Running head: EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
Effectiveness of Long-acting Beta-agonists Plus Inhaled Corticosteroids
in Improving Asthma Outcomes in Adults
Melissa French
University of Central Florida
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EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
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Abstract
Asthma is a very prevalent chronic illness that currently affects more than 230 million people
worldwide. The amount of people affected is expected to rise by an additional 100 million
people in the next ten years. This illness is responsible for an estimated annual deficit of $56
billion dollars from direct and indirect costs. Current U.S. guidelines recommend addition of
long-acting beta-agonists (LABA) to a low or medium dose of inhaled corticosteroid (ICS) when
asthma is not adequately managed; however there is concern of the safety of LABA when
included in the asthma regime. A comprehensive literature review was completed by electronic
database search of MEDLINE, CINAHL, and Cochrane Database for Systemic Reviews, and
TRIP Database for English written articles between the years of 2008 to 2013. Included articles
were systematic reviews and meta-analyses of random controlled trials (RCT) and retrospective
observational cohort studies to review the clinical outcomes of two comparable interventions in
order to answer the question: Does the use of an inhaled corticosteroid (ICS) in combination
with a long-acting beta-agonist (LABA), compared to the use of an ICS alone in adults, decrease
the need for oral corticosteroids and decreases the need for asthma related hospitalizations?
There was not adequate data to determine if one group was successful at preventing
asthma hospitalization but ample evidence was present to conclude that LABA plus ICS
group did decrease oral corticosteroid use.
Key words: asthma, adverse effects, oral corticosteroids, inhaled corticosteroids, long acting beta
agonist, LABA and ICS, ICS alone, safety, hospital* and mortality.
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
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Significance
According to the Asthma and Allergy Foundation of America (AAFA), the prevalence of
asthma worldwide is over 230 million people and affects about 25.9 million Americans (2015).
This number includes 8% of American adults and 10% of American children. The number of
asthmatics is expected to grow by 100 million people worldwide by the year 2025 (Spangler,
2012). Furthermore, results from the Asthma in America survey suggests that the United States
is not meeting asthma goals created by the National Heart, Lung, and Blood Institute which
include lack of sleep disruption, no missed school or work, minimal emergency room visits and
hospitalizations, maintenance of normal activity levels, and normal to almost normal lung
function. Asthma as a primary diagnosis is responsible for 14.2 million primary care visits, 1.8
million emergency department visits, and 439,000 hospital stays with an average length of stay
of 3.6 days every year (CDC, 2015). Economic costs related to direct and indirect costs are as
high as $56 billion dollars annually: $50.1 billion in direct costs and $5.9 billion in indirect costs
(AAFA, 2015). Direct costs consist mostly of hospitalizations and pharmaceuticals, emergency
department visits, medical equipment, lab work and diagnostic tests, ambulance use, nursing
care, doctor’s office visits, education, and research while indirect costs is related to reducing
productivity including school days lost, work days lost, waiting, and traveling (Bahadori, et al.,
2009).
Current U.S. guidelines for asthma recommend longstanding treatment with an inhaled
corticosteroid (ICS) in order to manage chronic airway inflammation associated with asthma
(Spangler, 2012). Many asthma patients gain control of their symptoms with the use of ICS and
occasional rescue short acting bronchodilators (SABA) If asthma is not controlled on a low dose
of ICS then it is time to either increase ICS dosage or to add another medication drug class to aid
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
4
in control (Thomas, et al, 2009). The addition of high dose ICS was once recommended but
some recent evidence has shown that the addition of a LABA may be advantageous for most
people. High dose of steroids is not without risk. Current US guidelines consider adding a longacting beta agonist (LABA) to a low or medium dose ICS as an acceptable step-up treatment
option when asthma is not controlled instead of a high ICS dose (Wells, et al, 2012). However,
the safeties of LABA’s have been examined since their appearance in the early 1990’s. In 2003
the US Food and Drug Administration (FDA) held multiple meetings to determine the risks and
benefits of LABA, termed the Salmeterol Multicenter Asthma Research Trial (SMART). There
was a higher ratio of deaths and serious asthma related complications associated with Salmeterol
(a LABA) especially in African Americans versus the placebo group so the trial was terminated.
