The clinical and economic burden of chronic obstructive pulmonary disease (COPD) is significant and is increasing. COPD is now the third leading cause of death in the United States, after heart disease and cancer.1 COPD reached this rank in 2008, more than a decade earlier than projected by the Global Burden of Disease Study.2 In the United States, mortality due to COPD is the only one among the 5 leading causes of death that showed an increasing rate between 2010 and 2011.3
In 2011, 6.3% of US adults (an estimated 15 million) contacted by the Behavioral Risk Factor Surveillance System (BRFSS) reported being told by their physician that they had COPD.4 This estimate is likely to be low. Spirometric testing performed for the National Health and Nutrition Examination Survey (NHANES; 2007-2010) indicated that an estimated 14% of US adults aged 40 to 79 years met the diagnostic criteria for COPD.5 The roughly 2-fold greater prevalence of COPD that is cited by NHANES is considered a better estimate than the BRFSS prevalence, because COPD is underdiagnosed in its earlier stages.6
Along with the growing prevalence, the death rate for COPD is also rising.1 Between the years 1980 and 2000, the overall death rate attributed to COPD increased by 67%, from 40.7 deaths to 66.9 deaths per 100,000 persons aged ≥25 years.6 Although the death rate for COPD has remained relatively constant through 2005, when it was 64.3 deaths per 100,000 persons aged ≥25 years, the absolute number of annual deaths continues to increase, as a result of the aging of the US population.7 Because the prevalence and severity of COPD increase with age, the impact on the healthcare system will likely continue to expand.8
COPD is a progressive disease and to date cannot be cured.9 Exacerbations of COPD, which are typically defined as an acute worsening of symptoms that results in a change in treatment and often hospitalization, are a major contributor to the high costs associated with the management of patients with COPD10,11 and are a significant risk factor for COPD-related mortality.12 The use of inhaled long-acting bronchodilators has been shown to reduce the incidence of COPD exacerbations,13 but their use remains suboptimal.14,15
The goal of this article is to summarize the current information about the prevalence and healthcare costs associated with COPD in the United States. In the remainder of this review we discuss the rising costs associated with COPD and expand on the evidence that maintenance therapy can improve outcomes and may reduce overall costs. In addition, obstacles that impede appropriate COPD management are also discussed.
Although this article is not a systematic review, detailed searches of the medical literature were conducted. To assess the changing economic impact of COPD in the United States, and, in particular, the contribution of exacerbations to the total cost and the influence of the use of maintenance medication on exacerbations, we conducted several searches on PubMed. The searches were conducted to identify studies that reported on the economic impact of COPD, estimated at 2 or more time periods; pharmacoeconomic studies of the costs of treatment of COPD exacerbations; and randomized, double-blind studies of the impact of maintenance therapy on COPD exacerbations.
The primary search terms were (“Pulmonary Disease, Chronic Obstructive/economics”[Majr] OR ((chronic obstructive [ti] OR COPD [ti])) AND (cost*[ti] OR economic*[ti])). The results for this search were further refined by combining results with additional search terms (eg, “AND exacerbation*”, “AND maintenance”). Only articles describing original research or meta-analyses that were written in English and were published in the year 2000 or later were considered for this review.
