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Respiratory Medicine (2010) 104, 1460e1472

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

A one-year trial of tiotropium Respimat plus


usual therapy in COPD patients
E.D. Bateman a,*, D. Tashkin b, N. Siafakas c, R. Dahl d, L. Towse e,
D. Massey e, D. Pavia e, N.S. Zhong f
a

Division of Pulmonology, Department of Medicine, University of Cape Town, George Street, Mowbray,
Cape Town 7700, South Africa
b
Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1690, USA
c
University of Crete, University General Hospital, Department of Thoracic Medicine, 7110 Heraklion, Greece
d
Department of Respiratory Diseases, Aarhus University Hospital, Norrebrogade, DK 8000 Aarhus C, Denmark
e
Clinical Research Department, Medical Division, Boehringer Ingelheim Limited, Ellesfield Avenue,
Berkshire RG12 8YS, Bracknell, UK
f
State Key Laboratory of Respiratory Disease/Guangzhou Institute of Respiratory Disease,
Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, China
Received 18 January 2010; accepted 4 June 2010

KEYWORDS
COPD;
Exacerbation;
Spirometry;
Tiotropium

Summary
In this randomised double-blind study, patients 40 years old with COPD, a smoking history of
10 pack-years, a pre-bronchodilator FEV1 of 60% predicted and an FEV1/FVC of 70% received
tiotropium 5 mg or placebo via Respimat inhaler once daily for 48 weeks. Other medications
were permitted except inhaled anticholinergics. Co-primary endpoints were trough FEV1 and
the time to first exacerbation. Adverse events were followed and vital status regularly assessed.
In all, 3991 patients (mean age, 65 years [SD, 9 years]) were evaluable. Mean baseline FEV1 was
1.11 L (0.40 L) or 40% (12%) of predicted normal. Adjusted mean differences in trough FEV1 and
trough FVC at Week 48 (tiotropium minus placebo) were 102 and 168 ml respectively (p < 0.0001,
both). Tiotropium delayed time to first exacerbation relative to placebo (hazard ratio [HR], 0.69
[95% CI, 0.63e0.77]) and time to first hospital-treated exacerbation (HR, 0.73 [0.59e0.90]).
SGRQ score at Week 48 was 2.9 units lower with tiotropium (p < 0.0001). Adverse and serious
adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials. The rate ratio for a major adverse cardiovascular event during the treatment period 30 days was 1.12 (0.67e1.86). By the end of planned treatment (Day 337) 52 patients on
tiotropium (incidence rate per 100 years, 2.94) and 38 on placebo (2.13) had died (HR Z 1.38
[0.91e2.10]; p Z 0.13).
Lung function, exacerbations and quality of life were improved by tiotropium 5 mg Respimat
but a numerical imbalance was seen in all-cause mortality.
The protocol is registered on the European Clinical Trials Database as trial number 2006-

* Corresponding author. Tel.: 27 21 406 6901; fax: 27 21 406 6902.


E-mail address: eric.bateman@uct.ac.za (E.D. Bateman).
0954-6111/$ - see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2010.06.004

Tiotropium Respimat in COPD patients

1461

001009-27 and in the ClinicalTrials.gov database as NCT00387088.


2010 Elsevier Ltd. All rights reserved.

Introduction
The clinical value of the long-acting anticholinergic tiotropium (Spiriva; Boehringer Ingelheim, Ingelheim,
Germany) in the maintenance treatment of chronic
obstructive pulmonary disease (COPD) was initially
demonstrated in a series of studies with a dry powder
inhaler presentation of the drug (Spiriva HandiHaler).
These trials showed that tiotropium improves lung function,
dyspnoea, exercise duration and health-related quality of
life (HRQoL), as well as reducing hyperinflation and the risk
of exacerbations and associated hospitalisations.1e6 More
recently, an alternative aqueous aerosol presentation of
tiotropium has been developed, which is delivered via the
Respimat Soft Mist Inhaler, a multidose propellant-free
device. The properties of the aerosol produced by this
inhaler, in particular its high fine particle fraction and its
low speed compared with aerosols from a pressurised
metered-dose inhaler (pMDI),7,8 result in more drug being
deposited in the lung and less in the mouth and throat.9,10
In two large multicentre trials of identical design in which
tiotropium 5 and 10 mg in the Respimat inhaler were given
to COPD patients once daily for 48 weeks, significant benefits
over placebo were shown for the four co-primary endpoints,
i.e. the trough response for forced expiratory volume in 1 s
(FEV1), HRQoL, dyspnoea and the rate of exacerbations.11
Apart from a higher incidence of typical anticholinergic
side-effects such as dry mouth and constipation, the adverse
event profile was similar to that of placebo.11 These results
have subsequently supported the approval in 55 countries to
date of 5 mg once daily in the Respimat inhaler as the
standard dose for use in COPD patients.
The objective of the current study was to assess clinical
efficacy and safety of one-years treatment with tiotropium
5 mg delivered via Respimat in COPD patients, particularly
its effect on exacerbations. However, to reflect more
closely the typical positioning of tiotropium in COPD
management, patients were permitted to use a wider range
of concurrent COPD medications during the study, including
long-acting b2-agonists (LABAs) and inhaled corticosteroids
(ICS); the only disallowed medications were inhaled anticholinergics. The two co-primary endpoints were trough
FEV1 (at 48 weeks) and time to first exacerbation. Safety
and tolerability were assessed during the on-treatment
period plus 30 days, and vital status was ascertained for all
patients (whether or not they had completed study treatment) until 30 days after the end of the planned 48 week
treatment period.

Methods
Study design and compliance
This clinical trial (Boehringer Ingelheim study number
205.372) used a randomised, double-blind, parallel-group
design, and was conducted in 336 outpatient centres

spanning five continents and involving 31 countries. The


trial was carried out in compliance with principles laid
down in the Declaration of Helsinki and in accordance
with the International Conference on Harmonisation
(ICH) Harmonised Tripartite Guideline for GCP. The
protocol and all amendments were approved by institutional review boards at each centre, and all participants
gave written informed consent. The protocol is registered
on the European Clinical Trials Database as trial number
2006-001009-27 and in the ClinicalTrials.gov database as
NCT00387088.

Patients
COPD patients of either sex were eligible for study entry if
they were aged 40 years, had pre-bronchodilator FEV1 of
60% of predicted normal12 and a ratio of FEV1 to forced
vital capacity (FVC) of 70%, and were current or exsmokers (smoking history of 10 pack-years). Patients
were excluded if they had a significant disease other than
COPD that, in the investigators judgment, could affect the
patients ability to complete the trial, or if they had clinically significant abnormal results of haematology, urinalysis, or blood chemistry tests, a history of asthma or
allergic rhinitis, or a blood eosinophil count of 600/mm3.
Other exclusion criteria included previous lung resection
surgery, participation in a pulmonary rehabilitation programme in the previous 6 weeks, and regular daytime
oxygen use (>1 h/day). Less stringent exclusion criteria
relating to cardiovascular disorders were employed, with
the aim of making the patient sample more representative
of the range of COPD patients typically encountered in
clinical practice, but patients with a history of unstable
arrhythmias, myocardial infarction (MI) in the previous 6
months or heart failure requiring in-hospital treatment in
the previous 12 months were excluded. Patients who had
previously used tiotropium delivered via Respimat were
also excluded, but those who had previously used tiotropium delivered via HandiHaler could enter the trial if
they stopped taking it at least 28 days before the randomisation visit.

