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Inhaled Combination Therapy With
Long-Acting 
2
-Agonists and
Corticosteroids in Stable COPD*
Mario Cazzola, MD, FCCP; and Ronald Dahl, MD
Long-acting 
2
-agonists (LABAs) have been shown to be effective first-line bronchodilators in the
treatment of COPD patients, and inhaled corticosteroids (ICSs) have been shown to reduce the
frequency and/or severity of exacerbations in COPD patients. The concomitant use of a LABA and
an ICS can influence both airway obstruction (ie, smooth muscle contraction, increased cholin-
ergic tone, and loss of elastic recoil), and airway inflammation (ie, increased numbers of
neutrophils, macrophages, and CD8ⴙ lymphocytes, elevated interleukin-8 and tumor necrosis
factor-␣ levels, and protease/antiprotease imbalance). They are also able to reduce the total
number of bacteria adhering to the respiratory mucosa in a concentration-dependent manner
without altering the bacterial tropism for mucosa, and to preserve ciliated cells. Several clinical
trials support the concept of inhaled combination therapy with LABAs and corticosteroids in
stable COPD patients. This type of therapy not only improves airflow obstruction but also
provides clinical benefits, as manifested by sustained reduction in overall symptoms, improve-
ments in health-related quality of life, and reductions in exacerbations. All of these effects are
very important because, despite recent advances in our understanding of COPD and its
treatment, therapy remains suboptimal for a considerable number of patients.
(CHEST 2004; 126:220 –237)
Key words: inhaled corticosteroids; long-acting 
2
-agonists
Abbreviations: cAMP ⫽ cyclic adenosine 3⬘5⬘-monophosphate; C/EBP ⫽ CCAAT-enhancer binding protein;
EUROSCOP ⫽ European Respiratory Society Study on COPD; GR ⫽ glucocorticoid receptor; ICS ⫽ inhaled cortico-
steroid; IL ⫽ interleukin; LABA ⫽ long-acting 
2
-agonist; NF-B ⫽ nuclear factor-B; PEF ⫽ peak expiratory flow;
QOL ⫽ quality of life; SABA ⫽ short-acting 
2
-agonist; SEK ⫽ Swedish kronor; SGRQ ⫽ St. George Respiratory
Questionnaire; TNF ⫽ tumor necrosis factor; TRISTAN ⫽ Trial of Inhaled Steroids and Long-Acting 
2
-Agonists
C
OPD is a multicomponent disease that includes
airway inflammation, airflow limitation, muco-
ciliary dysfunction, and airway structural changes
1
(Fig 1). In particular, obstruction is associated with
an airway inflammatory profile consisting mainly of
an increased number of T lymphocytes (predomi-
nantly CD8⫹ cells), macrophages, and neutro-
phils.
2,3
Airway inflammation also involves inflamma-
tory mediators such as leukotriene B4, interleukin
(IL)-8 and tumor necrosis factor (TNF)-␣,
4
which
are generally considered to be important mediators
in neutrophil recruitment. Oxidative stress and an
imbalance between proteases and antiproteases in
the lung also have been implicated in the pathophys-
iology of the condition.
4
All COPD components contribute to a complex of
lung function changes, symptoms, and exacerbations,
which affect the health status and, ultimately, the
survival of the patient.
1
It is obvious, therefore, that
a correct therapeutic approach must try to interfere
with these components. The recent evidence-based
Global Initiative for Chronic Obstructive Lung Dis-
ease guidelines
1
recommend that the overall ap-
proach to managing stable COPD patients should be
characterized by a stepwise increase in treatment,
*From the Department of Respiratory Medicine (Dr. Cazzola),
Unit of Pneumology and Allergology, Antonio Cardarelli Hospi-
tal, Naples, Italy; and the Department of Respiratory Diseases
(Dr. Dahl), University Hospital Aarhus, Aarhus, Denmark.
Dr. Cazzola has received fees for participating to Advisory Boards
from Altana, AstraZeneca, and Novartis, for consulting from
Chiesi Farmaceutici and GSK, and for speaking from AstraZen-
eca, Boehringer Ingelheim, GSK, Menarini Farmaceutici, Novar-
tis, and Pfizer, and research-related grants from GSK. Dr. Dahl
has received fees for participating in Advisory Boards from
Altana, Boehringer-Ingelheim, and GSK, for speaking from
Schering-Plough, MSD, and ALK-Abello, and research-related
grants from Astra-Zeneca, GSK, ALK-Abello, Pfizer, Boehringer-
Ingelheim, Novartis, Almirall, MSD, and UCB.
Manuscript received June 25, 2003; revision accepted October
14, 2003.
Reproduction of this article is prohibited without written permis-
sion from the American College of Chest Physicians (e-mail:
permissions@chestnet.org).
Correspondence to: Mario Cazzola, MD, FCCP, Via del Parco
Margherita 24, 80121 Napoli, Italy; e-mail mcazzola@qubisoft.it
220 Reviews
depending on the severity of the disease. To date, no
medication has been shown to alter the rate of
decline of FEV
1
, but bronchodilator medications are
central to symptom management in COPD.
5
Among
the currently available bronchodilators, long-acting
inhaled agents are the most convenient.
6
However,
many patients remain symptomatic despite the opti-
mal use of these bronchodilators, and, consequently,
it can be necessary to add other drugs to the
therapeutic regimen. A body of evidence indicates
that combining different bronchodilators may im-
prove efficacy and decrease the risk of side effects
compared to increasing the dose of a single agent.
1,5
The Global Initiative for Chronic Obstructive
Lung Disease guidelines
1
are more cautious in sug-
gesting the use of corticosteroids. They state that
regular treatment with inhaled corticosteroids (ICSs)
should be prescribed only for symptomatic COPD
patients with a documented spirometric response to
corticosteroids or in those with an FEV
1
⬍ 50% of
predicted values, and repeated exacerbations requir-
ing treatment with antibiotics and/or oral corticoste-
roids.
Use of Long-Acting 
2
-Agonists in COPD
Long-acting 
2
-agonists (LABAs) have been
shown to be elective first-line bronchodilators in the
treatment of patients with COPD.
5,6
They safely
attenuate airflow obstruction, decrease the fre-
quency and severity of symptoms by reducing the
amount of dynamic hyperinflation, and improve
quality of life (QOL). Interestingly, several studies
have documented that the LABAs formoterol
7,8
and
salmeterol
9,10
are more effective than ipratropium
bromide for the regular treatment of COPD. This
finding is important because for many years ipratro-
pium has been considered to be the first-line therapy
for long-term treatment of stable patients who are
symptomatic with COPD.
11
LABAs can usefully be prescribed for the com-
bined bronchodilator treatment of COPD.
12,13
In
particular, the addition of a LABA to an anticholin-
ergic compound appears to be more efficacious than
adding a short-acting 
2
-agonist (SABA) in stable
patients with COPD.
14
In addition to prolonged bronchodilatation,
LABAs exert other additive effects that may be of
clinical relevance in COPD
15
(Table 1). For exam-
ple, data indicate that LABAs can increase the level
of cyclic adenosine 3⬘5⬘-monophosphate (cAMP) in
neutrophils, thereby inhibiting neutrophil adhesion,
accumulation, and activation, and inducing apopto-
sis.
15
In particular, salmeterol inhibits neutrophil
adhesion to bronchial epithelial cells.
16
Formoterol
inhibits chemotaxis to platelet-activating factor
17
over the concentration range 10
⫺7
to 10
⫺4
mol/L.
Neutrophil activation also was attenuated, as evi-
denced by reductions in the release of superoxide,
18
IL-8,
19
and bacterial permeability-increasing pro-
tein,
20
which are not associated with the SABA
albuterol. However, in general, these effects were
only significant at relatively high concentrations (ie,
⬎ 10
⫺6
mol/L) and were not reversed by proprano
-
lol, suggesting that they were not mediated by

2
-adrenoceptors. The end result is a possible reduc
-
tion in the number and activation status of neutro-
phils in airway tissue and in the airway lumen
21
Figure 1. Pathophysiologic/clinical features of COPD. The multiple components of COPD combine
to produce airflow limitation, which is a key characteristic of the disease.
