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doi: 10.1136/thx.2009.116608
2010 65: 39-43Thorax
M Weatherall, M Wijesinghe, K Perrin, et al.
inhaled corticosteroid therapy
salmeterol and the effect of concomitant
Meta-analysis of the risk of mortality with
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Meta-analysis of the risk of mortality with salmeterol
and the effect of concomitant inhaled corticosteroid
therapy
M Weatherall,
1,2
M Wijesinghe,
2,3
K Perrin,
2,3
M Harwood,
3
R Beasley
2,3,4
cAdditional details are
published online only at http://
thorax.bmj.com/content/vol65/
issue1
1
University of Otago Wellington,
Wellington, New Zealand;
2
Capital & Coast District Health
Board, Wellington, New
Zealand;
3
Medical Research
Institute of New Zealand,
Wellington, New Zealand;
4
University of Southampton,
Southampton, UK
Correspondence to:
Professor R Beasley, Medical
Research Institute of New
Zealand, P O Box 10055,
Wellington 6143, New Zealand;
richard.beasley@mrinz.ac.nz
Received 15 March 2009
Accepted 20 October 2009
ABSTRACT
Background: There is concern that long-acting bagonist
(LABA) drugs may increase the risk of asthma mortality.
Methods: A meta-analysis was conducted of asthma
deaths in randomised controlled clinical trials from the
GlaxoSmithKline database that compared salmeterol with
a non-LABA comparator treatment in asthma. The Peto
one-step method was used to determine the risk overall
(all studies) and in derived datasets based on inhaled
corticosteroid (ICS) use.
Results: There were 35 asthma deaths in 215 studies
with 106 575 subjects. Two studies (SMART and SNS)
contributed 30/35 (86%) asthma deaths, the overall
findings largely reflecting the characteristics of these
studies. The odds ratio for risk of asthma mortality with
salmeterol was 2.7 (95% CI 1.4 to 5.3). In 54 placebo
controlled studies the risk of death from asthma in
patients not prescribed ICS was 7.3 (95% CI 1.8 to 29.4).
In 127 studies in which patients were prescribed ICS, the
risk of asthma death was 2.1 (95% CI 0.6 to 7.9). In 63
studies in which patients were randomised to receive the
combination salmeterol/fluticasone propionate inhaler or
ICS, there were no asthma deaths among 22 600
patients.
Conclusions: Salmeterol monotherapy in asthma
increases the risk of asthma mortality and this risk is
reduced with concomitant ICS therapy. There is no
evidence that combination salmeterol/fluticasone propio-
nate therapy is associated with an increased risk of
asthma mortality, although this interpretation is limited by
the low statistical power of available studies.
The role of long-acting bagonist (LABA) drugs in
asthma mortality represents the latest chapter in a
long running debate about the safety of inhaled b
agonist drugs in the treatment of asthma.
1–10
Evidence for a possible increased risk of asthma
mortality with LABA therapy was first raised in
1993 with publication of the Salmeterol
Nationwide Surveillance Study (SNS).
9
This study
reported a statistically non-significant threefold
increased risk of death in subjects treated with
salmeterol compared with regular salbutamol, but
no increase in hospital admissions or life-threaten-
ing events. These findings led to the Salmeterol
Multicentre Asthma Research Trial (SMART),
which reported a statistically significant fourfold
increase in asthma mortality with salmeterol
compared with placebo.
10
In subgroup analyses,
there was no increased risk in asthma mortality for
salmeterol in subjects prescribed concomitant ICS
therapy. Although limited by low power, this
finding raised the possibility that the mortality risk
was restricted to salmeterol as monotherapy and
that concomitant use of ICS therapy may protect
against the risk.
This interpretation was supported by the find-
ings of the large UK-based case-control study in
which there was no evidence of any positive
association between LABAs and asthma death.
11
As almost all patients in the UK during the period
of the study who were prescribed LABA therapy
were co-prescribed ICS therapy,
12
these findings
provided evidence that the use of LABAs with
concomitant ICS therapy does not increase the risk
of asthma mortality.