Treatments
All patients attended a screening visit at which they were
given training in the use of the Respimat inhaler. Seven
days later, patients meeting the entry criteria were
randomly assigned in a 1:1 ratio to 48 weeks treatment
with either tiotropium 5 mg (two puffs of 2.5 mg each) or
placebo (two puffs) both inhaled via the Respimat inhaler
once daily in the morning; identity of treatments was
blinded to investigators, assessors and patients. Treatment
allocation was determined by a computer-generated randomisation code provided by Boehringer Ingelheim. Randomisation was stratified by study centre and within
centres, and performed in blocks to ensure balanced
distribution of the treatment groups at any time.

1462
Individuals directly involved in the conduct and analysis of
the trial had no access to the allocation sequence until
after the trial was completed.
Salbutamol pMDI was provided to all patients for use as
rescue medication at any time during the study. All respiratory medications were permitted during the trial other
than inhaled anticholinergics.

Efficacy endpoints
The study had two co-primary efficacy endpoints: trough
FEV1 response, i.e. the difference between pre-dose FEV1
on Day 1 of the treatment period and the corresponding
value after 48 weeks of treatment, and time to first COPD
exacerbation. Exacerbations were defined as a complex of
respiratory events or symptoms that lasted 3 days and
required treatment with antibiotics and/or systemic
corticosteroids, or prompted the investigator to change the
patients regular respiratory medication. Secondary efficacy endpoints included trough FEV1 response after 4 and
24 weeks and trough FVC response at 4, 24 and 48 weeks,
the number of exacerbations per patient, the number of
patients with at least one exacerbation (exacerbations
requiring hospitalisation were counted separately), and
the time to the first exacerbation that required hospitalisation. HRQoL (change from baseline in total and domain
scores of the St. Georges Respiratory Questionnaire
[SGRQ] after 24 and 48 weeks) was also a secondary efficacy endpoint.
At the screening and baseline visits, and the visits at the
end of weeks 4, 24 and 48, the administration of concomitant medications before pulmonary function tests (PFTs)
was restricted to avoid interference with the tests. The
restricted period was 8 h for short-acting b2-agonists
(SABAs), 12 h for any LABA- or ICS-containing medication,
and 24e48 h for xanthines, depending on the drug release
kinetics of the formulation.

Safety
Adverse events were collected at all clinic visits. Electrocardiography (ECG) was performed at screening, after 4
weeks, and at the end of patient participation in the trial.
Mortality was assessed for the planned duration of the trial
for all patients, including those who prematurely discontinued study medication.

Statistical analysis
Changes in trough FEV1 and FVC were analysed using an
analysis of covariance (ANCOVA) with terms for study
centre, LABA use (LABA treatment that started no later
than the day of randomisation and that continued for at
least one more day) and treatment as fixed effects, and
baseline FEV1 and baseline FVC as covariates, respectively.
Time to first exacerbation was analysed with the Cox
proportional hazards model including terms for centre,
treatment and LABA use. The two co-primary endpoints
were tested sequentially, to preserve the Type I error rate
at 0.05. The co-primary endpoints were analysed in all
patients who were randomly assigned and treated and who

E.D. Bateman et al.


provided a trough FEV1 measurement at baseline and at
least one subsequent visit.
Analysis of other exacerbation endpoints was done using
the following tests: the log rank test (life-table method) for
time to first exacerbation, the WilcoxoneManneWhitney
test (both nave and exposure-adjusted) and generalised
linear regression modelling (assuming both a Poisson and
negative binomial distribution) for the number of exacerbations per patient, and logistic regression for the proportion of patients experiencing at least one exacerbation.
SGRQ scores were analysed by ANCOVA.
Assuming a standard deviation in trough FEV1 of 0.229 L,
1500 completed patients per treatment group would enable
detection of a difference between study treatments of
0.13 L in mean trough FEV1 response, with a significance
level of 5% (two-sided) and at least 99% statistical power.
This number of patients would also enable detection of
a proportional hazard of 0.85 (tiotropium relative to
placebo) for the time to first exacerbation in a log rank
test, with a significance level of 5% (two-sided) and 80%
statistical power, assuming that the proportion of patients
experiencing 1 exacerbation was 37.2 and 42.1% for tiotropium and placebo respectively.
For fatal events, Cox regression analysis (using treatment as a covariate) was used to estimate the hazard ratio
and 95% confidence interval (CI) for time to death, which
was defined as the time from first dose of study treatment
to the date of death. For the primary analysis of time to
death (for the planned treatment period), patients were
censored at the earlier of Day 337 or the last day they were
known to be alive. The probability of survival was also
analysed using KaplaneMeier analysis and the log rank test.
Incidence rates were calculated for all events by dividing
the number of patients reporting an event by the patientyears at risk, expressed per 100 patient-years at risk. Fatal
events, cause of death, and relationship between study
treatment and fatal events were reviewed by an independent committee consisting of two chest physicians,
a cardiologist and a statistician. For adverse events, 95% CIs
for hazard or rate ratios that excluded the value of 1
indicate a nominal p value of <0.05.

Results
Study population
Of 5483 patients screened, 3991 were randomly allocated
study treatment (Fig. 1). Seventy-four patients at one
centre were excluded from safety and efficacy analyses
because of uncertainty about assignment and administration of study treatment, and a further 25 patients at two
other centres were excluded from efficacy analyses
because of serious non-compliance or questionable data.
The treated set (for safety analyses) therefore comprised
3917 patients and the full analysis set (for efficacy analyses) comprised 3892 patients. Recruitment started in
October 2006 and finished in December 2007.
At the screening visit, demographic and clinical characteristics of patients in the treated set (including lung
function measurements) were well matched between
treatment groups (Table 1). The mean age of all patients

Tiotropium Respimat in COPD patients

1463
Screened (5483)
Withdrew or did not meet entry
criteria (1492)
Randomly assigned study treatment (3991)

Tiotropium Respimat 5 g
(1989)

Placebo (2002)

Discontinued tiotropium (318)

Discontinued placebo (373)

Adverse events: 143


Lack of efficacy: 28
Non-compliant with protocol:
47
Lost to follow-up: 22
Consent withdrawn: 20
Other: 58

Adverse events: 156


Lack of efficacy: 67
Non-compliant with protocol:
35
Lost to follow-up: 28
Consent withdrawn: 35
Other: 52

Completed tiotropium
(1671)

Completed placebo
(1629)

