Tiotropium in combination with placebo, salmeterol, or fluticasone- salmeterol for treatment of chronic obstructive pulmonary disease: A randomized trial

Article (PDF Available)inAnnals of internal medicine 146(8):545-55 · May 2007with43 Reads
DOI: 10.7326/0003-4819-146-8-200704170-00152 · Source: PubMed
Abstract
Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied. To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006. 27 academic and community medical centers in Canada. 449 patients with moderate or severe COPD. 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol. The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics. The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo. More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists. Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

Figures

Tiotropium in Combination with Placebo, Salmeterol, or
Fluticasone–Salmeterol for Treatment of Chronic Obstructive
Pulmonary Disease
A Randomized Trial
Shawn D. Aaron, MD; Katherine L. Vandemheen, BScN; Dean Fergusson, PhD; Franc¸ois Maltais, MD; Jean Bourbeau, MD;
Roger Goldstein, MD; Meyer Balter, MD; Denis O’Donnell, MD; Andrew McIvor, MD; Sat Sharma, MD; Graham Bishop, MD;
John Anthony, MD; Robert Cowie, MD; Stephen Field, MD; Andrew Hirsch, MD; Paul Hernandez, MD; Robert Rivington, MD;
Jeremy Road, MD; Victor Hoffstein, MD; Richard Hodder, MD; Darcy Marciniuk, MD; David McCormack, MD; George Fox, MD;
Gerard Cox, MB; Henry B. Prins, MD; Gordon Ford, MD; Dominique Bleskie, BHScN; Steve Doucette, MSc; Irvin Mayers, MD;
Kenneth Chapman, MD; Noe Zamel, MD; and Mark FitzGerald, MD, for the Canadian Thoracic Society/Canadian Respiratory Clinical
Research Consortium
Background: Treatment of moderate or severe chronic obstructive
pulmonary disease (COPD) with combinations of inhaled cortico-
steroids, long-acting
-agonists, and long-acting anticholinergic
bronchodilators is common but unstudied.
Objective: To determine whether combining tiotropium with sal-
meterol or fluticasone–salmeterol improves clinical outcomes in
adults with moderate to severe COPD compared with tiotropium
alone.
Design: Randomized, double-blind, placebo-controlled trial con-
ducted from October 2003 to January 2006.
Setting: 27 academic and community medical centers in Canada.
Patients: 449 patients with moderate or severe COPD.
Intervention: 1 year of treatment with tiotropium plus placebo,
tiotropium plus salmeterol, or tiotropium plus fluticasone–salmet-
erol.
Measurements: The primary end point was the proportion of pa-
tients who experienced an exacerbation of COPD that required
treatment with systemic steroids or antibiotics.
Results: The proportion of patients in the tiotropium plus placebo
group who experienced an exacerbation (62.8%) did not differ
from that in the tiotropium plus salmeterol group (64.8%; differ-
ence, 2.0 percentage points [95% CI, 12.8 to 8.8 percentage
points]) or in the tiotropium plus fluticasone–salmeterol group
(60.0%; difference, 2.8 percentage points [CI, 8.2 to 13.8 per-
centage points]). In sensitivity analyses, the point estimates and
95% confidence bounds shifted in the direction favoring tiotropium
plus salmeterol and tiotropium plus fluticasone–salmeterol. Tiotro-
pium plus fluticasone–salmeterol improved lung function (P
0.049) and disease-specific quality of life (P 0.01) and reduced
the number of hospitalizations for COPD exacerbation (incidence
rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations
(incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotro-
pium plus placebo. In contrast, tiotropium plus salmeterol did not
statistically improve lung function or hospitalization rates compared
with tiotropium plus placebo.
Limitations: More than 40% of patients who received tiotropium
plus placebo and tiotropium plus salmeterol discontinued therapy
prematurely, and many crossed over to treatment with open-label
inhaled steroids or long-acting
-agonists.
Conclusions: Addition of fluticasone–salmeterol to tiotropium ther-
apy did not statistically influence rates of COPD exacerbation but
did improve lung function, quality of life, and hospitalization rates
in patients with moderate to severe COPD.
Ann Intern Med. 2007;146:545-555. www.annals.org
For author affiliations, see end of text.
International Standard Randomised Controlled Trial registration number:
ISRCTN29870041.
M
ost patients with moderate or severe chronic ob-
structive pulmonary disease (COPD) experience
chronic progressive dyspnea that is not alleviated by short-
acting bronchodilators. It is therefore not surprising that
many patients are treated with multiple inhaled medica-
tions to optimize their lung function and minimize symp-
toms (1). Published guidelines on COPD state that the
goals of pharmacologic therapy should be to control symp-
toms, improve health status, and reduce the frequency of
COPD exacerbations (2, 3), and many published guide-
lines advocate combining different classes of long-acting
bronchodilators or inhaled steroids to achieve these goals
(2, 3).
In the past several years, several studies have shown
that treatment of COPD with the long-acting anticholin-
ergic tiotropium (4 –7); the long-acting
2
-agonist salmet-
erol (8 –10); or products that combine inhaled steroids and
long-acting
2
-agonists, such as fluticasone–salmeterol or
budesonide–formoterol (11–14), improve dyspnea and
quality of life and decrease exacerbation rates compared
See also:
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Editors’ Notes .............................546
Editorial comment..........................606
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© 2007 American College of Physicians 545
with placebo. However, no studies have assessed whether
therapy with a combination of these products provides
greater clinical benefit than does therapy with these agents
used alone.
2
-Agonists and anticholinergics work by different
mechanisms to cause bronchodilation (15), and inhaled
corticosteroids may have an anti-inflammatory effect in
COPD (16). Thus, it makes theoretical and intuitive sense
that combining these therapies might be more beneficial
than therapy with 1 agent alone. However, safety concerns,
such as side effects associated with long-term use of long-
acting
2
-agonists and inhaled corticosteroids, and eco
-
nomic issues related to the additional costs of these
medications may argue against routine use of inhaled med-
ication polypharmacy without evidence of efficacy. We
therefore conducted a randomized, double-blind, placebo-
controlled clinical trial to determine whether combining
tiotropium with salmeterol or fluticasone–salmeterol pro-
duces greater improvements in clinical outcomes for adults
with moderate or severe COPD compared with tiotropium
therapy alone.
METHODS
Design
We designed a parallel-group, 3-group, randomized,
double-blind, placebo-controlled trial in patients with
moderate or severe COPD that was conducted from Oc-
tober 2003 to January 2006. The study protocol has been
published elsewhere (17). The research ethics boards of all
participating centers approved the study, and all trial par-
ticipants provided written informed consent.
Setting and Participants
We enrolled patients with diagnosed moderate or se-
vere COPD from 27 Canadian medical centers. Twenty
centers were academic hospital– based pulmonary clinics, 5
were community-based pulmonary clinics, and 2 were
community-based primary care clinics. Eligible patients
had to have had at least 1 exacerbation of COPD that
required treatment with systemic steroids or antibiotics
within the 12 months before randomization. Additional
inclusion criteria were age older than 35 years; a history of
10 pack-years or more of cigarette smoking; and docu-
mented chronic airflow obstruction, with an FEV
1
–FVC
ratio less than 0.70 and a postbronchodilator FEV
1
less
than 65% of the predicted value.
We excluded patients with a history of physician-diag-
nosed asthma before 40 years of age; those with a history of
physician-diagnosed chronic congestive heart failure with
known persistent severe left ventricular dysfunction; those
receiving oral prednisone; those with a known hypersensi-
tivity or intolerance to tiotropium, salmeterol, or flutica-
sone–salmeterol; those with a history of severe glaucoma or
severe urinary tract obstruction, previous lung transplanta-
tion or lung volume reduction surgery, or diffuse bilateral
bronchiectasis; and those who were pregnant or were
breastfeeding. Persons with a recent COPD exacerbation
requiring oral or intravenous antibiotics or steroids were
required to wait until treatment with these agents had been
discontinued for 28 days before entering the study.