Table 1—LABA Mechanisms of Action in COPD
Bronchodilation
Reduced lung hyperinflation
Increased mucociliary transport
Mucosal cytoprotection
Antineutrophil activity
www.chestjournal.org CHEST / 126/1/JULY, 2004 221
(Table 2). LABAs also may decrease the number of
neutrophils that adhere to the vascular endothelium
at sites of inflammation and may reduce the amount
of plasma leakage,
22
but the relevance of these
findings to COPD patients is unclear. It is notewor-
thy that glucocorticoids have been shown to increase
high-affinity -agonist binding in human neutro-
phils.
23
It is also possible that LABAs may increase
the peripheral deposition of ICSs, thus enhancing
their antiinflammatory activity.
24
Use of Corticosteroids in COPD
The role of corticosteroids in the management of
COPD remains controversial. ICSs are commonly
prescribed in high doses on the basis that COPD is
like poorly responsive asthma, but evidence that they
are beneficial in patients with pure COPD is still
weak. In effect, although it is well-known that corti-
costeroids are effective at suppressing airway inflam-
mation, their effect on the inflammation in COPD is
still unclear.
Impact of Corticosteroids on Inflammation in
COPD
Some studies
25–28
have indicated that these agents
apparently do not exert a major influence on inflam-
matory cells and mediators in the sputum of stable
patients with COPD, but other reports
29–36
have
suggested that treatment with corticosteroids may
induce biological responses that may be associated
with changes in some clinical outcomes and endo-
scopic findings in these patients (Table 3).
In vitro corticosteroids attenuate neutrophil re-
cruitment and activation,
29
and reduce neutrophil
chemotaxis.
30
In vivo, they attenuate sputum chemo-
tactic activity, increase neutrophil elastase inhibitory
capacity,
31
and induce a decrease in both neutrophils
and total cells in induced sputum.
32,33
Moreover,
they reduce the numbers of mucosal mast cells
34
and
subepithelial mast cells, and reduce the epithelial
CD8/CD4 ratio,
35
although they have no effect on
the major inflammatory cell types in COPD. ICSs
also induce significant reductions in the BAL fluid
levels of IL-8 and myeloperoxidase, as well as reduc-
tions in cell numbers, the proportion of neutrophils,
symptom score, and bronchitis index.
36
These findings seem to support the use of ICSs in
treating COPD, although long-term treatment with
ICSs must be associated with a high risk of adverse
systemic effects and involves unnecessary expense.
37
Unfortunately, however, clinical trials on the effects
of corticosteroids in COPD have reported conflicting
results. Consequently, there is considerable contro-
versy concerning the utility of these agents for the
long-term treatment of patients with COPD.
37,38
Clinical Effects of Corticosteroids in COPD
Negative Findings: Some trials
39–41
have seemed
to indicate that only those patients with an asthmatic
component to their disease appear to benefit from
corticosteroids. Thus, in the study by Chanez and
colleagues,
39
12 of 25 unselected patients in whom
COPD had been clinically diagnosed responded to a
daily oral dose of prednisolone, 1.5 mg/kg body
weight, for 15 days, with an increase in FEV
1
of at
least 12% from the baseline value and an absolute
value of 200 mL, measured at the end of treatment.
By comparison with nonresponders, responders had
a significantly larger number of eosinophils and
higher levels of eosinophil cationic protein in their
BAL fluid, and the responders also had a thicker
reticular basement membrane than the nonre-
sponders. Pizzichini and colleagues
40
reported that
an improvement in QOL score and FEV
1
after a
short-term course of prednisone therapy in smokers
with chronic obstructive bronchitis was paralleled by
a significant reduction in eosinophilia and eosinophil
activation, as indicated by sputum eosinophil cationic
protein levels, but not by changes in neutrophils or
neutrophil proteases. Patients without sputum eosin-
ophilia did not show clinical benefit from short-term
prednisone therapy. Nishimura and colleagues,
41
in a
trial of patients with COPD, found a significant
improvement in FEV
1
in a minority of patients (5 of
30 patients) receiving 3,000 g per day beclometha-
sone dipropionate over a 4-week treatment period.
However, some of these responders showed a posi-
tive response to the bronchodilator challenge, as well
as an elevated serum IgE level or eosinophil count,
which is suggestive of the presence of an asthmatic
component to their airflow obstruction.
Besides, four large studies (ie, the European
Respiratory Society Study on COPD [EURO-
Table 2—Antineutrophil Effects of Salmeterol
21
Variables Placebo
Salmeterol,
50 g twice
daily ⫻ 6wk
Neutrophil numbers
BAL fluid, % 2.1 1.6*
Bronchial biopsy, cells/mm
2
21.4 14.3†
Neutrophil mediator release
BAL IL-8, pg/mL 73.0 61.0*
BAL lipocalin, mg/L 14.1 10.3‡
Serum myeloperoxidase, mg/L 302 249*
*p ⬍ 0.05.
†p ⬍ 0.04.
‡p ⬍ 0.03.
222 Reviews
SCOP]
42
; the Copenhagen City Lung Study
43
; the
Inhaled Steroids in Obstructive Lung Disease trial
44
;
and the American Lung Health-2
45
) have demon-
strated that these agents did not have any worthwhile
effect on the rate of decline in FEV
1
when asthma
was rigorously excluded (Table 4), indicating that
there is no effect of ICSs on the progressive inflam-
matory disease process.
37
In effect, there are three principal arguments
against the use of ICSs in COPD, as follows: neu-
trophilic inflammation (which is characteristic in
COPD) is generally resistant to corticosteroids; cor-
ticosteroids prolong the survival of neutrophils by
inhibiting apoptosis; and corticosteroid therapy fails
to suppress cytokines such as TNF-␣ and IL-8,
which are elevated in patients with COPD.
37
More-
Table 3—Impact of Corticosteroids on Inflammation in COPD*
Study Type of Patients Enrolled
Treatment, Study
Duration Outcomes
Negative studies
Thompson et al
25
Current smokers with chronic
bronchitis and at least mild
obstruction
Beclomethasone, 1 g/d for
6 weeks
Small increase in FEV
1
, small decrease in macroscopic
bronchioscopic index of bronchial inflammation, no
reduction in the number of neutrophils in BALF
Keatings et al
26
Patients with severe COPD
(mean FEV
1
, 35%
predicted)
Budesonide, 800 g twice
daily for 2 wk
No clinical benefit in either lung function or symptom
scores, no significant change in the inflammatory
indices as measured by total and differential cell
counts and concentrations of TNF-␣, eosinophil
activation markers, eosinophilic cationic protein, and
eosinophil peroxidase, and neutrophil activation
markers myeloperoxidase and human neutrophil
lipocalin
Oral prednisolone, 30 mg
daily for 2 weeks
Sputum eosinophil number, eosinophilic cationic
protein, and eosinophil peroxidase not modified
Culpitt et al
27
Patients with stable COPD Fluticasone, 500 g twice
daily for 4 wk
No clinical benefit in terms of lung function or
symptom scores, no change in induced sputum
inflammatory cells, percentage of neutrophils, IL-8
levels, supernatant elastase activity, MMP-1, MMP-
9, and the antiproteases secretory leukoprotease
inhibitor and tissue inhibitor of MMP-1 levels
Loppow et al
28
Patients with chronic
bronchitis (mean FEV
1
,
83.4% predicted)
Fluticasone, 500 g twice
daily for 4 wk
No improvement in lung function or inflammatory
parameters, such as the concentration of exhaled
nitric oxide, differential cell counts in induced
sputum, and the number of cells positive for
inducible nitric oxide synthase, as well as the levels
of lactate dehydrogenase, eosinophilic cationic
protein, neutrophil elastase and IL-8 in sputum
supernatants
Positive studies
Llewellyn-Jones et al
31
Patients with clinically stable,
smoking-related chronic
bronchitis and emphysema
(mean FEV
1
, 0.71 L)
Fluticasone, 1.5 mg/d for
8wk
No effect on peripheral neutrophils or on sputum
albumin and myeloperoxidase concentrations, but
reduction in the neutrophil chemotactic activity of
sputum and beneficial effect on the
proteinase/antiproteinase balance
Confalonieri et al
32
Patients with stable COPD
(mean FEV
1
, 60.2%
predicted)
Beclomethasone, 500 g
three times daily for 2
mo
Reduction in both neutrophils and total cells in
induced sputum, no change in spirometry and blood
gases
Yildiz et al
33
Clinically stable COPD
patients
Fluticasone, 1,500 g/d
for2mo
No significant changes in the number of peripheral
blood neutrophils, blood gases, and spirometry, but
decrease in the total cell number and the number of
neutrophils in induced sputum
Gizycki et al
34
Patients with mild-to-severe
COPD (FEV
1
,25–80%
predicted)
Fluticasone, 500 g twice
daily for 3 mo
Significant decrease in the numbers of mucosal mast
cells, improvement in symptoms
Hattotuwa et al
35
Patients with mild-to-severe
stable COPD (mean FEV
1
,
25–80% predicted)
Fluticasone, 500 g twice
daily for 3 mo
No effect on the major inflammatory cell types in
COPD, but reduced epithelial CD8/CD4 ratio and
subepithelial mast cell number
Balbi et al
36
Stable COPD patients with
mild disease
Beclomethasone, 1.5 mg/d
for6wk
Reductions in the lavage levels of IL-8 and
myeloperoxidase, in cell numbers, neutrophil
proportion, symptom score, and bronchitis index
*BALF ⫽ BAL fluid; MMP ⫽ matrix metalloproteinase.
