Occasional Reviews Long Acting Β2 Agonists and Theophylline in Stable

730 Thorax 1999;54:730–736

Occasional reviews Thorax: first published as 10.1136/thx.54.8.730 on 1 August 1999. Downloaded from

Long acting â2 agonists and theophylline in stable chronic obstructive pulmonary disease

Mario Cazzola, Claudio Ferdinando Donner, Maria Gabriella Matera

The natural history of chronic obstructive reversible obstructive airways disease eformot- pulmonary disease (COPD) is characterised by erol (formoterol in dry powder form) in a dose an accelerated annual decline in forced expira- of 12 and 24 µg twice daily was signiﬁcantly

tory volume in one second (FEV1). One of the more eVective than salbutamol dry powder most crucial factors in COPD is therefore the 400 µg four times daily and appeared to be means by which this annual decline can be associated with few adverse eVects.8 It was still delayed. Bronchodilator therapy is usually pre- active after 15 months of treatment.9 Airways scribed to relieve the symptoms, reverse airway resistance (Raw) decreased from a mean (SD) obstruction and, hopefully, to slow the rate of of 0.52 (0.26) kPa/l.s (range 0.06–2.11) at day disease progression and decelerate the decline in 0 to 0.33 (0.14) kPa/l.s (range 0.06–0.88) at pulmonary function. However, the Lung Health one year (–43.5%). FEV1 increased from 1.90 Study, in its five year observation of almost 6000 (0.80) to 2.54 (0.97) l (33.7%). patients at risk of developing COPD,1 reported Salmeterol was compared with placebo over that the rate of decline of lung function in smok- four week periods in a double blind, placebo ers with mild to moderate COPD could be sig- controlled, crossover study involving 63 pa- nificantly slowed by smoking cessation but not tients with moderately severe disease.10 During by bronchodilator therapy. salmeterol treatment subjects did better in Nonetheless, bronchodilators are an impor- terms of all the measured parameters than dur- tant form of treatment to reduce symptoms in ing the placebo period. Thus, morning peak COPD. As any improvement in airflow might expiratory flow rate (PEFR) increased (12 l/

be extremely important in these patients, the min (95% CI 6 to 17)), symptom score dimin- http://thorax.bmj.com/ recent BTS guidelines for the management of ished, and use of “rescue” medication fell, but 2 COPD state that bronchodilators are the cor- improvement in pulmonary function was mod- nerstone of symptomatic treatment for the est. In another study salmeterol produced a reversible component of airway obstruction. small but statistically significant improvement Short acting â2 agonists used as required are in FEV1 compared with placebo at six hours Clinical Pharmacology recommended to be tried first in view of their after both a single dose of 50 µg (0.16 (95% CI Unit and Respiratory more rapid relief of symptoms. If â agonists do 0.09 to 0.22) l) and after four weeks of Pharmacology Centre not control symptoms adequately or if regular M Cazzola treatment with salmeterol 50 µg (0.11 (95% CI maintenance therapy is desired, an anticholin- 11 on September 30, 2021 by guest. Protected copyright. M G Matera 0.03 to 0.19) l) in patients with COPD. ergic agent can be added or substituted. The Moreover, a large multicentre study which ran- Division of addition of oral theophylline should only be domised 674 patients to receive either salm- Pneumology considered if inhaled treatments have failed to eterol 50 µg twice daily, salmeterol 100 µg C F Donner provide enough benefit. twice daily, or placebo for a period of 16 weeks

