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(Chest. 2005;127:818-824.)
© 2005 American College of Chest Physicians

Detrimental Effects of ß-Blockers in COPD*

A Concern for Nonselective ß-Blockers

Hanneke J. van der Woude, MD, PhD; Johan Zaagsma, PhD; Dirkje S. Postma, MD, PhD; Trea H. Winter; Marinus van Hulst, MSc, PharmD and René Aalbers, MD, PhD

* From the Departments of Pulmonary Diseases (Drs. van der Woude and Aalbers, and Ms. Winter) and Clinical Pharmacy and Toxicology (Dr. van Hulst), Martini Hospital, Groningen; Department of Molecular Pharmacology (Dr. Zaagsma), University Centre for Pharmacy, Groningen; and Department of Pulmonary Diseases (Dr. Postma), University Hospital Groningen, Groningen, the Netherlands.

Correspondence to: Hanneke J. van der Woude, MD, PhD, Department of Pulmonary Diseases, Martini Hospital, Van Ketwich Verschuurlaan 82, 9721 SW Groningen, the Netherlands; e-mail: jvbhw{at}home.nl


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Introduction: ß-Blockers are known to worsen FEV1 and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring ß-blocker treatment.

Objective: To determine the effects of ß-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV1 [PC20]), FEV1, and response to formoterol in patients with COPD.

Design: A double-blind, placebo-controlled, randomized, cross-over study.

Setting: An ambulatory, hospital outpatient clinic of pulmonary diseases.

Patients: Patients with mild-to-moderate irreversible COPD and AHR.

Intervention: Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period ≥ 3 days. On day 4 of treatment, FEV1 and PC20 were assessed. Immediately hereafter, formoterol (12 µg) was administered and FEV1 was measured for up to 30 min.

Results: PC20 was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV1 deteriorated only after propranolol treatment (2.08 ± 0.31 L) [mean ± SD] compared with placebo (2.24 ± 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV1 at 3 min, 6.7 ± 8.9%) but was unaffected by the other ß-blockers (16.9 ± 9.8%, 22 ± 11.6%, and 16.9 ± 9.0% for placebo, metoprolol, and celiprolol, respectively).

Conclusions: Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV1 and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of ß-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a ß-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV1, AHR, and response to additional ß2-agonists.

Key Words: airway hyperresponsiveness • ß-blockers • COPD


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
COPD is a very common, smoking-related disease with a large morbidity and increasing mortality worldwide.1 It is characterized by persistent airway obstruction due to chronic bronchitis or emphysema, measured by a reduced FEV1. COPD is most prevalent in the elderly population, and other smoking-related diseases often accompany it. Particularly cardiovascular comorbidity is prevalent, which often requires treatment with ß-blockers to reduce morbidity and mortality. This treatment is known to worsen FEV1 and airway hyperresponsiveness (AHR) in asthma, and therefore reluctance exists to prescribe ß-adrenergic antagonists to COPD patients as well, despite the anticipated beneficial cardiovascular effects. A recent metaanalysis2 has demonstrated that cardioselective ß-antagonists do not have a negative effect on FEV1 in patients with COPD, but the effect of noncardioselective ß-blockers was not reported. In this metaanalysis, COPD has been defined by reduced FEV1 and the presence of respiratory symptoms rather than by reversibility criteria, because many studies did not measure reversibility, which may help to distinguish between asthma and COPD.

Many studies have concentrated on the effect of ß-blockers on FEV1 in COPD,2 but so far none has focused on AHR. This is, however, of interest since more severe AHR is associated with higher mortality3 and enhanced FEV1 decline in COPD.45 Clinical studies67 suggest that a difference in AHR between patients with COPD and asthma exists. Thus, it is not clear whether negative effects of ß-blockers on AHR, as present in asthma, also occur in COPD. Therefore, we compare the effects of three different ß-blockers on FEV1 and on methacholine-induced bronchoconstriction in patients with COPD, defined by limited reversibility to ß2-agonists.