www.chestjournal.org CHEST / 126/1/JULY, 2004 223
over, a population-based cohort study
46
documented
that ICS use after hospitalization for COPD was not
found to reduce mortality and morbidity, but this
study had only 979 persons and could not estimate
the benefit with great precision.
Positive Findings: Notwithstanding these nega-
tive findings, evidence is accumulating to support the
therapeutic use of corticosteroids, at least in patients
with more advanced COPD.
47
For example, it was
reported that treatment with an ICS for ⬎ 3 months
improved prebronchodilator airflow obstruction and
oxygenation while decreasing dyspnea in patients
with moderate-to-severe COPD.
48
Reductions in
exacerbation severity were seen in another study
49
of
patients with moderately severe disease who were
treated for 6 months with an inhaled glucocorticoid.
The Inhaled Steroids in Obstructive Lung Disease
study
44
reported that, in patients with moderate-to
severe-disease, 3 years of regular treatment with an
ICS resulted in fewer exacerbations, a reduced rate
of decline in health status, and higher FEV
1
values
than did placebo treatment. A recent systematic
review
50
of randomized placebo-controlled trials has
demonstrated a beneficial effect of ICSs in reducing
rates of COPD exacerbations. These agents also can
extend survival in patients with COPD.
51
Further-
more, the withdrawal of ICS therapy has been shown
to lead to deterioration in ventilatory function and to
increased exercise-induced dyspnea in patients with
severe irreversible airway obstruction.
52
All these findings lend support to the use of ICSs
in stable patients with COPD, and a convincing
demonstration of the effectiveness of these agents in
COPD patients has come from the COPE study (an
investigation of COPD in the Department of Pal-
monology, Enschede, the Netherlands).
53
This study
showed that the discontinuation of therapy with ICSs
was associated with a more rapid onset and a higher
risk of recurrence of exacerbations, and with a
significant deterioration in aspects of health-related
QOL, in the majority of patients.
53
However, 40% of
subjects in the COPE study experienced no unto-
ward effect from the withdrawal of ICSs.
53
This
finding indicates that there is an urgent need to
identify which subgroups of COPD patients respond
well to prolonged inhaled glucocorticoid therapy.
This is not an easy task, since COPD comprises
various diseases, which may differ in their pathologic,
clinical, and functional features, and in the biological
phenomena that cause and maintain airway inflamma-
tion. There also may be differences between the base-
line disease state (ie, in the absence of a current
exacerbation) and the disease state during an acute
exacerbation, and differences according to the degree
of airway obstruction or history of cigarette smoking.
Nevertheless, since very few therapies offer significant
benefits to patients with COPD, and since ICSs are
potentially beneficial in the treatment of this disease
(Table 5), the use of these agents remains a possible
therapeutic approach to stable patients with COPD.
Table 4—Long-term Effect of ICSs in COPD*
Study
Patients Enrolled, No./Study
Duration Rate of FEV
1
Decline vs Placebo
Health Outcomes
EUROSCOP
42
1,277 patients with mild COPD
(mean FEV
1
, 77% predicted)/
F/U at 36 mo
No change with budesonide, 400 g
twice daily
Not evaluated
Copenhagen City Lung Study
43
290 patients with mild to
moderate COPD (mean FEV
1
86% of predicted value)/F/U
at 30 mo
No change with budesonide, 800 g
plus 400 g daily for 6 mo
followed by 400 g twice daily for
30 mo
No change in exacerbations
ISOLDE
44
750 patients, with moderate to
severe COPD (mean FEV
1
50% of predicted value)/F/U
at 36 mo
No change with fluticasone, 500 g
twice daily
Decreased exacerbations; reduced
rate in decline of the disease-
specific SGRQ
Health Lung Study-2
45
1,116 patients with mild-to-
moderate COPD (mean
FEV
1
, 64% predicted)/F/U at
40 mo
No change with triamcinolone, 600
g twice daily
Less airway reactivity; reduced
respiratory symptoms; slightly
reduced hospitalizations; loss of
bone mineral density; increased
skin bruising
*F/U ⫽ follow up.
Table 5—Clinical Efficacy of ICSs in COPD
Increased lung function
Decreased symptoms
Decreased No./severity of exacerbations
Decreased morbidity/mortality
Increased health status
224
Reviews
Therefore, until a test is developed that can distinguish
potential corticosteroid responders from nonre-
sponders, it is worthwhile giving all patients with
COPD a trial (3 to 6 months) of an ICS to determine
whether or not they respond.
54
Pharmacologic Rationale for Combining a
LABA and an ICS in COPD
It must always be emphasized that the use of ICSs
should not leave the use of a LABA out of consider-
ation. The concomitant use of a LABA and an ICS
can influence airway obstruction (eg, smooth muscle
contraction, increased cholinergic tone, and, per-
haps, bronchial hyperreactivity), mucociliary dys-
function (eg, reduced mucociliary transport and
mucosal damage), and airway inflammation (eg, in-
creased numbers of neutrophils, macrophages, and
CD8⫹ lymphocytes, elevated levels of IL-8, TNF-␣,
and leukotrieneB4, protease/antiprotease imbalance,
and mucosal edema), as well as structural changes
(eg, glandular hypertrophy and goblet cell hyperpla-
sia) [Fig 2]. Furthermore, when a LABA is added to
an ICS, it has the potential for countering some of
the possible negative effects of the corticosteroid.
There is an exciting possibility that the observed
benefit from combining these two classes of drugs
might be due to a synergistic interaction, with the
resulting synergetic effect being greater than the
sum of responses achieved from each drug alone.
However, the basic molecular mechanism of such an
interaction is still to be fully identified (Fig 3).
Effect of Corticosteroids on LABAs
Corticosteroids can prevent, at least partially, ho-
mologous down-regulation of 
2
-adrenoceptor num
-
bers and can induce an increase in the rate of
receptor synthesis through a process of extended

2
-adrenoceptor gene transcription.
55
Although air-
way smooth muscle is among the tissues least sus-
ceptible to homologous down-regulation, long-term
treatment with a LABA may result in tolerance to its
bronchodilator effects.
