung function
(morning and evening PEF and FEV1) was also
significantly improved with the budesonide/
formoterol maintenance and reliever approach
(Table 2) as were night-time awakenings
(p50.001) and daily reliever use (p50.001)
(Table 3). Improvements in other symptom
measures were comparable between the two
regimens including the proportion of symptom-
free days and asthma control days; with both
regimens offering significantly greater improve-
ments compared with higher-dose budesonide
plus SABA (Table 3). The overall frequency of
adverse events was comparable between the three
treatment arms; 57% of patients reported at least
one adverse event in the higher-dose budesonide
plus SABA arm compared with 52% and 54%
in the budesonide/formoterol plus SABA and
the budesonide/formoterol maintenance and
reliever arms, respectively. Aggravated asthma
occurred in 2 patients treated with the budeso-
nide/formoterol maintenance and reliever regi-
men and 13 and 8 patients in the budesonide/
formoterol plus SABA and higher-dose budeso-
nide plus SABA arms, respectively.
The SMILE study was a 12-month study in
asthmatic patients 12 years of age and older
designed to compare the budesonide/formoterol
maintenance and reliever regimen (mean ICS
dose 514 mg/day BDP equivalent) with budeso-
nide/formoterol as maintenance (mean ICS
dose 500 mg/day BDP equivalent) combined
with either formoterol or a SABA (terbutaline)
for as-needed therapy [Rabe et al. 2006b].
The budesonide/formoterol maintenance and
reliever regimen significantly prolonged the time
to the first severe exacerbation (i.e. that requiring
hospital/ED room treatment or oral steroid ther-
apy for
3 days) compared with either of the two
alternative regimens (p ¼ 0.0048 vs budesonide/
formoterol plus formoterol as-needed; p50.0001
vs budesonide/formoterol plus terbutaline
as-needed). The rate of severe exacerbations
was 37, 29 and 19 per 100 patients/year for
budesonide/formoterol plus terbutaline as-
needed, budesonide/formoterol plus formoterol
http://tar.sagepub.com
Review
as-needed and budesonide/formoterol mainte-
nance and reliever therapy. The budesonide/for-
moterol maintenance and reliever regimen also
reduced the overall proportion of patients who
required hospital or emergency room visits
during the 12-month study period (5% vs 7%
[p ¼ 0.079] and 8% [p ¼ 0.0013] for the
formoterol and terbutaline as-needed regimens,
respectively) (Table 2). With the inclusion of
the budesonide/formoterol plus formoterol
as-needed treatment arm, the SMILE study pro-
vides compelling support for the contribution to
the effect of the ICS component alongside
formoterol when patients require additional
as-needed medication in order to reduce the
frequency of asthma exacerbations and the like-
lihood of requiring medical intervention. Lung
function improved to the greatest extent in the
budesonide/formoterol maintenance and reliever
arm (Table 2). Overall symptoms also improved
more for patients in the budesonide/formoterol
maintenance and reliever arm who achieved the
greatest number of asthma control days and the
greatest reductions in night-time awakenings and
daily as-needed inhalations (Table 3). No adverse
safety signals were revealed with all three regi-
mens being well tolerated throughout the study
period although fewer patients withdrew due to
adverse events in the budesonide/formoterol
maintenance and reliever arm (n ¼ 1) compared
with the formoterol as-needed (n ¼ 14) and ter-
butaline as-needed (n ¼ 10) groups.
Budesonide/formoterol maintenance and
reliever therapy vs alternative higher
doses of maintenance ICS/LABA
As discussed above, the alternative ICS/LABA
combination salmeterol/fluticasone is not sui-
table for a maintenance and reliever regimen.
However, the efficacy of budesonide/formoterol
maintenance and reliever has been compared
with a higher fixed-dose of salmeterol/fluticasone
plus SABA or a titrated dose of salmeterol/fluti-
casone in three studies, COMPASS [Kuna et al.
2007], COSMOS [Vogelmeier et al. 2005] and
AHEAD [Bousquet et al. 2007].
