Bronchodilators remain the mainstay of chronic obstructive pulmonary disease (COPD) management and are recommended for the treatment of symptomatic patients at all stages of this disease 1. For many years studies of these drugs focussed on changes in forced expiratory volume in one second (FEV1) or, occasionally, forced vital or slow vital capacity, believing that these robust and reproducible end-points were a legitimate surrogate for the changes in symptomatology, which were the real interest of patients and clinicians alike. By the 1990s, this comfortable assumption had been challenged when it became clear that individual improvement in exercise capacity and breathlessness were not closely related to changes in the magnitude of these spirometric indices 2. This stimulated research into the determinants of exercise performance and dyspnoea in COPD, and why spirometry was of so little help in predicting symptomatic improvement. A range of mechanisms have been identified and have recently been reviewed 3. Principal among these is the change in end-expiratory lung volume (EELV) during exercise in COPD patients. When healthy subjects exercise, EELV is reduced helping to keep the operating lung volumes on the steeper part of the pressure-volume relationship. COPD patients with tidal expiratory flow limitation must either allow EELV to rise 4, or try to overcome flow limitation at their initial lung volume an unsatisfactory strategy which limits exercise performance 5. Most patients with more severe disease adopt for the former approach which allows them to exercise longer, but at the cost of increasing difficulty in breathing as EELV approaches total lung capacity 6.
Several studies have examined exercise performance in light of this improved mechanistic understanding. Studies with the shorter acting anticholinergic drug ipratropium confirmed that the degree of spirometric change was unrelated to any improvement in exercise performance 7, but that increases in inspiratory capacity during exercise did identify individuals who could exercise for longer. Further data with both tiotropium and salmeterol 6, 8 have shown that these bronchodilator drugs lower resting EELV which creates more “room” within the thorax to accommodate the volume change that exercise produces. At any time during exercise the degree of breathlessness is less after the bronchodilator drug, although at end-exercise when the inspiratory reserve volume approaches 500 mL a rapid increase in self-reported breathlessness occurs. This reflects the substantial neuro-mechanical dissociation which occurs when EELV approaches total lung capacity. Data with salmeterol suggests that the main effect of this drug is to delay the time taken to reach this point 6, although other subtler mechanisms have been proposed 9.
Thus, changes in operating lung volume explain why bronchodilators make people less breathless and why small changes in mean FEV1, measured as an average change in groups of COPD patients, rather than individuals, can be accompanied by important clinical benefits. However, detailed mechanistic studies of this type are too complex to answer all our questions about how and when to use bronchodilator drugs, and in many circumstances we are still reliant on detecting small changes in spirometry to guide clinical practice. This is especially true when we determine the duration of action of drugs and whether combining drugs is better than using either one alone.
Although differences in the pharmacology of individual bronchodilators have been a topic of much discussion, the most useful practical development has been to prolong their duration of action. Despite differences in dissociation times for different muscarinic receptor subtypes, tiotropium improves exercise performance in COPD patients in a similar way to short-acting anticholinergic drugs 7, 8. However, tiotropium can be taken q.d. and produces improvements in spirometry for ≥24 h, including the overnight period 10. This sustained action maintains airway patency, which previously we have argued to be desirable in COPD 11. This is the most likely reason for the superior clinical performance of this agent compared with its short-acting counterparts 12.
Although tiotropium is a very effective anticholinergic drug, it is unlikely that the current dosing regime is on the flat part of the dose-response relationship 13, with the dose of 18 μg q.d. being chosen to represent a reasonable compromise between clinical efficacy and the risk of systemic absorption and toxicity. Indeed, combining anticholinergic and β-agonist in high doses can still produce significant improvements in lung function and lung volume irrespective of the presence of expiratory flow limitation 14. This has been the basis of the widely used regular short-acting combination drugs in COPD 15. Inevitably, clinicians would also like to know whether there is any benefit in combining long-acting inhaled drugs as well and in this issue of the European Respiratory Journal, a helpful study is reported which begins to address this complex problem 16.
In the present issue, van Noord et al. 16 compared tiotropium q.d., the long-acting inhaled β-agonist formoterol b.i.d., and the combination of tiotropium q.d. and formoterol q.d. in a randomised placebo-controlled crossover trial in 71 patients with stable COPD (mean FEV1 37% predicted). Patients took each treatment for 6 weeks at the end of which spirometry was recorded 17 times over the subsequent 24 h to identify early and more sustained changes in lung function after each drug. Regular peak flow recordings were made and rescue medication use was noted, but other measurements such as inspiratory capacity were not added to what was already a demanding protocol.
Several points emerged clearly. The patients enrolled were very similar to those reported in previous studies of tiotropium 12, 17–19 and, as anticipated, there was a significant improvement in mean trough FEV1 of ∼100 mL after this drug. This is comparable with other studies and was significantly greater than that after formoterol (b.i.d.). There was further significant improvement in spirometry over the first 12 h after the two drugs were taken together. As noted previously 10, the diurnal variation in lung function persists despite inhaled tiotropium therapy and there was no evidence of any residual effect from the morning dose of formoterol over the second half of the day. Similar changes were seen in peak expiratory flow and drug combination was well tolerated. There was a greater reduction in the daytime use of “rescue” salbutamol during treatment with the combination compared with the individual components, but this was the only clinically important comparator included in this study.
The present data are interesting although largely limited to spirometric outcomes and represent an unusual dosing regime for clinical purposes. The crossover design of the study is a considerable strength, as is the detailed time course data after sustained dosing with these drugs. There is clear evidence of additional benefit when the drugs are combined and this is lost as the formoterol effect wears off. There is currently considerable interest in developing q.d. inhaled therapy that combines the undoubted benefits of tiotropium with an equally long-acting β-agonist. Formoterol q.d. does not meet this requirement, but b.i.d. therapy would appear to be worth exploring in studies where relevant clinical end-points are evaluated.
The persistent increase in airflow obstruction that characterises chronic obstructive pulmonary disease is best addressed by improving lung function throughout the 24-h day and certainly during the period when patients are awake and most active. The new data from van Noord et al. 16 suggests that, to achieve this goal, we can do more than we currently are. In this setting, modest improvements spirometrically often indicate larger functionally important changes. The challenge for the future will be to establish whether the clinical benefit produced by combining these drug classes merits the additional expense and potential inconvenience of adding another inhaler to an already complex treatment regime.
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