visit of 60% predicted (calculated according to European Commission for Steel and Coal criteria and using predicted values from Morris) (Morris et al 1988; Quanier et al 1993) and screening FEV1/FVC <0.70. Patients were required to have a smoking history of 10 pack-years, and be able to perform all study related tests including acceptable pulmonary function tests and maintenance of daily diary card records. The main exclusion criteria were clinically signiﬁcant diseases other than COPD which, in the opin- ion of the investigator, had the potential to impact on the patient’s ability to participate in the study, as well as known symptomatic prostatic hypertrophy, bladder neck obstruc- tion, or narrow-angle glaucoma. Additionally, patients with a history of asthma, allergic rhinitis, or atopy or who had a total blood eosinophil count of 600/μL, patients requiring use of supplemental oxygen therapy for more than 1 hour per day, a history of life-threatening pulmonary obstruction, a history of cystic ﬁbrosis or bronchiectasis, thoracotomy with pulmonary resection, upper respiratory infection in the 6 weeks prior to the screening visit or during the run-in period were also excluded. Treatment with long-acting beta2-adrenergics and anti- cholinergics, other than study treatment, was discontinued at randomization. Patients were allowed to continue treatment with stable doses of ICS, theophyllines, and short-acting beta2-adrenergic medication as scheduled prior to the study. Patients using oral corticosteroids within or 6 weeks prior to the study were not included in the analysis. Efﬁcacy evaluations Pulmonary function testing was conducted prior to the start of therapy at 60 and 10 minutes pre-dose at the randomiza- tion visit and at 30 minutes, 60 minutes, 2, and 3 hours post-dosing. As only one study collected spirometry after 3 hours during clinic visits, only spirometry up to 3 hours post-dosing has been considered for the present analysis. Pulmonary function tests were repeated at the same time intervals after 2, 8, 16, and 24 weeks of therapy. The broncho- dilator efﬁcacy of tiotropium and salmeterol was primarily determined by trough FEV1 and FVC response, which was deﬁned as the change from baseline at the end of the dosing interval, approximately 24 hours post drug administration for tiotropium and approximately 12 hours post drug adminis- tration for salmeterol. Baseline values were the mean of the two pre-treatment values measured in the morning of the randomization visit prior to administration of the ﬁrst dose of study medication. Other spirometric parameters analyzed included the peak response and AUC0–3 response. International Journal of COPD 2007:2(2) Tiotropium or salmeterol plus treatment with ICS for COPD Patient and investigator administered questionnaires, including the St. George’s Respiratory Questionnaire (SGRQ) (Jones et al 1991) and Mahler’s Dyspnea Index (Mahler et al 1984), were administered at baseline and after 8, 16, and 24 weeks of therapy. Requirement for as-needed salbutamol (albuterol) was monitored throughout the study period. Exacerbations were reported as adverse events and were deﬁned as a complex of respiratory symptoms (ie, at least one of cough, sputum, dyspnea, wheeze, chest dis- comfort) lasting at least 3 days and usually associated with a therapeutic intervention. Statistical analysis Data from both studies were pooled for analysis. Patients receiving ICS at the time of randomization were separately analyzed from those patients without concurrent ICS treat- ment. For the spirometry measurements, SGRQ total score and TDI focal score, analysis of covariance was performed with the baseline as a covariate. In order to include the same patients at each time point in the 3 hour spirometry sum- maries, missing values were estimated using other values recorded for the patient on that test day. Linear interpolation between the two adjacent measurements was used to estimate random, middle, and missing spirometry measurements. For values at the end of the proﬁles that were missing because rescue medication was taken, the minimum observed FEV1 value on that test day was used as the estimate. The last available value was used as the estimate for data that were missing for other reasons. For the SGRQ, missing individual questions were imputed according to the guidelines established by the questionnaire developer. Data from missing SGRQ question- naires and TDI questions were imputed using last observa- tion carried forward, unless the patient discontinued due to worsening of COPD, in which case the least favorable observation was carried forward. The numbers of exacer- bations over the 6 months period were compared across treatment groups using Poisson regression with logarithm of exposure as offset and correction for overdispersion as recommended by Suissa (2006). Unless otherwise speciﬁed, data are presented as means ± standard error. Statistical signiﬁcance was considered at p < 0.05. Results A total 796 of 1207 patients (66%) in the two trials were concurrently treated with ICS. Demographic data and baseline characteristics for the treatment groups were 159