HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (55) Citing Articles via Google Scholar Google Scholar Articles by Friedman, M. Articles by Witek, T. J. Search for Related Content PubMed PubMed Citation Articles by Friedman, M. Articles by Witek, T. J., Jr.

Pharmacoeconomic Evaluation of a Combination of Ipratropium Plus Albuterol Compared With Ipratropium Alone and Albuterol Alone in COPD^*

^* From the Section of Pulmonary Disease, Critical Care Medicine, and Environmental Medicine (Dr. Friedman), Tulane University Medical Center, School of Medicine, New Orleans, LA; Boehringer Ingelheim Pharmaceuticals, Inc (Drs. Serby, Menjoge, Wilson, and Witek), Ridgefield, CT; and Department of Pharmacy Practice (Dr. Hilleman), Creighton University School of Pharmacy and Allied Health Professions, Omaha, NE. The post hoc pharmacoeconomic analysis was supported by Boehringer Ingelheim.

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
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 µg of ipratropium bromide, 240 µg 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 (FEV₁AUC_0–4) 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 FEV₁AUC_0–4, 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.

Key Words: albuterol • cost-effectiveness • ipratropium • pharmacoeconomics

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 

COPD is a progressive disorder characterized by airflow obstruction secondary to chronic bronchitis or emphysema.¹ Airflow obstruction is often associated with airway hyperreactivity that is partially reversible with bronchodilator therapy in most COPD patients.^{2 ,3} Exacerbations of disease are common in patients with COPD.^{4 ,5 ,6} Exacerbations are associated with symptoms that include increased dyspnea, cough, and sputum volume, as well as changes in sputum color.⁴ COPD exacerbations have also been associated with decrements in pulmonary function.⁴ Furthermore, successful treatment of COPD exacerbation with antibiotics has been shown to result in improvements in peak flow compared with placebo.⁴ Patients suffering an increased number of COPD exacerbations will incur excess health-care resource utilization and costs. Increased costs result from treatment of COPD exacerbations that typically include the addition of or increases in doses of pharmacologic agents (eg, bronchodilators, antibiotics, and corticosteroids).⁷ Furthermore, there will be additional costs related to an increased number of clinic visits and laboratory tests, and in some patients, hospitalizations for COPD exacerbations.⁸

There are two primary pharmacologic classes of inhaled bronchodilators used in the treatment of COPD: ß-adrenergic receptor agonists (eg, albuterol) and quarternary ammonium anticholinergic agents (eg, ipratropium).⁹ The combined use of ipratropium plus albuterol has been shown to produce superior bronchodilation compared to its individual components without additional side effects.¹⁰ However, it is unknown if this improvement in bronchodilation has benefit in terms of health-care resource utilization and the cost of management of COPD. The present study is a post hoc pharmacoeconomic evaluation of two double-blind, randomized, prospective, parallel group studies that were conducted to evaluate the long-term efficacy and safety of ipratropium combined with albuterol in a single inhalation aerosol canister against either bronchodilator agent alone in patients with COPD.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Data Reviewed
The efficacy and outcome data presented in this report include the results of two multicenter efficacy and safety trials (trial 627A and 627B) comparing ipratropium combined with albuterol (Combivent; Boehringer Ingelheim Pharmaceuticals; Ridgefield, CT) against albuterol alone and ipratropium alone. These studies used a common protocol and were designed to compare the bronchodilating efficacy and safety of the inhalation aerosol form of these drugs over an 85-day treatment period. The study design and the efficacy and safety results of one of these studies (627A) were published previously.¹⁰ An overview of this common study design is summarized below. Both studies conformed to the institutional review board and informed consent provision of the Code of Federal Regulations.

Study Design
Both trials enrolled patients with a diagnosis of COPD. Patients had to be >40 years of age with a 10 pack-year history of cigarette smoking. Patients had to have stable, moderately severe airflow obstruction defined as an FEV₁ of 65% of predicted normal and an FEV₁ <70% of FVC. Patients had to be using two or more pulmonary drugs (eg, ß-adrenergic agonist, ipratropium, theophylline, steroid) to control symptoms in the 3 months prior to study entry. Patients with a history of asthma, allergic rhinitis, atopy, an eosinophil count >500 mm³, or who were taking cromolyn or >10 mg of prednisone per day were excluded from the studies.