The COSMOS study directly compared budeso-
nide/formoterol maintenance (initial dose 160/
4.5 mg two inhalations bid) and reliever using
TurbuhalerÕ with fixed-dose salmeterol/flutica-
sone (initial dose 50/250 mg twice daily) plus
salbutamol as-needed in 2143 adolescents
and adults (mean FEV1 73% predicted,
mean daily ICS at study entry 884 mg)
293
Therapeutic Advances in Respiratory Disease
[Vogelmeier et al. 2005]. Dose-titration of the
maintenance medication was permitted within
normal clinical practice doses to obtain and
maintain control. The budesonide/formoterol
maintenance and reliever regimen (mean ICS
dose 1067 mg/day BDP equivalent vs salmeterol/
fluticasone mean ICS dose 1076 mg/day BDP
equivalent) significantly prolonged the time to
the first severe asthma exacerbation (a severe
exacerbation being defined as that requiring
hospitalisation/ED treatment, oral steroid ther-
apy for
3 days or an unscheduled visit leading
to treatment change) conferring a 25% reduction
in risk (Table 2). Moreover, the total number of
severe exacerbations was significantly lower
among patients treated with budesonide/formo-
terol maintenance and reliever than salmeterol/
fluticasone (255 vs 329, respectively). Lung
function and symptomatic improvements were
achieved with both treatment regimens with
similar overall ICS dose during treatment
(653 mg/day budesonide and 583 mg/day flutica-
sone). Both regimens were well tolerated with
the only notable difference in the safety profile
being a greater proportion of patients discontinu-
ing salmeterol/fluticasone therapy due to asthma
(eleven patients compared with three patients
in the budesonide/formoterol maintenance and
reliever arm).
The 6-month COMPASS study recruited 3335
symptomatic adults and adolescent asthmatics
with mean FEV1 of 73% predicted on treatment
with a mean ICS dose of 745 mg/day [Kuna et al.
2007]. Patients were randomised to receive bude-
sonide/formoterol (160/4.5 mg/day one inhalation
bid) plus additional inhalations as needed, salme-
terol/fluticasone (25/125 mg/day two inhalations
bid) plus as-needed terbutaline or a higher dose
of budesonide/formoterol (320/9 mg/day one inha-
lation bid) as maintenance therapy plus as-needed
terbutaline. The budesonide/formoterol mainte-
nance and reliever regimen (mean ICS dose
755 mg/day BDP equivalent) significantly pro-
longed the time to the first severe exacerbation
(that requiring hospital or emergency room treat-
ment or oral steroid therapy) compared with both
the higher-dose budesonide/formoterol mainte-
nance plus terbutaline as-needed (mean ICS
dose 1000 mg/day BDP equivalent) and the salme-
terol/fluticasone maintenance plus terbutaline
as-needed regimens (mean ICS dose 1000 mg/
day BDP equivalent) (p ¼ 0.0034 and p ¼ 0.023,
respectively) (Table 2). The overall 6-month
severe exacerbation rate was lowest among
294
patients treated with the budesonide/formoterol
maintenance and reliever therapy regimen
(12%, 16% and 19% of patients, respectively;
p ¼ 0.0048 and p50.001 vs higher-dose
budesonide/formoterol plus terbutaline as-needed
and salmeterol/fluticasone plus terbutaline
as-needed, respectively). Lung function was
improved in all three treatment arms to a similar
extent as were overall symptoms including
symptom-free days, asthma control days, night-
time awakenings and daily as-needed inhalation
use (Table 3). Tolerability was good in all three
treatment groups with upper respiratory tract
infections being the most commonly reported
adverse event. Finally, both ICS and oral steroid
use was lowest among patients randomised to the
budesonide/formoterol maintenance and reliever
arm (Fig. 3); the number of days on which
patients’ required oral steroids was 619 in the
budesonide/formoterol maintenance and reliever
arm compared with 1044 in the higher-dose
budesonide/formoterol and 1132 in the salme-
terol/fluticasone arms.
Finally, the AHEAD study [Bousquet et al. 2007]
compared budesonide/formoterol (160/4.5 mg two
inhalations bid) maintenance and reliever with
high-dose salmeterol/fluticasone (50/500 mg bid)
plus terbutaline as-needed in 2309 symptomatic
asthma patients aged 12 years and over. In this
study the time to the first severe exacerbation
(hospitalisation/ED treatment or oral steroid ther-
apy for
3 days) was not statistically significantly
different between the two treatment arms
(hazard ratio 0.82, p ¼ 0.12). However, budeso-
nide/formoterol maintenance and reliever
reduced the total number of exacerbations and
the number of exacerbations requiring hospital
or emergency room treatment to a greater extent
than did salmeterol/fluticasone (25% vs 31%;
p ¼ 0.039, respectively, and 9% vs 13%;
p ¼ 0.046, respectively) (Table 2). Of particular
interest is the observation that although the
incidence of occasional high reliever use was
rather similar between the two treatment groups
(more than four inhalations on any day during the
study occurred in 29% and 27% of patients,
respectively), the incidence of severe exacerba-
tions among high as-needed users was lower
among those treated with budesonide/formoterol
maintenance and reliever therapy (41% risk
reduction with budesonide/formoterol mainte-
nance and reliever; p ¼ 0.0012). Consistent with
both the COMPASS and COSMOS studies, lung
function and overall symptoms were improved to
http://tar.sagepub.com

a similar extent but was achieved with a lower
overall ICS dose (1238 mg/day BDP equivalent
with budesonide/formoterol and 2000 mg/day
BDP equivalent with salmeterol/fluticasone)
(Table 3). Again, tolerability was acceptable in
both treatment arms with comparable overall
adverse event rates (39% and 40%, respectively).
