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1832 nThe Annals of Pharmacotherapy n2008 December, Volume 42 www.theannals.com
Chronic obstructive pulmonary dis-
ease (COPD) is an increasingly rec-
ognizable cause of morbidity and mor-
tality.1An estimated 12 million individu-
als were diagnosed with COPD in
20052,3;most were older than 40 years
and typically had at least a 20-pack/year
history of tobacco use.4Furthermore, ac-
cording to the National Health and Nu-
trition Examination Surveys III (1988–
1994), an estimated 12 million adults
had undiagnosed COPD, based on evi-
dence of impaired lung function.2,3 Un-
derdiagnosis of the disease may be
somewhat due to the fact that patients
might not seek medical attention until
the symptoms associated with COPD
impact the individual’squality of life.
Therefore, patients may not present early
in the disease when airflow limitation is
present with absent or minimal symp-
toms. Alternatively,symptoms such as
progressive cough and sputum produc-
tion may precede the development of air-
flow limitation1;patients may perceive
these symptoms as being due to a long-
term smoking history and may not ini-
tially seek medical attention.4Thus, the
significance of the COPD symptoms
may not be initially recognized by pa-
tients or their healthcare providers.1
COPD is the fourth leading cause of
mortality in the US and is projected to be
the fourth leading cause of mortality
worldwide by 2030, according to the
World Health Organization (WHO).5,6 To
Long-Acting Bronchodilator Therapy for the Treatment of
Chronic Obstructive Pulmonary Disease
Andrea M Chen, Suzanne G Bollmeier, and Patrick M Finnegan
Pulmonary
Author information provided at the end of the
text.
OBJECTIVE:To review clinical data on the use of long-acting bronchodilator
agents as monotherapy and in combination for the treatment of moderate-to-
severe chronic obstructive pulmonary disease (COPD).
DATA SOURCES:Aliterature search was performed via MEDLINE (1966–April
2008). In addition, references from publications identified were reviewed. These
searches were limited to human data published in the English language.
Searches used the following terms: COPD, long-acting β2-agonists, long-acting
anticholinergics, combination therapy, pharmacoeconomics, safety, tiotropium,
salmeterol, and formoterol.
STUDY SELECTION AND DATA EXTRACTION:Relevant information on the pharma-
cology, safety, efficacy, pharmacoeconomics, adherence, and available agents
used in the treatment of COPD was selected. Randomized clinical trials and
retrospective reviews were included.
DATA SYNTHESIS:The Global Initiative for Chronic Obstructive Lung Disease
guidelines provide general management recommendations to guide providers
regarding treatment choices for COPD; however,they lack clarity regarding
which long-acting bronchodilator to use and when combining agents becomes
appropriate. Prospective trials evaluating short-acting anticholinergics and long-
acting β2-agonists have utilized spirometric endpoints that relate most to short-term
symptomatic relief. Tiotropium trials have focused more on patient-oriented out-
comes, with data being reported for one year.Tiotropium significantly lowers
exacerbation rates and improves health resource usage as well as health-related
quality of life. Tiotropium also provides superior bronchodilation and improvement in
dyspnea at all time points, although onset of bronchodilation is slower than with
long-acting β2-agonists. Combining these agents has been shown to decrease
daytime rescue inhaler use, improve morning and evening peak expiratory flow
rates, and improve bronchodilator efficacy compared with monotherapy. Pharma-
coeconomic data lend support to the recommendation of tiotropium as a first-line
long-acting agent.
CONCLUSIONS:Tiotropium appears to be the best option as a first-line drug for
patients with moderate-to-severe COPD because of its ability to sustain
bronchodilator effect, improve quality of life, reduce COPD exacerbations, and
reduce health resource usage. Patients who remain symptomatic may benefit
from the addition of a long-acting β2-agonist to tiotropium monotherapy.
KEY WORDS:combination therapy, COPD, formoterol, long-acting anticholinergics,
long-acting β2-agonists, pharmacoeconomics, safety,salmeterol, tiotropium.
Ann Pharmacother
2008;42:1832-42.
Published Online, 28 Oct 2008,
www.theannals.com
,DOI 10.1345/aph.1L250
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER:407-000-08-024-H01-P
A
For Our Patients
summary of this article is available at www.ForOurPatients.info
at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from at Fund Diag.Est Imstico PARENT on October 11, 2013aop.sagepub.comDownloaded from
increase awareness of COPD, the National Heart, Lung,
and Blood Institute and WHO developed the Global Initia-
tive for Chronic Obstructive Lung Disease (GOLD) docu-
ment as a consensus and evidence-based report.1The
GOLD guidelines provide guidance on the diagnosis, pre-
vention, and management of COPD.
Spirometry is the gold standard for diagnosis and as-
sessment of COPD. The GOLD guidelines provide COPD
therapy recommendations according to disease severity
(Table 1). Current pharmacologic therapy lacks the ability
to alter the progressive decline in lung function that is
characteristic of COPD; therefore, pharmacotherapy is fo-
cused on prevention and relief of symptoms.1
Pharmacotherapy
Bronchodilators, considered to be first-line therapy for
COPD, act on airway smooth muscle tone to improve
spirometric variables. These include forced vital capacity
(FVC), which measures the maximum amount of exhaled
air from a point of maximal inhalation; forced expiratory
volume in 1 second (FEV1), which measures the amount of
expired air in the first second of the FVC maneuver; and
the FEV1/FVC ratio. Small differences in spirometric im-
provement do not always indicate or predict symptomatic
benefit. Bronchodilators have, however,been shown to re-
duce the frequency and severity of exacerbations, improve
health-related quality of life (HRQOL), and improve exer-
cise endurance.1,7,8 Short-acting bronchodilators are recom-
mended in the mild stage of the disease for symptom re-
lief. Scheduled treatment with one or more long-acting
bronchodilators may be added to prevent or reduce symp-
toms as the disease progresses.
