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Conquering COPD: Value-Based Perspectives for Providers and Payers


Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in the United States, despite lower smoking rates and preventive efforts.1,2 A chronic, progressive lung disorder, COPD results in substantial disability, reduced quality of life, and increased risk for premature death.3 Nevertheless, COPD remains an underdiagnosed and undertreated condition.4

To discuss the challenges faced by the medical community in identifying and managing patients with COPD, and to brainstorm potential strategies to improve the diagnosis and treatment of COPD, an advisory group of respiratory specialists and payer stakeholders was convened on November 14, 2015, in Hoboken, NJ. The panel of experts included practicing pulmonologists with extensive research backgrounds, as well as medical and pharmacy directors from the payer side who represented the population-based value perspective.

The advisory panel was assembled to develop actionable strategic and tactical recommendations for all healthcare system stakeholders committed to delivering high-quality care for patients with COPD. To that end, the sponsor of the panel discussion sought to identify reasons for variation in the care of patients with COPD, discuss avenues for providers and payers to align on system-wide opportunities for care improvement, and share best practices with stakeholders so that they can consider them when developing optimal COPD management strategies.

This advisory panel reviewed the current standards of COPD care based on clinical guidelines and recent emerging data, and discussed the central role of pharmacotherapy in minimizing the frequency and the severity of acute COPD exacerbations. Looking forward, the panel discussed the research that will be needed to generate evidence required to support ongoing clinical innovation and value-driven care for patients with COPD. Within this context, the group also discussed the role of nebulized therapy for the treatment of patients with COPD in a value-based care paradigm, particularly with respect to clinical outcomes and patient adherence to therapy.

The Pathophysiology of COPD

COPD is an umbrella term representing a group of lung pathologies that include emphysema, chronic bronchitis, bronchiectasis, and nonreversible asthma, and is characterized by persistent airflow obstruction, frequent coughing, dyspnea, and sputum production.5,6

In COPD, chronic enhanced inflammatory processes lead to structural alterations that contribute to total airflow limitation.7 These pathophysiologic changes include mucosal inflammation and fibrosis, luminal obstruction with inflammatory exudate and mucus, and loss of alveolar attachments because of parenchymal destruction.7 Over time, these changes, which are not fully reversible, degrade the patient’s ability to breathe normally.7

Chronic bronchitis, which may develop independently as nonobstructive chronic bronchitis, is also a major component of COPD, and may precede or follow the development of airflow limitation; chronic bronchitis may also be associated with the development and/or the acceleration of fixed airflow limitation.7

Patients with COPD have an amplified inflammatory response to long-term irritants, such as tobacco smoke; biomass fuels; and other dusts, gases, or vapors.7 Although the mechanisms for this magnified response have not been fully elucidated, researchers believe that there may be a genetic component.7

Oxidative stress and an imbalance in proteases and antiproteases cause modified lung inflammation in patients with COPD, eventually leading to the pathologic changes that are characteristic of COPD.7 Inflammatory mediators have been shown to facilitate the inflammatory process through chemotactic factors, amplifying the inflammatory process via proinflammatory cytokines, and inducing structural changes via growth factors.7

Common symptoms of COPD include increased breathlessness, frequent coughing (with and without sputum), wheezing, and chest tightness.6 Individuals with early-stage COPD may not recognize their symptoms, or may attribute them to the normal aging process.6 Over time, however, symptoms become more apparent in the developed stages of the disease.6

Long-term cigarette smoking is widely recognized as the most significant risk factor for COPD in the United States, and the risk increases with the number of pack-years of tobacco use.8 Former smokers continue to be at risk for COPD as a result of loss of FEV1 as part of the normal aging process, as are individuals exposed to large amounts of secondhand smoke.8

Other risk factors for COPD include5,6,8:

  • Sustained occupational exposure to chemical fumes, vapors, and dusts
  • Poor indoor air quality in the home, especially in the developing world
  • Age
  • Genetics, particularly alpha-1 antitrypsin deficiency, although other genetic factors are thought to make smokers more susceptible to COPD.

COPD is frequently associated with a host of comorbid conditions, including cardiovascular disease, anxiety and depression, infections, lung cancer, osteoporosis, rheumatoid arthritis, and sleep disorders.9,10 These comorbidities have a greater negative impact in patients with COPD than in individuals without COPD; therefore, a holistic approach to treatment that includes diagnosis and management of comorbidities should be considered.9

Clinical and Economic Burden of COPD

COPD is the third leading cause of death in the United States, after heart disease and cancer.5,11 The mortality rate for patients with COPD is on the rise, and is higher among women than it is among men.11

In 2011, 15 million Americans reported that they had been diagnosed with COPD; however, one study showed that more than half of adults with impaired lung function were not aware that they had suboptimal lung function.5,12 Therefore, the true prevalence of COPD is thought to be considerably higher than what is currently reported.5

The prevalence of COPD varies considerably by geography (Figure). In 2011, the highest prevalence rates of COPD were concentrated in the East Central and Southern regions of the United States.11


The economic burden of COPD is substantial.13,14 Based on a national survey and epidemiologic data, Ford and colleagues reported that the national direct medical costs attributed to COPD were estimated to be $32.1 billion in 2010.13,14 The study estimated that, on average, adults with COPD paid $6000 more annually in medical care than adults without COPD.13,14 In addition, the same study reported that an estimated 16.4 million absentee days were attributed to COPD in 2010.13,14

Furthermore, an estimated 715,000 discharges where COPD was listed as the primary reason for inpatient admission were reported in 2010.1 COPD hospitalization rates are higher in the elderly; the discharge rate for patients aged older than 65 years was more than 4 times higher than that in the patients aged 45 to 64 years.1

Hospital readmissions within 30 days are also a concern for COPD.12 In an analysis of data from 2003-2004, nearly 23% of fee-for-service Medicare beneficiaries admitted to the hospital for COPD were readmitted within 30 days.15,16 A subsequent analysis by the Pittsburgh Regional Health Initiative found similar 30-day readmission rates, with an average length of stay of 4.9 days.16