13
To further investigate this issue we have under-
taken a meta-analysis of all randomised controlled
trials of salmeterol included in the GlaxoSmithKline
(GSK) database to determine whether its use is
associated with an increased risk of asthma mortality,
and whether ICS therapy influences any such risk.
METHODS
The meta-analysis was undertaken on the GSK
salmeterol safety database that was submitted to the
FDA. The database included all published and
unpublished chronic-dosing randomised controlled
trials of salmeterol, funded or sponsored by GSK,
completed by January 2008 (see online supplement).
Inclusion criteria
To be included in the meta-analysis, studies had to
be randomised, double-blind, controlled, repeat
dose, parallel group or crossover clinical trials that
compared salmeterol (when used as a separate
salmeterol or as a fixed dose combination salme-
terol/fluticasone propionate inhaler) with a com-
parator non-LABA treatment in the management
of asthma. Only the first period of crossover
studies was included in the meta-analysis.
Exclusion criteria
Non-randomised, open label and single dose trials
were excluded. Clinical pharmacology studies
(pharmacokinetic or pharmacodynamic analyses),
quality of life and pharmacoeconomic analyses and
studies in which no comparator non-LABA treat-
ment was examined (eg, studies in which formo-
terol was the sole comparator) were also excluded.
Outcome measures
The primary outcome variable was deaths due to
asthma. Secondary outcomes were total deaths (all
causes), admissions to hospital with asthma and
asthma intubations (see online supplement).
Asthma
Thorax 2010;65:39–43. doi:10.1136/thx.2009.116608 39
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To assess the effect of salmeterol when used with con-
comitant ICS therapy, three datasets were derived based on
information about ICS use. This approach was taken as not all
the studies had individual participant information on ICS use,
whereas most studies had aggregate information for the study
as a whole.
cSalmeterol monotherapy: subjects randomised to salmeterol
versus placebo in which subjects were not receiving ICS
therapy as randomised or background therapy and ICS was
not started during the course of the study.
cSalmeterol with ICS therapy: subjects randomised to
salmeterol and also taking ICS (including ICS as randomised
therapy or ICS as concurrent background medication at
randomisation which was continued per protocol after
randomisation, or ICS started during the period of the
study) versus subjects receiving ICS (including ICS as
randomised therapy or ICS as concurrent background
medication at randomisation which was continued per
protocol after randomisation, or ICS started during the
period of the study).
cSalmeterol as combination salmeterol/fluticasone propio-
nate therapy: subjects randomised to salmeterol via a
combination salmeterol/fluticasone propionate (Advair/
Seretide) inhaler versus subjects randomised to an ICS.
Subjects from one study could be included in more than one
ICS use group. For example, in the SMART study,
10
subjects
could be included in the salmeterol versus placebo comparison
(Group 1: salmeterol monotherapy) and the salmeterol and ICS
versus ICS comparison (Group 2: salmeterol with ICS therapy)
if they were taking ICS as concurrent background medication.
Further subgroup analyses based, for example, on ethnic
group, age, baseline asthma severity, dose, dose regime (once or
twice daily), specific ICS or inhaler device were not attempted
as we anticipated limited statistical power to detect associations
with the small number of events within subgroups.
Statistical methods
Three statistical methods were used to determine the risk of
mortality associated with salmeterol treatment (see online
supplement). The primary method was the Peto’s one-step odds
ratio carried out according to the formulae given by Bradburn
and colleagues.
14
The second method was the simple con-
tingency table odds ratio carried out by an exact method in SAS
Version 9.1 using the ‘‘FREQ’’ procedure. For the third, the
Bayesian method was implemented in WinBUGS 1.4 using the
package ‘‘R2WinBUGS’’ in the R statistical programme.
15
RESULTS
There were 263 studies included in the GSK clinical trial
database of salmeterol (fig 1; see online supplement); 48 studies
were excluded because there was no non-salmeterol compara-
tor, formoterol was the comparator treatment or the data were
incomplete. In one of the studies with incomplete data there
was one asthma death in a patient who was randomised to
treatment with salbutamol but not salmeterol. A total of 215
studies with 106 575 randomised subjects and 39 006 patient-
years of treatment were therefore included in the full dataset.
