Effect of tiotropium bromide on the cardiovascular response to exercise in COPD.

Abstract

Exercise limitation and exertional dyspnea are important symptoms of chronic obstructive pulmonary disease (COPD), which may be partially relieved by tiotropium. Although the mechanism of relief is multifactorial, improved dynamic ventilatory mechanics appear to be important. It is not however known whether tiotropium may also act by improving cardiovascular function during exercise.
We conducted a randomized, placebo-controlled crossover study in 18 COPD subjects with a FEV(1) 40+/-3% predicted (mean+/-SEM). Subjects inhaled either tiotropium 18 microg or placebo once daily for 7-10 days then the other intervention for a further 7-10 days after a 35-day washout period. Subjects performed constant work rate cycle exercise at 75% of maximum after each treatment period. Heart rate, blood pressure, oxygen uptake, operating lung volumes and breathing pattern were measured.
Heart rate was 7 beats/min lower at rest and throughout exercise with tiotropium compared to placebo (p=0.001). Oxygen uptake was unchanged throughout exercise. Oxygen pulse on exercise was greater by 7.4% (p<0.01) and systolic blood pressure was lower by 7 mmHg (p=0.03). The cardiac rate pressure product was reduced by 7.6% (p<0.01) with tiotropium. Exercise endurance tended to be greater with tiotropium. Reduction in heart rate on exercise correlated with an increase in inspiratory reserve volume (r=-0.50, p=0.04).
Tiotropium may improve cardiac as well as pulmonary function during exercise in COPD. We suggest that this effect may be due, in part, to improved cardiopulmonary interaction as a result of mechanical unloading of the ventilatory muscles however further study is required.

Full text

Page 1

Effect of tiotropium bromide on the cadiovascular
response to exercise in COPD
J. Traversa, P. Lavenezianaa, K.A. Webba, S. Kestenb, D.E. O’Donnella,?
aRespiratory Investigation Unit, Department of Medicine, Queen’s University, Kingston, Ont., Canada
bBoehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
Received 9 January 2007; accepted 16 March 2007
KEYWORDS
Dyspnea;
Placebo;
Heart rate;
Blood pressure
Summary
Introduction: Exercise limitation and exertional dyspnea are important symptoms of
chronic obstructive pulmonary disease (COPD), which may be partially relieved by
tiotropium. Although the mechanism of relief is multifactorial, improved dynamic
ventilatory mechanics appear to be important. It is not however known whether
tiotropium may also act by improving cardiovascular function during exercise.
Methods: We conducted a randomized, placebo-controlled crossover study in 18 COPD
subjects with a FEV14073% predicted (mean7SEM). Subjects inhaled either tiotropium
18mg or placebo once daily for 7–10 days then the other intervention for a further 7–10
days after a 35-day washout period. Subjects performed constant work rate cycle exercise
at 75% of maximum after each treatment period. Heart rate, blood pressure, oxygen
uptake, operating lung volumes and breathing pattern were measured.
Results: Heart rate was 7 beats/min lower at rest and throughout exercise with
tiotropium compared to placebo (p ¼ 0.001). Oxygen uptake was unchanged throughout
exercise. Oxygen pulse on exercise was greater by 7.4% (po0.01) and systolic blood
pressure was lower by 7mmHg (p ¼ 0.03). The cardiac rate pressure product was reduced
by 7.6% (po0.01) with tiotropium. Exercise endurance tended to be greater with
tiotropium. Reduction in heart rate on exercise correlated with an increase in inspiratory
reserve volume (r ¼ ?0.50, p ¼ 0.04).
Conclusion: Tiotropium may improve cardiac as well as pulmonary function during
exercise in COPD. We suggest that this effect may be due, in part, to improved
cardiopulmonary interaction as a result of mechanical unloading of the ventilatory muscles
however further study is required. ClinicalTrials.gov Identifier: NCT00274027.
& 2007 Elsevier Ltd. All rights reserved.
ARTICLE IN PRESS
0954-6111/$-see front matter & 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2007.03.008
?Corresponding author. Tel.: +16135482342; fax: +16135491459.
E-mail address: odonnell@post.queensu.ca (D.E. O’Donnell).
Respiratory Medicine (]]]]) ], ]]]–]]]
Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008