“Salvatore Maugeri” showed that FEV1 measurements improved Foundation, Institute moderately (+7%) but significantly in each sal- Bronchodilating eVect of long acting â2 of Care and Research, agonists in COPD meterol group at the end of the study.12 Medical Center of Formoterol 12 µg twice daily and salmeterol A long acting version of â2 agonists has also Rehabilitation, Veruno, 50 µg twice daily, both formulated as dry pow- Italy been developed. At present, long acting â agonist bronchodilators such as formoterol and ders, had similar eYcacy and safety profiles Correspondence to: salmeterol are an interesting new therapeutic after a six month treatment period in patients Dr M Cazzola, Unità di option for COPD, but their role in its treatment with reversible obstructive airways disease.13 Farmacologia Clinica e 3 Centro di Farmacologia is still debated. Salmeterol and formoterol Since there is only limited evidence as to the Respiratoria, Fondazione appear to be more eVective than short acting â eYcacy of long acting â2 agonists in COPD, the “Salvatore Maugeri”, agonists4 and, in patients with stable COPD, BTS guidelines recommend that use of these IRCCS, Centro Medico di Riabilitazione, Via per salmeterol is more eVective than anticholiner- bronchodilators be restricted to patients with a 56 Revislate 13, 28010 Veruno gic agents. demonstrable bronchodilator response to short (NO), Italy. In recent years several clinical studies have acting â2 agonists until more data are available. reported that the protracted treatment of In our opinion this limitation is no longer justi- Received 22 December 1998 Returned to authors COPD with long acting â2 agonists can lead to fiable. In fact, we have recently shown that 28 January 1999 an improvement in respiratory function. For- patients with COPD who do not manifest early Revised manuscript received moterol induced an improvement in airflow reversibility to salbutamol can still benefit from 12 February 1999 7 14 Accepted for publication limitation after one year of treatment. In a salmeterol. We must stress that the lack of 15 February 1999 three month multicentre trial in adults with correlation between early reversibility to a Long acting â2 agonists and theophylline in stable COPD 731

short acting â2 agonist and maximum response only slightly (about 13%) over the range of doses

to a long acting â2 agonist in several patients that induced steady state serum theophylline Thorax: first published as 10.1136/thx.54.8.730 on 1 August 1999. Downloaded from might reﬂect the poor reproducibility of revers- concentrations of 5–10 µg/ml, 10–15 µg/ml, and ibility tests in these patients. Nevertheless, 15–20 µg/ml, respectively. there is now a body of evidence in the literature Tsukino and colleagues28 suggested that high showing that these bronchodilators are eVec- doses of theophylline may be needed to induce

tive and safe in the management of COPD. a signiﬁcant increase in FEV1. However, even when care is taken to ensure a constant serum Oral versus inhaled bronchodilators concentration, the bronchodilator action is Optimal control of chronic obstructive airway limited in patients with stable COPD with 29 disorders is usually achieved with treatment changes in FEV1 ranging from 0 to 20%.

based on â2 adrenoceptor agonist administra- Researchers have tried to identify those pa- tion, inhalation being the most widely used tients with COPD who would be most likely to route.15 An advantage of administering bron- derive beneﬁt from theophylline. One study

chodilators by inhalation is that they do not indicated that an acute FEV1 response of have to be distributed to the rest of the body >25% to an inhaled â agonist could accurately and therefore may be given in very much predict improvement induced by smaller doses. Aerosols are highly eVective, theophylline,30 though another showed that the

have few side eVects, and allow for ﬁne adjust- acute FEV1 response is not an eVective ment of dosage to control symptoms.16 More- measure.31 In yet another study the change in over, by delivering drugs directly to the target pulmonary function after theophylline admin- organ, a much more rapid eVect is achieved. istration correlated with, but was usually Unfortunately, many patients with chronic smaller than, improvements after use of â obstruction of the airways use their inhaler adrenergic agents.32 These small changes in ineVectively.17 Poor inhalation technique leads lung function are unlikely to alter the progno- to insuYcient bronchodilating eVect and, con- sis. One of the reasons why theophylline sequently, to the prescription of more or addi- prescriptions are falling worldwide despite the tional medication with a higher probability of increase in prescriptions of respiratory drugs side eVects and higher costs. In these circum- generally is probably its inadequate broncho- stances, oral treatment may be considered a dilator action.33 rational alternative. Unfortunately, the eVect of Although these ﬁndings suggest that theo-

