A multicenter study of nebulized bronchodilator solutions in chronic obstructive pulmonary disease. Results of a multicenter study of nebulized inhalant bronchodilator solutions. Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials. Asthma control during and after cessation of regular beta 2-agonist treatment. Effect of three different bronchodilators during an exacerbation of chronic obstructive pulmonary disease. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Nebulized bronchodilators for outpatient management of stable chronic obstructive pulmonary disease. Severe exacerbations of COPD and asthma. Incremental benefit of adding ipratropium to usual therapy. Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease.
A multicenter, 85-day, double-blind, randomized study was conducted to compare the effects of a single-dose and chronic inhalation of ipratropium bromide solution (500 micrograms) to the beta-adrenergic agonist metaproterenol (5% solution, 15 mg) in patients with chronic obstructive pulmonary disease (COPD). Patients were required to have a relatively stable, moderately severe COPD, forced expiratory volume in 1 second (FEV1) < 65% of predicted normal, FEV1 <70% of forced vital capacity (FVC), and a smoking history of > 10 pack-years. Following a 2-week baseline period, patients were randomized into either the ipratropium bromide (106 patients) or metaproterenol (107 patients) study groups. Pulmonary function testing was performed on days 1, 43, and 85. Secondary efficacy variables examined included peak expiratory flow rates, physician's global evaluation, quality of life, COPD symptom score, and use of concomitant medications. FEV1 was comparable between the two groups on day 1 (1.00 and 1.02 liters, ipratropium bromide vs metaproterenol, respectively; p = nonsignificant). The baseline FEV1 increased significantly in the ipratropium bromide group between day 1 and 43 by 10% (from 1.00 to 1.10 liters, p < 0.002) and remained 7% elevated on day 85 (1.07 liters) compared to day 1 (p < 0.02); it did not change in the metaproterenol group across all three test days. A clinically significant (> 15%) mean FEV1 response was observed on each of the 3 test days following drug inhalation in both treatment groups. The median duration of action was similar between groups (5 hours) on test day 1, but on day 85 the median duration for ipratropium bromide was r.5 hours compared to 3.0 hours for metaproterenol (p < 0.04). The secondary efficacy variables were uniformly better in the ipratropium bromide than the metaproterenol group. Side effects were infrequent and generally mild in both groups. These data suggest that the availability of a high-dose ipratropium bromide solution offers a safe and effective means of producing prolonged bronchodilation in patients with COPD. The efficacy, persistence of bronchodilator action, and safety of the quaternary ammonium anticholinergic agent, ipratropium bromide (500 microgram), and placebo were compared when each was added in solution form to the beta-adrenergic agonist solution, metaproterenol sulfate (15 mg), and administered three times daily for 12 weeks to a total of 213 patients with chronic obstructive pulmonary disease (COPD). Subjects had a mean forced expiratory volume in 1 second (FEV1) of approximately 1 liter (37% of predicted) and were permitted to use nonanticholinergic therapy for COPD throughout the trial. The study was a randomized, double-blind, 85-day, parallel-group, eight-center study. On a 3 test days, 1, 43, and 85, mean peak responses for FEV1 and forced vital capacity and mean area under the curve were significantly higher for the iprathropium bromide-metaproterenol combination than for metaproterenol only. Duration of action was also significantly longer for the combination therapy than for the beta-agonist alone on test days 1 and 43. Neither treatment regimen produced an demonstrable effect on daily morning peak expiratory flow rates, reported respiratory symptoms, or quality of life. Both treatment regimens were similarly well tolerated with a comparable frequency of adverse events. These results suggest that the combination of iprathropium bromide and metaproterenol inhalation solutions offers a potential therapeutic advantage to patients with symptomatic COPD over nebulized metaproterenol alone without the risk of increased side effects. Bronchodilators are routinely used in the long-term therapy of patients with COPD. These drugs are generally evaluated for their short-term bronchodilatory effects. Long-term and short-term benefits, however, are not necessarily equivalent. We evaluated, therefore, the effects of extended therapy with inhaled bronchodilators in patients with COPD.