Clinical Guidelines for COPD Management

Several consensus medical guidelines have been developed in an effort to promote evidence-based identification and management of COPD. One such guideline for the identification and management of stable COPD was published in 2011 through a joint collaboration of 4 organizations, including the American College of Physicians (ACP), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and European Respiratory Society (ERS).17

Likewise, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) published its first report Global Strategy for the Diagnosis, Management, and Prevention of COPD in 2001 in collaboration with the National Heart, Lung, and Blood Institute; National Institutes of Health; and the World Health Organization. The GOLD guidelines were recently updated in December 2015.7

In addition, the National Institute for Health and Care Excellence (NICE), based in the United Kingdom, first published its guidelines on COPD in 2004. These guidelines were last updated in 2010, and are scheduled for another update in 2016.18

Important differences exist among the consensus guidelines promulgated by the aforementioned organizations. For example, the ACP/ACCP/ATS/ERS guidelines use forced expiratory volume in 1 second (FEV1) as the key metric in guiding treatment decisions.17 Specifically, the guidelines indicate that inhaled bronchodilators can be used for patients with FEV1 = 60% to 80% of predicted value, and monotherapy with long-acting inhaled anticholinergics or long-acting beta2-agonists (LABAs) are recommended for patients with FEV1 <60% of predicted value.17 In this patient population, combination inhaled therapies with long-acting anticholinergics, LABAs, or inhaled corticosteroids (ICSs) may also be considered.17

The GOLD guidelines combine the subjective and objective components of COPD to classify the severity of COPD and guide treatment recommendations.7 The GOLD guidelines categorize patients into 4 groups based on their symptoms, spirometric classification, and/or risk of exacerbations.7 Patients in group A are characterized by mild-to-moderate obstruction, minimal symptoms, and few exacerbations; in these patients, short-acting anticholinergics or short-acting beta2-agonists (SABAs) are recommended as needed.7 Patients in group B have mild-to-moderate obstruction, and relatively few exacerbations, but have developed more severe symptoms; as a result, long-acting anticholinergics or LABAs are recommended for these patients.7 Patients in groups C and D have severe obstruction, frequent exacerbations, and minimal (group C) or severe (group D) symptoms; the GOLD guidelines recommend long-acting anticholinergics or a combination of a LABA plus an ICS in these patients.7

The NICE guidelines focus on symptoms of breathlessness and exacerbations.19 SABAs or short-acting anticholinergics are recommended as needed in patients with breathlessness and with exercise limitation.19 In patients with persistent breathlessness or exacerbations despite initial therapy, long-acting anticholinergics or LABAs are recommended if FEV1 ≥50% of predicted value, and long-acting anticholinergics or a combination of a LABA and an ICS are recommended if FEV1 <50% of predicted value.19 In patients with persistent breathlessness or exacerbations despite use of the previously mentioned therapy, LABAs plus ICSs, or a combination of a long-acting anticholinergic, a LABA, and an ICS is recommended if FEV1 ≥50% of predicted value, and a combination of a long-acting anticholinergic, a LABA, and an ICS is recommended if FEV1 <50% of predicted value.19

The clinicians and payers participating on the advisory panel identified that COPD guidelines, particularly the earlier version of the GOLD guidelines, may not provide sufficiently clear, unequivocal guidance for the management of COPD, especially for primary care providers. This may be attributed in part to the lack of objective disease markers in COPD (such as glycated hemoglobin A1c levels in diabetes or lipid levels in dyslipidemia), which complicates the patient assessment process in COPD. In addition, one pulmonologist participating on the panel pointed out that the sheer length of the GOLD guidelines made it impractical for practicing physicians to use as a reference.

The Approach to Management of COPD

Some primary care providers lack awareness and knowledge regarding COPD; therefore patients often remain undiagnosed until the underlying disease process has progressed to the moderate-to-severe stage, limiting interventional options for the clinician.7,20 Patients may not recognize their symptoms, and if they do, they may attribute them to the normal aging process.6,20 Because of its progressive nature, it is important to diagnose COPD as early as possible, and initiate appropriate management strategies in a timely manner.7,20

In higher-risk, undiagnosed individuals, timely screening can detect COPD before major loss of lung function occurs.6


Spirometry is considered the gold standard for the diagnosis of COPD. Spirometry measures FEV1, and is the most reproducible and objective measurement of airflow limitation available for COPD.7 The ACP/ACCP/ATS/ERS guidelines and the GOLD guidelines recommend using spirometry to diagnose airflow obstruction in patients with respiratory symptoms.17 However, spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms.17

According to the GOLD guidelines, spirometry is required to make a confident diagnosis of COPD when COPD is suspected because of symptoms; a family history of COPD or other chronic respiratory pattern; and/or a history of hazardous exposures, such as tobacco smoke, occupational dusts, or fumes. The presence of a postbronchodilator FEV1/forced vital capacity <0.70 may be indicative of persistent airflow limitation and, therefore, of COPD.7 At the extremes of age, use of the lower limit of normal for FEV1/FVC is a more reliable indicator of airflow obstruction.

Participating panel pulmonologists agreed that using spirometry is critical to confirm airflow limitation; however, spirometry alone is not sufficient to make a definitive diagnosis of asthma or COPD. As one pulmonologist noted, “Spirometry is essential for confirming the diagnosis of airflow obstruction. Frankly, to treat someone on a presumptive diagnosis of COPD or asthma without spirometry is like giving an antihypertensive without measuring blood pressure. However, we have to realize that spirometry has its limitations. Its value is in identifying airflow obstruction, tracking progression of disease, and rate of decline of lung function. It doesn’t distinguish between asthma and COPD.”