oral â2 agonists on pulmonary function has not phylline produces minimal changes in pulmo- been studied to a signiﬁcant extent in patients nary function in patients with COPD, some with COPD. We have recently reported that investigators have pointed out a correlation both oral bambuterol and inhaled salmeterol between improvement observed with theophyl- resulted in good bronchodilation in patients line and length of treatment. In fact, the with stable COPD. However, bambuterol, but bronchodilator eVect of theophylline is gener- http://thorax.bmj.com/ not salmeterol, caused tremor in several ally achieved after prolonged treatment.24 The subjects and elicited signiﬁcant and long slow onset of action and the diYculties in lasting tachycardia.18 Because of the high achieving stable plasma levels mean that most

incidence of side eVects, oral â2 agonists are not eVects occur after 2–6 weeks rather than after a recommended unless patients are unable to use few hours as is the case with inhaled therapy.29 inhaled therapy.19 The study by Murciano and colleagues,34 which examined a large number of patients Bronchodilating eVect of theophylline in with stable, severe “irreversible” COPD, sup- on September 30, 2021 by guest. Protected copyright. COPD ports this conclusion. Sixty patients with severe

Theophylline is the most frequently prescribed COPD (mean FEV1 32% predicted) received oral bronchodilator for the chronic mainte- either theophylline or placebo for two months. nance treatment of chronic obstructive airway The mean serum concentration of theophylline disorders.20 It was regarded as a ﬁrst line or fre- in the active treatment group was 14.8 mg/l. quent second line bronchodilator in chronic Theophylline administration resulted in a 13%

bronchitis by 40% of 236 general practitioners increase in FEV1 which was statistically signiﬁ- in Nottinghamshire (UK).21 The advantages of cant compared with the placebo group. Higher

theophylline are ease of administration and awake PaO2, lower awake PaCO2, higher sleep

better compliance with sustained release for- SaO2, improved FEV1, and lower trapped gas mulations given once or twice daily. volume were seen with a theophylline level of Theophylline is an eVective bronchodilator in 11.8 µg/ml after three weeks of treatment.35 patients with asthma.22 Its short term adminis- Compared with salbutamol, evening administration results in improvement in ﬂow rates and tration of once daily theophylline results in lung volumes that is correlated with serum levels better nocturnal oxygen saturation and an in a classic dose-response relationship.23 How- improvement in the overnight change in ever, debate continues as to its role in COPD.324 pulmonary function in patients with COPD In fact, in patients with COPD it is not possible after a two week treatment period.36 Attempts to determine concentration-eVect curves to to withdraw theophylline, even at lower levels, theophylline because the reproducibility of the should be done with caution because of a pos- magnitude of the response is dependent on the sible deterioration in pulmonary function.37 functional index that has been used,25 26 al- Unfortunately, theophylline is a diYcult drug though there is evidence of a modest dose- to use clinically as there is considerable inter- response eVect. Chrystyn and colleagues27 ob- and intra-individual variation in drug handling.38

served that FEV1, FVC, and PEFR changed It has a narrow therapeutic margin and the dose 732 Cazzola, Donner, Matera

must be carefully titrated with routine blood during the second week of treatment, patients