Discussion
The clinical trial programme for budesonide/
formoterol maintenance and reliever therapy
has demonstrated marked and significant reduc-
tions in severe exacerbations resulting in hospita-
lisation/ED treatment or oral steroid therapy in
patients with mild to severe asthma. Compared
with patients receiving higher-dose ICS plus
SABA, significantly fewer patients taking bude-
sonide/formoterol maintenance and reliever ther-
apy experienced a severe exacerbation requiring
hospital/emergency room treatment or oral ster-
oid therapy (range: 45–76%) [Rabe et al. 2006a;
O’Byrne et al. 2005; Scicchitano et al. 2004]. The
budesonide/formoterol maintenance and reliever
regimen also offered benefits in this respect when
compared with an alternative reliever regimen
(plus SABA [O’Byrne et al. 2005] or formoterol
[Rabe et al. 2006b]) and in comparison with the
higher dose ICS/LABA combination of salme-
terol/fluticasone [Bousquet et al. 2007; Kuna
et al. 2007; Vogelmeier et al. 2005].
Improvements in lung function and asthma
symptoms, including daily reliever use, were at
least comparable with those for higher mainte-
nance doses of salmeterol/fluticasone and bude-
sonide/formoterol and improved in comparison
to higher-dose ICS alone and the same mainte-
nance dose of budesonide/formoterol plus alter-
native conventional as-needed medication. These
observations should provide confidence for pre-
scribing physicians that the budesonide/formo-
terol maintenance and reliever regimen can
provide as least as good clinical day-to-
day asthma control as existing fixed-dose regi-
mens using higher maintenance ICS/LABA
doses with the added benefit of a reduced
future risk of exacerbations and severe exacerba-
tions requiring hospital/emergency room visits.
The rationale for inclusion of an ICS component
as part of an as-needed medication focuses on the
need to treat the underlying inflammation at the
earliest signs of asthma worsening in addition to
providing effective bronchodilation and broncho-
protection. The increased reliever use exhibited
http://tar.sagepub.com
Review
by patients in the days before the onset of an
exacerbation provides a window of opportunity
to address the underlying cause of symptomatic
worsening and potentially ameliorate or avoid a
full exacerbation. Budesonide/formoterol for
both maintenance and reliever therapy automati-
cally adapts to patients changing asthma needs
providing appropriate adjustments in controller
therapy with greater simplicity than is possible
using separate maintenance and reliever inhalers
and complex action plans on how to adjust main-
tenance doses. The INSPIRE study has shown
that this is what patients want and do in practice
(Partridge et al. 2006). That the budesonide/for-
moterol maintenance and reliever regimen offers
comparable symptom control to that of higher
dose ICS/LABA combination while ameliorating
the future risk of exacerbation has perhaps been
most clearly demonstrated in the COSMOS
[Vogelmeier et al. 2007] and AHEAD studies
[Bousquet et al. 2007]. The use of four or more
inhalations of as-needed medication per week is
considered to be a marker for poor asthma con-
trol [Aalbers et al. 2004; Bateman et al. 2004].
Vogelmeier and coworkers (2007) found that
patients treated with salmeterol/fluticasone were
more likely to require four or more as-needed
inhalations per week than were those patients
randomised to budesonide/formoterol mainte-
nance and reliever therapy (odds ratio: 1.68;
95% CI: 1.38–2.05; p50.001). In the AHEAD
study, high reliever use (more than four, six or
eight inhalations on any day during the study)
was somewhat reduced in patients treated
with budesonide/formoterol maintenance and
reliever therapy compared with those receiving
maximum dose salmeterol/fluticasone, and in
the patients with high temporary reliever use
(four or more inhalations on any one day
during study) the subsequent incidence of
severe exacerbations in relation to this use was
significantly reduced (54 events/100 patients/
year vs 92 events/100 patients/year, respectively;
p ¼ 0.0012) [Bousquet et al. 2007]. Thus, it
appears that the addition of an ICS as part of
an as-needed medication can indeed offer
additional protection from exacerbation during
periods of symptomatic worsening that occur
even during maximum conventional therapy
with salmeterol/fluticasone.