The primary goals of COPD assessment are to determine the disease severity, its impact on the patient’s health status, and the risk for future events (eg, exacerbations, hospital admissions).7 According to the GOLD guidelines, clinicians assessing COPD must consider the following aspects of the disease separately to achieve these goals7:

  • Current level of patient’s symptoms
  • Severity of airflow limitation (as measured by spirometry)
  • Exacerbation risk
  • Presence of comorbidities

As previously mentioned, a thorough symptomatic assessment is combined with the patient’s spirometric classification and/or risk for exacerbations to assess the impact of COPD on an individual patient.7 Symptom assessment and management of COPD may be aided by validated, self-reported instruments.7 The GOLD guidelines recommend the use of 2 comprehensive patient questionnaires to assess the health status of patients with COPD. The COPD Control Questionnaire (CCQ) was specially developed to measure clinical control in patients with COPD; it is short, easy to administer, and is available in more than 60 languages.7,21,22 When administered to patients with GOLD stage I-III, the CCQ demonstrates validity, reliability, and responsiveness.21,22

Another tool available to providers is the COPD Assessment Test (CAT), is an 8-item unidimensional measure of health status impairment in patients with COPD.23 The CAT is also a reliable questionnaire, and validated translations are available in more than 50 languages.23 The CAT score correlates very closely with the health status measured using the St. George’s Respiratory Questionnaire.23 The CAT scale is recommended for assessing symptoms, with higher scores denoting a more severe impact of COPD on a patient’s life.23

In the absence of a CAT score, the GOLD guidelines note that the British Modified Medical Research Council (mMRC) scale scores provide an assessment of the impact of dyspnea.7

Participating pulmonologists indicated that although symptom-based assessment is important, current assessment tools available to the medical community have limited utility, noting that these assessment tools are not always reflective of patients’ real-world experiences and needs.

The GOLD guidelines indicate that 3 methods can be used to assess the risk for COPD exacerbations: (1) a population-based method using the GOLD spirometric classification; (2) a method based on the individual patient’s history of exacerbations, with 2 or more exacerbations in the preceding year indicating high risk; (3) a history of hospitalization because of an exacerbation in the preceding year.7 If there is a discrepancy between these criteria, the GOLD guidelines recommend using the assessment pointing to the highest level of risk.7

To use this approach in clinical practice, the GOLD guidelines recommend implementing 3 steps in the following sequence7:

  1. Assess COPD symptoms based on the CAT score or dyspnea based on the mMRC score
  2. Assess the risk for exacerbations using the GOLD classification of airflow limitation, a history of exacerbations, and a history of hospitalizations because of an exacerbation
  3. Choose the highest risk according to the GOLD grade or medical history.

Combining these items in a matrix approach allows clinicians to choose a patient category in 1 of 4 quadrants: A (less symptoms, lower risk); B (more symptoms, lower risk); C (lower symptoms, greater risk); and D (more symptoms, greater risk).7

The 4 GOLD categories for COPD can also be used to help guide treatment for COPD.7 Once COPD has been diagnosed, the effective management of COPD should be based on an individualized assessment of the disease to reduce both current symptoms and the future risk for exacerbations.7

The ATS recommends a slightly different approach to patient assessment from that of the GOLD guidelines. According to the ATS, the clinical assessment of patients with suspected COPD should be based on their medical history and on their physical examination.24 A thorough review of the patient’s medical history should assess the patient’s current symptoms, including cough, sputum production, and dyspnea (during exertion or at rest).24 Dyspnea can be quantified using the mMRC scale, because it predicts quality of life and survival.24

A patient’s medical history, including a history of COPD (eg, exacerbations or hospitalizations), asthma, allergy, respiratory infections, or other respiratory disease should be taken into account.24 Medical history should also account for any comorbidities, especially those that share a risk factor with COPD (such as tobacco smoke exposure), any history of unexplained weight loss, and nonspecific symptoms, such as wheezing and chest tightness or pain.24

In addition, evaluating the history of exposure to risk factors, such as occupational or environmental noxious agents, and a detailed smoking history, measured by pack-years, are essential parts of the clinical assessment process.24

According to the ATS, all patients should have their respiratory rate measured, weight and height determined, and their body mass index calculated during a physical examination to help identify the presence of the respiratory and systemic effects of COPD.24

In addition, patients should be inspected for barrel chest deformity; pursed-lips breathing; chest and abdominal wall paradoxical movements; and use of accessory respiratory muscles; all of these signs indicate severe airflow limitation, hyperinflation, and impairment of the mechanics of breathing.24 Likewise, patients should be evaluated for percussion, and auscultation of the lungs and heart.24 Systemic signs that may be indicative of COPD, including neck vein distension, liver enlargement, peripheral edema, loss of muscle mass, peripheral muscle weakness, or cyanosis, should also be evaluated.24

Payers and providers participating in the panel agreed that it is critical for systems of care to develop processes that facilitate the early diagnosis and treatment of COPD, noting that screening programs that identify less advanced disease, and timely, aggressive treatment have been shown to yield improved outcomes. Integrated health systems appear to be well-positioned to implement a holistic, coordinated approach to care.

As one pharmacy director from the payer side noted, “Our [health system’s] goal was the early identification of patients with newly enrolled COPD. Smokers are referred to aggressive smoking cessation programs. There is an exercise component to the program in an effort to improve exercise capacity. Pharmacy and pulmonology specialists are both involved in reviewing these patients. If patients encounter issues with their therapy, changes are made immediately, rather than waiting for the next appointment. All of this is done within the first hundred days of membership in our plan. As a result, we’ve seen substantial improvements in adherence and hospitalization rates.”