Analysis sets, tiotropium

Analysis sets, placebo

Treated set (safety): 1952


Full analysis set (efficacy): 1939

Treated set (safety): 1965


Full analysis set (efficacy): 1953

Figure 1

Patient flow through study.

was 64.8 years (SD, 9.0 years) and there were more exsmokers (64.2%) than current smokers (35.8%). There were
slightly more men in the tiotropium group (78.1 vs. 77.0%).
At the randomisation (baseline) visit, mean FEV1 was
1.11 L, equating to 40.3% of predicted normal (Table 1).
Concurrent use of other COPD medications was similar in
the two treatment groups. The most common medications
were LABAs and ICS, each used by just over half the
patients (Table 1).
The protocol required that the dosage of concomitant
pulmonary medications remain stable as far as possible
throughout the randomised treatment period, and that
dosage changes and any new medications added during the
study be documented. The 2091 patients who were taking
LABAs at randomisation continued to take them for 98.9%
(tiotropium) and 99.0% (placebo) of the randomised treatment period, whereas 1826 patients who were not taking
a LABA at randomisation took them for 2.1% and 3.3% of the
period, respectively. One hundred patients started LABAs
after randomisation (tiotropium, 35; placebo 65).
More patients in the placebo group discontinued (373;
18.6%) than in the tiotropium group (318; 16.0%), the most
common reason being adverse events (Fig. 1); in patients
with very severe COPD (Global Initiative for Chronic

Obstructive Lung Disease [GOLD] stage IV) at baseline, 92 of


291 (31.6%) on placebo and 56 of 207 (18.2%) on tiotropium
discontinued study treatment. Mean baseline FEV1 in all
patients who discontinued (1.07 L [SD, 0.38 L] for tiotropium and 0.99 L [SD, 0.40 L] for placebo) was lower than
in those who completed the study (1.12 L [0.40 L] and
1.13 L [0.39 L], respectively). Vital status was known for
99% of randomly allocated patients at the end of Day 337
(end of treatment period) and for 60% at Day 367 (30 days
after treatment completion).

Efficacy
Co-primary endpoints
After 48 weeks of the study, the adjusted mean increase
from baseline trough FEV1 was significantly greater in the
tiotropium group (119 ml) than the placebo group (18 ml).
The adjusted mean difference between treatments was
102 ml (95% CI, 85e118 ml; p < 0.0001) (Table 2).
The time to first exacerbation was delayed by treatment
with tiotropium. During the treatment period, 685 (35.3%)
patients in the tiotropium group and 842 (43.1%) in the
placebo group had at least one exacerbation, representing
a significant risk reduction with tiotropium (hazard ratio

1464

E.D. Bateman et al.

Table 1 Characteristics of all COPD patients at the screening and randomisation visits (treated set). Except for distribution
data, all values are means (with standard deviation in parentheses).

Screening visit
Men:women (%)
Age (years)
Current smoker:ex-smoker (%)
Smoking history (pack-years)
Time since COPD diagnosis (yrs)
Pre-bronchodilator FEV1 (L)
Pre-bronchodilator FEV1 (% predicted normal)
Pre-bronchodilator FVC (L)
Pre-bronchodilator FEV1/FVC (%)
Post-bronchodilator FEV1 (L)a
Post-bronchodilator FEV1 (% predicted normal)a
Reversibility of FEV1 (%)
Post-bronchodilator FVC (L)a
Post-bronchodilator FEV1/FVC (%)a
Randomisation visit (baseline)
FEV1 (L)
FEV1 (% predicted normal)
FVC (L)
Proportion taking pulmonary medications (%)b
Any medication
Long-acting b2-agonists
Short-acting b2-agonists
Inhaled corticosteroids
Oral corticosteroids
Xanthines
Mucolytics
Short-acting anticholinergics
Supplementary oxygen

Tiotropium 5 mg
Respimat (n Z 1952)

Placebo
(n Z 1965)

78.1:21.9
64.8 (9.1)
35.7:64.2
46.0 (26.1)
8.34 (7.00)
1.097 (0.392)
39.86 (12.03)
2.350 (0.737)
47.20 (10.81)
1.244 (0.442)
45.21 (13.54)
14.79 (16.69)
2.595 (0.789)
48.45 (11.26)

77.0:23.0
64.8 (9.0)
35.9:64.1
45.0 (26.5)
8.11 (6.52)
1.088 (0.395)
39.83 (11.95)
2.358 (0.769)
46.74 (10.69)
1.240 (0.449)
45.36 (13.64)
15.14 (17.01)
2.619 (0.836)
47.92 (11.26)

1.109 (0.394)
40.29 (12.02)
2.379 (0.728)

1.101 (0.397)
40.34 (12.11)
2.384 (0.760)

79.4
54.2
36.7
56.0
2.4
23.4
9.6
1.6
1.7

78.3
52.6
37.2
56.1
2.8
23.0
9.1
1.9
1.6

COPD Z chronic obstructive pulmonary disease; FEV1 Z forced expiratory volume in 1 s; FVC Z forced vital capacity.
a
Post-bronchodilator values measured 30 min after salbutamol 4  100 mg.
b
Medications taken before or on the randomisation day and for 1 day thereafter; only those taken by >1.5% of all patients are shown.

[HR] Z 0.69 [95% CI, 0.63e0.77]; p < 0.0001). A significant


difference was also found in a sensitivity analysis, in which
time to first exacerbation was calculated using life-table
analysis (Table 4). KaplaneMeier analysis of time to first
exacerbation is shown in Fig. 2a.
Secondary efficacy measures
Trough FEV1 values at weeks 4 and 24 were significantly
higher in the tiotropium group than in the placebo group,
differences being 93 and 103 ml respectively (p < 0.0001;
Table 2). In addition, trough FVC was significantly higher with
tiotropium than with placebo at weeks 4, 24 and 48, the
differences ranging between 151 and 168 ml (p < 0.0001;
Table 2).
The rate of exacerbations per patient-year was significantly lower with tiotropium during the treatment period
than with placebo (0.69 and 0.87 respectively), as was the
rate of exacerbations requiring hospitalisation (0.12 and
0.15 respectively) (Table 3).
The time to the first exacerbation requiring hospital
treatment was also delayed by treatment with tiotropium

(Table 3). At least one such exacerbation was recorded


for 161 (8.3%) patients in the tiotropium group and 198
(10.1%) in the placebo group during the treatment period,
representing a significantly lower risk with tiotropium
(HR Z 0.73 [95% CI, 0.59e0.90]; p < 0.005) and
a statistically significant difference between treatments
was also found in the life-table analysis. The
KaplaneMeier analysis of this endpoint is shown in
Fig. 2b.
Mean total SGRQ scores fell from baseline in both
groups, showing improvement in HRQoL, but the change
was significantly greater with tiotropium than placebo. At
week 24, the adjusted mean difference in total scores
between tiotropium and placebo was 2.2 and at week
48, it was 2.9 units (p < 0.0001 at both time points).
Although both these differences were smaller than the
minimum clinically important difference for the SGRQ of
4 units,13 the proportion of responders (those whose total
score fell by 4 units from baseline) was significantly
higher in the tiotropium group than the placebo group
(Table 4).