A history and physical examination, laboratory tests (hemogram, electrolytes, renal and hepatic function), and a 12-lead ECG were performed prior to and at the end of the study. Following a 2-week baseline period, patients were randomized to receive the ipratropium-albuterol combination (n = 358), ipratropium alone (n = 362), or albuterol alone (n = 347). The dose of each treatment was two puffs four times daily. Delivered doses for the three treatment groups were as follows: albuterol alone, 240 µg of albuterol sulfate four times a day; ipratropium alone, 42 µg of ipratropium bromide four times a day; albuterol plus ipratropium, 240 µg of albuterol sulfate plus 42 µg of ipratropium bromide four times a day. Prior theophylline and steroid use (either inhaled or <10 mg/d of prednisone) was continued during the baseline period and during the active treatment phase. Dosage increases or additions of corticosteroids or antibiotics were permitted during exacerbations. Clinic visits to record concomitant medications and evaluate treatment side effects were scheduled every 2 weeks during the 85-day treatment period.

Pulmonary function testing was performed on days 1, 29, 57, and 85 of active treatment. Prior to testing, treatment with theophylline preparations was withheld for 24 h and treatment with all corticosteroids and ß-agonists was withheld for 12 h. Pulmonary function was assessed just prior to drug administration and at 0.25, 0.5, and 1 h after drug administration and hourly thereafter for a total of 8 h.

Outcome Assessment and Health-Care Resource Utilization
Data concerning health-care resource utilization were collected and available through the clinical research reports for protocols 627A and 627B, but they have not been published previously. These health-care resource data included the number and length of acute pulmonary exacerbations of COPD, the number and length of hospitalizations due to exacerbations, and the number of patient days of increased doses or additions of corticosteroids and antibiotics. A pulmonary exacerbation was defined as a worsening of COPD-related symptoms (ie, cough, wheezing, dyspnea, sputum production, etc) for 3 consecutive days or longer.

Data Analysis
Data are presented as the mean ± SD where appropriate, and a priori level of significance of p < 0.05 was used. The primary efficacy end points included the peak change in FEV₁ and the area under the FEV₁ response-time curve (AUC) from time 0 to 4 h (FEV₁AUC_0–4) as calculated by the trapezoidal rule. All randomized patients with evaluable data (96.8% of patients) were included in the efficacy analysis. End point analysis in which last observed data carried forward for missing data was used to conduct the efficacy analysis. In all other analyses, all randomized patients were used. Analysis of covariance was used to evaluate the differences in peak FEV₁ and FEV₁AUC_0–4 between the treatment groups. The overall incidence of adverse events, events requiring discontinuation of drug therapy, and a number of patients with COPD exacerbation were compared using Fisher's Exact Test.

Total health-care expenditures for the three treatment groups were calculated by adding the costs of initial and add-on drug therapy, and hospitalization costs. Initial drug therapy included the costs of albuterol alone, ipratropium alone, and the combination of ipratropium-albuterol. The cost basis for their acquisition costs was the 1998 PC-Price Chek average wholesale price.¹¹ Add-on drug therapy included the cost of adding or increasing the dose of inhaled or oral corticosteroids and antibiotics. The cost basis for the add-on drug therapies was also the 1998 PC-Price Chek average wholesale price.¹¹ The costs of hospitalization, for purposes of this study, were estimated to be $600/d. Total costs among the three treatment groups were compared using the Kruskal-Wallis H statistic.

Cost-effectiveness ratios for each treatment were calculated using total treatment cost divided by the change in FEV₁AUC_0–4 and total costs divided by the combined total of exacerbation-free and hospitalization-free days. Incremental cost-effectiveness ratios were calculated where appropriate.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
A total of 1,067 patients were randomized in the two trials. Demographic and clinical characteristics of the randomized patients are summarized in Table 1 . There were no significant differences between the treatment groups with regard to baseline characteristics. Patients completing the study and reasons for study withdrawal are summarized in Table 2 . Overall, there was no significant difference in the percentage of patients discontinuing therapy for any reason in the three treatment groups.