Since the drugs had some symptomatic benefits they were not removed from the market but had
a black-box warning placed on them instead. Because of the controversy multiple studies have
been implemented to test the safety and efficacy of LABA in combination with ICS or ICS
medications alone for the treatment of asthma. Beneficial effects and or harmful effect of
LABA/ICS combination in terms of decreased asthma exacerbations and severe adverse
outcomes including requirement of oral corticosteroids, and ED visits and hospitalization have
been reviewed. The purpose of this review is to determine if the use of an inhaled corticosteroid
(ICS) in combination with a long-acting beta-agonist (LABA), compared to the use of an ICS
alone in adults, decreases the need for oral corticosteroids and decreases the need for asthma
related hospitalizations.
Methods
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
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A comprehensive formulation of the literature was obtained by searching the electronic
databases MEDLINE, CINAHL, Cochrane Database for Systemic Reviews, and TRIP Database
for English written articles between the years of 2008 to 2013.
In order to confirm comprehensive searches the four databases were used above multiple
times with key words, and medical subject headings. The searchable terms used were
combinations of the following: asthma, adverse effects, oral corticosteroids, inhaled
corticosteroids, long acting beta agonist, LABA and ICS, ICS alone, safety, hospital* and
mortality.
Articles were included if they were systematic reviews and meta-analyses of random
controlled trials (RCT) and retrospective observational cohort studies to review the clinical
outcomes of two comparable interventions in the treatment of adult asthma: the use of inhaled
corticosteroids (ICS) in addition to a long-acting beta 2 agonist (LABA) versus the use of an ICS
alone. The outcomes measured were the decreased risk of exacerbations requiring short
treatment of oral corticosteroids and hospitalizations related to asthma. The results reviewed
were from the years 2008-2013.
Articles were excluded if a control group of ICS alone was not included or if the use of a
LABA as a control group was included in the studies. Only studies that included the adult
population were included in review. Studies published greater than 6 years old were avoided.
Article quality and level of evidence were determined using criteria published by Melnyk and
Fineout-Overholt. (Melnyk & Fineout-Overholt, 2014).
Results
Search Results
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
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Eighty- seven articles were identified from electronic searches of MEDLINE,
CINAHL, Cochrane Database for Systemic Reviews and TRIP Databases. Despite a thorough
search, only six articles were kept and 81 were eliminated. Articles were excluded if they
included other treatment modalities and medication classifications for asthma control not
rescue, were published greater than six years ago, did not include adults, did not address
my PICOT question, or if they lacked a quantitative research design.
A summary of the study design, level of evidence, sample, characteristics of the
interventions, and results are included in Table 1. The articles are organized
chronologically and are classified by two themes: Risk for oral corticosteroids and risk for
asthma related hospitalizations.
Risk for Oral Corticosteroid Use
All six of the articles used in this review conveyed the risk of oral corticosteroid use
in the asthmatic patient of two treatment groups: those that were treated with an ICS alone
versus those were treated with an ICS in addition to a LABA. (See Table 1). One systematic
reviews using RCTs (Chroinin, et al., 2009) and one meta-analysis using observational
cohorts (Hernandez et al., 2014) determined that there was not a difference in the use of
oral corticosteroids between the two groups. Two systematic reviews that both used RCT
results (Ducharme et al., 2010a and Ducharme et al., 2010b) and 1 retrospective
observational cohort study (Thomas, et al., 2009) reported that there was a significant 30%
decreased risk of steroid use in the ICS plus LABA group compared to the ICS alone group.
Moreover, all three meta-analyses showed between 23% and 30% decrease in oral
corticosteroid use compared to ICS alone (Ducharme et al., 2010a, Ducharme, et al., 2010b,
& Thomas, et al., 2009). One smaller observational cohort (Wells, et al., 2012) had a very
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
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different and significant finding, concluding that there was an overall protective benefit
from using LABA in addition to ICS. However, the outcome for this study combined the
need for oral corticosteroid courses, asthma related emergency department visits and
asthma related hospitalizations instead of decreased course of oral steroids alone.