Page 2

Introduction
Exercise limitation and exertional dyspnea are often the
most important symptoms experienced by individuals with
chronic obstructive pulmonary disease (COPD). The cause of
exercise limitation is multifactorial. Dynamic pulmonary
hyperinflation during exercise with resulting neuromechani-
cal dissociation is likely to be important in individuals with
moderate to severe COPD.1Abnormalities of cardiovascular
function, pulmonary gas exchange, peripheral muscle
function, and perception of symptoms may also contri-
bute.2–4
Tiotropium bromide is a long acting anticholinergic agent
that has demonstrated efficacy as inhaled therapy for COPD
in improving exertional dyspnea, health status, spirometry,
exercise tolerance and exacerbation frequency.5–7It is as
effective or more effective than the short acting antic-
holinergic agent ipratropium and the long-acting b-adrenor-
eceptor agonist salmeterol.8,9Tiotropium therapy produces
a reduction in dynamic hyperinflation and neuromechanical
dissociation during exercise in COPD patients,10a potential
explanation for the improvements in exertional dyspnea and
exercise capacity.
What is not known is whether the beneficial effect of
tiotropium on exercise capacity may be due in part to
improvements in the cardiovascular response to exercise. No
study to date has examined the cardiovascular effects of
tiotropium during exercise. Tiotropium could affect the
cardiovascular system either directly or through its pulmon-
ary effects via a cardiopulmonary interaction. A direct
cardiac action is plausible as other anticholinergic agents
are known to exert direct effects on the cardiovascular
system. Atropine is a nonselective anticholinergic that
increases heart rate and myocardial work at rest and during
exercise.11In contrast, when the anticholinergic agents
ipratropium and oxitropium are inhaled, resting heart rate
may be slightly reduced.12,13Oxitropium has also been
shown to slightly attenuate the exercise-induced rise in
pulmonary artery pressure in COPD patients.13Like ipra-
tropium and oxitropium, tiotropium has not been associated
with classic anticholinergic effects such as tachycardia and
may also slightly reduce resting heart rate.14Tiotropium
however differs from traditional anticholinergic agents in its
relative kinetic selectivity for M1 and M3 airway muscarinic
receptor subtypes over the M2 cardiac muscarinic receptor
subtype15and its direct cardiac effects during exercise are
unknown.
Another possibility is that tiotropium may affect the
cardiovascular response to exercise by improving expiratory
airflow and pulmonary mechanics via a cardiopulmonary
interaction. Tiotropium improves dynamic hyperinflation
during exercise.7,16This allows tidal breathing to occur on
the more favorable, linear portion of the respiratory
pressure–volume curve and allows tidal breaths to be
generated using less negative inspiratory pleural pres-
sures.10Negative pleural pressures increase cardiac after-
load as the ventricles must overcome the transmural
pressure, the difference between thoracic and ventricular
pressure, in addition to arterial pressure.17,18This cardio-
pulmonary interaction may be a limiting factor for exercise
in individuals with severe COPD19and other cardiopulmon-
ary interactions may also be relevant.
We recently conducted a controlled clinical study
designed to assess the effect of tiotropium on the sensory
and pulmonary responses to exercise in COPD patients.10In
the current study, we assessed cardiovascular data obtained
at the time of this study to determine the effect of
tiotropium on the cardiovascular response to exercise in
COPD.
Methods
Subjects
Subjects were eligible for inclusion if they had COPD,20were
clinically stable, had a X20 pack-year cigarette smoke
exposure, a forced expiratory volume in 1s (FEV1) p65%
predicted, a functional residual capacity (FRC) X120%
predicted and a modified baseline dyspnea index score
p6.21Subjects were excluded if they had comorbid disease
that could contribute to dyspnea and exercise limitation, a
contraindication to exercise testing,22daytime oxygen use
or had participated in a pulmonary rehabilitation program in
the 6 weeks prior to the study.
Study design
The study incorporated a randomized, double-blind, place-
bo-controlled crossover design. Approval was obtained from
the local hospital and university research ethics board. After
giving written informed consent, subjects completed a
screening assessment to determine eligibility where medical
history, physical examination, chronic dyspnea evaluation,
pulmonary function testing and a symptom-limited incre-
mental cycle exercise test were performed. Eligible subjects
entered a baseline period during which further pulmonary
function tests and a constant load exercise test were
performed to familiarize subjects with testing procedures
in order to avoid possible learning effects. These tests were
performed again both prior to and at the end of each of two
7–10 day treatment periods separated by a 35 day washout
period. During each treatment period, subjects inhaled
visually identical study medication, either tiotropium 18mg
or placebo, once daily in addition to other regular
medication. Subjects were randomized in blocks of four
using commercial software (ClinPro/LBLVersion 5.2, Clinical
Systems Inc.) to have an equal chance of being allocated to
receive tiotropium during the first treatment period
followed by placebo during the second treatment period or
placebo during the first treatment period followed by
tiotropium during the second treatment period. Subjects
completed a follow up visit 1 week after completion of the
second treatment period consisting of a physical examina-
tion and pulmonary function tests.
Subjects avoided oral and long-acting b-agonists for 1
week before the screening visit and throughout the study
and short-acting anticholinergics for 1 day before and
throughout the study. Tiotropium or other long-acting
anticholinergics were avoided apart from the study medica-
tion. Salbutamol was provided as an aerosol inhaler as
rescue medication during the study. Concomitant regular
corticosteroids and theophylline were permitted throughout
the study except that before each study visit, short-acting
ARTICLE IN PRESS
J. Travers et al.2
Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008

