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A Systematic Review of the Effects of Bronchodilators on Exercise Capacity in Patients With COPD^*

^* From the Department of Pulmonary Diseases, University Hospital Groningen, Groningen, the Netherlands.

Correspondence to: Jeroen J. W. Liesker, MD, Department of Pulmonary Diseases, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands; e-mail: J.J.W.Liesker{at}int.azg.nl

	Abstract

TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 
One of the major goals of bronchodilator therapy in patients with COPD is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of treatment with ß-agonists, anticholinergics, and theophyllines on dyspnea, and steady-state and incremental exercise capacity. Thirty-three, double-blind, randomized, placebo-controlled studies written in English were selected. This review shows that approximately half of the studies showed a significant effect of bronchodilator therapy on exercise capacity. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting ß₂-mimetics have favorable effects on exercise capacity in more than two thirds of the studies; surprisingly, the situation is less clear for long-acting ß₂-agents. The majority of the results of the published reports on theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.

Key Words: anticholinergics • ß₂-agonists • bronchodilators • COPD • exercise capacity • long-acting ß₂-agonists

	Introduction

TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 
COPD is a major health problem worldwide, and both morbidity and mortality are rising.¹ There is currently no cure for COPD, and much attention has been paid to smoking cessation as the sole beneficial measure for both development and prognosis of COPD. Because this is only effective in 20% of patients,² symptomatic treatment with bronchodilators is the mainstream of therapy.^{3 4 5} One of the main goals of bronchodilator therapy is to decrease airflow limitation in the airways and, as a consequence, improve dyspnea and exercise tolerance. The focus of this systematic review is to assess the effects of bronchodilator treatment on exercise capacity. Based on a literature search in MEDLINE, the following questions will be addressed: (1) Does bronchodilator therapy improve exercise capacity in patients with COPD? (2) Is the effect different for three categories of bronchodilators, ie, anticholinergics, ß₂-mimetics, and xanthine derivates? (3) Does a combination of bronchodilators have an additional effect compared to bronchodilator monotherapy? (4) Is the effect of a specific bronchodilator category comparable in both steady-state and incremental exercise tests? To this aim, we will first describe the most frequently used exercise tests, classified as incremental and steady-state tests, as well as our literature search strategy.

	Exercise Tests

TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 
To assess exercise capacity, different protocols are used depending on the aim of the study. The tests can be classified as steady-state tests and incremental tests, both measuring a different aspect of exercise capacity (Table 1 ). The term steady state is employed to indicate a more or less constant work rate during the test. Incremental exercise tests assess maximal exercise capacity in terms of peak exercise level, whereas steady-state tests explore the maximal capacity that can be endured over a longer time period. The incremental tests are mostly performed on a cycle ergometer, but sometimes a treadmill or shuttle-walking test is used. The 6-min walking distance (6-MWD) and 12-min walking distance (12-MWD) tests are the most frequently used steady-state tests. Cycle endurance tests are also employed for the same goal.

Shuttle Walking Test: In the shuttle-walking test, subjects repeatedly walk a fixed distance of 10 m between two cones.^{7 17} The increasing speed is dictated by audio signals, between which the fixed distance has to be covered. The time available for each of the following 10-m distances decreases after each completed 10-m distance. The outcome parameter is the distance walked until the patient stops because of dyspnea or other complaints, when the patient walks too slowly to cover the distance in time, or when a heart rate of 85% of the maximal heart rate for age is attained.

Steady-State Tests
6-MWD and 12-MWD Tests: The 12-MWD and 6-MWD tests are self-paced tests that measure steady-state exercise capacity.^{18 19 20 21} Subjects are instructed to walk as far as possible in 12 min (12-MWD) and 6 min (6-MWD).¹⁹ McGavin et al¹⁹ demonstrated the usefulness of the 12-MWD test, and Butland et al¹⁸ subsequently demonstrated that the 6-MWD test yielded similar results. Guyatt and coworkers²² demonstrated that the results are to a certain extent dependent on the patient’s motivation and encouragement. Therefore, they advocated not to encourage patients during the test. Patients need time to learn their optimal exercise level and strategy. To eliminate the learning effects from the result, it is recommended to perform two test sessions.