View this table: [in this window] [in a new window]   Table 3. Percent Improvement* in Peak FEV1 Over Baseline FEV1 According to Treatment Group and Test Day

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1. COPD exacerbation frequency in the three treatment groups during the 85-day study.

The total cost of treating COPD over the 85-day follow-up period is summarized in Fig 2 . Although the acquisition cost of ipratropium alone ($94 per patient) and the combination product ($106 per patient) was greater than albuterol alone ($63 per patient), the mean total treatment cost of patients receiving ipratropium alone or the albuterol/ipratropium combination was significantly less than albuterol alone. The mean total per patient cost over the 85-day follow-up for ipratropium alone ($156 ± 69) and ipratropium plus albuterol ($197 ± 84) was significantly less than albuterol alone ($269 ± 108). The difference in total cost between ipratropium alone and the ipratropium plus albuterol combination product was not significant. Total cost adjusted by the percent of the combined number of days both exacerbation free and hospital free was $277 for albuterol, $159 for ipratropium, and $201 for the combination product. The reason for the lower total cost was a lower cost associated with add-on and dose-adjusted pulmonary drugs and lower hospitalization costs.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Total treatment costs over the 85-day follow-up period for the three treatment groups.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

The results of the present study demonstrate that the long-term use of ipratropium alone or the combination of ipratropium plus albuterol is associated with fewer exacerbations of COPD than the use of albuterol alone. Since the number of exacerbations was not significantly different between the two ipratropium treatment arms, it would appear that the inclusion of ipratropium in a pharmacologic treatment regimen alters the rate of exacerbations in COPD since the treatment arm containing both ipratropium and albuterol demonstrated a lower number of exacerbations, rather than albuterol usage alone increasing the number of exacerbations.

As pointed out by Anthonisen,¹³ COPD exacerbations occur with a frequency of approximately 0.1 per patient per month of follow-up. As a result, a large group of patients must be followed up for considerable periods of time to accumulate enough exacerbations to analyze. We have analyzed the results of two prospective randomized, double-blind, parallel-group studies that enrolled 1,067 patients who were followed up closely for 3 months. Based on the frequency of COPD exacerbations projected by Anthonisen,¹³ the present study had a sample size and a duration of follow-up with sufficient power to compare exacerbation rates between the treatment groups.¹³ In addition, the number and duration of exacerbations observed in the albuterol treatment arm are consistent with those predicted for a 3-month study, based on previously published reports.^{4 ,5}

The definition of exacerbation used in the present study is valid based on the following. Similar to the definition used in the present study, other published studies of COPD patients have also utilized changes in clinical symptoms to define exacerbations.^{4 ,5 ,12} For example, Anthonisen et al⁴ defined exacerbation as an increase in dyspnea or sputum production, or a change in sputum color, cough, or wheeze, which are similar to the criteria used to define exacerbations in the present study. In a more recent trial, Collet et al¹² defined COPD exacerbations as a change in sputum color, texture, or quantity, the presence of one additional symptom of shortness of breath or cough or fever, and either an unscheduled clinic visit or a prescription for an antibiotic. In another study, the symptoms of increased dyspnea, changes in sputum characteristics, malaise, etc, had to be present for at least 48 h.⁵ In the present study, a more stringent definition of 72 h of symptom duration was used to establish an exacerbation.

The reduction in total cost for the treatment arms containing ipratropium (Fig 2 ) has relevance to the management of COPD in which side effect profile, total cost, and improvement in lung function are all important factors involved in selecting an appropriate pharmacologic treatment regimen. First, in the present study of 1,067 patients with moderate-to-severe COPD, there was no difference in side effect frequency among the three treatment arms. Fewer exacerbations were noted in both treatment arms containing ipratropium (mean 33%) compared with the albuterol arm, translating into a 24% lower cost. These data are similar to preliminary results observed in a 3-year retrospective study in patients with COPD in which patients receiving ipratropium or ipratropium plus a ß-agonist had lower total health-care costs compared to treatment with a ß-agonist alone.⁸ The reduced costs observed in the present study resulted from reductions in add-on drug therapy and hospitalization. Third, superior bronchodilation (peak FEV₁ and FEV₁AUC_0–4) was observed in the ipratropium plus albuterol arm, compared to its individual drug components (ipratropium or albuterol). The addition of a ß-agonist to ipratropium in the combined treatment arm did not significantly increase total treatment cost, but did result in improved cost-effectiveness. When total cost was adjusted by improvement in FEV₁AUC_0–4, there was an average 42% lower cost for the ipratropium treatment arms compared with albuterol alone for all pulmonary function test days. Thus, the observed improvement in physiologic function in the combination treatment arm magnified the difference in total in costs relative to albuterol alone. These data, taken along with the convenience and assumed increased compliance with use of a single inhaler, suggest that an inhaler bronchodilator regimen combining ipratropium and albuterol differs from administration of albuterol or ipratropium alone with regard to physiologic improvement as well as lower health-care costs. As a result, this combination should be considered early in the management of moderate-to-severe COPD.