Risk for Asthma Related Hospitalizations
Three out of six articles, all of which were systemic reviews (Chroinin, et al., 2009,
Ducharme, et al, 2010a, and Ducharme, et al. 2010b) reported no difference in asthma
related hospitalizations between the two groups (see Table 1). The remaining three articles
had conflicting results and could not deem one group superior to another in decreasing
hospitalizations most likely related to sample size. Hernandez et al., featured a study from
a meta-analysis that had a different outcome than it’s other included studies because of a
large sample size of 467, 639 participants (2014). Overall this meta-analysis still
determined that there was a decreased incidence of hospitalization in the LABA group
although not statistically significant.
Limitations of Evidence
All three systematic reviews from the Cochrane Collaboration, made inquiries about
published or unpublished clinical trial data for pharmaceutical companies who make the
medications in question. (Chroinin, et al., 2009, Ducharme, et al., 2010a, Ducharme, et al.,
2010b) This could cause some bias. All included articles, although published within the last
six years have sought their data ranging from the 1990s to 2010 and therefore the data
may be out of date and further testing is required to include current figures if there are
now different medications available and different dosing being used. If there has been
change in treatment then this may decrease applicability of results as well as validity. Non-
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EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
random nature of observational studies has limitations because there may be confounding
factors that cannot be accounted for (Thomas, et al., 2009 and Wells, et al, 2012). Other
factors that effect validity is not knowing if participants were compliant with medication
regimes which can lead to error (Thomas, et al., 2009).
Table 1
Primary
Study,
Country
Chroinin, et
al. (2009)
Design, Level of
Evidence, Sample
Systematic review
Level I
Only RCTs with or
without placebo
were included in
this review.
Sample size:
ICS+ LABA=1693
ICS alone= 1707
Ducharme, et
al. (2010a)
Issue 5
Systematic Review
Level I
Only RCTs were
used in this review
ICS+ LABA: (n=
Characteristics of
Intervention
Randomized controlled
studies were found through
the Cochrane Central
Register of Controlled
Trials (CENTRAL),
MEDLINE, EMBASE,
CINAHL, AMED, and
PsycINFO electronic
databases to compare ICS
plus LABA therapy versus
similar dose of ICS therapy
alone in adults and children
with asthma who had not
been exposed to inhaled
corticosteroids within 28
days before study
membership began.
Duration of studies was at
least 4 weeks.
Reference lists were
reviewed to identify
possible relevant citations
and pharmaceutical firms
AstraZeneca and GSK were
reviewed by hand.
The primary investigated
outcome was the amount of
subjects who experienced
exacerbations that required
oral corticosteroid courses.
The review also looked at
secondary outcomes such as
hospital admission rates.
Randomized controlled
studies were found by using
Cochrane Central Register
of Controlled Trials
(CENTRAL), MEDLINE,
EMBASE, and CINAHL as
electronic databases as well
as manually searching
Results
Risk for Oral Steroids
12 (11 of which were adult and 1
pediatric) studies (n=3,400)
There was no significant
difference in the risk of oral
corticosteroid use between
groups. RR=1.04 (95% CI: 0.73
to 1.47)
Hospitalizations
3 studies (n was not available.)
There was no significant
difference between the two
groups RR= 0.38 (95% CI: 0.09
to 1.65)
Risk for Oral Steroids:
30 studies (n=6808)
ICS+ LABA (n= 3566)
ICS alone (n= 3242)
The addition of a LABA to ICS
therapy decreased the relative
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EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
3566)
ICS alone (n=3242)
ICS+LABA
(n=3774)
ICS alone=3523
Ducharme, et
al. (2010b)
Issue 4
Systematic Review
Level I
Only RCTs were
used in this review.
Sample size
LABA+ ICS=4930
Increased ICS
alone=4903
respiratory journals and
abstracts. Clinical trials
from pharmaceutical
companies AstroZeneca,
GSK, and Novartis were
searched. The goal was to
assess the safety and
effectiveness of adding
LABA to ICS in asthmatic
patients. Duration of studies
was at least 12 weeks.