The GOLD guidelines provide general management
recommendations to guide the provider in terms of treat-
ment choices; however, there is a lack of specific recommen-
dations regarding which long-acting bronchodilator to start
initially and when combining long-acting bronchodilators
would be more beneficial than monotherapy.1The GOLD
guidelines state that long-acting bronchodilators are more ef-
fective and convenient than short-acting agents. For these
reasons, this article focuses primarily on the selection of in-
haled long-acting β2-agonists (LABAs), long-acting anti-
cholinergic agents, and combination therapy.
Anticholinergic Agents
Tiotropium and ipratropium are anticholinergic agents
approved in the US for administration in patients with
COPD. These drugs provide benefit by reducing the char-
acteristic increased vagal cholinergic tone in the airways,
which is thought to be the only reversible component of
airflow limitation.9The bronchoconstriction and mucus se-
cretion associated with COPD are mediated primarily by
muscarinic receptors M1–M3.10 Tiotropium competitively
and reversibly antagonizes M1, M2,and M3receptors.10-13
M1receptors are located throughout the parasympathetic
ganglia and exocrine glands and mediate cholinergic trans-
mission, thereby enhancing cholinergic bronchoconstric-
tion. M3receptors mediate bronchoconstriction and mucus
secretion.10,13 M2receptors are found at postganglionic
parasympathetic nerves and act as autoreceptors by provid-
ing negative presynaptic feedback.10,13,14 Tiotropium blocks
M2receptors, resulting in increased acetylcholine release in
the airway. Tiotropium dissociates faster from M2than ei-
ther M1or M3receptors, resulting in a more selective an-
tagonism of the latter receptors.10,13 Conversely,the short-
acting anticholinergic agent ipratropium provides nonse-
lective antagonism of these muscarinic receptors.10 The
greater M1and M3receptor– drug complex half-life of
tiotropium allows for the prolonged duration of action ver-
sus ipratropium.10,13
Tiotropium Versus Ipratropium
The benefits of tiotropium in patients with COPD have
been established in comparison with both placebo15-18 and
ipratropium.9,16,18,19 Arandomized, double-blind, double-
dummy, parallel-group, 13-week study compared the effi-
cacy and safety of tiotropium 18 µgonce daily versus ipra-
tropium 40 µg 4 times daily in 288 patients with moderate-
to-severe COPD.9Patients receiving tiotropium achieved
significantly greater trough (p = 0.0001) and average (p =
0.003) FEV1levels versus ipratropium. Additionally, res-
cue inhaler use was significantly reduced in the tiotropium
group versus the ipratropium group (p < 0.05). Patients in
this trial were then enrolled into a one-year study.19
Vincken et al.19 reported the combined results of the pre-
vious study and a second large study of identical design.
The study patients (n = 535) received either tiotropium 18
µg once daily or ipratropium 40 µg 4 times daily. Results
of this study are summarized in Table 2. Trough FEV1was
The Annals of Pharmacotherapy n2008 December, Volume 42 n1833
www.theannals.com
Table 1. Classification of COPD by Severity
Severity Characteristics
Stage 1: mild FEV1/FVC <70%
FEV1≥80% predicted
Stage 2: moderate FEV1/FVC <70%
50% ≤FEV1<80% predicted
Stage 3: severe FEV1/FVC <70%
30% ≤FEV1<50% predicted
Stage 4: very severe FEV1/FVC <70%
FEV1<30% predicted odds ratio
FEV1<50% predicted + chronic respiratory
failure
COPD = chronic obstructive pulmonary disease; FEV1=forced expi-
ratory volume in 1 second; FVC = forced vital capacity.
significantly improved at the end of one year in patients re-
ceiving tiotropium versus those receiving ipratropium. Pa-
tients receiving tiotropium experienced a significantly low-
er number of exacerbations, as well as an improvement in
HRQOL (as evaluated by St. George’s Respiratory Ques-
tionnaire [SGRQ] total score), and improvements in morn-
ing and evening peak expiratory flow rate. Dyspnea was
also improved significantly with tiotropium versus ipra-
tropium. Transition Dyspnea Index (TDI) scores signifi-
cantly improved on all test days compared with ipratropi-
um (p < 0.05). The authors concluded that tiotropium
should be considered as first-line maintenance therapy in
patients with COPD. This study demonstrated that small
improvements in lung function were related to clinically
meaningful improvements in patient-oriented outcomes,
such as HRQOL and dyspnea.
Salmeterol Versus Formoterol
The inhaled LABAs include salmeterol and formoterol.
These agents are highly selective β2-adrenoreceptor ago-
nists that stimulate adenylyl cyclase to catalyze the conver-
sion of adenosine triphosphate to cyclic adenosine-3′,5′-
monophosphate. This increases relaxation of bronchial
smooth muscle and inhibits the release of mediators of cel-
lular hypersensitivity.20-22
The first inhaled LABA, salmeterol, was initially ap-
proved by the Food and Drug Administration (FDA) in
1994, with the addition of an approval for maintenance
treatment of bronchospasm associated with COPD in
2002.23 Much of the literature comparing the LABAs eval-
uates only the acute effects of these agents in COPD.24-27 A
study comparing salmeterol 50 µg and formoterol 24 µg
on 8 nonconsecutive days in patients with moderate-to-se-
vere COPD concluded that the drugs provided similar on-
set of action and both agents were effective in terms of im-
proving bronchodilation.24 In contrast, other studies have
found that formoterol provides a faster onset of bronchodi-
lation than does salmeterol.26,28 Similarly, studies have
found that formoterol elicited a faster onset of improve-
ment in resting inspiratory capacity, a predictor of im-
provement in symptoms.27,29 Cazzola et al.25 found that sal-
meterol provided a longer duration of bronchodilation in
severe COPD, but the mean peak bronchodilation
achieved was similar to that seen with formoterol. Some of
the variation between the 2 drugs may be due to their dif-
fering molecular structures and solubilities. Formoterol,
which is less lipophilic, may have a slightly different onset
or duration of action than does salmeterol.30-32 As much of
the literature is based on acute administration of both sal-
meterol and formoterol, more long-term studies are needed
to assess their effect on the progression of COPD.