As previously stated, the exact mechanisms responsible for COPD exacerbations are unknown. The present study, although designed to determine the frequency and duration of exacerbations, was not designed to examine the possible mechanisms involved in COPD exacerbations. It has been suggested that alterations in mucus production or rheology by glands, airway microvascular leakage, and/or inflammation (infectious or noninfectious) may be factors responsible for exacerbations.¹⁴ In the present study, lower numbers of exacerbations were only found in the treatment arms containing ipratropium.

There are several possible mechanisms by which alterations in cholinergic tone might affect exacerbation rates. As pointed out by Barnes and Jarnes,¹⁵ the mechanisms by which anticholinergic bronchodilators may have a greater effect on airway function in COPD are uncertain, since if cholinergic tone were the only reversible component, it might be predicted that ß₂-agonists would be equally effective in inhibiting cholinergic tone. Thus, it has been suggested that anticholinergics might have a greater effect than ß₂-agonists in COPD because of some additional effects on mucus secretion.¹⁵ Cholinergic nerve fibers travel down the vagus nerve and synapse in parasympathetic ganglia that are located within the airway wall.¹⁶ From these ganglia, short postganglionic fibers travel to airway smooth muscle and submucosal glands.^{15 ,16} Cholinergic effects on the airways are mediated by muscarinic receptors on target cells in the airways.^{17 ,18} Cholinergic agents are potent stimulators of mucus secretion in human airways in vitro and act predominantly on submucosal glands that are the major source of mucus in the proximal airways.¹⁹ Goblet cells, which are the major source for mucus in peripheral airways, are under cholinergic control.²⁰ Ipratropium has been shown to block the effects of some irritants and inhaled toxins, such as cigarette smoke, which are mediated via a cholinergic reflex.^{19 ,21} Thus, it may be that the inclusion of ipratropium in the treatment regimen reduced goblet cell secretion and thus improved airway obstruction in peripheral airways.

Another cause for changes in exacerbation frequencies may be related to alterations in airway mucociliary clearance, which has been shown to be decreased in patients with COPD.²² However, ipratropium bromide has no significant effect on either mucociliary clearance or on sputum volume.²³ Although ß₂-agonists have been shown to increase mucociliary clearance, the albuterol alone treatment arm has significantly higher exacerbations, thus making the effects on mucociliary clearance an unlikely cause for changes in the number of exacerbations.²³ However, the measurements of airway mucociliary function measure clearance of particles either from large airways, such as the trachea, or utilize clearance from entire lung segments.^{22 ,23} It may be possible that improvements in mucus clearance occur predominantly in smaller airways, a site not specifically examined using current measurement technology.

	Footnotes

 
Correspondence to: Daniel E. Hilleman, Pharm D, FCCP, Department of Pharmacy Practice, Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, NE 68178; e-mail: hilleman@creighton.edu

Abbreviations: FEV₁AUC_0–4 = area under the FEV₁ response-time curve from time 0 to 4 h

Received for publication July 2, 1998. Accepted for publication September 29, 1998.

