Early initiation of maintenance medication in patients with moderate to severe COPD exacerbations is associated with reduced risk of future exacerbations and lower costs.
Objectives: To examine the impact of timing of maintenance treatment (MTx) initiation (early vs delayed) on risk of future exacerbations and costs in chronic obstructive pulmonary disease (COPD) patients.
Study Design: Retrospective cohort design using data (January 1, 2003, through June 30, 2009) from a large, US-based integrated pharmacy and medical claims database.
Methods: Administrative claims from January 1, 2003, through June 30, 2009, were used. MTx-naïve patients (aged >40 years) with at least 1 COPD-related hospitalization/emergency department (ED) visit were included (discharge date was index date). Patients initiating MTx within the first 30 days and 31 to 180 days postindex were classified into early and delayed cohorts, respectively. Clinical and economic outcomes related to COPD exacerbations were assessed for 1 year post-index and compared between cohorts using regression models controlling for baseline characteristics. The incremental effect on outcomes of every 30-day delay in MTx initiation up to 6 months after the index event was also assessed.
Results: The majority of the 3806 patients (78.6%) received early MTx. A significantly higher proportion of patients in the delayed cohort had a COPD-related
hospitalization/ED visit compared with the early cohort (25.6% vs 18.0%; P <.001). After controlling for baseline differences, the delayed cohort had a 43% (P <.001) higher risk of a future COPD-related hospitalization/ED visit compared with the early cohort. Every 30-day delay was associated with 9% risk increase (P = .002). Treatment delay also increased COPD-related costs ($5012 vs $3585; P <.001).
Conclusion: Early MTx initiation is associated with reduced risk of future COPD exacerbations and lower costs.
(Am J Manag Care. 2012;18(9):e338-e345)
Chronic obstructive pulmonary disease (COPD) is the thirdleading cause of chronic morbidity and mortality in the United States,1 and exacerbations are recognized as the dominant cause of these outcomes. Exacerbations are defined as acute episodes of worsening respiratory symptoms (eg, dyspnea, sputum production, sputum purulence, cough), which can alter the clinical course of COPD by accelerating the decline in lung function.2,3 Depending on the severity, an exacerbation can disrupt usual activities and even incapacitate a patient, negatively impacting health-related quality of life.4 The societal impact is also felt; exacerbations are estimated to account for 50% to 75% of the healthcare costs for COPD.5 Two recent literature reviews of exacerbation costs identified hospitalizations as the primary driver, accounting for 38% to sometimes 93% of total costs, followed by outpatient costs that arise from contacts with a healthcare professional (eg, outpatient visits, emergency department [ED] visits).6,7 Hospitalization due to an exacerbation is a serious event, as inpatient mortality rates range from 10% to 40%.8-10 Consequently, the prevention and treatment of exacerbations are important components of COPD management in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.11
The GOLD guidelines recommend short- and long-term approaches to the treatment and prevention of COPD exacerbations. Short-term therapies include oral corticosteroids, antibiotics, and increased use of bronchodilator medications, which have been shown to hasten the recovery rate from exacerbations; early initiation of these therapies is associated with faster recovery time.12-15 Long-term therapies—including long-acting beta-agonists, long- and short-acting anticholinergics, and inhaled corticosteroid-containing products—have been shown to reduce the risk and frequency of exacerbations, and are recommended on a maintenance basis for prevention.16-18
Despite all the evidence of the beneficial impact of long-term therapies, there is little information on the effects of timing of initiation of long-term therapies to prevent exacerbations. Recent literature suggests that exacerbations cluster together, with the risk for a subsequent exacerbation being highest in the 8-week period following an initial exacerbation.19 Exacerbations that are moderate to severe in nature (ie, result in either a hospitalization or an ED visit) have been shown to contribute substantially to the morbidity and mortality in COPD, and are thus clinically relevant to the issue of timing of initiation of maintenance treatment (MTx).6,10 Therefore, our study focused on whether the timing of MTx initiation affects the future occurrence and frequency of COPD exacerbations.
A retrospective, observational cohort design was implemented using integrated pharmacy and medical claims data spanning January 1, 2003, through June 20, 2009. This US administrative database (Ingenix Impact National Managed Care Database) is generally representative of the insured US commercial population including patients 65 years and older enrolled in Medicare Risk and Medicare Advantage plans. The database contains information for more than 98 million lives from more than 46 different healthcare plans spanning 9 census regions of the United States. It captures person-specific utilization, expenditures (direct costs), and enrollment across inpatient, outpatient, and prescription drug services.