Tolerance
Controversy surrounding the issue of tolerance or tachy-
phylaxis associated with the use of β2-agonists has long
been debated. Concerns for tolerance to adrenergic drugs
appeared in the 1960s when increased mortality was re-
ported in patients with asthma.30,33-35 At that time, re-
searchers speculated a close correlation with the use of
pressurized aerosols containing sympathomimetics, as
these agents had been used in a large proportion of pa-
tients.33,34 Today,the GOLD guidelines maintain that stud-
ies have found no association between the use of β2-ago-
nists in COPD and accelerated loss of lung function or in-
creased mortality.1Astudy examining the effects of
LABAs found no difference in either duration or magni-
tude of bronchodilator response following administration
of formoterol for 12 weeks.36
Tiotropium Versus Salmeterol/Formoterol
Tiotropium maintains a sustained bronchodilatory effect
for approximately 24 hours, in contrast to the LABAs’ 12-
hour duration of action.37 Literature has evaluated tiotropi-
1834 nThe Annals of Pharmacotherapy n2008 December, Volume 42 www.theannals.com
AM Chen et al.
Table 2. Outcomes from Vincken Study19
Tiotropium Ipratropium
Outcome 18 µg once daily 40 µg 4 times daily p Value
Trough FEV1(mL)a120 –30 <0.001
SGRQ total scores (units), mean ± SEMb40.90 ± 0.69 44.20 ± 0.97 0.004
Pts. with ≥4units improvement in SGRQ total score,c% 52 35 0.001
Pts. with ≥1unit improvement in TDI focal score,d%31 18 0.004
Pts. experiencing ≥1COPD exacerbation, % 35 46 0.014
COPD = chronic obstructive pulmonary disease; FEV1=forced expiratory volume in 1 second; SGRQ = St. George's Respiratory Questionnaire; TDI
=transition dyspnea index.
aData presented as mean trough FEV1(difference from day 1 baseline).
bLower SGRQ score indicates improvement.
c≥4Units improvement indicates clinically meaningful difference.
d≥1Unit improvement indicates clinically meaningful difference.
um versus either salmeterol or formoterol to determine
which drug would be most effective in improving bron-
chodilation in patients with COPD.18,37-42 Two small pilot
studies evaluating the acute bronchodilator efficacy of sin-
gle doses of salmeterol or formoterol versus tiotropium in
this population found that both LABAs provided a faster
onset of bronchodilation and trended toward greater peak
effect versus tiotropium.38,39 As these studies were based
only on the acute effects of each agent, it is important to
evaluate studies with longer durations.
Donohue et al.40 compared the effects of tiotropium and
salmeterol in 623 patients with COPD during a 6-month
study. Tiotropium provided superior bronchodilation ver-
sus both placebo (p = 0.0001) and salmeterol (p = 0.0001).
Trough FEV1was improved significantly above placebo in
both the tiotropium group (137 mL) and the salmeterol
group (85 mL) at 24 weeks. Tiotropium also significantly
improved trough FEV1(52 mL; p < 0.01) and average
(0–12 h) FEV1(77 mL; p < 0.001) versus salmeterol.
Tiotropium resulted in a greater improvement in dyspnea
as evaluated by the percentage of patients achieving a clin-
ically meaningful improvement in TDI focal score (≥1
unit) versus placebo (p < 0.01). The differences in TDI fo-
cal score between tiotropium (42%) versus salmeterol
(35%) and salmeterol versus placebo (26%) were not sta-
tistically significant. Additionally,the percentage of pa-
tients achieving a clinically meaningful improvement in
SGRQ total score (≥4 units) was statistically superior in
the tiotropium group versus both salmeterol and placebo
(51%, 40%, and 42%, respectively; p < 0.05).
Brusasco et al.41 reported the combined results of the
Donohue et al.40 trial and their 6-month trial comparing
tiotropium with salmeterol. Results of this study are summa-
rized in Table 3. Tiotropium demonstrated greater improve-
ment in peak, trough, and mean FEV1(0–3 h) versus both
salmeterol and placebo. Tiotropium significantly exceeded
the benefits of placebo in terms of improvement in the num-
ber of exacerbations per patient-year, HRQOL, and dyspnea,
whereas the differences between tiotropium and salmeterol
did not reach statistical significance. The only significant dif-
ference in adverse events experienced among groups was dry
mouth associated with the use of tiotropium. It is important to
note that while tiotropium did not statistically differ from sal-
meterol in terms of outcomes other than bronchodilation,
tiotropium did performstatistically and clinically better than
placebo. Conversely,salmeterol generally did not provide a
clinically meaningful impact over that of placebo.
