Combined corticosteroid and longacting beta-agonist in one inhaler
for chronic obstructive pulmonary disease
Nannini L, Lasserson TJ, Poole P
This is a reprint of a Cochrane review, prepared and maintained by the Cochrane Collaboration and published in The Cochrane
Library 2003, Issue 4
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TABLE OF CONTENTS
ABSTRACT..................................................................................................................................................................1
BACKGROUND........................................................................................................................................................... 3
OBJECTIVES...............................................................................................................................................................3
CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW................................................................................3
SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES..................................................................................... 4
METHODS OF THE REVIEW......................................................................................................................................4
DESCRIPTION OF STUDIES...................................................................................................................................... 5
METHODOLOGICAL QUALITY...................................................................................................................................6
RESULTS.................................................................................................................................................................... 6
DISCUSSION...............................................................................................................................................................9
REVIEWER'S CONCLUSIONS................................................................................................................................. 10
ACKNOWLEDGEMENTS.......................................................................................................................................... 10
POTENTIAL CONFLICT OF INTEREST................................................................................................................... 10
SOURCES OF SUPPORT......................................................................................................................................... 10
SYNOPSIS.................................................................................................................................................................10
REFERENCES.......................................................................................................................................................... 12
TABLES..................................................................................................................................................................... 14
Characteristics of included studies..................................................................................................................... 14
Characteristics of excluded studies.................................................................................................................... 16
Characteristics of ongoing studies...................................................................................................................... 16
Table 01 Adverse events - Mahler 2002............................................................................................................. 16
Table 02 Adverse events - TRISTAN 2002........................................................................................................ 17
Table 03 Serious adverse events - Szafranski 2003.......................................................................................... 17
COVER SHEET......................................................................................................................................................... 17
SUMMARY TABLES..................................................................................................................................................18
GRAPHS AND OTHER TABLES............................................................................................................................... 23
01 Fluticasone/salmeterol (FPS) versus placebo (PLA)..................................................................................... 23
01 Exacerbations.........................................................................................................................................23
02 Mean exacerbation rate.......................................................................................................................... 23
03 Quality of life - SGRQ (absolute scores)................................................................................................ 23
04 Quality of life - Canadian Respiratory Disease Questionnaire (change scores).....................................23
05 SGRQ symptoms - Breathlessness (absolute scores)........................................................................... 24
06 Symptoms - Dyspnoea (change scores)................................................................................................ 24
07 Predose FEV1 (% change from baseline).............................................................................................. 24
08 Predose FEV1 (absolute scores)............................................................................................................24
09 Rescue medication usage (change scores)........................................................................................... 25
10 Adverse events - candidiasis.................................................................................................................. 25
11 Adverse events - any event.................................................................................................................... 25
12 Withdrawals due to adverse events........................................................................................................26
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - i
Copyright © John Wiley & Sons Ltd 2003
02 Fluticasone/salmeterol (FPS) versus salmeterol (SAL)................................................................................. 26
01 Exacerbations.........................................................................................................................................26
02 Mean exacerbation rate.......................................................................................................................... 26
03 Quality of life - SGRQ (absolute scores)................................................................................................ 27
04 Quality of life - Canadian Respiratory Disease Questionnaire (change scores).....................................27
05 Symptoms - Dyspnoea (change scores)................................................................................................ 27
06 SGRQ symptoms - Breathlessness (absolute scores)........................................................................... 27
07 Predose FEV1 (absolute scores)............................................................................................................28
08 Predose FEV1 (%change from baseline)............................................................................................... 28
09 Rescue medication usage (change scores)........................................................................................... 28
10 Adverse events - candidiasis.................................................................................................................. 28
11 Adverse events - any event.................................................................................................................... 29
12 Withdrawals due to adverse events........................................................................................................29
03 Fluticasone/salmeterol (FPS) versus fluticasone (FP)...................................................................................29
01 Exacerbations.........................................................................................................................................29
02 Mean exacerbation rates........................................................................................................................ 30
03 Quality of life - SGRQ (absolute scores)................................................................................................ 30
04 Quality of life - Canadian Respiratory Dsiease Questionnaire (change scores).....................................30
05 Symptoms - Dyspnoea (change scores)................................................................................................ 30
06 SGRQ symptoms - Breathlessness (absolute scores)........................................................................... 31
07 Predose FEV1 (%change from baseline)............................................................................................... 31
08 Predose FEV1 (absolute scores)............................................................................................................31
09 Rescue medication usage...................................................................................................................... 31
10 Adverse events - candidiasis.................................................................................................................. 32
11 Adverse events - any event.................................................................................................................... 32
12 Withdrawals due to adverse events........................................................................................................32
04 Budesonide/formoterol (BDF) versus placebo (PLA).....................................................................................33
01 Severe Exacerbations............................................................................................................................ 33
02 Mean severe exacerbation rates per patient per year............................................................................ 33
03 Quality of life - SGRQ (change scores).................................................................................................. 33
04 Symptoms - Dyspnoea (change scores)................................................................................................ 33
05 Symptoms - breathlessness (absolute scores).......................................................................................34
06 Mean FEV1 (% increase from baseline)................................................................................................. 34
07 Adverse events - 'serious events'........................................................................................................... 34
08 Adverse events - candidiasis.................................................................................................................. 34
09 Withdrawals due to worsening COPD symptoms................................................................................... 35
10 Withdrawals due to adverse events........................................................................................................35
05 Budesonide/formoterol (BDF) versus budesonide (BD)................................................................................ 35
01 Severe Exacerbations............................................................................................................................ 35
02 Mean exacerbation rates per patient per year........................................................................................ 35
03 Quality of life - SGRQ (change scores).................................................................................................. 36
04 Symptoms - Dyspnoea (change scores)................................................................................................ 36
05 Symptoms - breathlessness (absolute scores).......................................................................................36
06 Mean FEV1 (% increase from baseline)................................................................................................. 36
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - ii
Copyright © John Wiley & Sons Ltd 2003
07 Adverse events - 'serious' events........................................................................................................... 37
08 Adverse events - candidiasis.................................................................................................................. 37
09 Withdrawals due to worsening COPD symptoms................................................................................... 37
10 Withdrawals due to adverse events........................................................................................................37
06 Budesonide/formoterol (BDF) versus formoterol (F)......................................................................................38
01 Severe Exacerbations............................................................................................................................ 38
02 Mean exacerbation rates per patient per year........................................................................................ 38
03 Quality of life - SGRQ (change scores).................................................................................................. 38
04 Symptoms - Dyspnoea (change scores)................................................................................................ 38
05 Symptoms - breathlessness (absolute scores).......................................................................................39
06 Mean FEV1 (% increase from baseline)................................................................................................. 39
07 Adverse events - 'serious' events........................................................................................................... 39
08 Adverse events - candidiasis.................................................................................................................. 39
09 Withdrawals due to worsening COPD symptoms................................................................................... 40
10 Withdrawals due to adverse events........................................................................................................40
07 Budesonide/formoterol (BDF) versus fluticasone/salmeterol (FPS).............................................................. 40
01 Exacerbations.........................................................................................................................................40
02 Mean exacerbation rates per patient per year........................................................................................ 40
03 Quality of life - SGRQ (change scores).................................................................................................. 41
04 Symptoms - Dyspnoea (change scores)................................................................................................ 41
05 Symptoms - breathlessness (absolute scores).......................................................................................41
06 Predose FEV1 (% change from baseline).............................................................................................. 41
07 Adverse events - candidiasis.................................................................................................................. 42
08 Adverse events - any event.................................................................................................................... 42
09 Withdrawals due to worsening symptoms.............................................................................................. 42
10 Withdrawals due to adverse events........................................................................................................42
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - iii
Copyright © John Wiley & Sons Ltd 2003
Combined corticosteroid and longacting beta-agonist in one inhaler
for chronic obstructive pulmonary disease
Nannini L, Lasserson TJ, Poole P
This Review should be cited as:
Nannini L, Lasserson TJ, Poole P. Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive
pulmonary disease (Cochrane Review). In: The Cochrane Library, Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.
Date of most recent amendment: 21 March 2002
Date of most recent substantive amendment: 01 May 2003
ABSTRACT
Background
Long-acting beta-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive
pulmonary disease. However, they have only been available until recently via separate administration. They have been developed
in order to facilitate adherence to medication regimens, and to improve efficacy.
Objectives
To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations in the treatment of adults
with chronic obstructive pulmonary disease.
Search strategy
We searched the Cochrane Airways Group chronic obstructive pulmonary disease (COPD) trials register (March 2003), the
Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), LILACS (all years to March 2003) and
reference lists of articles. We also contacted manufacturers and researchers in the field.
Selection criteria
Studies were included if they were randomised, with adequate blinding procedures in place. Studies could compare a combined
inhaled corticosteroids and long-acting beta-agonist preparation with either component preparation or placebo. Studies comparing
different members of each class of combined therapies were included
Data collection and analysis
Two reviewers independently assessed trial quality and extracted data.
Main results
Four randomised trials with 2986 participants were included. Two different combination preparations (fluticasone/salmeterol and
budesonide/formoterol) were studied in the trials. No meta-analysis on clinical outcomes was possible due to different outcome
assessment across studies. All studies demonstrated a reduction in exacerbation rates versus placebo. Budesonide/formoterol was
more effective than formoterol in reducing exacerbations in one study from 1.84 to 1.42 exacerbations per year.
Fluticasone/salmeterol did not significantly reduce exacerbations compared with either of its component treatments.
Fluticasone/salmeterol led to better quality of life compared with placebo (two studies), although there were conflicting results
when compared with inhaled corticosteroid alone (two studies). There was no significant difference between fluticasone/salmeterol
and long-acting beta-agonist (two studies). Budesonide/formoterol led to statistically significant differences in quality of life
compared with placebo, but not when compared with component inhaled corticosteroid or beta-agonist (one study).
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 1 of 42
Copyright © John Wiley & Sons Ltd 2003
Reviewers' conclusions
For the primary outcome of exacerbations, budesonide/formoterol had a modest advantage over a component medication,
formoterol, in a single trial, but fluticasone/salmeterol did not result in a significant reduction in exacerbations compared to either
of its components. The combination of steroids and long-acting beta-agonist in one inhaler was effective in improving symptoms
compared with placebo and on certain clinical outcomes compared with one of the individual components alone. In order to draw
firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, including the assessment
of the comparative effects with separate administration of the two drugs in double-dummy trials.