Study Design and Patient Selection
Patients with at least 1 moderate-to-severe COPD exacerbation, defined as a hospitalization or ED visit with a primary discharge diagnosis code for COPD (International Classification of Diseases, Ninth Revision, Clinical Modification codes 491.xx, 492.xx, 496.xx) were selected as the initial population. The first COPD exacerbation requiring a hospitalization or ED visit (January 1, 2004, to June 30, 2008) followed by dispensing of MTx within 6 months of discharge was defined as the index event. Consequently, patients with a COPDrelated hospitalization or ED visit in the 1-year period before this index exacerbation or those without any MTx dispensed within 6 months of their first COPD-related hospitalization or ED visit were excluded. Maintenance treatment included a long-acting anticholinergic (tiotropium), a short-acting anticholinergic (ipratropium or combination ipratropiumalbuterol), long-acting beta-agonists (formoterol, salmeterol), inhaled corticosteroids (beclomethasone, budesonide, fluticasone, flunisolide, triamcinolone), and fluticasone-salmeterol (250/50 μg combination). The index date for hospitalizations and ED visits was the date of discharge or the date of the visit, respectively. The period 1 year prior to the index date (preperiod) was used to determine baseline characteristics for patients included in the analysis. The period 1 year after the index date (post-period) was used to calculate outcomes listed below in the Outcomes section. In addition, the first 6 months of the post-period were also used to identify the date of receipt of the first MTx prescription, because a prescription of MTx was considered related to the index exacerbation if it was prescribed within 180 days of the exacerbation.
Patients were >40 years of age and eligible for healthcare benefits during their pre- and post-periods. Patients were excluded if they had a COPD-related exacerbation or MTx in the pre-period (to ensure inclusion of MTx-naïve patients) or if they received their first MTx 181 to 365 days after the index date during the post-period. Additionally, patients were excluded if they had any of the comorbid conditions listed in the Appendix.
Patients meeting study criteria were classified into 2 cohorts (early and delayed), based on timing of MTx after the index date: 0 to 30 days and 31 to 180 days, respectively. A 30-day period was defined as early initiation, based on empirical information from our analysis and recent evidence demonstrating the increased risk of subsequent exacerbations during an 8-week period following an initial exacerbation.19 Outcomes were computed for and compared between cohorts. An incremental analysis evaluating the effect of delaying MTx by every 30 days was also conducted; patients were classified into 6 categories based on 30-day increments of starting MTx. Outcomes were then compared across the 6 categories, thereby allowing assessment for every 30-day increment up to 180 days after the index date.
The primary outcome was the presence of a subsequent COPD-related exacerbation requiring hospitalization or an ED visit during the post-period. Secondary outcomes included the presence of exacerbations requiring a physician/outpatient visit accompanied by a prescription for oral corticosteroids or antibiotics within 5 days of that visit, and the presence of any of these exacerbations. Additionally, the numbers of exacerbations were computed and compared between the cohorts. Annual total COPD-related costs per patient were also computed using paid amounts from the claims. COPD-related medical costs were identified as medical claims with a primary diagnosis code for COPD and classified into different medical components, including hospitalizations, ED visits, physician/outpatient visits having an evaluation or management Current Procedural Terminology code, other outpatient visits for laboratory tests and/or procedures, and “other.” COPDrelated pharmacy costs were defined as costs for maintenance medications, short-acting beta-agonists, oral corticosteroids, respiratory antibiotics, methylxanthines, and mucolytics. All costs were standardized to 2009 US dollars using the medical care component of the Consumer Price Index.20
Baseline differences and unadjusted outcomes between the early and delayed cohort were evaluated using t tests or c2 tests for continuous or categorical data, respectively. Logistic regression models were used to assess differences in risk of a COPD exacerbation between study cohorts, and to evaluate the change in risk with every 30-day delay in initiating MTx. Similarly, zero-inflated, negative-binomial models were used to assess difference in the number of exacerbations. A 2-part model was used to obtain adjusted annual COPD-related costs for the early and delayed cohorts by multiplying the adjusted probability obtained from a logistic regression model (part 1) by the predicted cost from a generalized linear model (part 2). A generalized linear model was used to evaluate the impact of a 30-day delay in MTx on COPD-related costs. Multivariate analysis of the impact of a 30-day delay on all outcomes was only conducted if a linear trend was demonstrated (details of linear trend test are presented in the Appendix). All models controlled for differences in baseline covariates.