A12-week study was performed in 653 patients with
COPD to compare daytime bronchodilator efficacy of
once-daily tiotropium 18 µg with that of twice-daily sal-
meterol 50 µg.42 Mean peak and average FEV1(0–12 h)
responses were significantly greater after the administra-
tion of tiotropium than with salmeterol (262 vs 216 mL
and 167 vs 130 mL, respectively). Conversely,the mean
Long-Acting Bronchodilator Treatment of COPD
The Annals of Pharmacotherapy n2008 December, Volume 42 n1835
www.theannals.com
Table 3. Outcomes from Brusasco Study41
Pts. with ≥1
Pts. with ≥4Hospital
Units Pts. with ≥1Hospitalizations Admission
Improvement Improvement Unit per Patient- Related to
Improvement in SGRQ in SGRQ Improvement Exacerbations Year for COPD COPD
in Trough Total Score Total in TDI Focal Pts. with ≥1per Patient- Exacerbation, Exacerbation,
Parameter FEV1(L)a(units)aScore,b%Score,c%Exacerbation, % Year, n n %
Tiotropium 18 µg once daily 0.12 ±0.1 4.2 ±0.7 48.9 43.1 32 1.07 0.10 3
Salmeterol 50 µg twice daily 0.09 ±0.1 2.8 ±0.7 43.2 41.2 35 1.23 0.17 5
Placebo NA 1.5 ±0.7 39.3 29.8 39 1.49 0.15 5
p Value <0.01d<0.01e<0.05e<0.01d>0.05f<0.05e>0.05f>0.05f
<0.05g
COPD = chronic obstructive pulmonary disease; FEV1= forced expiratory volume in 1 second; NA = not assessed or not reported; SGRQ = St. George's Respiratory Questionnaire; TDI = transition dyspnea
index.
aMean ±SE.
b≥4 units improvement indicates clinically meaningful difference.
c≥1 unit improvement indicates clinically meaningful difference.
dTiotropium and salmeterol vs placebo.
eTiotropium vs placebo.
fNo significant differences between treatment groups.
gTiotropium vs salmeterol.
trough FEV1response in the tiotropium group did not
reach statistical significance over that of salmeterol (88 vs
71 mL, respectively; p = 0.24). The data regarding exacer-
bations were not significantly different between the 2
groups. The incidence of adverse events was similar with
both tiotropium and salmeterol, except that more disorders
of the lower respiratory tract were seen in the salmeterol
group and there were more reports of dry mouth in the
tiotropium group. The results of this study are comparable
to the findings of previous trials performed by Donohue et
al.40and Brusasco et al.41in terms of the improvement in
bronchodilation achieved with tiotropium versus salme-
terol; however, this trial did not evaluate clinical improve-
ments in HRQOL or dyspnea.42
Initiating optimal maintenance therapy in the earlier
stages of COPD may provide additional benefit to the pa-
tient beyond that provided by as-needed therapy.43 Overall,
both LABAs and tiotropium are effective in improving
bronchodilation in patients with COPD. Based on the cur-
rently available literature, tiotropium provided greater bene-
fit in terms of spirometric variables, HRQOL, dyspnea,
COPD exacerbations, and use of health resources. The re-
sults of 2 meta-analyses that reviewed the safety and effica-
cy of tiotropium in COPD were also consistent with these
findings.18,44 Thus, tiotropium is suitable for first-line mainte-
nance therapy for patients with moderate-to-severe COPD
and may provide benefits beyond those of either LABA.
Combination Therapy
Studies have demonstrated that short-acting combina-
tion therapy, including an anticholinergic agent and a β2-
agonist, is superior to monotherapy with either drug in pa-
tients with COPD.45-48 In addition, the combination of ipra-
tropium plus an LABA has been shown to provide
additional benefit in terms of lung function.49,50 These find-
ings lend support to the use of combination therapy with
long-acting bronchodilators to provide additional benefit in
these patients.
The GOLD guidelines state that the combination of
bronchodilators with different mechanisms and durations
of action may improve the degree of bronchodilation with
equivalent or lesser adverse effects over what would result
from dose escalation of a single agent.1Combining long-act-
ing bronchodilators appears to provide additive benefits in
patients with COPD because of the distinct and complemen-
tary mechanisms of action of each drug in the airway.32 Liter-
ature comparing combination therapy with monotherapy has
become more prevalent in recent years; however, the guide-
lines still lack specific recommendations regarding the timing
of combination therapy initiation.1
Small single-dose studies were conducted to identify
whether a benefit existed with combination therapy over
monotherapy.38,39 The findings of these initial studies were
inconsistent. This was most likely related to small sample
sizes and the single-dose design of the studies.
A3-way crossover study compared once-daily tiotropi-
um, twice-daily formoterol, and a once-daily combination
in patients with moderate-to-severe COPD.37 Atotal of 71
patients received study medications for three 6-week peri-
ods. Once-daily combination therapy improved average
FEV1significantly versus tiotropium and formoterol
monotherapy over the 24-hour observation period. During
the daytime, the significant difference versus tiotropium
monotherapy was sustained until 13 hours after the morn-
ing dose (0.060 L; p < 0.02). The trough FEV1response in
the tiotropium group was the only FEV1value that was not
statistically significantly different between the once-daily
combination therapy and either agent alone (p = 0.08).
Daytime rescue inhaler use was significantly decreased
with combination therapy versus either agent alone; how-
ever, no significant difference was observed between sin-
gle agents. The authors concluded that once-daily combi-
nation therapy improved FEV1over either drug alone until
13 hours postdose, which suggests a correlation with the
duration of effect of formoterol. This study lacked the
evaluation of patient-oriented outcomes such as HRQOL
and symptom improvement. Furthermore, combination
therapy may have demonstrated a more pronounced effect
on bronchodilation had formoterol been administered
twice daily versus once daily.
These findings led the authors to examine the effect of
once- or twice-daily formoterol in combination with phar-
macodynamic steady-state tiotropium on airflow limitation
and hyperinflation at rest over a 24-hour period in 95 pa-
tients with moderate-to-severe COPD.48 Patients received
tiotropium for a 2-week pretreatment period prior to initia-
tion of three 2-week treatment periods. The combination of
tiotropium and formoterol, both once and twice daily, re-
sulted in statistically significant improvements in FEV1.