The Endurance Cycle Test: The endurance cycle test is performed with a constant workload. Moderate-intensity workloads result in steady-state responses that are comparable to many activities in daily life. High intensities of a constant workload will result in maximal values of exercise parameters. TTE, CO₂max, O₂max, maximal ventilation, and BSmax are frequently used as outcome measures.

	Materials and Methods

TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 
A systematic review of the literature searched with MEDLINE was performed including articles up to September 1999. Only randomized, controlled, double-blind trials written in English, were selected. Firstly, a database including all articles about obstructive lung diseases (key words: COPD, lung diseases, obstructive, plus all subheadings) was constructed. From this database, all articles that investigated patients with asthma were excluded (key-word strategy: database minus [asthma minus (asthma and COPD)]). A second database was defined including all articles about bronchodilators (key words: "exploding" adrenergic-ß-agonist plus all subheadings, ß₂-agonists, salmeterol, formoterol, adrenergic, long- and short-acting, "exploding" cholinergic-antagonist plus all subheadings, anticholinergics, ipratropium bromide, Oxivent, oxitropium, theophyllines, aminophyllines, sustained release, slow release). A third database was created with all articles describing exercise tests (key words: exercise, ergometry, treadmill, walking, cycling). Articles appearing in all three databases were selected. These articles were checked to see if they actually contained original, randomized, controlled, double-blind data on the effects of bronchodilator therapy on exercise capacity in patients with COPD.

	Results

TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 
Anticholinergics
Seventeen studies examining the effects of anticholinergics on exercise in patients with COPD were identified (Table 2 ). Ten studies applied ipratropium, 6 studies applied oxitropium, and 1 study applied atropine. At present, no tiotropium study is available. Twelve of 17 studies used a single-dose protocol; 16 of these studies primarily focusing on exercise testing showed a significant effect on FEV₁ (Table 2) .

Incremental Exercise: Three studies^{30 31 32} of five studies^{30 31 32 33 34} showed a significant effect of ipratropium bromide in an incremental cycle ergometer (ICE) test. There is a suggestion of a better effect on exercise capacity of higher doses of ipratropium compared to lower doses.^{30 31 32} A single dose of oxitropium had a good effect on exercise tolerance in four of five studies.^{24 25 35 36 37} The effect of maintenance treatment was investigated in two studies,^{32 38} one study with ipratropium for 1 week and one study with oxitropium for 1 year; both studies found significant improvements in exercise capacity.

ß₂-Agonists
Tables 3 , 4 summarize the studies focusing on the effects of treatment with ß₂-agonists on exercise capacity in patients with COPD. We identified 14 studies with short-acting ß₂-agonists and 4 studies with long-acting ß₂-agonists.

Incremental Exercise: Two studies^{45 46} could not detect a significant difference in O₂max between an incremental test after treatment with metaprotenerol and placebo. One study⁴⁹ with terbutaline yielded no difference compared to placebo treatment in an ICE test, which is similar to the lack of effect in the steady-state tests. Unfortunately, there is no study available assessing the effects of salbutamol in an ICE test. Therefore, we are unable to compare the outcomes of salbutamol directly to the results of steady-state exercise tests. Salmeterol was tested for its effect on exercise capacity by an ICE test in one study.⁴⁷ This group used the concept of physiologic strain according to Spiro et al,^{50 51} and, like in the walking test, found no significant difference between both single-dose and maintenance treatment compared with placebo treatment. Liesker et al³² tested for the effects of treatments with formoterol on exercise with an ICE test. In this study,³² three different doses of formoterol were administered for 1 week (delivered doses, 4.5 µg bid, 6 µg bid, and 12 µg bid). Significant differences in TTE for all doses compared to placebo treatment were found, with a significant but small negative dose-response relationship for formoterol, which is as yet unexplained.³²

Xanthine Derivates
We identified three single-dose studies and five maintenance-dose studies with theophyllines (Table 5 ).

Incremental Exercise: We identified six studies^{31 33 39 45 52 55} investigating the effect of theophylline by incremental exercise test (Table 5) . One single-dose study,³³ in which the medication was received orally, showed no effect in a treadmill test. Patients were treated with different doses of oral theophylline or aminophylline in five studies for 3 days, 7 days, 7 days, 28 days, and 1 month, respectively.^{31 39 45 52 55} These five studies checked for effective serum levels; if necessary, medication was adapted to achieve predefined effective blood levels.