Several classes of medications are typically used for the treatment of patients with COPD.7,17 Each pharmacologic treatment regimen needs to be patient-specific, guided by the severity of COPD symptoms, risk for COPD exacerbations, drug availability, and the patient’s response.7

The GOLD guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with either more COPD symptoms or who are at a higher risk for COPD exacerbations, noting that long-acting bronchodilators are more effective than short-acting bronchodilators at maintaining symptom relief.7 As a result, long-acting bronchodilators with or without ICS are the first or second choice controller therapies for the majority of patients with COPD.7

The ACP/ACCP/ATS/ERS clinical guidelines make treatment recommendations based on the degree of airflow limitation and respiratory symptoms.17 The guidelines suggest that treatment with inhaled bronchodilators is preferred in patients with stable COPD with respiratory symptoms and FEV1 between 60% and 80% of predicted value, but notes that there is limited and conflicting evidence regarding the initiation of inhaled bronchodilator therapy in this patient population; therefore, the recommendation is considered “weak.”17

For patients with stable COPD and respiratory symptoms and FEV1 <60% of predicted value, the ACP/ACCP/ATS/ERS guidelines strongly recommend treatment with inhaled bronchodilators, noting that patients who benefit the most from inhaled therapies are often typified as having respiratory symptoms and airflow obstruction with an FEV1 <60% predicted.17 This recommendation does not address the occasional use of short-acting inhaled bronchodilators for the relief of acute symptoms.17

For symptomatic patients with COPD and FEV1 <60% of predicted value, the ACP/ACCP/ATS/ERS consensus guidelines strongly recommend that clinicians prescribe monotherapy with long-acting inhaled anticholinergics or with inhaled LABAs. Although noting that adverse reactions, including cardiovascular events, may occur with LABAs and LAMAs, the guidelines indicate that monotherapy with a LABA or a long-acting inhaled anticholinergic is beneficial for reducing COPD exacerbations and for improving patients’ health-related quality of life.17 However, evidence was inconclusive regarding the effect of inhaled agents on mortality, hospitalizations, and dyspnea.17 The ACP/ACCP/ATS/ERS guidelines do not recommend the use of ICSs as preferred monotherapy for patients with stable COPD.17

The ACP/ACCP/ATS/ERS guidelines provide a weak recommendation for the administration of combination inhaled therapies (ie, long-acting anticholinergics, LABAs, or ICSs) for symptomatic patients with stable COPD and FEV1 <60% predicted, noting that evidence gaps remain in determining when monotherapy should be supplanted with combination therapy.17

In terms of nonpharmacologic therapy, the ACP/ACCP/ATS/ERS guidelines recommend that clinicians prescribe oxygen therapy for 15 or more hours daily in patients with COPD who have severe resting hypoxemia (defined as blood oxygen saturation level ≤88%).17 To accurately evaluate oxygen status, the assessment should ideally occur when patients are stable rather than during or immediately after an exacerbation.17

Based on the evidence, the ACP/ACCP/ATS/ERS guide­lines strongly recommend that clinicians prescribe pulmonary rehabilitation for symptomatic patients with an FEV1 <50% predicted, noting that clinicians may also consider pulmonary rehabilitation for symptomatic or exercise-limited patients with FEV1 >50% of predicted value.17

Pharmacologic Options

For patients at low risk and relatively few symptoms, a number of short-acting bronchodilators are available for use before physical activities.7,25 Short-acting bronchodilators include albuterol (eg, ProAir HFA, Ventolin HFA), levalbuterol (Xopenex), and ipratropium (Atrovent).25

Long-acting agents for the maintenance treatment of COPD include a number of US Food and Drug Administration–approved single-agent (Table 1) and combination therapies (Table 2) administered via a range of delivery devices and mechanisms.26

Table 1

Table 2

Delivery Devices

Several different delivery devices are available for administering drugs to patients with COPD.7,27,28 Each type of device has advantages and disadvantages; therefore, the choice of a specific device or a delivery mechanism is dependent on how well the patient’s individual needs align with the attributes and the therapeutic characteristics of each device.7,27,28

Metered-dose inhalers (MDIs) are handheld pressurized canisters containing a surfactant, a propellant, a mouthpiece, and the active ingredient (drug) in a suspension solution.27 MDIs are portable, with a low risk of bacterial contamination; however, they require shaking, actuation, and hand–breath coordination for optimal use.27 In addition, there may be some oropharyngeal deposition with MDIs.7,27,28

Although they require device actuation, pressurized MDIs (pMDIs) reduce the need for hand–breath coordination.28 However, drug administration with pMDIs may cause forceful impaction on the back of the throat, with oropharyngeal deposition.28 Furthermore, despite press-and-breathe actuation, use of pMDIs may result in suboptimal lung deposition.28

Dry powder inhalers (DPIs) are breath-actuated devices that deliver the drug in dry powder particulate form.27,28 DPIs are typically portable and do not require spacers; however, an adequate inspiratory flow rate is required for optimal drug delivery.27 Furthermore, DPIs may sometimes result in pharyngeal deposition.27,28

A novel delivery device, the Respimat Soft Mist Inhaler is not breath-actuated, is portable, and delivers a slow-moving mist, allowing the inhalation of medication independent of inspiratory effort.29,30 However, it may be difficult to load and prime for some patients, requiring hand strength and good coordination.31 In addition, the mandatory 3-step delivery process may be confusing and result in missed doses.31

Incorrect inhaler technique has been demonstrated in clinical trials among patients with COPD.32 In one study of geriatric, inhaler-naïve patients, only 60% of patients were able to use the DPI properly.32 The study authors concluded that in older patients, the correct use of DPIs can be limited by the decrease in the maximum inspiratory pressure, a reduction in the peak inspiratory flow, and the loss of cognitive function.32 In addition, arthritis, joint pain, or neuromuscular conditions such as Parkinson disease can impede proper handheld inhaler use.33

Error rates with MDIs and DPIs have been documented in several studies (Table 3).34-36 Because of the progressive nature of COPD, patients should be assessed periodically to determine which device is appropriate, as needs may change over the course of the disease.34-36

Table 3

The panel agreed that improper inhaler technique remains an issue for many patients, despite training and retraining efforts. One participant noted that studies evaluating the impact of suboptimal device utilization on health outcomes are needed to better understand the scope of the problem and to formulate potential solutions.