Randomization and Interventions
We randomly assigned patients to 1 of 3 treatment
groups for 52 weeks: tiotropium (Spiriva [Boehringer In-
gelheim Pharma, Ingelheim, Germany]), 18
g once daily,
plus placebo inhaler, 2 puffs twice daily; tiotropium, 18
g
once daily, plus salmeterol (Serevent [GlaxoSmithKline,
Research Triangle Park, North Carolina]), 25
g/puff, 2 puffs
twice daily; or tiotropium, 18
g once daily, plus fluticasone–
salmeterol (Advair [GlaxoSmithKline]), 250/25
g/puff,
2 puffs twice daily.
Randomization was done through central allocation of
a randomization schedule that was prepared from a com-
puter-generated random listing of the 3 treatment alloca-
tions, blocked in variable blocks of 9 or 12 and stratified by
site. Neither research staff nor patients were aware of the
treatment assignment before or after randomization.
All study patients were provided with inhaled albuterol
and were instructed to use it when necessary to relieve
symptoms. Any treatment with inhaled corticosteroids,
long-acting
2
-agonists, and anticholinergics that the pa
-
tient may have been using before entry was discontinued
on entry into the study. Therapy with other respiratory
medications, such as oxygen, antileukotrienes, and methyl-
xanthines, was continued in all patient groups.
Tiotropium was administered by using a Handihaler
device (Boehringer Ingelheim). Study drugs were adminis-
tered through a pressurized metered-dose inhaler using a
Context
Physicians use multiple medications to treat chronic ob-
structive pulmonary disease (COPD).
Contribution
In this multicenter trial, 449 adults with moderate or se-
vere COPD were randomly assigned to receive tiotropium
and placebo, tiotropium and salmeterol, or tiotropium and
fluticasone–salmeterol for 1 year. About 63%, 65%, and
60% of patients, respectively, had exacerbations. The third
group, but not the second group, had better lung function
and fewer hospitalizations than the first group.
Caution
Many patients discontinued assigned medications.
Implications
Adding fluticasone–salmeterol to tiotropium may improve
lung function and decrease hospitalizations, but it does
not affect reduce exacerbations in patients with moderate
or severe COPD.
—The Editors
Article Combination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
546 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 www.annals.org
spacer device (Aerochamber Plus, Trudell Medical, Lon-
don, Ontario, Canada), and patients were taught the cor-
rect inhalation technique to ensure adequate drug delivery.
The metered-dose inhalers containing placebo, salmeterol,
and fluticasone–salmeterol were identical in taste and ap-
pearance, and they were enclosed in identical tamper-proof
blinding devices. The medication canisters within the
blinding devices were stripped of any identifying labeling.
Adherence to therapy was assessed by weighing the re-
turned inhaler canisters.
Measurements and Outcomes
The primary outcome was the proportion of patients
in each treatment group who experienced a COPD exac-
erbation within 52 weeks of randomization. Respiratory
exacerbations were defined, according to the 2000 Aspen
Lung Conference Consensus definition, as “a sustained
worsening of the patient’s respiratory condition, from the
stable state and beyond normal day-to-day variations, ne-
cessitating a change in regular medication in a patient with
underlying COPD” (18). An acute change in regular
COPD medications was defined as physician-directed,
short-term use of oral or intravenous steroids, oral or intra-
venous antibiotics, or both therapies.
Secondary outcomes were the mean number of COPD
exacerbations per patient-year; the total number of exacer-
bations that resulted in urgent visits to a health care pro-
vider or emergency department; the number of hospitaliza-
tions for COPD; the total number of hospitalizations for
all causes; and changes in health-related quality of life,
dyspnea, and lung function. Health-related quality of life
was assessed by using the St. George’s Respiratory Ques-
tionnaire (19), dyspnea was assessed by using the Transi-
tional Dyspnea Index (20) and the dyspnea domain of the
Chronic Respiratory Disease Questionnaire (21), and lung
function was assessed by measuring the FEV
1
according to
established criteria of the American Thoracic Society.
Follow-up Procedures
Patients were monitored for exacerbations by monthly
telephone calls. Exacerbations and all secondary outcomes
were also assessed through patient visits at baseline and at
4, 20, 36, and 52 weeks after randomization. For every
suspected exacerbation, we contacted both the patient and
the patient’s treating physician to ensure that the medical
encounter had been prompted by acute respiratory symp-
toms and a full report, including physician, emergency de-
partment, and hospital records that described the circum-
stances of each suspected exacerbation, was prepared. The
assembled data from the visit for the suspected exacerba-
tion were presented to a blinded adjudication committee
for review, and the committee confirmed whether the en-
counter met the study definition of COPD exacerbation.
For the purposes of the trial, we considered that a patient
had experienced a new COPD exacerbation if he or she
had not been receiving oral steroids and antibiotics for at
least 14 days after the previous exacerbation.
Patients were followed for the full 52-week duration of
the trial, and primary and secondary outcomes were re-
corded throughout the 1-year period regardless of whether
patients had experienced an exacerbation or discontinued
treatment with study medications. We did not break the
study blinding for patients who prematurely discontinued
treatment with study medications.
Adverse events were captured by the research coordi-
nators through monthly patient telephone interviews and
at scheduled patient visits by using checklists of potential
side effects. Physicians rated events as expected or unex-
pected, and they were asked to rate event severity and at-
tribute causality of adverse events to the study drugs.
Statistical Analysis
We designed the study to detect an 18% absolute dif-
ference in the proportion of patients who had at least 1
exacerbation between the tiotropium plus placebo group
and the other 2 treatment groups. We chose this risk re-
duction on the basis of published clinical trial data dem-
onstrating that median rates of COPD exacerbation could
be reduced by 25% in patients treated with inhaled ste-
roids compared with those taking placebo (22). In addi-
tion, the trial steering committee, in consultation with a
survey of 16 Canadian respirologists, determined that a
20% difference in the proportion of relapse at 1 year be-
tween the tiotropium plus placebo group and the tiotro-
pium plus salmeterol group or tiotropium plus fluticasone–
salmeterol group was the minimal clinically significant
difference that would be important for the study to detect.
Assuming a baseline risk for exacerbation of 55%, an 18%
risk difference with an
value of 0.05, and 80% power, we
required 130 patients per group. To allow for a 5% drop-
out rate (Lachin formula) (23), we required a sample size
of 144 patients per group, or 432 patients in total.
The final analysis was conducted on an intention-to-
treat basis by using SAS software, version 9.0 (SAS Insti-
tute, Inc., Cary, North Carolina). Two pairwise compari-
sons were planned to compare the tiotropium plus placebo
group with the other 2 treatment groups. The study was
not designed or powered to compare differences between
the tiotropium plus salmeterol group and the tiotropium
plus fluticasone–salmeterol group. The primary compari-
son of the proportion of exacerbations in the tiotropium
plus placebo group versus the other 2 treatment groups was
done by using an unadjusted chi-square test. A logistic
regression procedure was then used to adjust the raw pro-
portions of exacerbations by using clinically important co-
variates (study site, age, sex, severity of airflow obstruction
at baseline, use of medication and home oxygen before
study entry, current smoking status, and comorbid ill-
nesses) that could influence outcomes. The statistician who
performed the analysis was initially blinded to patient
group assignments.
For the primary analysis, we conservatively assumed
that patients who prematurely discontinued use of study
ArticleCombination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
www.annals.org 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 547
medications and were lost to follow-up before having an
exacerbation event did not have an event. Other trials that
have examined COPD exacerbations as an outcome have
made the same assumption (7, 24). However, we also per-
formed 2 sensitivity analyses, in which we assumed that all
patients who prematurely withdrew from the study had an
exacerbation or that they had exacerbations at the same
rate as those who continued in the study.
Analysis of the total number of COPD exacerbations
per patient-year of observation was done according to
methods using a weighted Poisson regression model ap-
proach that accounted for heterogeneity in exacerbation
rates among patients by incorporating an overdispersion
parameter (25). This intention-to-treat analysis retained
patients in the group to which they were randomly as-
signed and counted exacerbations that occurred during the
1-year study period regardless of whether the patient con-
tinued to take study medications, as per Consolidated
Standards of Reporting Trials (CONSORT) guidelines
(26). An alternative compliance analysis was also done that
incorporated the overdispersion parameter and censored all
patients after they prematurely stopped using study medi-
cations.
