Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Efficacy and safety of tiotropium in COPD patients in primary care--the SPiRiva Usual CarE (SPRUCE) study. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Cost effectiveness of leukotriene receptor antagonists versus long-acting beta-2 agonists as add-on therapy to inhaled corticosteroids for asthma: a pragmatic trial.
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. 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 examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease (COPD), and to establish previously reported symptomatic efficacy.
                Randomized, double-blind, placebo-controlled, parallel-group study.
                Twelve outpatient investigational centers in the United States.
                One hundred ninety-six patients with COPD.
                Patients received either tiotropium 18 mug once/day or placebo, delivered by the HandiHaler device.
                Electrocardiography (predose and 5 min postdose) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo. Efficacy measures (spirometry, global COPD ratings, scores on the EuroQol Health Questionnaire [EQ-5D], albuterol inhaler as needed) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies. Mean baseline forced expiratory volume in 1 second (FEV1) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups. No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring. Frequency of premature beats and mean maximal changes in PR, QRS, QT, QTcB, and QTcF intervals were similar in both groups. No patients developed new-onset QT or QTc intervals greater than 500 msec, and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec, 30-60 msec, or greater than 60 msec. At 12 weeks, predose and postdose improvements in FEV1 were 184 and 265 ml, respectively, with tiotropium versus placebo (p<0.001). Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium (p<0.05); as-needed albuterol was reduced by 25% relative to placebo (p<0.05).
                Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate, rhythm, QT intervals, or conduction. A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD).
                288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV(1)) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 microg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 microg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV(1) and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV(1) and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92.
                During treatment tiotropium achieved a significantly greater improvement than ipratropium (p<0.05) in trough, average, and peak FEV(1) levels and in trough and average FVC levels. The trough FEV(1) response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI -0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0. 07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV(1) than ipratropium starting three hours after inhalation (p<0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p<0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p<0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients).
                Tiotropium in a dose of 18 microg inhaled once daily using the HandiHaler was significantly more effective than 40 microg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD. Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M(1) and M(3) receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV(1) = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 microg tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV(1) and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV(1) and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 microg delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 microg, and advantages suggested by the safety profile at doses below 36 microg in this study, a dose of 18 microg once daily was selected for use in long-term studies of the safety and efficacy of tiotropium. 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. 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. In patients with COPD, changes in inspiratory capacity (IC) have shown a higher correlation to patient-focused outcomes, such as dyspnea with exercise, than other standard spirometric measurements. Changes in IC reflect changes in hyperinflation. Tiotropium is a once-daily inhaled anticholinergic that has its effect through prolonged M3 muscarinic receptor antagonism and has demonstrated sustained improvements in spirometric and health outcomes. We sought to evaluate changes in resting IC and lung volumes after long-term administration of tiotropium.
                To evaluate the effect of tiotropium, 18 micro g/d, on IC, a 4-week, randomized, double-blind, placebo-controlled study was conducted in 81 patients with stable COPD. At each of the visits (weeks 0, 2, and 4) FEV(1), FVC, IC, slow vital capacity (SVC), and thoracic gas volume (TGV) were measured prior to study drug (- 60 and - 15 min) and after study drug (30 min, 60 min, 120 min, and 180 min).
                Mean age was 64 years; 62% were men. Mean baseline FEV(1) was 1.12 L (43% predicted). The mean differences (tiotropium - placebo) in FEV(1) trough (morning before drug), peak, and area under the curve over 3 h values (adjusted for baseline and center differences) at week 4 were 0.16 L, 0.22 L, and 0.22 L, respectively (p < 0.01 for all); differences in IC for these variables were 0.22 L, 0.35 L, and 0.30 L (p < 0.01 for all). Differences in TGV were - 0.54 L, - 0.60 L, and - 0.70 L, respectively (p < 0.01 for all). The percentage improvement in area under the curve above baseline with tiotropium was similar among FEV(1) and lung volumes (FEV(1), 18%; FVC, 20%; SVC, 16%; IC, 16%; TGV, 14%).
                Observed improvements in IC and reductions in TGV with once-daily tiotropium reflect improvements in hyperinflation that are maintained over 24 h. Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS).
                To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS.
                An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society.
                Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives.
                On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs.
                UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.
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.