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T
he burden of chronic obstructive pulmonary disease
(COPD) as a healthcare problem has increased over
the last 4 decades. Currently, it is the sixth leading cause of
death and the twelfth leading cause of morbidity world-
wide. By the year 2020, COPD is expected to be the third
leading cause of death and the fifth leading cause of mor-
bidity.
1
In the US, mortality related to the disease has in-
creased over 160% from 1965 to 1998.
2
Currently, COPD
affects >17 million people in the US and is responsible for
2.2 million disability-adjusted life years and one-half mil-
lion potential years of life lost.
3
Estimates of total direct
and indirect US costs are $30 billion/year (direct costs
>$18 billion/y).
3,4
The challenge in improving the prognosis of COPD pa-
tients is the development of medications that reverse the
progression of the disease, improve its symptoms, enhance
exercise tolerance, promote quality of life (QOL), and de-
crease the number of exacerbations. Since 1994, a number
of COPD treatment guidelines have been published.
5-7
In
addition, the National Heart, Lung and Blood Institute and
World Health Organization collaboratively developed the
Global Initiative for Chronic Obstructive Lung Disease
(GOLD) report.
8,9
The goal was to increase awareness of
and decrease morbidity and mortality from COPD.
The GOLD report
9
recommends bronchodilator agents
(i.e., anticholinergic agents, short-acting β
2
-agonists, long-
acting β
2
-agonists) as first-line therapies. This report gives
general information for the use of long-acting β
2
-agonists
(formoterol, salmeterol), but lacks specific recommenda-
tions. Agent choice is based on disease severity, comor-
The Annals of Pharmacotherapy
■
2003 September, Volume 37
■
1247
Long-Acting Inhaled β
2
-Agonists for Stable COPD
John A Dougherty, Bethany L Didur, and Loutfi S Aboussouan
ARTICLES
www.theannals.com
Pulmonary & Allergy
Author information provided at the end of the text.
Supported in part by a seed money grant from the Division of In-
ternal Medicine at Wayne State University.
OBJECTIVE
:
To describe the pathogenesis of chronic obstructive pulmonary disease (COPD) and mechanisms of benefit,
formulations available, drug costs, pharmacokinetic profiles, and pertinent clinical studies for long-acting β
2
-agonists.
DATA SOURCES: A MEDLINE search was conducted from July 1966 through October 2002.
STUDY SELECTION AND DATA EXTRACTION
:
Pertinent articles related to COPD and long-acting β
2
-agonists.
DATA SYNTHESIS: The incidence and subsequent morbidity and mortality of COPD have increased during the last 4 decades,
prompting worldwide initiatives to formulate guidelines to decrease the burden of this disease. COPD is a progressive, irreversible
disease state characterized by chronic cough, dyspnea, sputum production, and wheezing, in which no medication has been shown
to decrease mortality, excluding oxygen supplementation. Bronchodilators have been a mainstay of COPD treatment through their
ability to work by both smooth- and non–smooth-muscle mechanisms. Long-acting β
2
-agonists (i.e., formoterol, salmeterol) dosed
twice daily provide more convenient dosing than 4-times-daily regimens of traditional short-acting bronchodilators. Both formoterol
and salmeterol have acceptable adverse event profiles when used at recommended doses. There have been no direct clinical
outcome studies comparing formoterol and salmeterol, but both have shown some benefits over ipratropium and theophylline in
improving the symptoms, spirometric indices, exacerbations, and quality of life of patients with COPD.
CONCLUSIONS: Based on current evidence, long-acting β
2
-agonists are acceptable first-line agents for patients with COPD.
KEY WORDS
:
chronic obstructive pulmonary disease, formoterol, salmeterol.
Ann Pharmacother 2003;37:1247-55.
Published Online, 1 Aug 2003, www.theannals.com, DOI 10.1345/aph.1C436
bidities, agent availability, and patient response. Current data
should be considered to make prudent clinical decisions.
This article clarifies the role of long-acting β
2
-agonists
and provides recommendations by evaluating mechanisms
of benefit, formulations, dosages, drug costs, pharmacoki-
netic profiles, and clinical outcome studies.
Bronchodilator Pharmacology
Bronchodilators (e.g., anticholinergic agents, β
2
-ago-
nists, methylxanthines) are effective agents to improve air-
flow for symptomatic management of COPD.
10,11
Anti-
cholinergic agents reduce smooth muscle contraction by
antagonizing endogenous cholinergic tone. β
2
-Agonists di-
rectly relax airway smooth muscle by stimulating the β
2
-
adrenoceptor through increases in intracellular cyclic-3′,
5′adenosine monophosphate (cAMP). Methylxanthines
(e.g., theophylline) are hypothesized to cause bronchodila-
tion by several mechanisms.
12
Mechanisms of Airflow Limitation in COPD
Risk factors for COPD include host factors (i.e., defi-
ciency of α
1
-antitrypsin, airway hyperresponsiveness) and
exposures (e.g., tobacco smoke, occupational hazards, air
pollution, viral respiratory infections).
9
Smoking is consid-
ered the chief risk factor for COPD, but less than 25% of
smokers develop it.
13
In smokers, smoking cessation is the
only proven method to delay progression.
14
Further study
is needed regarding other risk factors and inflammation in
COPD.
COPD is characterized by a fixed expiratory airflow ob-
struction causing chronic cough, dyspnea, sputum produc-
tion, and wheezing.