monitoring to avoid the occurrence of plasma receiving salmeterol had a 10 l/min greater Thorax: first published as 10.1136/thx.54.8.730 on 1 August 1999. Downloaded from concentration related adverse eVects.39 Ap- increase in mean morning PEFR from baseline proximately 10–15% of patients receiving (95% CI 5 to 15) than those receiving theophylline will experience gastrointestinal theophylline.47 Similarly, in the second week 40 upset, insomnia, or other minor side eVect. the increase in mean evening PEFR from base- Both major and minor side eVects are less line observed with salmeterol was significantly likely if one resists the temptation to increase greater than that observed with theophylline. the blood theophylline level into the high Salmeterol also produced a significantly greater therapeutic range. A British survey showed increase in mean morning and evening PEFR that theophylline levels were never checked by than theophylline at weeks 3 and 4. 76% of practitioners at the start of treatment In particular, salmeterol was significantly or by 48% during long term treatment.21 It is obvious that this aspect of prescribing may more eVective than theophylline or placebo in compromise both safety and eVectiveness, improving mean morning PEFR over the entire especially as the rate of absorption of theo- 12 weeks (p<0.02) in 484 adult and adolescent 43 phylline will diVer depending on the sustained patients with moderate asthma. Mean pre- 41 release formulation administered. dose FEV1 improved significantly with salm- Due to toxicity, the use of theophylline as eterol compared with placebo (p<0.001); there monotherapy in COPD should be restricted to wasnodiVerence between theophylline and the rare cases where patients cannot adequately placebo. In asthmatic patients treated for 28 administer inhalers. days, salmeterol induced a significantly higher

increase in FEV1 than did theophylline + keto- Comparison of bronchodilating eVect of tifen, while no significant diVerences were 44 long acting â2 agonists with theophylline found in either FVC or PEFR. Fjellbirkeland Few studies have compared the bronchodilat- and colleagues48 demonstrated that, over a two ing eVect of long acting â2 agonists and week period, salmeterol in a dose of 50 µg twice theophylline. This lack of data might be due to daily was more eVective and better tolerated the fact that, on one hand, there is still than individually titrated oral doses of sus- diYdence concerning the use of long acting â2 tained release theophylline in the management agonists in the management of COPD and, on of moderate asthma, although FEV1 improved the other, that theophylline is now considered a to a similar extent during both treatments. third line choice.2 Consequently, many investi- However, the increase in PEFR with salmeterol gators assume a comparison between these two compared with theophylline was highest in a classes of bronchodilators to be of little point. We must stress that the analysis of studies in subgroup of patients new to theophylline therapy. http://thorax.bmj.com/ the literature or in press does not permit one to 49 establish whether the enrolled patients were Paggiaro and colleagues showed that the suVering from bronchial asthma or COPD. eVects of both salmeterol and theophylline on However, it is well known that there is difficulty pulmonary function in patients with moderate in distinguishing with certainty the diVerence to severe asthma were equivalent after a four between subjects with COPD who may show a week period of treatment. At the end of degree of reversibility and those older subjects treatment the changes in PEFR were relatively with asthma whose reversible airflow obstruc- small and not clinically significant. Nutini and tion has become more fixed.42 There may also colleagues50 also found that both treatments led on September 30, 2021 by guest. Protected copyright. be mixtures of asthma and COPD co-existing to an improvement in respiratory function over

in any one patient. For this reason we thought time. Morning and evening PEFR, FEV1, and it useful to report all studies in our knowledge FVC increased without a significant diVerence which have compared long acting â2 agonists between the two drugs at the end of the study. and theophylline in patients with reversible D’Amato and colleagues51 observed that sal- obstructive airways disease. We subsequently meterol at a higher dosage (100 µg twice daily) subdivided these studies into patients with was significantly more eVective than theophyl- asthma and those with COPD according to the line in increasing morning and evening PEFR title of each study. in patients with moderate to severe asthma, and diurnal PEFR variations were reduced starting COMPARISON IN ASTHMATIC PATIENTS from the first month of treatment in salmeterol Most of the clinical trials evaluated the long treated patients and from the second month term clinical control of asthma43 or the impact of these drugs on the control of nocturnal onwards in those receiving theophylline. Both 44–46 treatments induced improvements in FEV and asthma. Some also assessed the eVects of 1 FVC over the three month treatment period. long acting â2 agonists and theophylline on pulmonary function, though this was always After the first month FEV1 increased from a considered a secondary outcome. Analysis of mean (SD) of 1.7 (0.6) l to 2.1 (0.8) l in salm- the respiratory function indicates an improve- eterol treated patients and from 1.6 (0.5) l to 1.9 (0.8) l in those treated with theophylline. ment with both long acting â2 agonists and At all the visits during the three month theophylline, with long acting â2 agonists possessing only a slight advantage. treatment period salmeterol was found to pro- A recent meta-analysis of nine controlled duce a higher adjusted mean response than studies that compared the eYcacy and safety of theophylline, although this diVerence was salmeterol and theophylline showed that, never statistically significant. Long acting â2 agonists and theophylline in stable COPD 733