A total of 3806 patients met all study criteria. The majority of the sample (78.6%) received MTx in the first 30 days. Compared with the early cohort, the delayed cohort had a similar mean age but a larger proportion of patients aged >75 years (Table 1). Greater comorbid burden was seen in the delayed versus the early cohort, as evidenced by the Charlson Comorbidity Index score (1.8 vs 1.3; P <.001) and higher rates of asthma and lower respiratory tract infections. The delayed cohort also had more severe disease at baseline, with a higher proportion having a COPD-related exacerbation requiring a physician/outpatient visit accompanied by a prescription for oral corticosteroids or antibiotics within 5 days of that visit (12.2% vs 9.1%; P = .010) and higher COPD-related costs ($627 vs $294; P <.001). In summary, the early cohort was younger and had less severe COPD at baseline than the delayed cohort.
In the overall sample, approximately 20% of patients had a COPD-related exacerbation requiring hospitalization or an ED visit after the index exacerbation event. A significantly higher (unadjusted) proportion of patients in the delayed cohort had an exacerbation requiring hospitalization or an ED visit compared with the early cohort (Figure 1, 25.6% vs 18.0%; P <.001). Furthermore, a benefit for early treatment was observed even for exacerbations defined as a physician visit with an accompanying prescription for oral corticosteroids or antibiotics (Figure 1, 27.3% vs 31.5%; P = .019). Figure 1 also displays the adjusted odds ratio (OR) reflecting the risk for each type of exacerbation for the delayed cohort versus the early cohort after adjusting for differences in baseline characteristics. The delayed cohort had a 43% significantly higher risk of a COPD-related exacerbation requiring hospitalization or an ED visit (OR 1.43, P <.001). A similar trend was noted for any type of exacerbation and for ED visits separately, but not for exacerbations requiring hospitalization and exacerbations defined as a physician visit with a prescription for oral corticosteroids or antibiotics. However, the results for the latter were of borderline statistical significance.
Delay in MTx initiation was also associated with a significantly higher rate of exacerbations (on average, 20% to 35% higher than that in the early cohort; see Table 2 for the incidence rate ratio). The delayed cohort incurred higher total costs compared with the early cohort ($5294 vs $3484, P <.001; see Table 3). These cost differences were driven mainly by higher annual medical costs, attributable to increased expenditure due to hospitalizations ($2639 vs $1532, P = .015) (unadjusted costs are presented in the Appendix). Multivariate analysis revealed estimated predicted savings of nearly $1400 in total COPD-related costs when MTx was initiated earlier. COPD-related medical costs were almost $1200 lower for the early cohort compared with the delayed cohort (Table 3).
To permit an incremental assessment of how delay in MTx initiation affects the risk of COPD-related exacerbations, patients were categorized into 30-day categories based on the timing of MTx initiation (Figure 2). The linear-trend test showed a significant association between the 30-day categories and the risk of all types of COPD exacerbation, except for hospitalization alone. For every 30-day delay in MTx initiation, the risk of a COPD-related exacerbation requiring hospitalization or an ED visit increased by 9% after adjusting for differences in baseline characteristics (OR 1.09; P = .002). This effect was driven mainly by the risk of an ED visit, which was 10% higher for every 30-day delay in MTx initiation. No significant linear trend was observed for number of exacerbations or COPD-related costs; thus, the incremental change with every 30-day delay in initiating MTx was not evaluated for these outcomes.
The current study represents an important addition to the literature on the benefits of early MTx in patients with COPD. In particular, the risk of having a subsequent hospitalization/ED visit was 43% higher for those who delayed therapy versus those who did not. Furthermore, there was a 9% higher risk of a subsequent exacerbation requiring hospitalization or an ED visit with every 30-day delay in MTx initiation. The clinical rationale for earlier treatment initiation is increasingly recognized in the COPD literature.21 The presence of symptoms, even among those with mild COPD, has recently been shown to be associated with a faster decline in lung function, and early diagnosis and intervention may be vital to slowing disease progression.22,23 Also, data from 2 large, randomized controlled trials have shown that initiation of maintenance pharmacotherapy at earlier disease stages (moderate vs severe) potentially modifies disease progression in COPD.18,24
In addition to the clinical benefits of early treatment initiation demonstrated in this study, there were economic advantages. Initiation of early maintenance treatment after a COPD exacerbation (ie, within 30 days) was associated with significantly lower medical and total COPD-related costs. The reduction in medical costs offset the increased pharmacy expenditures one would expect with use of pharmacotherapy, such that total costs were significantly lower for the early cohort. This finding is important from a managed care perspective. Health plans are interested in risk identification and instituting targeted disease management initiatives in order to manage expenditures. Identifying highrisk COPD patients (ie, those with COPD exacerbations) and targeting them for appropriate and timely pharmacotherapy endorsed by clinical guidelines would ensure appropriate clinical and economic management. This study provides important support for this step.