The number of subjects and total years of exposure to
salmeterol and comparator treatment in the full dataset and
Figure 1 QUOROM figure showing
studies included in the meta-analysis.
GSK, GlaxoSmithKline; ICS, inhaled
corticosteroids; LTRA, leukotriene
receptor antagonist.
Asthma
40 Thorax 2010;65:39–43. doi:10.1136/thx.2009.116608
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in the patient groups based on ICS use are shown in table 1.
There were 35 deaths from asthma included in the full dataset,
of which 30 (86%) came from two clinical trials, the SNS
9
and
SMART
10
(see online supplement).
Overall analysis (all studies)
There were 28/57 607 asthma deaths in subjects taking
salmeterol and 7/48 968 in patients randomised to treatment
with a non-LABA. The odds ratio for risk of asthma mortality
associated with salmeterol was 2.7 (95% CI 1.4 to 5.3) using the
Peto method (table 2). A similar estimate of risk was observed
with the simple contingency table method but not with the
Bayesian method (see online supplement). The odds ratio for
the risk of all-cause mortality associated with salmeterol was 1.3
(95% CI 1.0 to 1.8) using the Peto method (table 2). A similar
estimate of risk was observed with the simple contingency table
method, but not with the Bayesian method (see online
supplement). The odds ratio for risk of hospital admissions
associated with salmeterol was 1.2 (95% CI 1.1 to 1.4) using the
Peto method. A similar estimate of risk was observed with both
the simple contingency table method and the Bayesian method.
The odds ratio for risk of intubations associated with salmeterol
was 1.6 (95% CI 1.0 to 2.5) using the Peto method. A similar
estimate of risk was observed with the simple contingency table
method but not with the Bayesian method.
Salmeterol monotherapy
There were 54 studies in which 18 395 subjects received
salmeterol or placebo as monotherapy, with no ICS as
randomised or baseline prescribed therapy (table 3). There were
eight deaths from asthma, all in the SMART study.
10
This
differs from the published study report,
10
as one subject
randomised to salmeterol who died was not taking ICS at
baseline but received an ICS prescription some time during the
study period and, as a result, was included in the ‘‘salmeterol
with ICS therapy’’ comparison group. The odds ratio for the
risk of asthma mortality was 7.3 (95% CI 1.8 to 29.4) using the
Peto method, although this is just the odds ratio for mortality
for the single study (SMART) which accounted for all the
asthma deaths in this analysis. It was not possible to calculate a
risk from simple contingency tables or the Bayesian method.
There was no statistically significant increased risk for all cause
mortality or intubations. There was an increased risk of hospital
admissions with an odds ratio of 1.4 (95% CI 1.0 to 2.0) by the
Peto method. There were similar estimates of risk of hospital
admissions with the single contingency table and Bayesian
methods, but these were not significant.
Salmeterol with ICS therapy (randomised and background)
There were 127 studies in which 48 715 subjects received ICS as
randomised or baseline prescribed therapy (table 4). There were
nine deaths from asthma, eight of which came from the
SMART study.
10
The odds ratio for the risk of asthma mortality
was 2.1 (95% CI 0.6 to 7.9) using the Peto method. A similar
estimate of risk was obtained from the single contingency table
method and it was not possible to calculate a risk with the
Bayesian method due to convergence problems (see online
supplement). There was no statistically significant increased
risk for all-cause mortality or intubations. There was an
increased risk of hospitalisations, with an odds ratio of 1.3
(95% CI 1.1 to 1.5) by the Peto method.
Salmeterol as combination salmeterol/fluticasone propionate
therapy
There were 63 studies with 22 600 subjects in whom the
combination salmeterol/fluticasone propionate inhaler was
compared with ICS therapy (table 5). There were no deaths
from asthma so it was not possible to calculate a risk of asthma
mortality. There was no statistically significant risk of all-cause
mortality and no events on which to calculate a risk of
intubations. There was no increased risk of hospitalisations by
any of the analytical methods used (see online supplement).