COMPARISON IN PATIENTS WITH COPD PHARMACOEPIDEMIOLOGICAL AND

Comparisons between theophylline and long PHARMACOECONOMIC CONSIDERATIONS Thorax: first published as 10.1136/thx.54.8.730 on 1 August 1999. Downloaded from

acting â2 agonists in patients suVering from It is widely held that, since the cost of long act-

COPD are even more scarce. ing â2 agonists is much higher than that of Di Lorenzo and colleagues52 compared the theophylline, the use of methylxanthines is eVects of salmeterol 50 µg twice daily for three preferable in those socioeconomic systems months with oral dose-titrated theophylline where, through cost or non-availability, it con- twice daily in 178 patients with chronic stitutes the most feasible means of controlling bronchitis. The morning PEF increased from a airway obstruction.57 However, we do not agree baseline value of 324 l/min to 360.7 l/min three with this approach because the price of drugs is months after salmeterol and from a baseline only a part of the total cost of treatment and it value of 298.8 l/min to 325 l/min three months is likely that the overall cost of theophylline is after theophylline (p<0.02). There was a simi- greater than that of other bronchodilators lar trend for evening PEF but diVerences were owing to its toxic eVects. In fact, it has been not statistically significant. documented that the total cost per year, A short term (two week) comparison be- including admission to hospital for toxic events tween salmeterol 50 µg twice daily or 100 µg and monitoring blood levels, was higher for twice daily and orally titrated slow release patients using theophylline despite the higher theophylline in 13 patients with moderate purchase price of other bronchodilators.58 COPD showed that salmeterol was always These considerations could have important more eVective than theophylline although the clinical implications at a time when high prior- diVerences were not significant.53 However, ity is given to the appropriate allocation of salmeterol 100 µg twice daily induced a signifi- health resources. cant improvement in morning PEFR when A recent study found that, although salm- compared with theophylline. eterol was prescribed preferentially to high risk A one year Italian multicentre study54 patients, after adjusting for baseline risk compared the eVects of inhaled salmeterol salmeterol recipients were not at greater risk (50 µg twice daily via Diskhaler) with those of than theophylline recipients for severe non- oral dose-titrated slow release theophylline in fatal asthma.59 This finding is important 138 patients with reversible COPD. Salmeterol because pharmacoepidemiological studies in- was found to be more eVective than theophyl- dicate a strong association between increased

line for the maximum value of morning PEF, â2 agonist use and â2 adrenoceptor downregu-

but diVerences in FVC, FEV1, and maximum lation and subsensitivity and consequent loss of value of evening PEF did not reach statistical airway control.60 61 In particular, Lipworth62 signiﬁcance although the eVect of salmeterol advised that physicians should be aware of the was slightly superior to that of theophylline. airway subsensitivity that develops with long http://thorax.bmj.com/ However, it must be stressed that both acting â2 agonist therapy and that patients asthmatic and COPD patients were enrolled in should be warned that they may have to use this study. higher than conventional dosages of short act-

ing â2 agonists to relieve acute bronchocon- striction in order to overcome this eVect. How- ever, we have shown that pretreatment with a Problems related to the use of long acting conventional dose of formoterol or salmeterol

