A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.

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.

The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group.

STUDY OBJECTIVE: To compare the bronchodilator efficacy and safety of tiotropium and placebo. DESIGN: A 3-month, randomized, double-blind, placebo-controlled, multicenter trial. SETTING: Outpatient. PATIENTS: Four hundred seventy patients with stable COPD (mean FEV(1) = 38.6% predicted). INTERVENTIONS: Tiotropium 18 microg (N = 279) or placebo (N = 191) given once daily via a lactose-based dry-powder inhaler device. MEASUREMENTS AND RESULTS: Spirometry was evaluated on days 1, 8, 50, and 92. Data were expressed as the mean trough (ie, before morning dose; 23 to 24 h after previous dose) and average response observed in the 3 h after the dose was received. Tiotropium produced significant improvement in trough FEV(1) and FVC, averaging 12% greater than baseline on day 8; these improvements were maintained on days 50 and 92. The average postdose FEV(1) was 16% greater than baseline on day 1 and 20% greater than baseline on day 92; FVC was 17% greater than baseline on day 1 and 19% greater than baseline on day 92. Tiotropium was significantly more effective than placebo in both trough and average FEV(1) and FVC response (p < 0.001). These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate, as well as a reduction in "as-needed" albuterol use. Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium, and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo. The most common reported adverse event after tiotropium was dry mouth (9.3% vs 1.6% relative to placebo; p < 0.05). CONCLUSIONS: These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD.

Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease.

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.

The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD.

STUDY OBJECTIVES: To determine whether the combination of ipratropium bromide and albuterol results in greater and more consistent pulmonary function test (PFT) response rates than ipratropium bromide or albuterol alone in patients with COPD. DESIGN: Retrospective review of two recently completed 3-month, randomized, double-blind, parallel, multicenter, phase III trials. SETTING: Outpatient. PATIENTS: A total of 1,067 stable patients with COPD. INTERVENTIONS: Ipratropium bromide (36 microg qid), albuterol base (180 microg qid), or an equivalent combination of ipratropium bromide and albuterol sulfate (42 microg and 240 microg qid, respectively). MEASUREMENTS AND RESULTS: PFT response rates were analyzed using 12% and 15% increases in FEV1 compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEV1 was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p < 0.05; all comparisons within 30 min). In addition, a 15% or more increase in FEV1 was seen in > 80% of patients who received the combination of ipratropium and albuterol sulfate during the initial PFT and continued to be observed 3 months after initial testing. CONCLUSIONS: Use of a combination of ipratropium bromide and albuterol sulfate is superior to the individual agents in identifying PFT reversibility in patients with COPD.

Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD.

STUDY OBJECTIVE: To conduct a post hoc pharmacoeconomic evaluation of two double-blind, randomized, prospective, parallel group studies comparing the long-term efficacy and safety of ipratropium combined with albuterol in a single inhalational canister against either bronchodilator agent alone in patients with COPD. PATIENTS: One thousand sixty-seven patients with COPD. METHODS: The dose of each bronchodilator was two puffs four times a day (42 microg of ipratropium bromide, 240 microg of albuterol sulfate). Pulmonary function testing was performed on days 1, 29, 57, and 85 of treatment. Outcomes, health-care resource consumption, and costs were compared for the three treatment groups over the 85-day study period. A total of 1,067 patients were randomized in the two studies (albuterol alone, n = 347; ipratropium alone, n = 362; albuterol plus ipratropium, n = 358). RESULTS: Improvement in FEV1 and area under the FEV1 response-time curve from time 0 to 4 h (FEV1AUC0-4) was significantly greater for the combination of albuterol plus ipratropium than either agent alone on all test days. Compared with albuterol, patients receiving ipratropium and ipratropium plus albuterol experienced significantly fewer COPD exacerbations and patient-days of exacerbation. In addition, the increased frequency of exacerbations observed in the albuterol group was associated with a significant increase in the number of patient hospital days and antibiotic and corticosteroid use. As a result, the total cost of treatment over the study period was significantly less for ipratropium ($156 per patient) and ipratropium plus albuterol ($197 per patient) than for albuterol ($269 per patient). Increased cost-effectiveness, defined as total estimated treatment cost per mean change in FEV1AUC0-4, was observed in both treatment arms containing ipratropium. CONCLUSIONS: The inclusion of ipratropium in a pharmacologic treatment regimen is associated with a lower rate of exacerbations in COPD. The result is lower total treatment costs and improved cost-effectiveness.