56
Thus, the effects of cortico-
steroids on 
2
-adrenoceptor expression have the
potential for enhancing the airway relaxant response
to -adrenergic stimulation. An in vitro experimental
finding suggests that, at least in the rabbit, this effect
is correlated with increased -adrenoceptor expres-
sion in the tissue.
57
Moreover, the efficiency of
coupling between the 
2
-adrenoceptor and Gs (the
G protein that mediates the stimulation of adenylyl
cyclase) also has been reported to be modulated by
glucocorticoids.
58
As a result, 
2
-adrenoceptor-stim
-
ulated adenylyl cyclase activity and cAMP accumu-
lation increase after glucocorticoid treatment.
Effect of Long-Acting

-Agonists on Corticosteroids
In addition to the beneficial effects of corticoste-
roids on LABA activity, LABAs also may enhance the
effects of corticosteroids. It has been observed in
vitro, using primary human lung fibroblasts and
vascular smooth muscle cells, that LABAs induce
glucocorticoid receptor (GR) translocation from the
cell cytosol to the nucleus and enhance GR-glu-
cocorticoid response element binding in the absence
of ligand.
59
Preliminary reports in vivo have con-
firmed this finding.
60
It seems likely, therefore, that
LABAs may be able to induce GR nuclear translo-
cation and that this may prime the receptor to be
more responsive to a concomitant or subsequent
challenge with glucocorticoids (Fig 3). LABAs also
may increase the sensitivity of the molecular path-
ways that are utilized by corticosteroids to suppress
Figure 2. Effects of LABA/ICS combination therapy on pathophysiology of COPD. The LABA/ICS
combination has additive effects on the pathophysiology of COPD affecting airway obstruction,
inflammation, structural changes, and mucociliary dysfunction. It addresses the multicomponent nature
of COPD more than does LABA or ICS treatment alone.
www.chestjournal.org CHEST / 126/1/JULY, 2004 225
inflammation, including their action on histone acet-
ylation and deacetylation,
61,62
or through effects on
the activation of transcription factors, such as nuclear
factor (NF)-B.
63
Recently, it has been docu-
mented
64
that the combination of glucocorticoids
and LABAs synchronizes the activation of the GR
and CCAAT-enhancer binding protein (C/EBP)-␣,
which belongs to a family of transcription factors that
are involved in the differentiation process of numer-
ous tissues. This action results in a faster and more
prolonged activation of p21(Waf1/Cip1) compared
with each drug given alone. In particular, when
administered alone, formoterol and budesonide ac-
tivate the two transcription factors with different
potency and kinetics. The combined administration
of the two drugs leads to a simultaneous activation of
the GR and C/EBP-␣, resulting in a synergistic
stimulatory effect on p21(Waf1/Cip1) promoter ac-
tivity. Furthermore, when administered together,
the drugs are effective at concentrations that are
ineffective when either drug is administered alone.
These data lend support to the idea that the com-
bined application of the two drugs has a beneficial
effect that is greater than that of increasing the dose
of either drug alone, at least in asthma.
65,66
Role of LACA/ICS Interactions in COPD
At present, the role of these interactions in COPD
patients cannot be clearly defined. GR does not
interact only with C/EBP-␣, but also affects the
action of other transcription factors, such as activating
protein 1, cAMP responsive element-binding protein,
and the inhibitor of NF-B.
67–70
A direct interaction
with the GR also has been shown for the signal
transducer and activator of transcription 3 and 5.
71,72
These findings suggest that we must also investigate the
possibility of an interaction between glucocorticoids
and LABAs at these levels, and evaluate the potential
impact on COPD management.
Figure 3. The basis for synergy between LABAs and ICSs. Glucocorticoids (GCS) freely diffuse from
the circulation across cell membranes into cells, where they activate the GR. On ligand binding, the
receptor is activated, dissociates from chaperone proteins, and translocates to the nucleus, where it can
bind as a dimer to specific DNA sequences (glucocorticoid response elements [GRE]) upstream of the
start site of transcription. The activated GCS-GR also binds to the 
2
-adrenoceptor gene, leading to an
increase in the number of 
2
-adrenoceptors in the cell membrane. On the other side, LABA stimulates

2
-adrenoceptors, leading to the priming of the GR and increasing translocation of the receptor into
the nucleus of the cell. The overall response is increased anti-inflammatory activity from a given steroid
dose. The primed GR also may have enhanced actions against other transcription factors such as
NF-B. Besides, LABAs may inhibit NF-B by inducing an increase in IB-␣ levels.
MAPK ⫽ mitogen-activated protein kinase; PKA ⫽ protein kinase A; AC ⫽ adenylate cyclase;
IKK ⫽ IB kinase coupler; Ub ⫽ ubiquitin; Pi ⫽ phosphatidyl inositol.
226 Reviews
In Vitro Interactions of LABA and ICS Useful in
COPD
Examples of interaction between these two classes
of drugs that might be useful in COPD patients
include the synergistic inhibition by glucocorticoids
and LABAs of TNF-␣-induced IL-8 release from
cultured human airway smooth muscle cells
63
and
alveolar macrophages in patients with COPD,
73
and
the capacity of corticosteroids to counteract the
enhancement of LABAs on TNF-␣-induced IL-8
production in cultured human bronchial epithelial
cells.
74
These effects are mediated through the

2
-adrenoceptor into a signal transduction pathway
that does not involve the GR, but other interactions
between glucocorticoid and 
2
-agonist cannot be
excluded.
74
The inhibition of transcription factors,
such as NF-B, by -agonists may occur as a result
of an increase in the levels of the inhibitor of NF-B.
One study
75
of monocytic THP-1 cells stimulated
with lipopolysaccharide showed that -agonists
could inhibit TNF-␣ and IL-8 production, and that
the effect was related to increased cytoplasmic con-
centrations of IB-␣, possibly through its decreased
degradation. Elevated cAMP levels can inhibit NF-
B-mediated gene transcription in human monocyte
and endothelial cells.
76
cAMP regulates cytokine
gene expression by induction of the cAMP-mediated
transcriptional repressor in human thymocytes.
77
The inhibitory effects mediated by induction of the
cAMP-mediated transcriptional repressor may be
related to its ability to bind (ie, mask) a wide range of
cyclic adenosine monophosphate response element
and activating protein-1 motifs and/or its ability
to inactivate certain transcription complexes via
protein-protein interactions.
76
In any case, IL-8 is a
potent chemoattractant and an activator for neutro-
phils, and this may result in a persistent inflamma-
tory cycle by establishing a positive feedback loop.
Reductions in neutrophil number and function could
reduce the severity of disease and the degree of
airflow obstruction in patients with COPD.
63
Another important finding is the capacity of both
ICSs and LABAs to reduce the total number of
bacteria adhering to the respiratory mucosa in a
concentration-dependent manner without altering
the bacterial tropism for mucosa, and to preserve
ciliated cells.
78
ICSs and LABAs, when administered
together at low concentrations, exhibited a synergis-
tic effect with respect to the preservation of ciliated
cells, showing a trend toward reduced damage and a
significant preservation of the number of ciliated
cells compared to either agent alone at the same
concentrations. This result may have clinical signifi-
cance as it is thought that ciliated cells are the most
sensitive to damage by bacterial infection.
79
It is
well-known that airway colonization and chronic
infection contribute to progressive pulmonary dam-
age in COPD patients via the action of proinflam-
matory substances in what is known as the “vicious
circle theory”
80
(Fig 4). Recently, the synergistic
Figure 4. The LABA/ICS combination breaks the COPD vicious cycle. LABAs can break the COPD
vicious cycle by increasing cilial beat frequency, and therefore enhancing mucus clearance, by
preventing bacterial damage to the epithelium, and by suppressing neutrophil activation and mediator
release. Besides, ICSs and LABAs when administered together at low concentrations exhibited a
synergistic effect with respect to the preservation of ciliated cells, showing a trend toward reduced
damage and a significant preservation of the number of ciliated cells compared to either agent alone
at the same concentrations.
www.chestjournal.org CHEST / 126/1/JULY, 2004 227
effects of salmeterol and fluticasone in human
rhinovirus-induced proinflammatory cytokine pro-
duction have been documented.
