Hodder et al comparable (Tables 1a, b). For patients concurrently treated with ICS, mean pre-bronchodilator FEV1 values were 39%, 38%, and 40% of predicted in the tiotropium, salmeterol, and placebo groups respectively. In general, at baseline, the group of patients taking ICS had slightly more airway obstruction and poorer health status scores than patients not on ICS (p < 0.05). The median daily doses and dose ranges of ICS used by the majority of these patients for at least 3 months prior to the study are shown in Table 2. Fluticasone was the most commonly used ICS (approximately 35%–40% in each group) with a median daily dose of 1000 μg. The apparent large dose ranges observed reflect extreme ICS dosing by one or two patients in each treatment group. Twenty-one patients from the original data sets, not taking ICS, but receiving regular treatment with oral corticosteroids, were excluded from the analysis. There were 168 patients concurrently taking ICS who were prematurely withdrawn from the studies for various reasons. Significantly fewer patients taking ICS withdrew in the tiotropium (17%) and sal- meterol (19%) groups compared with placebo (27%) (p < 0.05). Similarly, 68 patients not taking ICS treatment did not complete the studies. Of those not taking ICS, significantly fewer patients in the tiotropium group (11%) withdrew compared with those in the placebo group (23%) (p < 0.05). The percentages of patients who withdrew in the salmeterol group (18%) were not significantly dif- ferent from placebo. Overall, adverse events leading to discontinuation from the studies occurred in 9%, 16%, and 18% of ICS patients, and in 4%, 13%, and 15% of patients not using ICS, but these differences were not statistically significant. The main adverse event causing early withdrawal was worsening of COPD (ICS: 6% tio- tropium, 12% salmeterol, 12% placebo; non-ICS groups: 3%, 6%, and 10%, respectively). Lung function responses Patients treated with ICS Compared with placebo, patients in both the tiotropium and salmeterol groups concurrently treated with ICS achieved sta- tistically signiﬁcant improvements in FEV1 and FVC (trough, peak and AUC0–3 hours) throughout the study (p 0.001, all comparisons at day 15, 57, 113, and 169) (Figure 1 and Table 3a). After 169 days of treatment, the mean + SE im- provement above placebo in trough FEV1 was 110 + 20 mL for tiotropium (p < 0.001) and 80 + 20 mL for salmeterol (p < 0.001) (Table 3a). The numerical difference (10–30 mL) in trough FEV1 between tiotropium and salmeterol was not 160 signiﬁcant at 6 months (p = 0.11 tiotropium vs salmeterol). Tiotropium was superior in improving trough FVC of pa- tients using ICS from day 57 to 169 (p < 0.05, tiotropium vs salmeterol), and differences between active treatments were also statistically signiﬁcant in favor of tiotropium for peak FEV1 and FVC at the ﬁrst dose and at all subsequent visits (p < 0.05, tiotropium vs salmeterol). In addition, FEV1 AUC0–3,as well as FVC AUC0–3were consistently statistically signiﬁcant in favor of tiotropium (p < 0.01, tiotropium vs salmeterol) from day 15 to day 169. Patients not treated with ICS In those patients not taking ICS, the patterns of spirometric response according to treatment group were similar to those observed with the ICS group (Figure 2 and Table 4a). How- ever, because of the smaller sample size (n = 360) relative to the ICS treated group (n = 796), there was insufﬁcient power to detect statistically signiﬁcant differences between bronchodilators in this group of patients. Dyspnea responses Patients treated with ICS The mean baseline dyspnea index (BDI) of the patients using ICS was 6.2–6.3 in the various treatment groups, reflecting a moderate level of dyspnea for all patients at the start of the study (Table 1a). Compared with pla- cebo, ICS patients treated with tiotropium demonstrated a clinically and statistically significant improvement in TDI focal score throughout the study (p < 0.01 at all time points). Patients treated with salmeterol also achieved a statistically significant improvement in TDI focal score compared with placebo, only after 8 weeks of therapy (p < 0.01), but failed to sustain this improvement com- pared with placebo at 16 and 24 weeks. The difference in TDI focal score between the tiotropium and salmeterol groups was not statistically significant. However, only in patients treated with tiotropium did the improvement in TDI reach the minimal clinically important difference of 1 unit after 169 days of treatment (Table 3a). Patients not treated with ICS In patients not being treated with ICS, the mean improve- ment in dyspnea as measured by the TDI focal score after 169 days of treatment was above the minimal clinically important difference of 1.0 for both tiotropium and sal- meterol, but only in patients receiving tiotropium was this difference statistically significantly different from placebo (Table 4a). International Journal of COPD 2007:2(2)