Tiotropium Respimat in COPD patients

1465

Table 2 Changes from baseline in morning (pre-dose) trough spirometry measures by treatment group. Data shown are
adjusted means with standard error of the mean in parentheses unless otherwise stated.
Tiotropium 5 mg
Respimat
(n Z 1889)

Placebo
(n Z 1870)

Adjusted mean
difference
(95% CI)

P value

Co-primary endpoint
FEV1 (ml), Week 48

119 (7)

18 (7)

102 (85e118)

p < 0.0001

Secondary endpoints
FEV1 (ml), Week 4a
FEV1 (ml), Week 24
FVC (ml), Week 4a
FVC (ml), Week 24
FVC (ml), Week 48

110
121
176
179
168

17
18
25
19
1

93
103
151
160
168

p
p
p
p
p

(5)
(6)
(9)
(10)
(11)

(5)
(6)
(9)
(10)
(11)

(80e106)
(88e118)
(127e174)
(135e186)
(141e196)

<
<
<
<
<

0.0001
0.0001
0.0001
0.0001
0.0001

CI Z confidence interval; FEV1 Z forced expiratory volume in 1 s; FVC Z forced vital capacity.
a
Number of patients for Week 4 data: tiotropium, 1879; placebo, 1866.

Subgroup analysis by LABA use


When the study population was split into two subgroups
according to whether or not patients were taking LABAs at
randomisation, the tiotropium and placebo groups were still
well matched for demographic and clinical characteristics
and previous COPD medication in both subgroups (Table 5).
In the LABA users, the tiotropium group had slightly more
men (77.8 vs. 74.2%) than placebo; the opposite was true
(78.4 vs. 80.2%) for the LABA non-users. Comparison of LABA
users with LABA non-users showed minimal differences in
pre-bronchodilator lung function, although post-bronchodilator values showed the LABA users to have slightly more
severe disease and slightly less reversibility of FEV1 to salbutamol than the LABA non-users. In line with this, there

were more GOLD stage III and IV patients among LABA users
(64.5%) than LABA non-users (56.9%), and pre-study use
of most COPD medications, notably ICS, was higher in the
LABA users.
For change from baseline in trough FEV1 at week 48,
LABA use had no effect on the degree of superiority of
tiotropium over placebo, but the absolute changes from
baseline were larger (for tiotropium and placebo) in LABA
non-users than LABA users (Table 6). A very similar pattern
of results was seen for SGRQ scores: LABA non-users had
greater gains in HRQoL than LABA users, particularly at
week 48, and the proportion of responders at week 48 was
slightly higher in LABA non-users (Table 6). For other lung
function measures, there was no interaction between LABA

Table 3 Exacerbation measures by treatment group, including results of sensitivity analysis (time to exacerbation measured
by life-table analysis).
Tiotropium 5 mg
Respimat
Co-primary endpoint
Time to first exacerbation
Patients having 1 exacerbation
during treatment
Sensitivity analysis of time to
exacerbation (days, lower
quartile & 95% CI)

685 (35.3%)

842 (43.1%)

169 (153e200)

119 (108e134)

Secondary endpoints
Mean number of exacerbations per patient per year (& 95% CI)
Any exacerbation
0.69 (0.64e0.74)
Exacerbations requiring
hospitalisation

Placebo

0.12 (0.11e0.14)

Time to first exacerbation requiring hospitalisation


Patients having 1 exacerbation
161 (8.3%)
during treatment
Sensitivity analysis of time
NE
to exacerbation

0.87 (0.82e0.93)
0.15 (0.14e0.17)

198 (10.1%)
NE

CI Z confidence interval; NE Z lower quartiles for time to event not estimable.

Hazard ratio (HR) or


relative rate (RR);
95% CI; p value

HR Z 0.693 (0.625e0.769);
p < 0.0001
p < 0.0001

RR Z 0.79 (0.72e0.87);
p < 0.0001
RR Z 0.81 (0.70e0.93);
p < 0.005
HR Z 0.728 (0.589e0.901);
p < 0.005
0.0191

1466

E.D. Bateman et al.

Table 4

Change in health-related quality of life (St Georges Respiratory Questionnaire [SGRQ] scores) by treatment group.
Tiotropium 5 mg
Respimat

Placebo

Difference, mean and


95% CLs

Change from baseline in total score (units)


Week 24
4.8
Week 48
4.7

2.6
1.8

2.2 (3.1, 1.3); p < 0.0001


2.9 (3.9, 2.0); p < 0.0001

Number (%) of respondersa


Week 24
860 (50.9%)
Week 48
836 (49.5%)

701 (42.0%)
690 (41.4%)

8.9% (5.5, 12.2%); p < 0.0001


8.1% (4.7, 11.5%); p < 0.0001

CL Z confidence limit.
a
Patients with a reduction in SGRQ score from baseline of 4 units.

use and the direction or degree of difference between


tiotropium and placebo. Tiotropium was significantly
superior to placebo in LABA users and non-users in respect
of the co-primary exacerbation endpoint (Table 6),
although fewer LABA non-users (28.0% tiotropium; 38.5%
placebo) had at least one exacerbation during the treatment period than LABA users (41.5 and 47.3%, respectively). For the time to first exacerbation requiring
hospitalisation, the reduction in risk with tiotropium was
significant in LABA users (HR Z 0.70; 95% CI, 0.53e0.93;
p Z 0.014), but not in LABA non-users (HR Z 0.84; 95% CI,
0.59e1.20; p Z 0.341).

50
Probability of COPD exacerbation [%]

40

30

20
Hazard ratio = 0.693
(95% CI, 0.625, 0.769)
p = <.0001 (log-rank test)
Tiotropium
Placebo

10

No of patients
Tiotropium 1939
1953
Placebo

120
180
240
Duration of exposure [days]

300

360

1639

1444

1319

1214

1126

72

1566

1332

1168

1051

945

89

50
Probability of COPD exacerbation [%]

60

40
Hazard ratio = 0.728
(95% CI, 0.589, 0.901)
p = 0.0191 (log-rank test)
Tiotropium
Placebo

30

20

10

0
0
No of patients
Tiotropium 1939
1953
Placebo

60

120

180

240

300

360

Duration of exposure [days]


1814
1787

1732
1680

1671
1586

1616
1530

1567
1482

119
146

Figure 2 KaplaneMeier analysis of the probability of a COPD


exacerbation during the on-treatment period: a) for all exacerbations; b) for exacerbations requiring hospitalisation.

