Chronic obstructive pulmonary disease (COPD) is a preventable, treatable illness characterized by airflow limitation and persistent respiratory manifestations, including shortness of breath, chronic cough, and excess sputum production. Chronic lower respiratory diseases were the fourth leading cause of death in the United States in 2019.1 COPD is underdiagnosed by primary care physicians because of inconsistent patient reporting of symptoms, time constraints for management of multiple comorbidities, lack of access to spirometry, unfamiliarity with the most recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, and unfamiliarity with spirometry interpretation.2
Among chronic conditions, COPD is one of the most costly, estimated to total $49 billion in 2020.2,3 COPD-related medical costs increase with increasing disease severity; those with very severe COPD incurred nearly 3 times the annual costs of those with mild COPD ($18,070 vs $5945, respectively).4
Patients with COPD have substantial comorbid disease burden, including cardiovascular diseases, metabolic disorders, osteoporosis, skeletal muscle dysfunction, anxiety/depression, and gastrointestinal diseases,5 and this burden is associated with greater healthcare resource use,6 complexity of management, and costs of care (Figure 1).7 Thus, COPD should be a high-priority disease for US providers and payers to manage appropriately, especially in the context of COVID-19, for which COPD is a risk factor for severity and mortality.8,9
Patients with COPD who become infected with COVID-19 are at higher risk for severe illness and mortality; therefore, vaccination against COVID-19 is recommended.10,11 Considerations for device and medication selection for patients in the context of COVID-19, including strategies for at-home administration of aerosolized medications for patients with COPD, have been discussed elsewhere.12 A substantial reduction in COPD hospitalizations during the COVID-19 pandemic has been noted13 and has been attributed to the widespread use of masks and social distancing, which resulted in reductions in viral respiratory illness.
The objectives of this review are to describe the existing burden, unmet needs, and related economics of COPD in relation to quality of care and to discuss quality-of-care metrics and maintenance medications that could reduce the cost of managing COPD, including advancements in single-inhaler triple therapy.
Impact of Exacerbations
A COPD exacerbation is an acute worsening of respiratory symptoms that results in additional therapy; exacerbations are graded as mild, moderate, or severe based on the intensity of resources needed to treat the event.14 Exacerbations negatively affect patients and payers in terms of disease morbidity/mortality and healthcare costs, respectively. The ECLIPSE study found that a strong predictor of future exacerbations was a previous exacerbation.15
A subsequent US administrative claims database study found that patients with severe COPD had nearly twice the rate of exacerbations per 100 person-years versus patients with mild COPD.4 Patients with less severe COPD still experience exacerbations15,16; therefore, efforts toward exacerbation prevention should be considered across the spectrum of disease severity.
Links between exacerbation history and future risks may be explained in part by the long-term sequelae of exacerbations. Moderate and severe COPD exacerbations can accelerate loss of lung function most potently in patients with mild to moderate disease (GOLD grade 1 or 2) again emphasizing the importance of earlier identification and intervention for future exacerbation prevention.17 Even among those with less severe COPD, significant reductions in lung function were observed with severe (hospitalized) exacerbations.17
Exacerbation incidence is associated with increased risk for morbidity and mortality. In a large database study, patients who had ≥1 severe exacerbations at baseline had an increased risk for death (hazard ratio, 1.79; 95% confidence interval, 1.65-1.94) compared with those without exacerbations.18 A large multicenter study has shown that patients who experience COPD exacerbations had a nearly 4-fold increased risk for cardiovascular events within 30 days after a hospitalized exacerbation, with increased risk extending up to 1 year after an event.19
After a moderate COPD exacerbation, patients have double the risk for myocardial infarction within 5 days of the event compared with those with stable disease, whereas the risk for stroke was significantly increased during days 1 to 49 following exacerbation.20 Recognizing exacerbations and their relationship with other costly comorbidities and subsequently adjusting therapy accordingly may help prevent future events, thereby reducing overall burden.