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 2 of 42
Copyright © John Wiley & Sons Ltd 2003
BACKGROUND
Current Global Initiative for Chronic Obstructive Lung Disease
(GOLD) recommendations for the therapy of patients with
chronic obstructive pulmonary disease (COPD) state that
beta-agonists are central to the symptomatic management of
COPD, (Pauwels 2001 evidence A - randomised controlled
trials; rich body of data) and that inhaled long acting
beta-agonists (LABAs) are more convenient (Pauwels 2001
evidence B - randomised controlled trials; limited body of data).
Furthermore, several studies have suggested that it is preferable
to combine bronchodilators instead of increasing the dose of a
single beta-agonist. However, this may affect patient
compliance.
Prolonged treatment with inhaled glucocorticosteroids does not
modify the decline in forced expiratory volume in one second
(FEV1) (Pauwels 1999; Vestbo 1999; Burge 2000; Lung Health
2000) but has been shown in severe COPD to diminish the
number and severity of exacerbations (Burge 2000). GOLD
recommends that regular treatment with inhaled corticosteroids
should only be prescribed for symptomatic COPD patients with
a documented spirometric response to corticosteroids, or for
those with an FEV1 < 50% predicted and repeated exacerbations
requiring treatment with antibiotics or oral glucocorticosteroids
(Pauwels 2001).
In daily practice, at stages IIB and III (or grades III and IV in
the 2003 updated stages) of severity (Pauwels 2001), patients
typically seek medical attention because of dyspnoea or an
exacerbation of their disease that has an impact on their quality
of life. Therefore, it is important to know whether inhaled
corticosteroids combined with long-acting beta-agonist
(LABAs) preparations reduce the number of exacerbations and
improve other endpoints such as quality of life, despite the lack
of effect on FEV1 decline.
The fact that many asthmatic and COPD patients are treated
with both inhaled LABAs and inhaled corticosteroids has
prompted the development of combinations of LABAs and
inhaled steroids at fixed doses from a single inhaler device.
There are several possible advantages to fixed combination
therapy. The most obvious benefit is in terms of patient
convenience with the expectation that this may lead to greater
treatment adherence. In a previous study (Boyd 1995; Jones
1997) salmeterol 50µg twice daily was associated with a
significant improvements in both health related quality of life
measured by the St George Respiratory Questionnaire (SGRQ),
and FEV1 , compared with placebo. The effect on these
variables with salmeterol 100µg was less and not statistically
significant. The authors concluded that the higher dose may be
associated with a deterioration in some areas of health. In view
of this evidence, it seems preferable not to exceed 50µg of
inhaled salmeterol bidaily. In this regard, similar beta-agonist
response occurred with formoterol 12 and 24µg bidaily. (Lofdahl
1999), suggesting that the lower dose would achieve the same
benefits.
The aim of this review was to evaluate the effects of combined
corticosteroid and long acting beta-agonists in the one inhaler,
on clinical endpoints and pulmonary function, compared with
placebo and other agents such as ipratropium bromide. The
review also evaluated the evidence in support of the use of this
fixed combination therapy via single inhaler compared with the
administration of these agents by separate inhalers.
To our knowledge, the effect of combined corticosteroid and
long acting beta-agonists for stable COPD has not been
reviewed systematically previously.
OBJECTIVES
To determine the efficacy of combined inhaled corticosteroid
and long-acting beta-agonists for stable COPD, as measured
by clinical endpoints and pulmonary function testing.
CRITERIA FOR CONSIDERING STUDIES FOR
THIS REVIEW
Types of studies
Randomised, clinical trials comparing combined inhaled
corticosteroid and long acting beta-agonists with placebo, or
other agents such as ipratropium bromide, or long acting
beta-agonists alone, or inhaled corticosteroid plus long acting
beta-agonists by separate inhalers.
Types of participants
Adult patients (age > 45 years) with known, stable COPD
fulfilling American Thoracic Society (ATS), European
Respiratory Society (ERS) and Global Initiative for Chronic
Obstuctive Lung Disease (GOLD) diagnostic criteria. Patients
were to be clinically stable, without evidence of an exacerbation
for one month prior to study entry. Patients with significant
diseases other than COPD, a diagnosis of asthma, cystic fibrosis,
bronchiectasis, or other lung diseases, were to be excluded,
however patients with partial reversibility on pulmonary
function testing were included.
Types of intervention
(1) Fluticasone/salmeterol versus placebo
(2) Fluticasone/salmeterol versus ipratropium bromide.
(3) Fluticasone/salmeterol versus theophylline
(4) Fluticasone/salmeterol versus long acting beta2 agonist
(salmeterol or formoterol)
(5) Fluticasone/salmeterol versus fluticasone alone
(6) Fluticasone/salmeterol versus budesonide/formoterol
(7) Fluticasone/salmeterol versus budesonide alone
(8) Fluticasone/salmeterol versus fluticasone+salmeterol with
separate inhalers
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 3 of 42
Copyright © John Wiley & Sons Ltd 2003
(9) Any other steroid/long acting beta-agonist combinations
such as budesonide/formoterol versus placebo or above
treatments for a period of at least two weeks
Types of outcome measures
PRIMARY
Clinical outcomes - exacerbations, urgent visits and
hospitalisations
SECONDARY
(1) Change in forced expiratory volume in 1 second (FEV1)
and change in forced ventilatory capacity (FVC): trough, peak
and average; and other measures of pulmonary function
(2) Exercise performance - six minute walk and other measures
(3) Quality of life scales
(4) Self-rated symptom score/symptoms of breathlessness
(5) Inhaled rescue medication used during the treatment period
and other concomitant medication usage including antibiotics
and steroids
(6) "Bad days"
(7) Area under the curve as the beta-agonist response following
the first and the last morning dose of LABA/ICS (inhaled
corticosteroids)
(8) Per cent of response to salbutamol from baseline FEV1,
looking for tachyphylaxis
(9) Pharmacoeconomic advantages
(10)
Adverse
events
palpitations,
tremor,
hoarseness/dysphonia, oral candidiasis, cataracts, skin bruising,
bone fracture, bone density, plasma cortisol level
SEARCH STRATEGY FOR
IDENTIFICATION OF STUDIES
We searched the Cochrane Airways Group COPD register using
the following terms:
(((beta* and agonist*) and long-acting or "long acting") or
((beta* and adrenergic*) and long-acting or "long acting") and
(*steroid or *steroids or steroid*)) or ((fluticasone and
salmeterol) or Seretide or Advair) or ((formoterol and
budesonide) or Symbicort)
In addition, we performed a search of LILACS (all years to
March 2003) and the Cochrane Central Register of Controlled
Trials (CENTRAL) (The Cochrane Library Issue 1, 2003).
We reviewed reference lists of all primary studies and review
articles for additional references. We also contacted authors of
identified randomised trials about other published and
unpublished studies. In addition, we contacted Allen and
Hanburys for GlaxoSmithKline (GSK), the manufacturer of
Seretide, and other manufacturers of combination therapy,
regarding unpublished studies and handsearched abstracts of
recent respiratory conferences (European Respiratory Society
(ERS) 2002, British Thoracic Society (BTS) 2002 and American
Thoracic Society (ATS) 2002).
METHODS OF THE REVIEW
Step I. Two reviewers independently identified trials which
appeared potentially relevant.
Step II. Using the full text of each study, two reviewers
independently selected trials for inclusion in the review.
Agreement was by simple agreement; third party adjudication
was used to resolve differences.
Step III. After a preliminary review of all studies to confirm
the basic requirements, two reviewers assessed the
methodological quality of the included trials with particular
emphasis on the concealment of allocation, ranked using
Cochrane criteria (grade A: adequate concealment; grade B:
uncertain; grade C: clearly inadequate concealment).
In addition, each study was assessed using the 0 to 5 scale
described by Jadad, as summarised below:
(1) Was the study as randomised? (1 = yes; 0 = no)
(2) Was the study as double-blind? (1 = yes; 0 = no)
(3) Were withdrawals and dropouts described? (1 = yes; 0 =
no)
(4) Was the method of randomisation well described and
appropriate? (1 = yes; 0 = no)
(5) Was the double blinding well described and appropriate?
(1 = yes; 0 = no)
(6) Deduct 1 point if methods for randomisation or blinding
were inappropriate.
Step IV. Two reviewers independently extracted data from
included trials and entered results into the Cochrane
Collaboration software program (Review Manager 4.1.1). In
some cases, we estimated information regarding outcomes from
graphs. This was performed independently by the two reviewers.
Data extraction included the following items:
Population: age, gender, smoking status, study setting (country,
practice setting), inclusion and exclusion criteria.
Intervention: dose, duration
Control: concurrent treatments (ipratropium, beta2-agonist,
inhaled and systemic corticosteroids)
Outcomes: pulmonary function measures (baseline and
follow-up FEV1 and FVC), timing of pulmonary function
measures, 6-minute walk, urgent visits, admissions, self-rated
symptom score/symptoms, quality-of-life instruments, adverse
events (palpitations, dry mouth, blurred vision, urinary
obstruction and constipation), assessors, adjudicator of clinical
endpoints
Design: method of randomisation, presence and type of run-in
period, study design (parallel, cross-over)
STATISTICAL CONSIDERATIONS
Where appropriate, we combined trials using RevMan 4.2.1.
An intention-to-treat analysis was planned.
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 4 of 42
Copyright © John Wiley & Sons Ltd 2003
CONTINUOUS AND DICHOTMOUS DATA
For continuous variables, a fixed effects weighted mean
difference (WMD) was used for outcomes measured on the
same metric. For standardised mean difference (SMD) and 95%
confidence interval (CI) was calculated for outcomes where
data were combined from studies using different metrics. All
similar studies were to be pooled using fixed effect WMD/SMD
and 95% CIs.
For dichotomous variables, a fixed effect odds ratio (OR) with
95% confidence intervals (95% CI) were calculated for
individual studies. All similar studies were to be pooled using
fixed effect OR and 95% CIs.
HETEROGENEITY
For pooled effects, heterogeneity was to be tested using the
Breslow-Day test; p < 0.1 would have been considered
statistically significant. If heterogeneity was found, a random
effects model was to be used. In addition, the robustness of the
results was to be tested using a sensitivity analysis based on
the quality of the trials.
If possible, we planned on constructing funnel plots to check
for the presence of publication bias.
Where mean treatment differences were reported, data were
entered as generic inverse variance (GIV), provided a standard
error for the change could be extracted or imputed.