Safety
The proportion of adverse events and serious adverse
events reported by patients in the two treatment groups
during the on-treatment period (up to the last dose
taken 30 days follow-up) was similar (Table 7). When
adverse events were grouped by organ class, incidence
rates per 100 patient-years (IRs) for the two treatments
were mostly similar, with differences being statistically
significant for three: lower respiratory system disorders (IRs
of 70.5 and 87.0 for tiotropium and placebo respectively,
rate ratio (RR) Z 0.81 [95% CI, 0.74e0.89]), psychiatric
disorders (IRs, 2.92 and 4.27, RR Z 0.68 [0.48e0.98]) and
neoplasms (IRs, 2.63 and 1.65; RR Z 1.59 [1.00e2.53]).
Most of the frequently-reported adverse events were
reported by similar proportions of patients in the two
treatment groups. The notable exceptions to this were
COPD exacerbation (the most common event reported
overall), which was reported by 641 (32.8%) in the tiotropium group and 759 (38.6%) in the placebo group, and
dry mouth, reported by 60 (3.1%) and 27 (1.4%), respectively. After COPD exacerbations, the most common
adverse events across both groups were balanced between
groups, e.g. nasopharyngitis (8.0 and 7.7% respectively),
dyspnoea (7.0 and 7.7%), upper respiratory tract infection
(6.4 and 7.3%) and cough (6.4 and 5.5%) (Table 7).
Fatal events with onset of event and death during the
planned treatment period (up to Day 337) occurred in
52 patients (IR, 2.94) in the tiotropium group and 38 (IR, 2.13)
in the placebo group. The RR for all-cause mortality was 1.38
(95% CI, 0.91e2.10; p Z 0.13). The most common causes of
death as adjudicated by the committee were: a) general
disorders and administration site conditions, which include
the preferred terms death, unexplained death and
sudden death (31); b) lower respiratory system disorders
(25); c) cardiac disorders (13) and d) neoplasms (11), classified either as general neoplasms (excludes lung cancer) or
other respiratory system disorders (lung cancer and pulmonary embolism). Imbalances in event rates favoured tiotropium in lower respiratory system disorders and infections
and infestations, and placebo in the other classes (Table 8).
However, the numbers of events were small in some classes,
and CIs for the rate ratio included 1 for all classes.
A post-hoc analysis of major adverse cardiovascular events
was performed by defining a composite cardiovascular
endpoint that comprised fatal and non-fatal MI and stroke,

Tiotropium Respimat in COPD patients

1467

Table 5 Patient characteristics at screening and concomitant COPD medication use at randomisation, showing differences
between users and non-users of long-acting beta-agonists (LABAs) at randomisation.
LABA users

Screening visit
Men:women (%)
Age (years)
Current smoker:ex-smoker (%)
Smoking history (pack-years)
Time since COPD diagnosis (yrs)
Pre-bronchodilator FEV1 (L)
Pre-bronchodilator FEV1
(% predicted normal)
Pre-bronchodilator FVC (L)
Pre-bronchodilator
FEV1/FVC (%)
Post-bronchodilator FEV1 (L)a
Post-bronchodilator FEV1
(% predicted normal)a
Reversibility of FEV1 (%)
Post-bronchodilator FVC (L)a
Post-bronchodilator
FEV1/FVC (%)a

Placebo
(n Z 1033)

Tiotropium 5 mg
Respimat
(n Z 894)

Placebo
(n Z 932)

77.8:22.2
64.9 (9.0)
33.6:66.4
46.4 (24.7)
8.12 (6.28)
1.089 (0.383)
39.24 (11.71)

74.2:25.8
64.6 (8.8)
32.5:67.5
46.0 (26.0)
8.41 (6.43)
1.094 (0.390)
40.03 (11.55)

78.4:21.6
64.8 (9.2)
38.3: 61.6
45.5 (27.7)
8.59 (7.76)
1.105 (0.403)
40.58 (12.36)

80.2:19.8
65.0 (9.2)
39.6:60.4
43.9 (27.1)
7.78 (6.60)
1.082 (0.401)
39.61 (12.37)

2.371 (0.748)
46.53 (10.69)

2.366 (0.772)
46.92 (10.52)

2.324 (0.723)
48.00 (10.91)

2.349 (0.766)
46.53 (10.88)

1.218 (0.422)
43.85 (12.82)

1.219 (0.431)
44.63 (12.78)

1.275 (0.462)
46.82 (14.18)

1.262 (0.468)
46.16 (14.50)

13.26 (16.23)
2.595 (0.787)
47.50 (11.03)

12.56 (15.22)
2.601 (0.823)
47.49 (10.92)

16.60 (17.05)
2.595 (0.792)
49.58 (11.43)

18.00 (18.38)
2.638 (0.849)
48.39 (11.61)

1.091 (0.404)
39.97 (12.54)
2.364 (0.756)

1.111 (0.392)
39.94 (11.77)
2.410 (0.748)

1.110 (0.392)
40.68 (11.69)
2.402 (0.765)

100
100
40.0
91.0
3.1
26.1
10.4
20.2
1.7
2.4

55.0
0
35.1
16.2
1.7
21.8
7.4
4.3
2.1
1.0

54.2
0
34.0
17.5
2.5
19.5
7.6
6.2
2.1
0.8

Randomisation visit (baseline)


1.107 (0.396)
FEV1 (L)
40.70 (12.29)
FEV1 (% predicted normal)
FVC (L)
2.343 (0.703)
Proportion taking pulmonary medications (%)b
Any medication
100
Long-acting b2-agonists
100
Short-acting b2-agonists
38.0
Inhaled corticosteroids
89.7
Oral corticosteroids
2.9
Xanthines
24.7
Mucolytics
11.5
20.2
Tiotropiumc
Short-acting anticholinergics
1.2
Supplementary oxygen
2.3
a
b
c

LABA non-users

Tiotropium 5 mg
Respimat
(n Z 1058)

Post-bronchodilator values measured 30 min after salbutamol 4  100mg.


Before or on the randomisation day and for at least 1 day thereafter.
Proportion of patients taking drug at screening visit (tiotropium withdrawn 28 days before randomisation).

fatal events in the organ classes cardiac disorders and


vascular disorders, plus the terms sudden death, cardiac
death and sudden cardiac death, all as reported by investigators, for the on-treatment period only. Such events
occurred in 32 tiotropium and 28 placebo patients (IRs, 1.77
and 1.58 respectively; RR [tiotropium: placebo], 1.12 [95% CI,
0.67e1.86]). The frequency of stroke was similar in the tiotropium and placebo groups (affecting 10 and 11 patients,
respectively).
For all-cause, cardiac and cardiovascular deaths, the
risk was numerically higher in LABA users than in LABA nonusers (Table 9). However, LABA use was not significantly
associated with risk of fatal events when introduced as an
interaction term to a multivariate model that adjusted for

factors such as age, sex and disease severity, i.e. GOLD


stage (p Z 0.724). No clinically relevant differences
between treatment groups were found in vital signs, physical examination or electrocardiography.

Discussion
In this placebo-controlled study of one-years treatment in
3991 patients with moderate-to-severe COPD who were
allowed to continue their usual respiratory medications
(other than inhaled anticholinergics), we have shown that
once daily tiotropium 5 mg delivered via Respimat Soft
Mist Inhaler significantly improved the co-primary
endpoints of trough FEV1 at 48 weeks and the time to first

CL Z confidence limit; FEV1 Z forced expiratory volume in 1 s; SD Z standard deviation; SGRQ Z St Georges Respiratory Questionnaire.
a
Adjusted mean difference.
b
Patients with a reduction in SGRQ score from baseline of 4 units.