Page 3

theophylline and long-acting theophylline were withheld for
at least 24 and 48h, respectively. Subjects avoided b-agonist
use, caffeine, alcohol, heavy meals and major physical
exertion before study visits which were all held in the
morning. Post treatment assessments were performed
80–120min after the last study medication dose.
Procedures
Pulmonary function measurements were collected according
to recommended standards23–25
equipment (Vmax 229d with Autobox 6200 DL, SensorMedics,
Yorba Linda, CA) and expressed as percentages of predicted
normal values as previously described.10Predicted inspira-
tory capacity (IC) was calculated as predicted total lung
capacity (TLC) minus predicted FRC. Symptom-limited
exercise tests were conducted on an electronically braked
cycle ergometer (Ergometrics800S, SensorMedics) by use of
a cardiopulmonary exercise testing system (Vmax 229d,
SensorMedics) as previously described.7,26–28Incremental
exercise testing was performed using 1min increments of
10W each following a 1min warm up of unloaded pedaling.
Constant-load tests were performed at 75% of the maximal
incremental work rate for each subject. Endurance time was
defined as the duration of loaded pedaling.
Measurements were collected while subjects breathed
through a mouthpiece with a low-resistance flow transducer
while nose clips were worn. Standard cardiopulmonary
exercise test parameters29were collected on a breath-by-
breath basis. Intensity of dyspnea and leg discomfort was
recorded using the 10-point Borg scale30at rest, during the
last 30s period of every 1min interval during exercise and at
end exercise. Operating lung volumes were derived from IC
manoeuvres1,28performed at rest, within the last 30s period
of every 2min interval during exercise and at end exercise.
Blood pressure was measured by auscultation of the right
brachial artery, using a sphygmomanometer with an arm
cuff, at rest, within the first 30s period of every 2min
interval, at end exercise and every 5min during recovery
until blood pressure measurements returned to near base-
line. Oxyhemoglobin saturation was recorded continuously
via a pulse oximeter.
by use of automated
Analysis of exercise endpoints
All breath-by-breath measurements were averaged in 30s
intervals throughout each test stage, rest, exercise and
recovery. To avoid contamination of breath-by-breath data
by the artifact of the IC maneuver, symptom ratings and IC
measurements collected in a 30s period that included an IC
maneuver were linked to breath-by-breath data collected in
the previous 30s period. Systolic and diastolic blood
pressure measurements were linearly extrapolated where
necessary to give an estimated blood pressure that was
linked to breath-by-breath data and symptom ratings
obtained in between blood pressure measurements. Pre-
exercise rest was defined as the steady-state period after at
least 3min of quiet breathing on the mouthpiece while
seated at rest before exercise. Cardiopulmonary parameters
were averaged over the last 30s of this period and IC
measurements at rest were collected while breathing on the
same system immediately after completion of the quiet
breathing period. A standardized time near end exercise
(isotime) was defined as the highest common exercise time
achieved during post treatment constant-load tests per-
formed by a given subject, rounded down to the nearest
whole minute. Peak exercise was defined as the last 30s of
loaded pedaling, cardiopulmonary parameters were aver-
aged over this period, symptom ratings and IC measure-
ments were collected immediately at the end of this period.
The rate pressure product, a noninvasive marker of
myocardial oxygen consumption31was calculated as heart
rate multiplied by systolic blood pressure.
Statistical analysis
The sample size was chosen to have adequate power to
detect a 300ml difference in IC at isotime. po0.05
significance level was used for all analyses. Treatment
responses were compared by two-tailed paired t-tests.
Pearson correlations were used to establish associations
between cardiopulmonary variables. Data are shown as
mean plus or minus the standard error of the mean.
Results
Eighteen subjects completed the study (Table 1). No subject
experienced oxyhemoglobin desaturation below 88% or a
significant elevation of end-tidal carbon dioxide tension
during incremental exercise. No sequence or carryover
effects were found with respect to cardiovascular variables,
pulmonary variables or symptoms. The work rate for
constant load exercise was 5075W.
Effect of tiotropium at rest
Heart rate was lower at rest following tiotropium treatment
compared to placebo by 6.771.8 beats/min (95% confidence
interval 3.2–10.1, p ¼ 0.001). Diastolic blood pressure and
the rate pressure product were also lower by 4.071.5mmHg
(95% confidenceinterval
9007200mmHgbeats/min
400–1300, p ¼ 0.001), respectively (Table 2). Other cardi-
ovascular variables were not significantly changed. FEV1and
FVC increased at rest following tiotropium treatment
compared to placebo (Table 2). There was no significant
change in the FEV1/FVC ratio. Lung hyperinflation and
airway resistance decreased and airway conductance in-
creased with tiotropium. Breathing pattern during preex-
ercise rest was unchanged except that the ratio of
inspiratory time to total breath time increased with
tiotropium (p ¼ 0.003).
1.0–7.0,
(95%
p ¼ 0.014)
confidence
and
interval
Effect of tiotropium on the response to exercise
Post-treatment exercise endurance time was greater by
0.970.8min or 14% after tiotropium compared to placebo,
not a statistically significant difference. Selected mean
cardiovascular and pulmonary responses to exercise are
shown in Fig. 1. Heart rate was significantly lower with
tiotropium throughout exercise. Oxygen uptake (VO2) was
ARTICLE IN PRESS
Cardiovascular effects of tiotropium during exercise3
Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008