Hospitalization and Readmission Rates
Although the length of hospitalization among patients with COPD has decreased in recent years, the number of admissions remains unchanged, highlighting the continued burden of severe exacerbations for these patients.21
The 30-day hospital readmission rate for COPD was 19.2%; rates for frequent hospitalizations for COPD (≥2 events) and for patients with ≥4 comorbidities were 35.3% and 24.5%, respectively.22 Among patients with COPD and ≥2 severe exacerbations within the past year, COPD-related 30-day readmissions are most frequent for those with Medicare fee-for-service compared with patients with a commercial payer, managed Medicaid, or Medicare Advantage (Figure 2).23
This disparity suggests room for improvement in readmissions in Medicare fee-for-service, especially compared with Medicare Advantage, perhaps due to more focused COPD management in Medicare Advantage. Data suggest that, along with previous COPD hospitalization, age, comorbid anxiety, depression, asthma, diabetes, dyspnea, hypoxia, ischemic heart disease, and pneumonia are predictors for COPD-related readmissions.24
Given that patients with COPD can experience significant rates of hospitalization and readmission, it is important to note that COPD is considered an ambulatory care–sensitive condition, as are many of its comorbid conditions. The ambulatory care–sensitive condition designation means that severe exacerbations can be reduced with better primary care management, focus on prevention, and adherence to maintenance therapy, thus avoiding inpatient- and emergency department–related costs.25,26 Appropriate access to and coordination with pulmonary care specialists is also a significant factor in reducing hospitalization for COPD.27
Management of COPD from a Quality Measures Perspective
Due to the frailty of patients with COPD and the complexity of the condition, it is important that patients receive comprehensive high-quality care to relieve symptoms and to prevent future exacerbations and hospitalizations. Ultimately, this should reduce the overall burden and associated healthcare costs of COPD.
Several of the most widely used performance measures in the Healthcare Effectiveness Data and Information Set (HEDIS) are COPD-related, such as use of spirometry testing, yet data seem to indicate that minimal gains have been achieved with quality-of-care initiatives and that noticeable gaps remain.28 For example, despite the use of the HEDIS measure Hospitalization for Potentially Preventable Complications for Ambulatory Care Sensitive Conditions, COPD-related hospitalizations and readmissions remain high.29
Although several current quality measures focus on spirometry, these measures may fall short in truly supporting quality of care,28 perhaps due to structural barriers found in many local healthcare systems and primary care practices. For instance, spirometry may not be available to all patients and may not be practical to administer in a primary or specialty care setting.
In addition, the Pharmacotherapy Management of COPD Exacerbation measure does not take into consideration the evaluation of long-acting maintenance therapy after an exacerbation30; instead it is focused on short-term use of bronchodilators and systemic corticosteroids. Finally, although general measures of all-cause readmissions and follow-up after emergency department visits seek to improve care coordination, communications challenges persist, as the initiatives may not be specific enough to address the unique needs of patients with COPD, who may need specialist referrals or further treatment evaluation.31
The Centers for Medicare & Medicaid Services (CMS), a major payer of COPD-related care in the United States, levies financial penalties against hospitals with excess 30-day, all-cause readmissions after a hospitalization through their Hospital Readmissions Reduction Program (HRRP).32
CMS data show substantial differences in COPD 30-day readmission rates among hospitals (median, 19.7%; range, 16.2%-26.8%)33 and COPD-related costs by state, indicating significant regional variation.34 A recent study found that in Medicare’s HRRP hospitals, the excess readmissions ratio for COPD decreased by 3.8% from 2016 to 2019 compared with an increase of 3.7% in non-HRRP hospitals.35 It is worrisome, however, that the reduction in readmissions was associated with an increase in mortality, which highlights the continued complexity and need to further understand COPD patient care.36,37