13
At least 3 pathophysiologic mecha-
nisms are involved in the development of airflow limitation.
15
First, structural alterations such as goblet cell metaplasia,
inflammation, smooth muscle hypertrophy and prolifera-
tion, and fibrosis facilitate narrowing of the airway lumen.
Second, alveolar wall destruction decreases lung elastic re-
coil and disrupts the tethering effects of alveolar attach-
ments on the small airway, thereby promoting its collapse.
Third, chronic bronchitis, peribronchiolar inflammation,
and small airway fibrosis contribute to airflow limitation.
COPD involves inflammation in the bronchioles and
lung parenchyma. A concerted effort is focused on the
molecular and cellular changes in the disease and how
medications interact at this level. One hypothesis of COPD
pathogenesis proposes an imbalance between inflammato-
ry mediators and protective mechanisms in the lung. In-
flammatory cells involved include macrophages, T lym-
phocytes, and neutrophils.
11,16
Proteases released from
these cells, including neutrophil elastase, proteinase 3, and
matrix metalloproteinases, break down lung tissue. Neu-
trophil elastase causes mucus gland hyperplasia, mucus se-
cretion, and decreased ciliary beat frequency.
16
In people
without COPD, protease activity is counteracted by an-
tiproteases (i.e., α
1
-antitrypsin, secretory leukoprotease in-
hibitor, elafin, tissue inhibitors of matrix metalloproteinas-
es). In COPD patients, an increased protease burden and/or
diminished antiprotease activity tips the balance toward
lung destruction.
17-19
Mechanisms of Benefit of Long-Acting β
2
-Agonists
SMOOTH MUSCLE EFFECTS
Short-acting and long-acting β
2
-agonists relax airway
smooth muscle by stimulating β
2
-adrenoceptors. This acti-
vates adenylate cyclase, which catalyzes the conversion of
adenosine triphosphate to cAMP. Increased intracellular
cAMP concentration inhibits calcium ion release from in-
tracellular stores and activates protein kinase A. Protein ki-
nase A phosphorylates proteins involved in maintaining
smooth muscle tone and subsequently causes bronchodila-
tion.
12,15,20
β
2
-Agonists may also inhibit airway smooth mus-
cle proliferation as demonstrated in vitro with albuterol.
15
ANTIINFLAMMATORY EFFECTS
Increased numbers of neutrophils are found in the spu-
tum of COPD patients.
15,21,22
Long-acting β
2
-agonists affect
neutrophil numbers, activity, and function by acting on β
2
-
adrenoceptors on neutrophils.
15,23
Long-acting β
2
-agonists
inhibit neutrophil adhesion, accumulation, release, and ac-
tivation and induce apoptosis, which collectively reduces
the number and activation status of neutrophils in the air-
way.
15,21,24
ANTIBACTERIAL EFFECTS
Long-acting β
2
-agonists may protect against the effects
of microorganisms on respiratory epithelium through main-
tenance of intracellular cAMP concentrations. Maintaining
cAMP concentrations may decrease bacterial colonization
and render patients less prone to acute bacterial exacerba-
tions.
25
Long-acting β
2
-agonists also increase ciliary beat
frequency to aid in effective mucociliary transport.
15
Formulations and Dosage
Formoterol is supplied as an Aerolizer inhaler consist-
ing of a capsule of dry powder containing the salt for-
moterol fumarate. Each capsule contains formoterol 12 µg
to be administered every 12 hours. The total daily dose
should not exceed 24 µg.
26
A 1-month supply at 24 µg/d is
estimated to have an average wholesale price (AWP) of
$70.08.
27
Clinical trial results involving identical MDIs are report-
ed differently in European and US studies.
30
The US re-
quires manufacturers to report the dose delivered at the
mouthpiece, while in Europe slightly higher doses are re-
ported because they refer to the dose delivered at the valve.
For example, ipratropium 40 µg in Europe (at valve) is
equivalent to ipratropium 36 µg in the US (at mouthpiece).
In subsequent discussions, all doses will be reported as in
the original articles.
1248
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JA Dougherty et al.
The salmeterol inhalation aerosol has been discontinued
due to risks to the ozone layer from chlorofluorocarbon
propellants. The current salmeterol formulation is the
Diskus. It is a specially designed plastic inhalation system
containing a double-foil blister strip of powdered salme-
terol xinafoate. Each blister contains salmeterol 50 µg,
which, on activation, is dispersed into the patient’s
airstream. The recommended dosage is 50 µg every 12
hours.
31
A 1-month supply at 100 µg/d is estimated to cost
(AWP) $80.02.
29
Pharmacokinetic Profiles
ONSET AND DURATION OF ACTION
Comparison with Short-Acting β
2
-Agonists
β
2
-Agonists used in COPD treatment can be separated
into 2 categories (i.e., short- and long-acting) based on du-
ration of action. Short-acting β
2
-agonists such as albuterol
have a quick onset of action, producing bronchodilation
within minutes of inhalation. The duration of effect of
short-acting β
2
-agonists ranges from 4 to 6 hours; thus, they
require multiple daily doses.
9
Long-acting β
2
-agonists have
durations of at least 12 hours, making them convenient and
desirable for compliance.
9
Formoterol has a quicker onset
of action than salmeterol.
12
The following studies illustrate
the pharmacokinetic profiles of formoterol and salmeterol
and their effect on spirometric indices.
