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. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. The COMBIVENT Inhalation Solution Study Group. Individual results of treatment of COPD with low doses of fenoterol compared with treatment with ipratropium bromide. Nebulized bronchodilators for outpatient management of stable chronic obstructive pulmonary disease. Results of a multicenter study of nebulized inhalant bronchodilator solutions. Inhalation by nebulization of albuterol-ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. A multicenter study of nebulized bronchodilator solutions in chronic obstructive pulmonary disease. Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease. Extended therapy with ipratropium is associated with improved lung function in patients with COPD. A retrospective analysis of data from seven clinical trials.
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. We compared the long-term safety and efficacy of the combination ipratropium bromide (IB) and albuterol sulfate (ALB) inhalation solution with that of each separate component using three-times-daily administration.
                Using a parallel design, we randomized patients to receive 3.0 mg ALB, 0.5 mg IB, or the combination by small-volume nebulizer (SVN) for 85 days. Subjects were allowed to use up to two extra doses of study medication daily for control of symptoms on an as-needed basis. The main efficacy evaluation was the acute pulmonary function response to an aerosol of the maintenance study medication over the course of the investigation. Physician global evaluation, subject quality of life assessments, COPD symptom scores, and twice-daily peak expiratory flow rate (PEFR) were also assessed over the study period.
                Twenty-five centers participated in the investigation.
                We studied 652 patients with moderate to severe COPD.
                Over the course of the study, the acute spirometric response and evening PEFR values with the SVN combination of IB plus ALB were statistically significantly better compared to ALB or IB alone. The quality of life scores, physician global evaluations, symptom scores, and morning PEFR scores were unchanged over the duration of the study in all treatment groups. There was no significant difference in adverse events in the three treatment groups.
                In patients with COPD, maintenance SVN therapy with IB and ALB provides better bronchodilation than either therapy alone without increasing side effects. We compared the effects of 30-day treatments with fenoterol in low doses (4 x 100 mcg) and ipratropium bromide (4 x 40 mcg) on the lung function parameters (LFP), dyspnea and physical capacity of patients with severe chronic obstructive pulmonary disease (COPD) (FEV1 < 35% pred.) and analysed the individual response of patients to the administered therapy. The study included two groups of patients treated with fenoterol (n = 22) and ipratropium bromide (n = 22). The patients were matched by functional characteristics (age: 60 +/- 7 and 57 +/- 9 years; ATS Dyspnea Scale: 2.7 +/- 0.8 and 2.4 +/- 0.9; FEV1%: 25 +/- 7% and 23 +/- 6%; pO2: 62.4 +/- 5.3 mm Hg and 61.0 +/- 9.5 mm Hg; all values mean +/- SD). After 30 days of treatment we measured the lung function parameters (FEV1, FVC), dyspnea indices (ATS dyspnea scale, Borg scale) and the physical capacity of the patients (6-minute walking distance test). The results showed that in an open experiment fenoterol (4 x 100 mcg daily), unlike ipratropium bromide (4 x 40 mcg daily), cannot improve statistically and clinically significantly the lung function parameters, dyspnea and the physical capacity of the group as a whole. However, when the findings were assessed for each patient individually, 32% of the patients proved to have responded positively to the treatment. Therefore efficaciousness of fenoterol in low doses should be determined by assessing the lung function parameters, dyspnea and the physical capacity individually for each patient. 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. 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. Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) potentially can provide increased benefit over single-agent therapy. The objective of this double-blind, randomized, positive-control trial was to determine the effectiveness of an albuterol-ipratropium solution aerosol combination (Dey combination solution, Dey LP, Napa, Calif., USA) compared with solution aerosols of both component medications administered alone in patients with COPD. The trial consisted of a 6-week, 3-period crossover phase followed by a 6-week parallel phase during which patients self-administered study medications by inhalation from a nebulizer. A total of 863 patients were initially randomized to each of the six possible treatment sequences of the three study medications in the crossover phase and received each study medication in turn for a 2-week period. Patients continued to receive the same treatment administered during the last 2-week period of the crossover phase for an additional 6 weeks in the parallel phase. Assessment of 1-second forced expiratory volume (FEV1) curves before and after dosing on the last day of each 2-week period indicated that the combination was superior to either single agent in peak effect and area under the curve up to 8 h after dosing (FEV1-AUC0-8), in both phases of the trial. The use of Dey combination during the crossover phase resulted in 24% more improvement in peak FEV1 than was seen with albuterol alone (p < 0.001), and 37% more than was seen with ipratropium alone (p < 0.001). Similarly, when examining FEV1-AUC0-8, Dey combination resulted in 30% more improvement than was seen with albuterol alone (p < 0.001), and 32% more than was seen with ipratropium alone (p < 0.001). The combination affords a convenient dosing regimen and incorporates enhanced benefit without compromising the safety profile of either component agent. 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. 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. 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.
The available data from the trials included in this review suggest that the advantage of regular long term use of ipratropium alone or in combination with a short-acting beta-2 agonist or over a beta-2 agonist alone are small, if the aim is to improve lung function, symptoms and exercise tolerance. Until further data are available, the strategy of providing a short-acting beta-2 agonist on a PRN basis, and then either continuing with the short-acting beta-2 agonist regularly or conducting an "n of 1" trial of regular beta-2 agonist or regular anticholinergic to determine the treatment that gives the best relief of symptoms (and continuing with it), would seem cost effective. This strategy does need formal evaluation. Patient preference is also important, as is the relative importance of avoiding the use of systemic corticosteroids.