The potential for increased ICS exposure has
been raised as a concern with the maintenance
and reliever regimen; however, the clinical trial
programme described has consistently shown
295
Therapeutic Advances in Respiratory Disease
that the benefits in terms of asthma control and
severe exacerbation rate are achieved with
comparable or lower daily ICS and/or steroid
doses, a finding of particular importance when
managing children with asthma. Kuna and cow-
orkers [2007] found that patients randomised to
budesonide/formoterol maintenance and reliever
therapy required significantly lower daily ICS
doses during the study period than those rando-
mised to salmeterol/fluticasone or budesonide/
formoterol maintenance plus SABA regimens
(mean BDP equivalent doses: 755 vs 1000 and
1000 mg/day, respectively; p50.001). In the
AHEAD study [Bousquet et al. 2007] there was
a 38% reduction in the required BDP-equivalent
dose with budesonide/formoterol maintenance
and reliever compared with high-dose salme-
terol/fluticasone (792 vs 1238 mg, respectively;
p50.0001). Finally, in the dose-titration
COSMOS study [Vogelmeier et al. 2007]
around 40% of patients required the maximum
maintenance dose of salmeterol/fluticasone
(50/500 mg bid) at some point during the study
and 27% of patients remained on the highest
dose regimen at study completion. In contrast,
39% of patients randomised to budesonide/
formoterol maintenance and reliever were able
to halve their maintenance dose and 31%
remained on the lower maintenance dose at the
end of the study period.
No adverse safety signals were raised in the
clinical trial programme reviewed here which
included more than 15,000 asthmatic adults
and children for the budesonide/formoterol
maintenance and reliever regimen. The safety
and tolerability profile seen was similar to what
has been well established for higher-dose
budesonide plus SABA, fixed-dose budesonide/
formoterol plus SABA or LABA or standard
or high-dose salmeterol/fluticasone plus SABA.
As expected for a cohort of asthmatic patients,
the most frequent adverse event in any treatment
group in any of the studies described here
was respiratory tract infection. Thus, the
budesonide/formoterol maintenance and reliever
regimen would appear to be as well tolerated as
existing guideline-recommended medication
regimens for asthmatic patients.
Conclusion
Budesonide/formoterol maintenance and reliever
therapy is an effective strategy that provides better
overall asthma control (i.e. minimises symptoms
296
and their impact on daily life, reduces future risk
by preventing exacerbations and avoids unneces-
sary stepwise increases in maintenance therapy as
occurs with conventional fixed-dose regimens).
Thus, although both budesonide/formoterol and
salmeterol/fluticasone combinations are safe and
effective, the pharmacological and pharmacody-
namic differences between the LABA and ICS
components of the two combinations allow
maintenance and reliever therapy only with
budesonide/formoterol. Adequate and controlled
clinical studies indicate that the budesonide/for-
moterol maintenance and reliever regimen is the
best current use of combination therapy, provid-
ing superior overall asthma control while avoiding
over-reliance on SABAs or prolonged therapy
with higher-dose ICS.
Note: As previously noted, the two-actuation per
dose 80/4.5 mg and 160/4.5 mg strength pMDIs
that are commercially available in some markets,
including the US, are currently approved only as
fixed-dose therapy for asthma and are not appro-
priate for use as maintenance and reliever therapy
(Symbicort SMARTÕ ), which is approved only
for TurbuhalerÕ .
Acknowledgements
The author would like to thank Dr Ian Wright, of
Wright Medical Communications Ltd, UK, who
provided medical writing support funded by
AstraZeneca R&D, Lund, Sweden.
References
Aalbers, R., Backer, V., Kava, T.T., Omenaas, E.R.,
Sandstrom, T., Jorup, C. et al. (2004) Adjustable
maintenance dosing with budesonide/formoterol
compared with fixed-dose salmeterol/fluticasone
in moderate to severe asthma. Curr Med Res Opin
20(2): 225–240.
Adachi, M., Ohta, K., Morikawa, A., Nishima, S.,
Tokunaga, S. and Disantostefano, R.L. (2008)
Changes in asthma insights and reality in Japan (AIRJ)
in 2005 since 2000. Arerugi 57(2): 107–120 [in
Japanese].
Anderson, G.P. (1993) Formoterol: pharmacology,
molecular basis of agonism, and mechanism of
long duration of a highly potent and selective beta
2-adrenoceptor agonist bronchodilator. Life Sci
52(26): 2145–2160.