A total of 277 articles were identified by our search. Of these, 11 articles were selected for this review (Table), including 2 articles that presented longitudinal analyses of the changing COPD-related healthcare costs,16,17 and 7 articles that estimated the costs associated with the treatment of COPD exacerbations.16-22 In addition, 2 large, randomized, double-blind studies of the impact of maintenance therapy on the incidence of exacerbations were identified and included,23,24 as well as a recent meta-analysis of 35 clinical studies of maintenance therapy lasting at least 4 weeks.13 One recent comprehensive systematic review of pharmacoeconomic studies of maintenance therapy related to COPD was also included.25
The New Demographic for Patients with COPD
Smoking is a major risk factor for COPD. A meta-analysis that included 62 studies from 28 countries reported that the prevalence of COPD among smokers was 15.4% compared with 10.7% among nonsmokers.26 In the United States, smoking is estimated to be responsible for more than 77% of all deaths from COPD.27 There are currently 44 million smokers in the United States, approximately 78% of whom smoke daily.28 Together with the approximately 50 million former US smokers, approximately 94 million Americans are at an increased risk for COPD.28
Women may be more susceptible to the adverse effects of smoking than men,29 which may account for the increasing COPD-related mortality among women. The death rate from COPD among US women has increased steadily, nearly tripling between 1980 and 20006; since 2000, more women than men have died of COPD.7,30 This influence of COPD in women has changed the demographic characteristics of COPD from a disease of elderly men to a condition with a 58% prevalence among women, with an average age 16
The younger age and the changing sex ratio of the COPD population, together with the expansion of Medicare Advantage, have sharply increased the likelihood that a patient with COPD will be enrolled in a private health plan in the United States. In 1987, the National Medical Expenditure Survey (NMES) showed that only 16.2% of patients with COPD had private insurance coverage.16 By 2007, that percentage had increased to 40.6% during a period of little overall growth in private health insurance coverage.16
Patients with COPD have an average of 3.7 to 9 chronic medical comorbidities, including lung disease (often lung cancer), that contribute to their utilization of healthcare at a rate twice that of age- and sex-matched patients without COPD.31,32 Many of these comorbidities are at least in part related to smoking.32 The 2007 Medical Expenditure Panel Survey (MEPS) showed that common comorbidities included hypertension (65% of patients), asthma (41%), diabetes (26%), coronary heart disease (20%), stroke (16%), and myocardial infarction (14%).16 Other often occurring conditions included peripheral arterial disease, obesity, osteoarthritis, osteoporosis/osteopenia, depression, and gastroesophageal reflux disease.33,34 Comorbidities associated with COPD can be worsened by deteriorating COPD; conversely, these comorbidities can contribute to a more rapid COPD decline.35,36 Therefore, the treatment plans for patients with COPD should also include appropriate attention to these comorbidities.
Increasing Costs of COPD
Of the 11 articles included in this article, 2 presented analyses of change in costs in US-based populations. Blanchette and colleagues compared 2 cross-sectional, population-based surveys and analyzed data for patients aged ≥40 years with COPD (1987 NMES37; 2007 MEPS38), and found that the average direct per-patient medical costs (primarily based on payments by health insurance or federal plans)—including COPD-related and non–COPD-related costs—increased by 38% between 1987 and 2007, from $11,807 to $16,292 (constant 2007 US dollars).16 The largest absolute increase was for inpatient admissions, which increased by $2289 per admission. The prescription drug costs increased by 170% per patient, and the costs of emergency department services increased by 183% per visit.16
Dalal and colleagues compared the medical records of commercially insured and Medicare Advantage populations for the period from 2006 to 2009, and found that the direct COPD-related health service utilization (both medical and pharmacy claims) costs increased by approximately 6% annually in the commercially insured patients compared with an annual rate of 5% in the Medicare Advantage patients.17
Because the current prevalence of COPD is higher than it was projected 10 years ago, the overall costs associated with COPD are higher as well. Dalal and colleagues performed a retrospective claims-based analysis of commercially insured patients with COPD and estimated that in 2006, the direct COPD-associated medical and pharmacy costs were $15.7 billion (in 2008 US dollars).39 However, their estimate is likely low, because it does not reflect the impact of comorbidities on these costs. As mentioned earlier, the prevalence of comorbidities among patients with COPD is high, and COPD often exacerbates other chronic conditions. Therefore, including the impact of COPD on coexisting conditions may better represent the actual cost of COPD. The study by Blanchette and colleagues estimated that the all-cause direct costs of patients with COPD in the United States were more than $75 billion in 2007.16 Analysis of the distribution and allocation structure of the current costs of COPD may allow the identification of opportunities to reduce acute care costs via better management of the disease.
