|Pulmonary disease; Chronic obstructive; Adrenergic
beta-agonists; Randomized controlled trials; Bronchodilators
|COPD: Chronic Obstructive Pulmonary Disease;
LABA: Long Acting Beta Agonist; SABA: Short Acting Beta Agonist;
FEV1: Forced Expiratory Volume (in 1 second); BDI: Baseline Dyspnea
Index; TDI: Transitional Dyspnea Index; SGRQ: St. George’s Respiratory
Questionnaire; CRDQ: Chronic Respiratory Disease Questionnaire
|Chronic Obstructive Pulmonary Disease (COPD) is a progressive
disease affecting more than 24 million people in the United States [1,2].
It is the fourth-leading cause of death in the United States, with more
than 121,000 deaths due to COPD reported in 2009 . In 2002, the
direct costs to treat COPD in the United States were estimated at $18
billion and this value has been projected to climb to $29.5 billion in
2010 . Some of the burden of COPD is related to certain comorbid
conditions such as cardiovascular disease, respiratory infections, and
osteoporosis. In addition, COPD reduces quality of life by limiting the
functional and exercise capacity of affected individuals.
|Because no medications have been shown to alter the progression of
COPD, the aims of current pharmacotherapy are to decrease symptoms,
reduce the incidence and severity of exacerbations, and improve quality
of life and exercise tolerance . Inhaled bronchodilator medications
constitute the cornerstone of symptom management in COPD. Inhaled
β2-agonists work by activating the β2-adrenoceptor which relaxes the
smooth muscle cells of airways. These agents are further classified
based on duration of action into short-acting β2-agonists (SABAs) (e.g.,
levalbuterol, albuterol) and Long-Acting β2-Agonists (LABAs) (e.g.,
formoterol, arformoterol, indacaterol, and salmeterol). The duration of
action for most SABAs is 4 to 6 hours (for levalbuterol, up to 8 hours for
some patients), whereas the duration for LABAs is 12 or more hours.
|For maintenance therapy in patients with moderate to severe
COPD, the Global Initiative for Chronic Obstructive Lung Disease
(GOLD) guidelines recommend the use of long-acting bronchodilators
(including LABAs) because they are effective and convenient .
However, research has shown that many patients do not receive
maintenance therapies and primary care physicians are often unfamiliar
with the guidelines [7,8]. Some physicians or payers may consider
LABAs and SABAs to be functionally equivalent and interchangeable
as maintenance therapies.
|Randomized Controlled Trials (RCTs) of COPD treatments
differ in study design depending on the outcome variables. For RCTS
examining maintenance outcomes in COPD, the primary outcome
variables are related to the prevention of exacerbations or altering
disease progression. However, most COPD RCTsexamine improvement
in airflow obstruction and symptom relief (chronic cough, excess
sputum, and dyspnea). The Food and Drug Administration (FDA) in
the United States has offered guidance on primary outcome measures
and study durations depending on the indication sought for a COPD treatment. For studies measuring improvement in airflow, the
recommended primary outcome variable is post-dose FEV1 (forced
expiratory volume in 1 second) and the recommended study duration
is 3 to 6 months. For studies assessing the prevention of exacerbations,
whether based on severity, duration, frequency of exacerbations or time
to first exacerbation, the recommended study duration is 1 year. Finally,
for studies examining disease progression alteration the recommend
outcome variable is the reduced trajectory of serial FEV1 measured over
a 3-year period .
|Although both SABAs and LABAs appear to be used for long-term
treatment of COPD in usual clinical care , there have been no
comprehensive reviews or meta-analyses comparing the use of LABAs
versus SABAs for maintenance therapy. The objective of this study was
to summarize the evidence for LABAs and SABAs in maintenance
management of patients with COPD based on available published
RCTs. This review examined RCTs of LABAs and SABAs in patients
with stable COPD to compare their effects on lung function (FEV1),
incidence of exacerbations, and use of rescue medications, β-mediated
adverse events, and symptoms such as dyspnea and exercise-tolerance
|The focus of this review was published, RCTs involving adult
patients with stable COPD without asthma who received a LABA or
a SABA either alone or combined with other therapies. The outcomes
of interest were lung function as measured by FEV1, incidence of
exacerbations, use of rescue medications, dyspnea, exercise tolerance,
quality of life, and β-mediated adverse events (especially cardiovascular
|A systematic literature search was conducted using PubMed/
Medline, Embase, and the Cochrane Library to identify relevant studies
published and indexed between January 1, 1990 and July 16, 2010.