Tiotropium in combination with formoterol twice daily
provided the greatest response in average FEV1(0–24 h);
however, the combination of tiotropium and formoterol
once daily also demonstrated a statistically significant re-
sponse versus tiotropium monotherapy. The addition of
once-daily formoterol to tiotropium provided further im-
provement in FEV1over tiotropium alone; improvement
was sustained for at least 14 hours after the morning dose,
as reflected by a difference in average FEV1(0–12 h) of
0.11 L (p < 0.0001) and in average FEV1(12–24 h) of 0.05
L(p < 0.001). Twice-daily formoterol in combination with
tiotropium provided an additive effect on bronchodilation
after the evening dose. Average FEV1(12–24 h) and
trough FEV1were significantly improved compared with
both other treatment groups (p < 0.02). It is unknown
whether the additional dose of formoterol translates into
improvement in clinical outcomes. Results of both studies
by Van Noord et al.37,48 are summarized in Table 4.
1836 nThe Annals of Pharmacotherapy n2008 December, Volume 42 www.theannals.com
AM Chen et al.
Asmall crossover study evaluated the improvement in
bronchodilation achieved by twice-daily salmeterol and
fluticasone in combination with daily tiotropium versus ei-
ther bronchodilator alone in combination with twice-daily
fluticasone in patients with moderate-to-severe COPD.51
The combination of salmeterol, fluticasone, and tiotropium
demonstrated significantly improved preinhalation
(trough) and postinhalation (peak) FEV1versus the combi-
nation of bronchodilator monotherapy and fluticasone (p <
0.03 and p < 0.001, respectively). In addition, the peak ex-
piratory flow rate with the combination of both bron-
chodilators was significantly superior to that with salme-
terol or tiotropium alone (p < 0.04 in both cases). The
comparison of either agent as monotherapy in combination
with fluticasone revealed no significant differences in
FEV1or peak expiratory flow rate. The authors concluded
that the combination of salmeterol and tiotropium demon-
strated enhanced improvement in bronchodilation versus
either agent alone. All postinhalation FEV1values were
significantly higher than preinhalation values; however, as
the authors pointed out, the mean improvement demon-
strated by tiotropium did not achieve clinical significance.
In addition, the lack of a significant difference in FEV1val-
ues between salmeterol and tiotropium seems to contradict
previous findings in which tiotropium was superior to sal-
meterol.40 Even though this study used inhaled cortico-
steroids in combination with bronchodilators, other studies
have allowed patients to continue using inhaled corticos-
teroids throughout the treatment period without evaluating
outcomes related to the addition of these agents to bron-
chodilators.37,48 Moreover, this study had a very small sam-
ple size, evaluated only spirometric variables, and lacked
the evaluation of clinical outcomes.51
As COPD is a progressive disease with no current phar-
macotherapeutic agent known to alter the decline in lung
function, the majority of patients will most likely require
combination therapy during the course of the disease.52
Based on the literature reviewed, it appears that combina-
tion therapy should include a twice-daily LABA in addi-
tion to daily tiotropium.
Patient-Related Factors
Anumber of patient-related factors, including drug
costs, health plan coverage, manual dexterity,perceived
benefit from the drug, adverse effects experienced, and
continued smoking, influences treatment decisions. As
pulmonary function continues to decline, drug therapy typ-
ically becomes more complex. Medications are added to
improve dyspnea and quality of life and decrease exacer-
bation rates. Also, the newer long-acting agents are often
associated with a higher cost to the patient, either as a cash
cost that is typically more than $100 per month or as a
higher-tier insurance copayment.
Patients may have difficulty using the Spiriva Handi-
haler (tiotropium) or the Foradil Aerolizer (formoterol) be-
cause of the manual dexterity required to punch the cap-
sule from packaging and place it in the inhaler, as well as
the hand strength required to pierce the capsule. Patients
with decreased coordination or joint pain, as well as those
with poor vision, may find these steps difficult. The
Serevent Diskus (salmeterol) can be easier to use because
the drug is contained within the device and minimal steps
are required to prepare each dose. A recent study in geri-
atric patients revealed that up to 17% of patients rated dry-
powder inhalers difficult to use.53 Difficulties cited includ-
ed difficulty handling the device (27%) and hand-to-mouth
coordination problems during actuation (21%). Approxi-
mately 50% of patients using either a metered-dose inhaler
or dry-powder inhaler were unsure whether they derived
any benefit from their inhaler.
Patient age, drug acquisition cost, type of prescriber
(specialist vs generalist), and perceived benefit have been
described as barriers to adherence.53,54 Multiple studies
have shown that patients’ adherence to inhaled regimens is
poor,with most patients discontinuing treatment during the
first few months.54,55
Recently, a trial studied general adherence to a pre-
scribed regimen by examining claims data from the On-
tario Drug Benefit Program; the index drugs were for-
moterol, formoterol plus budesonide, ipratropium, ipratropi-
um plus salbutamol, salmeterol, salmeterol plus fluticasone,
and tiotropium.54 Patients were divided into groups based
on index drug and whether they were naïve or experienced
with that drug. One of the outcomes of the trial was adher-
ence, as demonstrated by patients renewing the medication
as indicated. A total of 31,368 patients were followed up to
18 months. Overall, adherence declined over time, with
15–63% and 5– 47% of patients remaining on the index
drug at 6 and 18 months, respectively.Treatment-naïve pa-
tients had significantly lower adherence rates than did
treatment-experienced patients. However,treatment-naïve
and -experienced patients had similar rates of adherence.
When looking at adherence rates at the index drug level,
tiotropium had the highest rates at all intervals. The au-
thors stated that one reason for the difference in adherence
rates between tiotropium and the other medications was
that it was the only drug that was administered once daily.
Given the information from this trial, it would seem that,
in order to maximize patient adherence to their prescribed
regimen, it would be necessary to design therapies with
once-daily administration schedules.
Adverse drug effects can also influence adherence.