A comparison of 1987 to 2007 cumulative expenditures for patients with COPD and the cumulative number of patients reveals nearly identical distributions, with only 20% of patients with COPD accounting for 74% of the total expenditures.16 This observation suggests that the nature of the underlying problem has not changed in those 20 years. Specifically, hospitalization costs have remained the greatest proportion of direct medical costs (85%) associated with COPD, and most of the total cost increase in that period is attributable to hospitalizations, largely resulting from COPD exacerbations.16
Of the articles identified by our search, 7 described the costs associated with hospitalizations for acute exacerbations of COPD in the United States. For example, Wier and colleagues analyzed data from the Healthcare Cost and Utilization Project for patients aged ≥40 years who were hospitalized with COPD in 2008.18 They estimated that the aggregate cost for hospital stays with COPD exacerbation as the primary diagnosis was $3.8 billion.18 A similar study using the same database reported that the aggregate costs for hospitalizations for acute COPD exacerbations increased from $2.96 billion in 2006 to $3.47 billion in 2010 (constant 2010 US dollars).19
Yu and colleagues conducted a retrospective analysis of the Thomson Reuters MarketScan administrative database and reported that the total COPD-related costs for patients with a severe exacerbation were $7014 per 90 days (or $28,056 annually) compared with $658 per 90 days in patients with no exacerbations.20 More than 90% of the costs in patients with severe exacerbations were for inpatient expenses.20 In a predominantly Medicare population, Pasquale and colleagues reported that the annual COPD-related healthcare costs were much higher in patients with a severe exacerbation ($12,765) than in patients with moderate exacerbations ($3356) or no exacerbations ($1425).21
In addition, 1 single article discussed the changes in emergency department or inpatient costs over time, showing that between 2005 and 2008, the inflation-adjusted mean costs for a COPD emergency department visit and for a simple COPD-related hospital admission increased by 4% and 5.9%, respectively.22 The researchers reported no change in the costs associated with COPD-related complex admissions during the same period.22
The Impact of Suboptimal COPD Management on Costs
COPD is a progressive disease, and although it cannot be cured, appropriate management can slow its progression, reduce the frequency and severity of exacerbations, and improve symptoms and a patient’s quality of life.9,40 Despite the existence of several evidence-based guidelines for the diagnosis and treatment of COPD,9 the diagnosis and management of COPD remains suboptimal.15 This “clinical inertia,” which includes physician-, patient-, and system-related factors,15 may contribute to increased morbidity, which in turn contributes to rising COPD-related costs.
The diagnosis of COPD is usually based on clinical signs or symptoms and is often made at a late stage, when the disease is overt. Only 32% of patients with COPD have spirometry performed within 2 years before or 6 months after their diagnosis.41 As a result, COPD is diagnosed later than it would be if spirometry was routinely done, and the opportunities for earlier, and less expensive, interventions are lost. One study showed that 76% of patients with COPD were categorized as having either moderate or severe disease at first diagnosis.42 Before their diagnosis, patients with COPD use 50% to 60% more inpatient and emergency services than matched controls without COPD, and their average incremental annual costs are at least $2627 more than those without COPD.43 Those increased costs are most frequently incurred in the month before COPD diagnosis.43 The investigators speculated that some of these additional costs might have been avoided by earlier diagnosis and earlier initiation of treatment, but no evidence was presented.43
As noted, after delayed diagnosis, opportunities for early intervention are lost. A recent large survey of patients with COPD from 19 health plans (including private plans and private plans offering Medicare Advantage) showed that 66% of patients in commercial plans were not prescribed any maintenance pharmacotherapy, and 7% of patients were given only short-acting betaagonists.44 Patients with Medicare Advantage coverage managed by private health plans fared not much better, with 71% prescribed no maintenance prescriptions and approximately 5% prescribed short-acting beta-agonists only.44 “High complexity” patients (ie, using comorbidities and procedures as markers for advanced COPD) were similarly undertreated despite their higher risk, with 59% and 69% of the patients in commercial and Medicare plans, respectively, receiving no maintenance therapy at all.44 In addition to the suboptimal use of COPD medications, other aspects of treatment guidelines were similarly underutilized. For example, fewer than 20% of the population had received a current influenza vaccination, and more than 80% of current smokers had not received any smoking cessation intervention.44 Smoking cessation is the most effective method of slowing the progression of COPD.9
Maintenance therapy with long-acting bronchodilators has been shown in 2 large, randomized, double-blind studies to significantly reduce the incidence of exacerbations and related hospitalization. In the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, tiotropium (18 µg daily) reduced the relative risk of exacerbation by 14% compared with placebo during the 4-year study.23 A similar reduction in the risk of hospitalization was also observed. In the Towards a Revolution in COPD Health (TORCH) trial, the rate of exacerbations requiring hospitalization was reduced by 18% in the group treated with salmeterol (50 µg twice daily) alone compared with placebo.24 The addition of fluticasone propionate (500 µg twice daily) to the treatment regimen had no further benefit (ie, risk reduction of 17% compared with placebo).24