7.6% (2.6, 12.6%);


p Z 0.0030
340/779 (43.6%)
8.7% (4.1, 13.2%);
p Z 0.0002
350/889 (39.4%)
449/935 (48.0%)

387/755 (51.3%)

3.0 (4.4, 1.5);


p < 0.0001
2.9 [n Z 779]
2.8 (4.0, 1.5);
p < 0.0001

5.8 [n Z 755]
0.9 [n Z 889]
3.6 [n Z 935]

Mean trough FEV1 (SD)


at Week 48, ml
Patients (n and %) having
1 exacerbation
during treatment
Mean change from
baseline in total SGRQ
score (units), Week 48
Number (%) of
responders, Week 48b

104 (82, 127);a


p < 0.0001
HR, 0.759 (0.660,
0.873); p Z 0.0001

249/888 (28.0)
485/1025 (47.3%)
436/1051 (41.5%)

357/928 (38.5)

32 (12) [n Z 888]
134 (12) [n Z 862]
1 (9) [n Z 982]
105 (9) [n Z 1027]

Placebo
Tiotropium 5 mg
Respimat
Placebo
Tiotropium 5 mg
Respimat

Mean difference or
hazard ratio (HR)
and 95% CLs

LABA non-users
LABA users

Results for main efficacy endpoints showing differences between users and non-users of long-acting beta-agonists (LABAs) at randomisation.
Table 6

101 (74e129);a
p < 0.0001
HR, 0.633 (0.531,
0.755); p < 0.0001

E.D. Bateman et al.


Mean difference or
hazard ratio (HR)
and 95% CLs

1468

exacerbation. Improvements were also observed in


secondary endpoints including trough FVC, exacerbation
rate, time to the first exacerbation requiring hospitalisation, and HRQoL.
The improvements in bronchodilation and exacerbation
rate seen in our study are consistent with those of a pooled
analysis of two one-year trials that compared tiotropium
Respimat 5 and 10 mg with placebo in nearly 2000 COPD
patients with a similar disease profile to our study but
which did not permit concurrent use of LABAs.11 In that
pooled analysis, the difference between tiotropium 5 mg
and placebo for the trough FEV1 endpoint was 127 ml after
one-years treatment. The corresponding difference in our
study (102 ml) is of the same order, considering that the
majority of patients were concurrently using LABAs (alone
or in combination with ICS). Of note, the proportions with
at least one exacerbation in our study were 35.3% in the
tiotropium group and 43.1% for placebo, representing
a relative risk reduction (RRR) of 31%, compared with a 22%
reduction in the previous 1-year trials.11 In addition, there
was a 27% reduction in the relative risk of exacerbations
requiring hospitalisation in our study. These results are in
line with those of other reported tiotropium trials,
including the 4-year UPLIFT study with tiotropium 18 mg
delivered via HandiHaler.14
Subgroup analysis according to LABA use at randomisation was pre-defined in the study protocol, and the
protocol required that drugs being taken at that point be
continued for the rest of the study, which was achieved for
LABAs (99% success rate). Approximately twice as many
patients in the placebo group started LABA therapy after
randomisation as in the tiotropium group. The difference
might have reflected poorer disease control in the placebo
group than in the tiotropium group, which would be
consistent with the efficacy results and could be considered
as a surrogate outcome of efficacy. Improvement in trough
FEV1 and HRQoL throughout the study with tiotropium was
superior to placebo irrespective of LABA co-treatment, but
larger absolute changes from baseline were seen in LABA
non-users than LABA users (for both study treatments). This
probably reflects a greater potential for improvement in
the LABA non-users, who were less heavily treated with
COPD medications before and during the study than LABA
users and had slightly less severe disease. In line with these
results, we also found that fewer LABA non-users than LABA
users (33.4 vs. 44.4%) had at least one exacerbation during
the treatment period. Considering LABA users only, the
superior bronchodilator efficacy of tiotropium relative to
placebo in our study is consistent with the results of shortand long-term studies that have compared tiotropium and
LABA combinations with LABA only.15e17
More patients discontinued prematurely in the placebo
group than in the tiotropium group, and this effect was
more marked in patients with very severe COPD at baseline.
In both treatment groups, adverse events were the most
common single reason for withdrawal. Safety outcomes
showed few clear differences between the two treatment
groups. Incidence rates for adverse and serious adverse
events were similar, apart from COPD exacerbation and
bronchitis (more common in the placebo group) and dry
mouth (more common in the tiotropium group), for which
the CIs of the rate ratio excluded 1. COPD exacerbation was

Tiotropium Respimat in COPD patients

1469

Table 7 Number of patients reporting adverse events during the actual treatment period, with incidence rates per 100
patient-years in parentheses (unless otherwise stated). Events are listed by most common organ class and preferred term
(treated set).

Mean (SD) exposure to treatment,


days
Any adverse event
Any serious adverse event

Tiotropium 5 mg
Respimat
(n Z 1952)

Placebo
(n Z 1965)

Rate ratio
(tiotropium:placebo),
95% CIa

308.5 (85.9)

299.5 (97.2)

1369 (155.6)
342 (20.4)

By organ class (events reported by 5% of patients in either group)


Cardiac disorders
141 (8.03)
Gastrointestinal disorders
278 (16.9)
General disorders and
176 (10.2)
administration site conditions
Infections and infestations
175 (10.2)
Musculoskeletal and connective
199 (11.8)
tissue disorders
Nervous system disorders
160 (9.29)
Lower respiratory system disordersb
902 (70.5)
Upper respiratory system disordersb
459 (30.0)
Preferred term (events reported by 3% of patients in either group)
COPD exacerbation
641 (44.1)
Nasopharyngitis
157 (9.16)
Dyspnoea
136 (7.83)
Upper respiratory tract infection
124 (7.13)
Cough
124 (7.13)
Bronchitis
67 (3.79)
Pneumonia
65 (3.65)
Productive cough
60 (3.38)
Dry mouth
60 (3.41)

1361 (157.4)
336 (20.6)

0.99 (0.92e1.07)
0.99 (0.85e1.15)

131 (7.64)
238 (14.5)
156 (9.26)

1.05 (0.83e1.33)
1.16 (0.98e1.38)
1.11 (0.89e1.37)

201 (12.1)
163 (9.7)

0.85 (0.69e1.04)
1.21 (0.99e1.49)

139 (8.18)
1013 (87.0)
439 (29.1)

1.14 (0.90e1.43)
0.81 (0.74e0.89)
1.03 (0.91e1.18)

759
151
152
144
108
95
74
61
27

(56.8)
(8.95)
(9.02)
(8.51)
(6.31)
(5.52)
(4.25)
(3.52)
(1.54)

