Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study.
Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied.
                To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone.
                Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006.
                27 academic and community medical centers in Canada.
                449 patients with moderate or severe COPD.
                1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol.
                The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics.
                The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo.
                More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists.
                Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041. Combined use of beta(2)-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to compare combination treatment with formoterol (FORM) plus tiotropium (TIO) versus treatment with TIO alone in patients with COPD. In this active-controlled, double-blind, multicenter trial, a total of 255 subjects with diagnosed COPD were randomized to 12 weeks of either a combination of FORM 12 microg twice-daily plus TIO 18 microg once-daily in the morning (QD AM) or monotherapy with TIO 18 microg QD AM. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing (FEV(1) AUC(0-4h)). Significantly greater improvements in the FEV(1) AUC(0-4h) were seen with FORM + TIO (n = 116) versus TIO (n = 124) at all time points. The increase in FEV(1) 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO (p < 0.001). At endpoint, FEV(1) AUC(0-4h) increased 340 mL with FORM + TIO versus 170 mL with TIO (p < 0.001). Improvements in trough FEV(1) with FORM + TIO versus TIO were 180 mL and 100 mL, respectively (p < 0.01). Significantly greater reductions from baseline in symptom scores (p < 0.05) and daytime albuterol use (p < 0.04) were seen at endpoint with combination FORM + TIO versus TIO monotherapy. Both treatments were well tolerated. This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone. Although guidelines recommend combining long-acting bronchodilators in COPD, data are limited. We examined the clinical efficacy and safety of formoterol, tiotropium and the combination in patients with COPD. Eight hundred and forty-seven patients with COPD (mean FEV(1) 52% predicted; FEV(1)/FVC 53%) were randomized to receive one of the following four treatments for 24 weeks: formoterol 10 microg b.i.d. plus tiotropium 18 microg o.d.; formoterol 10 microg b.i.d.; tiotropium 18 microg o.d., or placebo. The study was partially blinded (formoterol and placebo). For the primary endpoint, FEV(1) 2h post-dose after 24 weeks, there were small differences in favour of the combination therapy versus formoterol (0.07 L, p=0.044) or tiotropium (0.06 L, p=0.066). All three treatments were superior to placebo (p<0.001). The combination was statistically superior to monotherapy for: the primary endpoint (p=0.044 vs. formoterol); FEV(1) 5 min after the first dose (p<0.001) and at 12 weeks (p<0.05 vs. tiotropium); and peak expiratory flow averaged over the first 6 weeks (p<0.001 vs. both). The three active treatments were significantly more effective than placebo for secondary endpoints: COPD-related 'bad days', symptoms, use of rescue medication and peak expiratory flow, and aspects of health-related quality of life. The overall incidence of adverse events was similar with all active treatments, although COPD-related adverse events were more common with tiotropium. Combined bronchodilator therapy may be a valuable treatment option for patients with COPD.
The results from this review indicate a small mean improvement in health-related quality of life for patients on a combination of tiotropium and long-acting beta2-agonist compared to tiotropium alone, but it is not clear how clinically important this mean difference may be. Hospital admission and mortality have not been shown to be altered by adding long-acting beta2-agonists to tiotropium. There were not enough data to determine the relative efficacy and safety of tiotropium plus long-acting beta2-agonist compared to long-acting beta2-agonist alone. There were insufficient data to make comparisons between the different long-acting beta2-agonists when used in addition to tiotropium.