SUB-GROUP/SENSITIVITY ANALYSES
A priori, heterogeneity was planned using the following
subgroups:
(1) Disease severity (related to baseline FEV1 and placebo
group exacerbation rate) according to the GOLD staging = IIA,
IIB (moderate COPD, characterised by deteriorating lung
function (A = FEV1 </=80% predicted; B = </=50% predicted)
and progression of symptoms) and III (severe COPD,
characerised by severe airflow limitation (FEV1 <30%
predicted) and presence of respiratory failure or clinical signs
of right heart failure. (Pauwels 2001)
(2) Prior inhaled corticosteroid plus long acting beta agonists
use (dichotomised as yes/no)
(3) Concurrent therapy with routine beta-agonist use (short or
long-acting) and corticosteroid (systemic or inhaled) use (both
dichotomised as yes/no)
(4) Reversibility of airflow obstruction with beta2-agonist
therapy (dichotomised as partial/none)
Definition: >12% and > 200 ml from baseline FEV1 or > 12%
as a per cent of the predicted normal value following PMDI
salbutamol 200 to 400
(5) Dose, duration and delivery method of therapy
(6) Clinical description of COPD (dichotomised as
emphysema/chronic bronchitis)
In addition, sensitivity analyses were to be performed using the
following domains:
(1) Methodological quality: using a quality-weighted analysis
to allow for the use of all trials
(2) Random effects versus fixed effect modelling
DESCRIPTION OF STUDIES
For a full description of baseline characteristics, methods used
and inclusion and exclusion individual studies, please refer to
the "Characteristics of Included Studies" section of the review.
• DESIGN
All trials had a randomised, double-blind, placebo controlled
parallel group design. Methods of randomisation were described
in one study (Mahler 2002). Method of blinding was not fully
described in all studies, although following correspondence
from GSK information on randomisation and blinding were
obtained for TRISTAN 2002. AstraZeneca provided information
on randomisation and blinding for the Szafranski 2003. One
trial described as 'double-blind' was confirmed as also
randomised by the trialists (Dal Negro 2002).
• INTERVENTIONS
In three studies (Mahler 2002; TRISTAN 2002; Szafranski
2003), the combined inhaled steroid and long acting beta-agonist
preparation was compared with three other treatment regimens,
namely: (i) component inhaled steroid alone; (ii) component
long acting beta-agonist alone and (iii) placebo. In the remaining
study (Dal Negro 2002) combination therapy was compared
with component long acting beta-agonist and placebo.
In
two
studies
the
combination
of
inhaled
corticosteroid/long-acting
beta-agonist
was
fluticasone/salmeterol (FPS) at doses of 500µg fluticasone (FP)
and 50µg salmeterol (SAL) daily (Mahler 2002; TRISTAN
2002). In Dal Negro 2002 the dose was 250µg FP and 50µg
SAL daily. Dal Negro 2002, Mahler 2002, and TRISTAN 2002
compared combination therapy with both component inhaled
steroid or long acting beta-agonist at equivalent doses to those
of the combined preparation. In Szafranski 2003 the
combination inhaled corticosteroid/long-acting beta agonist
was budesonide/formoterol (BDF) (320µg/9µg daily). This was
compared with budesonide (BD - 400µg daily) and formoterol
(F - 9µg daily).
The dosage of the combined preparation and the separate
medications remained stable throughout the studies.
Concomitant therapy was restricted to as-needed short-acting
beta agonist, or oral steroids and/or antibiotics in the case of
exacerbations. Mahler 2002 did not measure oral steroid and/or
antibiotic use in patients whose condition became exacerbated,
as they were withdrawn from the study at exacerbation. In Dal
Negro 2002 all participants received 400µg theophylline daily.
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 5 of 42
Copyright © John Wiley & Sons Ltd 2003
• DURATION
Mahler 2002 was six months in duration, and Dal Negro 2002;
Szafranski 2003 and TRISTAN 2002 were one year in duration.
• PARTICIPANTS
Across three trials, participants suffered from COPD, with
variable definition of COPD and reversibility. COPD was
defined by ATS (Mahler 2002) ERS (TRISTAN 2002) and
GOLD (Szafranski 2003) guidelines. Confirmation of diagnosis
was not available for Dal Negro 2002 although baseline lung
function and reversibility data were reported. Patient populations
in Mahler 2002, TRISTAN 2002 and Szafranski 2003 suffered
from moderate and severe COPD. However, the proportion of
severe patients, albeit with differing definitions of severe
disease, was greater in Szafranski 2003 (all participants had
</= 50% predicted FEV1 as an inclusion criterion, mean FEV1
36% pred and mean reversibility 6%) compared with TRISTAN
2002 (949/1465 (64.78%) patients with less than 50% FEV1)
and with Mahler 2002 (51% to 56% patients across treatment
regimens had an increase of 12% or more and 200 ml FEV1 in
response to beta-agonist at baseline). Mahler 2002 withdrew
participants when an exacerbation occurred. Dal Negro 2002
reported that participants were suffering from moderate COPD.
• OUTCOMES
Outcomes measured in Mahler 2002, TRISTAN 2002 and
Szafranski 2003 were lung function, exacerbations, safety and
tolerability, symptom scores, quality of life, and supplemental
use of rescue medication. Dal Negro 2002 reported data on lung
function. Other clinical outcomes were measured and will be
published separately. There were slight variations in the
classification of exacerbations in the studies. Exacerbations
were defined as worsening of symptoms requiring a course of
oral corticosteroids and/or antibiotics (Mahler 2002; TRISTAN
2002; Szafranski 2003). In the Szafranski 2003 study
hospitalisations, the requirement of oral steroids and/or
antibiotics were all classed as 'severe exacerbations' . Szafranski
2003 also defined mild exacerbations as an increase in reliever
medication >/=4 inhalations above mean run-in use. The Mahler
2002 study did not assess hospitalisation. Hospitalisations were
recorded separately from exacerbations requiring additional
medication in TRISTAN 2002.
METHODOLOGICAL QUALITY
Overall study quality was adequate. Unpublished information
was made available and regarding TRISTAN 2002 from GSK.
An intention-to treat analysis was undertaken and methods of
randomisation and blinding were confirmed. The study was
deemed of high methodological quality (Jadad score: 5). Mahler
2002 did not report randomisation and blinding fully and also
withdrew participants when they exacerbated and subsequently
there was a high attrition rate (30%). However, there was an
intention-to-treat analysis for certain outcomes (Jadad score:
3). Szafranski 2003 reported withdrawals and conducted an
intention-to-treat analysis, following contact with AstraZeneca
details on randomisation and blinding were obtained (Jadad
score: 5). Dal Negro 2002 made some details regarding the
methodology available, but information on blinding and
randomisation were not forthcoming (Jadad score: 2).
RESULTS
Electronic and handsearches identified a total of 34 references.
From the electronic searches we retrieved seven articles for
further scrutiny. We excluded three studies (Cazzola 2000;
Chapman 2002; Soriano 2002 - for further details please see
Characteristics of Excluded Studies). From handsearching the
2002 ATS , ERS and BTS abstracts, we identified one
unpublished study (Dal Negro 2002) and one which is awaiting
assessment pending information from the study authors
(Hanania 2001); two further trials identified were excluded as
their focus fell outside the scope of the review (Cazzola 2002a;
Cazzola 2002b).
Four studies met the inclusion criteria of the review (Dal Negro
2002; Mahler 2002; TRISTAN 2002; Szafranski 2003). One
study is ongoing (COSMIC 2002).
Meta-analysis was not possible on the primary outcome due to
the paucity of data presented in the unpublished and published
studies. We have managed to obtain SDs for a limited number
of continuous variables, and event rate data for dichotomous
variables have not been forthcoming. Data are presented under
each outcome or set of linked outcomes. Subgroup analysis was
undertaken according to baseline reversibility of the populations
in the trials. Trials were classified as having recruited 'partially
reversible/mixed' or 'poorly reversible' populations and were
stratified on that basis (See Methods of the review for
definitions of reversibility).
For purposes of clarity, the following abbreviations have been
used to describe the different treatments:
FPS (fluticasone/salmeterol combination); SAL (salmeterol);
FP (fluticasone); PLA (placebo).
BDF (budesonide/formoterol combination); F (formoterol); BD
(budesonide); PLA (placebo).
Unless other wise indicated, all data are from published sources.
EXACERBATIONS,
HOSPITALISATIONS
URGENT
VISITS
AND
• FPS versus comparators (SAL, FP or PLA)
Mahler 2002 reported no difference in the number of
participants who exacerbated once (PLA: 8.8%; SAL: 5.6%;
FP: 10.1%; FPS: 8.5%, no p value presented). Mahler 2002
reported no difference between the groups in the time to
exacerbation (no data or p values reported).
In TRISTAN 2002 there was a significant difference in the
mean exacerbation rate per participant per year in favour of
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 6 of 42
Copyright © John Wiley & Sons Ltd 2003
FPS when compared with placebo (FPS: 0.97 versus PLA: 1.30,
p < 0.0001). There was no significant difference when FPS was
compared with SAL and FP groups (SAL: 1.04 and FP: 1.05).
Combined therapy reduced exacerbations requiring oral
corticosteroids compared with PLA (0.46 versus 0.76
exacerbations per year, p < 0.0001) but not compared with SAL
and FP (0.46 versus 0.54 and 0.50 respectively, p value FPS
versus SAL and FP, p = 0.12 and 0.45 respectively).
No pooled analysis was possible due to the different types of
data reporting exacerbations.
• BDF versus comparators (F, BD or PLA)
Szafranski 2003 reported a reduction in the number of severe
exacerbations by 24% in the BDF group versus PLA (p = 0.035),
by 23% versus formoterol (p = 0.043) and 11% versus BD (p
= ns). This reflects a mean reduction in the average annual
exacerbation rates of 0.42 (95% CI 0.14 to 0.70) from 1.84 to
1.42 exacerbations per year. Mild exacerbations were also
reduced on BDF when compared with PLA (62%, p < 0.001),
BD (35%, p < 0.05) and F (15%,p = ns). In the BDF, BD, F
and PLA groups there were 1.4, 1.6, 1.8 and 1.9 exacerbations
per patient per year respectively. No p values were reported.
QUALITY OF LIFE
• FPS combination versus comparators (SAL, FP or PLA)
Mahler 2002 reported significant improvement in health status
as measured by the Chronic Respiratory Disease Questionnaire
(CRDQ) for those treated with FPS compared with PLA and
FP. Mean change in CRDQ score from baseline was 10 in the
FPS group, versus 5 in the PLA group (p = 0.007), and versus
4.8 in the FP group (p = 0.017). The difference between FPS
and Salmeterol was not significant (mean change score in the
SAL group was 8, p value versus FPS not published).