Continuous outcomes, such as the values for the St.
George’s Respiratory Questionnaire, the Transitional Dys-
pnea Index, and the FEV
1
, were analyzed by using repeat
-
ed-measures mixed models that provided estimates for the
treatment minus placebo difference at 52 weeks, controlled
for baseline, treatment, visit, and visit-by-treatment inter-
action effects. The frequencies of urgent visits and hospi-
talizations were compared by using incidence rate ratios
that were estimated from weighted Poisson regression
models. The Kaplan–Meier estimates of the time to first
exacerbation were tested for significance by using the log-
rank test. Subsequently, Cox proportional hazards model-
ing was done to adjust for baseline variables that may affect
the time to next exacerbation. Because survival curves for
tiotropium plus placebo and tiotropium plus salmeterol
Figure 1. Study flow diagram.
COPD chronic obstructive pulmonary disease.
Article Combination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
548 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 www.annals.org
crossed, the tiotropium plus salmeterol group was not in-
cluded in the Cox proportional hazards models.
Role of the Funding Sources
The Canadian Institutes of Health Research and The
Ontario Thoracic Society provided peer-reviewed funding
for this study. The sponsors of this study had no role in
study design, data collection, data analysis, data interpreta-
tion, or writing of the report. The corresponding author
had full access to all the data in the study and had final
responsibility for the decision to submit for publication.
RESULTS
Sample
Nine hundred five patients were screened, and 629
(70%) were eligible for the study (Figure 1). Of these 629
patients, 130 declined to participate and 50 were excluded
for other reasons (such as planned prolonged travel out of
Canada during the study period). Four hundred fifty-one
randomization numbers were assigned; however, 2 patients
were withdrawn before undergoing randomization and
never received study medications. One of these patients
was withdrawn because metastatic lung cancer was discov-
ered on the day of the randomization visit, and 1 was
withdrawn because her private insurance company would
not provide health care coverage if she entered a clinical
trial. Therefore, 449 patients underwent randomization.
One hundred fifty-six patients were assigned to receive
tiotropium plus placebo, 148 were assigned to receive
tiotropium plus salmeterol, and 145 were assigned to re-
ceive tiotropium plus fluticasone–salmeterol. The 3 groups
had similar baseline characteristics (Table 1). A similar
proportion of patients in each group was receiving inhaled
corticosteroids or inhaled corticosteroids and long-acting
2
-agonist combination products at the time of random
-
ization (77%, 79%, and 73% of patients in the tiotropium
plus placebo, tiotropium plus salmeterol and tiotropium plus
fluticasone–salmeterol groups, respectively).
During the 12-month trial, 7%, 6%, and 8% of pa-
tients in the tiotropium plus placebo, tiotropium plus sal-
meterol, and tiotropium plus fluticasone–salmeterol
groups, respectively, enrolled in a pulmonary rehabilitation
program; 3%, 1%, and 3%, repectively, quit smoking; 4%,
5%, and 5%, respectively, began using home oxygen; and
Table 1. Baseline Characteristics
Characteristic Tiotropium Plus
Placebo
(
n
156)
Tiotropium Plus
Salmeterol
(
n
148)
Tiotropium Plus
Fluticasone–Salmeterol
(
n
145)
Mean age (SD), y 68.1 (8.9) 67.6 (8.2) 67.5 (8.9)
Women, % 46.2 42.6 42.1
White, % 97.4 98.0 99.3
Body mass index (SD), kg/m
2
27.6 (6.0) 27.2 (5.8) 27.8 (6.2)
Smoking status
Current smoker, % 26.9 24.3 32.4
Pack-year history (SD), n 51.8 (28.0) 48.7 (27.1) 50.3 (23.1)
Duration of reported dyspnea (SD), y 11.3 (8.8) 10.7 (8.7) 10.3 (8.1)
Medication use, %
Ipratropium 34.4 44.5 42.9
Tiotropium 57.8 55.5 46.4
Short-acting
2
-agonists
77.9 82.2 80.0
Long-acting
2
-agonists
11.7 19.2 17.9
Combination of inhaled steroid and long-acting
2
-agonist
51.9 43.9 45.7
Inhaled corticosteroids 25.3 34.9 27.1
Antileukotrienes 2.0 2.7 2.9
Methylxanthines 7.1 11.6 5.7
Home oxygen 11.7 13.7 10.0
Influenza vaccine 74.8 74.0 77.3
Prebronchodilator lung function
Mean FEV
1
(SD), L
1.01 (0.38) 1.00 (0.44) 1.05 (0.38)
Mean percent predicted FEV
1
(SD)
38.7 (12.9) 38.0 (13.1) 39.4 (11.9)
Mean FVC (SD), L 2.30 (0.69) 2.36 (0.80) 2.39 (0.75)
Mean FEV
1
–FVC ratio (SD)
0.44 (0.11) 0.43 (0.12) 0.45 (0.12)
Postbronchodilator lung function
Mean FEV
1
(SD), L
1.08 (0.40) 1.08 (0.43) 1.12 (0.41)
Mean percent predicted FEV
1
(SD)
42.1 (13.5) 41.2 (13.0) 42.2 (12.2)
Mean FVC (SD), L 2.50 (0.83) 2.51 (0.79) 2.51 (0.83)
Mean dyspnea index score (SD) 6.3 (1.8) 6.5 (1.9) 6.5 (2.0)
Comorbid conditions, %
Hypertension 43.0 43.9 41.4
Coronary artery disease 16.0 21.0 22.8
Congestive heart failure 3.9 1.4 3.5
Cancer 5.8 9.5 6.9
ArticleCombination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
www.annals.org 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 549
67%, 61%, and 72%, respectively, received the influenza
vaccine.
Seventy-four of 156 patients (47%) in the tiotropium
plus placebo group discontinued use of study medications
before completing 1 year of therapy, compared with 64 of
148 patients (43%) in the tiotropium plus salmeterol
group (P 0.54) and 37 of 145 patients (26%) in the
tiotropium plus fluticasone–salmeterol group (P 0.001).
Premature discontinuation of study medication was largely
due to patients’ perceived lack of medication efficacy or
physician-directed discontinuation of study therapy be-
cause of a patient’s deteriorating health status. Of the pa-
tients who discontinued use of study medications, 74% in
the tiotropium plus placebo group, 70% in the tiotropium
plus salmeterol group, and 54% in the tiotropium plus
fluticasone–salmeterol group received an open-label in-
haled steroid and long-acting
2
-agonist combination in
-
haler for the remainder of the study.
Primary Outcome
The proportion of patients who experienced at least 1
COPD exacerbation during the trial did not significantly
differ between the tiotropium plus placebo group and the 2
other treatment groups (Table 2). In the tiotropium plus
placebo group, 62.8% of patients experienced an exacerba-
tion, compared with 64.8% in the tiotropium plus salme-
terol group and 60.0% in the tiotropium plus fluticasone–
salmeterol group. The absolute risk reduction was 2.0
percentage points (95% CI, 12.8 to 8.8 percentage points)
for tiotropium plus salmeterol versus tiotropium plus pla-
cebo (P 0.71) and 2.8 percentage points (CI, 8.2 to
13.8 percentage points) for tiotropium plus fluticasone–
salmeterol versus tiotropium plus placebo (P 0.62).
Table 2 shows the results of sensitivity analyses that
made alternative assumptions for patients who prematurely
withdrew from the trial. Results of the sensitivity analyses
were statistically nonsignificant; however, shifts in the
point estimates and 95% confidence bounds were in the
direction favoring tiotropium plus salmeterol and tiotro-
pium plus fluticasone–salmeterol.