The Role of Nebulized Therapy in COPD

Nebulized therapy is a proved maintenance strategy in COPD, and is associated with key benefits.37,38 Nebulizers can be used with patients at any age, regardless of disease severity and acuity, and are appropriate in all clinical settings. Today’s nebulizers are portable and typically battery-operated, making them less cumbersome to carry from one setting to another. In addition, compared with pMDIs and DPIs, nebulizers require little or no hand–breath coordination and effort during inhalation; the aerosol is continuously produced by the nebulizer, allowing the patient to rest comfortably while taking the medication, using tidal-volume breathing.37,38

Although there may be some variability depending on the nebulizer device, the aerosol output is typically in the respirable range (1-5 µm), and the use of unit-dose packaging facilitates accurate administration of individual dosages.39,40

Nebulized therapy may be preferred in some clinical scenarios when the drug is available in an aqueous solution.37 In particular, nebulized therapy may benefit patients with impaired manual dexterity, severe pain or muscle weakness as a result of a neuromuscular disease, debilitation because of hospitalization or chronic illness, and inadequate symptom relief despite the appropriate use of MDIs or DPIs.37

Nebulizer administration may be particularly useful in certain sites of care. For example, it may be helpful for patients transitioning from a hospital to a long-term care facility.41 Nebulizers may also be the preferred mode of medication delivery for patients who administer their COPD therapies at home, particularly those with certain physical or cognitive limitations.7 Therefore, the need for home nebulizers should be routinely assessed after hospital discharge.7

Furthermore, nebulized therapy may be considered in patients who are nonadherent to therapy with MDIs or DPIs, which may occur for a variety of reasons, including cognitive issues, muscle weakness, difficulty with inhaler technique, and/or prohibitive cost.37 Nebulized therapy may also be a more efficient means of administration than other devices for those patients who require high doses of a bronchodilator or an ICS, or if the coadministration of multiple agents is required.37

Affordability may also factor into patients’ decisions when selecting a device for their COPD therapy. Some patients may prefer nebulizers, because the costs of the equipment and medications are covered by fee-for-service Medicare, whereas pMDIs and DPIs typically require separate coverage under Medicare Part D.37

In addition to its ease of administration and affordability, nebulizers have also been shown to improve patients’ quality of life.42 A 2013 survey evaluated the quality-of-life benefits of nebulized therapy for patients with COPD and their caregivers. Patients reported that nebulizers allowed them to breathe easier (91%), have more control of their symptoms (85%), be more physically active in their daily life (74%), depend less on help from friends and/or family (73%), and make fewer unscheduled visits to the physician or hospital (71%). In the survey, the caregiver responses were very closely aligned with the patient responses (maximum of 4% variance for all of the items cited above).42

Some of the disadvantages of nebulized therapy pertain to older devices. For example, older nebulizers require a source of compressed air, periodic equipment maintenance, and daily cleaning for infection control. In addition, these older devices have been cited as bulky and cumbersome to transport.38,42

Nebulizers are also more time-consuming than MDIs or DPIs.38 In addition, because nebulizers can aerosolize several drugs, their performance efficiency may be highly variable and dependent on several factors, such as the driving gas, flow, and fill volume. As a result, the amount of drug available for lung deposition is not predictable unless that particular device has been studied with the drug of interest.38

Types of Nebulizers

Several different types of nebulizers are available to deliver respiratory therapies. These include29,43:

  • Active mesh
  • Passive mesh
  • Smart mesh
  • Jet
  • Respimat Soft Mist Inhaler
  • Ultrasonic.

Similar to inhaler devices, each type of nebulizer has its advantages and disadvantages. Jet nebulizers are an established option for patients with pulmonary diseases, but they are bulky and require a power source.43 Ultrasonic nebulizers are more efficient and more compact than jet nebulizers, but they cannot deliver proteins or suspensions.43 Mesh nebulizers use lower-frequency waves, eliminating heating issues that denature proteins during aerosol therapy. Mesh nebulizers are versatile, and are suitable for the delivery of proteins, suspensions, liposomes, and nucleic acids.43

Respiratory therapies available for use in nebulized form include the LABAs formoterol fumarate (Perforomist) and arformoterol tartrate (Brovana); the SABA levalbuterol tartrate (Xopenex); the SABA/short-acting muscarinic agonist combination agent ipratropium bromide plus albuterol sulfate (DuoNeb); as well as several formulations of generic albuterol sulfate.44-46

Long-acting agents formoterol fumarate and arformoterol tartrate currently serve as the mainstays of nebulized maintenance therapy for COPD.44,45,47 Although the chemical compositions of formoterol fumarate and arformoterol tartrate vary slightly (ie, aformoterol is an R-enantiomer and formoterol is a racemic mixture of D- and L-forms), both agents have demonstrated a significant reduction in FEV1 levels for 12 weeks without the evidence of tachyphylaxis.45,47 In addition, in clinical trials, maintenance therapy with formoterol fumarate and arformoterol tartrate demonstrated a 42% reduction and a 37% reduction in the use of rescue albuterol, respectively.47,48

Participating panel clinicians support the use of nebulized maintenance therapy with long-acting agents for appropriate patients, agreeing that maintenance treatment with long-acting nebulizers may lead to the reduced use of short-acting bronchodilators. The participating panel members agreed that, in some situations, the criteria guiding the decision to recommend nebulized therapy were relatively straightforward, particularly in patients discharged from hospitals after an inpatient stay; in patients demonstrating consistent difficulty using inhalers, even after training; and in patients with impaired manual dexterity, chronic muscle weakness, or cognitive impairment.

Overall, the participating clinicians indicated that they were more likely to recommend nebulized therapy for older patients with more severe disease.

Several participants, however, expressed the need for more objective data to help guide decision-making. One participant suggested that the peak inspiratory flow rates may serve as a metric to help guide clinical recommendations for nebulized therapy, stating, “In our research, we found that the people who had low peak inspiratory flow rates in the hospital had a significantly shorter duration of time to readmission. It would be interesting to see if it made a difference if we used nebulizers for those patients.”

In the absence of more evidence, several participating clinicians agreed that patient preference will continue to be a major factor in decisions regarding delivery methods.