DISCUSSION
The findings from these meta-analyses suggest that salmeterol
as monotherapy in poorly controlled asthma increases the risk
of asthma mortality, and that this risk is reduced with
concomitant ICS therapy. There is no evidence to suggest that
combination salmeterol/fluticasone propionate therapy is asso-
ciated with an increased risk of asthma mortality, although this
interpretation is limited by the low statistical power of available
studies to detect important differences in asthma mortality.
Meta-analysis of trials with rare outcome measures is
problematic and three methods of statistical analyses were
undertaken. Peto’s one-step odds ratio was the primary method
of analysis as it performs best under certain conditions in the
meta-analysis of trials with rare events.
14
These conditions—
which include event rates ,1%, no substantial imbalance
between control and treatment group sizes within trials and
treatment effects not particularly large—were met for the trials
included in the meta-analysis. However, the Peto method can
only use information from those trials with at least one event in
one arm of the trial to calculate a relative risk and ignores
information on the length of the trial. A secondary method of
analysis was the single two-by-two table of events which treats
all trials as one large trial and may be applicable if the trials have
Table 1 Summary of exposure by population
Population
No of
studies
Salmeterol-containing
product Comparator
No of
subjects
Total exposure
(years)
No of
subjects
Total
exposure
(years)
Salmeterol-containing product vs non-LABA 215 57607 20573 48968 18433
Salmeterol vs placebo (without ICS) 54 9463 3787 8932 3682
Salmeterol +ICS (BK/RD)* vs ICS (BK/RD)* 127 24542 10285 24173 10243
Fluticasone/salmeterol combination (RD){vs ICS
(RD){
63 11437 5020 11163 5008
*BK/RD, ICS received as background medication or as randomised study drug.
{RD, ICS received as randomised study drug.
ICS, inhaled corticosteroid; LABA, long-acting bagonist.
Asthma
Thorax 2010;65:39–43. doi:10.1136/thx.2009.116608 41
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similar clinical samples and designs, but ignores the hetero-
geneity of the trials. The Bayesian approach has the advantage
that it can use the information from trials with no event in
either arm to contribute to an overall estimate of event rate and
can also incorporate information about the different length of
follow-up. However, even this method was problematic owing
to the sparse data, with failure of the numerical implementation
to converge on estimates in some of the analyses.
A key issue is that the SNS
9
and SMART
10
studies contributed
86% of all asthma deaths and, as a result, the findings for the
full database predominantly relate to the clinical practice that
applied within these studies. The SNS was undertaken almost
20 years ago, with about one in three patients in the study not
receiving ICS therapy, and combination salmeterol/fluticasone
propionate inhaler therapy was not available. In the SMART
study just over half of the patients did not receive concomitant
ICS therapy despite having unstable asthma. The SMART
study contributed all eight deaths to the database in which
salmeterol was prescribed as monotherapy, from which a 7.3-
fold increased risk of mortality was identified. Based on this
analysis, one of our main findings is that the use of salmeterol
without concomitant ICS therapy in unstable asthma increases
the risk of death from asthma.
The next issue is whether there is a risk of asthma mortality
with salmeterol when used in association with ICS. When
analyses were restricted to this management approach there
were only nine asthma deaths in more than 48 000 subjects,
with eight of the deaths coming from the SMART study. While
the lack of a statistically significant increase in asthma
mortality with salmeterol and ICS therapy provides some
reassurance, the analysis lacked statistical power to rule out
important associations. This interpretation is consistent with
that of the recent Cochrane review
16
in which unpublished SNS
data were obtained from GSK on the use of ICS at baseline for
each of the asthma-related deaths and the proportion of subjects
taking baseline ICS. This enabled a combined analysis of the risk
of asthma mortality with salmeterol in association with ICS use
from the SNS and SMART studies. In the subgroup taking ICS
at baseline the increase in asthma mortality was small and not
statistically significant but associated with wide confidence
intervals (odds ratio 1.49, 95% CI 0.54 to 4.11).