The 3-day and 28-day studies found a significant improvement of exercise in terms of both Wmax and O₂max.^{31 55} Both 1-week studies and the 1-month study could not detect any significant improvement in exercise capacity.^{39 45 52}

Studies Comparing Two Separate Bronchodilators
Eight studies^{25 26 31 32 33 34 45 53} performed a head-to-head comparison of two bronchodilators of a different class, all in relatively small numbers of patients (range, 10 to 24 patients). None of these studies showed a significant difference between two bronchodilators in their bronchodilating capacity nor in the steady-state exercise test (Table 6 ). In seven studies, no significant differences were found in exercise tolerance while comparing theophyllines to anticholinergics,²⁷ theophyllines to ß₂-agonists,^{45 53} and anticholinergics to ß₂-agonists.^{25 26 31 34} One maintenance study³² in which subjects were treated for 7 days showed a longer cycle time in an ICE test with the use of ipratropium, 80 µg tid, than with formoterol, 18 µg bid.

Steady-State Exercise: One study²⁶ showed a significant advantage of the combination of single-dose ipratropium with salbutamol vs placebo treatment in the 12-MWD test. Although better than placebo treatment, combination therapy was not better than either ipratropium or salbutamol alone.²⁶ Dullinger et al⁴⁵ and Leitch et al⁵³ investigated the combination of ipratropium plus theophylline using the 12-MWD test. Combination therapy was not better than either monotherapy, but was better than placebo treatment.

Incremental Exercise: Three studies tested a combination of bronchodilators (fenoterol plus ipratropium,³⁴ metaproterenol plus theophylline,⁴⁵ and ipratropium plus theophylline³¹ ) vs the respective monotherapies and vs placebo treatment. Two of these studies did not find a difference in O₂max between the combination therapy and monotherapy, nor between the monotherapies. Tsukino et al³¹ found a significant improvement in Wmax and FEV₁ by treatment with ipratropium, 160 µg, plus salbutamol, 200 µg, compared to placebo treatment and both monotherapies. Although Tobin et al³⁴ found a significant improvement of the combination therapy (fenoterol, 400 µg, plus ipratropium, 40 µg) compared to monotherapy with fenoterol, there was, strangely enough, no improvement compared to placebo treatment.

Dyspnea in Relation to Exercise
Many authors (and patients) have claimed improvement in dyspnea scores in patients with COPD even in the absence of improvements in level of airflow limitation or exercise capacity. Therefore, we compared not only objective but also subjective improvements in exercise capacity by bronchodilators. It proved very difficult to aggregate the dyspnea ratings during exercise from the studies discussed in this article. Problems encountered were differences in exercise tests (steady-state and incremental tests); differences in dyspnea rating (BSmax, visual analog scale, breathlessness rating); differences in expression of results (eg, BSmax, end-exercise Borg score, Borg score slope); and, last but not least, difficulties in interpretation of the results. The most important interpretation problem in the dyspnea evaluation arises when a significant improvement in exercise is seen without an improvement in dyspnea. In this case, it is very likely that the dyspnea score would have shown an improvement if it had been measured at the same exercise level before and after the intervention, instead of at different end-exercise levels. This is illustrated nicely in at least in one study,²⁹ which showed no difference in the end-exercise Borg score, but significant lower Borg scores before compared to after the intervention, when measured at the same exercise duration. Therefore, we also scored this latter situation as an improved dyspnea score. Only studies assessing both exercise capacity and dyspnea related to exercise were included in this part of the analyses.

Steady-State Exercise: All four studies^{23 24 25 29} traced in the literature assessing dyspnea during exercise with anticholinergics showed positive results. Four of five studies^{25 28 47 48} with ß₂-agonists showed an improved dyspnea rating. Only one study³¹ with a dyspnea rating was found for theophyllines, the results of which were negative.

Incremental Exercise: Studies of ß₂-agonists^{32 47} and theophyllines^{31 39} contained data on exercise and on dyspnea; findings of two of these studies^{31 32} were positive. With anticholinergics, all eight studies^{24 30 31 32 35 36 37 38} containing information about exercise and dyspnea showed positive effects on dyspnea and/or exercise.

	Discussion

TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 
We identified 33 double-blind, randomized, controlled studies investigating the effects of bronchodilators on exercise capacity in patients with COPD. Only a few studies have been published with a head-to-head comparison between different types of bronchodilators. Bronchodilators are frequently prescribed to patients with COPD in order to improve exercise intolerance. Nevertheless, our systematic review shows that approximately half of the studies with bronchodilators do not show a significant improvement in exercise capacity. Why is this?