Although the prevalence of COPD is highest among the Medicare-aged population (≥65 years),36 the Medicare Stars ratings related to managing chronic (long-term) conditions for Medicare Part C plans make no specific mention of COPD.38 A component of the Medicare Stars measurements for Part D plans includes a comprehensive medication review for patients with COPD within 30 days post discharge; furthermore, CMS mandates that health plans administer pharmacologic management programs at no cost to qualified members.39
In addition to focusing on readmissions, the American Thoracic Society has recommended that programs address quality of care using other patient-centered metrics, such as mortality, patient satisfaction, adherence, self-efficacy, symptoms, and exercise tolerance to evaluate programs aimed to reduce readmissions and improve COPD care.40 In light of these current measures and apparent gaps, quality measures should advance beyond current measures to include the following: improved coordination at the time of diagnosis, care transitions, and clinical deterioration; improved patient identification and prompt access to outpatient healthcare; proper disease management, including high-quality outpatient care; attempts to improve maintenance medication adherence29; and recognition of high-risk factors associated with hospital readmissions.22
Specific interventions recommended as best practices by the American Thoracic Society that could be integrated into new quality measures include smoking cessation, inhaler device use instruction, follow-up care with a multidisciplinary team, and referrals to pulmonary rehabilitation.40 Implementation of integrated care for patients with COPD has demonstrated cost-savings driven by reduced hospitalizations.41
A Proactive Approach to COPD Management
Importance of Appropriate and Effective Therapy
Although maintenance pharmacotherapy for COPD has not been proved to modify long-term lung function decline, appropriate treatment can reduce symptoms and the frequency and severity of exacerbations, improving exercise tolerance and health status for patients.14 The classifications of medications used to treat COPD according to GOLD guidelines include short- and long-acting bronchodilators (β2-agonists and antimuscarinic drugs prescribed individually or in combination), inhaled corticosteroids (ICS), methylxanthines, phosphodiesterase-4 inhibitors, mucolytic agents, and chronic macrolide therapy.14
Severity of symptoms, airflow limitation, severity of exacerbations, and availability and cost of medication should be taken into consideration when prescribing initial maintenance therapy, which should achieve a favorable clinical response balanced against side effects.14 The value of prompt initiation of maintenance therapy after a COPD-related hospitalization has been demonstrated through reduced COPD-related costs and risk for future exacerbations.42
Equally important is the continual assessment of the effectiveness of treatment; GOLD guidelines provide recommendations for therapy escalation/de-escalation based on the persistence of exacerbations and other symptoms derived from evidence from randomized controlled trials and clinical experience.14
A recent study found that 49.2% of patients across payers did not fill any maintenance therapy over 12 months after initial diagnosis of COPD, demonstrating an apparent lack of treatment initiation and the loss of substantial opportunities for earlier intervention and improved patient outcomes.43
The current approach of accelerating treatment in response to treatment failure leaves patients susceptible to recurrent exacerbations, which are associated with worsening of symptoms and lung function decline.44 Furthermore, given that nearly half of exacerbation events may go unreported and thus untreated,45 this approach may come too late for many patients. Instead, providers should ensure that patients are receiving the appropriate maintenance therapy with superior efficacy in reducing the rate of exacerbations.
Adherence to maintenance therapy is critical to manage symptoms but more importantly to decrease future exacerbation risk, as nonadherence is associated with higher exacerbation rates and therefore increased healthcare costs. Individualizing inhalation devices according to patient preference, including inhaler training; broadening access to various therapies; and simplifying treatment regimens could potentially improve adherence and outcomes.14,46,47
The GOLD report emphasizes the importance of training in inhaler technique, citing the relationship between poor inhaler technique and symptom control.14 Thus, proper device selection and training are important for optimal COPD care.47 Although GOLD recommendations do not explicitly mention assessing a patient’s underlying socioeconomic status when evaluating treatment options, it is likely that these factors should be considered in daily practice to ensure patient access and understanding of treatment options.