In considering the potential influence of concomitant ICS
therapy on the risk of asthma mortality, there are likely to be
differences in risk depending on the form in which they are
prescribed. In standard clinical practice, compliance with ICS is
poor, with patients taking on average no more than half of all
prescribed doses.
17 18
As a result, many patients prescribed
LABAs with ICS will be taking LABA as monotherapy for
variable periods of time. The only way in which it can be
ensured that patients cannot take LABA as monotherapy is
through their prescription as a combination LABA/ICS inhaler.
When the analysis was restricted to the 63 studies in which the
combination salmeterol/fluticasone propionate product was
used, there were no asthma deaths or intubations and no
increase in risk of hospital admissions for asthma. As a result,
there is no evidence from this meta-analysis that combination
salmeterol/fluticasone propionate therapy influences the risk of
asthma death, life-threatening attacks or hospital admissions,
with the proviso that this interpretation is limited by the low
power from available studies.
This systematic review and meta-analysis did not address the
potential mechanisms whereby salmeterol may influence the
risk of asthma mortality in certain circumstances. The long-
term use of salmeterol has the potential to reduce bronchodi-
lator sensitivity to bagonists
19
and to induce tolerance to their
bronchoprotective effects
20
which may not be restored by
concurrent use of ICS.
21
Patients using salmeterol may also be
at potential risk of severe exacerbations if the symptom control
achieved with salmeterol leads to a discontinuation of ICS
therapy. Conversely, salmeterol in the form of a combination
salmeterol/fluticasone propionate product may increase com-
pliance with ICS
22 23
and, for this reason, have the potential to
reduce the risk owing to the dose-dependent reduction in
asthma mortality associated with ICS therapy.
24
At the
population level, combination LABA/ICS products also have
the potential to reduce the risk of asthma mortality if the strong
patient and doctor preference for this therapeutic approach
leads to a greater overall use of ICS therapy than would
otherwise have occurred. This issue cannot be addressed by
randomised controlled trials as it relates to patterns of
prescribing. However, observational data suggest that the
widespread use of LABAs in the form of combination LABA/
ICS therapy may have led to a reduction in asthma mortality
through the greater prescription of ICS.
13 25 26
It is informative to compare our findings with those of the
recent meta-analysis of formoterol based on the AstraZeneca
database.
27
When a comparable statistical approach was used
with analyses restricted to studies with a non-LABA compara-
tor, the risk of asthma mortality associated with formoterol was
2.53 (95% CI 0.45 to 26.0).
28
In patients prescribed ICS the risk
Table 2 Odds ratio for risk of death and other outcomes associated
with salmeterol treatment: any salmeterol versus non-LABA (215
studies)
Primary analyses: Peto method
Outcome
No of studies
with data
Odds ratio (95% CI)
Fixed effect Random effects
Asthma deaths 7 2.7 (1.4 to 5.3) 2.6 (1.1 to 5.9)
All deaths 15 1.3 (1.0 to 1.8) 1.3 (1.0 to 1.8)
Hospitalisations 104 1.2 (1.1 to 1.4) 1.4 (1.1 to 1.7)
Intubations 14 1.6 (1.0 to 2.5) 1.6 (0.9 to 2.8)
Table 3 Odds ratio for risk of death and other outcomes associated
with salmeterol treatment: salmeterol versus placebo (54 studies)
Primary analyses: Peto method
Outcome
No of studies
with data
Odds ratio (95% CI)
Fixed effect Random effects
Asthma deaths 1 7.3 (1.8 to 29.4) NA
All deaths 2 1.1 (0.6 to 2.0) 1.1 (0.5 to 2.3)
Hospitalisations 23 1.4 (1.0 to 2.0) 1.4 (1.0 to 2.0)
Intubations 4 1.5 (0.7 to 3.3) 1.4 (0.4 to 4.9)
Table 4 Odds ratio for risk of death and other outcomes associated
with salmeterol treatment: salmeterol/ICS (randomised or background)
versus ICS (randomised or background) (127 studies)
Primary analyses: Peto method
Outcome
No of studies
with data
Odds ratio (95% CI)
Fixed effect Random effects
Asthma deaths 2 2.1 (0.6 to 7.9) 2.2 (0.5 to 9.3)
All deaths 8 1.5 (0.8 to 2.7) 1.5 (0.8 to 2.7)
Hospitalisations 55 1.3 (1.1 to 1.5) 1.4 (1.1 to 1.8)
Intubations 6 1.7 (0.9 to 3.4) 1.7 (0.9 to 3.4)
Asthma
42 Thorax 2010;65:39–43. doi:10.1136/thx.2009.116608
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of asthma mortality with formoterol was 3.67 (95% CI 0.41 to
174.0).