Methacholine-induced bronchoconstriction is a well-known model to determine AHR, but despite its sensitivity it is a less well-known model to determine functional impairment of ß2-agonists.8 During a situation of increased bronchus tone, for example, induced by methacholine, relaxation of the airway smooth muscle may require more ß2-receptor activity and functional impairment is easier to demonstrate. Since ß-blockers and ß2-agonists can compete with the ß2-receptor, ß-blocker treatment may hamper the rapid bronchodilating effects of rapidly acting ß2-agonists to relieve a methacholine-induced bronchoconstriction.9 Formoterol is such a rapidly acting bronchodilator.10 It has also a long duration of action and is an effective maintenance treatment in COPD.11 Therefore, we also study the onset of action of formoterol to reverse a methacholine-induced bronchoconstriction in the presence of ß-blockers.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients with stable mild-to-moderate COPD participated in the study.4 Inclusion criteria were as follows: age 40 to 70 years, FEV1 ≥ 1.5 L and from 60 to 80% predicted,12 FEV1/FVC ≤ 0.7, pulse rate ≥ 60 beats/min, ≥ 15 pack-years smoking history, and reversibility ≤ 12% of predicted FEV1 after inhalation of 400 µg salbutamol. Major exclusion criteria were a history of asthma, the use of ß-blocking agents, and the presence of significant diseases other than COPD, which could have put the patient at risk (eg, the presence of a contraindication for using ß-blockers or anticholinergic) or which influenced the study. The Medical Ethics Committee of the Martini Hospital, Groningen, approved the study. Written informed consent was obtained prior to any study procedures.

This single-center study had a crossover, randomized, double-blind, placebo-controlled design and consisted of four periods of 4 treatment days followed by a washout of ≥ 3 days. During and 6 weeks before the start of the study, no change in inhaled corticosteroids dosing or use of oral steroids was allowed. After an initial screening, patients came back for a methacholine provocation test and were included when the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) was ≤ 32 mg/mL. Treatment consisted of once-daily propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo. Propranolol is a nonselective ß-blocker. The doses of the cardioselective ß-blockers metoprolol and celiprolol were administered at the maximum dose that guarantees cardioselectivity.13 Celiprolol has some intrinsic ß2-sympathomimetic activity and a weak {alpha}2-antagonistic effect in contrast to metoprolol. The medication was administered in blinded, visually identical capsules made in the hospital pharmacy, which also generated the randomization list. The researchers responsible for seeing the patients allocated the next available number on entry into the trial. The code was revealed once recruitment and data collection were completed.

During the study, ipratropium bromide delivered by aerosol was provided as rescue medication. On day 4 of each period, 2 h after the intake of study medication, BP, heart rate, and FEV1 were measured, followed by a methacholine provocation test. The methacholine provocation test and PC20 were assessed as described previously.14 There were at least 7 days between the test days. Patients were asked to withhold long-acting ß2-agonists for 12 h and short-acting ß2-agonists for 8 h before all provocation tests.

At the enrolment day, at the end of the provocation test, placebo was inhaled within 1 min of reaching a ≥ 20% fall in FEV1, followed by single assessments of spirometry at 1, 3, 5, 10, 15, 20, 25, and 30 min. At the other study test days, formoterol, 12 µg (Turbuhaler; AstraZeneca; Mölndal, Sweden), was inhaled. Counting the returned medication assessed the compliance. The number of enrolled subjects was estimated to be 15, assuming that a dose step of one doubling concentration would be detectable with 80% probability using a significance level of 5%.

Statistics
The primary parameter was the difference in PC20 (obtained by linear interpolation of log dose vs percentage response in FEV1) between active treatments and placebo. Secondary parameters were baseline FEV1 at day 4 (before the start of the methacholine provocation test), percentage increase in FEV1 at 3 min after inhalation of formoterol or placebo, and recovery time, ie, the time needed to increase FEV1 to 90% of baseline FEV1. In cases where FEV1 did not return to 90% of baseline value, the recovery time was arbitrarily set at 45 min.