Anderson, G.P. (2000) Interactions between
corticosteroids and beta-adrenergic agonists
in asthma disease induction, progression,
http://tar.sagepub.com

and exacerbation. Am J Respir Crit Care Med
161(3 Pt 2): S188–S196.
Bai, T.R., Vonk, J.M., Postma, D.S. and Boezen, H.M.
(2007) Severe exacerbations predict excess lung func-
tion decline in asthma. Eur Respir J 30(3): 452–456.
Barnes, P.J. (2007) Scientific rationale for using a single
inhaler for asthma control. Eur Respir J 29(3): 587–595.
Bateman, E.D., Boushey, H.A., Bousquet, J.,
Busse, W.W., Clark, T.J., Pauwels, R.J. et al. (2004)
Can guideline-defined asthma control be achieved?
The Gaining Optimal Asthma Control Study.
Am J Respir Crit Care Med 170(8): 836–844.
Bennett, J.A. and Tattersfield, A.E. (1997) Time
course and relative dose potency of systemic effects
from salmeterol and salbutamol in healthy subjects.
Thorax 52(5): 458–464.
Bisgaard, H., Le Roux, P., Bjåmer, D., Dymek, A.,
Vermeulen, J.H. and Hultquist, C. (2006)
Budesonide/formoterol maintenance plus
reliever therapy: a new strategy in pediatric asthma.
Chest 130(6): 1733–1743.
Boonsawat, W., Charoenratanakul, S., Pothirat, C.,
Sawanyawisuth, K., Seearamroongruang, T.,
Bengtsson, T. et al. (2003) Formoterol (OXIS)
Turbuhaler as a rescue therapy compared with
salbutamol pMDI plus spacer in patients with
acute severe asthma. Respir Med 97(9): 1067–1074.
Bousquet, J., Boulet, L.P., Peters, M.J.,
Magnussen, H., Quiralte, J., Martinez-Aguilar, N.E.
et al. (2007) Budesonide/formoterol for
maintenance and relief in uncontrolled
asthma vs. high-dose salmeterol/fluticasone.
Respir Med 101(12): 2437–2446.
Busse, W., Chervinsky, P., Condemi, J., Lumry, W.R.,
Petty, T.L., Rennard, S. et al. (1998) Budesonide
delivered by Turbuhaler is effective in a
dose-dependent fashion when used in the
treatment of adult patients with chronic asthma.
J Allergy Clin Immunol 101(4 Pt 1): 457–463.
Cazzola, M. and Curradi, G. (2007) How to prevent
relapse after acute exacerbation of asthma? Pol Arch
Med Wewn 117(11–12): 487–490.
Cazzoletti, L., Marcon, A., Janson, C., Corsico, A.,
Jarvis, D., Pin, I. et al. (2007) Asthma control in
Europe: a real-world evaluation based on an interna-
tional population-based study. J Allergy Clin Immunol
120(6): 1360–1367.
Chapman, K.R., Boulet, L.P., Rea, R.M. and
Franssen, E. (2008) Suboptimal asthma
control: prevalence, detection and consequences
in general practice. Eur Respir J 31(2): 320–325.
Cheung, D., van Klink, H.C. and Aalbers, R. (2006)
Improved lung function and symptom control with
formoterol on demand in asthma. Eur Respir J 27(3):
504–510.
Currie, G.P., Jackson, C.M., Ogston, S.A. and
Lipworth, B.J. (2003) Airway-stabilizing effect
http://tar.sagepub.com
Review
of long-acting beta2-agonists as add-on therapy to
inhaled corticosteroids. QJM 96(6): 435–440.
Dahl, R., Chuchalin, A., Gor, D., Yoxall, S. and
Sharma, R. (2006) EXCEL: A randomised trial
comparing salmeterol/fluticasone propionate and
formoterol/budesonide combinations in adults with
persistent asthma. Respir Med 100(7): 1152–1162.
Desfougeres, J.-L., Sohier, B. and Freedman, D.
(2007) Has asthma control improved since AIRE?
Results of a survey in 5 European countries.
Eur Respir J 30(Suppl.): 249s.
D’Urzo, A.D., Chapman, K.R., Cartier, A.,
Hargreave, F.E., Fitzgerald, M. and Tesarowski, D.
(2001) Effectiveness and safety of salmeterol in
nonspecialist practice settings. Chest 119(5): 714–719.