Tiotropium has a safety profile consistent with anticholin-
ergic effects, particularly constipation and decreased sali-
vation. Adverse effects from LABAs may include tachy-
cardia, tremor, and hypokalemia. In a recent comparative
study analyzing over 2000 patients with COPD, the au-
Long-Acting Bronchodilator Treatment of COPD
The Annals of Pharmacotherapy n2008 December, Volume 42 n1837
www.theannals.com
thors concluded that risk of total mortality and
cardiac endpoints were similar for users of
tiotropium and LABAs.56 Cardiac events oc-
curred less with tiotropium; however, these re-
sults need further study. The cardiac safety of
formoterol and nebulized formoterol has been
evaluated and no clinically significant cardiac
effects were found.57,58
Recently, the FDA reported early communi-
cations regarding ongoing safety monitoring
being completed by the manufacturer to evalu-
ate a possible increased incidence of stroke in
users of tiotropium.59 Preliminary data re-
ceived by the FDA from the UPLIFT (Under-
standing the Potential Long-Term Impacts on
Function with Tiotropium) trial reported by the
manufacturer showed no increased risk of
stroke with tiotropium versus placebo. The
FDA plans to update the ongoing safety re-
view of tiotropium once the final analysis of
the results of the UPLIFT trial is complete.
The information is based on a pooled analysis
of 29 trials that found a preliminary increase in
the risk of stroke in patients taking tiotropium.
Pharmacoeconomic Impact
The cost of treating patients with COPD re-
lates to direct medical costs, including drug ac-
quisition, and indirect medical costs, such as
time lost from work or due to disability, care-
giver costs, and premature mortality.1The total
cost of COPD in 2004 was $37.2 billion, in-
cluding healthcare expenditures of $20.9 billion
in direct healthcare costs, $7.4 billion in indirect
morbidity costs, and $8.9 billion in indirect
mortality costs. In the US, most COPD direct
healthcare costs can be attributed to hospitaliza-
tions that result from exacerbations.60 There is a
direct relationship between worsening disease,
exacerbations, and hospitalizations.1
In an attempt to elucidate the direct costs of
medical care for COPD, Friedman et al.61 ret-
rospectively evaluated 921 patients treated
with tiotropium plus usual care versus placebo
in a US healthcare setting. Two identical one-
year studies of inhaled tiotropium were evalu-
ated between January 1997 and May 1998.
Spirometric testing was evaluated, as well as
dyspnea, health status, and quality of life via
the SGRQ. Frequency of exacerbations was
also monitored. When an assessment of health-
care resources used and costs associated with
these resources was completed, the authors
1838 nThe Annals of Pharmacotherapy n2008 December, Volume 42 www.theannals.com
AM Chen et al.
Table 4. Outcomes from Van Noord Studies37,48
Nighttime Rescue
Daytime Rescue Inhaler Use
Average FEV1Morning PEFR Evening PEFR Inhaler Use (puffs/day),
Reference/Treatment (0–24 h, L), mean ± SE (L/min), mean ± SE (L/min), mean ± SE (puffs/day), mean ± SE mean ± SE
Van Noord (2005)37
Tiotropium 18 µg once daily 0.085 ±0.01 262 ±2.6 274 ±2.8 2.41 ±0.14 0.56 ±0.05
Formoterol 12 µg twice daily 0.062 ±0.01 259 ±2.6 266 ±2.8 2.37 ±0.14 0.52 ±0.05
Combination once daily 0.160 ±0.01 268 ±2.5 283 ±2.6 1.81 ±0.13 0.52 ±0.05
p Value combination vs tiotropium, <0.0001 combination vs formoterol, <0.02 combination vs tiotropium, <0.01 combination vs tiotropium >0.05a
combination vs formoterol, <0.0001 combination vs formoterol, and formoterol, <0.003
tiotropium vs formoterol, 0.17 <0.0001
Van Noord (2006)48
Tiotropium 0.080 ±0.01 NA NA NA NA
Tiotropium + formoterol once daily 0.162 ±0.01 NA NA NA NA
Tiotropium + formoterolb0.198 ±0.01 NA NA NA NA
p Value tiotropium + formoterolbvs tiotropium + formoterolbvs tiotropium tiotropium + formoterolband tiotropium + formoterolbtiotropium +
tiotropium + formoterol once daily + formoterol once daily + tiotropium tiotropium + formoterol once and tiotropium + formoterolbvs
and tiotropium, <0.05 and tiotropium (9; <0.01)cdaily vs tiotropium (9; <0.01)cformoterol once daily tiotropium, <0.05
tiotropium + formoterol once daily vs tiotropium, <0.01
vs tiotropium, <0.05
FEV1= forced expiratory volume in 1 second; NA = not assessed or not reported; PEFR = peak expiratory flow rate.
aNo significant differences between treatment periods.
bFormoterol twice daily.
cDifference between groups.
found 0.76 exacerbations per patient-year for the tiotropi-
um group versus 0.95 exacerbations per patient-year for
the placebo group (p < 0.05). The frequency of exacerba-
tions that led to hospitalizations was also reduced by 44%
in the tiotropium group compared with the placebo group (p
<0.05). Tiotropium-treated patients spent fewer days in the
hospital compared with those receiving placebo (0.59 vs 1.17
days/patient-year; p < 0.05). The mean total healthcare costs
per patient ± SEM, excluding the cost of medication, were
$3926 ± 282 in the tiotropium group and $4970 ± 480 in the
placebo group, resulting in a difference of over $1000. A re-
duction in hospital costs in the tiotropium group was respon-
sible for the reduction in total healthcare costs.