The unadjusted odds ratio of risk for exacerbation was
1.03 (CI, 0.63 to 1.67) with tiotropium plus salmeterol
versus tiotropium plus placebo and 0.85 (CI, 0.52 to 1.38)
for tiotropium plus fluticasone–salmeterol versus tiotro-
pium plus placebo. Adjustments for clinically important
covariates (site, age, sex, severity of airflow obstruction at
baseline, medication and home oxygen use before entering the
study, current smoking status, and comorbid illnesses) did not
appreciably change the odds ratios or CIs around the esti-
Table 2. Exacerbations of Chronic Obstructive Pulmonary Disease and Health Care Utilization during 1 Year*
Outcome Tiotropium
plus Placebo
(
n
156)
Tiotropium plus
Salmeterol
(
n
148)
Tiotropium
plus Fluticasone–
Salmeterol
(
n
145)
Primary analysis†
Patients with 1 acute exacerbation of COPD, n (%) 98 (62.8) 96 (64.8) 87 (60.0)
Absolute risk reduction compared with tiotropium plus placebo (95% CI),
percentage points
2.0 (12.8 to 8.8) 2.8 (8.2 to 13.8)
Sensitivity analysis 1‡
Patients with 1 acute exacerbation of COPD, n (%) 117 (75.0) 107 (72.3) 96 (66.2)
Absolute risk reduction compared with tiotropium plus placebo (95% CI),
percentage points
2.7 (7.2 to 12.6) 8.8 (1.5 to 19.0)
Sensitivity analysis
Patients with 1 acute exacerbation of COPD, n (%) 112 (71.8) 104 (70.3) 93 (64.1)
Absolute risk reduction compared with tiotropium plus placebo (95% CI),
percentage points
1.5 (8.7 to 11.7) 7.6 (2.9 to 18.1)
Exacerbations of COPD
All exacerbations, n 222 226 188
Duration of follow-up, patient-years 138.0 129.4 137.1
Mean exacerbations per patient-year, n 1.61 1.75 1.37
Incidence rate ratio compared with tiotropium plus placebo (95% CI) 1.09 (0.84 to 1.40) 0.85 (0.65 to 1.11)
Urgent physician or emergency department visits for COPD exacerbation
Total, n 185 184 149
Incidence rate ratio compared with tiotropium plus placebo (95% CI) 1.06 (0.87 to 1.30) 0.81 (0.65 to 1.01)
Hospitalizations for acute exacerbations of COPD
Total, n 49 38 26
Incidence rate ratio compared with tiotropium plus placebo (95% CI) 0.83 (0.54 to 1.27) 0.53 (0.33 to 0.86)
All-cause hospitalizations
Total, n 62 48 41
Incidence rate ratio compared with tiotropium plus placebo (95% CI) 0.83 (0.57 to 1.21) 0.67 (0.45 to 0.99)
* COPD chronic obstructive pulmonary disease.
Assuming that all patients who were lost to follow-up did not have an exacerbation.
Assuming that all patients who were lost to follow-up had an exacerbation.
§ Assuming that all patients who were lost to follow-up had exacerbations at the same rate as those who continued in the study.
Accounting for between-patient variability.
Article Combination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
550 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 www.annals.org
mates; adjusted odds ratios were 1.01 (CI, 0.59 to 1.73)
and 0.84 (CI, 0.47 to 1.49), respectively.
Secondary Outcomes
Exacerbations per Patient-Year
The mean number of COPD exacerbations per pa-
tient-year of observation did not significantly differ be-
tween the tiotropium plus placebo group and the other 2
treatment groups. Patients who received tiotropium plus
placebo experienced 1.61 exacerbations per patient-year of
follow-up, compared with 1.75 exacerbations per patient-
year in the tiotropium plus salmeterol group and 1.37 ex-
acerbations per patient-year in the tiotropium plus flutica-
sone–salmeterol group (Table 2). The incidence rate ratio
was 1.09 (CI, 0.84 to 1.40) for tiotropium plus salmeterol
compared with tiotropium plus placebo (P 0.51) and
0.85 (CI, 0.65 to 1.11) for tiotropium plus fluticasone–
salmeterol versus tiotropium plus placebo (P 0.24).
Alternative Compliance Analysis of Mean Number of
Exacerbations per Patient-Year
An alternative compliance analysis was done in which
patients were censored after they prematurely discontinued
use of study medications. This analysis showed that pa-
tients who were randomly assigned to receive tiotropium
plus placebo experienced 1.66 exacerbations per patient-
year, compared with 1.78 exacerbations per patient-year in
the tiotropium plus salmeterol group and 1.31 exacerba-
tions per patient-year in the tiotropium plus fluticasone–
salmeterol group. The incidence rate ratio was 1.07 (CI,
0.74 to 1.55) for tiotropium plus salmeterol versus tiotro-
pium plus placebo (P 0.71) and 0.79 (CI, 0.54 to 1.14)
for tiotropium plus fluticasone–salmeterol versus tiotro-
pium plus placebo (P 0.21).
Time to First Exacerbation
The median time to first exacerbation was 130 days in
the tiotropium plus placebo group, 128 days in the tiotro-
pium plus salmeterol group, and 217 days in the tiotro-
pium plus fluticasone–salmeterol group (Figure 2). These
differences were not statistically significant. Compared
with tiotropium plus placebo, tiotropium plus fluticasone–
salmeterol did not statistically prolong the time to first
exacerbation; the adjusted hazard ratio was 0.80 (CI, 0.60
to 1.08) (P 0.15).
Hospitalizations
Patients treated with tiotropium plus fluticasone–sal-
meterol had lower rates of severe exacerbations of COPD
requiring hospitalization than did patients treated with
tiotropium plus placebo; the incidence rate ratio was 0.53
(CI, 0.33 to 0.86) (P 0.01) (Table 2). All-cause hospi-
talizations were also reduced in patients treated with tiotro-
pium plus fluticasone–salmeterol compared with patients
treated with tiotropium plus placebo (P 0.04) (Table 2).
Similar significant benefits were not seen for the group
treated with tiotropium plus salmeterol compared with
tiotropium plus placebo.
Health-Related Quality of Life
One year of therapy with tiotropium plus salmeterol
or tiotropium plus fluticasone–salmeterol improved health-
related quality of life significantly more than did therapy
with tiotropium plus placebo. The 1-year change in total
score on the St. George’s Respiratory Questionnaire was
4.5 points in the tiotropium plus placebo group, 6.3
points in the tiotropium plus salmeterol group (P 0.02),
and 8.6 points in the tiotropium plus fluticasone–salme-
terol group (P 0.01) (Figure 3).
Lung Function
Tiotropium plus fluticasone–salmeterol improved the
FEV
1
more than did tiotropium plus placebo (Figure 3).
Over 52 weeks, the absolute prebronchodilator FEV
1
in
-
creased by 0.027 L in the tiotropium plus placebo group
compared with 0.086 L in the tiotropium plus fluticasone–
salmeterol group (P 0.049), and the percent predicted
FEV
1
increased by 1.3% in the tiotropium plus placebo
group compared with 4.6% in the tiotropium plus flutica-
sone–salmeterol group (P 0.005). Lung function was
not significantly better in the tiotropium plus salmeterol
group than in the tiotropium plus placebo group.
Figure 2. Kaplan–Meier estimates of the probability of
remaining free of exacerbations, according to treatment
assignment.
The unadjusted hazard ratio was 1.02 (95% CI, 0.77 to 1.37) for tiotro-
pium plus placebo versus tiotropium plus salmeterol (P 0.87) and
0.80 (CI, 0.60 to 1.08) for tiotropium plus placebo versus tiotropium
plus fluticasone–salmeterol (P 0.15). COPD chronic obstructive
pulmonary disease.
ArticleCombination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
www.annals.org 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 551
Dyspnea
Dyspnea scores improved over 1 year of observation
but did not significantly differ among the treatment
groups. Mean transitional dyspnea index scores at 1 year
were 1.78 (SD, 4.08) in the tiotropium plus placebo
group, 1.40 (SD, 3.96) in the tiotropium plus salmeterol
group (P 0.35), and 1.84 (SD, 3.86) in the tiotropium
plus fluticasone–salmeterol group (P 0.38).
Deaths and Adverse Events
During the study, 4 patients (2.6%) in the tiotropium
plus placebo group died, as did 6 patients (4.1%) each in
the tiotropium plus salmeterol and tiotropium plus flutica-
sone–salmeterol groups (Table 3). In total, 28 patients ex-
perienced serious adverse events associated with hospital-
ization (other than for COPD), admission to the intensive
care unit, or death. Ten serious adverse events occurred in
the tiotropium plus placebo group, 9 occurred in the
tiotropium plus salmeterol group, and 9 occurred in the
tiotropium plus fluticasone–salmeterol group.
