Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Assessing the Impact of Tiotropium on Lung Function and Physical Activity in GOLD Stage II COPD Patients who are Naïve to Maintenance Respiratory Therapy: A Study Protocol. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. [Combination of inhaled salmeterol/fluticasone and tiotropium in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial]. The Canadian Optimal Therapy of COPD Trial: design, organization and patient recruitment. Efficacy and safety of tiotropium in COPD patients in primary care--the SPiRiva Usual CarE (SPRUCE) study. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD.
Tiotropium, a novel once-daily inhaled anticholinergic, has been shown to improve lung function over a 24-h period. In order to extend these findings, health-outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease (COPD) patients. Spirometric results, peak expiratory flow rate (PEFR), salbutamol use and effects on dyspnoea, health-related quality of life and COPD exacerbations were assessed in two identical 1-yr randomized double-blind double-dummy studies of tiotropium 18 microg once daily (n=356) compared with ipratropium 40 microg q.i.d. (n=179). Screening forced expiratory volume in one second (FEV1) were 1.25+/-0.43 L (41.9+/-12.7% of the predicted value) (tiotropium) and 1.18+/-0.37 L (39.4+/-10.7% pred) (ipratropium). Trough FEV1 at 1 yr improved by 0.12+/-0.01 L with tiotropium and declined by 0.03+/-0.02 L with ipratropium (p<0.001). Significant improvement in PEFR, salbutamol use, Transition Dyspnea Index focal score, and the St George's Respiratory Questionnaire total and impact scores were seen with tiotropium (p<0.01). Tiotropium reduced the number of exacerbations (by 24%, p<0.01), and increased time to first exacerbation (p<0.01) and time to first hospitalization for a COPD exacerbation (p<0.05) compared with ipratropium. Apart from an increased incidence of dry mouth in the tiotropium group, adverse events were similar between treatments. Tiotropium was effective in improving dyspnoea, exacerbations, health-related quality of life and lung function in patients with chronic obstructive pulmonary disease, and exceeds the benefits seen with ipratropium. The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease. Physical activity status is increasingly recognized as a reliable predictor of mortality and hospitalization in patients with chronic obstructive pulmonary disease (COPD). The reduction in physical activity occurs earlier in the clinical course of COPD than previously appreciated, possibly arising from breathlessness, reduced exercise tolerance, and adoption of a more sedentary lifestyle. To date, no clinical trial has evaluated the impact of pharmacotherapy on both lung function and physical activity. We recently designed a study that evaluates the impact of tiotropium (a once-daily inhaled anticholinergic) on lung function and physical activity in a maintenance/treatment-naïve Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II COPD cohort. Previous studies have demonstrated that tiotropium improves lung function and exercise tolerance; whether these benefits translate into improvements in physical activity is the focus of the current work. Here we describe the rationale and challenges in developing and implementing this study and review its unique features and novel design, including: utility of direct activity monitoring in multicenter clinical trials; importance of behavioral-modification techniques (including motivational interviewing to improve patient self-efficacy and adherence for a healthy, more active lifestyle); utility of individualized activity plans that provide an integrated approach with pharmacotherapy and behavioral modification to help patients achieve a more active lifestyle. Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy. To observe the efficacy of combination therapy with inhaled salmeterol/fluticasone and tiotropium in reducing the frequency of acute episodes of symptom exacerbation and improving lung function and health status in chronic obstructive pulmonary disease (COPD).
                One hundred and twenty-six patients (M/F: 92/34) with COPD were treated in a randomised, parallel-group, controlled study with salmeterol/fluticasone (50/250 microg) twice daily and tiotropium 18 microg once daily (n = 33, M/F: 23/10); salmeterol/fluticasone (50/250 microg) twice daily (n = 32, M/F: 24/8); or tiotropium 18 microg once daily (n = 32, M/F: 23/9) for 12 months. Patients in the blank control group (n = 29, M/F: 22/7) did not receive any inhaled anticholinergic drugs, long-acting beta(2) agonists or glucocorticoid therapy. Intention-to-treat analysis (n = 161) and per-protocol analysis (n = 126, age 45 - 71 years) were performed.
                Three active treatments significantly improved symptoms and health status. The use of rescue medication in the combination group [1 (0 - 7) time, 95% CI] was significantly decreased compared with those in the blank group [2 (0 - 29) times], salmeterol/fluticasone alone [2 (0 - 13) times], tiotropium alone [1 (0 - 11) time], F = 4.914, P < 0.01. The frequency of exacerbations in the combination group was (0.7 +/- 0.5) time, significantly lower than that in the blank group [(1.5 +/- 0.9) times], salmeterol/fluticasone alone [(1.2 +/- 0.6) times], and tiotropium alone [(1.1 +/- 0.5) times], F = 8.513, P < 0.01. The FEV(1) in the combination group after the trial was (1.19 +/- 0.03) L, significantly improved compared to that before treatment (1.09 +/- 0.04) L, a 9.5% increase, which was greater than the blank (0.9%), tiotropium alone (8.2%) and salmeterol/fluticasone alone (6.3%), t = -5.024 to -15.58, P < 0.01.
                Combination therapy with salmeterol/fluticasone and tiotropium leads to better control of symptoms and improved lung function, with no greater risk of side-effects, as compared to salmeterol/fluticasone or tiotropium alone in the treatment of COPD. There are no published studies that have assessed whether adding long-acting beta 2-agonist bronchodilators and/or inhaled steroids to chronic therapy with tiotropium would provide additional clinical benefit to patients with moderate to severe chronic obstructive pulmonary disease (COPD).