Pharmacologic Therapy Considerations
The most recent addition to the available classes of pharmacologic therapy for COPD is single-inhaler triple therapy, consisting of combinations of ICS and bronchodilators. The GOLD report recommends single-inhaler triple therapy for patients with a history of frequent and/or severe exacerbations currently receiving separate triple therapy, dual ICS/long-acting β2-agonist (LABA), or single or dual long-acting bronchodilators, based on the results of several pivotal clinical trials within this population.14
As with maintenance therapy in general, prompt initiation of triple therapy after a COPD-related hospitalization or emergency department visit may reduce future costs and subsequent exacerbations.48,49 Single-inhaler triple therapy has not been studied in patients naïve to pharmacologic treatment and therefore may not be appropriate as initial maintenance therapy for every patient with COPD. Nonetheless, real-world evidence within and outside of the United States indicates that 20.4% of patients naïve to maintenance therapy were deemed to have disease severe enough to warrant initiation of triple therapy.50
The single-inhaler triple therapies currently available in the United States include an ICS plus a long-acting muscarinic antagonist (LAMA) and a LABA in 1 inhaler device. The first single-inhaler triple therapy study was the IMPACT trial, which assessed fixed-dose ICS/LAMA/LABA triple therapy (fluticasone furoate/umeclidinium/vilanterol) compared with ICS/LABA and LAMA/LABA in 10,355 patients with symptomatic, moderate to severe COPD and ≥1 exacerbation in the year before the trial, over a 52-week period. Single-inhaler triple therapy significantly reduced the rate of moderate or severe COPD exacerbations compared with ICS/LABA and LAMA/LABA.51
The most recent large single-inhaler triple-therapy trial (ETHOS) assessed budesonide/glycopyrrolate/formoterol fumarate (BGF) inhaler versus ICS/LABA and LAMA/LABA in 8588 symptomatic patients with moderate to severe COPD (including forced expiratory volume in 1 second from 25% to 65% and ≥1 moderate or severe exacerbations in the previous year) over 52 weeks; all interventions were administered via metered-dose inhalers. The 320/18/9.6-µg BGF (BGF 320) and the 160/18/19.6-µg BGF (BGF 160) groups demonstrated significantly lower annual rates of moderate or severe exacerbations compared with patients receiving LAMA/LABA and ICS/LABA.52
The KRONOS study compared BGF 320 with LAMA/LABA, ICS/LABA, and an open-label ICS/LABA dry-powder inhaler in 1902 patients with moderate to severe COPD over 24 weeks.53 Unlike the other triple-therapy studies, 74% of the patients in KRONOS had no exacerbations in the previous year. BGF 320 significantly improved lung function versus ICS/LABA at 24 weeks, with a numerical difference versus LAMA/LABA. As a secondary end point, BGF 320 reduced moderate or severe exacerbations by 20% versus the LAMA/LABA comparator.53
All-cause mortality was assessed in 2 trials, as a predefined secondary end point in ETHOS and an end point in IMPACT.54,55 In the final data set from ETHOS, all-cause mortality over 52 weeks, on and off treatment, was significantly reduced by 49% for BGF 320 versus LAMA/LABA. A 28% reduction was observed versus ICS/LABA.54 In IMPACT, all-cause mortality was reduced by 28% compared with LAMA/LABA and by 11% versus ICS/LABA for on- and off-treatment deaths.51,55 The recent GOLD guidelines have acknowledged that the results emerging from these large trials suggest a beneficial trend of single-inhaler triple therapy versus fixed-dose LABA/LAMA to reduce mortality risk, although additional evidence may help determine whether survival benefits are greater within specific patient subgroups.14
In addition to preventing exacerbations and reducing mortality, single-inhaler triple therapy has the potential benefit of improving patient adherence by simplifying treatment,56 provided that single-inhaler triple therapy has equivalent or superior efficacy to multiple-inhaler triple therapies. In a recent study, Ferguson and colleagues conducted identical phase 4 trials comparing the efficacy and safety of 2 ICS/LAMA/LABA combination therapies: a single-inhaler triple therapy (fluticasone furoate, umeclidinium, and vilanterol) and a multiple-inhaler triple therapy (budesonide, formoterol fumarate, and tiotropium) in patients with symptomatic COPD.57 The single-inhaler triple therapy was noninferior to multiple-inhaler triple therapy, demonstrating similar improvements in lung function and health status, although the study’s 12-week duration precluded assessment of exacerbation frequency.57 A meta-analysis of studies comparing single-inhaler triple therapy and multiple-inhaler triple therapy found no difference in risk of moderate or severe exacerbations.58 These results support single-inhaler triple therapy as a viable option to simplify treatment for patients receiving multiple-inhaler triple therapy.