Edsbäcker, S., Wollmer, P., Selroos, O., Borgström, L.,
Olsson, B. and Ingelf, J. (2008) Do airway clearance
mechanisms influence the local and systemic effects
of inhaled corticosteroids? Pulm Pharmacol Ther 21(2):
247–258.
Edwards, S.J., Gruffydd-Jones, K. and Ryan, D.
(2007) Systematic review and meta-analysis
of budesonide/formoterol in a single inhaler.
Curr Med Res Opin 23(8): 1809–1820.
Faulds, D., Hollingshead, L.M. and Goa, K.L. (1991)
Formoterol. A review of its pharmacological
properties and therapeutic potential in reversible
obstructive airways disease. Drugs 42(1): 115–137.
Fitzgerald, J.M., Becker, A., Sear, M.R., Mink, S.,
Chung, K. and Lee, J. (2004) Doubling the dose
of budesonide versus maintenance treatment in
asthma exacerbations. Thorax 59(7): 550–556.
Foresi, A., Morelli, M.C. and Catena, E. (2000)
Low-dose budesonide with the addition of an
increased dose during exacerbations is effective in
long-term asthma control. Chest 117(2): 440–446.
Global Initiative for Asthma (GINA) (2007) Global
strategy for asthma management and prevention –
updated 2007. Available at: www.ginasthma.com,
accessed January 2008.
Guhan, A.R., Cooper, S., Osbourne, J., Lewis, S.,
Bennett, J. and Tattersfield, A.E. (2000) Systemic
effects of formoterol and salmeterol: a dose-response
comparison in healthy subjects. Thorax 55(8): 650–656.
Greening, A.P., Ind, P.W., Northfield, M. and Shaw, G.
(1994) Added salmeterol versus higher-dose corticos-
teroid in asthma patients with symptoms on existing
inhaled corticosteroid. Lancet 344(8917): 219–224.
Harrison, T.W., Oborne, J., Newton, S. and
Tattersfield, A.E. (2004) Doubling the dose of inhaled
corticosteroid to prevent exacerbations: randomised
controlled trial. Lancet 363(9405): 271–275.
Harrison, T.W. and Tattersfield, A.E. (2003)
Plasma concentrations of fluticasone propionate
and budesonide following inhalation from dry
powder inhalers by healthy and asthmatic subjects.
Thorax 58(3): 258–260.
297
Therapeutic Advances in Respiratory Disease
Heyneman, C.A., Crafts, R., Holland, J. and
Arnold, A.D. (2002) Fluticasone versus
salmeterol/low-dose fluticasone for long-term
asthma control. Ann Pharmacother 36(12):
1944–1949.
Jaeschke, R., Mejza, F., Lesniak, W., Brozek, J.,
Schunemann, H.J., Guyatt, G. et al. (2007)
The safety of formoterol among patients with
asthma using inhaled corticosteroids. Am J Respir
Crit Care Med 175: A57.
Juniper, E.F., Kline, P.A., Vanzielegham, M.A.,
Ramsdale, E.H., O’Byrne, P.M. and Hargreave, F.E.
(1990) Effect of long-term treatment with an
inhaled corticosteroid (budesonide) on airway
hyperresponsiveness and clinical asthma in
non-steroid dependent asthmatics. Am Rev Respir Dis
142(4): 832–836.
Kuna, P., Peters, M.J., Manjra, A.I., Jorup, C.,
Naya, I.P., Martinez-Jimenez, N.E. et al. (2007)
Effect of budesonide/formoterol maintenance
and reliever therapy on asthma exacerbations.
Int J Clin Pract 61(5): 725–736.
Laitinen, L.A., Laitinen, A. and Haahtela, T. (1992)
A comparative study on the effects of an inhaled
corticosteroid, budesonide, and a b2-agonist,
terbutaline, on airway inflammation in newly
diagnosed asthma: a randomized, double-blind,
parallel-group controlled trial. J Allergy
Clin Immunol 90(1): 32–42.
Levy, M.L. (2008) Guideline-defined asthma
control: a challenge for primary care. Eur Respir J
31(2): 229–231.
Lötvall, J. (2001) Pharmacological similarities
and differences between beta2-agonists. Respir Med
95(Suppl B): S7–S11.
Lötvall, J., Langley, S. and Woodcock, A. (2006)
Inhaled steroid/long-acting beta-2 agonist combination
products provide 24 hours improvement in lung
function in adult asthmatic patients. Respir Res
7(Aug 18): 110.
Masoli, M., Fabian, D., Holt, S. and Beasley, R.
(2004) The global burden of asthma: executive
summary of the GINA Dissemination Committee
report. Allergy 59(5): 469–478.