SPIROMETRIC INDICES
Spirometric indices are evaluated in long-acting β
2
-ago-
nist studies. These indices are included to ade-
quately detect and measure the severity of air-
way obstruction in COPD. An obstructive pat-
tern on spirometry usually consists of a
reduction in the forced expiratory volume in
the first second (FEV
1
), particularly in relation
to the forced vital capacity (FVC). The
FEV
1
/FVC ratio is therefore typically reduced.
Other spirometry measures include peak expira-
tory flow and mid-flow rates (FEF
25-75%
, a mea-
sure of small airway obstruction).
Comparison of Salmeterol and Formoterol
The intrinsic properties of long-acting β
2
-
agonists affect their interaction with lung tis-
sue and β
2
-receptors. Anderson’s microkinetic
diffusion theory
32
suggests that hydrophilicity
and lipophilicity of the long-acting β
2
-agonist
are important factors to explain the onset and
duration of effect, respectively. Several small,
single-dose, pharmacokinetic studies have com-
pared salmeterol and formoterol in patients with
COPD.
33-36
Studies’ objectives were to com-
pare the onset of action, peak bronchodilator
effect, and bronchodilator effect over 12 hours.
Specific results are available in Table 1.
A single-blind, randomized, crossover study was con-
ducted in 16 patients with moderate-to-severe COPD
(mean FEV
1
15–69% predicted).
33
The study compared
MDI doses of salmeterol 50 µg, formoterol 24 µg, and al-
buterol 200 µg. The time of onset required to improve FEV
1
by 15% was similar for salmeterol 50 µg and formoterol
24 µg. However, the time of onset for both of these agents
was delayed compared with albuterol 200 µg. The mean
peak bronchodilation response was 1 hour, 4 hours, and 5
hours for albuterol, formoterol, and salmeterol, respectively.
Cazzola et al.
34
conducted a single-blind, crossover, ran-
domized, dose–response study in 12 patients with severe
COPD (FEV
1
12–32% predicted). Salmeterol 25, 50, and
75 µg and formoterol 12, 24, and 36 µg were administered
by MDI. The onset of action was similar between salme-
terol 50 µg and formoterol 12 or 24 µg. Peak bronchodila-
tion was reached 1 hour after any formoterol dose and 2
hours after any salmeterol dose. Salmeterol 50 µg had a
statistically higher improvement in mean FEV
1
(p < 0.05)
and mean FEV
1
AUC (p < 0.05) compared with for-
moterol 12 or 24 µg. The inconsistency in mean peak
bronchodilation results in these 2 studies can be explained
by different patient populations, number of doses, and
small sample sizes.
33,34
A double-blind, randomized, crossover, placebo-con-
trolled study evaluated 22 patients with mild-to-severe
COPD (mean FEV
1
35.5 ± 9.8% predicted) with salmeterol
50 µg and formoterol 12 µg administered by MDI.
35
For-
moterol 12 µg had a quicker onset for bronchodilator action
compared with salmeterol 50 µg. Peak bronchodilator effects
were seen at 1 hour for formoterol and 2 hours for salme-
terol. The drugs showed similar FEV
1
effects over 12 hours.
Long-Acting Inhaled
β
2
-Agonists for Stable COPD
The Annals of Pharmacotherapy
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2003 September, Volume 37
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www.theannals.com
Table 1. Pharmacokinetic Studies Comparing Long-Acting
β
2
-Agonists on Spirometry
Time Course
Onset of Time (h) to of Broncho-
Treatment Effect Peak Effect dilating
Reference (µg) (mean) (mean) Effect
c
Cazzola et al. albuterol 200 3 min 56 sec
a
1
(1994)
33
salmeterol 50 10 min 8 sec
a
5
formoterol 24 10 min 52 sec
a
4
Cazzola et al. salmeterol 25 75%
b
2 1.8
(1995)
34
salmeterol 50 100%
b
2 2.9
salmeterol 75 92%
b
2 2.5
formoterol 12 92%
b
1 2.4
formoterol 24 83%
b
1 2.3
formoterol 36 92%
b
1 3.2
Celik et al. salmeterol 50 18%
d
2 3.2
(1999)
35
formoterol 12 9%
d
1 3.5
Kottakis et al. salmeterol 50 15 min 2
(2002)
36
salmeterol 100 10 min 2.5
formoterol 12 5 min 1
formoterol 24 5 min 1
FEV
1
= forced expiratory volume in 1 second.
a
Mean time of onset of bronchodilating effect — increase in FEV
1
of at least 15%.
b
Percentage of patients with a >15% in FEV
1
15 minutes after inhalation.
c
AUC in liters (1 h) over the 12-h postinhalation period.
d
Mean percentage change in FEV
1
after 10 minutes.
Recently, Kottakis et al.
36
published results of a double-
blind, randomized, crossover, placebo-controlled trial in 47
patients with moderate-to-severe COPD (FEV
1
<50% pre-
dicted). The study compared salmeterol 50 and 100 µg
with formoterol 12 and 24 µg delivered as dry powder for-
mulations. Drug effect on spirometric indices was mea-
sured over 4 hours after administration. Formoterol had a
shorter onset of bronchodilation compared with salmeterol.