Novel Therapies for COPD

Novel therapies for the treatment of COPD are in various stages of clinical development, and include new LABAs, long-acting muscarinic antagonists (LAMAs), muscarinic beta2-agonists (MABAs), and biologic agents (Table 4).49

Table 4

There continues to be considerable activity in developing LAMA agents; 2 LAMA investigational compounds, SUN-101 and TD-4208 (also referred to as revefenacin), are being studied for use as nebulized therapy.50-52 TD-4208, a once-daily, nebulized LAMA, is in development for the treatment of patients with COPD. TD-4208 is designed to be a lung-selective inhibitor with a prolonged effect and improved tolerability over other LAMAs. Theravance Biopharma is partnering with Mylan to develop TD-4208, and registrational phase 3 studies have been initiated in 2015.50,51

It is expected that SUN-101, a nebulized, twice-daily formulation of glycopyrrolate that was developed by Sunovion, will utilize the investigational eFlow nebulizer system, a portable, high-efficiency nebulizer customized for the delivery of Sunovion’s drug candidates.52

Bifunctional MABA agents are a novel approach to “dual” bronchodilator therapy in that they combine muscarinic antagonism and b2-agonism in a single molecule.53 This intriguing approach may offer several ad­vantages over combination therapy with 2 separate therapeutic agents. For example, by delivering a fixed ratio of the drug into every region of the lung, MABAs have the potential to reduce the complexity of combination inhalers via a single pharmacokinetic profile, a uniform ratio of activities at the cellular level, and a simplified clinical development program. An important limitation of MABA molecules is that the ratio of muscarinic antagonism and b2-agonism activities cannot be adjusted with a single compound, thereby limiting the dosing flexibility.53

A number of combination therapies, including new ICS/LABA, ICS/MABA, LAMA/LABA, and LAMA/LABA/ICS pairings, are also being investigated in clinical studies (Table 5).49

Table 5

Clinicians and payers participating on the advisory panel indicated that there remain unmet needs in managing patients with COPD; therefore, additional new treatment options are welcomed. According to participants, based on emerging data, the broad adoption of LABA/LAMA combination treatment, and, for some patients, ICS/LABA/LAMA triple therapy is envisioned in the relatively near future. As the COPD market continues to move toward combination therapies, participating clinicians expressed the desire for a LABA/LAMA nebulized option. One participating pulmonologist noted, “We all think that a nebulized LABA/LAMA combination would be intriguing. Although we expect LABA/LAMA combo (inhalers) to dominate COPD for outpatient care, it would be beneficial to have a nebulized option.”

In addition to novel agents, participating panel clinicians and payers anticipate the approval of new generic entries, although some voiced concerns about the potential overuse of generic fluticasone propionate/salmeterol for the short-term relief of COPD. With numerous generic drugs already available and others poised to enter the market, participants anticipate “an era of therapeutic substitution” in COPD; participating clinicians did not voice strong objections to therapeutic substitution, as long as it is clinically appropriate.

Practical Considerations for COPD Management in the Primary Care Setting

In recent years, there have been substantial changes in the way primary care is organized and delivered.54 Driven in large part by the Affordable Care Act, efforts are being made to deliver better coordinated care through medical homes and accountable care organizations. Likewise, there has been a move toward team-based care, and the growing use of nonphysician providers, including nurse practitioners and physician assistants in the primary care setting.54

Efforts have also been made to expand access to primary care, in part through retail clinics.55 Although there may be some limitations in the types of care that retail clinics provide, retail clinics are convenient and provide a broad range of services under one roof. In addition, retail clinics are beginning to enter into arrangements with health systems to improve patient access to care. Under one such contract, Henry Ford Health System has been providing physician medical directors to CVS MinuteClinics in the metropolitan Detroit area to oversee clinical operations and to supervise nurse practitioners, while allowing Henry Ford Medical Group patients unlimited access to the clinics.55

The number of retail clinic visits has increased sharply, from 1.5 million visits in 2007 to 10 million in 2012.55 Nearly half of the retail clinic visits take place during evenings and weekends, when physician offices are typically closed.56

Role of Primary Care Providers

As the first point of contact for patients seeking medical care, physician and nonphysician primary care providers play a critical role in identifying and managing COPD.3 However, COPD often remains undiagnosed until significant clinical progression has already occurred.57 A recent analysis of the National Health and Nutrition Examination Survey data found that more than 70% of Americans with spirometry-confirmed obstruction were undiagnosed with asthma or COPD.57

Although primary care providers care for the majority of patients with mild-to-moderate COPD, many remain unfamiliar with the COPD guidelines and continue to diagnose COPD on the basis of clinical findings alone.58 Unfortunately, patient factors may sometimes hinder the clinical assessment of COPD. For example, patients may not recognize their symptoms, or they may be unwilling to report them.3 In addition, patients may attribute their symptoms to normal aging or as a consequence of smoking, making patients less likely to report their symptoms.3

The GOLD guidelines and ACP/ACCP/ATS/ERS guidelines stress the importance of using spirometry to diagnose COPD, as well as for the ongoing assessment of patients with COPD.7,17 Although it has its limitations, spirometry is the best screening tool for COPD, and is sensitive enough to detect COPD in its early stages, before symptoms become apparent.3 Therefore, spirometry should be used to confirm the presence of COPD in patients thought to be at risk for the disease.3

Despite guideline recommendations, however, spirometry remains underutilized in the primary care setting, attributed in part to time constraints, cost, poor training, and inaccurate interpretation of results.59 Not surprisingly, COPD therapies are frequently not prescribed according to guideline recommendations that base treatment decisions on disease severity, as determined by spirometry results.59

One study that used feedback from primary care physician focus groups to identify attitudes and barriers of primary care physicians to performing spirometry for patients with possible COPD supports the view that some primary care providers may be ill-equipped to diagnose and manage patients with COPD.60 For example, primary care physicians in the focus group reported that spirometry was not always needed to confirm the diagnosis of COPD when the probability of having COPD was felt to be high (eg, smoking, COPD symptoms).60

Furthermore, primary care physicians felt comfortable treating COPD based on patients’ symptoms and on their medical history alone without objective evidence of airway obstruction using a spirometry test.60 Compared with other chronic conditions, primary care physicians thought that the evaluation of COPD was more subjective and that there was lack of scientific evidence demonstrating that COPD therapy improved patient outcomes. Furthermore, the majority of the providers did not consider lack of access to spirometry a barrier in their everyday practice.60

The advisory panel participants echoed these perceptions, underlining that shortcomings in the primary care of patients with COPD are caused by a lack of awareness and knowledge about the disease, lack of confidence in the use of spirometry to assess patients’ airflow limitation, and the perception that current therapeutic options have limited effectiveness.