Miller-Larsson, A., Mattsson, H., Hjertberg, E.,
Dahlbäck, M., Tunek, A. and Brattsand, R. (1998)
Reversible fatty acid conjugation of budesonide:
novel mechanism for prolonged retention of
topically applied steroid in airway tissue.
Drug Metab Dispos 26(7): 623–630.
Miyamoto, T., Takahashi, T., Nakajima, S.,
Makino, S., Yamakido, M., Mano, K. et al. (2000)
A double-blind, placebo-controlled dose-response
study with budesonide Turbuhaler in Japanese asthma
patients. Respirology 5(3): 247–256.
Naya, I.P. and Andersson, T.L. (2007) Post hoc
analysis and claims of superiority in the EXCEL trial.
Respir Med 101(3): 681–682.
298
Nelson, H.S., Beasley, R., Yancey, S.W., Kral, K.M.,
Edwards, L.D., Sutton, L.B. et al. (2007)
No increase in asthma-related hospitalizations
following the addition of salmeterol to an
inhaled corticosteroid in patients with asthma: a
meta-analysis. Am J Respir Crit Care Med 175: A59.
NICE Technology Appraisal Guidance 138 (2008)
Inhaled corticosteroids for the treatment of
chronic asthma in adults and in children aged
12 years and over. Available at: www.nice.org.uk/
TA138
O’Byrne, P.M., Barnes, P.J., Rodriguez-Roisin, R.,
Runnerstrom, E., Sandstrom, T., Svensson, K. et al.
(2001) Low dose inhaled budesonide and formoterol
in mild persistent asthma: the OPTIMA randomized
trial. Am J Respir Crit Care Med 164(8 Pt 1):
1392–1397.
O’Byrne, P.M., Bisgaard, H., Godard, P.P.,
Pistolesi, M., Palmqvist, M., Zhu, Y. et al. (2005)
Budesonide/formoterol combination therapy as
both maintenance and reliever medication in asthma.
Am J Respir Crit Care Med 171(2): 129–136.
Palmqvist, M., Arvidsson, P., Beckman, O.,
Peterson, S. and Lotvall, J. (2001) Onset of
bronchodilation of budesonide/formoterol versus
salmeterol/fluticasone in single inhalers.
Pulm Pharmacol Ther 14(1): 29–34.
Palmqvist, M., Ibsen, T., Mellen, A. and Lotvall, J.
(1999) Comparison of the relative efficacy of
formoterol and salmeterol in asthmatic patients.
Am J Respir Crit Care Med 160(1): 244–249.
Papi, A., Paggiaro, P.L., Nicolini, G., Vignola, A.M.
and Fabbri, L. (2007) Beclomethasone/formoterol
vs budesonide/formoterol combination therapy
in asthma. Eur Respir J 29(4): 682–689. Erratum in:
Eur Respir J (2007) 29(6): 1286.
Partridge, M.R., Van der Molen, M.T., Myrseth, S.E.
and Busse, W.W. (2006) Attitudes and actions
of asthma patients on regular maintenance
therapy: the INSPIRE study. BMC Pulm Med
6(June 13): 13.
Pauwels, R.A., Löfdahl, C.G., Postma, D.S.,
Tattersfield, A.E., O’Byrne, P.M., Barnes, P.J., et al.
(1997) Effect of inhaled formoterol and
budesonide on exacerbations of asthma.
Formoterol and Corticosteroids Establishing
Therapy (FACET) International Study Group. N Engl
J Med 337(20): 1405–1411. Erratum in: N Engl J Med
(1998) 338(2): 139.
Pauwels, R.A., Sears, M.R., Campbell, M.,
Villasante, C., Huang, S., Lindh, A. et al. (2003)
Formoterol as relief medication in asthma: a world-
wide safety and effectiveness trial. Eur Respir J 22(5):
787–794.
Pohunek, P., Matulka, M., Rybnicek, O., Kopriva, F.,
Honomichlova, H. and Svobodova, T. (2004)
Dose-related efficacy and safety of formoterol (Oxis)
Turbuhaler compared with salmeterol
http://tar.sagepub.com

Diskhaler in children with asthma. Pediatr Allergy
Immunol 15(1): 32–39.
Rabe, K.F., Adachi, M., Lai, C.K., Soriano, J.B.,
Vermeire, P.A., Weiss, K.B. et al. (2004) Worldwide
severity and control of asthma in children and
adults: the global asthma insights and reality surveys.
J Allergy Clin Immunol 114(1): 40–47.