There was a dose-dependent increase in FVC and FEV
1
with formoterol (12 and 24 µg), but not with salmeterol
(50 and 100 µg). Although the mean peak bronchodilation
was similar with salmeterol and formoterol doses, for-
moterol 24 µg reached the highest mean peak response and
was statistically significantly better than salmeterol 50 µg
(p = 0.0004). These pharmacokinetic studies provide an in-
dication of the action of these drugs, but caution should be
used for their applicability based on the small sample size
and single-dose design.
FORMOTEROL VS. SALMETEROL AS RESCUE
MEDICATIONS
Studies in COPD patients have shown that formoterol
can potentially eliminate the need for short-acting β
2
-ago-
nists for acute symptom relief.
37-39
Benhamou et al.
37
stud-
ied 24 COPD patients (FEV
1
between 30% and 60% of
predicted) in a double-blind, randomized, crossover, place-
bo-controlled trial. Active treatment groups (both dry pow-
der) were formoterol 24 µg and albuterol 400 µg. Mean
FEV
1
increase was similar from 5 minutes to 3 hours after
administration of formoterol or albuterol, with maximal in-
crease of about 200 mL over placebo occurring at 30 minutes
and 80% of maximal effect seen at 5 minutes for both drugs.
Sixteen patients with COPD were assessed in a double-
blind, randomized, crossover, placebo-controlled study.
38
The onset of bronchodilation with formoterol 12 and 24
µg, albuterol 400 µg, and albuterol 800 µg was compared
with the onset with placebo. No significant differences in
onset of action were seen among any of the active groups.
Acute exacerbations of COPD in 20 patients was as-
sessed in a double-blind, randomized, cross-over, placebo-
controlled trial.
39
The study evaluated formoterol 12, 24,
and 36 µg (MDI) in relieving bronchospasm and found a
dose-dependent increase in FEV
1
.
These trials show that formoterol has a similar onset of
bronchodilation as albuterol, but the clinical significance
of these findings is unknown. Further trials with a larger
number of patients are needed to clarify the role of for-
moterol versus albuterol for acute exacerbations and as a
rescue medication in COPD. Conversely, salmeterol should
not be used as a rescue bronchodilator for patients experi-
encing acute symptoms due to its slow onset of action.
40
Cazzola et al.,
41
in a double-blind, randomized, crossover,
placebo-controlled study, examined the effect of giving an
extra dose of salmeterol 50 µg (dry powder) to patients un-
dergoing salmeterol maintenance treatment. The extra dose
was well tolerated and caused no further increase in mean
peak FEV
1
but increased the duration of action of the drug.
Clinical Outcome Studies
The following studies evaluated the clinical efficacy of
salmeterol and formoterol against other bronchodilators in
patients with stable COPD (Table 2).
31,42-54
Disease stability
was defined as the absence of pulmonary infections and
stable respiratory status for at least 4 weeks prior to enroll-
ment. Parameters evaluated included spirometric indices,
dyspnea scales, effect on QOL, the use of rescue medica-
tions, walking distance, and number of exacerbations.
LONG-ACTING β
2
-AGONISTS IN PATIENTS WITH STABLE
COPD
Salmeterol vs. Ipratropium
In 2 randomized, double-blind, parallel-group, 12-week
studies of patients with stable COPD, salmeterol 42 µg
twice daily was compared with ipratropium 36 µg 4 times
daily and placebo.
42,43
Compared with ipratropium, salme-
terol had similar, although delayed, maximal bronchodila-
tion, a more sustained bronchodilator effect, and a longer
duration of action. Mahler et al.
42
showed that the mean
change in FEV
1
AUC was significantly better for salme-
terol than ipratropium at weeks 4 and 8, while the mean
change in FEV
1
was significantly better for salmeterol than
ipratropium 4 and 6 hours postdose at weeks 0 and 12. In
one study,
43
there was no difference between salmeterol
and ipratropium in spirometric measures. The magnitude
of increase in mean peak FEV
1
with both drugs was about
200 mL (~15%) less than placebo. Although not signifi-
cantly different, salmeterol showed a greater reduction in
rescue albuterol use (by 0.5–0.6 puffs/d)
42,43
and improved
QOL compared with ipratropium. The improved QOL was
seen with the Chronic Respiratory Disease Questionnaire,
particularly in the subset of patients with bronchodilator
responsiveness. There were conflicting results between
studies when assessing the number of patients who experi-
enced exacerbations over 12 weeks. Mahler et al.
42
showed
that the percentage of patients who experienced ≥1 exacer-
bation was 20.7% and 30.8% in the salmeterol and iprat-
ropium groups, respectively. Alternatively, exacerbation
percentages in Rennard et al.’s
43
study were 28.8% and
26.8%, respectively. The number of adverse events was
similar in all groups.
These 2 trials are particularly limited in their failure to
show significant improvements in endpoint measures that
are of crucial importance for patients with COPD. For in-
stance, they failed to document sustained significant im-
provements in the 6-minute walking distance with salme-
terol compared with ipratropium.
42,43
Similarly, dyspnea
scales as assessed by the Borg Scores and Transitional
Dyspnea Index (TDI) were not consistently improved with
salmeterol over ipratropium. Limitations when applying
these results to clinical practice include the ipratropium
dose (lower than often seen in clinical practice) and length
of the study.
In smaller studies that more specifically evaluated the
effects of salmeterol or ipratropium on exertional dysp-
1250
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JA Dougherty et al.
nea,
44,45
salmeterol and ipratropium equally reduced the
sensation of dyspnea with exercise,
44,45
and improved the
recovery from postexercise oxygen desaturation.