TRISTAN 2002 reported data on mean absolute and change
scores on the St Georges Respiratory Questionnaire (SGRQ).
There was a clinically significant improvement in health status
in participants treated with FPS compared with baseline (-4.5,
SD 12.9). This was statistically significant when compared with
the change in PLA scores (-1.9), p = 0.008, and also when
compared with the improvement in those treated with FP (-2.5),
p = 0.039. Absolute scores were presented in the published
paper and extracted and entered into RevMan. There were
statistically significant differences between FPS and PLA and
between FPS and FP (FPS: 44.1 +/-0.5 versus PLA: 46.3 +/-0.5
versus FP: 45.5 +/-0.4 (FPS versus PLA: p = 0.0003; FPS versus
FP: p = 0.021). Absolute score versus SAL was not significantly
different (p = 0.071).
• BDF versus comparators (F, BD or PLA)
Szafranski 2003 reported a clinically significant improvement
in health status as measured on the SGRQ in favour of BDF
versus PLA. Treatment with BDF led to a mean reduction of
-5.4 in the BDF group, versus -2.3 in the PLA group, p = 0.048.
BDF did not lead to statistically significant differences versus
F or BD.
SYMPTOM SCORE
• FPS combination versus comparators (SAL, FP or PLA)
Mahler 2002 reported statistically and clinically significant
improvements in mean Transition Dyspnoea Index (TDI) score
for those treated with FPS (2.1) when compared with PLA (0.4),
p < 0.001; compared with FP (1.3), p = 0.033; and compared
with SAL (0.9), p < 0.001.
TRISTAN 2002 reported improvements in symptoms after
treatment in favour of FPS versus PLA, FP and SAL on
breathlessness scores (FPS mean: 1.47; FP mean: 1.59 (p value
versus FPS = 0.006); SAL mean: 1.58 (p value versus FPS =
0.010); PLA mean: 1.66 (p value versus FPS < 0.001).
Improvement in night time awakenings compared with SAL
and PLA were reported (FPS mean number of nights per week:
2.31; SAL mean: 2.94 (p value versus FPS = 0.011); PLA mean:
3.01 (p value versus FPS = 0.006). Mean FPS score was not
statistically significant compared with FP score (2.45, p =
0.591). Cough scores were not significantly different compared
with SAL and FP (p = 0.639 and p = 0.34 respectively), but
there was a significant difference versus PLA (FPS: 1.35 versus
P: 1.44, p = 0.018).
• BDF versus comparators (F, BD or PLA)
Szafranski 2003 reported significant differences in favour of
BDF versus PLA and BD in days free from shortness of breath.
Compared with PLA, BDF led to a 12% reduction in days free
from shortness of breath (p < 0.001), 9% reduction in days free
from shortness of breath versus BD (p = 0.001). There was no
statistically significant difference observed versus F (2%, p =
ns).
Total symptom score was also improved significantly by BDF
versus all other comparators. BDF led to a mean decrease of
1.61 in symptom scores compared with a decrease of 0.49 with
PLA treatment (p < 0.001), 0.77 with BD treatment (p < 0.001)
and 1.20 with F (p < 0.05).
Symptom controlled days were increased by 7% with BDF
versus PLA (p = 0.001), by 1% versus BD (p = ns). No data on
the comparison with F were available, although there was a
significant difference in favour of F versus PLA (7%, p <
0.001).
Awakening free nights were increased by 14% with BDF
compared with PLA (p < 0.001), by 10% with BDF versus BD
(p = 0.003). No data on the comparison with F were available,
although there was a significant difference in favour of F versus
PLA (10%, p = 0.001).
LUNG FUNCTION
• FPS combination versus comparators (SAL, FP or PLA)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 7 of 42
Copyright © John Wiley & Sons Ltd 2003
Dal Negro 2002 reported no statistically significant
improvement in FEV1 from baseline to 12 months (FPS: 49.9
+/-3.01(baseline) versus 53.4 +/-2.3 (12 m); SAL: 47.9 +/-5.6
(baseline) versus 48.1 +/-4.9 (12 m); PLA: 50.1 +/-7.5 (baseline)
versus 48.4 +/-7.4 (12 months)).
Mahler 2002 reported an improvement in predose FEV1 in the
group treated with FPS versus PLA (156 ml versus -4ml
respectively, p < 0.001). There was also a significant increase
in those treated with FPS versus those treated with SAL and
FP (156ml versus 107ml and 109ml respectively, p = 0.012
(FPS versus S); p = 0.038 (FPS versus F)). The increase in
predose FEV1 represented a 14.5% increase over baseline
values. No significant differences were observed in a subgroup
analysis stratified by partial/no reversibility with short-acting
beta-agonist defined a priori as an increase of 12% or more and
200 ml in FEV1.
TRISTAN 2002 reported an increase in predose FEV1 in those
treated with FPS versus all other comparators (treatment
difference for adjusted means averaged over 52 weeks: FPS
versus SAL: 73 ml (95% CI 46 to 101], p < 0.001; FPS versus
FP: 95 ml (95% CI 67 to 122], p < 0.001; FPS versus PLA: 133
(95% CI: 105 to 161), p < 0.001.
• BDF versus comparators (F, BD or PLA)
Szafranski 2003 reported statistically significant improvements
in FEV1 for BDF compared with PLA (by 15%, p < 0.001) and
versus BD (by 9%, p < 0.001), which were sustained throughout
the 12 month study. The difference versus F was not significant
(1%). After one week, BDF increased morning PEF by 15.6
L/min, compared with a mean increase in PLA treated
participants of 1.1 L/min p < 0.001, an increase in BD-treated
participants of 3.4 L/min, p < 0.001 and an increase in F group
of 8.8 L/min, p < 0.002. At 12 months, morning PEF was
improved by 26.4 L/min from baseline in the BDF group,
compared with improvements of 2.4 L/min in the PLA group
(p < 0.001), 10.6 L/min in the BD group (p < 0.001) and 14.7
L/min in the F group (p < 0.001).
RESCUE MEDICATION
• FPS combination versus comparators (SAL, FP or PLA)
Mahler 2002 reported significant reduction in short-acting
beta-agonist usage for FPS versus FP and placebo. Mean change
score at the end of treatment in the FPS group was -1.2 puffs
per day versus an increase of 0.5 puffs per day in the PLA group
(p < 0.045), and in the FP group was -0.4 (p < 0.032). No
significant difference was observed versus SAL. There were
also significant increases in the percentage of nights with no
awakenings requiring short-acting beta-agonist in favour of
FPS versus PLA (5.7% versus -4.3% respectively, p < 0.031).
SAL and FP treatment also resulted in significant improvement
in night awakenings versus PLA (6.8% and 3% respectively, p
< 0.031 for both treatments versus PLA). No significant
differences were reported between FPS and SAL or FP for this
outcome.
TRISTAN 2002 reported a significant difference in median %
of days without use of relief medication: FPS: 14%; SAL: 3%
(p value versus FPS = 0.004); FP: 2% (p value versus FPS <
0.001); PLA: 0% (p value versus FPS < 0.001).
• BDF versus comparators (F, BD or PLA)
In the Szafranski 2003 study, BDF reduced the need for reliever
medication by 1.3 and 0.7 inhalations per day versus PLA and
BD respectively (both p = 0.001), and increased reliever free
days versus PLA by 8.6% (p = 0.003). No comparison versus
F was available.
SAFETY AND TOLERABILITY
• FPS versus comparators (SAL, FP or PLA)
For full details of safety profile from Mahler 2002 please refer
to Table 01. FPS resulted in higher instances of candidiasis
versus PLA and SAL, but there were fewer participants with
candidiasis versus FP (12/169 versus 17/173 respectively, no
p value published). No differences were found in Holter monitor
results between the groups (one from PLA, one from SAL, two
from FP and one from FPS).
For full details of safety profile in the TRISTAN 2002 study,
please refer to Table 02. FPS resulted in higher instances of
candidiasis in the groups treated with FPS and FP compared
with SAL and PLA. No p values were reported.
In a pooled analysis of FPS versus PLA, candidiasis occurred
more frequently in the FPS group compared with PLA (OR
6.10; 95% CI 2.71 to 13.76]; Risk difference: 0.06 (95% CI
0.04 to 0.09])
In a pooled analysis of FPS versus SAL, candidiasis was more
frequent in the FPS group compared with SAL (OR 4.72; 95%
CI 2.26 to 9.86).
In a pooled analysis of FPS versus FP, there was no difference
in the odds of candidiasis affecting those treated with FPS
compared with FP (OR 0.91; 95% CI 0.58 to 1.43).
• BDF versus comparators (F, BD or PLA)
Please see Table 03 for an overview of serious adverse events
presented in Szafranski 2003. Adverse events in the study were
reported to be similar across all the treatment groups. No data
were reported on specific events such as candidiasis or
headaches. No difference was detected on serious adverse events
per 1000 treatment days (no p values were presented).
WITHDRAWALS
• FPS versus comparators (SAL, FP or PLA)
Mahler 2002 reported a high attrition rate over the course of
the study. This may in part be attributable to the withdrawal of
participants when an exacerbation occurred. From 181
participants in the PLA group 112 remained in the study at 24
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 8 of 42
Copyright © John Wiley & Sons Ltd 2003
weeks, compared with 114/160 in the SAL group, 99/168 in
the FP group and 113/165 in the FPS group. Most common
causes for withdrawal were adverse events (P: 9.4%; S: 6.9%;
F: 12.5%; FPS: 6.7%), exacerbations (P: 8.8%; S: 5.6%, F:
10.1%; FPS: 8.5%) and study protocol violations (P: 4.4%; S:
6.3%; F: 8.3%; FPS: 4.6%).
TRISTAN 2002 reported the number of withdrawals due to
adverse events: FPS: 46/358; FP: 55/374; SAL: 61/372; PLA:
68/361.
Pooled analyses of data from the two trials indicated that
participant withdrawal occurred less frequently in the FPS group
compared with PLA (OR 0.65 [95% CI: 0.45 to 0.93]), but not
when compared with FP (OR 0.74 [95% CI: 0.51 to 1.07]) or
with SAL (OR 0.79 [95% CI: 0.54 to 1.14]).