â2 agonists and theophylline in COPD does not preclude the possibility of inducing a Unfortunately, there are few studies in the further bronchodilation with salbutamol in on September 30, 2021 by guest. Protected copyright. literature comparing the bronchodilator effects patients suVering from partially reversible 63 64 of long acting â2 agonists and theophylline in COPD. Bjermet and Larsson have recently patients with COPD. In the short term the reviewed some data related to the debate warn-

adrenergic agent appears to be more active ing against the use of long acting â2 agonists than theophylline, but the diVerence between and observed that the bronchodilatory eVect the two drugs becomes less marked with long seems to be fairly stable after regular treatment term treatment. However, the diVerent inci- with these bronchodilators, even though some dence of side eVects, which is much higher with reports claim that this eVect diminishes over theophylline,40 evokes the need for a continu- time. ous appraisal of the cost/beneﬁt relationship. For the present time we think that the BTS IMPACT OF LONG ACTING â AGONISTS AND 2 guidelines are correct in suggesting that theo- THEOPHYLLINE ON THE HEART phylline is a third line choice of treatment. The impact of bronchodilators on the heart is, However, we do not share the cautious in our opinion, a very important point. Cardiac

approach to long acting â2 agonists. In fact, arrhythmias are common in patients with

there is now evidence that long acting â2 respiratory failure due to COPD. Several agonists are an acceptable option as bronchodi- factors are potentially arrhythmogenic in these lators in the treatment of COPD, although they patients including hypoxaemia, hypercapnia, should not be used for acute shortness of acid-base disturbances,65 and the use of â ago- breath.55 In particular, some of the advantages nists or theophylline.66 We cannot exclude the of theophylline can be found in a long acting possibility that adverse cardiac events might inhaled â agonist.56 For this reason, as the occur in COPD patients with pre-existing car- acceptance of these agents becomes greater, diac arrhythmias and hypoxaemia if they use

theophylline may be further displaced as a use- long acting â2 agonists, although the recom- ful agent in the treatment of COPD. mended single dose of salmeterol (50 µg) and 734 Cazzola, Donner, Matera

formoterol (12 µg) ensures a relatively higher theophylline occur for reasons other than sim-

safety margin than formoterol in a dose of ple bronchodilatation. Nevertheless, we must Thorax: first published as 10.1136/thx.54.8.730 on 1 August 1999. Downloaded from 24 µg.67 However, neither formoterol68 nor stress that several studies suggest that the salmeterol69 elicit significant cardiovascular eVect of long term theophylline34 and long act- eVects in normal subjects and patients with ing â agonist79 use in patients with COPD may reversible airway obstruction. Conversely, go beyond bronchodilation to an improvement theophylline causes tachycardia and serious in various measures of patients’ functional arrhythmias even at serum concentrations con- state and well being. In particular, theophyl- sidered to be therapeutic.70 These findings line may improve mucociliary clearance in the strongly support limiting the use of theophyl- airways, respiratory muscle strength, and right line to those patients who are incapable of ventricular and left ventricular ejection frac- inhaling drugs as suggested by the ATS.71 Only tion; it may decrease pulmonary artery studies comparing the eVects of the two drug pressure, stimulate central respiratory activity, classes on the airways after treatment periods and elicit anti-inflammatory action at concen- lasting several years will be able to clarify their trations which are therapeutically real impact in the treatment of COPD. significant.24 80 For example, Mahler and colleagues81 have shown that theophylline sig- COMBINED USE OF THEOPHYLLINE AND A LONG nificantly reduced dyspnoea in patients with ACTING â AGONIST IN PATIENTS WITH COPD non-reversible obstructive airway disease with-