A recent meta-analysis by Puhan and colleagues supports this concept that inhaled maintenance therapy reduces the incidence of exacerbations in patients with stable COPD.13 In their meta-analysis, Puhan and colleagues reviewed 35 studies of inhaled maintenance therapies with durations of ≥4 weeks and concluded that, compared with placebo, long-acting beta-agonists (LABAs), long-acting anticholinergics, inhaled corticosteroids, or the combination of LABAs plus inhaled corticosteroids significantly reduced the odds of having at least 1 exacerbation (Figure). The authors concluded that each of these pharmacotherapies was equally effective in their ability to reduce the risk of exacerbation.13 In addition, a recent systematic review of long-acting bronchodilators reported that in more than 70% of the 51 studies included in that review, a minimally important difference (defined as the smallest change perceived as important by patients) in health-related quality of life was reported.45
The results of the TORCH and the UPLIFT trials changed the emphasis of pharmacotherapy from the palliation of symptoms to the prevention of exacerbations.46 Exacerbations of COPD contribute to disease progression and to loss of lung function, and mortality increases directly with severe exacerbation frequency, particularly if hospital admission is required. Patients who are hospitalized for 1 exacerbation annually have a significantly elevated mortality risk (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.72), and patients with ≥3 exacerbations in 5 years have a much higher mortality risk (HR, 4.31; 95% CI, 2.7-6.88) compared with patients with COPD who do not have exacerbations.12
The high cost of exacerbations suggests that their incidence rate is the primary element affecting treatment cost-effectiveness in COPD10,11; therefore, a reduction in the number of exacerbations is key to COPD management as well as for lowering overall costs. In a 9-year study of Medicare beneficiaries with COPD, the use of maintenance medication was significantly associated with a lower risk for hospitalization (odds ratio [OR], 0.70; 95% CI, 0.61-0.79) and rehospitalization (OR, 0.74; 95% CI, 0.63-0.87) compared with the cohort not using maintenance therapy.47 Of note, the group using maintenance therapy incurred significantly lower annual Medicare expenses (–$3916; 95% CI, –$4977 to –$2854). This was a retrospective study, and the 2 observation groups had many significant differences in baseline disease severity and other characteristics.47 Therefore, these results cannot be used to support the concept that adding maintenance therapy for nonusers would have reduced costs.
However, although summary analyses of clinical studies of inhaled pharmacologic maintenance therapy in COPD have concluded that the incidence of exacerbations is reduced by this therapy,13 estimates of the cost-effectiveness of maintenance therapy show considerable variation, including cost increases and decreases, and dependent on the patient population, the country being studied, the length of observation, and the pharmacoeconomic models used.25 A recent systematic review of maintenance therapy concluded that the cost-benefit is likely greatest in patients with a high risk for exacerbations.25 Furthermore, in other diseases, it has been difficult to demonstrate cost reduction after the implementation of prophylactic therapy.48
Obstacles to COPD Maintenance Therapy
The reduction of COPD exacerbation frequency may not occur unless maintenance pharmacotherapy is more consistently adopted.15 In the period from 1987 to 2007, despite the advent of new and effective maintenance therapies, the average number of COPD medications per patient did not change.16 Drug costs have continued to increase and are sometimes seen as easy targets for cost reductions. However, prescribed drugs account for only 2.3% of the annual direct expenditures associated with COPD,16 and efforts to reduce this cost may have unintended consequences. For example, in British Columbia, efforts to reduce pharmacy costs by increasing the cost-sharing of prescription drugs for COPD led to the desired decrease in payer drug costs, but they also led to an increase in the net health plan expenditures caused by increased hospitalizations associated with lower adherence rates.49
The proper management of COPD critically depends on the effective delivery of inhaled medications to the lungs. Despite the apparent simplicity of handheld inhaler devices, including pressurized metered-dose inhalers and dry powder inhalers, misuse is common and may negatively influence inhaled drug administration.50 In practice, effective inhaler use depends on a number of factors, such as manual dexterity, cognitive function, and hand strength, that are sometimes impaired in the COPD population.50
In a meta-analysis by Brocklebank and colleagues, 77% of patients using a metered-dose inhaler made ≥1 error during administration.51 The correct use of metered-dose inhalers is reported to decline with advancing age,52 which is important in the aging patient population with COPD. This disease may also negatively influence the ability to properly use a dry powder inhaler because of the need to consistently provide adequate inspiratory airflow to disperse and deliver the drug properly.53,54
The use of a nebulizer to administer inhaled medications may improve drug delivery in patients who are unable to effectively use handheld inhalers. Nebulizers are well received by patients with COPD,55-57 because they require only tidal breathing,58 which facilitates adherence.59 The use of nebulized medication administration may benefit patients with COPD and muscle wasting and weakness, a common systemic effect of COPD that can make operating an inhaler difficult,50,60,61 or patients with borderline or mild cognitive impairment.62 In the United States, nebulized formulations of LABAs (ie, formoterol and arformoterol) and corticosteroids (ie, budesonide) for maintenance therapy of COPD are currently available.9,63 Patients with COPD who are unable to properly use metered-dose inhaler–, or dry-powder inhaler–delivered maintenance medications, may be best served by nebulized formulations of maintenance medications.
