Comparison of Ipratropium Bromide and Albuterol in Chronic Obstructive Pulmonary Disease: A Three-Center Study SHELDON M.D.,
R.
BRAUN,
M.D.,
C&unbia,
Missouri, SHARON
F.
LEVY,
M.D.,
Seventy-two subjects who had severe chronic obstructive pulmonary disease and a history of heavy smoking completed a study to compare the effect of single doses of ipratropium bromide (0.036 mg), albuterol (0.18 mg>, and placebo on the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), heart rate, and blood pressure during a period of 6 hours. During initial testing for reversibility, 40 subjects did not demonstrate a 15% increase in FEV, from baseline after metaproterenol. Ipratropium produced a significantly greater response than albuterol in FEVl at 3, 4, and 5 hours and in FVC at 1, 2, 3, 4, and 5 hours. For the entire 6-hour period, ipratropium produced a 25% greater response than albuterol in FEV, and a 50% greater response in FVC. The difference between the two drugs was even greater between 3 and 6 hours. There were no significant differences between the three treatments as regards adverse reactions, heart rate, and blood pressure measurements. In patients who have chronic obstructive pulmonary disease, ipratropium bromide has apparent benefits over pz agonist therapy, including a longer duration of action. Ipratropium may also be effective when p2 agonists are not effective.
From the Department of Medicine, University of Missouri, Columbia, Missouri; the Medical College of Pennsylvania, VA Medical Center, Philadelphia, Pennsylvania; and the Albany Allergy and Asthma Services, Albany, New York. This study was funded by a grant from Boehringer lngelheim Pharmaceuticals, Inc., Ridgefield, Connect&. Requests for reprints should be addressed to Sheldon R. Braun, M.D., Room MA419, Health Sciences Center, One Hosprtal Drive, Columbia, Missouri 65212.
4A-28s
Philadeipha, Pennsylvania, JAY GROSSMAN,
Albany, New York
October
21, 1991
The American Journal of Medicine
A
nticholinergic therapy provides effective bronchodilation in patients who have chronic obstructive pulmonary disease (COPD)[l-41, and its effect remains stable for a period of 3 months of therapy [5]. The use of the quaternary ammonium anticholinergic compound ipratropium bromide is generally free of major adverse reactions [6] and can be used without fear of “drying” the sputum [‘7]. However, since several bronchodilators are effective in COPD, the exact role of ipratropium in clinical practice is still being determined. An understanding of its effectiveness compared with other bronchodilators is therefore important. In recent years several anticholinergic compounds, including atropine sulfate, atropine methonitrate, and ipratropium, have been tested against other commonly used bronchodilators. Studies have varied considerably as regards the dose of the anticholinergic compound used, the drug chosen for comparison, and the study design. Oral atropine and oral terbutaline produced equal improvement in forced expiratory volume in 1 second (FEV1) and airway resistance in 39 patients who had bronchitis [8]. Compared with isoproterenol, both ipratropium [4] and atropine sulfate [9] produced significant improvement in FEVi, which lasted at least 1 hour. Atropine sulfate produced urinary hesitancy in five of 15 patients, blurred vision in four, and dry mouth in five [9]. In both studies, the time to onset of action for the two drugs was similar, which indicates a rapid onset for both drugs. Comparison with the newer, longer-acting p2 agonists indicates equal, if not better, results from anticholinergic therapy. Starke et al [lo] compared atropine methonitrate, albuterol, a combination of the two drugs, and placebo when each was given for 4 days. They found that the FEVi 12 hours after treatment was greater for atropine methonitrate alone and in combination therapy than for albuterol or placebo. It is not clear whether this represents a 12-hour residual response to therapy. Based on the graphic information presented in the study, atropine methonitrate, either alone or in combination, produced a response that returned to baseline or
Volume 91 (suppl 4A)
OBSTRUCTIVE
below baseline within 4 hours of drug administration. The general impression gained by a review of the literature indicates that anticholinergic compounds produce an increase in FEVi or other markers of airway function that is equal to that of p2 agonists at 15 minutes to 2 hours and greater at later time points [1,4,5,9,11-131. With isoproterenol the bronchodilator effect decreases after 1 hour. Metaproterenol has been well studied for up to 6 hours after administration. There seems to be a greater response to ipratropium than to metaproterenol during the last 3-4 hours [5]. Compared with albuterol [1,13], ipratropium seems to produce a greater effect at 4 and 6 hours after administration. Although atropine methonitrate has been studied for more than 4 hours after administration [lo], clear improvement in FEVi from the pretreatment baseline has not been clearly demonstrated beyond 4 hours. The present study was designed to compare the acute effects of ipratropium and albuterol for a period of 6 hours after administration, without consideration of residual effects from long-term therapy.