Rabe, K.F., Atienza, T., Magyar, P., Larsson, P.,
Jorup, C. and Lalloo, U.G. (2006b) Effect of budeso-
nide in combination with formoterol for reliever ther-
apy in asthma exacerbations: a randomised controlled,
double-blind study. Lancet 368(9537): 744–753.
Rabe, K.F., Pizzichini, E., Stallberg, B., Romero, S.,
Balanzat, A.M., Atienza, T. et al. (2006a) Budesonide/
formoterol in a single inhaler for maintenance and
relief in mild-to-moderate asthma: a randomized,
double-blind trial. Chest 129(2): 246–256.
Rabe, K.F., Vermeire, P.A., Soriano, J.B. and
Maier, W.C. (2000) Clinical management of asthma in
1999: the Asthma Insights and Reality in Europe
(AIRE) study. Eur Respir J 16(5): 802–807.
Scicchitano, R., Aalbers, R., Ukena, D., Manjra, A.,
Fouquert, L., Centanni, S. et al. (2004) Efficacy and
safety of budesonide/formoterol single inhaler therapy
versus a higher dose of budesonide in moderate to
severe asthma. Curr Med Res Opin 20(9): 1403–1418.
Seberová, E. and Andersson, A. (2000) Oxis
(formoterol given by Turbuhaler) showed as rapid
an onset of action as salbutamol given by a pMDI.
Respir Med 94(6): 607–611.
Shrewsbury, S., Pyke, S. and Britton, M. (2000)
Meta-analysis of increased dose of inhaled steroid
or addition of salmeterol in symptomatic asthma
(MIASMA). BMJ 320(7246): 1368–1373.
Tattersfield, A.E., Postma, D.S., Barnes, P.J.,
Svensson, K., Bauer, C.A., O’Byrne, P.M. et al. (1999)
Exacerbations of asthma: a descriptive study of 425
severe exacerbations. The FACET International Study
Group. Am J Respir Crit Care Med 160(2): 594–599.
Tattersfield, A.E., Lofdahl, C.G., Postma, D.S.,
Eivindson, A, Schreurs, A.G., Rasidakis, A. et al.
(2001) Comparison of formoterol and terbutaline
http://tar.sagepub.com
Review
for as-needed treatment of asthma: a randomised trial.
Lancet 357(9252): 257–261.
Thorsson, L., Edsbäcker, S., Källén, A. and
Lofdahl, C.-G. (2001) Pharmacokinetics and systemic
activity of fluticasone via Diskus and pMDI, and of
budesonide via Turbuhaler. Br J Clin Pharmacol 52(5):
529–538.
Toogood, J.H., Baskerville, J.C., Jennings, B.,
Lefcoe, N.M. and Johansson, S.A. (1982) Influence
of dosing frequency and schedule on the response
of chronic asthmatics to the aerosol steroid
budesonide. J Allergy Clin Immunol 70(4): 288–298.
Tunek, A., Sjödin, K. and Hallström, G. (1997)
Reversible formation of fatty acid esters of
budesonide, an antiasthma glucocorticoid, in human
lung and liver microsomes. Drug Metab Dispos 11(11):
1311–1317.
van den Nieuwenhof, L., Schermer, T., Heins, M.,
Bottema, B., van Weel, C., Bindels, P. et al. (2008)
Tracing uncontrolled asthma in family practice
using a mailed asthma control questionnaire.
Ann Fam Med 6(Suppl. 1): S16–S22.
van der Woude, H.J., Boorsma, M., Bergqvist, P.B.,
Winter, T.H. and Aalbers, R. (2004)
Budesonide/formoterol in a single inhaler
rapidly relieves methacholine-induced
moderate-to-severe bronchoconstriction.
Pulm Pharmacol Ther 17(2): 89–95.
Vogelmeier, C., D’Urzo, A., Pauwels, R.,
Merino, J.M., Jaspal, M., Boutet, S. et al. (2005)
Budesonide/formoterol maintenance and reliever
therapy: an effective asthma treatment option?
Eur Respir J 26(5): 819–828.
Wieslander, E., Delander, E.-L., Sjödin, K. and
Miller-Larsson, A. (1998) Fatty acid conjugation
in normal human bronchial epithelial cells. Am J Respir
Crit Care Med 157: A402.
Woolcock, A., Lundback, B., Ringdal, N. and
Jacques, L.A. (1996) Comparison of addition of Visit SAGE journals online
http://tar.sagepub.com
salmeterol to inhaled steroids with doubling of the
dose of inhaled steroids. Am J Respir Crit Care Med
153(5): 1481–1488.
299