According to the panel participants, COPD is frequently misdiagnosed in the primary care setting, and patients often receive guideline-discordant care that includes inappropriate prescribing. Although participating pulmonologists acknowledged the central role of primary care in treating patients with stable COPD, they indicated that specialty providers possess the training and resources to accurately diagnose patients with suspected COPD and manage their care appropriately. The payer participants agreed with this assessment, especially for higher-risk patients. In fact, one participating pharmacy director representing an integrated health system described a process that facilitated specialty reevaluation and comprehensive care planning for potentially misdiagnosed patients, saying, “In our analysis, we found many patients diagnosed with COPD on ICS/LABA treatment. Most of these patients were rounded back to the pulmonologists. If they truly had COPD, they were put on LAMA/LABA therapy. If they were not and there was an asthma component, an ICS was added. To monitor lung capacity, we also required spirometry at every visit. We developed a matrix with blood pressure, weight, lung function, and other clinical parameters that was updated with each patient encounter.”

As primary care delivery has evolved, there has been a greater emphasis on primary prevention and coordinated care delivery. To aid in the prevention of COPD, the advisory panel participants agreed that the primary care team should actively counsel patients to stop smoking, regardless of patients’ spirometry results. In addition, providers indicated that COPD disease education could help to encourage patients to discuss their symptoms with their primary care providers and thereby facilitate the earlier identification of COPD.

Despite efforts to improve care delivery, several participants noted that barriers to patient access continued to hinder the ability of primary care providers and specialists to provide optimal care. For example, many patients are from underserved populations and may be difficult to reach. For individuals with financial, transportation, or cultural barriers, it can be a huge challenge to continue smoking cessation efforts, attend regular office visits, and remain adherent to COPD maintenance treatment.

Role of the Pharmacist

Pharmacists can play an important role in counseling patients and helping them to manage their care in a number of clinical settings, including retail clinics, retail pharmacy, and long-term care facilities.61

Several key areas have been identified where pharmacists can have a positive impact on patients with COPD, by reinforcing guideline-concordant recommendations for the appropriate management and treatment of COPD.61 Because of their accessibility and training, pharmacists are well-positioned to identify and assist patients with medication adherence issues. In addition, pharmacists can advise patients with affordability concerns about their medications, and help them to stay on track by suggesting generic options or sources of financial assistance. Furthermore, pharmacists can discuss adherence strategies in patients with multiple comorbidities who may have complex medication regimens.61

Pharmacists can also participate in support groups, education programs, and smoking cessation programs. Patients often have difficulty in mastering inhaler technique, particularly if they have been prescribed medications with multiple inhaler devices requiring different techniques; pharmacists can help educate these patients on the proper inhaler technique. In addition, pharmacists can educate patients on the proper maintenance, cleaning, and infection control procedures of delivery devices, including inhalers and nebulizers.61

In addition to education and support, pharmacists engage in medication regimen reviews and medication therapy management (MTM) efforts. When conducting MTM, pharmacists collect patient-specific information, assess medication therapies, identify and document medication-related issues, and develop a plan to address these issues. In addition to developing plans to resolve medication-related problems, pharmacists educate patients about their condition and treatment, which can empower patients to self-manage their condition.61

With regard to nebulized therapy, the panel members agreed that it is essential that pharmacists understand the dispensing and reimbursement mechanisms for a product that has both pharmacy and durable medical equipment (DME) components.

With nebulized therapy, this may be a challenge for patients and providers, because the drug may be covered under the pharmacy benefit, and the device may be covered as a DME under the medical benefit. At the point of dispensing, pharmacists would benefit from a deeper understanding of how this dynamic may affect drug and DME acquisition and cost-sharing for patients. In turn, they would be better equipped to counsel patients regarding these challenges.

Payer Considerations in Managing COPD

COPD is a high-priority medical condition for the majority of US payers. Even though smoking rates have declined, the prevalence of COPD is still on the rise, in large part because of the aging US population, many of whom are current or former smokers.2,62,63

The medical costs directly attributed to COPD in the United States are increasing.14 The projected annual cost associated with COPD in the United States is estimated to be $49.9 billion in 2020, of which $29.5 billion is attributed to direct healthcare expenditures, $8.0 billion is attributed to indirect morbidity costs, and $12.4 billion accounts for indirect, mortality-related costs.1 Indirect costs related to morbidity include lost productivity because of illness, whereas indirect costs related to mortality reflect loss of productivity as a result of early death.1

An analysis of the rising cost of COPD that was published in 2014 found that the average per-patient medical costs for patients diagnosed with COPD increased by 38% between 1987 and 2007, and continued to increase by approximately 5% annually between 2006 and 2009. Although the hospitalization rates for COPD have remained flat, the per-patient cost of hospitalizations for patients with COPD increased by $2289 per admission during this period.63

The medical costs outstrip the pharmacy costs in COPD, especially as patients’ condition progresses to more advanced stages of the disease (Table 6).64 In fact, hospitalization costs account for approximately 85% of the direct medical costs associated with COPD, and the majority of that cost is attributable to COPD exacerbations.63

Table 6

The panel payers agreed that the hospitalization costs were the primary driver of COPD costs at their respective health plans, and the panel pulmonologists recognized the importance of reducing acute exacerbations of COPD, because they often result in hospitalizations. “The entire medical community needs to start thinking about exacerbation frequency in COPD because that’s where 50% to 75% of the cost is,” stated one panel pulmonologist.

For this reason, many payers have instituted aggressive care management programs in an effort to reduce inpatient admissions for COPD. Participating panel payers noted that they identify high-risk patients with COPD through their claims data, ICD-10 (International Classification of Diseases, Tenth Revision) diagnosis codes, and National Drug Codes, and may assign patients to a case manager to follow up with members and monitor their medication utilization and adherence. The participating panel payers are continuing their efforts to integrate medical and pharmacy data, which improves their ability to evaluate utilization patterns, assess outcomes, and tailor interventions to member subpopulations.