Page 4

no different and oxygen pulse tended to be higher with
tiotropium, significantly so at isotime and at peak exercise.
Systolic and diastolic blood pressures were lower with
tiotropium at all stages of exercise however the statistical
significance of these differences was marginal. The rate
pressure product was significantly lower with tiotropium at
rest and at isotime. Inspiratory reserve volume (IRV) was
significantly greater at rest and throughout exercise.
Cardiovascular and pulmonary variables at isotime near
peak exercise after tiotropium and placebo treatment are
given in Table 3.
Correlates of reduced heart rate on exercise
The difference in heart rate at isotime with tiotropium
compared to placebo correlated with the difference in end-
inspiratory lung volume (EILV) as a percent of TLC (partial
multiple r ¼ 0.53, p ¼ 0.02) and the difference in IRV
(partial multiple r ¼ ?0.50, p ¼ 0.04) more strongly than
with any other measured cardiopulmonary variables.
ARTICLE IN PRESS
Table 1
Subject characteristics.
Study subjects
n ¼ 18
72
6072
26.871.2
5878
5.270.3
6577 (41)
Male gender, %
Age, yr
Body mass index, kg/m2
Cigarette smoke exposure, pack-years
Baseline Dyspnea Index Focal score
Symptom limited peak incremental
work rate, W
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Heart rate, beats/min
FEV1, l
FEV1/FVC, %
FEF50, l/s
SVC, l
IC, l
TLC, l
RV, l
FRC, l
MIP at FRC, cmH2O
MEP at TLC, cmH2O
DLCO, mL/min/mmHg
12773
8371
7372
1.1370.09 (40)
4472 (62)
0.4570.06 (11)
2.9770.17 (75)
1.9470.12 (67)
7.4570.25 (122)
4.4870.19 (216)
5.5170.20 (171)
6075 (71)
108710 (58)
14.271.2 (64)
Values are means7SE (percent of predicted normal values
are given in parentheses).
FEV1, forced expiratory volume in 1s.
FVC, forced vital capacity.
FEF50, forced expiratory flow at 50% of FVC.
SVC, slow vital capacity.
IC, inspiratory capacity.
TLC, total lung capacity.
RV, residual volume.
FRC, functional residual capacity.
MIP, maximal inspiratory mouth pressure.
MEP, maximal expiratory mouth pressure.
DLCO, diffusing capacity of the lung for carbon monoxide.
Table 2
pulmonary function and breathing pattern measurements
at the end of each treatment period.
Post dose resting cardiovascular variables,
PlaceboTiotropium
Cardiovascular variables
Heart rate,
beats/min
VO2, l/min
Oxygen pulse,
mL/beat
Systolic blood
pressure, mmHg
Diastolic blood
pressure, mmHg
Oxyhemoglobin
saturation, %
Rate pressure
product,
mmHg.beats/min
79727272*
0.3270.02
4.1370.32
0.3170.02
4.3770.35
124.472.7123.673.0
82.472.078.471.1
95.770.395.570.3
9800740089007300*
Pulmonary function
FEV1, l
FEV1/FVC, %
FEF50, l/s
SVC, l
TLC, l
RV, l
FRC, l
1.1870.10 (42)
4472 (62)
0.5270.07 (53)
3.0570.19 (77)
7.3670.17 (121) 7.2770.25 (119)
4.3170.23 (208) 3.9770.20 (192)*
5.3870.24 (167) 5.0970.22 (158)*
1.3870.11 (49)*
4572 (63)
0.5770.06 (14)
3.3170.20 (84)*
Steady-state breathing pattern
IC, l
IRV, l
EELV, l
VT, l
Respiratory rate,
breaths/min
VT/TI, l/s
VT/TE, l/s
TI, s
TI/Ttot
2.0270.12
1.3570.13
5.3370.23
0.6870.03
18.670.9
2.2570.13*
1.5770.13*
5.0070.20*
0.6870.04
18.871.0
0.5870.03
0.3570.02
1.2070.06
0.3670.01
0.5870.03
0.3570.02
1.3370.08
0.4070.01*
Values are means7SE (percent of predicted normal values
are given in parentheses). *po0.01 tiotropium versus
placebo.
VO2, oxygen uptake.
FEV1, forced expiratory volume in 1s.
FVC, forced vital capacity.
FEF50, forced expiratory flow at 50% of FVC.
SVC, slow vital capacity.
TLC, total lung capacity.
RV, residual volume.
FRC, functional residual capacity.
IC, inspiratory capacity.
IRV, inspiratory reserve volume.
EELV, end-expiratory lung volume.
VT, tidal volume.
TI, inspiratory time.
TE, expiratory time.
Ttot, total breath time.
J. Travers et al.4
Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008