• BDF versus comparators (F, BD or PLA)
Szafranski 2003 reported significant differences in favour of
BDF versus PLA in terms of participants who withdrew due to
deterioration of COPD (20/208 versus 43/205, p < 0.001). There
was no significant difference when compared with BD or F
(BD: 23/198; F: 29/201).
There was no significant difference between BDF and
comparators on the number of participants who withdrew due
to adverse events other than COPD deterioration (BDF: 16/208;
BD: 13/198; F: 12/201; PLA: 17/205 no p values reported).
DISCUSSION
Data from four randomised controlled trials assessing the
effectiveness of combined inhaled corticosteroid and long-acting
beta-agonist in the treatment of chronic obstructive pulmonary
disease are currently available. There is a further trial which is
ongoing (COSMIC 2002). One unpublished study is awaiting
assessment and verification of study details from the trialists
(Hanania 2001).
• PATIENT POPULATIONS
There is much debate as whether 'chronic obstructive pulmonary
disease' includes patients who have a significant bronchodilator
response to short-acting beta-agonists, although recent
definitions permit some reversiblility. There have been attempts
made in Mahler 2002 and TRISTAN 2002 to identify a response
to treatment by stratifying results according to baseline lung
function. Although mean baseline FEV1s were similar in the
two trials, there were more participants with reversible airways
obstruction as defined by Pauwels 2001 in Mahler 2002. There
were differences in the inclusion criteria in the two FPS trials,
notably in the Mahler 2002 study there was a substantial
proportion of participants with reversible airflow obstruction.
Mahler 2002 undertook a subgroup analysis according to
reversibility and reported that there was a modestly greater
response to treatment in the reversible subgroup than in the
non-reversible subgroup for pre and postdose FEV1 and TDI
with individual component therapy as well as combined therapy.
A subgroup analysis for patients with < 50% FEV1 and = 50%
FEV1 in TRISTAN 2002 found that those with more
compromised lung function responded more favourably to
treatment on exacerbation rates than those with = 50% FEV1,
but this must be interpreted with caution as there are no reported
tests of between group differences in the paper. The patient
population in Szafranski 2003 was classified as moderate to
severe with all participants having poor lung function (mean
36% predicted) and poor reversibility.
There was also a high proportion of current smokers in Mahler
2002 and TRISTAN 2002. A recent study has demonstrated a
diminished response to dexamethasone in vitro following the
simulation of smoking effects. Smoke effects induced the
inhibition of the histone deacetylases (HDAC) enzyme which
is necessary in the process of gene repression (Ito 2001). Whilst
one in vivo study has demonstrated the resistance to steroid
action in asthmatic smokers (Pedersen 1996), there may
nevertheless be a similar inhibition of the expression of
corticosteroids at the genetic level when inhaled or systemic
steroids are used in current smokers with COPD, resulting in
compromised corticosteroid effectiveness.
• CLINICAL PARAMETERS
The outcomes that we identified a priori of primary significance
related to exacerbations and hospitalisations. No data were
presented in the trials on hospitalisations. Previous studies have
indicated that ICS can lead to a reduction in the mean rate of
exacerbations (Burge 2000) in patients with moderate and severe
COPD. Although overall exacerbation rates in TRISTAN 2002
did not indicate a synergistic effect of the combination of
salmeterol and fluticasone, exacerbations requiring oral steroids
were reduced significantly versus placebo but not versus
salmeterol and fluticasone alone. In Szafranski 2003
exacerbation rates were lower in the combined therapy group
versus formoterol, but not compared with budesonide. Further
assessment of the impact of the combination therapy upon
hospitalisations and exacerbations is required.
The combination of inhaled corticosteroids and salmeterol led
to benefits over single treatments on certain clinical outcomes
but not in others. In Mahler 2002 and TRISTAN 2002 there
were consistent benefits in health status of combined therapy
over fluticasone alone but not when compared with salmeterol.
However, on symptom scores and lung function combined
therapy led to significant differences over salmeterol and
fluticasone alone. Assessment of combination therapy versus
separate administration of inhaled corticosteroid and
beta-agonists would be justified in order to determine the extent
of any synergistic effect.
The advantages associated with combination therapy extend
beyond potentially greater patient compliance with a convenient
delivery system of two therapies. The component treatments
have complementary mechanisms of action, whereby the smooth
muscle relaxation of the beta-agonist combined with the
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 9 of 42
Copyright © John Wiley & Sons Ltd 2003
anti-inflammatory action of the steroid, offer greater scope of
clinical benefits than they would do alone. Cazzola 2000
reported a single-blind trial assessing the additive benefit of
long-acting beta-agonist and inhaled steroids. When
administered in separate inhalers there was no significant
improvement in lung function until three months of treatment.
However, the addition of 500µg FP to SAL did not result in
statistically significant changes in lung function compared with
50µg SAL alone. The results from the trials in this review have
not addressed the question of synergistic effects, and further
research comparing combination therapy in a single versus
separate inhaler devices could elucidate this issue more clearly.
an evaluation of patient compliance and patient preference. A
pharmacoeconomic analysis would be very helpful to assist
purchasers of health care. Documentation of serious adverse
events such as hospitalisation and intensive care support would
be important.
Fixed dose therapy may be an effective pharmacological
strategy in clinically stable moderately severe COPD, but if
patients become unstable different strategies to manage
symptoms such as an increase in regular treatment with one or
more beta-agonists would be adopted (Pauwels 2001).
Consensus guidelines recommend oral corticosteroids and/or
antibiotics depending of the cardinal symptoms of the
exacerbation of COPD (Pauwels 2001). Hence, it might be
inappropriate to manage a clinically unstable situation with
combined fixed therapy on its own.
ACKNOWLEDGEMENTS
REVIEWER'S CONCLUSIONS
Implications for practice
Based on a very small number of trials in this review, in
participants with moderate and severe COPD, there is a
suggestion of some additional clinical benefit when long acting
beta-agonist and inhaled corticosteroid are co-administered
compared to treatment with a single class of medication, but
the results are not consistent across the different drugs used.
For
the
primary
outcome
of
exacerbations,
budesonide/formoterol had a modest advantage over a
component medication, formoterol, in a single trial, but
fluticasone/salmeterol but did not result in a significant
reduction in exacerbations compared to either of its components.
There is no evidence of an increase in adverse effects over and
above that seen with the component medications alone ( e.g.
candidiasis). There has been no direct comparison with the two
treatments given separately. In order to draw firmer conclusions
about the effects of combination therapy in a single inhaler,
assessment of the comparative effects with separate
administration of the two drugs in double-dummy trials is
necessary. Ongoing and future trials should allow better
clarification of any additional benefits of combined therapy.
Implications for research
Combined therapy should be compared with separate
administration of long acting beta-agonist and inhaled
corticosteroid in a double-dummy design study in large scale
multi-centre studies, in order to assess whether combined
therapy confers benefits over the simple addition of beta-agonist
to steroid treatment in separate inhalers. This should include
Additional studies could consider the effects of combined
therapy compared with inhaled corticosteroids and tiotropium
administered separately, and also the comparative effectiveness
of FP and BD. An assessment of the effects of smoking on
inhaled corticosteroid effectiveness could also be made.
The authors are indebted to the Hamam Ellis Charitable Trust
who very generously funded the return travel for Dr Nannini
to London in order to spend a week working on the development
of the review from 25th November until 2nd December 2002.
Thanks to Karen Blackhall, Jo Picot and Sarah Tracy for
technical and clerical support. The editorial support of Prof
Paul Jones and Dr Chris Cates was gratefully received. We
would also like to acknowledge the efforts of Inge Vestbo and
Diane Grimley of GSK who helped us in our attempts to obtain
unpublished information on the TRISTAN 2002 and COSMIC
2002 studies, and those of Moira Coughlan and Roger Metcalf
of AstraZeneca in helping us obtain information on Szafranski
2003. We thank Nick Hanania for informing us as to the
publication status of the study Hanania 2001.
POTENTIAL CONFLICT OF INTEREST
The authors who have been involved in this review have done
so without any known conflicts of interest. None of the authors
is considered a paid consultant by any pharmaceutical company
which produces agents discussed in this review.
SOURCES OF SUPPORT
External sources of support
• No sources of support supplied
Internal sources of support
• Hamam Ellis Charitable Trust UK
SYNOPSIS
Limited evidence shows that combination therapy may improve
some outcomes in people with chronic obstructive pulmonary
disease, but more research is required.
Chronic obstructive pulmonary disease (COPD) is a disease
which is characterised by severely obstructed airflow from the
lungs. The main cause of COPD is smoking. Recently,
combinations of two classes of medication in one inhaler have
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 10 of 42
Copyright © John Wiley & Sons Ltd 2003
been developed as it is thought that this approach may provide
a better effect than taking the two therapies separately or alone.
Possible benefits include quality of life, reduction in
exacerbations and improved lung function. In this review the
combination of a inhaled corticosteroid (anti-inflammatory
therapy) and long-acting beta agonist (bronchodilator therapy)
was assessed. Very few studies were included. The combined
medications in one inhaler was better than placebo (dummy
medication) for all of the outcomes that were measured,
however, at this time there seems to be only a small benefit of
the combination over either one of the active component
medicines in terms of reducing the frequency of flare ups of
COPD.
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 11 of 42
Copyright © John Wiley & Sons Ltd 2003
REFERENCES
References to studies included in this review
Dal Negro 2002 {unpublished data only}
Dal Negro R, Micheletto C, Trevsian F, Tognella S. [A98] Salmeterol and
fluticasone 50ug/250ug BiD versus salmeterol 50ug bid and versus placebo
in the long term treatment of COPD. Proceedings of the 98th International
American Thoracic Society Conference.
2002:http://www.abstracts-on-line.com/abstracts/ATS.
Mahler 2002 {published data only}
Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, Shah T.
American Journal of Respiratory Critical Care Medicine 2002;166:1084-91.
Szafranski 2003 {unpublished data only}
Anderson P. Thorax 2002;BTS Winter meeting 2002.
Calverly PMA. [S145] Effect of budesonide/formoterol on severe
exacerbations and lung function in moderate to severe COPD. Thorax
2002;BTS Winter meeting 2002.
Campbell LM, Szafranski W. Thorax 2002;BTS Winter meeting 2002.
Campell LW, Szafranski W. Thorax 2002;BTS Winter meeting 2002.
Dahl R, Cukier A, Olsson H. European Respiratory Journal 2002;20 Suppl
(38):242.