44
Al-
though these studies used larger doses of ipratropium (120
and 72 µg, respectively), limitations included their small
size (<20 patients for each), single-dose design, and lack
of long-term follow-up.
44,45
Salmeterol vs. Tiotropium
Tiotropium is a once-daily anticholinergic M3 receptor
antagonist recently introduced in Europe. It is currently un-
der Food and Drug Administration review. In a large ran-
domized, double-blind, placebo-controlled clinical trial,
tiotropium 18 µg (dry powder) once daily was compared
Long-Acting Inhaled
β
2
-Agonists for Stable COPD
The Annals of Pharmacotherapy
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Table 2. Clinical Trials Assessing Outcomes of Treatment with Long-Acting β
2
-Agonists
Sample Treatment
Reference Size (n) Design/Length (µg) Clinical Outcome
Mahler et al. 411 R, DB, DD, PC, PG/12 wk S 42, IB 36, P S superior to IB and P in improving lung function (i.e., FEV
1
(1999)
42
AUC) and time to first exacerbation; S and IB reduced
dyspnea-related activities of daily living and supplemental A
use >P; S and IB improved QOL (i.e., CRDQ)
Rennard et al. 405 R, DB, DD, PC, PG/12 wk S 42, IB 36, P S superior to IB and P in improving lung function (i.e., FEV
1
(2001)
43
AUC) and time to first exacerbation; S more constant effect
and longer duration of action than IB; S and IB reduced sup-
plemental A use >P; S and IB improved QOL (i.e., CRDQ)
Donohue et al. 623 R, DB, DD, PC, PG/6 mo T 18, S 50, P T and S superior to P in improving lung function (i.e., FEV
1
),
(2002)
46
with T also superior to S; T statistically significantly better than
P but not S for dyspnea; T superior to P and S for QOL (i.e.,
SGRQ)
Patakas et al. 15 R, PC, C/3 d IB 120, S 50, P bronchodilating effect of S similar to IB (i.e., FEV
1
) at rest; S
(1998)
44
and IB superior to P in recovery of postexercise oxygen
desaturation and sensation of dyspnea with exercise
Ayers et al. 16 R, DB, PC, C/7 d S 42, IB 72, P S and IB showed similar bronchodilation at rest; S > IB for
(2001)
45
dyspnea ratings during exercise at 6 h
Dahl et al. 780 R, DB, DD, PG, PC/12 wk F 12 or 24, IB 40, P F and IB superior to P; F superior to IB in improving lung
(2001)
30
function (i.e., FEV
1
AUC); F superior to IB and P in improving
QOL (i.e., SGRQ), diary scores, and use of rescue A, with
no difference in IB and P
Sichletidis et al. 27 R, SB, DD, PC, C/6 d IB 40 or 80, F 12 or F + IB > IB, F 24 > IB 40, all treatments > P in improving
(1999)
52
24, F 12 + IB 40, P lung function (FEV
1
)
Di Lorenzo et al. 178 R, OL, PG/12 mo S 50, T S > T in improving bronchodilation (i.e., FEV
1
, FVC, PEFR) and
(1998)
47
QOL measures (i.e., SF-36); statistically less use of rescue
A, greater % of symptom-free days/nights, and improved
auscultatory findings for S > T
Rossi et al. 854 R, DB, PC, PG, OA/12 mo F 12 or 24, P, TF and T > P; F > T in improving bronchodilation (i.e., FEV
1
(2002)
48
AUC); F > P in improving QOL (i.e., SGRQ); F > T in use of
rescue A, decrease in exacerbations, and total diary symp-
tom score
Van Noord et al. 144 R, DB, DD, PC, PG/12 wk S 50, S 50 + IB 40, P S + IB > S alone in improving lung function (FEV
1
); no differ-
(2000)
49
ence between S and S + IB in symptoms or need for rescue
A
Matera et al. 12 R, SB, DD, PC, C/4 d S 50, IB 40, S 50 + S and S + IB > IB and P in producing bronchodilation > 12 h; all
(1996)
50
IB 40, P treatments better than P
D’Urzo et al. 172 R, DB, DD, C/6 wk F 12 + IB 40, A 200 F + IB > A + IB in improving lung function (i.e., FEV
1
AUC),
(2001)
51
+ IB 40 morning peak flow, and improved total symptom scores
ZuWallack et al. 943 R, DB, DD, PG/12 wk S 42 + T, S 42, T S + T > T alone in improving lung function, decreasing
(2001)
53
symptoms, dyspnea, and A use, and COPD exacerbations;
S > T in improving lung function and patient satisfaction, S
less AEs
Cazzola et al. 80 R, PG/12 wk S 50, S 50 + Fl 250, all arms showed statistically significant results for increases in
(2000)
54
S 50 + Fl 500, S 50 FEV
1
over 3 mo when compared with baseline, but arms not
+ T statistically significantly different at 3 mo; a 400-µg dose-de-
pendent increase in FEV
1
when added to arms
A = albuterol; AE = adverse effects; C = crossover; COPD = chronic obstructive pulmonary disease; CRDQ = Chronic Respiratory Disease Questionnaire;
DB = double-blind; DD = double-dummy; F = formoterol; FEV
1
= forced expiratory volume in 1 second; Fl = fluticasone; FVC = forced vital capacity;
IB = ipratropium; OA = open-arm; OL = open-label; P = placebo; PC = placebo-controlled; PEFR = peak expiratory flow rate; PG = parallel group;
QOL = quality of life; R = randomized; S = salmeterol; SB = single-blind; SF-36 = 36-Item Short Form Health Survey; SGRQ = St. George’s Respiratory
Questionnaire; T = theophylline.
with salmeterol 50 µg twice daily.