DISCUSSION
We found that adding fluticasone–salmeterol or sal-
meterol to therapy with tiotropium did not reduce the
proportion of patients who experienced 1 or more COPD
exacerbations during 1 year. The addition of fluticasone–
salmeterol to tiotropium therapy resulted in a 2.8-percent-
age–point absolute reduction in the percentage of patients
who experienced at least 1 exacerbation during 1 year. Be-
cause our trial was powered to show a larger expected per-
centage difference in these proportions, we could not show
a statistically significant difference in this outcome, if the
difference is real and not due to chance.
Of note, treatment with tiotropium plus fluticasone–
salmeterol improved clinically important secondary out-
comes. The rates of hospitalizations for COPD exacerba-
tions and all-cause hospitalizations were statistically lower
in patients who received tiotropium plus fluticasone–sal-
meterol than in those who received tiotropium plus pla-
cebo. This finding suggests that although adding flutica-
sone–salmeterol to tiotropium therapy did not affect
overall exacerbation rates, combined therapy of tiotropium
plus fluticasone–salmeterol may modify the severity of ex-
acerbations, so that these patients may be less likely to
require hospitalization when they do experience exacerba-
tions. In contrast, therapy with tiotropium plus salmeterol
did not result in lower hospitalization rates.
Other important secondary outcomes, such as health-
related quality of life and lung function, were also im-
proved by adding fluticasone–salmeterol to tiotropium
therapy. A difference of 4 points in total score on the St.
George’s Respiratory Questionnaire has been shown to be
clinically significant. Patients treated with tiotropium plus
fluticasone–salmeterol experienced an improvement in to-
tal scores on the St. George’s Respiratory Questionnaire
that was more than 4 points greater than that in those
treated with tiotropium plus placebo, indicating that the
differences between the 2 treatment groups in health-
related quality of life were statistically and clinically signif-
icant.
An English-language article search of MEDLINE to
November 2006 revealed several clinical trials that have
demonstrated the efficacy of tiotropium (4 –7), salmeterol
(8–10), or combination products with inhaled steroids
plus long-acting
2
-agonists (11–14) when used individu
-
ally for treating COPD. In addition, 2 recent studies with
a crossover design have evaluated the effects of 2 weeks and
Figure 3. Changes in health-related quality of life and FEV
1
over 1 year.
Top. Scores on the St. George’s Respiratory Questionnaire (SGRQ).
Lower scores indicate improvements in quality of life. P 0.02 for
tiotropium plus placebo versus tiotropium plus salmeterol at 52 weeks;
P 0.01 for tiotropium plus placebo versus tiotropium plus fluticasone–
salmeterol at 52 weeks. Bottom. Mean prebronchodilator FEV
1
. P
0.87 for tiotropium plus placebo versus tiotropium plus salmeterol at 52
weeks; P 0.049 for tiotropium plus placebo versus tiotropium plus
fluticasone–salmeterol at 52 weeks.
Article Combination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
552 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 www.annals.org
6 weeks of therapy with tiotropium plus formoterol (a
long-acting
-agonist) on lung function. However, these
studies did not assess clinical outcomes other than daytime
and nighttime albuterol use (27, 28). Thus, we believe that
our study is the first clinical trial to evaluate clinically im-
portant outcomes in patients with COPD treated with
combinations of different classes of agents, and our study
provides clinical trial evidence to potentially support
COPD guideline recommendations.
Our results are somewhat at odds with those of other
studies and of a meta-analysis suggesting that treatment of
COPD with the inhaled corticosteroid fluticasone may de-
crease mean rates of COPD exacerbation per patient-year
(22, 29). However, these discrepancies may be due to dif-
ferences among study analytic techniques rather than ac-
tual biological differences. We used recommended tech-
niques to analyze the mean number of exacerbations per
patient-year by performing an intention-to-treat analysis
and using a weighted Poisson regression model that pro-
vides a more accurate estimation of the effect of a medica-
tion on exacerbations by accounting for all sources of vari-
ability (25). However, this type of analysis, although
statistically correct, widens the CIs around estimates of
mean exacerbation rates. Our results show a tendency to-
ward fewer exacerbations per patient-year in the group
treated with tiotropium plus fluticasone–salmeterol, and if
our sample had been larger, this difference, if real, may
have become statistically significant.
An important consideration in a trial that does not
find a statistically significant treatment effect for the pri-
mary outcome is whether the negative findings were due to
a true absence of clinically important effects or a lack of
statistical power. The CIs for our primary outcome of the
proportion of patients who experienced a COPD exacer-
bation, and for the associated sensitivity analyses, can be
used to determine the effect size that can be “ruled out” by
our results (Table 2). For the comparison of tiotropium
plus placebo with tiotropium plus fluticasone–salmeterol,
the point estimate for the absolute difference in exacerba-
tion proportions varies from 2.8 percentage points favoring
tiotropium plus fluticasone–salmeterol (assuming that pa-
tients who withdrew had no exacerbations) to 8.8 percent-
age points favoring tiotropium plus fluticasone–salmeterol
(assuming that all patients who withdrew early had an ex-
acerbation), and the 95% CIs range from 1.5 to 8.2 per-
centage points favoring tiotropium plus placebo and from
13.8 to 19.0 percentage points favoring tiotropium plus
fluticasone–salmeterol. Of note, the 19-percentage point
difference in exacerbation proportions favoring tiotropium
plus fluticasone–salmeterol seen in the sensitivity analysis is
the largest possible effect that can be consistent with the
data; however, this difference, if real, might be clinically
significant.
A potential limitation of our study is that more pa-
tients in the tiotropium plus placebo and the tiotropium
plus salmeterol groups prematurely stopped taking study
medications compared with patients in the tiotropium plus
fluticasone–salmeterol group. Many patients stopped using
the study medications because of a perceived lack of effi-
cacy, and many crossed over to open-label fluticasone–sal-
meterol on the advice of their physicians. Study inhalers
were identical in taste and appearance, and blinding de-
vices were all returned intact; it is therefore unlikely that
patients prematurely discontinued use of study medica-
tions because they realized that they were not receiving
fluticasone–salmeterol.
Other clinical trials in COPD have dealt with the issue
of differential compliance by dropping patients from the
trial when they discontinued use of study medications.
These trials did not record exacerbations that occurred af-
ter use of study medications was stopped (12, 14, 22). In
contrast, we continued to follow patients for the full dura-
tion of the trial, even after they discontinued use of study
medications, and we recorded subsequent exacerbations in
Table 3. Mortality and Adverse Event Rates
Adverse Event Tiotropium
plus Placebo
(
n
156)
Tiotropium
plus Salmeterol
(
n
148)
Tiotropium
plus Fluticasone–
Salmeterol
(
n
145)
All-cause deaths, n (%) 4 (2.6) 6 (4.1) 6 (4.1)
Serious adverse events, n (%) 10 (6.4) 9 (6.1) 9 (6.2)
Patients who stopped the trial because of an adverse event, n (%) 8 (5.1) 6 (4.1) 8 (5.5)
Patients with adverse events, n (%)
Total 37 (23.7) 32 (21.6) 44 (30.3)
Respiratory failure leading to mechanical ventilation or death 7 (4.5) 3 (2.0) 2 (1.4)
Pneumonia leading to mechanical ventilation or death 0 (0) 1 (0.7) 1 (0.7)
Cancer (other than skin) 1 (0.6) 1 (0.7) 1 (0.7)
Myocardial infarction or acute arrhythmia 2 (1.3) 2 (1.4) 2 (1.4)
Dry or sore mouth 10 (6.4) 10 (6.8) 15 (10.3)
Oral candidiasis 0 (0) 1 (0.7) 6 (4.1)
Voice hoarseness 1 (0.6) 2 (1.4) 9 (6.2)
Tremor 0 (0) 2 (1.4) 1 (0.7)
Dizziness 3 (1.9) 3 (2.0) 1 (0.7)
Coughing on administration of study medications 2 (1.3) 3 (2.0) 0 (0)
ArticleCombination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
www.annals.org 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 553
our intention-to-treat analysis, as recommended in the
CONSORT guidelines (26). This unavoidable crossover
effect may have diluted differences in the mean number of
exacerbations per patient-year among the 3 groups. How-
ever, a secondary compliance analysis of our results, in
which patients were censored when they prematurely dis-
continued use of study medications, still failed to show
statistically significant differences in mean exacerbation
rates per patient-year.