The primary investigated
outcome was the amount of
patients with asthma
exacerbations requiring oral
corticosteroid treatment.
Secondary outcomes were
observed such as hospital
admissions from severe
acute exacerbations.
Electronic database used
were The Cochrane Central
Register of Controlled
Trials (CENTRAL),
EMBASE, MEDLINE, and
CINAHL. Also, 20 most
productive respiratory
journals were hand searched
and data from
pharmaceutical companies
who manufacture used
drugs, GSK, AstraZeneca
and Novartis were reviewed.
The goal was to determine
the result of combination
LABA and ICS compared to
higher doses of ICS alone to
decrease asthma
exacerbations over at least 4
weeks.
The primary investigated
outcome was the amount of
patients with asthma
exacerbations requiring oral
corticosteroid treatment.
Secondary outcomes
included amount of subjects
requiring asthma related
hospitalizations.
According to review, adult
data was more abundant
compared to pediatric data
in this review. Forty studies
risk of patients experiencing one
or more exacerbations needing
oral corticosteroids by 23%.
RR=0.77 (95% CI: 0.68 to 0.87)
p< 0.0001
Hospitalizations
24 studies (15 contributed
numerical data)
ICS+LABA (n=3774)
ICS alone (n=3523)
There was no dissimilarity in the
risk of exacerbations requiring
hospitalization between groups.
RR= 1.13 (95% CI: 0.70 to1.82)
Risk for oral corticosteroids:
25 studies (n=9833)
Sample size
LABA+ ICS=4930
Increased ICS alone=4903
LABA in addition to ICS
regimen led to a decreased
risk for oral corticosteroid use
compared to higher doses of
ICS. RR= 0.88 (95% CI: 0.78 to
.98) p=0.02
Asthma related hospitalizations
were not significantly affected
by treatment regimen
RR= 1.02 (95% CI: 0.67 to
1.56, N= 33) In fact 10 studies
did not even verify any
hospitalizations.
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EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
concentrated on adults while
only six focused on
children.
Hernandez, et
al. (2014)
Systematic Review/
Meta Analysis
US & UK
Level I
Most studies were
retrospective
observational
cohorts (16/19), 1
prospective
observational
cohort 1 case
control study, and 1
before-after study
Sample size for oral
corticosteroid risk:
105, 855 patients
No direct intervention in
this study. Non-randomized
studies in all languages on
adults, adolescents, or
children with asthma
diagnosis were used to
evaluate risk of adverse
events with LABAS and
ICS in comparison with ICS
alone. Studies included
treatment with LABAs plus
ICS compared with IC
monotherapy regardless of
dose were considered. Other
medications such as
immunomodulators and
leukotriene modifiers were
excluded.
Sample size for
asthma related
hospitalizations:
624,303 patients
Thomas, et
al. (2009)
UK
Retrospective
Observational
Cohort Study
Level IV
Sample size:
ICS step up cohort
had a total of
46,930 patients.
LABA addition
cohort had 17,418
patients.
This study used the General
Practice Research Database
(GPRD) in the United
Kingdom was to
retrospectively find clinical
and prescribing information
to form two cohorts of
patients with asthma. One
cohort would add a LABA
to ICS monotherapy while
the other cohort would
remain on ICS therapy alone
but at a higher dose. The
study’s goal was to see if
step up to higher ICS dose
or step up to addition of
LABA had better success at
preventing hospital
admission or ED visit, no
prescription for oral
corticosteroid use and no
more than an average dose
of daily SABA. (termed
successful outcome) A
partial success was defined
as no hospital attendance, a
Risk for oral corticosteroid use:
4 studies (n=105,855)
Summary OR =1.02 (95% CI:
0.94 to1.10). There was not an
increased risk of systemic
corticosteroid use with the
addition of LABA to ICS but
results are not significant.