46
Tiotropium had signifi-
cantly greater increases in mean FEV
1
and FVC compared
with salmeterol, with the difference increasing with time.
Mean peak FEV
1
increase over placebo was 244 mL
(~22%) with tiotropium and 161 mL (~15%) with salme-
terol. Additionally, unlike salmeterol, tiotropium improved
dyspnea as assessed by the TDI. Tiotropium was also su-
perior to salmeterol in improving health-related QOL us-
ing the St. George’s Respiratory Questionnaire (SGRQ).
Tiotropium and salmeterol equally reduced the need for
rescue albuterol by approximately 1.45 puffs/d compared
with placebo. A significant limitation of this study is that it
did not address the effect of either salmeterol or tiotropium
on the 6-minute walking distance.
Formoterol vs. Ipratropium
A randomized, double-blind, parallel-group, 12-week
study compared formoterol 12 and 24 µg twice daily with
ipratropium 40 µg 4 times daily and with placebo in pa-
tients with stable COPD.
30
Compared with ipratropium,
both formoterol doses had significantly higher mean FEV
1
peak, higher mean FEV
1
AUC, improved diary symptom
scores, reduced rescue medications use, and improved
QOL (measured by SGRQ).
30
Mean peak FEV
1
increase
over placebo was 300–350 mL (~20–25%) with for-
moterol and <200 mL (~15%) with ipratropium. Daily res-
cue inhaler use was lower in the formoterol 12- and 24-µg
groups (1.2 and 1.7 puffs/d, respectively) than in the ipra-
tropium group (2 puffs/d). The percentage of “bad” days
(defined as days with ≥2 individual symptom scores of ≥2
[6 clinical symptoms evaluated on a scale of 0 = best to 3 =
worst] and/or a reduction in peak expiratory flow [PEF]
from baseline >20%) was significantly reduced in the for-
moterol groups compared with the ipratropium group.
However, the number of days of additional therapy for
COPD exacerbations and the number of hospitalizations
were not different between formoterol groups, the ipra-
tropium group, or the placebo group. This study is limited
in that it did not address the impact of the study drugs on
dyspnea and the 6-minute walking distance. Also, the dose
of ipratropium was lower than used clinically and the ef-
fects of the drugs are unknown after 12 weeks.
Long-Acting β
2
-Agonist Inhalers vs. Theophylline
An open-label, randomized, parallel-group study com-
pared salmeterol 50 µg twice a day with oral theophylline
(goal concentration 10–20 µg/mL).
47
Compared with the-
ophylline, salmeterol increased mean morning PEF rates
(45 L/min with salmeterol, 25 L/min with theophylline),
mean FEV
1
, mean FVC (up to 130 mL, a 10% increase),
and had a greater percentage of symptom-free days and
nights (59.7% vs. 46.2% for salmeterol and theophylline,
respectively). Salmeterol also reduced rescue albuterol use,
improved auscultatory findings, and improved QOL as as-
sessed on the 36-Item Short Form Health Survey. A signif-
icant limitation of this study was the open-label design; it
also did not assess the 6-minute walking distance.
Rossi et al.
48
compared formoterol 12 or 24 µg twice
daily with oral theophylline (goal concentration 8–20 µg/
mL) in a randomized, parallel-group, double-blind, place-
bo-controlled study for formoterol and an open-label de-
sign for theophylline. The mean 12-hour FEV
1
AUC after
12 months of treatment was significantly greater for for-
moterol 12 µg compared with theophylline and placebo.
Interestingly, formoterol 24 µg was not statistically signifi-
cantly better than theophylline. In a subset of patients with
irreversible or poorly reversible disease, formoterol 12 and
24 µg did not show statistically significant results compared
with theophylline or placebo. Compared with theophylline,
either dose of formoterol reduced the use of rescue medica-
tions by about 1 puff/d, decreased exacerbations of COPD,
and showed a decreased trend in total diary symptom
score. Formoterol 12 and 24 µg and theophylline improved
QOL (measured via SGRQ) compared with placebo. Limi-
tations include the open-label arm design for theophylline
and the absence of the 6-minute walking distance as an
endpoint.
Concomitant Long-Acting β
2
-Agonist Inhalers
and Other Bronchodilators
Ipratropium. In a randomized, double-blind, placebo-
controlled, parallel-group study, salmeterol 50 µg twice
daily combined with ipratropium 40 µg 4 times daily im-
proved FEV
1
and specific airway conductance compared
with salmeterol alone.
49
However, the combination did not
significantly add to symptom control or the need for rescue
medications, although the study may not have been suffi-
ciently powered to address those issues. Contrary to these
findings, Matera et al.
50
reported no significant benefit
from the addition of ipratropium to salmeterol except for
possible earlier onset of effect compared with salmeterol
alone.
A randomized, double-blind, 2-period, crossover study
compared formoterol 12 µg twice daily plus ipratropium
40 µg 4 times daily with albuterol 200 µg 4 times daily
plus ipratropium 40 µg 4 times daily.