0.78
1.02
0.87
0.84
1.13
0.69
0.86
0.96
2.21

(0.70e0.86)
(0.82e1.28)
(0.69e1.09)
(0.66e1.07)
(0.87e1.46)
(0.50e0.94)
(0.62e1.20)
(0.67e1.37)
(1.41e3.49)

CI Z confidence interval; COPD Z chronic obstructive pulmonary disease; SD Z standard deviation.


a
Rate ratios calculated from incidence rates.
b
The organ class respiratory, thoracic and mediastinal disorders was split into lower, upper and other respiratory disorders.

the most common adverse event, reported by 36% of


patients. Other adverse events reported by more than 5% of
patients in either group were mainly upper and lower
respiratory events such as nasopharyngitis, dyspnoea,
upper respiratory tract infections and cough. This is similar
to the pattern seen in a pooled analysis of 19 placebocontrolled trials that compared tiotropium with placebo.18
A numerical imbalance was found in the incidence of
fatal events, which occurred more frequently in the tiotropium group. Although inhibition of vagal tone by
systemic anticholinergic agents can result in increased
heart rate, tachycardia has not been observed in this or
other tiotropium trials. A recent meta-analysis of randomised controlled trials in COPD found a significantly higher
rate of cardiovascular death and non-fatal MI or stroke in
patients receiving any inhaled anticholinergics compared
with control,19 but in analyses of tiotropium trials only, the
risk of cardiovascular or all-cause mortality was either
unchanged or reduced compared with placebo.20e22 There
was no indication in our study of a higher risk of stroke in
the tiotropium group, in line with the findings of the
UPLIFT study.14 Fatal events attributed to neoplasms
occurred more often in the tiotropium group than the
placebo group. Considering the diversity of the diagnoses

and their timing in relation to the duration of study (fewer


than 100 days for most patients), it is likely that onset predated study entry. Thus, a causal relationship to tiotropium
treatment is not biologically plausible. In patients concurrently using LABAs in our study, there was a numerically
higher risk of all-cause, cardiac and cardiovascular death
with tiotropium, although the association was not significant. The use of b2-agonists in patients with asthma and
COPD is itself associated with an increased risk of cardiovascular events.23
The mortality results from the current study are inconsistent with those of the UPLIFT study, in which the risk of
a fatal event was lower with tiotropium treatment (in the
HandiHaler formulation) than with placebo.14 However, in
the previous 1-year tiotropium Respimat trials, the slight
imbalance in mortality rates favoured placebo although the
difference was not significant.11 In those two trials, the
difference in discontinuation rates between placebo
(31.4%) and tiotropium (18.8% overall) was even more
pronounced than in the current study, and discontinued
patients had more severe lung disease at baseline, particularly in the placebo group.11
Greater systemic exposure to tiotropium after inhalation
from the Respimat inhaler compared with the

1470

E.D. Bateman et al.

Table 8 Number of fatal adverse eventsa (by organ class) where both onset of event and death occurred during the planned
treatment period (up to Day 337).

Patients with any fatal event


General disorders and
administration site conditions
Lower respiratory system
disorders
Cardiac disorders
Infections and infestations
Other respiratory system
disordersc
Neoplasms benign, malignant
and unspecifiedd
Other organ classes with 2
events in totale

Tiotropium 5 mg
Respimat (n Z 1952)

Placebo
(n Z 1965)

Number of
events

Incidence
rateb

Number of
events

Incidence
rateb

52
19

2.94
1.07

38
12

2.13
0.67

1.38 (0.91e2.10)
1.60 (0.78e3.29)

0.51

16

0.89

0.57 (0.25e1.28)

9
3
5

0.51
0.17
0.28

4
5
2

0.22
0.28
0.11

2.27 (0.70e7.37)
0.61 (0.14e2.53)
2.52 (0.49e13.01)

0.23

0.11

2.02 (0.37e11.02)

NC

NC

NC

Rate ratio
(tiotropium:placebo),
95% CI

CI Z confidence interval; NC Z not calculated.


a
Adjudicated assignment to organ classes; number of events categorised by class exceeds number of patients in first table row
because some deaths were due to 2 or more events in different classes.
b
Per 100 patient-years.
c
Comprising lung cancer (tiotropium, 5 events; placebo, 1) and pulmonary embolism (placebo, 1).
d
Excluding lung cancer.
e
Comprising gastrointestinal disorders (tiotropium 1; placebo, 1); nervous system disorders (tiotropium, 1); psychiatric disorders
(placebo, 1); renal and urinary disorders (tiotropium, 1), reproductive system disorders (tiotropium, 1) and upper respiratory system
disorders (tiotropium, 1).

HandiHaler could potentially have influenced outcomes in


the current study. However, a 4-week phase 2 crossover
study that compared daily tiotropium doses of 5 and 10 mg
from Respimat inhaler and 18 mg from the HandiHaler
found that the two inhalers performed similarly in regard to
efficacy and tolerability, and that systemic exposures were
also similar.24 The choice between these two inhalers,
where both are licensed, will depend mainly on the use
characteristics of the device for subgroups of patients with
different needs, and the adequacy of the patients inhaler
technique. Patient satisfaction with the Respimat inhaler
has been shown to be high in controlled clinical studies.25,26

In conclusion, once daily tiotropium delivered via


the Respimat inhaler to patients who continued to take
their usual maintenance therapy for COPD produced
improvements in lung function, exacerbation risk and
quality of life after 48 weeks treatment. The adverse
event profile was essentially not different from previous
tiotropium trials, except that more fatal events occurred in
the tiotropium Respimat group. Although the clinical
significance of this finding is uncertain given the imprecise
estimate of hazard ratio for all-cause mortality, the
potential influence of trial-related factors and the inconsistency with the results reported for tiotropium

Table 9 Hazard ratios (HRs) for deaths occurring during the planned treatment period (up to Day 337) according to use of longacting beta2-agonists (LABAs) at baseline, from multivariate analyses. Ratios adjusted for age, sex, GOLD (Global Initiative for
Chronic Obstructive Lung Disease) stage, body mass index and cardiac disorders.
Patients using LABAs

All-cause deathsa
Cardiac deathsb
Cardiovascular deaths

Patients not using LABAs

Number of
patients
analysed

HR (tiotropium:
placebo) and
95% CI

Number of
patients
analysed

HR (tiotropium:
placebo) and
95% CI

Tiotropium, 26;
Placebo, 16
Tiotropium, 10;
Placebo, 2
Tiotropium, 10;
Placebo, 4

1.40 (0.75e2.62)

Tiotropium, 26;
Placebo, 22
Tiotropium, 10;
Placebo, 8
Tiotropium, 12;
Placebo, 8

1.16 (0.66e2.06)

4.45 (0.97e20.38)
2.25 (0.70e7.18)

CI Z confidence interval.
a
Also adjusted for blood and lymphatic system disorders.
b
Also adjusted for renal and urinary disorders (excluding nephropathies).

1.32 (0.52e3.38)
1.55 (0.63e3.81)

Tiotropium Respimat in COPD patients


HandiHaler in the larger UPLIFT trial, it will be investigated further in future studies.