A multiplicative analysis of variance model was used to determine treatment differences with patient, period, and treatment as fixed parameters. A two-sided test was used, and p < 0.05 was considered a significant difference. In case a variable turned out to be significant, analysis of covariance was used. PC20 values were 2log transformed and the recovery times 10log transformed in order to reach normal distributions.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Between April 2001 and February 2002, 35 patients were recruited from our outpatient clinic. Twenty patients failed to fulfil all inclusion and exclusion criteria. Reasons for not entering the study were FEV1 out of range (n = 13), no methacholine threshold (n = 2), heart rate too slow (n = 1), reversibility (n = 1), and administrative reasons (n = 3).

The remaining 15 patients were randomized, and all completed the study. The compliance rate was 100%. Treatments were well tolerated, although fatigue was more reported after active treatment. The baseline characteristics of randomized patients are listed in Table 1 .


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  		Table 1.. Baseline Characteristics of the Randomized Patients*

 
At the end of the 4 days of treatment, geometric mean PC20 was highest with celiprolol treatment (3.41 mg/mL; range, 0.84 to 7.36 mg/mL), followed by placebo (3.16 mg/mL; range, 0.22 to 16.20 mg/mL), propranolol (2.06 mg/mL; range, 0.53 to 7.57 mg/mL), and metoprolol (2.02 mg/mL; range, 0.36 to 4.06 mg/mL; Table 2 ). PC20 values with metoprolol and propranolol both differed significantly from values with celiprolol and placebo (p < 0.01, Table 2). The individually assessed changes in 2log PC20 are presented in Figure 1 .


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  		Table 2.. Variables at the End of Treatment (Day 4)*

 


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  		Figure 1.. Individual data of 2log PC20 on day 4 of treatment (horizontal lines represent geometric mean value). A comparison is made between placebo and active treatment (celiprolol, metoprolol, and propranolol, respectively). *Significantly different from placebo. {dagger}Significantly different from celiprolol.

 
At day 4, 2 h after the last dose with study medication, mean FEV1 (± SD) was highest with celiprolol treatment (2.32 ± 0.29 L) followed by placebo (2.24 ± 0.37 L), metoprolol (2.16 ± 0.36 L), and propranolol (2.08 ± 0.32 L). FEV1 with propranolol treatment was significantly lower than with placebo (p < 0.01, Table 2). The individually assessed changes are presented in Figure 2 .



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  		Figure 2.. Individual data of the FEV1 on day 4 of treatment (horizontal lines represent mean value). A comparison is made between placebo and active treatment (celiprolol, metoprolol, and propranolol, respectively). *Significantly different from placebo. {dagger}Significantly different from celiprolol.

 
After inhalation of formoterol at the end of the methacholine challenge, a fast improvement in FEV1 was observed with metoprolol, celiprolol, and placebo (Table 2), without significant differences between these treatments (p > 0.05, Table 2). The differences with propranolol were significant, however (p < 0.05, Table 2).

A similar profile was observed for the recovery time (Table 2, Fig 3 ); in 7 of 15 patients with propranolol treatment, FEV1 did not return to 90% of premethacholine FEV1. The recovery with propranolol treatment was almost identical as observed during the screening period, when placebo was administered after reaching a fall in FEV1 ≥ 20% (ie, the natural recovery).



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  		Figure 3.. Recovery time in minutes after ≥ 20% fall in FEV1 during methacholine provocation. Patients are treated for 4 days with placebo (PL), propranolol (PR), metoprolol (M), or celiprolol (C). On day 4, a methacholine provocation was performed, followed by inhalation of formoterol 12 µg (time = 0 min). FEV1 was observed during the next 30 min. The natural recovery from the methacholine provocation (N) was determined at screening when no ß-blocker treatment was administered, and no formoterol was inhaled after provocation.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we found evidence of the negative effects of ß-blocker treatment on lung function (FEV1) and AHR in patients with mild-to-moderate, irreversible COPD. FEV1 deteriorated significantly during 4 days of propranolol treatment only, whereas AHR deteriorated both during propranolol and metoprolol treatment when compared to placebo.

