O R I G I N A L A RT I C L E
193..200
Key words
chronic obstructive pulmonary disease,
bronchodilator response, beta-agonist,
beta-blocker, exercise tolerance.
Correspondence
Robert J. Hancox, Department of Respiratory
Medicine, Waikato Hospital, Hamilton,
New Zealand.
Email: bob.hancox@otago.ac.nz
Received 5 September 2008; accepted 17
January 2009.
doi:10.1111/j.1445-5994.2009.01943.x
Abstract
Background: Patients with chronic obstructive pulmonary disease (COPD)
often have co-existing cardiovascular disease and may require beta-blocker
treatment. There are limited data on the effects of beta-blockers on the
response to inhaled b2-agonists and exercise capacity in patients with COPD.
Objective: To determine the effects of different doses of cardio-selective and
non-selective beta-blockers on the acute bronchodilator response to betaagonists in COPD, and to assess their effects on exercise capacity.
Methods: A double-blind, randomized, three-way cross-over (metoprolol
95 mg, propranolol 80 mg, placebo) study with a final open-label high-dose
arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator
response to salbutamol was measured after first inducing bronchoconstriction
using methacholine. Exercise capacity was assessed using the incremental
shuttle walk test.
Results: Eleven patients with moderate COPD were recruited. Treatments
were well-tolerated although two did not participate in the high-dose metoprolol phase. The area under the salbutamolresponse curve was lower after
propranolol compared with placebo (P = 0.0006). The area under the curve
also tended to be lower after high-dose metoprolol (P = 0.076). The per cent
recovery of the methacholine-induced fall was also lower after high-dose
metoprolol (P = 0.0018). Low-dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all betablocker treatments (P = 0.046).
Conclusion: Non-selective beta-blockers and high doses of cardio-selective
beta-blockers may inhibit the bronchodilator response to b2-agonists in patients
with COPD. Beta-blockers were also associated with lower oxygen saturation
during exercise. The clinical significance of these adverse effects is uncertain in
view of the benefits of beta-blocker treatment for cardiovascular disease.
Introduction
Many patients with chronic obstructive pulmonary
disease (COPD) also have cardiovascular disease and
have a high risk of cardiovascular mortality.16 betaadrenergic blocker therapy reduces mortality and has
symptomatic benefits for many forms of cardiovascular
disease.712 Although patients with COPD also appear
to benefit from beta-blocker treatment for their cardiovascular disease,13 they are often avoided in patients
with concomitant airways disease because of fear of
drug-induced bronchoconstriction.14
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Chang et al.
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Methods
Subjects
All participants had stable COPD diagnosed by a respiratory physician. Inclusion criteria were: fixed airflow
obstruction (post-bronchodilator forced expiratory
volume in 1 s (FEV1)/forced vital capacity (FVC) < 70%,
FEV1 < 80% predicted, reversibility >15% of baseline
FEV1 after inhalation of 200 mg of salbutamol); lifetime
history of cigarette smoking >15 pack years; 40 years of
age; and 20% fall in FEV1 with a cumulative methacholine dose (PD20) of <7.5 mg. Exclusion criteria were:
current beta-blocker use or contraindication to betablocker use, history of asthma, current use of tiotropium
bromide or long-acting beta-agonist, and contraindications to methacholine inhalation including severe COPD
(FEV1 < 30% predicted or <1.0 L).
Study design
This was a randomized, placebo-controlled, doubleblinded, three-way cross-over study with a final
open-label high-dose metoprolol arm. Each study period
consisted of 710 treatment days (to ensure adequate
loading of study drug and wash-out from previous treatment) followed by a methacholine provocation test and a
shuttle walking test performed on different days. Treatments consisted of slow release once daily propranolol
80 mg, metoprolol 95 mg, or placebo in random order
followed by metoprolol 190 mg. All medications apart
from the open-label 190 mg metoprolol were administered in identical capsules made up by the hospital pharmacy. Randomization was generated by an independent
hospital pharmacist and unblinding only occurred
after all recruitment and treatments were completed.
The patients were instructed to take one capsule each
morning. During the study, subjects were asked to withhold all beta-agonist inhalers if possible and an ipratropium bromide (20 mg) inhaler was provided as rescue
medication. Subjects were also instructed to withhold all
bronchodilators for at least 8 h before the methacholine
challenge tests.