The fact that we did observe significant positive effects
in quality of life, lung function, and hospitalization rates
for patients who received tiotropium plus fluticasone–sal-
meterol compared with patients who received tiotropium
plus placebo in the intention-to-treat analysis (even though
more than one third of the patients in the latter group
crossed over to open-label fluticasone–salmeterol for at
least part of the study) argues for the strength of the ben-
eficial effect of tiotropium plus fluticasone–salmeterol on
these outcomes.
An important consideration when deciding whether to
treat patients with COPD with fluticasone–salmeterol is
that patients with advanced COPD are often elderly, and
long-term treatment with inhaled corticosteroids has been
associated with reductions in bone mineral density and
osteoporosis in these patients (30). The clinical benefits of
combining these drug classes must be balanced against the
additional expense and potential inconvenience of adding
another inhaler to an already complex treatment regimen
(31). Nonetheless, our findings suggest that combined
therapy with fluticasone–salmeterol plus tiotropium may
have beneficial effects on quality of life, lung function, and
hospitalizations without an increase in serious adverse
events over the course of 1 year. Further methodologically
rigorous, large studies are required to support our findings
and to determine whether combined therapy with flutica-
sone–salmeterol plus tiotropium leads to definitive im-
provements in rates of COPD exacerbation.
From The Ottawa Health Research Institute and University of Ottawa,
Ottawa, Ontario, Canada; The University of Toronto, Toronto, On-
tario, Canada; McMaster University, Hamilton, Ontario, Canada;
Queen’s University, Kingston, Ontario, Canada; Scarborough Centenary
Hospital, Scarborough, Ontario, Canada; University of Western On-
tario, London, Ontario, Canada; St. Lawrence Medical Clinic, Morris-
burg, Ontario, Canada; University of British Columbia, Vancouver,
British Columbia, Canada; Centre de Recherche, Hoˆpital Laval, Univer-
site´ Laval, Que´bec, Que´bec, Canada; McGill University, Montre´al, Que´-
bec, Canada; Dalhousie University, Halifax, Nova Scotia, Canada; Uni-
versity of Manitoba, Winnipeg, Manitoba, Canada; University of New
Brunswick, St. John, New Brunswick, Canada; University of Saskatche-
wan, Saskatoon, Saskatchewan, Canada; University of Calgary, Calgary,
Alberta, Canada; University of Alberta, Edmonton, Alberta, Canada;
Memorial University, St. John’s, Newfoundland, Canada; and The
Woolcock Institute of Medical Research, Sydney, Australia.
Acknowledgments: The authors thank the following people for their
assistance. Study investigators: Drs. Elizabeth Powell, Gregory Berg,
Thomas Baitz, Matthew Stanbrook, Ted Marras. Study coordinators: Gay
Pratt, Shobha Chakravorty, Rommel Mangaser, Elizabeth Sukhdeo,
Heidi Haupt, Margot Underwood, Diane Conley, Kathleen Currie,
Sarah Goodwin, Linda Hui, Gladys Wolters, Erin Condon Pennell,
Bruce Krip, Kim Danovitch, Myra Slutsky, Marie-Jose´e Breton, Jose´e
Picard, Brigitte Jean, Lenny Scharfstein, Janet Baron, Janet Knechtel,
Andrea Dale, Scott Fulton, Ian McBride, Veronica Harris-McAllister,
Tracy Bonifacio, Deborah Sciberras, Nicole Marten, Kym Wiebe,
Shauna Leeson, Patricia McClean, Pearl Latty, Krisha Berg, Cheryl
McIntyre, Wendy Casselman, Wendy Hoogeveen, Goulnar Kasym-
janova, Sylvain Gagne´, Ginette Ferguson, Bonnie Chubb, Lisa Cour-
neya. Study pharmacists: Anne Marie Dugal, Susan Fetzer. Data manag-
ers: Mohammed Jahangir Kabir, Sheryl Domingo. Statistical consultant:
Jennifer Clinch. They also thank Boehringer Ingelheim, Inc. (Ridgefield,
Connecticut), for supplying placebo inhalers and blinding devices and
Trudell Medical, Inc. (London, Ontario, Canada), for supplying Aero-
chamber Plus spacer devices.
Grant Support: By the Canadian Institutes of Health Research (grant
MCT-63139; $1 464 139) and the Ontario Thoracic Society ($50 000).
Dr. Aaron is supported by a Canadian Institutes of Health Research New
Investigator Award. This study was not funded by the pharmaceutical
industry.
Potential Financial Conflicts of Interest: Consultancies: S.D. Aaron
(AstraZeneca, Boehringer Ingelheim), F. Maltais (ALTANA Pharma,
Boehringer Ingelheim, GlaxoSmithKline), J. Bourbeau (Boehringer In-
gelheim, GlaxoSmithKline, Pfizer), M. Balter (Boehringer Ingelheim,
GlaxoSmithKline), S. Sharma (AstraZeneca, Boehringer Ingelheim,
GlaxoSmithKline), G. Bishop (AstraZeneca, GlaxoSmithKline), R. Cowie
(ALTANA Pharma, GlaxoSmithKline), S. Field (ALTANA Pharma,
AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb,
GlaxoSmithKline, Johnson & Johnson, Merck & Co. Inc., Novartis,
Pfizer Inc., Wyeth), P. Hernandez (Actelion, ALTANA Pharma, AstraZen-
eca, Boehringer Ingelheim, GlaxoSmithKline, Pfizer Inc.), R. Rivington,
J. Road (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmithKline),
D. Marciniuk (ALTANA Pharma, Boehringer Ingelheim, GlaxoSmith-
Kline, Pfizer Inc.), G. Cox (AstraZeneca, Boehringer Ingelheim, Pfizer
Inc.), G. Ford (Abbott Canada, ALTANA Pharma Canada Inc., Astra-
Zeneca, Boehringer Ingelheim Canada Ltd., GlaxoSmithKline, Pfizer
Canada), K. Chapman (ALTANA Pharma, AstraZeneca, Biovail, Boehr-
inger Ingelheim, Genpharm, GlaxoSmithKline, Hoffmann-La Roche,
Merck Frosst Laboratories, Novartis, Pfizer Inc., Roche, Schering-
Plough, Telacris), M. FitzGerald (3M, ALTANA Pharma, AstraZeneca,
Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche); Hono-
raria: S.D. Aaron (Boehringer Ingelheim), F. Maltais (ALTANA
Pharma, Boehringer Ingelheim, GlaxoSmithKline) J. Bourbeau (Astra-
Zeneca, Boehringer Ingelheim, Pfizer, GlaxoSmithKline), M. Balter
(GlaxoSmithKline), A. McIvor (ALTANA Pharma, AstraZeneca, Boehr-
inger Ingelheim, GlaxoSmithKline, Merck Frosst Laboratories, Novartis), S.
Sharma (AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), G. Bishop
(AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline), R. Cowie
(ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline),
S. Field (ALTANA Pharma, AstraZeneca, Bayer, Boehringer Ingelheim,
Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck & Co.
Inc., Pfizer Inc., Wyeth), A. Hirsch (GlaxoSmithKline), P. Hernandez
(Actelion, ALTANA Pharma, AstraZeneca, Boehringer Ingelheim,
GlaxoSmithKline, Pfizer Inc.), R. Rivington (AstraZeneca, Pfizer Inc.), J.