In addition, the fast bronchodilating effect of the ß2-adrenergic agonist formoterol was significantly impaired after propranolol treatment, but unaffected both after metoprolol and celiprolol treatment. Thus, propranolol treatment induces a significant ß2-receptor blockade in the airways. Celiprolol appears to be safe at the used dose, since it neither changes lung function and AHR nor retards the recovery of bronchoconstriction by a ß2-adrenergic agonist.

In this study, celiprolol and metoprolol are administered at the maximal doses that guarantee cardioselectivity. These doses are the lowest doses of maintenance treatment in hypertension. In contrast, a lower dose of propranolol (80 mg) was studied for safety reasons, because propranolol may have well-known deleterious effects in asthmatic patients such as bronchoconstriction and increased AHR. The effect of propranolol in our COPD patients on the deterioration of FEV1 was small, yet unexpected, because two earlier studies1516 have suggested that patients with poorly reversible COPD are resistant to the airway obstructive effects of ß-blockers. In these former studies,1516 a ß-blocker with intrinsic sympathomimetic activity was used, and different effect parameters were monitored (wheezing or fall in FEV1 > 30%).1516

In addition to the effect on FEV1, propranolol also worsens AHR, which makes patients more vulnerable to environmental stimuli like cold air and fog; in the meantime, propranolol hampers the bronchodilating effect of formoterol to reverse such a bronchoconstriction: the bronchodilating effect of formoterol was almost similar as during the screening day, when no bronchodilator was administered after provocation. Thus, the bronchodilating effect of formoterol is blocked in the presence of propranolol, although a double-blind, randomized comparison with additional inhaled placebo may have been more conclusive. Nevertheless, this finding implies that the postbronchodilatory FEV1 worsens, which impairs prognosis.17 We interpret our data in that propranolol may have additive deleterious effects in patients with COPD: it worsens FEV1, increases susceptibility to bronchoconstrictor stimuli, and impairs the bronchodilating effects of ß2-agonists like formoterol. Therefore, the anticipated beneficial cardiovascular effects of propranolol have to be weighed against its deleterious pulmonary effects, and alternatives should be considered. Alternatives are, for example, the cardioselective ß-blockers celiprolol and metoprolol. In our study, like others,218 both cardioselective ß-blockers neither impair FEV1 nor alter the response to ß2-agonist compared with placebo: the patients remain sensitive to ß2-agonists. Unlike to other studies, however, we have measured the ß2-response after methacholine-induced bronchoconstriction, which is a more sensitive method to measure functional impairment of ß2-receptors.814 Another advantage of this method is that it mimics daily life of COPD patients, when environmental stimuli like cold air and fog can induce airway constrictions that have to be reversed by inhaling ß2-agonists, such as formoterol. Formoterol reverses the obstruction effectively, which is remarkable since all patients were irreversible to a ß2-agonist at screening. The explanation is that relaxation of airway smooth muscle as a response to inhaled ß2-agonists is easier to demonstrate in a situation of contractile agonist-induced bronchomotor tone. It demonstrates the potential of formoterol to be used "as needed" to relief dyspnea, especially because the onset has been shown as fast as salbutamol.19 The observed delay of formoterol induced recovery after propranolol treatment warrants caution as to using nonselective or higher doses of selective ß-blockers, when ß2-receptor blockade is likely to occur and ß2-agonists become less effective.

In our study, we have demonstrated that celiprolol and metoprolol differ in their effect on AHR, despite their similar ß2-sparing effect. Hence, the increase in AHR can unlikely be attributed to ß2-receptor blockade. In fact, the effect of the cardioselective ß-blocker metoprolol on AHR is the same as the nonselective ß-blocker propranolol on AHR in these patients with COPD. Thus, other properties than non ß1-selectivity are likely involved to enhance AHR in patients with COPD.

In patients with COPD, the presence of AHR accelerates the decline in lung function3 and worsens the prognosis.45 In COPD, AHR is associated with tissue collapsibility, dysregulation of cholinergic and adrenergic tone, and possibly with airway wall inflammation. ß-Blockers have an effect on the adrenergic tone and lipophilic ß-blockers probably also on the cholinergic tone.20 Future studies have to establish whether the negative effects of ß-blockers on AHR indeed alter the course of disease in COPD or if the anticipated cardiovascular beneficial effects outweigh the deleterious pulmonary effects.