AIRWAYS DlSEASEiBRAUN
ETAL
FEVi. On each of the test days, theophylline was withheld for 36 hours and all pa agonist therapy for 10 hours before pulmonary function tests were done. Subjects were not to drink caffeine-containing beverages for 10 hours before testing. Baseline pulmonary functions obtained at each visit had to be within 10% of the FEVl on the first day; otherwise the subject was requested to return on another day. Baseline blood pressure and pulse rate were obtained. If the FEVi reproducibility criteria were met, the subject was treated with two inhalations of one of three aerosols (albuterol 0.18 mg, ipratropium 0.036 mg, or placebo). These were delivered by metered dose inhaler by the same technician, who was not involved in later testing. The study was carried out in a double-blind crossover design with each of the three treatments administered separately at one of three visits. Patients were randomly assigned to each of the six possible treatment sequences according to a randomization schedule. Follow-up spirometry was obtained at 15 minutes; 30 minutes; and at 1,2,3,4, 5, and 6 hours after drug administration. Pulse rate and blood pressure were obtained at the same time intervals.
METHODS
The purpose of this study was to compare the efficacy and safety of single doses of ipratropium, albuterol, and placebo when each was administered by metered dose inhaler. To accomplish this, a three-center study of 72 patients who had COPD was undertaken. Entry Criteria
Subjects were selected from patients who had a known diagnosis of COPD. They had to have at least a 10 pack-years smoking history, be between 35 and 80 years of age, and have stable disease with an FEVi of ~65% of predicted value. (“Pack-years” is the number of packs of cigarettes smoked per day, times the number of years the individual has smoked at that rate: no. packs/day x years = packyears.) Subjects were excluded if they had significant cardiovascular, renal, hepatic, endocrine, metabolic, or other systemic disease. For safety reasons, subjects were excluded if they had urinary retention, prostatic hypertrophy, or glaucoma. All subjects signed an informed consent form, as approved by each site’s institutional review board. Study Design
At admission to the study a complete history and physical examination were performed. Spirometry was done before and after administration of metaproterenol to determine baseline FEVi, forced vital capacity (FVC), and reversibility (15%) of
Data Analysis EFFICACY: The mean FEVi and FVC of all 72 subjects at each time and for each treatment were compared to determine efficacy over time. In addition, the effect at O-6 hours and at 3-6 hours was evaluated by measurement of the area under the time-response curve for FEVi and FVC. Further evaluation involved maximum post-treatment FEVi, time to onset of a 15% increase in FEVl from baseline, and duration of a 15% increase in FEVi from baseline. SAFETY: The maximum heart rate reached during the study and heart rate at each observation time were determined. The mean of the greatest increase and the area under the curve at each observation time were compared. Tachycardia was deemed to occur if baseline heart rate was ~100 beatsimin and heart rate after treatment increased from baseline by at least 10% and was >lOO beats/ min. Other adverse reactions were recorded. STATISTICAL METHODS: General linear model analyses of variance were used in conjunction with least-squares means to test for differences between treatments with respect to average areas under the time-response curve, peak spirometric values, and average spirometric values at each observation time. The same methods were used to estimate mean percent change from baseline at each spirometric observation time.