Methacholine challenges were performed using a
modified Yan technique.26,27 Subjects inhaled doubling
doses of nebulized methacholine from 0.0073 to
3.728 mg from a dosimeter and the test was stopped once
the FEV1 had fallen by 20% from baseline. The PD20
2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians
Ethical considerations
Given the potential risk of beta-blocker-induced bronchospasm, arrhythmias and hypotension, all subjects
were given a test dose of short-acting propranolol 40 mg
before entry into the study. Spirometry, blood pressure
and an electrocardiogram were measured at 90 min after
the test dose had been given. The maximal dose of metoprolol (190 mg controlled release) had not been previously studied in COPD and was therefore administered in
an open-label arm to enhance safety. The study was
approved by the Northern X Regional Ethics Committee
of New Zealand. All subjects provided written informed
consent.
Analysis
The primary outcomes for the effect of beta-blockers on
bronchodilator response were: (i) the area under the
salbutamol doseresponse curve (AUC, expressed as FEV1
recovery in litres*min) after the methacholine-induced
fall and (ii) the percentage recovery of the FEV1 after
the methacholine-induced fall. These were compared
between treatment groups using repeated-measures
analysis of variance (ANOVA). If the initial ANOVA model
indicated a significant difference between treatments
(P < 0.05), each beta-blocker was compared with placebo
using paired t-tests.
The primary outcomes for the effects of beta-blockers
on exercise tolerance were the distance walked in the
shuttle test and oxygen saturation at maximal exercise.
These were compared using ANOVA and paired t-tests as
above. The adequacy of beta-blockade was determined by
analysis of heart rates before exercise.
Bronchodilator response
The area under the salbutamolresponse curves was
significantly different between treatments (ANOVA
P = 0.0025). Paired t-tests indicated that the AUC following propranolol was significantly lower than placebo
(P = 0.0006). The AUC following metoprolol was not significantly different from placebo for the low-dose metoprolol (P = 0.20) but showed a trend towards a significant
difference for high-dose metoprolol (P = 0.0760) (Fig. 2,
Table 2). The percentage recovery (final FEV1 as a
percentage of the methacholine-induced fall) was
also significantly different between treatments (ANOVA
P = 0.0008). Paired t-tests showed no significant difference in percentage recovery between placebo and
low-dose metoprolol treatment (P = 0.16) but significant
lower percentage recovery in the high-dose metoprolol
(P = 0.0018) and propranolol (P = 0.0002) treatment
groups compared with placebo (Fig. 3, Table 2).
Previous studies in asthma have indicated that the
baseline FEV1, the fall in FEV1 induced by methacholine
and/or the PD20 methacholine may be significant covariates of the AUC using the challengerescue technique.27
However, none of these were significant covariates when
included in the analyses of covariance in this study,
and their inclusion made no material difference to the
findings.
Exercise tolerance
Results
Forty patients were recruited between June 2005 and
July 2007 from respiratory outpatient clinics and the
local pulmonary rehabilitation programme. Twenty-six
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Journal compilation 2010 Royal Australasian College of Physicians
195
Chang et al.
Randomized (n = 14)
2 withdrew consent
Discussion
This study provides evidence that the bronchodilator
response to salbutamol may be impaired by beta-blocker
treatment. Predictably, this effect was most apparent for
the non-selective beta-blocker, propranolol. Indeed, the
response to salbutamol after methacholine challenge in
the propranolol group was little better than the natural
rate of recovery from methacholine, indicating almost
complete b2-receptor blockade (Fig. 3). However, we
also found that high doses of the selective b1-blocker
196
Value
65 years (4776)
8
3
5
6
49 (20100)
1.64 (0.53)
59% (15%)
0.58 (0.09)
79.8 (10.0)
Placebo (n = 11)
Metoprolol 95 mg (n = 11)
Propranolol (n = 11)
Metoprolol 190 mg (n = 9)
Signicance (ANOVA)
1.60 (0.53)
0.69 (1.03)
3.12 (1.16)
114.1 (54)
78.8 (12)
480.9 (181)
94.2 (5.0)
1.54 (0.58)
0.60 (0.79)
2.55 (1.81)
97.2 (72)
62.9 (11)
458.2 (202)
92.5 (5.0)
1.48 (0.50)*
0.45 (0.69)
1.20 (1.32)
38.3 (36)**
61.2 (11)
435.5 (186)
91.2*** (6.2)
1.59(0.55)
0.76 (0.84)
2.31 (1.14)
82.4 (40)||
61.6 (10)
504.4 (213)
90.1 (6.8)
NS
NS
P = 0.0025
P = 0.0008
P < 0.0001
NS
P = 0.046
Paired t-tests against placebo value: *P = 0.0289, P = 0.0006, P = 0.0760, **P = 0.0002, ||P = 0.0018, P = 0.0015, ***P = 0.0830, P = 0.0302. ANOVA,
analysis of variance; FEV1, forced expiratory volume in 1 s; ISWT, incremental shuttle walking test; NS, not signicant.
metoprolol appeared to partially inhibit the bronchodilator responsiveness to beta-agonists. There was little difference between the bronchodilator responses after lowdose metoprolol compared with placebo.