Similarly, Oba60 conducted a cost-effectiveness analysis
to examine published evidence for using long-acting anti-
cholinergics and LABAs in the treatment of COPD. Trials
included were published between January 1980 and April
2006, were placebo-controlled, and included patients older
than 40 years with similar baseline characteristics. Esti-
mates of improvement in quality of life were measured via
SGRQ and scored by pooled analysis. The analysis was
performed from a third-party payer perspective, so only di-
rect costs were included. Tiotropium use resulted in signif-
icantly fewer hospitalizations per patient-year versus
placebo (95% CI –0.10 to – 0.02). When salmeterol was
compared with placebo, there was no significant decrease
in hospitalization rates or unscheduled physician visits.
Both agents improved HRQOL as measured by the
SGRQ. The cost-effectiveness ratio for salmeterol was
$41,000, compared with $26,094 for tiotropium, per quali-
ty-adjusted life years gained versus placebo.
Comparable trials conducted outside the US were also
evaluated for cost-effectiveness data in patients treated for
COPD.62,63 These trials also point to decreased costs over-
all associated with the use of tiotropium versus salmeterol.
Tiotropium had the highest expected net benefit as the
severity of COPD disease worsened.63 As with results from
other large-scale trials, tiotropium trends showed decreas-
ing exacerbation rates and improvement in quality of life,
as well as an overall improvement in lung function and
dyspnea.40,41,60 The higher acquisition cost of tiotropium
was offset by the overall reduced healthcare costs.60
In summary, by reducing exacerbation rates and im-
proving patients’ overall quality of life, tiotropium seems
to be the most cost-effective long-acting agent available.
Discussion/Limitations
Common limitations of studies evaluating agents used
to treat COPD are their short durations of therapy and use
of primarily disease-oriented outcomes, such as spiromet-
ric variables. With the development of tiotropium, we have
seen a transition toward increased study durations and the
inclusion of patient-oriented outcomes such as symptomat-
ic improvement, exacerbation rates, and HRQOL. While
the data presented seem to favor the use of tiotropium as a
first-line bronchodilator, they are limited in that most cur-
rently available literature focuses on the sustained efficacy
of tiotropium for up to 1 year. The UPLIFT (Understand-
ing the Potential Long-Term Impacts on Function with
Tiotropium) trial is a 4-year study examining tiotropium’s
effect on accelerated loss of lung function in COPD and its
long-term safety implications.64 These results may further
define the role of tiotropium.
Based on the currently available literature and guide-
lines, combination therapy with a long-acting anticholiner-
gic agent and an LABA seems to be an attractive option
for patients with moderate-to-severe COPD. Studies evalu-
ating long-acting combination therapy need to focus not
only on improvement in lung function but also on indices
of health status, such as HRQOL, number of exacerba-
tions, and symptom relief.65 Larger long-term studies are
needed to solidify combination long-acting bronchodilator
therapy as a necessary component of treatment in patients
with moderate-to-severe COPD.
Using an LABA and a long-acting anticholinergic in
combination allows providers to take advantage of the
medications’ synergistic actions on lung function. The
complementary actions allow lower doses to be used, mini-
mizing the risk of adverse effects that may be seen with dose
escalation of a single drug.66 While trials have shown the
benefits of combination therapy,there are presently no com-
mercially available products containing both an LABA and
along-acting anticholinergic. A once-daily combination in-
haler will be an advantageous choice as COPD progresses
and the disease can no longer be managed optimally with a
single long-acting agent. This may be possible in the near
future, as indacaterol, an LABA currently being investigat-
ed, has a 24-hour duration of activity.67
Summary
COPD requires optimal therapy to manage the chronic,
progressive nature of the disease. Traditionally, patients
with mild COPD have been managed with a combination
of short-acting bronchodilators. Disease progression typi-
cally requires the addition of long-acting drugs. It appears
that tiotropium may be an optimal choice for first-line
maintenance therapy because of its ability to sustain bron-
chodilator effect, improve quality of life, reduce COPD ex-
acerbations, and reduce health resource usage. Patients
who remain symptomatic may benefit from the addition of
an LABA to tiotropium monotherapy.
Andrea M Chen PharmD, Clinical Instructor,Postgraduate Year 2
Internal Medicine Resident, St. Louis College of Pharmacy,St. Louis,
MO
Suzanne G Bollmeier PharmD BCPS AE-C, Associate Professor,
Pharmacy Practice, St. Louis College of Pharmacy
Long-Acting Bronchodilator Treatment of COPD
The Annals of Pharmacotherapy n2008 December, Volume 42 n1839
www.theannals.com
Patrick M Finnegan PharmD BCP, Assistant Professor of Phar-
macy Practice, St. Louis College of Pharmacy
Reprints: Dr. Finnegan, St. Louis College of Pharmacy, 4588
Parkview Pl., St. Louis, MO 63110, fax 314/446-4500, pfinnegan@stl-
cop.edu
Dr. Finnegan has served as a paid consultant to Pfizer.
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Terapia con Broncodilatadores de Larga Duración en el Tratamiento
de Enfermedad Crónica Obstructiva del Pulmón
AM Chen, SG Bollmeier, y PM Finnegan
Ann Pharmacother 2008;42:1832- 42.
EXTRACTO
OBJETIVO: Resumir la información clínica sobre el uso en monoterapia o
en combinación de agentes broncodilatadores de larga duración en el
tratamiento de enfermedad crónica obstructiva del pulmón, conocida
como COPD, moderada a severa.
FUENTES DE INFORMACIÓN: Se realizó una búsqueda de la literatura
utilizando la base de datos de MEDLINE de 1966–abril 2008. Además,
se revisaron las listas de referencias de las publicaciones identificadas.
Estas búsquedas se limitaron a estudios realizados en humanos y publi-
cados en el idioma inglés. Para la búsqueda se utilizaron los siguientes
términos: COPD, agonistas β2de larga duración, anticolinérgicos de larga
duración, terapia de combinación, farmacoeconomía, seguridad, tiotropi-
um, salmeterol, y formoterol.