October 21, 1991
The American Journal of Medicine
Volume 91 (suppl 4A)
4A-29s
OBSTRUCTIVE
AIRWAYS DISEASE / BRAUN ET AL r-
TABLE I Baseline Findings for Pulmonary Function in Study Population
Pulmonary Function Total lung capacity Vltal capacity $sing capacity (n = 71) WC’
Percentage Predicted’ 106.2 2 n.2 t 58.6 i 38.0 61.5 i
2.3 2.0 3.3 2.1 1.7
Change After Metap;;/;renol
14.6 14.9:t 1.8 1.7
I”*n >,*JIIne iCCM
easeline 1
2 time
RESULTS Subject Characteristics Eighty-three subjects were admitted to the study, 73 of whom completed all aspects of the study. Of the 10 subjects who did not complete the study, seven withdrew because of exacerbation of COPD or chest wall pain; the remaining three were withdrawn because of an inability to reproduce a baseline FEVl at three visits (two subjects) and noncompliance (one subject). Five of the 10 subjects who withdrew were last treated with placebo, three subjects were last treated with albuterol, and two subjects were last treated with ipratropium. One of the ‘73 subjects was withdrawn because of loss of data. Thus, 72 subjects (60 men and 12 women) were available for the final analysis. Their mean age was 61.2 years 2 0.7 years; their mean duration of COPD was 9.0 years + 7.7 years. Table I shows the mean baseline findings for pulmonary function in the study population. There were no significant differences among the three study sites. All subjects had severe obstructive lung disease. All subjects had smoked for at least 10 pack-years: for the 56 subjects who provided packyear histories, the average smoking history was 50 pack-years. Efficacy During initial testing for reversibility, 32 (44%) of the 72 subjects achieved a 15% increase in FEVl from baseline after two inhalations of metaproterenol; 40 (56%) did not. During the 6 hours of testing, 61 (85%) of the subjects responded to ipratropium whereas 55 (76%) responded to albuterol. None of the subjects responded to the placebo. A 15% increase in FEVl at 15 minutes was achieved by 44 (61%) of the 72 subjects after albuterol and by 43 (60%) of the subjects after ipratropium. Fifty-nine (82%) achieved a 15% improvement at some time during the study after albuterol, and 61 (85%) achieved that improvement after ipratropium. Most patients reached a 15% increase within 30 minutes of receiving albuterol and 4A-30s
October 21, 1991
The American Journal of Medicine
3 (Hours)
4
5
6
igure 1. Mean response in FEV, to the three treatments during the 6-hour observation period (n = 72; * = p 15% at 6 hours after albuterol, whereas 36% maintained that level after ipratropium. Figures 1 and 2 show that there was a significantly greater response in FEVr to ipratropium than to albuterol at 3, 4, and 5 hours (p ~0.01) and in FVC at 1 hour (p ~0.05) and 2, 3, 4, and 5 hours (p
R.
BRAUN,
M.D.,
C&unbia,
Missouri, SHARON
F.
LEVY,
M.D.,
Seventy-two subjects who had severe chronic obstructive pulmonary disease and a history of heavy smoking completed a study to compare the effect of single doses of ipratropium bromide (0.036 mg), albuterol (0.18 mg>, and placebo on the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), heart rate, and blood pressure during a period of 6 hours. During initial testing for reversibility, 40 subjects did not demonstrate a 15% increase in FEV, from baseline after metaproterenol. Ipratropium produced a significantly greater response than albuterol in FEVl at 3, 4, and 5 hours and in FVC at 1, 2, 3, 4, and 5 hours. For the entire 6-hour period, ipratropium produced a 25% greater response than albuterol in FEV, and a 50% greater response in FVC. The difference between the two drugs was even greater between 3 and 6 hours. There were no significant differences between the three treatments as regards adverse reactions, heart rate, and blood pressure measurements. In patients who have chronic obstructive pulmonary disease, ipratropium bromide has apparent benefits over pz agonist therapy, including a longer duration of action. Ipratropium may also be effective when p2 agonists are not effective.
From the Department of Medicine, University of Missouri, Columbia, Missouri; the Medical College of Pennsylvania, VA Medical Center, Philadelphia, Pennsylvania; and the Albany Allergy and Asthma Services, Albany, New York. This study was funded by a grant from Boehringer lngelheim Pharmaceuticals, Inc., Ridgefield, Connect&. Requests for reprints should be addressed to Sheldon R. Braun, M.D., Room MA419, Health Sciences Center, One Hosprtal Drive, Columbia, Missouri 65212.