28
While it is difficult to compare the salmeterol and
formoterol findings, different patterns appear to exist with the
risk with salmeterol being reduced with concomitant ICS
therapy but not with formoterol. It will be important to
determine the extent to which these different patterns of risk
might be driven by the ‘‘as required’’ use of formoterol in the
studies in which formoterol was co-prescribed with ICS
therapy. This regime inherently carries a risk of overuse in the
situation of a severe attack. Further evidence to suggest that a
difference in risk may exist between salmeterol and formoterol
when combined with ICS therapy comes from the recent FDA
meta-analysis.
29
From patient level data in 110 randomised
placebo controlled trials of LABAs in asthma, the risk of
composite asthma-related death, intubation or hospitalisation
was 7.49 events per 1000 subjects (95% CI 21.47 to 16.44) with
Symbicort (combination formoterol/budesonide inhaler) and
20.15 events per 1000 subjects (95% CI 22.01 to 1.70) with
Advair (salmeterol/fluticasone propionate).
It is also relevant to consider the case-control studies of LABA
therapy and near fatal and/or fatal attacks of asthma which
have reported no statistically significant increased risk after
adjusting for confounding variables.
11 30–33
The most important
of these was the large UK-based study in which there was no
evidence of any positive association between LABAs and
asthma.
11
However, most of these studies have low power and
report upper confidence limits that would support an increased
risk of asthma death and/or life-threatening attacks.
30–33
In conclusion, we suggest that the potential risk of asthma
mortality associated with the LABAs salmeterol and formoterol
requires further investigation. The priority is to investigate the
risk with combination LABA/ICS therapy, the preferred LABA
product which represents the only form in which the prescriber
can be certain that LABAs are not used as monotherapy.
Different regimes would need to be assessed to determine
whether the risk is influenced by patterns of LABA use,
particularly variable dose regimes. In addition to large rando-
mised controlled trials, case-control studies would also be
informative in the investigation of the risk of such a rare
outcome as mortality.
34
Acknowledgements: The authors thank GSK for providing the salmeterol clinical
trials safety database for independent analysis.
Funding: The study was funded by a grant of NZ$24 000 from MedSafe, New Zealand
Ministry of Health. MW is a Wellington Hospitals and Health Foundation Research Fellow
and KP is a Health Research Council of New Zealand Training Fellow. The studysponsors
had no role in study design, data collection, analysis, data interpretation, writing of the
report or in the decision to submit the paper for publication.
Competing interests: The Medical Research Institute of New Zealand has received
research grants from AstraZeneca, GlaxoSmithKline and Novartis. RB has received fees
for consulting and speaking and reimbursement for attending symposia from
AstraZeneca, GlaxoSmithKline and Novartis. All other authors have no conflict of interest.
Provenance and peer review: Not commissioned; externally peer reviewed.
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Table 5 Odds ratio for risk of death and other outcomes associated
with salmeterol treatment: Advair versus ICS (as study drug) (63 studies)
Primary analyses: Peto method
Outcome
No of studies
with data
Odds ratio (95% CI)
Fixed effect Random effects
Asthma deaths 0 NA NA
All deaths 4 0.6 (0.2 to 2.4) 0.6 (0.2 to 2.4)
Hospitalisations 20 1.0 (0.6 to 1.7) 1.0 (0.6 to 1.7)
Intubations 0 NA NA
Asthma
Thorax 2010;65:39–43. doi:10.1136/thx.2009.116608 43
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