                Data were obtained from seven clinical trials in which ipratropium was compared with a beta-agonist over a 90-day treatment interval. This comprised all the available data from clinical trials performed for registration of ipratropium and included 1,445 evaluable patients. Results of pulmonary function tests were evaluated prior to and after short-term administration of bronchodilator both before and after the 90-day treatment period. In addition, data were analyzed after stratification for smoking status and for lung function.
                Long-term therapy with ipratropium resulted in improvement in baseline (ie, before short-term administration of bronchodilator) FEV1 (28 mL; p < 0.01) and FVC (131 mL; p < 0.01), while long-term therapy with beta-agonist resulted in no significant change in FEV1 (1-mL decline; p > 0.2) or in FVC (20-mL improvement; p > 0.2). The improvement in baseline function in the ipratropium-treated patients was most marked in ex-smokers (average duration of abstinence, 9 years). Short-term administration of ipratropium following the 90-day treatment interval resulted in similar response in average FEV1 (6 mL more improvement after the extended therapy; p > 0.2) and an increased response in average FVC (44 mL more improvement after extended therapy; p < 0.01). In contrast, extended therapy with beta-agonist resulted in significantly less response to the short-term administration of beta-agonist for both FEV1 (49 mL less response; p < 0.0001) and FVC (74 mL less response; p < 0.0001). Assessed as the percentage of patients who achieved a 15% improvement in lung function, most patients responded to both treatments both before and after extended therapy. There was, however, a significant decline in the number of patients who responded after extended therapy, and this was more marked for the beta-agonist treated group.
                Long-term benefits of bronchodilator therapy appear to differ from short-term effects. Extended administration of ipratropium appears to be associated with improved baseline lung function and perhaps with improvement in the response to acute bronchodilation. Extended administration of beta-agonist, in contrast, appears to have little effect on baseline lung function, but may decrease response to acute bronchodilation. It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS) This study evaluates the effect of three different bronchodilators (beta 2-adrenergic, anticholinergic and methylxanthine) alone and in randomized sequence, during an exacerbation in thirteen patients with chronic obstructive pulmonary disease. Dose-response curves were obtained for inhaled salbutamol and inhaled ipratropium bromide. The bronchodilator effect of a perfusion of aminophylline was also assessed. When a plateau of bronchodilatation was achieved with one agent, one dose of a second bronchodilator was administered to see whether additional bronchodilation could be achieved. The increments in FEV1 and FVC were similar with the three agents. The addition of a second bronchodilator did not result in significant increments in most of the patients. In at least half of the patients the doses of salbutamol and ipratropium that produced the maximal bronchodilatation were twice that currently employed. Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) is available widely throughout the world except in North America. Previous studies have yielded conflicting results regarding the advantages of combining anticholinergic therapy with sympathomimetic therapy in COPD. We report the results of a 12-week prospective, double-blind, parallel-group evaluation of the use of the following: albuterol, a beta-adrenergic agent; ipratropium, an anticholinergic agent; or a combination of the two, administered by metered-dose inhaler to patients with moderately severe stable COPD. Following baseline studies, 534 patients were given one of the three test bronchodilator preparations to be used at home four times daily in addition to oral theophylline and corticosteroids as required. The doses of the latter two drugs were kept stable. Subjects were tested on days 1, 29, 57, and 85. Analysis of 1-s forced expiratory volume (FEV1) curves on those test days indicated that the combination was superior to either single agent alone in peak effect, in the effect during the first 4 h after dosing, and in the total area under the curve of the FEV1 response. The mean peak percent increases in FEV1 over baseline on the four test days were 31 to 33 percent for the combination, 24 to 25 percent for ipratropium, and 24 to 27 