4A-28s
Philadeipha, Pennsylvania, JAY GROSSMAN,
Albany, New York
October
21, 1991
The American Journal of Medicine
A
nticholinergic therapy provides effective bronchodilation in patients who have chronic obstructive pulmonary disease (COPD)[l-41, and its effect remains stable for a period of 3 months of therapy [5]. The use of the quaternary ammonium anticholinergic compound ipratropium bromide is generally free of major adverse reactions [6] and can be used without fear of “drying” the sputum [‘7]. However, since several bronchodilators are effective in COPD, the exact role of ipratropium in clinical practice is still being determined. An understanding of its effectiveness compared with other bronchodilators is therefore important. In recent years several anticholinergic compounds, including atropine sulfate, atropine methonitrate, and ipratropium, have been tested against other commonly used bronchodilators. Studies have varied considerably as regards the dose of the anticholinergic compound used, the drug chosen for comparison, and the study design. Oral atropine and oral terbutaline produced equal improvement in forced expiratory volume in 1 second (FEV1) and airway resistance in 39 patients who had bronchitis [8]. Compared with isoproterenol, both ipratropium [4] and atropine sulfate [9] produced significant improvement in FEVi, which lasted at least 1 hour. Atropine sulfate produced urinary hesitancy in five of 15 patients, blurred vision in four, and dry mouth in five [9]. In both studies, the time to onset of action for the two drugs was similar, which indicates a rapid onset for both drugs. Comparison with the newer, longer-acting p2 agonists indicates equal, if not better, results from anticholinergic therapy. Starke et al [lo] compared atropine methonitrate, albuterol, a combination of the two drugs, and placebo when each was given for 4 days. They found that the FEVi 12 hours after treatment was greater for atropine methonitrate alone and in combination therapy than for albuterol or placebo. It is not clear whether this represents a 12-hour residual response to therapy. Based on the graphic information presented in the study, atropine methonitrate, either alone or in combination, produced a response that returned to baseline or
Volume 91 (suppl 4A)
OBSTRUCTIVE
below baseline within 4 hours of drug administration. The general impression gained by a review of the literature indicates that anticholinergic compounds produce an increase in FEVi or other markers of airway function that is equal to that of p2 agonists at 15 minutes to 2 hours and greater at later time points [1,4,5,9,11-131. With isoproterenol the bronchodilator effect decreases after 1 hour. Metaproterenol has been well studied for up to 6 hours after administration. There seems to be a greater response to ipratropium than to metaproterenol during the last 3-4 hours [5]. Compared with albuterol [1,13], ipratropium seems to produce a greater effect at 4 and 6 hours after administration. Although atropine methonitrate has been studied for more than 4 hours after administration [lo], clear improvement in FEVi from the pretreatment baseline has not been clearly demonstrated beyond 4 hours. The present study was designed to compare the acute effects of ipratropium and albuterol for a period of 6 hours after administration, without consideration of residual effects from long-term therapy.
AIRWAYS DlSEASEiBRAUN
ETAL
FEVi. On each of the test days, theophylline was withheld for 36 hours and all pa agonist therapy for 10 hours before pulmonary function tests were done. Subjects were not to drink caffeine-containing beverages for 10 hours before testing. Baseline pulmonary functions obtained at each visit had to be within 10% of the FEVl on the first day; otherwise the subject was requested to return on another day. Baseline blood pressure and pulse rate were obtained. If the FEVi reproducibility criteria were met, the subject was treated with two inhalations of one of three aerosols (albuterol 0.18 mg, ipratropium 0.036 mg, or placebo). These were delivered by metered dose inhaler by the same technician, who was not involved in later testing. The study was carried out in a double-blind crossover design with each of the three treatments administered separately at one of three visits. Patients were randomly assigned to each of the six possible treatment sequences according to a randomization schedule. Follow-up spirometry was obtained at 15 minutes; 30 minutes; and at 1,2,3,4, 5, and 6 hours after drug administration. Pulse rate and blood pressure were obtained at the same time intervals.