	References

TOP Abstract Introduction Materials and Methods Results Discussion References

 

1. . American Thoracic Society. (1995) Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152,S77-S121
2. Gross, N (1986) COPD: a disease of reversible air-flow obstruction. Am Rev Respir Dis 133,725-726[ISI][Medline]
3. Anthonisen, N, Wright, E (1986) IPPB Trial Group: bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis 133,814-819[ISI][Medline]
4. Anthonisen, R, Manfreda, J, Warren, C, et al (1987) Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 106,196-204
5. . British Thoracic Society Research Committee. (1985) Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airway obstruction. Thorax 40,832-835[Abstract]
6. Nicotra, M, Rivera, M, Awe, R (1982) Antibiotic therapy in acute exacerbations of chronic bronchitis: a controlled study using tetracycline. Ann Intern Med 97,18-21
7. Dompeling, E, van Schayek, C, Van Grunsven, P, et al (1993) Slowing the deterioration of asthma and chronic obstructive pulmonary disease observed during bronchodilators therapy by adding inhaled corticosteroids. Ann Intern Med 118,770-778[Abstract/Free Full Text]
8. Hilleman, D, Wadibia, E, Shinn, B (1996) Outcomes and costs of chronic COPD: impact of disease severity and treatment approaches [abstract]. Pharmacotherapy 16,494
9. Chapman, K (1991) Therapeutic algorithm for chronic obstructive pulmonary disease. Am J Med 91,175-235
10. . Combivent Inhalational Aerosol Study Group. (1994) In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial. Chest 105,1411-1419[Abstract/Free Full Text]
11. Price-Chek PC: version 2.16. St. Louis, MO: Medi-Span, 1998
12. Collet, J, Shapiro, S, Ernst, P, et al (1997) Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 156,1719-1724[Abstract/Free Full Text]
13. Anthonisen, N (1997) OM-85 BV for COPD. Am J Respir Crit Care Med 156,1713-1714[Free Full Text]
14. Lloberes, P, Ramis, L, Montserrat, J, et al (1988) Effect of three different bronchodilators during an exacerbation of chronic obstructive pulmonary disease. Eur Respir J 1,536-539[Abstract]
15. Barnes, P, Jarnes, P (1986) Neural control of human airways in health and disease. Am Rev Respir Dis 134,1289-1314[ISI][Medline]
16. Barnes, P (1993) Autonomic pharmacology of the airways. Chung, K Barnes, P eds. Pharmacology of the respiratory tract ,415-455 Marcel Decker New York, NY.
17. Nadel, J, Barnes, P (1984) Autonomic regulation of the airways. Ann Rev Med 35,451-467[CrossRef][ISI][Medline]
18. Barnes, P (1987) Muscarinic receptors in the lung. Postgrad Med J 63,13-19
19. Gross, N, Skorodin, M (1984) Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 129,856-870[ISI][Medline]
20. Tokuyama, K, Kuo, H-P, Rohde, J, et al (1990) Neural control of goblet cell secretion in guinea pig airways. Am J Physiol 259,L108-L115[Abstract/Free Full Text]
21. Kuo, H-P, Barnes, P, Rogers, D (1992) Cigarette smoke induced goblet cell secretion: dose-dependent differential nerve activation. Am J Physiol 7,L161-L167
22. Wanner, A (1977) Clinical aspects of mucociliary clearance. Am Rev Respir Dis 116,73-125[ISI][Medline]
23. Kobayashi, K, Wanner, A (1993) Mucociliary clearance and ciliary activity. Chung, K Barnes, P eds. Pharmacology of the respiratory tract ,621-654 Marcel Dekker New York, NY.

This article has been cited by other articles:

				B. R. Celli Update on the Management of COPD Chest, June 1, 2008; 133(6): 1451 - 1462. [Abstract] [Full Text] [PDF]

				B. R. Celli Roger S. Mitchell Lecture. Chronic Obstructive Pulmonary Disease Phenotypes and Their Clinical Relevance Proceedings of the ATS, August 1, 2006; 3(6): 461 - 465. [Abstract] [Full Text] [PDF]

				T. A. Lee, B. Bartle, and K. B. Weiss Spirometry Use in Clinical Practice Following Diagnosis of COPD Chest, June 1, 2006; 129(6): 1509 - 1515. [Abstract] [Full Text] [PDF]

				A. O. D'Souza, M. J. Smith, L. A. Miller, and J. Kavookjian An Appraisal of Pharmacoeconomic Evidence of Maintenance Therapy for COPD Chest, June 1, 2006; 129(6): 1693 - 1708. [Abstract] [Full Text] [PDF]

				S Scott, P Walker, and P M A Calverley COPD exacerbations {middle dot} 4: Prevention Thorax, May 1, 2006; 61(5): 440 - 447. [Abstract] [Full Text] [PDF]