SELECCIÓN DE ESTUDIOS Y EXTRACCIÓN DE INFORMACIÓN: Se seleccionó
información relevante sobre la farmacología, seguridad, eficacia, farmaco-
economía, adherencia, y agentes disponibles utilizados en el tratamiento
de COPD. Se incluyeron estudios clínicos aleatorios y resúmenes retro-
spectivos.
SÍNTESIS: Las guías de la Iniciativa Global para COPD, conocida como
GOLD por sus siglas en ingles, proveen recomendaciones generales de
manejo para ayudar a los proveedores en relación a las alternativas de
tratamiento para COPD. Sin embargo, no han sido claras en relación a
cuál broncodilatador de larga duración utilizar y cuándo es apropiado
utilizar una combinación. Estudios prospectivos que han evaluado el uso
de anticolinérgicos de corta duración y β2agonistas de larga duración
han utilizado pruebas de espirometría como indicadores que más se rela-
cionan a alivio sintomático a corto plazo. Estudios con tiotropium se han
enfocado más en indicadores relacionados al paciente con información
que se extiende hasta un año. Tiotropium baja la tasa de exacerbaciones
significativamente, mejora la utilización de servicios de salud y mejora
la calidad de vida relacionada a la salud. Tiotropium también provee una
broncodilatación superior y mejora la disnea en todo momento, aunque
el inicio de acción es más lento que los β2agonistas de larga duración.
Se ha demostrado que combinar estos agentes disminuye el uso de inhala-
dores de rescate durante el día, mejora el flujo máximo espiratorio de la
mañana y de la tarde y mejora la eficacia broncodilatadora al compararse a
la monoterapia. La data farmacoeconómica apoyaría la recomendación
de utilizar tiotropium como agente de larga duración de primera linea.
CONCLUSIONES: Tiotropium parece ser la mejor alternativa de tratamiento
como primera linea para pacientes con COPD moderado a severo por su
abilidad para producir un efecto broncodilatador sostenido, mejorar la
1842 nThe Annals of Pharmacotherapy n2008 December, Volume 42 www.theannals.com
AM Chen et al.
calidad de vida, reducir las exacerbaciones de COPD y reducir la utiliza-
cion de servcios de salud. Los pacientes que continuen experimentando
sintomas podrian beneficiarse de la combinacion de tiotropium y un agente
β2-agonista de larga duracion.
Traducido por Annette Pérez
Thérapie Bronchodilatatrice à Longue Action dans le Traitement de
la Maladie Pulmonaire Obstructive Chronique
AM Chen, SG Bollmeier, et PM Finnegan
Ann Pharmacother 2008;42:1832- 42.
RÉSUMÉ
OBJECTIF: Revoir les données cliniques sur l’utilisation des bronchodila-
tateurs à longue action en monothérapie et en combinaison lors du traite-
ment de la maladie pulmonaire obstructive chronique modérée à sévère
(MPOC).
SOURCE DE L’INFORMATION: Une recherche informatisée sur MEDLINE a
été effectuée entre 1966–avril 2008. De plus, les bibliographies des publi-
cations identifiées ont été révisées. La recherche fut limitée aux données
humaines publiées en langue anglaise. Les termes utilisés pour la recherche
étaient: MPOC, agoniste β2àlongue action, anticholinergique à longue
action, thérapie de combinaison, pharmacoéconomique, innocuité, tiotropi-
um, salmétérol, et formotérol.
SÉLECTION DES ÉTUDES ET DE L’INFORMATION: Les données pertinentes sur
la pharmacologie, l’innocuité, l’efficacité, la pharmacoéconomie, la fidélité
au traitement, et les agents disponibles dans le traitement de la MPOC
furent sélectionnées. À la fois, les études cliniques randomisées et les
études rétrospectives furent inclues dans cette analyse.
RÉSUMÉ: Les recommandations provenant du Global Initiative for Chronic
Obstructive Lung disease (GOLD) sont d’ordre générales; cependant,
elles manquent de clarté quant au choix de l’agent bronchodilatateur à
longue action et quant au moment du besoin d’initier une combinaison
appropriée. Les études prospectives évaluant les anticholinergiques à
courte action et les agonistes β2àlongue action ont utilisé des résultats
de spirométrie associés à un soulagement symptomatique de courte durée.
Les études du tiotropium ont mis l’accent sur des résultats cliniques et non
spirométriques allant jusqu’à 1 an. Le tiotropium a réduit de façon signi-
ficative le taux d’exacerbation, amélioré l’usage des ressources de santé, et
amélioré aussi la qualité de vie de ces patients. Le tiotropium permet une
bronchodilatation supérieure et une amélioration de la dyspnée, cependant
le début de cette bronchodilatation est tardif par rapport à celui obtenu
des agonistes β2àlongue action. La combinaison de ces agents a permis
de réduire l’utilisation d’inhalateur pris au besoin durant la journée,
d’améliorer le taux de flot expiratoire maximal du matin et du soir, et
d’améliorer l’efficacité bronchodilatatrice comparée à celle d’une mono-
thérapie. Les données pharmacoéconomiques supportent la recommand-
ation du tiotropium comme agent à longue action de première intention.
CONCLUSIONS: Letiotropium semble être la meilleure option en tant
qu’agent de première ligne pour les patients avec MPOC modéré à
sévère à cause de sa capacité à maintenir un effet bronchodilatateur, à
améliorer la qualité de vie des patients, à réduire le nombre d’épisodes
d’exacerbations et à réduire également l’utilisation des ressources de
soins de santé. Les patients qui demeurent symptômatiques malgré une
monothérapie au tiotropium pourront bénéficier de l’addition d’un
agoniste β2àlongue action.
Traduit par Marc M Perreault