51
There was a greater
increase in mean FEV
1
AUC, increased mean morning
PEF, and improved total symptom scores in the formoterol
plus ipratropium group. Limitations include short duration
(3 wk) and lack of data on clinically relevant outcome
measures except for symptom scores. Another trial found
that formoterol 12 µg plus ipratropium 40 µg resulted in
significantly higher increase in mean peak FEV
1
(335 mL;
~25% increase) than with ipratropium 40 or 80 µg alone.
52
This study was limited by its small size, short duration, ad-
ministration of single doses, and its predominant focus on
spirometric variables.
Theophylline. A randomized, double-blind, parallel-
group trial compared salmeterol 42 µg twice daily plus the-
ophylline (goal concentration 10–20 µg/mL) with salme-
terol or theophylline given alone.
53
The salmeterol plus
theophylline group increased spirometric indices (i.e.,
mean FEV
1
, FVC, FEV
1
AUC), improved dyspnea scores,
reduced albuterol use, and improved QOL and overall sat-
1252
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2003 September, Volume 37
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JA Dougherty et al.
isfaction compared with either salmeterol or theophylline
alone. No evaluation of exercise capacity was done in this
12-week study. A smaller study found a trend for im-
proved spirometric indices, but concluded that there was
no advantage of adding theophylline to salmeterol.
54
A ma-
jor limitation of this study was the exclusive focus on spiro-
metric indices as endpoints of treatment without a QOL or
dyspnea score assessment.
CORRELATION BETWEEN CHANGES IN FEV
1
AND
CLINICAL IMPROVEMENT
It is noteworthy that clinical improvements resulting
from bronchodilator treatment correlate poorly with im-
provements in FEV
1
.
9
For instance, there was a weak cor-
relation between changes in QOL and changes in FEV
1
with salmeterol 50 µg twice daily.
55,56
Higher doses of salme-
terol (100 µg twice daily) showed no clinically significant
impact on QOL.
55
Additionally, in several large, randomized
studies, there were clinical benefits from long-acting β
2
-ago-
nists even with limited increases in mean peak FEV
1
(200–300 mL).
30,42,43
A discordance is also noted in some
studies where benefits of salmeterol on QOL, use of rescue
medications, and number of exacerbations were not ac-
companied by objective improvements in dyspnea scores
or 6-minute walking distance.
42,43
These findings suggest
that other pathophysiologic mechanisms besides effects on
FEV
1
may account for the improvement noted with in-
haled β
2
-agonists. Alternative proposed mechanisms in-
clude reduction of work of breathing
57
and improvement in
parameters of forced inspiration rather than expiration.
58
Adverse Events
In randomized trials, there was no significant difference
in the number of adverse events with long-acting β
2
-ago-
nists compared with ipratropium or placebo. One potential
exception is an increase in upper respiratory tract infec-
tions and sore throat occurring with salmeterol and ipra-
tropium compared with placebo,
43
but this was not con-
firmed in another similarly designed trial.
42
In 2 large trials of patients with stable COPD, 24-hour
cardiac monitoring revealed no significant differences in
ventricular and supraventricular ectopic cardiac contrac-
tions with salmeterol, ipratropium, or placebo.
42,43
In 1 re-
port, there was a reduction in total ventricular events with
salmeterol and ipratropium compared with placebo 4
weeks into the trial and an increase in supraventricular
contractions with ipratropium compared with placebo at 8
weeks.
42
Further, in healthy subjects and those with airway ob-
struction, high doses of salmeterol (100 µg twice daily for
3 d) did not cause significant increases in heart rate, blood
pressure, or ventricular or supraventricular contractions.
59
Although these data demonstrate the safety of long-acting
β
2
-agonists, both salmeterol and formoterol have been
shown to increase heart rate.
60
A single dose of formoterol
24 µg increased supraventricular and ventricular contrac-
tions and significantly decreased plasma potassium for 9
hours (p value not reorted). Thus, care must be exercised
when these agents are administered to COPD patients with
preexisting cardiac arrhythmias and hypoxemia.
Khoukaz et al.
61
studied the transient decreases in arteri-
al oxygen tension (PaO
2
) after administration of albuterol,
ipratropium, or salmeterol in patients with stable COPD.
This decrease in PaO
2
has been demonstrated in asthmatic
patients and attributed to the pulmonary vasodilator effect
of bronchodilators, with resulting increased perfusion to
poorly ventilated areas of the lung and consequent mis-
matching of ventilation and perfusion.
62
Salmeterol and al-
buterol resulted in small, but statistically significant, drops
in PaO
2
of –2.74 mm Hg and –3.45 mm Hg, respectively.
61
The decline in PaO
2
was more prolonged with salmeterol
(90 min) than with albuterol (30 min). These transient
changes were not considered clinically significant. Com-
paratively, there was a smaller and statistically insignifi-
cant drop in PaO
2
with ipratropium.
Summary
The pharmacokinetic benefits of long-acting β
2
-agonists
over ipratropium, short-acting β
2
-agonists, and theophyl-
line justify their use as first-line therapy for treatment of
patients with stable COPD. This may be particularly true if
there are concerns regarding adherence, presence of noc-
turnal or early morning symptoms, impaired QOL, or fre-
quent exacerbations. With current information, formoterol
is recommended over salmeterol based on cost data and its
somewhat more favorable clinical outcome data, but this
recommendation is contingent on future studies.
A patient with COPD who needs additional therapies
should receive a long-acting β
2
-agonist plus ipratropium.