Other Considerations in Managing COPD
Respiratory infections are the leading cause of COPD exacerbations; GOLD and various guidelines indicate that rates of acute exacerbations are lower among those who have received influenza and pneumococcal vaccines.59,60 Lifestyle interventions can also lessen COPD burden: smoking cessation slows lung function decline and reduces hospitalization and mortality.61
Pulmonary rehabilitation as part of integrated patient management can improve symptoms, health-related quality of life, and physical and social participation in daily activities; it also reduces readmission rates, emergency department visits, and medical costs,14,47,62 and may reduce mortality after COPD hospitalization.63
Although pulmonary rehabilitation and triple therapies have clear benefits, the lack of care coordination throughout the health system suggests that appropriate discharge protocols or transitions of care programs from the inpatient to outpatient settings after a severe exacerbation are needed to ensure appropriate consideration of these treatment options.64 Discontinuation of maintenance therapy is known to increase risk of exacerbations65; the transition of care between the hospital and outpatient setting requires further focus to ensure discontinuation does not occur.
Finally, holistic strategies including improved surveillance, education of healthcare providers and the public about COPD, improved access to cost-effective and affordable healthcare, emphasis on smoking cessation, and minimizing environmental and occupational exposures could help alleviate the burden of COPD in people of lower socioeconomic status.66 Opportunities exist to improve quality of care for patients while reducing the economic burden for payers.67,68
Individual and societal burdens of COPD are high. Multiple strategies exist to reduce exacerbation and hospitalization rates, including ensuring high-quality outpatient care, implementing transitions of care, improving physician awareness of current treatment guidelines, and increasing patient adherence to medications and disease management strategies. Earlier diagnosis and more proactive treatment with appropriate maintenance therapies that account for patients’ comorbidities are critical for improving patient health-related quality of life and reducing costs, exacerbations, and mortality.
Practitioners should consider the most recent scientific data and pharmacotherapy available, including single-inhaler triple therapies that show better reductions of exacerbations and improvements in all-cause mortality compared with monotherapy or dual therapy in patients with frequent exacerbations. Although HEDIS and CMS activities provide valuable strategies to the payer and encourage the reduction of readmissions, there is still a relative lack of quality measures designed specifically to improve quality of care for patients with COPD. Additional opportunities to develop quality measures targeting care coordination and treatment escalation should include lessons from other disease states to ensure that quality care is being delivered in a proactive and appropriate manner. Overall, better coordination between primary, specialty, and inpatient care teams, and the optimization of pharmacologic management can improve quality of life for patients and reduce the substantial emergency department and hospitalization costs associated with COPD.
Medical writing support was provided by Analise Berkelbach, PhD, of MedErgy/Cello Health Communications.
The funding for this article was provided by AstraZeneca, including the funding for the medical writing support, in accordance with Good Publication Practice (GPP3) guidelines. The decision to submit the manuscript for publication was made by the authors.
Author Disclosure Statement
Dr Gandhi, Mr Pollack, Dr Feigler, and Dr Patel are employees and shareholders of AstraZeneca. Dr Wise has received compensations from AstraZeneca, Boehringer Ingelheim, Chiesi, ContraFect, Novartis, Roche-Genentech, GlaxoSmithKline, Merck, Verona, Mylan/Theravance, AbbVie, Chimerx, Kiniksa, Bristol Myers Squibb, Galderma, Kamada, Pulmonx, Kinevant, PureTech, and Arrowhead. Mr Larsen has no conflicts of interest to report.
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