Analysis of inhaled corticosteroid and oral theophylline use among patients with stable COPD from 1987 to 1995.

STUDY OBJECTIVE: To document temporal usage trends for commonly used respiratory medications in patients with COPD. DESIGN: We retrospectively evaluated baseline concomitant medications of 3,720 patients with COPD enrolled in 10 bronchodilator clinical trials from 1987 to 1995. The proportion of patients in each trial using inhaled corticosteroids, inhaled beta-adrenergics, inhaled anticholinergics, oral theophylline, and oral corticosteroids was analyzed using the Cochran-Armitage trend test. PATIENTS: All patients had stable, moderate-to-severe COPD without evidence of asthma or atopy. Reversibility to beta3-agonists was not a requirement. RESULTS: The percentage of patients using inhaled corticosteroids increased significantly over time (p < 0.001) from 13.2% in 1987 to 41.4% in 1995. The percentage of patients receiving oral theophylline decreased significantly (p < 0.001) over this same time interval (63.4 to 29.0%). In addition, the percentage of patients using oral corticosteroids and the percentage using oral beta-adrenergics decreased moderately (p < 0.05) (30.1 to 16.4% and 11.7 to 4.5%, respectively); the percentage of patients using inhaled anticholinergics increased slowly (p < 0.05) (48.2 to 53.8%). The percentage of patients receiving inhaled beta-adrenergics did not significantly (p > 0.05) change. CONCLUSIONS: The observed changes in use of inhaled corticosteroids and theophylline were not likely related to differences in disease severity or other patient characteristics in the evaluated trials, but related to changing prescribing and COPD management practices.

A comparison of ipratropium and albuterol vs albuterol alone for the treatment of acute asthma.

To evaluate the role of inhaled ipratropium bromide in acute asthma, a double-blind study of 384 emergency department patients compared the effect of the combination of ipratropium and albuterol with that of albuterol alone. Patients were randomized to receive nebulizer treatments with either 2.5 mg of albuterol or 2.5 mg of albuterol mixed with 0.5 mg of ipratropium bromide at entry and at 45 min. Spirometry, vital signs, and oxygen saturation were measured before and at 45 and 90 min following the nebulizer treatments. Serum potassium levels were obtained at entry and 90 min. The two groups did not differ significantly in age (mean +/- SD = 33.4 +/- 9.3 and 32.5 +/- 9.7 years for the albuterol and ipratropium group and the albuterol group, respectively), baseline FEV1 (mean +/- SD = 1.22 +/- 0.42 and 1.25 +/- 0.44 L respectively), or prior use of asthma medications. At 45 min, there were significantly more responders (15% increase in FEV1 over baseline) in the group receiving albuterol and ipratropium compared with albuterol and saline solution (85% and 78%, respectively; p = 0.045), but the median change in FEV1 from baseline did not differ (0.530 L for the albuterol and ipratropium group and 0.420 L for the albuterol and saline solution group; p = 0.347). By 90 min, the percentage of responders did not differ (88% and 89%, respectively), and the median change in FEV1 was 0.680 L for the group receiving albuterol and ipratropium and 0.650 L for the group receiving albuterol and saline solution (p = 0.693). There were no significant adverse events experienced by patients in either group. Furthermore, there were no significant differences in the number of patients requiring additional therapy in the emergency department or hospitalization. We conclude that in this population of inner city asthmatics, we were unable to demonstrate significant additive benefit of nebulized ipratropium bromide to nebulized albuterol.