81
Rhinoviruses are
implicated in many acute exacerbations of COPD,
perhaps by inducing proinflammatory cytokines.
82
Inhaled Combination Therapy With LABAs
and Corticosteroids in Stable COPD
Patients
Several clinical trials support the concept of in-
haled combination therapy with LABAs and cortico-
steroids in stable COPD patients, although some
reports have not been published yet. Nonetheless,
the currently available information has recently in-
duced the European Agency for the Evaluation of
Medicinal Products to issue a positive opinion
83
on
the use of combination therapy with LABAs and
ICSs in the maintenance treatment of patients with
severe COPD and a history of exacerbations.
Clinical Effects in Adding an ICS to a LABA
The results of a recent small study
84
have indi-
cated that the addition of budesonide amplifies the
fast onset of action of formoterol, but does not
induce systemic effects, in patients with COPD. It
has been shown that glucocorticoids act on steroid
receptors to increase 
2
-adrenoceptor expression by
augmenting the rate of 
2
-adrenoceptor gene tran
-
scription.
85
However, the glucocorticoid-induced in-
crease in the accumulation of 
2
-adrenoceptor mes
-
senger RNA could be detected at 15 min, the
maximal accumulation occurred at 2 h, and the
glucocorticoid-induced increase in 
2
-adrenoceptor
messenger RNA returned to the control level by
17 h. In contrast, the increase in the 
2
-adrenocep
-
tor values was slower, reaching a maximum between
17 and 24 h. These findings indicate that another
type of interaction may underlie the rapid onset of
action of combination therapy with formoterol and
budesonide. It is likely that a nongenomic action of
budesonide might explain this effect. Thus, it is
possible that corticosteroids might induce a fall in
intracellular Ca
2⫹
that might result, in part, from the
inhibition of Ca
2⫹
entry through voltage-gated ion
channels.
86
The capacity of corticosteroids to prevent homol-
ogous down-regulation of 
2
-adrenoceptor values
and to induce an increase in the rate of synthesis of
these receptors may be important when a patient is
receiving regular treatment with LABAs. The addi-
tion of an ICS to a LABA was initially studied in a
3-month trial that enrolled 80 COPD patients. The
association therapy progressively improved lung
function over the 3-month period compared to long-
acting bronchodilator treatment alone, although the
difference was not statistically significant.
87
How-
ever, the association of therapy with salmeterol
(50 g twice daily) with that with fluticasone (250 or
500 g twice daily) allowed a significantly greater
improvement in lung function after salbutamol ther-
apy alone than salmeterol therapy (50 g twice daily)
alone. It is likely that this effect was due to the
prevention of the homologous down-regulation of

2
-adrenoceptors and the induction of an increase in
the rate of synthesis of receptors through a process of
increased 
2
-adrenoceptor gene transcription in
-
duced by fluticasone. This may be considered clini-
cally important, because when airway obstruction
becomes more severe the preferred therapeutic op-
tion is to add a fast-acting inhaled 
2
-agonist as
rescue medication to produce rapid relief of bron-
chospasm.
Combination Therapy With Salmeterol/Fluticasone
The value of regular combination therapy with
LABAs and corticosteroids delivered via a single
inhaler to COPD patients has been documented
repeatedly (Table 6). Since the overall goals for
improving clinical outcomes are to reduce symp-
toms, especially dyspnea, to improve exercise capac-
ity, to reduce exacerbations and the possible need for
hospitalization, and to enhance health status,
1
the
different trials have not only evaluated the efficacy of
combination therapy on lung function, but also its
impact on these other clinical outcomes.
A 24-week study with the combination therapy of
salmeterol, 50 g twice daily, and fluticasone propi-
onate, 500 g twice daily, explored the potential for
increasing airflow, reducing symptoms (including
dyspnea), and improving health status, compared
with the individual components and placebo.
88
The
results showed that the salmeterol/fluticasone propi-
onate combination not only improved airflow ob-
struction but also provided clinical benefits, as man-
ifested by reduced severity of dyspnea, reduced use
of rescue salbutamol, and improved health status.
A 52-week multicenter, randomized, double-
blind, placebo-controlled trial (Trial of Inhaled Ste-
roids and Long-Acting 
2
-Agonists [TRISTAN])
89
compared the safety and efficacy of the salmeterol,
50 g twice daily/fluticasone propionate, 500 g
twice daily, combination with that of the individual
drugs alone in 1,465 patients with COPD (mean
FEV
1
, 45% predicted). Following a year of treat
-
ment with the salmeterol/fluticasone propionate
combination, patients with COPD experienced sig-
nificant and clinically meaningful improvements in
health status, as measured by the St. George Respi-
ratory Questionnaire (SGRQ), compared with pla-
228 Reviews
cebo or fluticasone alone therapy. In addition, pa-
tients treated with combination therapy had greater
reductions in symptom scores compared with all
other treatments, and greater reductions in activity
(limitation) scores compared with placebo and fluti-
casone therapy alone. These findings could have a
real impact on the management of COPD. Patients
with COPD have significant and measurable de-
creases in health status, which worsen with disease
progression. The fatigue and emotional distress re-
sulting from COPD symptoms such as dyspnea,
cough, and phlegm production reduce the ability of
patients to work or carry out their normal activities.
As there is currently no cure for COPD, the goals of
therapy are to prevent symptoms and exacerbations,
to preserve lung function, and to maintain health
status.
The prevention of exacerbations is a key goal for
the effective management of COPD,
1
since exacer-
bations are known to reduce QOL and are cost
drivers in the treatment of COPD patients. There-
fore, controlling exacerbations is important from
both economic and patients’ perspectives. Subgroup
analyses of the TRISTAN trial
89
have been per-
formed to determine the relative efficacy of the
salmeterol, 50 g twice daily/fluticasone, 500 g
twice daily, combination therapy in reducing exacer-
bations in COPD patients with FEV
1
values of
⬍ 50% predicted at baseline (ie, the more severe
subgroup) or FEV
1
values of ⱖ 50% predicted at
baseline (ie, the less severe subgroup). Exacerbations
were defined a priori as a worsening of COPD
symptoms that required treatment with antibiotics,
oral corticosteroids, or both. Episodes that required
corticosteroid treatment or hospital admission were
noted separately. A total of 949 patients (65%) had a
prebronchodilator FEV
1
of ⬍ 50% predicted and
were classified into the more severe subgroup, and
513 patients (35%) had FEV
1
values of ⱖ 50%
predicted and were classified into the less severe
Table 6—Long-term Effect of Combination Therapy in COPD*
Study
Patients Enrolled, No./Study
Duration
Changes in FEV
1
Over Baseline at
the End of Treatment Health Outcomes
S/FP
Mahler et al
88
691 patients with moderate-
to-severe COPD (FEV
1
,
⬎ 65% predicted)/F/U at
24 wk
Pretreatment FEV
1
: ⫹156 mL after
S, 50 g/FP, 500 g twice daily,
⫹107 mL after S, 50 g twice
daily; ⫹104 after FP, 500 g
twice daily; ⫺ 4 mL after placebo
Greater improvements in the transition
dyspnea index with S/FP compared with
FP, S, and placebo; greater increase in
chronic respiratory disease questionnaire
score with S/FP compared with FP and
placebo, but not with S
Calverley et al
89
1,465 patients, with
moderate-to-severe COPD
(mean FEV
1
, 45%
predicted)/F/U at 52 wk
⫹10% after S, 50 g/FP 500, g
twice daily; ⫹2% after S, 50 g
twice daily; ⫹2% after FP, 500
g twice daily; ⫺3% after
placebo
Significantly greater reduced rate in
decline of the disease-specific SGRQ
after S/FP than after FP and placebo;
No. of exacerbations per patient per year
reduced by 25% after S/FP, 20% after S,
and 19% after FP, all vs placebo, but
30% reduction with S/FP vs placebo
when baseline FEV
1
⬍ 50% predicted,
and 10% reduction when baseline FEV
1
⬎ 50% predicted
Dal Negro et al
90
18 patients with moderate
COPD (mean FEV
1
,
49.1% predicted)/F/U at
52 wk
⫹6.6% after S, 50 g/FP 250 g
twice daily; ⫹0.3% after S 50 g
twice daily; ⫺2.6% after placebo
Decrease in exacerbations only after S/FP
F/B
Szafranski et al
91
812 patients with moderate-
to-severe COPD (mean
FEV
1
, 36% of predicted)/
F/U at 52 wk
⫹15% after F, 6 g/B, 200 g
twice daily vs placebo; ⫹9% after
F, 6 g/B, 200 g twice daily vs
B, 200 g twice daily; ⫹1% after
F, 6 g/B, 200 g twice daily vs
F, 6 g twice daily
Significantly greater reduced rate in
decline of the disease-specific SGRQ
after F/B than after placebo; No. of
severe exacerbations per patient per year
reduced after F/B by 24% vs placebo,
23% vs F, and 11% vs B
Calverley and
Olsson,
92
Jones and
Ståhl,
93
and
Calverley and
Peterson
94
1,022 patients with
moderate-to-severe COPD
(mean FEV
1
, 36%
predicted)/F/U at 52 wk
⫹14% after F, 12 g/B, 400 g
twice daily vs placebo; ⫹11%
after F, 12 g/B, 400 g twice
daily vs B, 400 g twice daily;
⫹5% after F, 12 g/B, 400 g
twice daily vs F, 12 g twice daily
Significantly greater reduced rate in
decline of the disease-specific SGRQ
after F/B than after F, B, and placebo;
No. of exacerbations per patient per year
reduced by 24% after F/B, 11.6% after
B, and 3% after FP, all vs placebo
*S ⫽ salmeterol; FP ⫽ fluticasone propionate; F ⫽ formoterol; B ⫽ budesonide. See Table 4 for abbreviation not used in the text.