The GOLD guidelines currently recommend MTx at different disease stages, but do not specify a time frame for initiation. By defining early initiators as patients receiving treatment within 30 days of discharge from an exacerbation requiring hospitalization or an ED visit, we emphasized the importance of timing of therapy initiation in COPD patients. The time frame of 30 days for early initiation also is in accord with recent literature in that the 2 months following an initial exacerbation represent a high-risk period for subsequent exacerbations, and thus should be an opportune time to initiate appropriate therapy.19
To our knowledge, this study is the first to provide empirical evidence of the clinical and economic advantages of initiating early MTx. In this analysis, certain baseline characteristics of the study population increase the probability that patients are more likely to have moderate rather than severe COPD. First, all patients were naïve to MTx at baseline, and treatment only commenced after the index exacerbation. Additionally, the rate of exacerbations at baseline was below 1. A recent systematic review found rates of exacerbations to be below 1 for those with forced expiratory volume in 1 second percent predicted above 50% (moderate severity).25 Considering all these factors, information from the current study can serve as preliminary real-world evidence of the impact of early MTx, if “early” is defined as MTx initiation in patients with moderate COPD.
The study findings also showcase an important quality-of-care aspect. Of the total sample of patients having an index event and meeting all study criteria, 3806 (37.1%) received MTx within 180 days of the index date, but 6439 (62.9%) did not receive any MTx during the entire year after the index date. The prevalence of undertreatment seems high compared with other studies.26,27 One explanation for this difference could be that the subset of patients evaluated in other studies had more severe COPD compared with our study patients, and thus may have been more likely to be given MTx. However, the presence of a single exacerbation requiring hospitalization or an ED visit should provide sufficient justification to institute MTx, without waiting for the patient to experience repeated exacerbations or progress to a higher COPD severity level.
Our study has potential limitations. The early cohort by definition was hypothesized to have more severe COPD, thereby introducing possible selection bias. However, the baseline comparison revealed a higher comorbid burden and COPD severity level for the delayed cohort compared with the early cohort. Thus, it is unlikely that selection bias was present. Also, we lacked information on appropriateness of treatment or the reason for treatment initiation because that would have required additional clinical information such as lung function measures not available in the data. However, we would expect that at the very minimum patients would need to begin some maintenance treatment after discharge from the hospital/ED for COPD. Additionally, differences in baseline covariates were adjusted for in the multivariate analysis so that the higher COPD severity in the delayed cohort would not confound the comparison of outcomes in the follow-up period between the cohorts. However, in any claims database analysis, clinical data are unavailable; at best, proxy measures of COPD severity may be used. Thus, the possibility of residual confounding due to unmeasured differences in COPD severity still remains.
It is also possible that we misclassified our cohorts. For example, the delayed cohort might have received maintenance medication upon discharge from the hospital and that was the main reason these patients filled their prescription later. If this practice was prevalent among the delayed cohort, the impact of the misclassification would have been to make the delayed cohort almost similar to the early cohort, and we would not have found a difference between the 2 cohorts. However, the possibility of misclassification bias is low because significant differences were found between the early and delayed cohort. As almost 80% of the study sample initiated MTx within 30 days of the index exacerbation, it was not possible to conduct a sensitivity analysis on the definition of early initiation. Also, results may not be generalizable to other populations because the sample included only commercial managed care enrollees.
The study results have important implications for both clinicians and health plans, as well as for future research. Our results suggest that patients who require hospitalization or an ED visit for an exacerbation should be actively managed and given appropriate MTx soon after discharge, especially if it is their first-ever exacerbation requiring a hospitalization or ED visit. Additionally, if patient or physician factors preclude therapy initiation during this crucial 30-day period, therapy should be initiated as soon as possible, given that the risk of subsequent exacerbations is incremental with every 30-day delay. Although the objective of the current study was to assess the impact of timing of initiation of MTx after initial exacerbation, future research may be needed to assess the impact of initiation or changes in MTx after discharge from recurrent exacerbations, because patients may not begin MTx until they have recurrent exacerbations.
In summary, we found that early initiation of MTx in COPD is beneficial in reducing the risk and number of subsequent exacerbations. Economic advantages from reduced COPDrelated total and medical costs (offsetting increased pharmacy expenditures) are also realized and serve as an incentive to advocate earlier treatment for the appropriate patients.Author Affiliations: From GlaxoSmithKline (AAD, GDC), Research Triangle Park, NC; Xcenda (MBS, AOD, ADD), Palm Harbor, FL.