Page 5

Discussion
The novel finding of this study is a consistent, statistically
significant and potentially clinically important effect of
tiotropium on the cardiovascular response to exercise in
subjects with COPD. Heart rate was lower with tiotropium at
rest and throughout exercise by 7 beats/min with a
corresponding increase in oxygen pulse, a surrogate measure
of cardiac stroke volume, and a reduction in the rate
pressure product, a surrogate measure of myocardial work
at isotime during exercise. The reduction in heart rate at
isotime during exercise correlated best with indices of
dynamic hyperinflation, suggesting an association between
the cardiac effects of tiotropium and improved pulmonary
mechanics. These results suggest that either tiotropium
exerts a direct effect on the cardiovascular system or that
ARTICLE IN PRESS
0.0
0.5
1.0
1.5
2.0
0
Exercise time (min)
IRV (l)
0
2
4
6
8
10
12
14
O2 pulse (ml/beat)
120
130
140
150
160
170
SBP (mmHg)
75
80
85
90
95
DBP (mmHg)
8
10
12
14
16
18
20
RPP (x1000 mmHg.beats/mn)
0
1
2
3
4
5
6
7
Dyspnea (Borg)
60
70
80
90
100
110
120
Heart rate (beats/min)
Tiotropium
Placebo
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
VO2 (l/min)
**
**
**
**
**
**
**
**
**
**
*
*
*
*
**
*
2
4
6
8
0
Exercise time (min)
2
4
6
8
0
Exercise time (min)
2
4
6
8
0
Exercise time (min)
2
4
6
8
0
Exercise time (min)
2
4
6
8
0
Exercise time (min)
2
4
6
8
0
Exercise time (min)
2
4
6
8
0
Exercise time (min)
2
4
6
8
Figure 1
means of all subjects. *po0.05 tiotropium versus placebo. **po0.01 tiotropium versus placebo. VO2, oxygen uptake, RPP, rate
pressure product, SBP, systolic blood pressure, DBP, diastolic blood pressure, IRV, inspiratory reserve volume.
Cardiovascular, IRV and dyspnea response to exercise. Open circles, placebo. Filled circles, tiotropium. Data points are
Cardiovascular effects of tiotropium during exercise5
Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008