In the past decade, pharmacotherapeutic advances in the management of COPD have brought the possibility of improving patient outcomes while lowering expenditures, largely through reducing the rate of exacerbations with the optimal use of maintenance medications. Extending the benefits of maintenance therapy to all patients with COPD must take into account the specific characteristics and capabilities of each patient and the need to administer the appropriate drug most effectively.64 Closer attention to the needs and abilities of patients with COPD to handle specific therapies can improve patient outcomes and reduce overall costs for patients and for payers.
The authors wish to thank Zaid Smith, PhD, of PharmaWrite, LLC, Princeton, NJ, for providing medical writing and editorial assistance.
Mylan Specialty LP provided funding support for the development of this manuscript.
Author Disclosure Statement
Dr Blanchette has received grants from AstraZeneca, Auxilium, Eli Lilly, Endo, GlaxoSmithKline, and Merck. Dr Gross is a consultant to Boehringer Ingelheim and Mylan Specialty; has served as a board member for Alexza, Boehringer Ingelheim, Elevation, Mylan Specialty, and Pfizer; has received honoraria and lecture fees from Boehringer Ingelheim, Forest, and Mylan Specialty; is on the Speaker’s Bureau for AstraZeneca, Boehringer Ingelheim, and Forest; is a research grantee for Boehringer Ingelheim; is an advisor to Almirall, AstraZeneca, Elevation, Forest, Nycomed, and Skye; and has provided expert testimony for Alexza. Dr Altman was an employee of Mylan Specialty at the time of writing of this manuscript.
Dr Blanchette is Research Associate Professor, Department of Public Health Sciences, College of Health & Human Services, University of North Carolina at Charlotte, and Director, Health Economics & Outcomes Research, Otsuka America Pharmaceutical, Inc, Charlotte, NC; Dr Gross is President and CEO, University Medical Research, LLC, Farmington, CT; Dr Altman was Medical Director, Medical Affairs, Mylan Specialty LP, Basking Ridge, NJ, at the time of writing.
- Miniño AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. Natl Vital Stat Rep. 2010;59:1-52.
- Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J. 2006;27:397-412.
- Hoyert DL, Xu J. National Center for Health Statistics. Deaths: preliminary data for 2011; October 2012. www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed April 3, 2014.
- Centers for Disease Control and Prevention (CDC). Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61:938-943.
- Tilert T, Dillon C, Paulose-Ram R, et al. Estimating the U.S. prevalence of chronic obstructive pulmonary disease using pre- and post-bronchodilator spirometry: the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Respir Res. 2013;14:103.
- Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance—United States, 1971-2000. MMWR Surveill Summ. 2002;51:1-16.
- Centers for Disease Control and Prevention (CDC). Deaths from chronic obstructive pulmonary disease—United States, 2000-2005. MMWR Morb Mortal Wkly Rep. 2008;57:1229-1232.
- Blanchette CM, Berry SR, Lane SJ. Advances in chronic obstructive pulmonary disease among older adults. Curr Opin Pulm Med. 2011;17:84-89.
- Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. February 2014. www.goldcopd.org/uploads/users/files/GOLD_Report2014_Feb07.pdf. Accessed April 3, 2014.
- Hertel N, Kotchie RW, Samyshkin Y, et al. Cost-effectiveness of available treatment options for patients suffering from severe COPD in the UK: a fully incremental analysis. Int J Chron Obstruct Pulmon Dis. 2012;7:183-199.