This recommendation is especially important for patients
with persistent symptoms after long-acting β
2
-agonist ther-
apy. Patients who continue to have persistent symptoms
with a long-acting β
2
-agonist plus ipratropium should have
theophylline added or substituted for ipratropium.
John A Dougherty MBA PharmD, Assistant Administrative Di-
rector, Clinical Services, Pharmacy Department, Florida Hospital,
Orlando, FL
Bethany L Didur, PharmD Student, Wayne State University, Detroit,
MI
Loutfi S Aboussouan MD, Associate Professor of Medicine,
Wayne State University; Harper University Hospital, Detroit
Reprints: John A Dougherty MBA PharmD, Pharmacy Department,
Florida Hospital, 601 E. Rollins St., Orlando, FL 32803-1248, FAX
407/303-9448, john.dougherty@flhosp.org
We thank K Dougherty PhD for critical analysis of this manuscript.
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EXTRACTO
OBJECTIVO: Describir la patogénesis de enfermedad pulmonar
obstructiva crónica (EPOC), mecanismos beneficiosos, formulaciones
disponibles, costo de los medicamentos, perfil farmacocinético, y
estudios clínicos pertinentes del uso de agentes β
2
-agonistas de larga
duración.
FUENTES DE INFORMACIÓN: Se realizó una busqueda de literatura
publicada hasta octubre 31 de 2002 utilizando MEDLINE.
SELECCIÓN DE ESTUDIOS: Artículos relacionados a EPOC y a agentes β
2
-
agonistas de larga duración.
SÍNTESIS: La incidencia, morbilidad, y mortalidad asociada a EPOC ha
aumentado durante las últimas 4 décadas, obligando a crear iniciativas
mundiales hacia las formulaciones de guías que disminuyan el impacto
de esta enfermedad. EPOC es una enfermedad progresiva e irreversible
caracterizada por tos crónica, dificultad respiratoria, producción de
esputo, y sibilancias en la que ninguna terapia, a excepción de la
administración de oxigeno, ha logrado demostrar una disminución en
mortalidad. Los broncodilatadores han sido la terapia principal en el
tratamiento de EPOC por su capacidad para trabajar en el músculo liso y
por otros mecanismos. Los agentes β
2
-agonistas de larga duración
(formoterol y salmeterol) al poder ser administrados 2 veces al día
proveen una más conveniente administración que los broncodilatadores
tradicionales que requieren de una administración 4 veces al día. Tanto
salmeterol como formoterol poseen un perfil de seguridad aceptable
cuando se utilizan en las dosis recomendadas. No existen estudios
clínicos que comparen formoterol con salmeterol, pero ambos han
demostrado un mayor beneficio al compararse con teofilina o
ipratropium en mejorar síntomas, valores de pruebas de espirometría,
exacerbaciones, y calidad de vida en pacientes con EPOC.
CONCLUSIONES:Basada en la evidencia actual, los agentes β
2
-agonistas de
larga duración son una alternativa aceptable como agentes de primera
línea en el tratamiento de EPOC.
Annette Pérez
RÉSUMÉ
OBJECTIF: Décrire la pathogénèse de la maladie pulmonaire obstructive
chronique (MPOC), les formes pharmaceutique disponibles, le coût des
médicaments, les profils pharmacocinétiques, ainsi que les essais
cliniques pertinents avec des β
2
-agonistes à longue durée d’action.
SOURCE DES DONNÉES: Une recherche MEDLINE effectuée jusqu’à
octobre 2002.
SÉLECTION DES ÉTUDES: Les articles pertinents à la MPOC et aux β
2
-
agonistes à longue durée d’action.
RÉSUMÉ: L’incidence et la morbidité/mortalité subséquentes de la MPOC
a augmenté au cours des 4 dernières décennies, menant à la mise en
place de lignes directrices visant à réduire les conséquences de cette
maladie. La MPOC est une maladie progressive chronique caractérisée
par des symptômes de toux chronique, de dyspnée, de production de
mucus, ainsi que par une respiration sifflante pour lesquels aucun
médicament n’a démontré de réduction de la mortalité, à l’exception de
la thérapie avec l’oxygène. Les broncho-dilatateurs ont été les
principaux agents dans la thérapie de la MPOC à cause de leur double
action sur les muscles lisses et non-lisses du système respiratoire. Les
β
2
-agonistes à longue durée d’action (i.e., salmétérol et formotérol)
administrés à une fréquence de 2 fois par jour procurent un dosage plus
acceptable que les 4 administrations requises pour les β
2
-agonistes à
courte durée d’action. Le salmétérol et le formotérol ont tous 2 un profil
d’effets indésirables acceptable lorsque administrés aux doses
recommandées. Il n’y pas eu d’essais cliniques comparatifs entre le
formotérol et le salmétérol, mais les 2 agents ont démontré des bénéfices
par rapport à l’ipratropium et à la théophylline quant à l’amélioration de
la spirométrie, des exacerbations, et de la qualité de vie.
CONCLUSIONS:Sur la base des données disponibles à ce jour, les β
2
-
agonistes à longue durée d’action sont des agents de première ligne
acceptables pour le traitement des patients atteints de MPOC.
Nicolas Paquette-Lamontagne
Long-Acting Inhaled
β
2
-Agonists for Stable COPD
The Annals of Pharmacotherapy
■
2003 September, Volume 37
■
1255
www.theannals.com
