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Dr. Lipworth is Professor of Allergy and Respiratory Medicine, Ninewells Hospital and Medical School, University of Dundee. Dr. Lipworth and the Asthma and Allergy Research group have received financial support for equipment, clinical trials, attending meetings, or giving occasional postgraduate lectures from the following pharmaceutical companies who make long-acting ß2-agonists or theophylline: GlaxoWellcome, AstraZeneca, Boehringer Ingelheim, Innovata Biomed, Novartis, Aventis, and 3M Healthcare.
Correspondence to: Brian J. Lipworth, MD, Professor of Allergy and Respiratory Medicine, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY; e-mail: b.j.lipworth{at}dundee.ac.uk
The current American and British guidelines for COPD highlight the limited available treatment options for this condition.1 2 This was also shown in a 1999 evidence-based systemic review3 of interventions in patients with stable COPD, where randomized controlled trials found short-term benefits from anticholinergics and ß2-agonists administered alone or in combination, with the need for frequent blood monitoring limiting the usefulness of theophyllines. Long-term trials with high doses of inhaled corticosteroids have been disappointing, as they do not seem to arrest the progressive decline in lung function and only have small and inconsistent effects on symptoms, quality of life, or exacerbations, while at the same time having the propensity for producing systemic adverse effects, including skin bruising, adrenal suppression, or loss of bone density.4 5 6 To date, only two interventions, namely smoking cessation and long-term oxygen administration, have been found to alter the long-term course in COPD.
Against this rather pessimistic background, some new data published by ZuWallack and colleagues in this issue of CHEST (see page 1661) provide cause for cautious optimism. They reported on 943 patients with severe COPD (FEV1 = 40% predicted) who were randomized to receive 3 months of treatment with either inhaled salmeterol alone, an optimized dose of oral theophylline, or the combination. All three treatment groups produced significant improvements, although the combination group, as compared to monotherapy with either drug, exhibited significant superiority for a variety of outcome measures, including lung function, symptoms, albuterol use, exacerbations, quality of life, and overall satisfaction.
At screening, approximately 50% of patients in each group were reversible to inhaled albuterol, and it was particularly noticeable that there was the same rank order (combination greater than salmeterol greater than theophylline) of improvement in FEV1 response in patients characterized as being reversible or nonreversible, although the absolute magnitude of response was attenuated in nonreversible patients. Thus, a negative reversibility test to a single dose of albuterol should not necessarily preclude patients from being given a therapeutic trial with salmeterol and theophylline. The magnitude of bronchodilator response showed no diminution when comparing the area under curve over 12 h after day 1 vs week 12, indicating that tolerance to the effects of salmeterol did not occur with long-term dosing. Although the absolute magnitude of the improvement in lung function with the combination was relatively small, this may assume greater importance in patients starting with a lower baseline. Moreover, the improvements in lung function were translated into commensurate effects on other outcomes, such as symptoms and quality of life.
There are some other important points that may be drawn from this study. First, the dose of theophylline was titrated to within the conventional therapeutic window for bronchodilator efficacy (ie, 10 to 20 µg/mL) prior to randomization, in order to optimize the response. One hundred seven patients were withdrawn during this period due to theophylline-related adverse events, while an additional 30 patients failed to achieve the target theophylline concentration. In real-life clinical practice, particularly in primary care, a requirement for theophylline titration and associated blood monitoring would markedly restrict its use. Furthermore, the reporting of GI adverse events during randomized treatments was significantly higher in both of the groups that received theophylline compared with salmeterol monotherapy. One wonders whether theophylline tolerability would have been improved or its efficacy diminished if a lower target range associated with its anti-inflammatory activity (5 to 10 µg/mL) was employed. Indeed, the empiric use of low-dose theophylline without drug monitoring rather than optimized titrating is the more common scenario in everyday clinical practice. It may well be that this would be an acceptable trade-off in terms of losing some of the concentration-related bronchodilator activity while retaining its other effects on airway inflammation or respiratory muscle.7 8
It was perhaps surprising to see such a good response to salmeterol, given that it was administered via a pressurized metered-dose inhaler, which is notoriously difficult to use and has relatively poor lung deposition when used on its own without a spacer. It would therefore be relevant to know whether the improvement with salmeterol would be even greater with a device that is easier to use, such as a multidose dry powder inhaler or perhaps a metered-dose inhaler in conjunction with a spacer device to facilitate lung deposition.9 Unfortunately, no measure of exercise capacity was evaluated in this study, although in a previous report of patients with severe COPD (FEV1 = 42% predicted with 12.5% albuterol reversibility), treatment for 4 weeks with salmeterol compared to placebo showed only a small improvement in spirometry along with reduced perceived exertion on walking, but no effects on parameters of exercise capacity.10 There was no mention of the oxygenation status of the patients at screening or throughout the study, and it would be pertinent to know whether greater improvements in lung function with combination therapy might be associated with commensurate effects on oxygenation status at rest and with exercise.