- Nielsen R, Johannessen A, Benediktsdottir B, et al. Present and future costs of COPD in Iceland and Norway: results from the BOLD study. Eur Respir J. 2009;34: 850-857.
- Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925-931.
- Puhan MA, Bachmann LM, Kleijnen J, et al. Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Med. 2009;7:2.
- Dalal AA, Shah MB, D’Souza AO, et al. Observational study of the outcomes and costs of initiating maintenance therapies in patients with moderate exacerbations of COPD. Respir Res. 2012;13:41.
- Cooke CE, Sidel M, Belletti DA, Fuhlbrigge AL. Review: clinical inertia in the management of chronic obstructive pulmonary disease. COPD. 2012;9:73-80.
- Blanchette CM, Dalal AA, Mapel D. Changes in COPD demographics and costs over 20 years. J Med Econ. 2012;15:1176-1182.
- Dalal AA, Liu F, Riedel AA. Cost trends among commercially insured and Medicare Advantage-insured patients with chronic obstructive pulmonary disease: 2006 through 2009. Int J Chron Obstruct Pulmon Dis. 2011;6:533-542.
- Wier LM, Elixhauser A, Pfuntner A, Au DH. Overview of hospitalizations among patients with COPD, 2008: statistical brief #106. February 2011. In: Healthcare Cost and Utilization (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Policy (US); February 2006.
- Perera PN, Armstrong EP, Sherrill DL, Skrepnek GH. Acute exacerbations of COPD in the United States: inpatient burden and predictors of costs and mortality. COPD. 2012;9:131-141.
- Yu AP, Yang H, Wu EQ, et al. Incremental third-party costs associated with COPD exacerbations: a retrospective claims analysis. J Med Econ. 2011;14:315-323.
- Pasquale MK, Sun SX, Song F, et al. Impact of exacerbations on health care cost and resource utilization in chronic obstructive pulmonary disease patients with chronic bronchitis from a predominantly Medicare population. Int J Chron Obstruct Pulmon Dis. 2012;7:757-764.
- Dalal AA, Shah M, D’Souza AO, Rane P. Costs of COPD exacerbations in the emergency department and inpatient setting. Respir Med. 2011;105:454-460.
- Tashkin DP, Celli B, Senn S, et al; for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359: 1543-1554.
- Calverley PM, Anderson JA, Celli B, et al; for the TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789.
- Rutten-van Mölken MP, Goossens LM. Cost effectiveness of pharmacological maintenance treatment for chronic obstructive pulmonary disease: a review of the evidence and methodological issues. Pharmacoeconomics. 2012;30:271-302.
- Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523-532.
- Centers for Disease Control and Prevention (CDC). Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997-2001. MMWR Morb Mortal Wkly Rep. 2005;54:625-628.
- Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary health statistics for U.S. adults: National Health Interview Survey, 2010. Vital Health Stat 10. January 2012:1-207.
- Sørheim IC, Johannessen A, Gulsvik A, et al. Gender differences in COPD: are women more susceptible to smoking effects than men? Thorax. 2010;65:480-485.
- Heron M. Deaths: leading causes for 2010. Natl Vital Stat Rep. 2013;62:1-97.
- Mapel DW, Hurley JS, Frost FJ, et al. Health care utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization. Arch Intern Med. 2000;160:2653-2658.
- Barr RG, Celli BR, Mannino DM, et al. Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med. 2009; 122:348-355.
- Reid WD, Yamabayashi C, Goodridge D, et al. Exercise prescription for hospitalized people with chronic obstructive pulmonary disease and comorbidities: a synthesis of systematic reviews. Int J Chron Obstruct Pulmon Dis. 2012;7:297-320.
- Patel AR, Hurst JR. Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art. Expert Rev Respir Med. 2011;5:647-662.
- Antonelli Incalzi R, Fuso L, De Rosa M, et al. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J. 1997;10:2794-2800.
- Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest. 2005;128: 2005-2011.
- Strassels SA, Smith DH, Sullivan SD, Mahajan PS. The costs of treating COPD in the United States. Chest. 2001;119:344-352.
- Agency for Healthcare Research and Quality. Medical Expenditure Panel Survey. http://meps.ahrq.gov/mepsweb/about_meps/survey_back.jsp. Accessed April 3, 2014.
- Dalal AA, Christensen L, Liu F, Riedel AA. Direct costs of chronic obstructive pulmonary disease among managed care patients. Int J Chron Obstruct Pulmon Dis. 2010;5:341-349.