Multiple search terms were used and the reference sections in other
literature reviews or meta-analyses were examined to identify additional
studies. Maintenance therapy was broadly defined as 2 or more weeks
of regular dosing of a LABA or SABA; studies with durations of less
than 2 weeks were excluded. Based on a preliminary review of the
literature, few direct comparative studies of SABAs versus LABAs were
expected and the most common comparators for indirect meta-analysis
were placebo and ipratropium. Studies that did not directly compare
a LABA versus a SABA or compare a LABA or SABA with placebo or
ipratropium were excluded.
|Data abstraction was performed by a single investigator using a prespecified
extraction form. The following information was abstracted
from each study: (1) author identification, (2) year of publication, (3)
study design (parallel or crossover) and quality, (4) sample size, (5) key
inclusion criteria and exclusion criteria, (6) drug and dosing for each
treatment arm, and (7) baseline characteristics (mean age, gender, and
predose FEV1/forced vital capacity [FVC]). The quality assessment
examined the blinding of patients, care providers, and outcome
assessors; similarity of treatment groups at baseline; imbalances
between treatment groups in dropout rates; completion rates; whether
the analysis was on the intention-to-treat patient set; how missing data
were addressed; and selective reporting of outcomes .
|For each outcome of interest, abstracted data included the outcome
definition, the analysis time point, sample size, and reported summary
measures (e.g., mean, standard deviation). For the outcomes with
highly variable definitions, such as FEV1, Area Under the Curve (AUC),
and rescue medication use, we extracted values for a broad range of definitions. Other outcomes extracted included: exercise tolerance and
related dyspnea scores on the Borg scale ; dyspnea as measured by
Baseline Dyspnea Index (BDI) and Transitional Dyspnea Index (TDI)
; incidence of exacerbations; quality of life assessments measured by
the St. George’s Respiratory Questionnaire (SGRQ)  or the Chronic
Respiratory Disease Questionnaire (CRDQ) ; and incidence of
beta-mediated adverse events, cardiac adverse events, and metabolic
|The initial search yielded 938 studies. Following abstract review, 873
studies were excluded based on criteria specified in the study protocol
(Figure 1). Full-text review of the remaining 65 studies resulted in 3
additional exclusions, leaving 62 studies for data extraction. Among
these 62 studies, only one study directly evaluated a SABA versus a
LABA , 49 studies evaluated a LABA versus placebo or ipratropium
[17-65], and12 evaluated a SABA versus placebo or ipratropium [66-77]. There was insufficient data to complete a direct meta-analysis of
SABA versus LABA. Due to the variations in outcomes and definitions
and the small number of SABA studies, there was also insufficient data
to allow meaningful indirect comparisons of LABAs and SABAs on the
extracted endpoints. Below is a description of the limitations for FEV1
and exacerbations, which were the most common outcome variables. A
brief summary follows for other outcome variables.
|Thirty-one studies reported numerical FEV1 outcomes [20,22-24,26,27,29,30,33-36,38-40,42,44-46,48,49,51, 56,58,59,61,63,66,67,72-77], but only 17 studies reported change in peak FEV1 (occurring
within 1-4 hours after dosing) from baseline [16,27,34-36,40,44,45,48,58,63,66,67,70,74,77]. None of these 17 studies included
an analysis of a LABA versus ipratropium, eliminating the possibility
of an indirect comparison through ipratropium. Among the placebocontrolled
studies, 10 LABA [34-36,45,48,58,63] studies and 5 SABA
studies [66,67,74,75,77] reported change in peak FEV1, but only 2 of
the SABA studies (both 2-weeks in duration) reported the variance
for the outcome variable. Similarly, for serial measurements of FEV1
after bronchodilator administration, there was only a single placebo
controlled SABA study .