Acknowledgements
The authors acknowledge the help of all investigators who
recruited patients to this study, listed here by country.
Australia: A Garfield, P Seale, M Philips, AM Southcott, P
Carroll, R Watts, M Chia, C Steinfort, G Simpson, P Fogarty;
Brazil: A Cukier, F Lundgren, J Jardim, M Moreira, R Stirbulov, S Eis, E Pizzichini; Canada: M Alexander, J Anthony,
J Bartlett, K Bayly, G Bishop, J Bouchard, S Field, R Hart,
K Ho, A Kelly, A Lam, S Lam, R Luton, A Nayar, M OMahony,
W Ramesh, P Wilcox, W Yang, E York; China: Y Tang, T Sun,
W Cheng, W Yao, P Chen, J Kang, J Xin, Y Wu, C Liu, Q Xiu,
C Bai, L Huiping; Denmark: V Backer, P Lange, N Hansen,
T Sorensen, P Revsbech; Finland: S Saarelainen, K Venho,
J Kotaniemi, A Hakulinen; France: D Caillaud, J Jasnot,
P Zuck, G Peiffer, M Legendre, B Pigearias, B Bugnas,
H Pegliasco, C Aldegheri, C Raspaud, L Kedziora, M Boukhana, D Muller, L Fouquert, C Le Merre, A Proust, B Picavet, D Milosevic, J Dupouy, P Tarodo de la Fuente,
C Brousse, O Castelnau, J Roujon, P Greillier, L Vives,
J Cabrera, M Larrousse, G Chaigneau; Germany: R Redlich,
H Arievich, R Dichmann, J Eller, W Feussner, W Gams,
T Ginko, V Grimm-Sachs, R Hu
ting, J Lehnert, R Malek,
W Schro
der-Babo, T Schultz, L Volgmann, W Vorderstrasse,
P Hofbauer; Greece: G Tatsis, G Stratakos, N Georgatou,
G Patlakas, V Ioannidis, N Galanis, E Vlachogianni, A Antoniadis, E Zervas, M Gaga, M Skoumbourdis, I Zagoreos,
L Ganavias, A Vetoulis; Hong Kong: W Yu, D Hui, C Chu;
Hungary: J Strausz, Z Csontos, B Balint, Z Gyori, Z Szalai,
K Fonay; India: D Talwar, R Rananathan, G DSouza,
A Mahashur, S Jaganmani, K Rao, K Jagannath, P Niphadkar,
A Bhattacharya, V Thansekaraan, S Bhargava, S Salvi,
M Kulmar, J Whig, D Behera, S Saboo, R Chetambath;
Ireland: A OBrien; Italy: P Paggiaro, G Anzalone, G Barisione, V Brusasco, S Centanni, M Confalonieri, R Dal Negro,
L Fabbri, C Gulotta, F Mazza, P Palange, A Papi; Korea:
Y Kim, C Son, S Jeong, C Yoo, K Lee, H Yum, S Lim, Y Lee,
S Jung, K Jung; Lithuania: A Bagdonas, R Nargela, B Sitkauskiene; Malaysia: T Saifudin, C Loh, H Muttalif, C Aminuddin, A Ahmad Mahayiddin, M Harun, N Tarekh; Mexico:
M Kaldman, A Ramirez, J Castanon, N Flores, R Peregrina,
R Valay, L Mendoza, M Vaca, F Llamas, F Merida, A Sanchez,
H Gil, O Chanona, M Loustauna, A Ramirez, A Perea;
Netherlands: R Aalbers, E Dubois, W Evers, J van Helmond,
J De Jong, H Los, H Pasma, H Sinninghe Damaste,
W Strankinga, C Melissant, N Schloesser; Norway: P Lier,
F Wammer, S Steinshamm; Portugal: C Barbara, R Ribeiro
Costa, J de Almeida, J Cardoso, J Albino; Singapore:
K Narendran, A Ng, J Azman; Slovakia: D Branislav, P Demo;
South Africa: J Joubert, A Abdullah, I Abdullah, G Ras,
H Van Rensburg, J Jansen, A Bruning; Spain: J Heredia,
R Blanquer Olivas, G Rodriguez, J Masa, J Munoz; Sweden:
A Lindberg, E Onkamo, K Romberg, P Jakobsson, V Ukale;
Switzerland: E Russi, M Pons, J Tschopp; Taiwan: C Yu,
D Perng, C Wu, W Perng, Y Tsai, T Hsiue, M Huang, T ChiWei; Turkey: R Ozacar, L Erkan, E Uzaslan, B Caglayan,
S Umut, T Tatlicioglu, N Capan, I Gulmez, T Caglar,
M Suerdem; UK: J Corne, M Britton, T Cahill, A Ellery,

1471
N Keaney, R Lawson, W Coulson, P Marazzi, G Martin,
A Middleton, A Millar, M Parashchak, B Penney, J Purohit,
A Winning, J Ryan, M Ward, T Hall, M Blagden, C Strang,
M Anderson, R Reed, R Russell; USA: C Corder, M Kaye,
D Lorch, D Ostransky, A Pollack, A Wachtel, J Fine, S Brazinsky, A Cooper, M Eichenhorn, T Hyers, R Kahn, J Bernstein, D Webster, D Millar, K Rock, N Ettinger, W Henderson,
D Rowe, J Ilowite, J Donahue, A Heyder, G Greenwald,
J Condemi, R Lenox, T Lowdermilk, S Truong, K Murphy,
L Oftadeh, C Laforce, W Lumry, F Hampel, R Baughman,
B Corser, A Captain, M Conway, J McFeely, G San Pedro,
W Rousseau, P Ratner, F Fakir, J Schul, K Mahutte, I Leech,
M Janes, A Siebert, K Jacobson, J Taylor, M Milam, J Grady,
D Nyanjom, P Arcuri, T Ahmed. Medical writing support for
this article was provided by Roger Nutter at Lexeme,
Chester, UK, and funding for this support was provided by
Boehringer Ingelheim. The study was funded by Boehringer
Ingelheim.

Conflict of interest statement


EDB has received remuneration from Boehringer Ingelheim
and Pfizer for lectures and advisory board participation,
and his institution has received funds from the same
companies for self-initiated and contract research projects.
DPT has received speaking fees, research funding and
consultation fees from Boehringer Ingelheim. NMS has
received speaking fees, research funding and consultation
fees from Boehringer Ingelheim. RD has received remuneration for lectures and advisory board work for Boehringer Ingelheim, GSK, Novartis, Almirall, ALK, UCB,
Airsonett, Astra Zeneca, Teva and Pfizer and worked as an
unpaid investigator on clinical trials for Boehringer Ingelheim, Novartis, Astra Zeneca, Allergopharma, Airsonett,
Stallergen, GSK, and ALK. LT, DM and DP are employees of
Boehringer Ingelheim Ltd, the sponsors of the trial, and
contributed to study design, data interpretation, manuscript review and the collective decision to submit the
manuscript for publication.

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