In our study, we have included COPD patients with mild-to-moderate airway obstruction because guidelines recommend FEV1 values > 60% predicted or > 1.5 L when testing AHR.21 It remains to be established whether the results can be translated to patients with more severe disease. This is of clinical relevance, since the impact of ß-blocker treatment at lower lung function levels in patients with severe disease may be even larger. The included patients had a clinical diagnosis of COPD made by pulmonary physicians in an outpatient clinic. More than that, they showed limited airway reversibility, confirmed by spirometry, after inhaling of a high dose of salbutamol. Several criteria have been proposed to define a significant bronchodilator response, with important differences between guidelines.9222324 A recent study by Calverley et al25 demonstrated that classifying patients as ‘poorly reversible" might be misleading because of spontaneous variations in airway caliber. The diagnosis of COPD should be made on clinical grounds and spirometry data, as in our study.26

The main focus in this study was the pulmonary effects of ß-blockers in patients with COPD. It might be questioned whether similar levels of ß1-receptor blockade were achieved with the selected dosages. Heart rate and, to some extent, BP may be considered informative in this respect. Indeed, the reduction in heart rate was similar for both metoprolol and propranolol. In contrast, celiprolol reduced the heart rate to a lower extent, suggesting less ß1-receptor blockade. However, it has been demonstrated previously that the negative chronotropic effect of celiprolol is less compared to metoprolol and propranolol even with similar reduction of BP.27 This might be due to the ß2-agonistic and {alpha}2-antagonistic properties of celiprolol,27 which may compensate for some extend the ß1-receptor blockade. In our study, no reduction of BP was observed, since all COPD patients had BPs within the normal range.

A major indication for the use of ß-blockers is hypertension. There are many classes of drugs besides ß-blockers that can be used to treat hypertension. Two reviews on the pharmacologic treatment of systemic hypertension in COPD by Cazzola et al28 and by Dart et al29 advised to be very cautious with the use of ß-blockers in patients with airway dysfunction, especially when reversible disease exists. Indeed, without exception, modern drugs used to treat hypertension are safe and effective in the reduction of BP and the prevention of stroke, a major complication in hypertensive disease. Other major complications of hypertension are myocardial infarction and sudden death. Antihypertensive agents differ in the capacity to decrease the risks of myocardial infarction and sudden death (cardioprotection).30 Some ß-blockers, like metoprolol and propranolol, provide a clear cardioprotective effect.3031 It still remains a matter of debate if this is due to the lipophilicity of the ß-blocker.

The protocol we used can be applied in clinical practice to determine the short-term effects of a ß-blocker in a COPD patient. It assesses important clinical pulmonary parameters: pulmonary function (FEV1), airway responsiveness, and response to formoterol. In this way, the individual risks (pulmonary effects) and benefits (provided by the use of ß-blocker) can be determined. Thus, one can weigh the risk/benefit ratio of the use of ß-blockers for those patients unable to perform a methacholine provocation test. However, this study only informs about short-term effects of ß-blockers in patients with mild-to-moderate severe COPD. Long-term effects still need to be investigated.

In conclusion, in patients with COPD, different classes of ß-blockers may have different pulmonary effects. The anticipated beneficial cardiovascular effects of a ß-blocker must therefore be weighed against the anticipated detrimental pulmonary effects, ie, effect on FEV1, airway responsiveness, and response to additional ß2-agonists, especially when nonselective ß-blockers are used. Celiprolol has, of the ß-blockers investigated, the least negative effects on pulmonary function.


   Acknowledgements
 
We thank G. D. Nossent, I. P. Smit, E. F. Smit, L. H. Steenhuis, C. G. Tol, and S. H. Wills for their contribution for the clinical part of the study; and M. Boorsma and P. Gobbens for assistance with data analysis.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1

This work was sponsored by an unconditional grant from AstraZeneca.

Received for publication February 24, 2004. Accepted for publication October 19, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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QJM, September 1, 2005; 98(9): 706 - 707.
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