Doctors prescribe a bronchodilator to patients with COPD in the hope of improving symptoms, among others, dyspnea during exercise and exercise capacity. This carries the implicit assumption that patients with COPD are primarily limited in their exercise by dyspnea due to a limited ventilatory capacity.⁵⁶ Additionally, it implicates that this limitation can be (partly) improved by bronchodilator therapy. First of all, it is unclear whether the patients in the studies reported in this review were actually limited by their ventilatory capacity. This situation occurs if the demand for ventilation during exercise rises above approximately 80% of the maximal minute ventilation (37.5 x FEV₁).⁵⁷ None of the studies state if they checked at baseline (before bronchodilation) whether their patients were ventilatory limited in the exercise protocol used (type and time of exercise) by measuring maximal ventilation. If, for instance, patients with mild COPD do not reach their ventilatory limitation in a steady-state exercise protocol, it is doubtful whether bronchodilator therapy will provide any benefit. The same is true if patients are limited by nonventilatory reasons, such as cardiovascular limitation (maximal heart frequency), muscle performance (diminished lower-extremity force by atrophy or change of muscle type in COPD), motivation,¹² or diminished diffusion capacity.

The second reason for finding nonsignificant results can be the selection of the study population. In the case that patients with COPD are indeed limited by their ventilatory capacity, and thus by their airway obstruction, and additionally show a decrease in their airway obstruction by a bronchodilator, then these patients can be expected to improve their exercise capacity by bronchodilator therapy. However, some studies^{36 37 38 39 41 43 45 46 48 49 52 54 58} assessing the effects of bronchodilators on exercise exclude patients with reversibility to avoid inclusion of asthmatics in the study. Other studies of COPD did not use an exclusion criterion of reversibility of airflow limitation to select patients. Thus, the chance of finding positive effects on the measured exercise parameters is enhanced.^{23 24 25 26 27 28 30 31 33 35 39 42 44 47 53 55 59} In Figure 1 , we show that a positive correlation exists between the mean level of reversibility in different studies and the respective mean improvement in 12-MWD. All together, when looking at Tables 2 3 4 5 6 , the majority of studies did find a significant effect of bronchodilator therapy on FEV₁. However, in general, the improvements are small, which makes a significant effect on exercise capacity less likely.

View larger version (9K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Relation between 12-MWD and improvement in FEV1 with different bronchodilators (closed circles = ß2-agonists; open circle = theophylline; crossed lines = anticholinergic; open square = ß2-agonist plus anticholinergic). Only tests were included with a significant increase in both 12-MWD and in FEV1 due to a bronchodilator.

The fourth possibility for the lack of effect by bronchodilators with respect to exercise capacity may be potential negative effects of bronchodilators, like an increase in ventilation/perfusion mismatch,⁶⁰ or diminution of peripheral muscle function, eg, by the ß₂-agonist.^{61 62}

The fifth point of concern is that the tests can be sensitive to a learning effect. This learning effect has been described for the walking tests, but as far as we are aware, it has not been investigated whether this is also the case in other tests of exercise capacity. Two training sessions are necessary to eliminate a learning effect in walking tests.^{18 19} However, some of the studies^{27 40} failed to incorporate two practice sessions in their protocols. In uncontrolled studies, the increase in exercise capacity, as a consequence of learning, can be interpreted as an effect of the bronchodilator (false-positive effect). By contrast, in randomized, controlled studies, this phenomenon normally increases the variability in the results, thereby increasing the chance of false-negative results.

The last reason for lack of effects in exercise studies with bronchodilators in patients with COPD as evaluated in the current review is that the number of included subject in most of the studies was rather small (10 to 60 subjects). Thus, a lack of power may simply explain the lack of effect. On the other hand, no studies showed deleterious effects of bronchodilators on exercise capacity in patients with COPD.

