Table 4 Outcomes in patients not using ICS (tiotropium: n = 135; salmeterol: n = 120; placebo: n = 135) (a) Treatment response (spirometry,TDI, and SGRQ score) after 169 days Tiotropium vs placebo 150 + 30* FEV1 220 + 30* † 220 + 30* † Salmeterol vs placebo 110 + 30* 150 + 30* 150 + 30* Trough Peak AUC 0-3 Trough Peak AUC 0-3 FVC TDI focal score SGRQ total score *p < 0.05 vs placebo; †p < 0.05, tiotropium vs salmeterol. (b) Treatment response (exacerbations) after 169 days % patients with >1 exacerbation Number of exacerbations/patient-year (% reduction vs. placebo) Exacerbation days/patient-year *p < 0.05 vs placebo. 190 + 50* 300 + 60* 290 + 50* 1.35 + 0.5* –2.05 + 1.7 Tiotropium 17% 0.52* (–48%) 8.0* Tiotropium or salmeterol plus treatment with ICS for COPD 130 + 50* 200 + 60* 200 + 50* 1.02 + 0.55 –1.66 + 1.8 Salmeterol 26% 0.74 (–36%) 18.4 Placebo 27% 1.00 16.9 ﬂuticasone had signiﬁcantly fewer hospitalizations (Aaron et al 2007). Recent prospective studies have observed a positive impact of adding an ICS to a long-acting beta2-adrenergic on spirometric response, health status, and COPD exacerbations (Calverley et al 2003a, 2007; Mahler et al 2002; Szafranski et al 2003). The effect of this treatment strategy on mortal- ity in COPD has also been recently studied, but although an absolute reduction in mortality of 2.6% was observed, with the combination therapy, this did not achieve statistical sig- niﬁcance (Calverley et al 2007). Prospective trials designed to assess the effect of adding an ICS to an anticholinergic bronchodilator alone have not been published. The role of ICS without long-acting bronchodilators in the treatment of COPD continues to be a matter of debate. Many patients with COPD appear to be steroid-resistant based on in vitro studies (Barnes et al 2004, 2005; Culpitt et al 2003). However, because clinical trials usually report only mean treatment responses, it could be postulated that ICS are beneﬁcial in COPD, but only for certain sub-sets of patients who are not otherwise identiﬁed in clinical trials. For example, ICS may have beneﬁcial effects by modulating inﬂammation driven by eosinophils when present (Pizzichini et al 1998; Leigh et al 2006), or mast cells (Hattotuwa et al 2002). ICS have also been shown to reduce some of the systemic markers of inﬂammation in COPD patients (Sin et al 2004) and to modulate oxidative damage in COPD (Sadowska et al 2005). International Journal of COPD 2007:2(2) The parasympathetic nervous system is felt to be the main determinant of airway smooth muscle tone (Douglas et al 1979; Cazzola et al 1997; Barnes 2004; Gross 2004) and there is evidence that cholinergic tone is increased in COPD (Gross and Skorodin 1984; Gross et al 1989). It has therefore been suggested that COPD could be more effectively treated with anticholinergic drugs than by sympathomimetics (Barnes 2004; Gross 2004). Clinical data about the co-administration of tiotropium with inhaled long-acting beta2-adrenergics is also beginning to emerge and it would seem that such additivity does indeed occur (Cazzola et al 2004a, b; Tashkin and Cooper 2004; van Noord et al 2000, 2005, 2006). In summary, the present post-hoc analysis of two large-scale trials, comparing the M3 receptor antagonist tiotropium and the long-acting beta2-adrenergic salme- terol to placebo in COPD subgroups with or without con- current treatment with ICS, confirms that both, tiotropium and salmeterol are effective bronchodilators. Clinically important endpoints such as dyspnea, health status and frequency of exacerbations were also observed and were superior with tiotropium compared to salmeterol, regard- less of concomitant ICS use. While the direct effect of ICS on COPD outcomes was not studied in this post-hoc analysis, we conclude that concurrent use of ICS neither augmented nor impeded the relative efficacy of the two bronchodilators tested. 165