Hodder et al repeated exacerbations requiring antibiotics and/or therapy with oral corticosteroids (Pauwels 2001; O’Donnell et al 2003; NICE 2004). Despite what guidelines recommend, ICS are commonly prescribed for patients with COPD, while the merits of this practice continue to be debated (Barnes 2000; Calverley 2000; Suissa 2006). This empiric practice may have some justiﬁcation, as it has been demonstrated that withdrawal of ICS from patients with COPD is associ- ated with an increase in exacerbation rates and worsening health status, as well as a deterioration in lung function and increased exertional breathlessness (O’Brien et al 2001; van der Valk et al 2002; Wouters et al 2005). A few studies (Paggiaro et al 1998; Weir et al 1999; Burge et al 2000; Lung Health Study Research Group 2000; Pauwels 2002) have suggested a beneﬁcial effect from ICS at reducing the number of COPD exacerbations for patients with advanced disease (FEV1 <50% predicted), and a meta-analysis of such trials reported a 30% reduction in COPD exacerbations with ICS (Alsaeedi et al 2002). However, other randomized clinical trials have not shown beneﬁt from ICS in COPD (Bourbeau et al 1998; Calverley et al 2003a; Szafranski et al 2003). Recently, the methodology of statistical analysis used in many of these trials has been questioned (Suissa 2006). According to this line of reasoning, conclusions concerning the effect of ICS on the frequency of COPD exacerbations should be considered ﬂawed whenever the overall rate of COPD exacerbations has been calculated by treating all patients equally and simply averaging indi- vidual patient exacerbation rates. This so-called unweighted approach is overly sensitive to individual follow-up times which usually vary signiﬁcantly within a given trial, and can therefore lead to a biased estimate of exacerbation rate ratios (Suissa 2006). While long-acting beta2-adrenergics appear to be effective when added to inhaled steroids for many outcomes in patients with advanced COPD (Mahler et al 2002; Calverley et al 2003a, b, 2007), there are no data yet available assessing the efﬁcacy of adding tiotropium, a long-acting anticholinergic inhaled bronchodilator for once-daily inhalation (Maesen et al 1995; Disse et al 1999; Littner et al 2000; Gross 2004) to ICS alone in COPD patients. At least in theory, if ICS could reduce airway inﬂammation, peripheral mucus plugging and airway wall compliance might be expected to improve, lead- ing to a greater response to bronchodilator therapy. Whether differential effects might also be observed between different classes of bronchodilators is also unknown. Donohue et al reported results from a placebo-control- led study over 6 months comparing tiotropium and the 158 long-acting beta2-adrenergic, salmeterol, in patients with moderately advanced COPD (Donohue et al 2002, 2003). Tiotropium provided sustained and superior improvement in 12-hour lung function compared to salmeterol. When the data from this trial were combined with a similar 6-month trial in COPD patients for the analysis of patient-centred outcomes, additional beneﬁts for tiotropium over salm- eterol were indicated in symptoms, health status and the frequency of COPD exacerbations (Brusasco et al 2003). In these latter two studies, 66% of the patients enrolled had been prescribed ICS on a regular basis. The completion of these two placebo-controlled 6-month clinical studies has presented the opportunity to retrospectively analyze the relative efﬁcacy of tiotropium and salmeterol as a function of the concomitant use of ICS in patients with moderately advanced COPD. Patients and methods Study design This is a retrospective analysis of the pooled results of two similar 6-months, randomized, double-blind, double- dummy, placebo-controlled, parallel group studies of inhaled tiotropium bromide (18 μg once daily via the HandiHaler®) and salmeterol (50 μg twice daily via a CFC metered dose inhaler) in the treatment of patients with COPD (study codes 205.130 and 205.137). The only difference in the two studies was the duration of serial spirometry in the clinic (12 hours in one study, 3 hours in the second) (Brusasco et al 2003; Donohue et al 2002, 2003). The studies were conducted in 18 countries. All patients provided written consent and the studies were approved by the respective ethics committees and institutional review boards. The study design has previously been described (Brusasco et al 2003; Donohue et al 2002, 2003). In brief, following an initial screening to assess eligibility, patients had entered a 2-week baseline period. Patients who successfully completed this phase were randomized into the double-blind portion of the study during which they received tiotropium, salme- terol or placebo for a period of 24 weeks. The drugs were administered in a double-dummy design with tiotropium or placebo inhalation capsules taken once daily in the morning and salmeterol or placebo inhalation aerosol taken twice daily (every 12 hours). Clinic visits were scheduled after 2, 8, 16, and 24 weeks following randomization. Study patients The main inclusion criteria were: age 40 years, a diag- nosis of COPD with pre-bronchodilator FEV1 at screening International Journal of COPD 2007:2(2)