				B. R. Celli Change in the BODE index reflects disease modification in COPD: lessons from lung volume reduction surgery. Chest, April 1, 2006; 129(4): 835 - 836. [Full Text] [PDF]

				B. R. Celli Chronic Obstructive Pulmonary Disease: From Unjustified Nihilism to Evidence-based Optimism. Proceedings of the ATS, January 1, 2006; 3(1): 58 - 65. [Abstract] [Full Text] [PDF]

				V Brusasco, R Hodder, M Miravitlles, L Korducki, L Towse, and S Kesten Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD Thorax, January 1, 2006; 58(5): 399 - 404. [Abstract] [Full Text] [PDF]

				J. F. Donohue Combination Therapy for Chronic Obstructive Pulmonary Disease: Clinical Aspects Proceedings of the ATS, November 1, 2005; 2(4): 272 - 281. [Abstract] [Full Text] [PDF]

				W. Vincken Bronchodilator treatment of stable COPD: long-acting anticholinergics Eur. Respir. Rev., September 1, 2005; 14(94): 23 - 31. [Abstract] [Full Text] [PDF]

				B.R. Celli, W. MacNee, A. Agusti, A. Anzueto, B. Berg, A.S. Buist, P.M.A. Calverley, N. Chavannes, T. Dillard, B. Fahy, et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper Eur. Respir. J., June 1, 2004; 23(6): 932 - 946. [Full Text] [PDF]

				P. M. A. Calverley Reducing the Frequency and Severity of Exacerbations of Chronic Obstructive Pulmonary Disease Proceedings of the ATS, April 1, 2004; 1(2): 121 - 124. [Abstract] [Full Text] [PDF]

				B. R. Celli, C. G. Cote, J. M. Marin, C. Casanova, M. Montes de Oca, R. A. Mendez, V. Pinto Plata, and H. J. Cabral The Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease N. Engl. J. Med., March 4, 2004; 350(10): 1005 - 1012. [Abstract] [Full Text] [PDF]

				B. R. Celli A 62-Year-Old Woman With Chronic Obstructive Pulmonary Disease JAMA, November 26, 2003; 290(20): 2721 - 2729. [Full Text] [PDF]

				M. Miravitlles Exacerbations of chronic obstructive pulmonary disease: when are bacteria important? Eur. Respir. J., July 1, 2002; 20(36_suppl): 9S - 19s. [Abstract] [Full Text] [PDF]

				P.J. Rees Tiotropium in the management of chronic obstructive pulmonary disease Eur. Respir. J., February 1, 2002; 19(2): 205 - 206. [Full Text] [PDF]

				W. Vincken, J.A. van Noord, A.P.M. Greefhorst, Th.A. Bantje, S. Kesten, L. Korducki, and P.J.G. Cornelissen Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium Eur. Respir. J., February 1, 2002; 19(2): 209 - 216. [Abstract] [Full Text] [PDF]

				N. Roche, T. Lepage, J. Bourcereau, and P. Terrioux Guidelines versus clinical practice in the treatment of chronic obstructive pulmonary disease Eur. Respir. J., December 1, 2001; 18(6): 903 - 908. [Abstract] [Full Text] [PDF]

				S. D. Sullivan, S. D. Ramsey, and T. A. Lee The Economic Burden of COPD Chest, February 1, 2000; 117(2_suppl): 5S - 9S. [Abstract] [Full Text] [PDF]

				S. D. Ramsey Suboptimal Medical Therapy in COPD : Exploring the Causes and Consequences Chest, February 1, 2000; 117(2_suppl): 33S - 37S. [Abstract] [Full Text] [PDF]

				P. M. A. Calverley The Future for Tiotropium Chest, February 1, 2000; 117(2_suppl): 67S - 69S. [Abstract] [Full Text] [PDF]

				Ipratropium Plus Albuterol in COPD Journal Watch (General), April 9, 1999; 1999(409): 3 - 3. [Full Text]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (55) Citing Articles via Google Scholar Google Scholar Articles by Friedman, M. Articles by Witek, T. J. Search for Related Content PubMed PubMed Citation Articles by Friedman, M. Articles by Witek, T. J., Jr.