This study is unique in assessing the effect of the addition of salmeterol to existing treatment, which could include an ICS, in a population of poorly reversible patients, particularly because the patients are investigated in a “real life” setting over a long period of 12 months. Analysis of the primary end point—the number of moderate/severe exacerbations—showed that, although treatment with salmeterol was associated with a 21% reduction compared with placebo in the ITT population, this failed to reach significance. However, a similar reduction in exacerbations has been observed in studies with other long acting bronchodilators such as tiotropium,16
In addition, one year trials with formoterol, using the same definition of exacerbations as the current study, have not shown such a reduction in exacerbations,17,18
which suggests that the reduction in the current study is not a feature of all LABAs.
While it is possible that the lack of significance between the active and placebo treatment groups may be due to the low frequency of exacerbations experienced by the patients, the reasons underlying the lower than expected rates of exacerbations observed in the present study are not clear, particularly in view of the fact that only patients experiencing at least two exacerbations in the previous year were recruited. It is possible that patients who had experienced a maximum of two exacerbations of COPD in the previous year may have been less prone to exacerbations than patients who had experienced a greater number of exacerbations. It is also possible that the placebo effect may have been exaggerated in these patients by merely entering a clinical trial with close monitoring, or that the severity of COPD in the patients recruited was milder than anticipated.
A lower than expected exacerbation rate, however, is not unique in COPD exacerbation studies, and similar issues arose in the study reported by Calverley et al
Additionally, we used the same event based definition of exacerbations, which has been endorsed as the most unambiguous and practical approach to clearly defining episodes,11
and has been used in other recently reported long term studies.17,18
The reduction in exacerbations observed in recent studies clearly needs to be taken into account in the design of future intervention studies on exacerbations. A more symptom related definition should perhaps have been used, or more rigorous physiological impairment criteria may need to be used to recruit patients to ensure a more consistent incidence of exacerbations. Further studies are needed to clarify these issues.
Removal of patients deemed to be protocol violators resulted in a higher overall incidence of moderate/severe exacerbations in patients on placebo, although this was still less than two per year. Two of the main criteria for classifying this population (determined before analysis) were 90% compliance with study medication (measured by the dose counter on the Diskus) and/or that they completed at least 50 weeks of treatment. The latter was chosen as it emphasises any benefit of high compliance. If the threshold for compliance in the per protocol population was lowered to 80% (post hoc analysis), there was no significant difference between salmeterol and placebo (p
0.062). This suggests that a reduction in exacerbations in the salmeterol group was clearly influenced by compliance, and highlights the need for patients to keep taking their medication to obtain a benefit related to the frequency of exacerbations.
The dose of ICS taken by patients during the study was similar between the groups and is therefore unlikely to account for the overall difference in exacerbation rate seen between salmeterol and placebo in these patients. In addition, the number of patients who changed their dose of ICS during the study was small and balanced between the groups, and is also unlikely to have influenced the results. Investigation into the role of prior ICS use on exacerbations showed that, although the addition of salmeterol reduced moderate/severe exacerbations by 27%, the difference in exacerbation rates between ICS or non‐ICS users was not significant. Similarly, while a numerical trend towards a reduction in the rate of exacerbations was observed with salmeterol for patients receiving short acting anticholinergic agents, this was not statistically significant. Although previous data have shown that administration of both a LABA and a short acting anticholinergic is more beneficial than either drug alone,6,20,21
our study was not powered to show a difference in these sub‐groups of ICS and anticholinergic users and non‐users. At the time of the current study, the long acting anticholinergic tiotropium was not available and further research is therefore required to determine whether a LABA and tiotropium have additive effects in COPD, as seen with other combinations of treatment.16,17,18,22
In COPD, expiratory airflow limitation—the pivotal pathophysiological abnormality—is traditionally measured by FEV1
. Salmeterol has been shown to improve FEV1
after 4 weeks,6
as in the current study. An improvement of >100 ml, which was maintained over the 12 months and was greater than placebo at all time points, is likely to be of clinical benefit in patients with a poor baseline lung function and poor reversibility and would be supported by the improvement in health status (particularly the activity domain) observed in the present study. There was no evidence of tolerance to the bronchodilator effects of salmeterol in this long term trial, which confirms the findings of shorter studies.5,6,7
FVC also showed a similar improvement on salmeterol. However, improvement in both FEV1
and FVC is poorly predictive of dyspnoea and exercise tolerance.23
On the other hand, spirometric IC, which indirectly reflects the end‐expiratory lung volume and exercise capacity, can be diminished even at rest in COPD24,25
and provides an indirect measure of hyperinflation which may contribute complementary information to the FEV1
in therapeutic evaluation.23
In the current study salmeterol improved IC within 4 weeks, which was reflected by the reduction in breathlessness and symptoms, as well as improvement in exercise capacity measured by the shuttle walk test. Furthermore, patients receiving salmeterol had a significantly higher percentage of days when they did not use their short acting β2
agonist for relief of symptoms, which may also reflect this improvement in dyspnoea and exercise capacity.
Health status is an established outcome measure for evaluating the efficacy of therapeutic interventions in COPD.26
It has been suggested that exacerbation frequency is an important determinant of health status in COPD and hence an important outcome measure.2
A significant decrease of four units in the SGRQ was seen in patients receiving salmeterol over 52 weeks. Health status was improved in our study as early as 4 weeks after treatment began, and was not only maintained but increased throughout the treatment period—consistent with some previous results27
but greater than in other studies with salmeterol.16,20
Some of these differences may reflect the “real life” situation as patients were allowed to continue with ICS in the current study while in other studies ICS were not permitted.16
Clearly, comparisons between studies need to take into account permitted treatment as well as other inclusion and exclusion criteria.
This study confirms that salmeterol is an effective treatment for patients with COPD. The addition of salmeterol significantly improved lung function (including reduced lung hyperinflation) and dyspnoea, increased exercise capacity, and resulted in an enhanced quality of life. A modest reduction in exacerbations was also seen, but only in patients who showed good compliance with study medication.