These results raise potential concerns about the safety
of cardio-selective beta-blockers at high, but clinically
relevant, doses. These findings need to be interpreted
with caution the difference in bronchodilator response
was small and only significant in the percentage recovery
analysis, although there was a similar trend for the
AUC (P = 0.076). These findings require confirmation in
further studies. Whether other cardio-selective betablockers have a similar effect to bronchodilator response
at high doses is unknown.
The safety of beta-blockers in COPD is an important
issue. The role of beta-blockers in primary and secondary
prevention as well as treatment of cardiovascular diseases
is well-established and the use of beta-blockers is
1.7
1.6
1.5
1.4
1.3
Placebo (n = 11)
1.2
1.1
Metoprolol 95mg
(n = 11)
Propranolol 80mg
(n = 11)
Metoprolol 190mg
(n = 9)
Baseline
Post methacholine
100mcg
200mcg
400mcg
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Chang et al.
100
80
Metoprolol 195mg (n = 9)
Natural Recovery (n = 11)
60
40
20
Post methacholine
100mcg
200mcg
400mcg
198
Although any reduction in exercise capacity is undesirable, it is unclear whether this difference is clinically
important. Singh et al. estimated the minimum clinically
important difference in distance walked for the shuttle
test to be 47.5 m.31 In our study, the difference between
the mean distances walked during placebo and propranolol treatments was slightly less than that at 45.5 m
(Table 2).
All beta-blockers were associated with lower oxygen
saturations (measured by pulse oximetry) at peak exercise. This was only statistically significant in the highdose metoprolol group, but there were trends towards
lower oxygen saturations in all active treatment groups.
This is a novel observation in patients with COPD. A
potential explanation is that beta-blockade reduces
cardiovascular compensation during exercise resulting in
reduced oxygen delivery when the respiratory system
is impaired. This is supported by evidence that betablockade exaggerates exercise-induced oxygen desaturation at altitude and reduces cardiovascular oxygen flow
in hypoxia.32,33 It has been postulated that there is betaadrenoceptor-mediated vasodilation in hypoxic exercise
states and that blockade of these receptors may lead to
significant tissue hypoxia.34 The clinical implications of
this in the setting of COPD and exercise are uncertain.
The main limitation of this study is the small number
of subjects involved. Hence the study may be underpowered to detect small differences between placebo and
metoprolol treatment. Despite this, we observed a nonsignificant trend to a reduced response to bronchodilator
2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians
with high-dose metoprolol which was statistically significant when analysed as percentage recovery. Based on
previous studies in asthma,25,27,28 we calculated a sample
size of 10 subjects in a cross-over design to provide 80%
power to show a 35% reduction in the response to
salbutamol. Such a reduction in response is typically
seen during regular short- or long-acting beta-agonist
therapy25,27 and effects smaller than this in response to
beta-blocker therapy may be of doubtful clinical
significance.
Another limitation is that, for safety reasons, the highdose metoprolol arm was unblinded and not in randomorder. We believe it is unlikely that this introduced bias to
the measurement of bronchodilator response because an
objective outcome (FEV1) was used. However, as this
open-label arm was conducted last, a learning effect may
explain the non-significant trend to an increased walk
distance in this treatment arm. The number of patients
who were not eligible for this study also raises the issue of
the generalizability of its findings. More than half of the
potential volunteers were excluded because of their
pre-existing treatment (long-acting anti-cholinergic
treatment which would preclude methacholine challenges, or long-acting beta-agonists which would induce
tolerance to the beta-agonist response) or because they
had COPD which was either too mild or too severe for the
protocol. We believe it is unlikely that these selection
criteria have biased the findings.
Although cardio-selective beta-blockers appear to be
safe in stable COPD, little is known about their effects in
exacerbations. This is the first time that the bronchodilator response to beta-agonist has been measured after
full recommended-dose cardio-selective beta-blocker
therapy. Our findings confirm that non-selective betablockers block the bronchodilator response and raise
concerns that high doses of cardio-selective beta-blockers
may partially inhibit the bronchodilator response to
b2-agonists. We also observed lower oxygen saturations
during exercise with beta-blocker therapy. These findings
need to be interpreted in the context of recent studies
regarding the safety profile and benefits of cardioselective beta-blockers in chronic stable COPD. Even
though cardio-selective beta-blockers may provide
overall benefit to these patients, our study identifies
potential drawbacks to this treatment.
Acknowledgements
The authors wish to thank the volunteer subjects, the
Waikato Cardiorespiratory Investigation Unit and staff,
the Waikato Respiratory Research Unit for funding and
Dr Michelle Head for database support.
2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians
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