Page 6

the bronchodilating and lung deflating actions of tiotropium
result in improved cardiac function via a cardiopulmonary
interaction.
Potential direct cardiovascular effects of tiotropium
Tiotropium administered by inhalation is mostly swallowed,
very little of which is absorbed systemically.32The fraction
that reaches the lung has a high bioavailability giving peak
plasma concentrations approximately 60% of that achieved
by intravenous administration and persisting in plasma for
longer.32Although systemically available, the current results
cannot be explained by tiotropium antagonism at cardiac M2
muscarinic receptors as this effect would produce an
increase rather than a decrease in heart rate. Tiotropium
antagonism of the M3 receptors of the pulmonary vascu-
lature may result in both inhibition of vasoconstriction and
inhibition of endothelial-dependent vasodilatation. It is
possible that the net effect of these actions may reduce
resting or exercise-induced pulmonary vascular tone and
pulmonary arterial pressure.
Studies of the cardiovascular effects of tiotropium at rest
have reported few clinically significant effects.33A recent
meta-analysis34suggests that there is an increased rate of
cardiac arrhythmias, primarily atrial fibrillation, with
tiotropium although this increase was statistically significant
only after one study responsible for significant heterogene-
ity was excluded. An increased rate of cardiac death with
ipratropium was noted in the Lung Health study35but this
finding was not replicated in other studies36and has not
been reported with tiotropium.
Potential cardiopulmonary interactions
Tiotropium significantly improved measures of dynamic
hyperinflation during exercise, confirming the findings of
other studies.7,16As described above, this effect could
result in reduced cardiac afterload which may explain the
observed improvement in cardiac function. The association
of improvement in EILV and IRV, both measures of dynamic
hyperinflation, with improvement in heart rate is consistent
with this hypothesis but the association does not imply
causation. Other potential interactions mediating the effect
of tiotropium include improved pulmonary blood flow
associated with reduced air trapping,13reduction in heart
rate due to reduced discharge from slowly adapting
pulmonary stretch receptors,37reduction in left ventricular
compression from right ventricular overfilling38and reduc-
tion in positive pleural pressure during expiration.39
Relation to other research
We are not aware of any other study that has examined the
effect of tiotropium on the cardiovascular response to
exercise. The reduction in heart rate during exercise that
we observed with tiotropium was not seen with either the
short-acting anticholinergic oxitropium or the short-acting
b-agonist fenoterol in a study of exercise hemodynamics.13A
study of the effects of the long-acting b-agonist salmeterol
during exercise also showed no reduction in heart rate
despite a similar degree of improvement in dynamic
hyperinflation to that observed with tiotropium.26The
apparent difference between tiotropium and salmeterol is
suggestive of a direct cardiovascular effect of tiotropium.
The alternative explanation is that both agents act to
reduce heart rate during exercise via improved cardiopul-
monary interactions but in the case of salmeterol the effect
is obscured by the tachycardia resulting from systemic b-
adrenergic stimulation.
Clinically and statistically significant differences in