www.chestjournal.org CHEST / 126/1/JULY, 2004 229
subgroup. During the study, there was a higher
incidence of exacerbations in the more severe sub-
group compared with the less severe subgroup (567
patients [60%] vs 226 patients [44%], respectively).
In the total population, the salmeterol/fluticasone
combination treatment produced a significant reduc-
tion in the exacerbation rate of 25%, compared with
placebo treatment. This reduction was 30% in the
more severe subgroup, compared with a 10% reduc-
tion in the less severe subgroup. These effects of
combination therapy were more pronounced when
considering exacerbations requiring oral corticoste-
roids, which were reduced by 39% in the total
population, 43% in the more severe subgroup, and
24% in the less severe subgroup. Salmeterol/flutica-
sone combination treatment also reduced the num-
ber of exacerbations requiring therapy with oral
corticosteroids by 19%, compared with therapy with
salmeterol alone, in the more severe subgroup.
Although twice-daily therapy with salmeterol/flutica-
sone was effective in significantly reducing the num-
ber of exacerbations across both categories of disease
severity, there was a trend for a larger reduction in
exacerbations and exacerbations requiring oral corti-
costeroids in the more severe subgroup.
Recently, Dal Negro et al
90
have compared ther-
apy with salmeterol, 50 g twice daily/fluticasone,
250 g twice daily, via a single inhaler with therapy
with salmeterol, 50 g twice daily, alone and placebo
in 52-week study that has enrolled a small group of
ICS-naive patients with moderate COPD who had
already been treated with theophylline, 400 mg per
day, and SABAs on demand. The mean (⫾ SD)
number of exacerbations per year decreased from
3.5 ⫾ 0.8 to 1.16 ⫾ 0.75 in the salmeterol/flutica-
sone group (p ⬍ 0.001), from 3.0 ⫾ 0.89 to
2.3 ⫾ 0.81 in the salmeterol group (difference not
significant), and from 3.16 ⫾ 1.16 to 4.16 ⫾ 0.75 in
the placebo group (difference not significant). Pa-
tients receiving salmeterol/fluticasone therapy
showed the highest mean improvement in FEV
1
(mean increase, 6.6 ⫾ 2.4%) over the baseline pre-
treatment value (p ⬍ 0.001), with FEV
1
remaining
unchanged after 52 weeks of treatment in the salme-
terol group (mean increase, 0.3 ⫾ 0.9%) and with a
substantial decrease following placebo therapy
(mean decrease, 2.6 ⫾ 0.5; p ⬍ 0.001).
Combination Therapy With Formoterol/Budesonide
The effects of formoterol/budesonide combination
treatment in COPD patients also have been investi-
gated. In a 12-month, randomized, double-blind,
placebo-controlled, parallel-group, multicenter
study,
91
812 adults with moderate-to-severe COPD
(mean age, 64 years; mean FEV
1
, 36% predicted;
median time since diagnosis, 5 years) received two
inhalations twice daily of formoterol (6 g)/budes-
onide (200 g), budesonide (200 g) alone, formot-
erol (6 g) alone, or placebo. Formoterol/budes-
onide treatment increased FEV
1
by 15% vs placebo,
9% vs budesonide alone, and 1% vs formoterol alone.
Significant improvements in morning and evening
peak expiratory flow (PEF) values were seen during
the 12 months of therapy with formoterol/budes-
onide compared with all other treatment groups
(adjusted mean change from run-in: morning PEF,
24, 16, and 12 L/min vs placebo, budesonide alone,
and formoterol alone, respectively; evening PEF, 20,
15, and 11 L/min vs placebo, budesonide alone, and
formoterol alone, respectively; all p ⬍ 0.001). These
lung function improvements were maintained
throughout the 12-month study. The improvement
in lung function observed after formoterol/budes-
onide treatment must be considered to be important,
but the greater capacity of formoterol/budesonide to
decrease the mean total symptom score (p ⬍ 0.001
vs placebo; p ⬍ 0.001 vs budesonide alone; p ⫽ 0.103
vs formoterol alone), to increase the number of days
free from shortness of breath by 12% vs placebo
(p ⬍ 0.001), and to increase the number of awaken-
ing-free nights by 14% vs placebo (p ⬍ 0.001), each
of which is equivalent to approximately 1 extra
day/night per week, is likely to have a more substan-
tial impact on health status. Formoterol/budesonide
also significantly reduced the use of reliever medi-
cation by 1.3 and 0.7 inhalations per 24 h vs placebo
and budesonide alone, respectively (both p ⬍ 0.001).
The sustained reduction in overall symptoms, in-
cluding the number of sleep-disturbed nights, in
patients with moderate-to-severe COPD was re-
flected in improvements in health-related QOL.
Mean reductions from baseline were ⫺3.9, ⫺1.9,
⫺3.6 and ⫺0.03, respectively, after therapy with
formoterol/budesonide, budesonide, formoterol, and
placebo.
91
Compared with treatment with placebo,
treatment with formoterol/budesonide significantly
improved the SGRQ total score (p ⫽ 0.009), and the
symptom domain score (p ⬍ 0.001) and impact do-
main score (p ⫽ 0.006). Greater improvements were
seen with formoterol/budesonide compared with the
other active treatments, but these did not achieve
statistical significance.
Formoterol/budesonide therapy also produced
clinically significant reductions in the number of
exacerbations in patients with moderate-to-severe
COPD.
91
It reduced the number of severe exacer-
bations per patient per year by 24% vs placebo
therapy (p ⫽ 0.035), by 23% vs formoterol therapy
(p ⫽ 0.043), and by 11% vs budesonide therapy
(p ⫽ 0.385). Moreover, budesonide/formoterol ther-
apy also reduced the number of mild exacerbations
230 Reviews
compared with therapy with placebo (62%;
p ⬍ 0.001), budesonide alone (35%; p ⫽ 0.022); and
formoterol alone (15%; p ⫽ 0.403).