The panel payers were also concerned about the hospital readmission rate for COPD. As part of their Hospital Readmissions Reduction Program, the Centers for Medicare & Medicaid Services expanded the list of applicable conditions to include patients admitted for an acute COPD exacerbation beginning in 2015, putting hospitals and health systems at financial risk for excess readmissions that can result in payment reductions.65

Despite the fact that 78% of eligible hospitals received a penalty for excess hospital readmissions in 2015, and government statistics have shown that the overall rate of readmissions has seen only a modest decline, the participating panel payers noted that hospital readmissions, even for conditions included in the Hospital Readmissions Reduction Program, remain an issue for them.66,67

One panel participant noted that in COPD, some readmissions occurring outside of the 30-day window may be related to the index admission. In integrated health systems, the payer side may benefit from the reduced hospital readmissions, but that may be offset by penalties on the hospital side.

Because of the focus on acute exacerbations of COPD and resulting hospitalizations, the participating panel payers indicated that they offer relatively open access to COPD therapies (monotherapy and combination), with few restrictions, albeit members may have higher copayments for nonpreferred drugs. Preferred status is typically determined by contracts negotiated with manufacturers, either by the health plan or by the pharmacy benefit manager that manages the health plan’s pharmacy benefit.

“It’s very important for us to offer access to COPD drugs. Our typical (monthly) copay is $35 for a preferred product and $50 for a nonpreferred product. I also don’t see any barriers to combination therapies in the near-term,” noted one panel payer.

Another payer said, “If [COPD drugs] are not on tier 2 as a result of a contract, they’re going to be on tier 3 and patients can get them. We’re trying to get more and more drugs on tier 2 through contracting. Some of those will be combinations.”

The participating panel payers indicated that as with inhaled agents, they do not place restrictions on nebulized therapies. One participating medical director noted that nebulizers were relatively inexpensive compared with the cost of many other drugs; therefore, there was no compelling reason for his organization to restrict their availability. However, another participant added that his plan may restrict the approval of more than 1 nebulizer for the same drug within a 12-month period.

During the panel discussion, it was also noted that the Centers for Medicare & Medicaid Services does not have a national coverage policy regarding nebulizers; the decision is left to regional Medicare Administrative Contractors.

In terms of nebulizer utilization, the participating clinicians and payers agreed that the ideal nebulizer should be versatile, with the ability to accommodate as many drugs as possible. One payer noted that the development of nebulizers with multidrug capacity would likely stimulate increased utilization.

In the future, clinicians and payers seek outcomes data to differentiate long-acting therapies, including nebulization, for the treatment of COPD. The key outcome metrics of interest to the group included the hospital length of stay, readmission rates, intensive care unit utilization, overall cost of care, and patient satisfaction. These themes extended to the nebulized therapy formoterol fumarate, and participating clinicians and payers both expressed their desire for more outcomes-related end points in clinical trials. However, the panel participants also acknowledged that the clinical trial design was critical, because the number of patients required to sufficiently power some studies may be impractical and cost-prohibitive.

In general, payers defer to pulmonary specialists’ recommendations and do not actively manage utilization of drugs or delivery devices in the COPD category.


COPD is underdiagnosed and undertreated. A low awareness of COPD and the initial symptoms of the disease among the general population, acceptance of these symptoms as a consequence of aging or smoking, clinical similarities to asthma, and failure of healthcare providers to use spirometry to guide COPD diagnosis all contribute to its suboptimal identification and treatment.

In addition, challenges exist in managing patients diagnosed with the disease, and reducing the burden of COPD will require improved management of chronic symptoms. Acute exacerbations and hospitalizations are the primary driver of cost and morbidity in COPD; therefore, high priority should be given to interventions aimed at delaying the progression of disease, preventing exacerbations, and reducing the risk for comorbidities to alleviate the clinical and economic burden of COPD.

Short- and long-acting bronchodilators remain the mainstays of pharmacologic treatment for COPD. Bronchodilators are most frequently given in an inhaled form using an MDI, DPI, or a nebulizer. Although current guidelines recommend inhalation therapy as the preferred route of drug administration for treating COPD, inhaler misuse remains a common problem in clinical practice, limiting its effectiveness and resulting in the suboptimal symptom relief for patients with COPD.

Evidence suggests that nebulizer use for maintenance therapy in patients with moderate-to-severe COPD, including use during exacerbations, is comparable, and, in some respects superior, to the efficacy provided by MDIs and DPIs. In fact, nebulized therapy may be preferred in elderly patients, those with severe disease and frequent exacerbations, and those with physical and/or cognitive limitations.

In an advisory meeting that included practicing pul­monologists and representatives from payer organizations, there was considerable agreement regarding the importance of specialty care in COPD; maintaining open access to pharmacologic therapy; and the need for redoubled focus on reducing acute exacerbations, hospital admissions, and hospital readmissions associated with COPD. Because payers do not want to hinder the effective management and control of COPD, they do not restrict access to specific short- and long-acting therapies.

Participating pulmonologists recognized the value of nebulized therapy, but maintained that a good understanding of the patient clinical presentation and life circumstances were necessary to make informed treatment recommendations. In addition, they agreed that better clinical markers are needed to identify optimal candidates for nebulized therapy.

In terms of unmet pharmacologic needs, participating pulmonologists noted that a nebulized LAMA option would likely increase the use of combination LABA/LAMA nebulized therapy. Both pulmonologists and payers voiced the need for clinical studies to include outcomes measures to help clinicians make better informed decisions about therapeutic selection.

Author Disclosure Statement

Dr Ohar is on the advisory board for AstraZeneca, Boehringer Ingelheim, CSL Behring, Mylan, Novartis, and Sunovion, and is a consultant to Theravance. Dr Schaecher reported no conflicts of interest.

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Last modified: August 30, 2021