Funding Source: This research was funded by GlaxoSmithKline.
Author Disclosures: Drs Dalal and Crater report employment with GlaxoSmithKline, as well as stock ownership in the company. Drs D’Souza and Shah and Mr Dhamane reports employment with Xcenda, LLC, which received funding from GlaxoSmithKline to conduct research for this study.
Authorship Information: Concept and design (AAD, MBS, AOD, ADD, GDC); acquisition of data (AOD); analysis and interpretation of data (AAD, MBS, AOD, ADD, GDC); drafting of the manuscript (AAD, MBS, AOD, ADD, GDC); critical revision of the manuscript for important intellectual content (AAD, AOD, GDC); statistical analysis (AOD, ADD); provision of study materials or patients (AAD, MBS, ADD); obtaining funding (AAD, MBS, ADD); administrative, technical, or logistic support (AAD, MBS, ADD); and supervision (AAD).
Address correspondence to: Anand A. Dalal, PhD, MBA, 5 Moore Dr, Bide West, Mail Stop B.3204, Durham NC 27709. E-mail: firstname.lastname@example.org. Miniño AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. National Vital Statistics Report. 2010;59(2):1-70. http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdf. Accessed May 3, 2011.
2. Wedzicha JA, Donaldson GC. Exacerbations of chronic obstructive pulmonary disease. Res Care. 2003;48(12):1204-1213.
3. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852.
4. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157(5, pt 1):1418-1422.
5. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2012 Chart Book on Cardiovascular, Lung and Blood Diseases. http://www.nhlbi.nih.gov/resources/docs/cht-book. Bethesda, Maryland: US Department of Health and Human Services, Public Health Service, National Institutes of Health.
6. Simoens S, Decramer M. Pharmacoeconomics of the management of acute exacerbations of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2007;8(5):633-648.
7. Toy EL, Gallagher KF, Stanley EL, Swensen AT, Duh MS. The economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review. COPD. 2010;7(3):214-228.
8. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive pulmonary disease: the SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments) [published correction appears in Am J Respir Crit Care Med. 1997;155(1):386]. Am J Respir Crit Care Med. 1996;154(4, pt 1):959-967.
9. Soto FJ, Varkey B. Evidence-based approach to acute exacerbations of COPD. Curr Opin Pulm Med. 2003;9(2):117-124.
10. Dalal AA, Shah M, D’Souza AO, Rane P. Costs of COPD exacerbations in the emergency department and inpatient setting. Respir Med. 2011;105(3):454-460.
11. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. http://www.goldcopd.org/Guidelines/guideline-2010-gold-report.html. Updated 2010. Accessed March 31, 2011.
12. Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106(2):196-204.
13. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet. 1999; 354(9177):456-460.
14. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease: Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340(25):1941-1947.
15. Wilkinson TMA, Donaldson GC, Hurst JR, Seemungal TAR, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;169(12):1298-1303.
16. Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.
17. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a oncedaily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143(5):317-326.
18. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT Investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009;374(9696):1171-1178.
19. Hurst JR, Donaldson GC, Quint JK, Goldring JJ, Baghai-Ravary R, Wedzicha JA. Temporal clustering of exacerbations in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179(5):369-374.
20. Bureau of Labor Statistics, US Dept of Labor. Consumer Price Index—All Urban Consumers. http://data.bls.gov/cgi-bin/surveymost?cu. Updated 2012. Accessed October 5, 2010.
21. Russell R, Anzueto A, Weisman I. Optimizing management of chronic obstructive pulmonary disease in the upcoming decade. Int J Chron Obstruct Pulmon Dis. 2011;6:47-61.
22. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med. 2009;180(1):3-10.
23. Bridevaux PO, Gerbase MW, Probst-Hensch NM, Schindler C, Gaspoz JM, Rochat T. Long-term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax. 2008;63(9):768-774.
24. Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of salmeterol/ fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res. 2009;10:59.
25. Hoogendoorn M, Feenstra TL, Hoogenveen RT, Al M, Mölken M. Association between lung function and exacerbation frequency in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2010;5:435-444.
26. Diette GB, Orr P, McCormack MC, Gandy W, Hamar B. Is pharmacologic care of chronic obstructive pulmonary disease consistent with the guidelines? Popul Health Manag. 2010;12(1):21-26.
27. Feifer RA, Aubert R, Verbrugge RR, Khalid M. Disease management opportunities for chronic obstructive pulmonary disease: gaps between guidelines and current practice. Dis Manag. 2002;5:143-156.