                The Canadian Optimal Therapy of COPD Trial is a randomized, prospective, double-blind, placebo-controlled, multicentre trial funded by the Canadian Institutes of Health Research that has been designed to determine which combination of inhaled medications will most effectively prevent exacerbations and optimize disease-specific quality of life in patients with COPD. The trial is the first to evolve from the Canadian Thoracic Society Clinical Trials Group. The study will randomize 432 patients with moderate to severe COPD to one of three parallel treatment arms for 52 weeks: tiotropium and fluticasone/salmeterol; tiotropium and salmeterol; or tiotropium and placebo inhaler. The participants will be allowed to use salbutamol as required throughout the trial period.
                The primary outcome measure is the proportion of patients in the three treatment groups who experienced a respiratory exacerbation within 52 weeks of randomization. Other outcomes that will be assessed over the 52-week trial period will include: changes in disease-specific quality of life and changes in dyspnea, health care use and changes in lung function. A pharmacoeconomic analysis will also be performed to evaluate the cost of these therapies.
                The study commenced recruitment in October 2003. It is currently operating at 22 centres across Canada and has randomized 137 patients during the first four months of recruitment. Recruitment is scheduled to continue until April 2005 or until 432 patients have been randomized.
                The present randomized, placebo-controlled trial offers a unique opportunity to answer the question, what is the best combination of inhaled medications to use for COPD patients? It is hoped that optimal use of inhaled medications will improve patient health and quality of life, reduce patient respiratory exacerbations, and ultimately, reduce health care resource use. Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease (COPD), and typically had included limitation of concomitant medication. In primary care, which is the most common setting for COPD management, many patients may have milder disease, and also may take a broad range of concomitant medication.
                This randomised, placebo-controlled, parallel-group, 12-week, 44-centre study investigated the efficacy (trough forced expiratory volume in 1 second [FEV1] response) and safety of additional treatment with once-daily tiotropium 18 mug via the HandiHaler in a primary care COPD population (tiotropium: N = 191, FEV1 = 1.25 L [47.91% predicted]; placebo: N = 183, FEV1 = 1.32 L [49.86% predicted]). Secondary endpoints included: trough forced vital capacity (FVC) response, weekly use of rescue short-acting beta-agonist, and exacerbation of COPD (complex of respiratory symptoms/events of >3 days in duration requiring a change in treatment). Treatment effects were determined using non-parametric analysis.
                At Week 12, median improvement in trough FEV1 response with tiotropium versus placebo was 0.06 L (p = 0.0102). The improvement was consistent across baseline treatment and COPD severity. Median improvement in FVC at 2, 6 and 12 weeks was 0.12 L (p < 0.001). The percentage of patients with > or =1 exacerbation was reduced (tiotropium 9.5%; placebo 17.9%; p = 0.0147), independent of disease severity. Rescue medication usage was significantly reduced in the tiotropium group compared with placebo. Adverse event profile was consistent with previous studies.
                Tiotropium provides additional benefits to usual primary care management in a representative COPD population.
                The identifier is: NCT00274079. 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. Patients with chronic obstructive pulmonary disease (COPD) frequently develop exacerbations, leading to major clinical and health resource use ramifications.
                To prospectively evaluate the effectiveness of a long-acting inhaled anticholinergic bronchodilator, tiotropium, in reducing COPD exacerbations and exacerbation-related health care utilization.
                Randomized, double-blind study.
                26 Veterans Affairs medical centers.
                1829 patients with moderate to severe COPD (mean baseline FEV(1), 36% predicted).
                Once-daily tiotropium (18 microg) or placebo for 6 months. Patients otherwise received usual care, except for other anticholinergic bronchodilators.
                The coprimary end points were the percentage of patients with a COPD exacerbation and the percentage of patients with a COPD-related hospitalization.
                Tiotropium significantly reduced the percentage of patients experiencing 1 or more exacerbations compared with placebo (27.9% vs. 32.3%, respectively; difference, -5.7 percentage points [95% CI, -10.4 to -1.0 percentage points]; P = 0.037). Fewer tiotropium patients were hospitalized because of COPD exacerbation (7.0% vs. 9.5%, respectively; difference, -3.0 percentage points [CI, -5.9 to -0.1 percentage points]; P = 0.056), although this difference was of borderline statistical significance. Analysis of secondary outcomes indicates that tiotropium may lengthen the time to first COPD exacerbation (P = 0.028) and reduce health care utilization for exacerbations, including the frequency of hospitalizations (P = 0.047), unscheduled clinic visits (P = 0.019), and days of antibiotic treatment (P = 0.015). Tiotropium did not statistically significantly reduce all-cause hospitalization rates.
                Trial participants were enrolled from 1 health care system, and 99% were men. The follow-up period extended for only 6 months.
                Tiotropium reduces COPD exacerbations and may reduce related health care utilization in patients with moderate to severe COPD. 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.
To date there is uncertainty regarding the long-term benefits and risks of treatment with tiotropium in addition to inhaled corticosteroid and long-acting beta2-agonist combination therapy on mortality, hospitalisation, exacerbations of COPD and pneumonia. The addition of combination treatment to tiotropium has shown improvements in average health-related quality of life and lung function.