- Qaseem A, Wilt TJ, Weinberger SE, et al; for the American College of Physicians, American College of Chest Physicians, American Thoracic Society, European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155:179-191.
- Han MK, Kim MG, Mardon R, et al. Spirometry utilization for COPD: how do we measure up? Chest. 2007;132:403-409.
- Mapel DW, Dalal AA, Blanchette CM, et al. Severity of COPD at initial spirometry-confirmed diagnosis: data from medical charts and administrative claims. Int J Chron Obstruct Pulmon Dis. 2011;6:573-581.
- Akazawa M, Halpern R, Riedel AA, et al. Economic burden prior to COPD diagnosis: a matched case-control study in the United States. Respir Med. 2008;102: 1744-1752.
- Make B, Dutro MP, Paulose-Ram R, et al. Undertreatment of COPD: a retrospective analysis of US managed care and Medicare patients. Int J Chron Obstruct Pulmon Dis. 2012;7:1-9.
- Braido F, Baiardini I, Cazzola M, et al. Long-acting bronchodilators improve health related quality of life in patients with COPD. Respir Med. 2013;107:1465-1480.
- Mapel DW, Schum M, Lydick E, Marton JP. A new method for examining the cost savings of reducing COPD exacerbations. Pharmacoeconomics. 2010;28:733-749.
- Stuart BC, Simoni-Wastila L, Zuckerman IH, et al. Impact of maintenance therapy on hospitalization and expenditures for Medicare beneficiaries with chronic obstructive pulmonary disease. Am J Geriatr Pharmacother. 2010;8:441-453.
- Cohen JT, Neumann PJ, Weinstein MC. Does preventive care save money? Health economics and the presidential candidates. N Engl J Med. 2008;358:661-663.
- Dormuth CR, Neumann P, Maclure M, et al. Effects of prescription coinsurance and income-based deductibles on net health plan spending for older users of inhaled medications. Med Care. 2009;47:508-516.
- Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2011;68:1221-1232.
- Brocklebank D, Ram F, Wright J, et al. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature. Health Technol Assess. 2001;5:1-149.
- Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002;19:246-251.
- Lavorini F, Magnan A, Dubus JC, et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med. 2008;102:593-604.
- Broeders ME, Vincken W, Corbetta L; for the ADMIT Working Group. The ADMIT series—Issues in Inhalation Therapy. 7. Ways to improve pharmacological management of COPD: the importance of inhaler choice and inhalation technique. Prim Care Respir J. 2011;20:338-343.
- Barta SK, Crawford A, Roberts CM. Survey of patients’ views of domiciliary nebuliser treatment for chronic lung disease. Respir Med. 2002;96:375-381.
- Lowe DO, Lummis H, Zhang Y, Sketris IS. Effect of educational and policy interventions on institutional utilization of wet nebulization respiratory drugs and portable inhalers. Can J Clin Pharmacol. 2008;15:e334-e343.
- Yamamoto LG, Okamura D, Nagamine J, et al. Dispensing home nebulizers for acute wheezing from the hospital is cost-effective. Am J Emerg Med. 2000;18:164-167.
- Dolovich MB, Ahrens RC, Hess DR, et al; for the American College of Chest Physicians, American College of Asthma, Allergy, and Immunology. Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005;127:335-371.
- Small M, Anderson P, Vickers A, et al. Importance of inhaler-device satisfaction in asthma treatment: real-world observations of physician-observed compliance and clinical/patient-reported outcomes. Adv Ther. 2011;28:202-212.
- Behara SR, Larson I, Kippax P, et al. Insight into pressure drop dependent efficiencies of dry powder inhalers. Eur J Pharm Sci. 2012;46:142-148.
- Self TH, Pinner NA, Sowell RS, Headley AS. Does it really matter what volume to exhale before using asthma inhalation devices? J Asthma. 2009;46:212-216.
- Allen SC. Competence thresholds for the use of inhalers in people with dementia. Age Ageing. 1997;26:83-86.
- US Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. www.accessdata.fda.gov/scripts/Cder/ob/default.cfm.
- Charles MS, Blanchette CM, Silver H, et al. Adherence to controller therapy for chronic obstructive pulmonary disease: a review. Curr Med Res Opin. 2010;26:2421-2429.