In another randomized, double-blind, active-con-
trolled study, 1,022 patients (mean age, 64 years;
FEV
1
, 0.99 L and 36% predicted) with moderate-to-
severe COPD and a history of exacerbations had
their condition optimized with therapy with formot-
erol, 12 g twice daily, and oral prednisolone prior to
being given formoterol (12 g twice daily)/budes-
onide (400 g twice daily), budesonide alone (400
g twice daily), formoterol alone (12 g twice daily),
or placebo for 1 year.
92–94
The study, which has not
been published yet, was designed to determine
whether these treatments prevented COPD exacer-
bations. Formoterol/budesonide therapy was signifi-
cantly better than that with long-acting 
2
-agonists
alone, corticosteroids alone, or placebo in maintain-
ing the lung function improvement achieved after
optimization.
92
Mean FEV
1
in the budesonide/
formoterol group remained 14% above the value in
the placebo group (p ⬍ 0.001), 11% above the value
in the budesonide group (p ⬍ 0.001), and 5% above
the value in the formoterol group (p ⬍ 0.01). Morn-
ing PEF in the budesonide/formoterol group was 18
L/min above the value in the placebo group
(p ⬍ 0.001), 15 L/min above the value in the budes-
onide group (p ⬍ 0.001), and 7 L/min above the
value in the formoterol group (p ⬍ 0.01). The value
for evening PEF in the budesonide/formoterol group
was 14 L/min above the value in the placebo group
(p ⬍ 0.001), 12 L/min above the value in the budes-
onide group (p ⬍ 0.001), and 5 L/min above the
value in the formoterol group (p ⫽ 0.056). For FVC,
the value in the formoterol/budesonide group was
9% above that in the placebo group (p ⬍ 0.001), 8%
above that in the budesonide group (p ⬍ 0.001), and
2% above that in the formoterol group. These
changes, which occurred soon after treatment began,
showed no sign of tachyphylaxis over the 12-month
study period. Formoterol/budesonide therapy also
improved SGRQ total score.
93
In particular, it im-
proved all domain scores vs placebo (p ⬍ 0.01),
activity score by 3.6 vs budesonide therapy
(p ⬍ 0.05) and 3.5 vs formoterol therapy (p ⬍ 0.05),
and impact score by 5.7 vs budesonide (p ⬍ 0.001)
and 3.7 vs formoterol (p ⬍ 0.05).
Interestingly, formoterol/budesonide therapy pro-
vided significantly better protection against exacer-
bations than either LABA alone, corticosteroid ste-
roid alone, or placebo treatment.
94
It prolonged the
time to the first exacerbation requiring medical
intervention (ie, hospitalization and/or the use of oral
steroids/antibiotics) compared with therapy with
budesonide alone (p ⬍ 0.05), formoterol alone
(p ⬍ 0.01), or placebo (p ⬍ 0.05). The median dura-
tions to the first exacerbation were as follows:
formoterol/budesonide, 254 days; budesonide alone,
178 days; formoterol alone, 154 days; and placebo, 96
days. Formoterol/budesonide therapy also reduced
the risk of a first exacerbation by 29% vs placebo
(p ⬍ 0.01), 30% vs formoterol alone (p ⬍ 0.01), and
23% vs budesonide alone (p ⬍ 0.05). Fewer exacer-
bations per patient per year were recorded in the
formoterol/budesonide group (1.38) than in the
budesonide alone group (1.60), the formoterol-alone
group (1.85), or the placebo group (1.80). The
reduction in the mean exacerbation rate, compared
with placebo, was 11.6% in the budesonide-alone
group (difference not significant), 3.0% in the
formoterol-alone group (difference not significant),
and 24% in the formoterol/budesonide group
(p ⬍ 0.05). The numerically larger reduction in the
formoterol/budesonide group suggests that synergy
may occur. Furthermore, formoterol/budesonide
treatment significantly reduced the mean number of
oral steroid courses by 45% vs placebo (p ⬍ 0.001),
28% vs budesonide alone, and 30% vs formoterol
alone (both p ⬍ 0.05). Budesonide therapy alone
reduced the mean number of oral steroid courses by
23% vs placebo (p ⬍ 0.05).
Comparison Between Combination Therapy With
Salmeterol/Fluticasone and Formoterol/Budesonide
Apparently, there is no substantial difference be-
tween salmeterol/fluticasone and formoterol/budes-
onide in patients with COPD when these combina-
tions are prescribed at the dosages recommended for
this pathology, at least after acute administration.
95
Systemic Adverse Effects Using
Combination Therapy With LABAs and
Corticosteroids
Consideration of the risk/benefit ratio is important
when using inhaled combination therapy with
LABAs and ICSs in patients with COPD, mainly
because of the potential systemic adverse effects
induced by ICSs.
Side Effects of Long-term Treatments With High-
Dose ICSs
It is well-known that long-term treatments with
high-dose ICSs have the potential to produce sys-
temic adverse effects. Patients with COPD may be
particularly vulnerable to these systemic effects as
they are often elderly, immobile, and have poor
nutrition, thus increasing the risk of osteoporosis.
37
However, the results of different trials have been
variable. In the Lung Health Study,
45
a significantly
www.chestjournal.org CHEST / 126/1/JULY, 2004 231
lower bone density in the lumber spine and femur
was observed, whereas the EUROSCOP study
42
reported no difference between study arms. A recent
Cochrane review
96
of the effects on bone metabo-
lism in COPD patients reported that there is no
evidence of an effect of ICS treatment on bone
mineral density or vertebral fracture when given at
conventional doses for 2 or 3 years. Higher doses
have been associated with biochemical markers of
increased bone turnover, but data on bone mineral
density and the incidence of fractures at these doses
are not available. There is a need for further, even
longer term, prospective studies of conventional and
high doses of ICSs.
Elderly patients also may have an increased risk of
developing cataracts, glaucoma, and diabetes.
37
However, no differences in the rates of cataract were
seen in the most important long-term trials.
42–45,49
In
the EUROSCOP study,
42
10% of patients developed
skin bruising compared to 4% in the control group. It
is generally accepted that any discussion of the use of
high-dose ICSs in patients with COPD must weigh
the real risk of systemic side effects against the
minimal clinical value provided by this treatment.
37
Side Effects of Combination Therapy With
Salmeterol/Fluticasone
Although there is clear evidence that the concen-
tration of ICSs can be reduced when combined with

2
-agonists, thus minimizing the risk of side ef
-
fects,
64
there is a real need to establish whether any
side effects induced by combination therapy with
LABAs and ICSs are outweighed by the clinical
advantages.
The combined use of salmeterol and fluticasone
propionate in a single formulation provides additive
benefit in the treatment of COPD but with compa-
rable safety to the individual components used
alone.
88,89
The safety profile of salmeterol/flutica-
sone combination treatment was consistent with that
observed with the administration of salmeterol plus
fluticasone, and was not different from that for the
monocomponents alone after a 12-week treatment
period.
87
The overall adverse event profile of the
combination therapy showed no new or unexpected
adverse events. There was no evidence that combi-
nation treatment with the salmeterol/fluticasone
combination was associated with any increased risk
of clinically relevant hypothalamic-pituitary-adrenal
axis suppression (as assessed by cosyntropin stimula-
tion testing) compared with treatment with flutica-
sone, salmeterol, or placebo alone. No unexpected
cardiovascular effects, as assessed by Holter moni-
toring and routine ECG, were observed in those
patients receiving salmeterol/fluticasone combina-
tion treatment compared with patients receiving
salmeterol or placebo. In the TRISTAN study,
89
all
treatments were well-tolerated, although the per-
centage of patients with oropharyngeal candidiasis
was higher in groups receiving fluticasone-containing
treatment (placebo treatment, 2%; salmeterol treat-
ment alone, 2%; fluticasone treatment alone, 7%;
salmeterol/fluticasone combination treatment, 8%).