Road (Boehringer Ingelheim), D. Marciniuk (ALTANA Pharma, Boehr-
inger Ingelheim, GlaxoSmithKline, Pfizer Inc.), G. Cox (AstraZeneca,
Boehringer Ingelheim, GlaxoSmithKline, Merck & Co. Inc., Pfizer Inc.),
G. Ford (Abbott Canada, ALTANA Pharma Canada Inc., AstraZeneca,
Boehringer Ingelheim Canada Ltd., GlaxoSmithKline, Merck Canada,
Pfizer Canada), K. Chapman (3M, ALTANA Pharma, AstraZeneca,
Article Combination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
554 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 www.annals.org
Boehringer Ingelheim, GlaxoSmithKline, Merck Frosst Laboratories, Novar-
tis, Pfizer Inc., Telacris), M. FitzGerald (3M, ALTANA Pharma, Astra-
Zeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La Roche);
Grants received: F. Maltais (ALTANA Pharma, Boehringer Ingelheim, Glaxo
SmithKline, Merck), J. Bourbeau (ALTANA Pharma, AstraZeneca, Boehr-
inger Ingelheim, GlaxoSmithKline, Novartis, Pfizer), G. Bishop (Astra-
Zeneca, GlaxoSmithKline), S. Field (AstraZeneca, Boehringer Ingelheim,
GlaxoSmithKline), P. Hernandez (Boehringer Ingelheim), J. Road
(Boehringer Ingelheim), D. Marciniuk (ALTANA Pharma, Boehringer
Ingelheim, GlaxoSmithKline, Pfizer Inc.), G. Ford (Alberta Lung Asso-
ciation/AstraZeneca/Boehringer Ingelheim/GlaxoSmithKline, ALTANA
Pharma, AstraZeneca, Boehringer Ingelheim, Calgary Health Region,
Canadian Institutes of Health Research, GlaxoSmithKline, Pfizer Canada,
University of British Columbia/GlaxoSmithKline), K. Chapman (3M,
ALTANA Pharma, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim,
GlaxoSmithKline, Hoffmann-La Roche, Merck Frosst Laboratories,
Novartis, Roche, Telacris, Theratechnologies), M. FitzGerald (3M,
ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,
Hoffmann-La Roche; Other: F. Maltais (AstraZeneca), P. Hernandez
(ALTANA Pharma, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,
Novartis), G. Cox (AstraZeneca, GlaxoSmithKline).
Requests for Single Reprints: Shawn Aaron, MD, The Ottawa Hospi-
tal, General Campus, 501 Smyth Road, Ottawa, Ontario K1H 8L6,
Canada; e-mail, saaron@ohri.ca.
Current author addresses and author contributions are available at www
.annals.org.
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ArticleCombination Inhaler Therapy for Chronic Obstructive Pulmonary Disease
www.annals.org 17 April 2007 Annals of Internal Medicine Volume 146 • Number 8 555
Current Author Addresses: Dr. Aaron and Ms. Vandemheen: The Ot-
tawa Hospital, Mailbox 211, 501 Smyth Road, Ottawa, Ontario K1H
8L6, Canada.
Dr. Fergusson: The Ottawa Hospital, Mailbox 201-CEP Unit, 501
Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
Dr. Maltais: Hoˆpital Laval, 2725 chemin Sainte-Foy, Que´bec, Que´bec
G1V 4G5, Canada.
Dr. Bourbeau: Montreal Chest Institute Foundation, McGill University
Health Centre, 3650 rue Saint-Urbain, Montre´al, Que´bec H2X 2P4,
Canada.
Dr. Goldstein: 82 Buttonwood Avenue, West Park Healthcare Centre,
Toronto, Ontario M6M 2J5, Canada.
Dr. Balter: 640-600 University Avenue, Mount Sinai Hospital, Toronto,
Ontario M5G 1X5, Canada
Dr. O’Donnell: 102 Stuart Street, Richardson House, Kingston, Ontario
K7L 2V6, Canada.
Dr. McIvor: 50 Charlton Avenue East, St. Joseph’s Healthcare, Hamil-
ton, Ontario L8N 4A6, Canada.
Dr. Sharma: St. Boniface General Hospital, Bg034-409 Tache Avenue,
Winnipeg, Manitoba R2H 2A6, Canada.
Dr. Bishop: 640 Manawagonish Road, St. John, New Brunswick E2M
3W5, Canada.
Dr. Anthony: Scarborough Professional Centre, 423-1371 Neilson
Road, Scarborough, Ontario M1B 4Z8, Canada.
Dr. Cowie: Faculty of Medicine, Health Science Centre, 3330 Hospital
Drive NW, Calgary, Alberta T2N 4N1, Canada.
Dr. Field: Foothills Medical Centre, 1403 29 Street NW, Calgary, Al-
berta T2N 2T9, Canada.
Dr. Hirsch: Sir Mortimer B. Davis Jewish General Hospital, 3755 che-
min Coˆte-Sainte-Catherine, Montre´al, Que´bec H3T 1E2, Canada.
Dr. Hernandez: 4458-1796 Summer Street, Halifax, Nova Scotia B3H
3A7 Canada.
Dr. Rivington: Canadian Medical Protective Association, PO Box 8225,
Station T Crescent, Ottawa, Ontario K1G 3H7, Canada.
Dr. Road: Respiratory Medicine, 2775 Heather Street, Vancouver, Brit-
ish Columbia V5Z 3J5, Canada.
Dr. Hoffstein: St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario
M5B 1W8, Canada.
Dr. Hodder: The Ottawa Hospital-Civic Campus, 1053 Carling Avenue,
Ottawa, Ontario K1Y 4E9, Canada.
Dr. Marciniuk: Royal University Hospital, 103 Hospital Drive, Saska-
toon, Saskatchewan S7N 0W8, Canada.
Dr. McCormack: London Health Sciences Centre, Victoria Campus, PO
Box 5375, Station B, London, Ontario N6A 4G5, Canada.
Dr. Fox: Health Sciences Centre, 300 Prince Philip Drive, St. John’s,
Newfoundland A1B 3V6, Canada.
Mr. Cox: St. Joseph’s Healthcare, 50 Charlton Avenue East, Hamilton,
Ontario L8N 4A6, Canada.
Dr. Prins: St. Lawrence Medical Clinic, PO Box 772, Morrisburg, On-
tario K0C 1X0, Canada.
Dr. Ford: Rockyview General Hospital, 4A183-7007 14 Street SW,
Calgary, Alberta T2V 1P9, Canada.
Ms. Bleskie and Mr. Doucette: The Ottawa Hospital, Mailbox 208, 501
Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
Dr. Mayers: University of Alberta Hospital, 2E438-8440 112 Street
NW, Edmonton, Alberta T6G 2B7, Canada.
Dr. Chapman: University Health Network-Toronto Western Hospital,
Room 7-451 West Wing, 399 Bathurst Street, Toronto, Ontario M5T
2S8, Canada.
Dr. Zamel: University Health Network-Toronto General, En207-200
Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
Dr. FitzGerald: Vancouver Coastal Health Research Institute, 703-828
West 10th Avenue, Vancouver, British Columbia V5Z 1M9, Canada.
Author Contributions: Conception and design: S.D. Aaron, K.L. Van-
demheen, D. Fergusson, F. Maltais, J. Bourbeau, M. Balter, D.
O’Donnell, A. McIvor, S. Sharma, P. Hernandez, R. Hodder, K. Chap-
man, M. FitzGerald.
Analysis and interpretation of the data: S.D. Aaron, K.L. Vandemheen,
D. Fergusson, F. Maltais, J. Bourbeau, A. McIvor, J. Anthony, P. Her-
nandez, R. Hodder, D. Marciniuk, D. McCormack, G. Fox, G. Ford, S.
Doucette, I. Mayers, M. FitzGerald.
Drafting of the article: S.D. Aaron, K.L. Vandemheen, D. Fergusson, F.
Maltais, J. Bourbeau, A. McIvor, J. Anthony, D. McCormack, G. Fox, I.
Mayers, K. Chapman, M. FitzGerald.
Critical revision of the article for important intellectual content: S.D.
Aaron, K.L. Vandemheen, D. Fergusson, M. Balter, A. McIvor, S.
Sharma, R. Cowie, S. Field, A. Hirsch, P. Hernandez, J. Road, R. Hod-
der, D. Marciniuk, G. Ford, S. Doucette, K. Chapman, M. FitzGerald.
Final approval of the article: S.D. Aaron, K.L. Vandemheen, M. Balter,
A. McIvor, S. Sharma, G. Bishop, R. Cowie, S. Field, A. Hirsch, R.
Rivington, J. Road, R. Hodder, D. Marciniuk, G. Ford, N. Zamel, M.