Conclusions in randomized, controlled trials are based on statistical significance, yet a statistical significance does not always reflect clinical significance. For the 6-MWD test, Redelmeier and coworkers⁶³ showed that subjects have to improve their walking distance by 54 m in order to appreciate this increase as a beneficial effect. For the 12-MWD test, the minimal clinically relevant distance is unknown. None of the studies^{23 24 27 40 42 43 44 48 54 58} performed with a 6-MWD test that did find statistically significant results reached the minimal clinical significance limit of Redelmeier and coworkers.⁶³ Thus the relevance of the observed effect to the patient remains debatable. As far as we are aware, the minimal clinical significance levels in the other tests of exercise capacity have not been defined.

The BSmax was used in 11 ICE studies.^{24 25 30 31 32 35 36 37 38 43 47} In only two of these studies,^{24 36} a significant difference was found in end-exercise BSmax. These results are not surprising. Since maximal exercise tests are limited by dyspnea, the individual BSmax should be expected not to change even if the exercise improves with the intervention. Therefore, we advocate not to use the BSmax score in incremental exercise tests, but other parameters or other dimensions of the Borg score, eg, the Borg scale slope (Borg score/O₂max). This parameter indicates the rise in dyspnea when patients increase their oxygen consumption during exercise. Four of five studies^{29 31 36 37 38} using this parameter found a significant improvement in the Borg scale slope, while no difference in BSmax score was found.^{31 36 37 38} This signifies that patients experienced less dyspnea at the same level of oxygen consumption during exercise with the investigated treatment than with placebo treatment.

A point of interest to us was whether the effects varied for different classes of bronchodilators. Eight studies^{25 26 31 32 33 34 45 53} evaluated two bronchodilators of different classes in a head-to-head comparison. Most of these studies could not find a difference between the effects of the bronchodilator classes. However, Tables 2 3 4 5 6 show more positive study findings with anticholinergics and ß₂-agonists than when theophyllines are being used.

Whether the effect of a specific bronchodilator category is similar in both steady-state and incremental exercise tests cannot be answered, since only six studies^{24 39 45 46 47 52} assessed both tests. Five of these studies showed a concordant result, ie, results of both tests were not significant, or results of both tests were significant.^{24 39 45 47 52} Although it has been often suggested that steady-state exercise tests have more relevance to daily life activities in patients with COPD, no empirical preference can be deduced for a certain type of exercise protocol from the available studies in this systematic review.

In summary, this review shows that the effects of bronchodilators on exercise capacity in general are limited. Anticholinergic agents have significant beneficial effects in the majority of studies, especially when measured by steady-state exercise protocols. There is a trend toward a better effect of high-dose compared to low-dose anticholinergics. Short-acting ß₂-mimetics have favorable effects on exercise capacity in more than two third of the studies, but surprisingly, the situation is less clear for long-acting ß₂-agents. The majority of findings of the published reports with theophyllines and their effects on exercise are negative. Direct comparisons of different classes of bronchodilators have not been made in a sufficient number of studies for a rational preference. The addition of a second bronchodilator has no proven advantage for improving exercise test results, but this has not been studied extensively and not in sufficiently large studies. The majority of studies reporting a measure of dyspnea found improvements, even in the absence of improvement in exercise capacity.

Until recently, only two large-scale studies have been performed to investigate the effect of bronchodilators (salmeterol⁴⁷ and ipratropium^{47 48} ) on exercise capacity in patients with COPD. Studies with a small number of patients found variable effects of bronchodilators. Additionally, no large-scale study used the endurance cycle by O’Donnell et al,²⁹ which seems to be the most responsive test used until now. For a better understanding of the effects of bronchodilators on exercise capacity in patients with COPD, it would be of clinical and pathophysiologic interest to perform larger-scale studies with TTE on an endurance cycle test as the primary outcome, and additionally lung function parameters of the small airways as secondary outcomes. Also, the relationship of measurements of exercise capacity to measurements of daily life activities, for instance with an actometer, which documents body activity 24 h/d, could be a valuable additional research topic.

	Footnotes

 
Abbreviations: BSmax = maximal Borg score; ICE = incremental cycle ergometer; 6-MWD = 6-min walking distance; 12-MWD = 12-min walking distance; TTE = time to exhaustion; CO₂max = maximal carbon dioxide production; O₂max = maximal oxygen consumption; Wmax = maximal workload

Dr. Liesker received research stipendium from AstraZeneca BV, Zoetermeer, the Netherlands.

Received for publication November 2, 2000. Accepted for publication May 23, 2001.

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TOP Abstract Introduction Exercise Tests Materials and Methods Results Discussion References

 

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