The majority of patients (96%) had serum cortisol
levels that were within the reference range or not
significantly changed from baseline. The incidence
of skin bruising was low and was comparable among
treatment groups (placebo group, 6%; salmeterol
alone group, 6%; fluticasone alone group, 7%;
salmeterol/fluticasone combination group, 8%).
ECG findings were unchanged by therapy.
Side Effects of Combination Therapy With
Formoterol/Budesonide
Formoterol/budesonide therapy also was shown to
be well-tolerated and to have a safety profile similar
to that for therapy with placebo and the monocom-
ponents in patients with moderate-to-severe COPD
during 12 months of treatment.
91
Most adverse
events were reported for respiratory system disor-
ders, particularly COPD (formoterol/budesonide
group, 17%; placebo group, 26%; budesonide-alone
group, 13%; and formoterol-alone group, 19%). No
treatment-related patterns were discernible regard-
ing death (26 deaths) or serious adverse events
(number of serious adverse events per 1,000 treat-
ment days: formoterol/budesonide group, 0.8; pla-
cebo group, 0.9; budesonide-alone group, 0.7; for-
moterol-alone group, 0.7). Discontinuations due to
disease deterioration were highest in the placebo
group (placebo group, 21%; formoterol/budesonide
group, 10%; budesonide-alone group, 12%; formot-
erol-alone group, 14%), while the frequency of
discontinuations due to other adverse events was
similar in all groups (6 to 8%). No clinically impor-
tant between-group differences were identified for
laboratory or ECG measurements (including QTc
prolongation).
Effect of LABA/ICS Combination Therapy on

2
-Adrenoceptor Tolerance
These clinical findings regarding combination
treatment with both salmeterol/fluticasone and for-
moterol/budesonide are important. Tolerance gener-
ally develops to systemic 
2
-mediated adverse ef
-
fects, but it has been reported
97
that concomitant
therapy with inhaled budesonide resensitized the
response of cardiac 
2
-adrenoceptors to salbutamol
in subjects who were receiving regular twice-daily
formoterol therapy, which could suggest an in-
232 Reviews
creased propensity for the development of systemic

2
-mediated adverse effects. However, a previous
study
98
has demonstrated that the addition of the
recommended dose of formoterol to ICS therapy did
not induce significant nonpulmonary consequences,
except tremor, which may sometimes be a limiting
effect.
Need for Further Studies
First of all, there is a need to assess the antiin-
flammatory effects of long-term inhaled combination
therapy with LABAs and ICSs. There is little knowl-
edge at present about the effects of regular treat-
ment with LABAs and/or ICSs on airway inflamma-
tion in COPD patients. Studies
99
using bronchial
biopsy specimens obtained during fiberoptic bron-
choscopy in patients with COPD have yielded valu-
able information about the inflammatory process in
the large airways of patients with this disease. Bron-
choscopic biopsy provides specimens of airway wall
tissue from which tissue morphology can be as-
sessed, inflammatory cells can be quantified, and
gene products can be identified. Consequently, the
immunopathology of bronchial biopsy specimens
could be used to evaluate the antiinflammatory
effects of combination therapy. Obviously, less inva-
sive methods also can be used.
100
Another important point is the need to relate the
short-term response to either ICSs or LABAs to a
long-term benefit with inhaled combination therapy.
This information is extremely important when we
consider that only a positive response to a 2-week
course of oral prednisolone (eg, 30 mg per day) or a
6-week course of ICSs (eg, beclomethasone, 500 g
twice daily, or equivalent) would justify the prescrip-
tion of regular inhaled steroids to COPD patients,
and that a limitation on the use of LABAs to patients
with a demonstrable response to SABAs also has
been recommended.
101
It should be noted that
formoterol/budesonide combination treatment was
effective even in patients who had not been opti-
mized with oral corticosteroid therapy.
93
There is also a clear need for a study to examine
whether adding a LABA to ICS therapy produces
greater improvements in lung function and symptom
control than increasing the ICS dose. On the other
hand, we also need to know whether adding an ICS
to a regular LABA treatment produces greater im-
provements in lung function and symptom control
than increasing the dose of LABA alone. In other
words, we need to know whether more integrated
medical treatment can be more effective and safer
than more aggressive therapy with the individual
agent alone. Obviously, it is also important to inves-
tigate whether such integrated therapy can change
the natural history of COPD.
Information on the economic impact of the various
treatment options in COPD is also required. To date,
few studies have examined the clinical and economic
impact of treatments in COPD patients. One
study
102
has examined the use of a LABA in COPD
patients, and has demonstrated that significant im-
provements in health and QOL may be obtained at a
moderate cost. In another study,
103
early interven-
tion with an ICS resulted in significant health gains
at a relatively low cost. We do not know whether the
higher medication cost of combination therapy with
a LABA and ICS, compared with monotherapy, is
really justified from a pharmacoeconomic point of
view for COPD patients. Looking at the results of
studies that have been published in the literature
or have been presented as abstracts to relevant
international meetings,
88–94
it is likely that the higher
cost of medication is almost completely offset by
savings in other costs, such as consultations and
hospital admissions for treating exacerbations. Exac-
erbations are particularly important as they are major
cost drivers, the costs varying considerably with the
severity of the exacerbation. One study
104
found that

2
-agonist therapy in conjunction with corticosteroid
therapy resulted in improved health outcomes at a
small increase in cost compared to 
2
-agonist ther
-
apy alone. The addition of an ICS to a 
2
-agonist
resulted in net additional health-care costs of $201
per patient-year compared to therapy with a 
2
-
agonist alone, but more than half of the additional
cost of adding the ICS was offset by a reduction in
the costs of other health-care services. A recent
health economic analysis
105
comparing formoterol/
budesonide therapy (12/400 g, respectively, bid)
with therapy with formoterol (12 g bid), budes-
onide (400 g bid), and placebo was performed on
data from a 1-year multinational, prospective, ran-
domized, parallel-group clinical study among 1,022
patients with COPD. The difference in total health-
care costs (eg, hospitalizations, emergency depart-
ment visits, general practitioner visits, study drugs,
and concomitant medication use) associated with the
different treatments was analyzed using Swedish unit
costs. Health-care costs were numerically, but not
statistically, significantly lower for formoterol/budes-
onide therapy (22,893 Swedish kronor [SEK] per
year) compared with therapy with formoterol
(33,211 SEK per year), budesonide (28,134 SEK per
year), and placebo (29,207 SEK per year). The
results were robust, as this pattern remained the
same when applying UK unit costs (formoterol/
budesonide therapy, £1,595 per year; formoterol,
£2,577 per year; budesonide, £2,748 per year; pla-
cebo, £2,044 per year), and when analyzing sub-
www.chestjournal.org CHEST / 126/1/JULY, 2004 233
groups of severe patients (FEV
1
⬍ 40% predicted)
and European patients separately.
Conclusions
There is an increasing volume of evidence showing
that combination treatment with both salmeterol/
fluticasone and formoterol/budesonide can provide
an effective treatment option for COPD patients.
However, it must always be considered that the trials
that explored the effect of these therapies recruited
a select group of patients with COPD, and the
results may not be generalizable to patients with
extremely advanced or mild forms of the disorder.
106
Nevertheless, since the goals of COPD therapy are
to control symptoms, to prevent exacerbations, and
to improve lung function and health status, the
efficacy of combination therapy in inducing long-
lasting bronchodilation, improving QOL, and pre-
venting exacerbations must be considered a real
advancement in a disease for which treatment re-
mains suboptimal for a considerable number of
patients.
The capacity of combination treatment to reduce
exacerbations is particularly important. As correctly
stressed by Calverley and coauthors,
89
the low rate of
acute episodes might be attributable to regression to
the mean in the number of exacerbations or an effect
of improved care associated with clinical trials, but
suggests that a study of longer duration and with a
larger number of participants would be needed to
show a difference. Such long-term studies are un-
derway. They will allow us to better evaluate the
effect of such combination therapy on disease pro-
gression and mortality, and to determine the long-
term tolerability of combination therapy in patients
with COPD.
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