FitzGerald.
Provision of study materials or patients: S.D. Aaron, M. Balter, A.
McIvor, G. Bishop, J. Anthony, R. Cowie, S. Field, A. Hirsch, P. Her-
nandez, R. Rivington, V. Hoffstein, R. Hodder, D. Marciniuk, D. Mc-
Cormack, G. Fox, G. Ford, I. Mayers, K. Chapman, N. Zamel, M.
FitzGerald.
Statistical expertise: S.D. Aaron, D. Fergusson, J. Road, S. Doucette.
Obtaining of funding: S.D. Aaron, K.L. Vandemheen, D. Fergusson, A.
McIvor.
Administrative, technical, or logistic support: S.D. Aaron, K.L. Vandem-
heen, A. McIvor, G. Ford, D. Bleskie, M. FitzGerald.
Collection and assembly of data: S.D. Aaron, K.L. Vandemheen, M.
Balter, A. Hirsch, P. Hernandez, R. Rivington, V. Hoffstein, G. Ford.
Annals of Internal Medicine
W-144 17 April 2007 Annals of Internal Medicine Volume 146 Number 8 www.annals.org
    • "(3 months) study of triple therapy versus tiotropium corroborates these findings [18]. As high dropout rates may confound many long-term exacerbation studies performed in high-risk patients [17, 19], the approach of pooling data from short-term studies may provide an alternative insight on how best to examine exacerbations in higher-risk patients with COPD. However, it is important to recognize a key limitation of our findings: that they have been obtained as part of a post hoc analysis. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction Data on triple therapy (long-acting muscarinic antagonist [LAMA] + inhaled corticosteroid/long-acting beta2-agonist [ICS/LABA]) in symptomatic patients with chronic obstructive pulmonary disease (COPD) are limited. This post hoc analysis aimed to determine the efficacy of once-daily umeclidinium (UMEC; 62.5 μg) or placebo (PBO) plus open-label fixed-dose ICS/LABA in symptomatic patients with COPD. Methods Data were pooled from four randomized, double-blind, parallel-group trials (ClincalTrials.gov identifiers: NCT01772134, NCT01772147, NCT01957163, NCT02119286). Inclusion criteria included COPD diagnosis, modified Medical Research Council dyspnea scale score ≥2 and forced expiratory volume in 1 s (FEV1) <70% predicted. Following a 4-week run-in with once-daily or twice-daily ICS/LABA, patients were randomized to UMEC 62.5 μg or PBO as add-on therapy for 12 weeks. The efficacy of UMEC 62.5 μg + ICS/LABA or PBO + ICS/LABA in the intent-to-treat (ITT) population and subgroups with Global initiative for chronic Obstructive Lung Disease (GOLD) B and D COPD, and once-daily or twice-daily ICS/LABA was investigated. Outcomes included: trough FEV1, rescue-medication use, St George’s Respiratory Questionnaire (SGRQ) score, moderate/severe exacerbations. Adverse events (AEs) were assessed. Results UMEC 62.5 μg + ICS/LABA (ITT: n = 819) provided clinically important improvements in trough FEV1 versus PBO + ICS/LABA [ITT: n = 818; 130 mL (95% CI 112, 147); P < 0.001] at Day 85. Similar improvements occurred in all four subgroups (119–147 mL; all P < 0.001). In the ITT population, UMEC 62.5 μg + ICS/LABA decreased rescue-medication use, improved SGRQ score, and reduced short-term exacerbation risk (all P ≤ 0.004 versus PBO + ICS/LABA). These three outcomes also improved consistently with UMEC 62.5 μg + ICS/LABA versus PBO + ICS/LABA with both ICS/LABAs and in the GOLD D subgroup. In the GOLD B subgroup a statistically significant benefit was observed in lung function and proportion of SGRQ responders. AE incidences were similar with UMEC 62.5 μg + ICS/LABA versus PBO + ICS/LABA. Conclusion In symptomatic patients with COPD, triple therapy with UMEC 62.5 μg + ICS/LABA improved lung function, reduced rescue-medication use, improved health-status and reduced exacerbation risk versus PBO + ICS/LABA, with similar safety profiles. Funding GSK (study number 202067).
    Full-text · Article · Feb 2016
    • "One RCT study has been conducted comparing triple therapy to LAMA (tiotropium) use, finding a reduced but not significant OR for triple therapy (0.85, 95 % CI 0.52–1.38) using an ITT analysis during a 52-week study period [26]. Similar to our study, discontinuation of triple therapy among patients was differential between treatment arms: 47 % for tiotropium, and 26 % for triple therapy subjects. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective Results from three observational methods for assessing effectiveness of long-acting bronchodilator therapies for reducing severe exacerbations of chronic obstructive pulmonary disease (COPD) were compared: intent-to-treat (ITT), as protocol (AP), and an as-treated analysis that utilized a marginal structural model (MSM) incorporating time-varying covariates related to treatment adherence and moderate exacerbations. Study Design and Setting Severe exacerbation risk was assessed over a 2-year period using claims data for patients aged ≥40 years who initiated long-acting muscarinic antagonist (LAMA), inhaled corticosteroid/long-acting beta-agonist (ICS/LABA), or triple therapy (LAMA + ICS/LABA). Results A total of 5475 COPD patients met inclusion criteria. Six months post-initiation, 53.5 % of patients discontinued using any therapy. The ITT analysis found an increased severe exacerbation risk for triple therapy treatment (hazard ratio [HR] 1.24; 95 % confidence interval [CI] 1.00–1.53). No increased risk was found in the AP (HR 1.00; 95 % CI 0.73–1.36), or MSM analyses (HR 1.11; 95 % CI 0.68–1.81). The MSM highlighted important associations among post-index events. Conclusion Neglecting to adjust for treatment discontinuation may produce biased risk estimates. The MSM approach is a promising tool to compare chronic disease management by illuminating relationships between treatment decisions, adherence, patient choices, and outcomes.
    Full-text · Article · Jun 2015
    • "Aaron and Coll, in 2007, published the results of the Optimal study, in which the effects of two bronchodilation treatments on FEV 1 were studied. The patients were divided in two groups: tiotropium + placebo in one group and tiotropium + salmeterol in the second group [77]. The FEV 1 pre-broncodilator was shown to be superior in the tiotropium + salmeterol group, in all the evaluations, completed at 4, 20, 36, and 54 weeks. "
    [Show abstract] [Hide abstract] ABSTRACT: The most recent guidelines define COPD in a multidimensional way, nevertheless the diagnosis is still linked to the limitation of airflow, usually measured by the reduction in the FEV1/FVC ratio below 70%. However, the severity of obstruction is not directly correlated to symptoms or to invalidity determined by COPD. Thus, besides respiratory function, COPD should be evaluated based on symptoms, frequency and severity of exacerbations, patient's functional status and health related quality of life (HRQoL). Therapy is mainly aimed at increasing exercise tolerance and reducing dyspnea, with improvement of daily activities and HRQoL. This can be accomplished by a drug-induced reduction of pulmonary hyperinflation and exacerbations frequency and severity. All guidelines recommend bronchodilators as baseline therapy for all stages of COPD, and long-acting inhaled bronchodilators, both beta-2 agonist (LABA) and antimuscarinic (LAMA) drugs, are the most effective in regular treatment in the clinically stable phase. The effectiveness of bronchodilators should be evaluated in terms of functional (relief of bronchial obstruction and pulmonary hyperinflation), symptomatic (exercise tolerance and HRQoL), and clinical improvement (reduction in number or severity of exacerbations), while the absence of a spirometric response is not a reason for interrupting treatment, if there is subjective improvement in symptoms. Because LABA and LAMA act via different mechanisms of action, when administered in combination they can exert additional effects, thus optimizing (i.e. maximizing) sustained bronchodilation in COPD patients with severe airflow limitation, who cannot benefit (or can get only partial benefit) by therapy with a single bronchodilator. Recently, a fixed combination of ultra LABA/LAMA (indacaterol/glycopyrronium) has shown that it is possible to get a stable and persistent bronchodilation, which can help in avoiding undesirable fluctuations of bronchial calibre.
    Full-text · Article · Oct 2014
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