Asthma related hospitalizations:
The intervention of LABA plus
ICS decreased asthma related
hospitalizations but was not
significant. Summary OR= 0.88
(95% CI: 0. 69 to 1.12, n=
624,303). One study had a very
different result, which had a
heavy weight on the summary
value because of a large sample
size of 467, 639. It’s OR was
4.52 (95% CI 0.28-72.53). It is
difficult to show significance
since one study had such
different result.
After adjusting for multiple
confounding variables, there
remained a significantly lower
likelihood of 1 or more courses
associated with ICS compared to
LABA OR= 0.7(95% CI: 0.71 to
0.78).
Within 12 months of step-up
therapy 1.3% in the ICS cohort
and 1.7% in the LABA cohort
had been hospitalized after the
step up.
Respiratory admission was
significantly lower in the ICS
cohort compared to the LABA
cohort
aOR= 0.69 (95% CI: 0.59-0.81)
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EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
maximum of 2 oral
corticosteroid prescriptions,
and an average daily dose of
SABA. Unsuccessful
outcome included 1 or more
hospitalizations, more than
2 prescriptions for oral
corticosteroids and more
than average daily SABA
use.
This study also looked at
secondary outcomes
individually, oral
corticosteroid use and
respiratory hospitalization.
Wells, et al.
(2012)
US
Observational
Cohort Study
Level IV
There were a total
of 1,828
participants. ICS
group n=846
ICS/LABA n= 982
Individuals for study were
between ages 12-56 and
were of African American
or white race-ethnicity and
had at least one asthmarelated event between
January 1, 2003 and
December 31, 2010 and at
least 2 refills of an ICS or
ICS/LABA combination
within the same time frame.
Subjects were excluded if
they had any LABA
monotherapy, or diagnosis
of CHF, or COPD. All
enrolled were members of
an affiliated HMO in
southeastern Michigan.
Patients were put into
groups based on ICS or
ICS/LABA. Asthma
severity and ICS exposure
were taken into
consideration.
There was an overall protective
benefit of ICS/LABA
combination compared to ICS
alone.
Unweighted controller estimate
(not adjusted to steroid dose)
ICS group: aHR 0.56 (95% CI
0.42-0.76)
ICS/LABA group: aHR
0.41(0.29-0.60)
Weighted controller estimate
(adjusted for steroid dose)
ICS group: aHR 0.72 (95%CI
0.53-0.98)
ICS/LABA group: aHR
0.65(95% CI 0.47-0.90)
Risk for oral corticosteroid use
and
Asthma related hospitalizations
were included as serious asthma
exacerbations in this study.
Recommendations
Conclusion
After examining the available evidence for review it has been determined that the use of
an inhaled corticosteroid (ICS) in combination with a long-acting beta-agonist (LABA),
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
12
compared to the use of an ICS alone in adults, decreases the need for oral corticosteroids but did
not decrease the need for asthma related hospitalizations. Although not all data was conclusive,
all research determined that there was either no significant difference in the risk for oral
steroids or there was a decreased risk of use. On the contrary, not enough evidence was
available to determine if one group was superior to the other at preventing asthma related
hospitalizations.
Patient Education and Nurse Training
Public programs are needed to educate about asthma including what it is, what may
trigger exacerbations and how seeing a doctor to prescribe preventative medications may
prevent emergency department visits and hospitalizations. Many people may have asthma
and may not recognize their symptoms as such. These programs can also include risk
factors for exacerbations. Nurses should receive training on how to educate their patients
on proper use of medications, side effects, and importance of regular use of medications to
decrease the risk of exacerbations. Nurses must also be able to teach the difference
between prophylactic medications and rescue medications (not discussed in this review)
so appropriate interventions can be made during attacks.
Ideas for Future Research
One idea for future asthma research is seeking ways to promote compliance of
medications for asthma. A second prospect research topic would be determining how many
adults with asthma do not seek regular management from medical providers and then
determine how barriers can be eliminated so long term care of asthma can be achieved to
prevent complications. According to The American Journal of Managed Care (2015) the
EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
numbers of asthmatics world wide is going to continue to rise and both of these proposed
research topics can help decrease these growing numbers.
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EFFECTIVENESS OF LONG-ACTING BETA-AGONISTS
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