Egede F, Menga G. European Respiratory Journal 2002;20 Suppl (38):242.
Jones PW, Stahl E, Svensson K. European Respiratory Journal 2002;20
Suppl (38):250.
Korsgaard J, Sansores R. European Respiratory Journal 2002;20 Suppl
(38):242.
Lange P, Saenz C. European Respiratory Journal 2002;20 Suppl (38):242.
Milanowski J, Nahabedian S. European Respiratory Journal 2002;20 Suppl
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*Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian
S et al. Efficacy and safety of budesonide/formoterol in the management
of chronic obstructive pulmonary disease. European Respiraory Journal
2003;21:74-81.
TRISTAN 2002 {published data only}
Calverley PMA, Pauwels RA, Vestbo J, Jones PW, Pride NB, Gulsvik A,
et al. [A98] [Poster: 306] Salmeterol/Fluticasone propionate combination
for one year provides greater clinical benefit than its individual components.
Proceedings of the 98th International American Thoracic Society
Conference. 2002:http://www.abstracts-on-line.com/abstracts/ATS.
*Calverly P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A et al.
Combined salmeterol and fluticasone in the treatment of chronic obstructive
pulmonary disease: a randomised controlled trial. The Lancet
2003;361(9356):449-56.
Calverly PMA, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A et al.
[P1572] Safety of salmeterol/fluticasone propionate combination in the
treatment of chronic obstructive pulmonary disease. European Respiratory
Journal 2002;20 Suppl (38):242.
Jones PW, Edin HM, Anderson J. [A39] [Poster K39] Salmeterol/fluticasone
propionate combination improves health status in COPD patients.
Proceedings of the 98th International American Thoracic Society
Conference 2002:http://www.abstracts-on-line.com/abstracts/ATS.
Pauwels RA, Calverly PMA, Vestbo J, Jones PW, Pride N, Gulsvik A et
al. [P1569] Reduction of exacerbations with salmeterol/flutciasone
combination 50/500 mcg bd in the treatment of chronic obstructive
pulmonary disease. European Respiratory Journal 2002;20 Suppl (38):240.
Vestbo J, Calverley PMA, Pauwels R, Jones P, Pride N, Gulsvik A et al.
[P1570] Absence of gender susceptibility to the combination of salmeterol
and fluticasone in the treatment of chronic obstructive pulmonary disease.
European Respiratory Journal 2002;20 Suppl (38):240.
References to studies excluded from this review
Cazzola 2000
Cazzola M, Di Lorenzo G, Di Perna F, Calderaro F, Testi R, Centanni S.
Additive effects of salmeterol and fluticasone or theophylline in COPD.
Chest 2000;118(6):1576-81.
Cazzola 2002a
Cazzola M, Santus P, Di Marco F, Boveri B, Castagna F, Carlucci P.
[P2396] Bronchodilator effect of an inhaled combination therapy with
salmeterol + fluticasone and formoterol + budesonide in patients with
COPD. European Respiratory Journal 2002;20 Suppl (38):386.
Cazzola 2002b
Cazzola M, Noschese P, D'Amato G, Santus P, Centanni S. [P2393]
Salmeterol/fluticasone propionate in a single inhaler device (SLM/FP)
versus theophyliine (TEHO) + FP in patients with COPD. European
Respiratory Journal 2002;20 Suppl (38):386.
Chapman 2002
Chapman KR. Seretide for obstructive lung disease. Expert Opinion on
Pharmacotherapy 2002;3(3):341-50.
Soriano 2002
*Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC. Survival
in COPD patients after regular use of fluticasone propionate and salmeterol
in general practice. European Respiratory Journal 2002;20(4):797-8.
References to studies awaiting assessment
Hanania 2001
Hanania NA, Ramsdell J, Payne K, Davis S, Horstman D, Lee B et al.
Improvements in airflow and dyspnea in COPD patients following 24 weeks
treatment with salmeterol 50mcg and fluticasone propionate 250mcg alone
or in combination via the diskus. American Journal of Respiratory &
Critical Care Medicine 2001;163(5 Suppl):A279.
References to ongoing studies
COSMIC 2002
Study contact information not provided. Contact reviewer for more
information. COSMIC. Ongoing study Starting date of trial not provided.
Contact reviewer for more information.
Additional references
Boyd 1995
Boyd G, Crawford C. Salmeterol for the treatment of patients with chronic
obstructive pulmonary disease (COPD). European Respiratory Journal
1995;8 Suppl (19):167.
Burge 2000
Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK.
Randomised, double blind, placebo controlled study of fluticasone
propionate in patients with moderate to severe chronic obstructive
pulmonary disease: the ISOLDE trial y of fluticasone propionate in patients
with moderate to severe chronic obstructive pulmonary disease: the ISOLDE
trial. British Medical Journal 2000;320:1297-1303.
Campbell 2001
Campbell D, Kelly K, Manser R. Combined corticosteroid and longacting
bronchodilator in one inhaler for chronic asthma (Cochrane Review). In:
The Cochrane Library, 4, 2001. Oxford: Update Software. CD002998.
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 12 of 42
Copyright © John Wiley & Sons Ltd 2003
Dahl 2001
Dahl R, Greefhorst LAPM, Nowak D, Nonikov V et al. Inhaled formoterol
dry powder versus ipratroprium bromide in chronic obstructive pulmonary
disease. American Journal for Respiratory and Critical Care Medicine
2001;164:778-84.
Ito 2001
Ito K, Lim S, CaramorI G, Chung KF, Barnes PJ, Adcock IM. Cigarette
smoking reduces histone deacetylase 2 expression, enhances cytokine
expression, and inhibits glucocorticoid actions in alveolar macrophages.
The FASEB Journal 2001;15:1110-2.
Jones 1997
Jones PW, Bosh TK. Quality of life changes in COPD patients treated with
salmeterol. American Journal of Respiratory and Critical Care Medicine
1997;155:1283-9.
Lofdahl 1999
Lofdahl C, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV.
Long-term treatment with inhaled budesonide in persons with mild chronic
obstructive pulmonary disesease who continue smoking. New England
Journal of Medicine 1999;340:1948-53.
Lung Health 2000
The Lung Health Study Research Group. Effect of inhaled triamcinolone
on the decline in pulmonary function in chronic obstructive pulmonary
disease. New England Journal of Medicine 2000;343:1902-9.
NHLB/WHO 2001
NHLBI/WHO. Global Strategy for the diagnosis, management, and
prevention of chronic obstructive pulmonary disease. American Journal of
Respiratory and Critical Care Medicine 2001;163:1256-76.
Pauwels 1999
Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride
NB et al. Long-term treatment with inhaled budesonide in persons with
mild chronic obstructive pulmonary disease who continue smoking.
European Respiratory Society Study on Chronic Obstructive Pulmonary
Disease. New England Journal of Medicine 1999;340(25):1948-53.
Pauwels 2001
Pauwels RA, Buist AS, Ma P, Jenkins CR, Hurd SS. GOLD Scientific
Committee. Global strategy for the diagnosis, management, and prevention
of chronic obstructive pulmonary disease: National Heart, Lung, and Blood
Institute and World Health Organization Global Initiative for Chronic
Obstructive Lung Disease (GOLD): executive summary. Respiratory Care
2001;46(8):798-825.
Pedersen 1996
Pedersen B, Dahl R, Karlstrom R, Peterson CG, Venge P. Eosinophil and
neutrophil activity in asthma in a one-year trial with inhaled budesonide.
The impact of smoking. American Journal of Respiratory and Critical Care
Medicine 1996;153(5):1519-29.
Rossi 2002
Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J et al.
Comparison of the efficacy, tolerability, and safety of formoterol dry powder
and oral, slow-release theophylline in the treatment of COPD. Chest
2002;121(1058-64).
Vestbo 1999
Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term
effect of inhaled budesonide in mild and moderate chronic obstructive
pulmonary disease: a randomised controlled trial. The Lancet
1999;353:1819-23.
* Indicates the major publication for the study
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 13 of 42
Copyright © John Wiley & Sons Ltd 2003
TABLES
Characteristics of included studies
Study
Dal Negro 2002
Methods
Randomised, double-blind placebo controlled single centre trial. Trial duration: 12
months.
Participants
18 participants were randomised as follows: FPS: n = 6; PLA: n = 6; SAL: n = 6.
Participants had 'moderate' COPD. Baseline characteristics: FEV1 (%): FPS: 49.9
+/-3.01; SAL: 47.9 +/-5.6; PLA: 50.1 +/-7.5.
Interventions
FPS (SAL: 50ug; FP: 250ug BiD) versus SAL 50ug BiD versus PLA. Participants were
on concomitant therapy: SABA prn and theophylline 400ug/day, for 12 months.
Outcomes
FEV1, Delta FEV1, PEF am, symptom scores, rescue medication use, exacerbations
(mean number per year).
Notes
Classified as 'mixed population'. Jadad score: 2
Abstract stated double-dummy but the study was actually double-blind and did not use
double-dummy.
Allocation concealment
B
Study
Mahler 2002
Methods
Randomised, double blind, placebo-controlled, multicentre trial. Single-blind run-in
period (2 weeks). Trial duration 24 weeks. Randomisation: stratified by reversibility
and investigative site.
Participants
Participants with COPD according to ATS guidelines were recruited by 65 centers.
1352 screened. 691 randomised and treated. Data from 46 patients were unevaluable.
Patients were randomised as follows: PLA: 181; SAL:160; FP:168; FPS: 165. Baseline
characteristics: Age = PLA: 64; Sal: 63.5; F:64.4; FPS:61.9. FEV1(ml) PLA: 1,317;
SAL: 1,237;FP: 1233; FPS:1268. BD% response = PLA: 19.3; SAL: 21.2; FP:19.2;
FPS: 20.6.
Interventions
FPS (SAL 50mcg; FP 500mcg BiD) was compared with SAL (50 mcg BiD), FP (500mcg
BiD) and PLA for 24 weeks.
Outcomes
FEV1; morning PEF; supplemental albuterol use, dyspnea (TDI), CBSQ; CRDQ; adverse
events
Notes
Classified as 'mixed population' subgroup. Jadad score: 3
Allocation concealment
B
Study
Szafranski 2003
Methods
Randomised, double-blind, placebo-controlled parallel group trial. Duration: One year.
Methods of randomisation: The randomisation scheme was generated using a computer
program at AstraZeneca, Lund, Sweden. At each centre, eligible patients received an
enrolment code and then after run-in, each
patient who satisfied the randomisation criteria was allocated the next consecutive
patient number.