percent for albuterol. The differences between the combination and its components were statistically significant on all test days. The AUC0-4 means for the combination were 21 to 44 percent greater than the ipratropium means and 30 to 46 percent greater than the albuterol means. Similar changes were noted in the forced vital capacity curves. Symptom scores did not change over time and did not differ among the treatment groups. We conclude that the combination of ipratropium and albuterol, when given by metered-dose inhaler to patients with COPD, is more effective than either of the two agents alone. The advantage of the combination is apparent primarily during the first 4 h after administration. The availability of combination therapy by metered-dose inhaler should help to improve patient compliance. The bronchodilator efficacy, safety, and persistence of effect of the anticholinergic agent ipratropium bromide and the beta-adrenergic agonist albuterol, both given by nebulization, were compared in 223 patients with stable, severe chronic obstructive pulmonary disease (COPD). The study was a randomized, double-blind, parallel group trial conducted over 85 days. Patients took the study drugs (either 500 micrograms of ipratropium bromide or 2.5 mg of albuterol) three times daily on an outpatient basis throughout the study. The acute bronchodilator responses to nebulized ipratropium bromide and albuterol were studied on days 1, 43, and 85. The forced expiratory volume in 1 second (FEV1) response was similar for both drugs on day 1 (33% peak increase after ipratropium bromide and 36% peak increase after albuterol). However, albuterol's effect on FEV1 decreased over time. Clinical improvement was noted in both study groups, but the ipratropium bromide group had a greater symptomatic benefit. Patients receiving ipratropium bromide scored higher on a quality-of-life questionnaire evaluating dyspnea, fatigue, emotional function, and mastery. Side effects were relatively infrequent and generally mild for both study drugs. These results show that ipratropium bromide, given by nebulization, is safe and effective in the outpatient treatment of COPD. Single dose studies have assessed the utility of ipratropium bromide alone or with beta agonists in the short- and long-term management of chronic obstructive lung disease and asthma. We performed a randomized, double-blind trial to assess the incremental benefit over 24 hours of adding ipratropium vs placebo to a standardized regimen of medications commonly used in the acute and subsequent hospital management of COPD and asthma. Sixty-eight subjects received nebulized salbutamol, intravenous methylprednisolone, intravenous aminophylline, and antibiotics and were randomized to receive either 80 micrograms of ipratropium or placebo via metered dose inhaler and spacing device with each salbutamol treatment (6 to 8 times per day). Among the 50 patients who completed the study, there were no significant differences between ipratropium and placebo groups with respect to baseline FEV1, FVC, and PaCO2. The improvement of FEV1 from baseline to 24 hours was 294 (SD = 568) ml in the ipratropium group vs 393 (SD = 622) ml in placebo group. Adjusting FEV1 by age, gender, and smoking did not significantly alter the findings. Those with an admission diagnosis of asthma showed larger 24 hour FEV1 responses (487 ml in ipratropium vs 801 ml in placebo) than those with COPD (149 ml ipratropium vs 102 ml in placebo). However, within these two strata, there were no significant differences in FEV1 improvement between ipratropium and placebo groups. This study suggests that if ipratropium is used in the initial emergency treatment of COPD or asthma, it could safely be discontinued by 24 hours in order to reduce the cost and complexity of therapy. A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital capacity (FVC) and 25-75% forced expiratory flow (FEF25-75%). On test day 1 the peak increase in FEV1 for the ipratropium bromide + albuterol subjects was 26% greater than those on placebo + albuterol (p < 0.003). The area under the 8-hour FEV1 curve was 64% greater in those given ipratropium bromide on test day 1 (p < 0.0002). Similar increases were seen in FVC and FEF25-75%. The peak improvements in FEV1 and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.
There was no evidence that the degree of bronchodilation achieved with ipratropium bromide was greater than that using a short-acting beta2-agonist. The combination of a beta2-agonist and ipratropium did not appear to increase the effect on FEV1 more than either used alone.