exercise endurance time with tiotropium have been pre-
viously reported in large trials.7,16In the present study,
mean exercise endurance time was increased with tiotro-
pium however the study was not powered to detect a
statistically significant difference.
Limitations of this study
The data presented here were derived from a study
primarily designed to assess the pulmonary and symptomatic
response to exercise in COPD so a full range of hemodynamic
measurements was not undertaken. Oxygen pulse and rate
pressure product are only surrogate measures of stroke
volume and myocardial work, respectively. We have no
reason to suspect that the changes in these measures
observed with tiotropium do not reflect similar changes in
ARTICLE IN PRESS
Table 3
measurements at isotime near peak exercise.
Post dose cardiovascular and pulmonary
PlaceboTiotropium
Heart rate, beats/min
VO2, l/min
Oxygen pulse, mL/beat
Systolic blood pressure,
mmHg
Diastolic blood pressure,
mmHg
Oxyhemoglobin saturation, %
Rate pressure product, mmHg
beats/min
VE, l/min
VE/VCO2
Respiratory rate, breaths/min
VT, l
IC, l
IRV, l
EILV, %TLC
Dyspnea, Borg scale
Leg discomfort, Borg scale
11274
1.1270.10
10.170.9
15676
10574*
1.1470.11
10.971.0*
14875*
88728571
94.170.4
173007900 156007900*
93.570.6
35.873.1
34.371.7
29.871.6
1.2070.08
1.6370.09
0.4470.07
9471
4.470.6
4.270.5
35.473.2
34.871.7
27.671.2*
1.2670.09
1.8670.13*
0.6070.11*
9271
3.670.4
4.270.5
Values are means7SE. *po0.05 tiotropium versus placebo.
VO2, oxygen uptake.
VE, minute ventilation.
VCO2, carbon dioxide production.
VT, tidal volume.
IC, inspiratory capacity.
IRV, inspiratory reserve volume.
EILV, end-inspiratory lung volume.
TLC, total lung capacity.
J. Travers et al.6
Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008

Page 7

stroke volume and myocardial work, but further study
utilizing invasive hemodynamic measurement is required to
conclusively determine this. Likewise, we were not able to
directly measure cardiac output, ejection fraction or
pulmonary artery pressure to help explain the mechanism
or mechanisms by which tiotropium affects the cardiac
response to exercise and determine whether the effect of
tiotropium on the cardiovascular system is physiologically
beneficial or not. From our data, we observed that exercise
endurance was at least as good with tiotropium while
measures of myocardial work were reduced suggesting that
the effect of tiotropium is more likely to be beneficial than
not. As the current analysis was performed post hoc, the
chance that the results presented here represent a type I
error is increased. The consistency of the effect throughout
exercise suggests that the effect is real however prospective
validation is required.
Conclusion
Tiotropium may improve cardiac as well as pulmonary
function during exercise in COPD. We hypothesize that this
is due to a reduction in negative inspiratory pressure
brought about by alleviation of dynamic hyperinflation
through bronchodilation rather than a direct effect of
tiotropium on the heart. Further study is required to
determine the mechanism of this effect.
Conflict of interest statement
This research was supported by the Ontario Ministry of
Health, Boehringer Ingelheim (Canada) and Pfizer Canada.
Steven Kesten is an employee of Boehringer Ingelheim
Pharmaceuticals, Inc.
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Please cite this article as: Travers J, et al. Effect of tiotropium bromide on the cadiovascular response to exercise in COPD. Respir Med
(2007), doi:10.1016/j.rmed.2007.03.008