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Internal Medicine Journal 40 (2010) 193200

O R I G I N A L A RT I C L E

Cardio-selective and non-selective beta-blockers in chronic


obstructive pulmonary disease: effects on bronchodilator
response and exercise
imj_1943

193..200

C. L. Chang, G. D. Mills, J. D. McLachlan, N. C. Karalus and R. J. Hancox


Respiratory Research Unit, Department of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand

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

Funding: Waikato Respiratory Research Fund.


Conflict of interest: None
2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians

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.

The airway effects of beta-blockers are likely to vary


substantially between different classes of the drug.
Cardio-selective or b1-adrenoceptor blockers have a
negligible effect on b2-adrenoceptors, except at very high
doses,15 and therefore pose less risk of bronchoconstriction than non-selective beta-blockers.16 Indeed, the
safety of cardio-selective beta-blockers in stable COPD (in
terms of respiratory function) has been demonstrated
in multiple studies17,18 and a recent observational study
suggested that beta-blockers may even be associated with
reduced mortality from COPD exacerbations.19 However,
the effects of beta-blockers on the airway during an
exacerbation of COPD are not known. In particular, the
interaction between beta-blockers and b2-agonist bronchodilators has been poorly studied. This is of considerable clinical importance because b2-agonists are one of
the first-line treatments for COPD exacerbations.20 Since
beta-blockers and b2-agonists can competitively bind to
the b2-receptor, beta-blocker therapy may impede the
bronchodilator response of b2-agonist inhalers.
Van der Woude and colleagues found that a nonselective beta-blocker (propranolol 80 mg) reduced the
bronchodilator response to beta-agonist while the selective beta-blockers (metoprolol 100 mg and celiprolol
200 mg) did not.21 This study used low doses of
cardio-selective beta-blockers in order to ensure
cardio-selectivity. As b1 selectivity is a dose-dependent
phenomenon,15 the effects of cardio-selective betablockers on the airway at higher doses remain unknown.
In addition to the possible antagonism between betablockers and beta-agonists, there are other potential concerns with the use of beta-blockers in COPD. A reduced
capacity for exercise is an important cause of disability in
COPD and exercise training improves symptoms and
health-related quality of life.22 In patients with a low
respiratory reserve, cardiac output is an important compensatory mechanism for the increased oxygen demand
of exercise. It is plausible that beta-blockade may reduce
this compensation through its effects on heart rate and
sympathetic tone and thus reduce exercise capacity. On
the other hand, beta-blockers reduce exercise dyspnoea
and prolong exercise time in patients with heart failure,
although they have no effect on measured exercise
capacity or 6-min walk distances.23 We are aware of only
one study to address directly this issue in COPD this
found no evidence that the cardio-selective beta-blockers
atenolol and metoprolol reduced the exercise capacity of
patients with COPD.24
This study was designed to assess the effects of clinically relevant doses of cardio-selective and non-selective
beta-blockers on the acute bronchodilator response to
beta-agonist in COPD. Bronchodilator responses to salbutamol were measured in the setting of methacholine-

194

induced bronchoconstriction using the challenge


rescue technique.25 In addition, the effect of betablockers on exercise capacity was measured using the
incremental shuttle walking test.

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

Effects on bronchodilator response and exercise

(cumulative dose) was calculated by linear interpolation.


Salbutamol 100 mg, 100 mg and 200 mg via metered dose
inhaler and Volumatic spacer were given at 0, 5 and
10 min after the methacholine challenge respectively.
The FEV1 was measured 5 min after each dose of salbutamol, giving a total response time of 15 min.
Incremental shuttle walk tests were conducted using
the protocol described by Singh et al.28 Oxygen saturation
by pulse oximetry, blood pressure and heart rate were
measured at rest before starting the test and at maximal
exercise. All patients had a practice shuttle test before
randomization to allow for a learning effect.

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.

patients were excluded after initial screening and three


more patients withdrew after randomization. Eleven
patients completed the study protocol and nine completed the high-dose metoprolol arm (Fig. 1). The treatments were well tolerated but two patients elected not to
participate in the final phase of the study. The baseline
characteristics of the subjects are listed in Table 1.
Significant beta-blockade was achieved in all active
treatment arms compared with placebo with reductions
in mean heart rate of nearly 20 b.p.m. in all active arms
(P < 0.0001). The mean heart rate was not different
between different beta-blockers (Table 2).
There were no significant differences between baseline
FEV1 (immediately before methacholine inhalation) or
PD20 between treatment periods by ANOVA, although
baseline FEV1 tended to be lower following propranolol
treatment compared with placebo (P = 0.0289 paired
t-test) (Table 2).

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
2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians

The mean distances walked in the shuttle tests at the end


of each treatment period are shown in Table 2. There was
no significant difference overall between treatment
groups by ANOVA but there was a trend to lower distances

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Chang et al.