â2 agonists are eVective bronchodilators and act out altering lung function. Moreover, predominantly on airway smooth muscle. Re- Ashutosh and colleagues82 have reported that

cent evidence suggests that â2 receptors in theophylline increases respiratory drive in airway smooth muscle are coupled directly to clinically employed doses independently of its maxi-K channels and may thereby bronchodi- bronchodilator or metabolic eVects. Theo- late without an increase in cyclic AMP. Theo- phylline is a respiratory stimulant, a feature phylline has an anti-inflammatory and immu- that may be of benefit to COPD patients who nomodulatory activity that is more important hypoventilate, particularly overnight.83 In view than its bronchodilator action.72 It has been pro- of the recent developments in the concept of posed that the observed anti-inflammatory COPD as a chronic inflammatory disease of eVects of theophylline could be attributed to the airways, the anti-inflammatory activities of phosphodiesterase (PDE) inhibition, and re- theophylline may play a more important role cently type III and IV isoenzymes have been than the mere bronchodilating properties in its characterised in a number of inflammatory treatment.84 It is therefore possible that cells.73 PDE type IV inhibitors, which have anti- theophylline might also attenuate the airflow inflammatory properties, could also provide limitation caused by airway inflammation in adequate bronchodilation when used in combi- COPD.85 http://thorax.bmj.com/ nation with lower than usual doses of â2 agonists.74 It is therefore not surprising that a number of clinical studies support the combined Conclusion use of theophylline and a â agonist in patients A point of controversy is whether all the with COPD.75 For example, theophylline benefits of these two classes of bronchodilators (12.9 µg/ml) and salbutamol improved pulmo- in COPD are class eVects. Although both nary function in patients with irreversible theophylline and long acting â2 agonists elicit COPD, but the combination was better than bronchodilation, they have significant pharma- either alone.76 Unfortunately it has yet to be codynamic diVerences. It is possible that some on September 30, 2021 by guest. Protected copyright. established whether the association of a long of these specific properties mediate non- bronchodilator benefits. However, interest in acting â2 agonist with theophylline induces an increase in the bronchodilator eVect caused by these non-bronchodilator eVects should be either of the two drugs. Only if this eVect were balanced by an awareness of the possible documented could the addition of theophylline adverse eVects of the drugs. Clarification of the diVerences in response to these agents in to a treatment with long acting â2 agonists be justified. In any case, it has recently been shown COPD is an essential part of tailoring a that regular theophylline treatment neither management plan to each individual patient, prevents nor worsens the development of considering that physicians must always choose tolerance to the bronchoprotective eVect of a drug that is highly eYcacious, safe, and inex- salmeterol.77 pensive.

NON-BRONCHODILATOR ACTIVITY OF 1 Anthonisen NR, Connett JE, Kiley JP, et al.EVects of smoking intervention and the use of an inhaled anticholinergic THEOPHYLLINE AND LONG ACTING â AGONISTS bronchodilator on the rate of decline of FEV1: the Lung The ﬁnding that exercise performance after the Health Study. JAMA 1994;272:1497–505. 2 COPD Guidelines Group of the Standards of Care 12 minute walking test increased signiﬁcantly Committee of the BTS. BTS guidelines for the manage- at the end of an eight week treatment with ment of chronic obstructive pulmonary disease. Thorax 1997;52(Suppl 5):S1–28. 50 µg salmeterol twice daily but not after orally 3 Cazzola M, Spina D, Matera MG. The use of bronchodila- dose-titrated slow release theophylline twice tors in stable chronic obstructive pulmonary disease. Pulm Pharmacol Ther 1997;10:129–44. daily and, moreover, that the rating of daily 4 Cazzola M, Santangelo G, Piccolo A, et al.EVect of breathlessness assessed by the oxygen cost dia- salmeterol and formoterol in patients with chronic obstructive pulmonary disease. Pulm Pharmacol 1994;7: gram was lower only after salmeterol treat- 103–7. ment, which also reduced weekly inhalations of 5 Matera MG, Cazzola M, Vinciguerra A, et al. A comparison 78 of the bronchodilating eVects of salmeterol, salbutamol and rescue bronchodilator, supports the notion ipratropium bromide in patients with chronic obstructive that it is unlikely that the useful eVects of pulmonary disease. Pulm Pharmacol 1995;8:267–71. Long acting â2 agonists and theophylline in stable COPD 735

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