|Definitions for the incidence of exacerbations varied across
the 35 studies reporting this outcome [16,19-21,23-30,32-34,37,41,43,47,49,50,52,56,58-60,62,64,66-70,74,76]. However, 33
studies included definitions of exacerbations that were moderate
to severe based on the requirement for a change in the baseline
medication regimen to improve respiration [16,19-21,23-30,32-34,37,41,43,47,49,50,52,58-60,62,64,66-70,74]. Among the 27 studies
reporting the percentage of patients experiencing exacerbations: 21
studies evaluated LABA therapy versus placebo [19-21,23,27,29,30,32-34,37,41,43,47,49,50,52,58,60,62,64], but only 3 studies evaluated SABA
therapy versus placebo [66,67,74]. The 3 SABA studies were all 12 weeks
in length and changes in exacerbation frequency for studies shorter
than 24 weeks in duration are not considered clinically meaningful.
|Other outcome variables
|Among the other outcome variables there were insufficient SABA
studies for indirect comparisons. The number of SABA studies for each
variable was dyspnea (1), use of rescue medications (1), tremor (2), sixminute
walking test (2), CDRQ (4, but only 1 with sufficient numerical
information), and SGRQ (1).
|The goal of this review was to complete a meta-analysis of
published randomized clinical trials comparing LABAs and SABAs for
maintenance treatment in COPD. Unfortunately, only a single study was
found preventing the completion of a direct meta-analytic comparison.
The single study was a 3-week randomized, double blind crossover trial
comparing the addition of formoterol or salbutamol to ipratropium
. The primary outcome variable, peak expiratory flow, as well as
post-dose FEV1 and the SGRQ symptom score improved significantly
more during the formoterol/ipratropium treatment period than the
salbutamol treatment period. There were no significant differences
on SGRQ total, activity, or impacts sores, exacerbation rates, rescue
medication use, or adverse events. The single RCT directly comparing
SABA versus LABA found better outcomes for adding LABA to
ipratropium than SABA to ipratropium
|The direct meta-analytic comparison was not possible due to
the lack of studies, so the possibility of an indirect comparison was
examined. Indirect comparisons meta-analyses have a greater potential
to produce biased results due to uncontrolled differences between
patients or procedures in the different studies . However, there
was an insufficient number of SABA studies of two or more weeks
in duration, with a placebo or ipratropium comparator, and with a
relevant outcome variable reported with sufficient detail to allow
for even an indirect meta-analysis. Further efforts to increase the
number of SABA papers (such as including non-English publications,
contacting authors to get variances or numeric estimates, adding the
most recent publications) may have allowed an indirect meta-analysis
on one or more outcome variables to be completed, but it is unlikely to
yield particularly relevant information. In addition to the limitations of
indirect comparisons, the SABA treatments were not used in any trials
longer than 12 weeks rendering any findings for maintenance outcomes
suspect. Because the goal of this research was to compare LABAs versus
SABAs for use as maintenance therapy for COPD; we included only
studies with duration of 2 weeks or longer. This restriction eliminated
many of the studies of SABAs identified in the initial literature search,
which were only 2- or 3-day studies.
|The GOLD treatment guidelines for COPD recommend the use of long-acting bronchodilators (including LABAs) because they are
effective and convenient . Due to their longer duration of action,
LABAs can control COPD symptoms throughout the night, whereas
SABAs would lose effectiveness. In this review, we did not find any data
supporting the use of SABAs for maintenance therapy. The single RCT
that compared adding a LABA (formoterol) or a SABA (albuterol) to
ipratropium, found better airflow outcomes for the LABA treatment
|LABAs have been studied extensively as maintenance therapies in
patients with COPD and have long-term safety and efficacy evidence.
Although many patients with COPD are only treated with SABAs
in usual clinical care, there is an absence of empirical support for
the use of SABAs as maintenance therapy. This review supports the
current evidence-based guidelines for COPD, which recommend the
preferential use of LABAs for maintenance treatment of COPD and
reserves the use of SABAs for rescue treatment.
|Funding for this study was provided by Sunovion Pharmaceuticals Inc.
Technical writing support was provided by Michael Stensland of Agile Outcomes
Research Inc, Rochester, Minnesota, USA.
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