Eligible for screening


(n = 40)
Excluded after screening (n = 26)
FEV1 < 1.0L or 30% predicted n = 8
Reversibility > 15% after bronchodilator n = 8
No change to FEV1 after methacholine inhalations n = 3
FEV1 > 80% predicted n = 2
Patient declined participation after screening n = 2
Bronchospasm after test dose of -blocker n = 1
Inability to perform shuttle-shuttle walk test n = 1
Exacerbation of COPD after screening n = 1

Randomized (n = 14)

3 withdrew after randomization


Exacerbation of COPD (n = 2)
Other health related (n = 1)
11 completed randomized, double-blinded 3-way
cross-over study periods
(metoprolol 95mg, propranolol 80mg, placebo)

2 withdrew consent

9 completed open-label high dose metoprolol


(190mg) study period
Figure 1 CONSORT ow diagram of trial prole.

after propranolol treatment than placebo (paired t-test,


P = 0.0015). Oxygen saturation at the end of exercise was
significantly different between groups (ANOVA P = 0.046)
and was lower in the high-dose metoprolol group (paired
t-test, P = 0.0302) (Table 2).

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

Table 1 Study subject baseline characteristics


Characteristic
Age, mean (range)
Sex
Male
Female
Smoking status (n)
Current smoker
Ex-smoker
Pack-years, mean (range)
Lung function (mean (SD))
FEV1 (L)
FEV1 % predicted
FEV1/FVC
Heart rate (b.p.m.) (mean (SD))

Value
65 years (4776)
8
3
5
6
49 (20100)
1.64 (0.53)
59% (15%)
0.58 (0.09)
79.8 (10.0)

FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity.


2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians

Effects on bronchodilator response and exercise

Table 2 Variables at the end of each treatment period


Variables
Mean baseline FEV1 (L) (SD)
Mean PD20 (mg) (SD)
Mean AUC (L/min) (SD)
Mean recovery, % of fall (SD)
Mean heart rate (b.p.m.) (SD)
Mean ISWT distance (m) (SD)
Mean O2 Sat after ISWT (SD)

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.

becoming increasingly common in the COPD population.


Despite several publications in recent years citing the
safety of cardio-selective beta-blockers in COPD disease,
there is very little evidence of their effects in the setting of
an exacerbation of airways disease.17,18 In particular the
impact of prior beta-blocker treatment on the response to
beta-agonist bronchodilators has received little attention.
To our knowledge, the only other study to examine
bronchodilator response in this setting found that a nonselective beta-blocker (propranolol 80 mg) reduced the
bronchodilator response to beta-agonist while low doses
of selective b1-blockers (metoprolol 100 mg and celiprolol
200 mg) did not.21 However, the doses of the cardioselective beta-blockers had been intentionally limited to
doses that guarantee cardio-selectivity that is, in the
lower range of clinically recommended doses. Our study
also found no significant difference between placebo
and low-dose metoprolol. However, we found that

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

Figure 2 Mean FEV1 values and response to


salbutamol after each treatment period. The
baseline FEV1 appears higher in the highdose metoprolol arm because the two participants who declined to participate in this
arm had baseline lung function below the
group mean.

1.7

Bronchodilator dose-response after beta-blocker treatment

1.6

Mean FEV1 (L)

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

Cumulative salbutamol dose


2010 The Authors
Journal compilation 2010 Royal Australasian College of Physicians

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Chang et al.

Figure 3 Percentage recovery in response


to salbutamol after each treatment
(expressed as percentage of the fall in FEV1
induced by methacholine). The natural
recovery curve was obtained from the
screening methacholine challenge when no
bronchodilators were given.

Recovery after methacholine challenge


120
Placebo (n = 11)

% Recovery of total fall in FEV1

100

Metoprolol 95mg (n = 11)


Propranolol 80mg (n = 11)

80

Metoprolol 195mg (n = 9)
Natural Recovery (n = 11)

60

40

20

Post methacholine

100mcg

200mcg

400mcg

Cumulative dose salbutamol

metoprolol at higher doses did appear to have an effect


on bronchodilator response. The subjects in our study
also had more severe COPD than those previously
studied21 and therefore may be more representative of
the patients with moderatesevere COPD that are most
likely to develop cardiovascular comorbidities and benefit
from beta-blocker treatment.
Our study used the challengerescue technique to
measure the response to beta-agonists after beta-blocker
treatment. This technique has now been used in both
asthma25,27,29 and COPD21 and has proven to be a sensitive method to demonstrate functional impairment of
b2-agonist bronchodilation. Measuring the bronchodilator response after methacholine-induced bronchoconstriction attempts to replicate the experience of patients,
who use bronchodilators to relieve symptoms caused
by bronchoconstriction. Although the airflow limitation
associated with exacerbations of COPD is far more
complex than simple airway smooth muscle-induced
bronchoconstriction, it is this aspect of airway narrowing
that is the main target of b2-agonist treatment. Methacholine responsiveness is common in COPD30 and the
challengerescue technique enabled the measurement of
a bronchodilator response in this group of COPD patients
who had fixed airflow obstruction with no significant
response to beta-agonist at screening.
We also observed a trend towards worsening exercise
capacity with the non-selective beta-blocker propranolol
while the selective beta-blocker metoprolol made little
difference to exercise capacity even at high dose.

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

Effects on bronchodilator response and exercise

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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2010 The Authors


Journal compilation 2010 Royal Australasian College of Physicians

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