One of the strengths of this study was the evaluation of a variety of different end points. This is likely to be clinically relevant, because in patients with severe COPD, effort-dependent tests such as FEV1 are relatively insensitive due to the effects of dynamic airway compression, particularly pressure-dependent airway closure in emphysema.11 Indeed, the use of relaxed capacity compared to FVC has been shown to be more sensitive at detecting bronchodilator responders to ß2-agonist and anticholinergic therapy.12 The findings on health-related quality of life as assessed by the chronic respiratory disease questionnaire are worth pointing out, in that a significantly higher percentage of patients who received combination therapy had clinically meaningful improvements in scores compared with monotherapy. Using the same score in another study also over 12 weeks, salmeterol and ipratropium both showed a significantly greater proportion of patients who had a clinically meaningful improvement compared to placebo, reinforcing the sensitivity of this outcome measure in assessing treatment response.13
The authors speculate that some of the improvements due to salmeterol, particularly those seen in nonreversible patients, may have been attributable to the nonbronchodilator effects of this drug, such as its putative anti-inflammatory activity. However, as more potent anti-inflammatory agents, such as inhaled corticosteroids, have only minimal effects on COPD, it is unlikely that this property is relevant to the improvements seen with salmeterol. Whether the effects of theophylline in COPD are due to its weak bronchodilator activity, its weak anti-inflammatory activity, or a combination of both is also open to conjecture. Another possible therapeutic strategy would be to use the combination of a long-acting ß2-agonist and a long-acting anticholinergic such as tiotropium, which will soon be licensed for once-daily administration in patients with COPD.14 It would also be relevant to know whether adding in theophylline on top of such combined ß2-agonist/anticholinergic therapy would confer any benefits, although the likelihood is that long-term compliance would be compromised with such a complicated regime.
In summary, the findings of ZuWallack and colleagues indicate that it is worth trying to achieve even a small improvement in lung function in COPD using combination bronchodilator therapy, as this may result in meaningful improvements in disease control, quality of life, and exacerbations, even in some patients with apparent nonreversibility to albuterol. Further studies are required to evaluate the long-term effects of salmeterol in combination with a lower dose of theophylline, in particular to focus on other outcome variables such as exercise capacity and oxygenation status, as well as to perform airway biopsy studies to evaluate whether these drugs exhibit any putative anti-inflammatory activity in addition to their known bronchodilator properties. In the new millennium, the old altitude of therapeutic nihilism toward COPD is inappropriate; as clinicians, we should look forward with new optimism to further improvements in the management of this debilitating condition.
References
This article has been cited by other articles:
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  B. R. Celli Update on the Management of COPD Chest, June 1, 2008; 133(6): 1451 - 1462. [Abstract] [Full Text] [PDF]
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D. A. Mahler, S. Huang, M. Tabrizi, and G. M. Bell Efficacy and Safety of a Monoclonal Antibody Recognizing Interleukin-8 in COPD: A Pilot Study Chest, September 1, 2004; 126(3): 926 - 934. [Abstract] [Full Text] [PDF]
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 D. A. Mahler, P. Wire, D. Horstman, C.-N. Chang, J. Yates, T. Fischer, and T. Shah Effectiveness of Fluticasone Propionate and Salmeterol Combination Delivered via the Diskus Device in the Treatment of Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., October 15, 2002; 166(8): 1084 - 1091. [Abstract] [Full Text] [PDF]
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 P.J. Rees Tiotropium in the management of chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2002; 19(2): 205 - 206. [Full Text] [PDF]
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