Blinding: All the Turbuhaler inhalers were identical to ensure that the patient, pharmacist
and the investigator were blinded to the allocated treatment
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 14 of 42
Copyright © John Wiley & Sons Ltd 2003
Characteristics of included studies
Participants
812 participants enrolled in study. BDF group: n = 208; F: n = 201; BUD: n = 198; PLA:
n = 205. Mean FEV1 36%, median 5 years since diagnosis, Mean age: 64 years. No.
current smokers: 280. Previous medication (%): BDF: ICS - 26; LABAs - 17;
Anticholinergics - 24: SABAs - 67. BUD: ICS - 24; LABAs - 17; Anticholinergics - 31;
SABAs - 70. F: ICS - 28; LABAs - 16; Anticholinergics - 27; SABAs - 71. PLA: ICS 26; LABAs - 20; Anticholinergics - 29; SABAs - 69. Mean reversibility (%): FBD: 6;
BUD: 5; F: 6; PLA: 5. Inclusion criteria: Age >/= 40 years; COPD for >/= 2 years;
smoking history >/= 10 pack years; FEV1 </= 50% predicted; FEV1/FVC </=70%;
Symptom score >/= 2 during at least 7 days of run-in; use of bronchodilators for reliever
medication; >/= 1 severe COPD exacerbation within 2-12 months before study entry.
Interventions
BDF (F 9mcg; BUD 320ug (Symbicort) BiD versus BUD (400ug BiD) versus F (9ug
BiD) versus PLA for 12 months.
Outcomes
Symptoms, adverse events, exacerbations, lung function.
Notes
Classified as 'poorly reversible' subgroup. Jadad score: 5. Exacerbation defined as
requirement of oral steroids and/or antibiotics and/or hospitalisation for respiratory
symptoms. Mild exacerbation defined as requirement of >/= 4 inhalations per day.
Allocation concealment
A
Study
TRISTAN 2002
Methods
Randomised, multi-centre, double-blind, parallel group trial. Randomisation was
conducted by computer programme. Numbers were generated off-site. Once a treatment
number had been assigned to a participant, it could not be assigned to any other
participant. Participants received identically packaged and presented placebos.
Participants
1465 participants with moderate to severe COPD as defined by the European
Respiratory Society were recruited from multiple centres. Mean age: 63.2 +/-8.6 years.
Current smokers: SFC: 52%; SAL: 51%; FP: 53%; PLA 47%. FEV1(%): SFC: 44.8;
SAL: 44.3; FP: 45; PLA: 44.2. Reversibility (%): SFC: 4 +/-4.7; SAL: 3.7 +/-4.3; FP: 3.7
+/-3.9; PLA: 4 +/-4.5. Inclusion criteria: age 40-79; pre-BD FEV1 25-70% predicted;
FEV1/FVC </=70%. Reversibility <10% FEV1; >/=10 pack-years smoking history;
History of exacerbations (>/=1 in the last year) requiring OCS and/or antibiotics. At
least one episode of acute COPD per year in the previous 3 years.
Exclusion criteria: Current diagnosis of asthma, eczema and allergic rhinitis; Other
active lung disease (eg TB, lung cancer); Requirement of daily oxygen therapy;
Antibiotics, OCS or high dose ICS (>1000mcg BDP or equivalent) during 2 week run-in
period.
Interventions
FPS (SAL 50mcg; FP 500ug BiD) was compared with SAL (50ug BiD), FP (500ug BiD)
and PLA for 52 weeks. Treatment preceded by two week run-in phase.
Outcomes
Exacerbation rates, lung function, safety, tolerability, withdrawals, symptom score,
quality of life (SGRQ).
Notes
Classified as 'poorly reversible' as a subgroup. Jadad score: 5
Allocation concealment
A
Footnotes:
BD: bronchodilator; BDF: Budesonide/formoterol combination; BiD: bidaily; BUD: Busesonide; CBSQ: Chronic bronchitis symptom questionnaire; CRDQ:
Canadian respiratory disease questionnaire; F: Formoterol; FEV1: Forced expiratory volume in one second; FP: Fluticasone; FPS: Fluticasone/salmeterol
combination; FVC: Forced vital capacity; ICS: inhaled corticosteroid; LABA: long acting beta agonist; OCS: oral corticosteroids; PLA: Placebo; PRN: as needed;
SABA: short acting beta agonist SAL: Salmeterol; SGRQ: St George respiratory questionnaire;
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 15 of 42
Copyright © John Wiley & Sons Ltd 2003
Characteristics of excluded studies
Study
Reason for exclusion
Cazzola 2000
Single-blind assessment of additive benefit of inhaled fluticasone to salmeterol. Although
dosage was identical to Seretide/Advair (ie FP 500ug: SAL 50mcg), treatment was
administered through separate inhalers.
Cazzola 2002a
Single-blind randomised crossover study comparing combination salmeterol and fluticasone
with formoterol and budesonide - excluded as duration of study was too short (12 hours).
Cazzola 2002b
Randomised trial comparing combination salmeterol/fluticasone with separately administered
fluticasone and theophylline for 4 months. Excluded as the comparison was not within the
scope of the review.
Chapman 2002
Review article.
Soriano 2002
Non-randomised retrospective survival analysis.
Characteristics of ongoing studies
Study
COSMIC 2002
Trial name or title
COSMIC
Participants
Participants with COPD
Interventions
FPS versus component therapies
Outcomes
Starting date
Contact information
Notes
Randomised, double-blind clinical trial. Ranomisation: computer-generated random numbers.
ADDITIONAL TABLES
Table 01 Adverse events - Mahler 2002
Adverse event
Placebo (n = 185)
SAL (n = 164)
FP (n = 173)
FPS (n = 169)
Any event
127 (69%)
119 (73%)
138 (80%)
131 (78%)
Headaches
25 (14%)
30 (18%)
35 (20%)
30 (18%)
URTI
18 (10%)
20 (12%)
25 (14%)
28 (17%)
Musculoskeletal pain 23 (12%)
21 (13%)
13 (8%)
20 (12%)
Throat irritation
14 (8%)
17 (10%)
11 (6%)
19 (11%)
Viral respiratory
infection
6 (3%)
12 (7%)
17 (10%)
14 (8%)
Candidiasis
1 (< 1%)
1(< 1%)
17 (10%)
12 (7%)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 16 of 42
Copyright © John Wiley & Sons Ltd 2003
Table 02 Adverse events - TRISTAN 2002
Adverse event
FPS (n = 358) (%)
SAL (n = 372) (%)
FP (n = 374) (%)
PLA (n = 361) (%)
Any adverse event
285 (80)
295 (79)
302 (81)
283 (78)
Drug-related events
58 (16)
46 (12)
70 (19)
49 (14)
Withdrawn due to
adverse event
46 (11)
55 (16)
61 (14)
68 (18)
Oral
4 (1)
inflammation/nausea/vomiting
3 (< 1)
3 (< 1)
8 (2)
Cough/breathing
disorder/lower
respiratory infection
3 (< 1)
7 (2)
6 (2)
6 (2)
Headaches
4 (1)
10 (3)
2 (< 1)
4 (1)
Candidiasis
27 (8)
8 (2)
27 (7)
6 (2)
Throat irritation
13 (4)
10 (3)
17 (5)
20 (6)
Hoarseness/dysphonia 6 (2)
2 (< 1)
8 (2)
3 (< 1)
Cataracts
0
2 (< 1)
0
0
Fractures
5 (1)
2 (< 1)
5 (1)
6 (2)
Table 03 Serious adverse events - Szafranski 2003
BDF
BD
F
PLA
Patients number
208
198
201
205
Deaths
6
5
6
9
SAEs other than
death
43
35
37
37
Patients with SAEs
(%)
46 (22)
35 (18)
39 (19)
42 (20)
COVER SHEET
Title
Combined corticosteroid and longacting beta-agonist in one inhaler for
chronic obstructive pulmonary disease
Reviewer(s)
Nannini L, Lasserson TJ, Poole P
Contribution of reviewer(s)
LN and PP developed the protocol. Studies were assessed by LN and TJL. TJL
and LN checked data and entered into RevMan. TJL and LN conducted the
analysis. TJL and LN developed the discussion with input from PP.