METHODS
The purpose of this study was to compare the efficacy and safety of single doses of ipratropium, albuterol, and placebo when each was administered by metered dose inhaler. To accomplish this, a three-center study of 72 patients who had COPD was undertaken. Entry Criteria
Subjects were selected from patients who had a known diagnosis of COPD. They had to have at least a 10 pack-years smoking history, be between 35 and 80 years of age, and have stable disease with an FEVi of ~65% of predicted value. (“Pack-years” is the number of packs of cigarettes smoked per day, times the number of years the individual has smoked at that rate: no. packs/day x years = packyears.) Subjects were excluded if they had significant cardiovascular, renal, hepatic, endocrine, metabolic, or other systemic disease. For safety reasons, subjects were excluded if they had urinary retention, prostatic hypertrophy, or glaucoma. All subjects signed an informed consent form, as approved by each site’s institutional review board. Study Design
At admission to the study a complete history and physical examination were performed. Spirometry was done before and after administration of metaproterenol to determine baseline FEVi, forced vital capacity (FVC), and reversibility (15%) of
Data Analysis EFFICACY: The mean FEVi and FVC of all 72 subjects at each time and for each treatment were compared to determine efficacy over time. In addition, the effect at O-6 hours and at 3-6 hours was evaluated by measurement of the area under the time-response curve for FEVi and FVC. Further evaluation involved maximum post-treatment FEVi, time to onset of a 15% increase in FEVl from baseline, and duration of a 15% increase in FEVi from baseline. SAFETY: The maximum heart rate reached during the study and heart rate at each observation time were determined. The mean of the greatest increase and the area under the curve at each observation time were compared. Tachycardia was deemed to occur if baseline heart rate was ~100 beatsimin and heart rate after treatment increased from baseline by at least 10% and was >lOO beats/ min. Other adverse reactions were recorded. STATISTICAL METHODS: General linear model analyses of variance were used in conjunction with least-squares means to test for differences between treatments with respect to average areas under the time-response curve, peak spirometric values, and average spirometric values at each observation time. The same methods were used to estimate mean percent change from baseline at each spirometric observation time.
October 21, 1991
The American Journal of Medicine
Volume 91 (suppl 4A)
4A-29s
OBSTRUCTIVE
AIRWAYS DISEASE / BRAUN ET AL r-
TABLE I Baseline Findings for Pulmonary Function in Study Population
Pulmonary Function Total lung capacity Vltal capacity $sing capacity (n = 71) WC’
Percentage Predicted’ 106.2 2 n.2 t 58.6 i 38.0 61.5 i
2.3 2.0 3.3 2.1 1.7
Change After Metap;;/;renol
14.6 14.9:t 1.8 1.7
I”*n >,*JIIne iCCM
easeline 1
2 time
RESULTS Subject Characteristics Eighty-three subjects were admitted to the study, 73 of whom completed all aspects of the study. Of the 10 subjects who did not complete the study, seven withdrew because of exacerbation of COPD or chest wall pain; the remaining three were withdrawn because of an inability to reproduce a baseline FEVl at three visits (two subjects) and noncompliance (one subject). Five of the 10 subjects who withdrew were last treated with placebo, three subjects were last treated with albuterol, and two subjects were last treated with ipratropium. One of the ‘73 subjects was withdrawn because of loss of data. Thus, 72 subjects (60 men and 12 women) were available for the final analysis. Their mean age was 61.2 years 2 0.7 years; their mean duration of COPD was 9.0 years + 7.7 years. Table I shows the mean baseline findings for pulmonary function in the study population. There were no significant differences among the three study sites. All subjects had severe obstructive lung disease. All subjects had smoked for at least 10 pack-years: for the 56 subjects who provided packyear histories, the average smoking history was 50 pack-years. Efficacy During initial testing for reversibility, 32 (44%) of the 72 subjects achieved a 15% increase in FEVl from baseline after two inhalations of metaproterenol; 40 (56%) did not. During the 6 hours of testing, 61 (85%) of the subjects responded to ipratropium whereas 55 (76%) responded to albuterol. None of the subjects responded to the placebo. A 15% increase in FEVl at 15 minutes was achieved by 44 (61%) of the 72 subjects after albuterol and by 43 (60%) of the subjects after ipratropium. Fifty-nine (82%) achieved a 15% improvement at some time during the study after albuterol, and 61 (85%) achieved that improvement after ipratropium. Most patients reached a 15% increase within 30 minutes of receiving albuterol and 4A-30s
October 21, 1991
The American Journal of Medicine
3 (Hours)
4
5
6
igure 1. Mean response in FEV, to the three treatments during the 6-hour observation period (n = 72; * = p 15% at 6 hours after albuterol, whereas 36% maintained that level after ipratropium. Figures 1 and 2 show that there was a significantly greater response in FEVr to ipratropium than to albuterol at 3, 4, and 5 hours (p ~0.01) and in FVC at 1 hour (p ~0.05) and 2, 3, 4, and 5 hours (p