Issue protocol first published
2002/3
Issue review first published
2003/4
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 17 of 42
Copyright © John Wiley & Sons Ltd 2003
Date of most recent amendment
21 March 2002
Date of most recent
SUBSTANTIVE amendment
01 May 2003
Most recent changes
Information not supplied by reviewer
Date new studies sought but
none found
Information not supplied by reviewer
Date new studies found but not
yet included/excluded
Information not supplied by reviewer
Date new studies found and
included/excluded
31 January 2003
Date reviewers' conclusions
section amended
Information not supplied by reviewer
Contact address
Dr Luis Javier Nannini Jr
Head
Pulmonary Section
Hospital G. Baigorria
Ruta 11 Y Jm Estrada
G. Baigorria
2152
Santa Fe - Rosario
ARGENTINA
Telephone: 54-341-4711828
E-mail: nanninilj@cimero.org.ar
Facsimile: 54-3414482068
Cochrane Library number
CD003794
Editorial group
Cochrane Airways Group
Editorial group code
HM-AIRWAYS
SUMMARY TABLES
01 Fluticasone/salmeterol (FPS) versus placebo (PLA)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Exacerbations
Odds Ratio (Fixed) 95% CI Subtotals only
02 Mean exacerbation rate
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 18 of 42
Copyright © John Wiley & Sons Ltd 2003
01 Fluticasone/salmeterol (FPS) versus placebo (PLA)
04 Quality of life - Canadian
Respiratory Disease
Questionnaire (change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 SGRQ symptoms Breathlessness (absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
06 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
07 Predose FEV1 (% change from
baseline)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
08 Predose FEV1 (absolute
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
09 Rescue medication usage
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
10 Adverse events - candidiasis
2
1073
Odds Ratio (Fixed) 95% CI 6.10 [2.71, 13.76]
11 Adverse events - any event
2
1073
Odds Ratio (Fixed) 95% CI 1.24 [0.93, 1.65]
12 Withdrawals due to adverse
events
2
1073
Odds Ratio (Fixed) 95% CI 0.65 [0.45, 0.93]
02 Fluticasone/salmeterol (FPS) versus salmeterol (SAL)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Exacerbations
Odds Ratio (Fixed) 95% CI Subtotals only
02 Mean exacerbation rate
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
04 Quality of life - Canadian
Respiratory Disease
Questionnaire (change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
06 SGRQ symptoms Breathlessness (absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
07 Predose FEV1 (absolute
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
08 Predose FEV1 (%change from
baseline)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
09 Rescue medication usage
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
10 Adverse events - candidiasis
2
1063
Odds Ratio (Fixed) 95% CI 4.72 [2.26, 9.86]
11 Adverse events - any event
2
1063
Odds Ratio (Fixed) 95% CI 1.11 [0.83, 1.48]
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 19 of 42
Copyright © John Wiley & Sons Ltd 2003
02 Fluticasone/salmeterol (FPS) versus salmeterol (SAL)
12 Withdrawals due to adverse
events
2
1063
Odds Ratio (Fixed) 95% CI 0.79 [0.54, 1.14]
03 Fluticasone/salmeterol (FPS) versus fluticasone (FP)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Exacerbations
Odds Ratio (Fixed) 95% CI Subtotals only
02 Mean exacerbation rates
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
04 Quality of life - Canadian
Respiratory Dsiease
Questionnaire (change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
06 SGRQ symptoms Breathlessness (absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
07 Predose FEV1 (%change from
baseline)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
08 Predose FEV1 (absolute
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
09 Rescue medication usage
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
10 Adverse events - candidiasis
2
1074
Odds Ratio (Fixed) 95% CI 0.91 [0.58, 1.43]
11 Adverse events - any event
2
1074
Odds Ratio (Fixed) 95% CI 0.91 [0.68, 1.23]
12 Withdrawals due to adverse
events
2
1074
Odds Ratio (Fixed) 95% CI 0.74 [0.51, 1.07]
04 Budesonide/formoterol (BDF) versus placebo (PLA)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Severe Exacerbations
Rate ratio (% reduc) (Fixed) Totals not selected
95% CI
02 Mean severe exacerbation
rates per patient per year
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ (change
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
04 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 Symptoms - breathlessness
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 20 of 42
Copyright © John Wiley & Sons Ltd 2003
04 Budesonide/formoterol (BDF) versus placebo (PLA)
06 Mean FEV1 (% increase from
baseline)
% increase (Fixed) 95% CI Totals not selected
07 Adverse events - 'serious
events'
Odds Ratio (Fixed) 95% CI Subtotals only
08 Adverse events - candidiasis
Odds Ratio (Fixed) 95% CI Subtotals only
09 Withdrawals due to worsening
COPD symptoms
Odds Ratio (Fixed) 95% CI Subtotals only
10 Withdrawals due to adverse
events
Odds Ratio (Fixed) 95% CI Subtotals only
05 Budesonide/formoterol (BDF) versus budesonide (BD)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Severe Exacerbations
Rate ratio (% reduc) (Fixed) Totals not selected
95% CI
02 Mean exacerbation rates per
patient per year
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ (change
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
04 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 Symptoms - breathlessness
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
06 Mean FEV1 (% increase from
baseline)
% increase (Fixed) 95% CI Totals not selected
07 Adverse events - 'serious'
events
Odds Ratio (Fixed) 95% CI Subtotals only
08 Adverse events - candidiasis
Odds Ratio (Fixed) 95% CI Subtotals only
09 Withdrawals due to worsening
COPD symptoms
Odds Ratio (Fixed) 95% CI Subtotals only
10 Withdrawals due to adverse
events
Odds Ratio (Fixed) 95% CI Subtotals only
06 Budesonide/formoterol (BDF) versus formoterol (F)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Severe Exacerbations
Rate ratio (% reduc) (Fixed) Totals not selected
95% CI
02 Mean exacerbation rates per
patient per year
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ (change
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 21 of 42
Copyright © John Wiley & Sons Ltd 2003
06 Budesonide/formoterol (BDF) versus formoterol (F)
04 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 Symptoms - breathlessness
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
06 Mean FEV1 (% increase from
baseline)
% increase (Fixed) 95% CI Totals not selected
07 Adverse events - 'serious'
events
Odds Ratio (Fixed) 95% CI Subtotals only
08 Adverse events - candidiasis
Odds Ratio (Fixed) 95% CI Subtotals only
09 Withdrawals due to worsening
COPD symptoms
Odds Ratio (Fixed) 95% CI Subtotals only
10 Withdrawals due to adverse
events
Odds Ratio (Fixed) 95% CI Subtotals only
07 Budesonide/formoterol (BDF) versus fluticasone/salmeterol (FPS)
Outcome title
No. of
studies
No. of
participants
Statistical method
Effect size
01 Exacerbations
Odds Ratio (Fixed) 95% CI Subtotals only
02 Mean exacerbation rates per
patient per year
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
03 Quality of life - SGRQ (change
scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
04 Symptoms - Dyspnoea
(change scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
05 Symptoms - breathlessness
(absolute scores)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
06 Predose FEV1 (% change from
baseline)
Weighted Mean Difference Subtotals only
(Fixed) 95% CI
07 Adverse events - candidiasis
Odds Ratio (Fixed) 95% CI Subtotals only
08 Adverse events - any event
Odds Ratio (Fixed) 95% CI Subtotals only
09 Withdrawals due to worsening
symptoms
Odds Ratio (Fixed) 95% CI Totals not selected
10 Withdrawals due to adverse
events
Odds Ratio (Fixed) 95% CI Subtotals only
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 22 of 42
Copyright © John Wiley & Sons Ltd 2003
GRAPHS AND OTHER TABLES
Fig. 01 Fluticasone/salmeterol (FPS) versus placebo (PLA)
01.01 Exacerbations
01.02 Mean exacerbation rate
01.03 Quality of life - SGRQ (absolute scores)
01.04 Quality of life - Canadian Respiratory Disease Questionnaire (change scores)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 23 of 42
Copyright © John Wiley & Sons Ltd 2003
01.05 SGRQ symptoms - Breathlessness (absolute scores)
01.06 Symptoms - Dyspnoea (change scores)
01.07 Predose FEV1 (% change from baseline)
01.08 Predose FEV1 (absolute scores)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 24 of 42
Copyright © John Wiley & Sons Ltd 2003
01.09 Rescue medication usage (change scores)
01.10 Adverse events - candidiasis
01.11 Adverse events - any event
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 25 of 42
Copyright © John Wiley & Sons Ltd 2003
01.12 Withdrawals due to adverse events
Fig. 02 Fluticasone/salmeterol (FPS) versus salmeterol (SAL)
02.01 Exacerbations
02.02 Mean exacerbation rate
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 26 of 42
Copyright © John Wiley & Sons Ltd 2003
02.03 Quality of life - SGRQ (absolute scores)
02.04 Quality of life - Canadian Respiratory Disease Questionnaire (change scores)
02.05 Symptoms - Dyspnoea (change scores)
02.06 SGRQ symptoms - Breathlessness (absolute scores)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 27 of 42
Copyright © John Wiley & Sons Ltd 2003
02.07 Predose FEV1 (absolute scores)
02.08 Predose FEV1 (%change from baseline)
02.09 Rescue medication usage (change scores)
02.10 Adverse events - candidiasis
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 28 of 42
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02.11 Adverse events - any event
02.12 Withdrawals due to adverse events
Fig. 03 Fluticasone/salmeterol (FPS) versus fluticasone (FP)
03.01 Exacerbations
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 29 of 42
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03.02 Mean exacerbation rates
03.03 Quality of life - SGRQ (absolute scores)
03.04 Quality of life - Canadian Respiratory Dsiease Questionnaire (change scores)
03.05 Symptoms - Dyspnoea (change scores)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 30 of 42
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03.06 SGRQ symptoms - Breathlessness (absolute scores)
03.07 Predose FEV1 (%change from baseline)
03.08 Predose FEV1 (absolute scores)
03.09 Rescue medication usage
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 31 of 42
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03.10 Adverse events - candidiasis
03.11 Adverse events - any event
03.12 Withdrawals due to adverse events
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 32 of 42
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Fig. 04 Budesonide/formoterol (BDF) versus placebo (PLA)
04.01 Severe Exacerbations
04.02 Mean severe exacerbation rates per patient per year
04.03 Quality of life - SGRQ (change scores)
04.04 Symptoms - Dyspnoea (change scores)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 33 of 42
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04.05 Symptoms - breathlessness (absolute scores)
04.06 Mean FEV1 (% increase from baseline)
04.07 Adverse events - 'serious events'
04.08 Adverse events - candidiasis
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 34 of 42
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04.09 Withdrawals due to worsening COPD symptoms
04.10 Withdrawals due to adverse events
Fig. 05 Budesonide/formoterol (BDF) versus budesonide (BD)
05.01 Severe Exacerbations
05.02 Mean exacerbation rates per patient per year
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 35 of 42
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05.03 Quality of life - SGRQ (change scores)
05.04 Symptoms - Dyspnoea (change scores)
05.05 Symptoms - breathlessness (absolute scores)
05.06 Mean FEV1 (% increase from baseline)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 36 of 42
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05.07 Adverse events - 'serious' events
05.08 Adverse events - candidiasis
05.09 Withdrawals due to worsening COPD symptoms
05.10 Withdrawals due to adverse events
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 37 of 42
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Fig. 06 Budesonide/formoterol (BDF) versus formoterol (F)
06.01 Severe Exacerbations
06.02 Mean exacerbation rates per patient per year
06.03 Quality of life - SGRQ (change scores)
06.04 Symptoms - Dyspnoea (change scores)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 38 of 42
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06.05 Symptoms - breathlessness (absolute scores)
06.06 Mean FEV1 (% increase from baseline)
06.07 Adverse events - 'serious' events
06.08 Adverse events - candidiasis
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 39 of 42
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06.09 Withdrawals due to worsening COPD symptoms
06.10 Withdrawals due to adverse events
Fig. 07 Budesonide/formoterol (BDF) versus fluticasone/salmeterol (FPS)
07.01 Exacerbations
07.02 Mean exacerbation rates per patient per year
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 40 of 42
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07.03 Quality of life - SGRQ (change scores)
07.04 Symptoms - Dyspnoea (change scores)
07.05 Symptoms - breathlessness (absolute scores)
07.06 Predose FEV1 (% change from baseline)
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 41 of 42
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07.07 Adverse events - candidiasis
07.08 Adverse events - any event
07.09 Withdrawals due to worsening symptoms
07.10 Withdrawals due to adverse events
Combined corticosteroid and longacting beta-agonist in one inhaler for chronic obstructive pulmonary disease - page 42 of 42
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