More than 13 million people in the United States have been diagnosed with chronic obstructive pulmonary disease (COPD),¹ a complex, heterogeneous respiratory condition characterized by persistent, and usually progressive, airflow limitation.^2,3 The prevalence of COPD is rising: It has been declared the third leading cause of death in the United States,⁴ and the World Health Organization has predicted that it will become the third leading cause of death worldwide by 2030.⁵ This increase is driven by an aging population, and tobacco smoking, which is the primary risk factor for COPD in high-income countries.⁶

Symptoms of COPD, as well as the severity of these symptoms, can vary, but patients typically present with dyspnea, chronic cough, and sputum production.² These symptoms are often underreported by patients with COPD,² but have a significant impact on patients’ day-to-day lives, adversely affecting their quality of life and their ability to engage in physical activity, further contributing to disease progression.^7,8

Comorbidities are common in patients with COPD, and can pose significant challenges to the diagnosis and management of the condition. Some of these comorbidities, such as lung cancer and ischemic heart disease, share a common etiologic pathway with COPD—smoking; while others, such as anxiety and depression, appear to be unrelated to COPD pathogenesis, although they may share a systemic inflammatory basis, and are highly prevalent in patients with COPD.⁹

Primary care physicians are the key point of contact for most patients with COPD,¹⁰ and play a critical role in diagnosis, drug and device selection, and long-term disease management of COPD and associated comorbidities. A number of pharmacologic and nonpharmacologic treatment options are available to manage COPD symptoms, which can confer considerable benefits to patients. Selection of pharmacologic treatment should be based on an individual patient’s symptom burden and their exacerbation history, and it is important that physicians are aware of when therapy should be escalated, and indeed stopped if no longer required.²

Proper device selection is an important part of choosing treatments for patients with COPD. A variety of inhaler devices are available for COPD medications, and it is important that devices are matched to patients’ needs and preferences based on device characteristics and individual patient capabilities.

The aim of this supplement is to provide readers with an introduction to 4 key topics critical to the effective management of COPD in primary care, highlighting best practices to optimize patient care and outcomes. In the first article, Dr. Marchetti and Dr. Kaplan review physical activity in COPD, discussing its inter-relationship with dyspnea and hyperinflation, and its importance in modifying disease progression.

The second article examines anxiety and depression in COPD. Prof. Yohannes, Dr. Kaplan, and Dr. Hanania review the prevalence, mechanisms, and impact of the 2 often overlooked and undertreated psychologic comorbidities in patients with COPD. The authors provide guidance on how anxiety and depression can be detected and managed in patients with COPD in a primary care setting.

The third article is authored by Dr. Dhand, Dr. Cavanaugh, and Dr. Skolnik, and reviews the device options available for COPD pharmacologic therapy. It summarizes the key features of each respective inhaler device, discusses considerations for patient-device matching, and emphasizes the importance of training in correct device use.

Finally, Dr. Victor Kim and I assess different COPD treatment options in the supplement’s fourth article. We review the latest updates in recommendations from both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the COPD Foundation, discuss the importance of personalized treatment goals for patients, and review how to address current unmet needs in patient management.

More than 13 million people in the United States have been diagnosed with chronic obstructive pulmonary disease (COPD),¹ a complex, heterogeneous respiratory condition characterized by persistent, and usually progressive, airflow limitation.^2,3 The prevalence of COPD is rising: It has been declared the third leading cause of death in the United States,⁴ and the World Health Organization has predicted that it will become the third leading cause of death worldwide by 2030.⁵ This increase is driven by an aging population, and tobacco smoking, which is the primary risk factor for COPD in high-income countries.⁶

Symptoms of COPD, as well as the severity of these symptoms, can vary, but patients typically present with dyspnea, chronic cough, and sputum production.² These symptoms are often underreported by patients with COPD,² but have a significant impact on patients’ day-to-day lives, adversely affecting their quality of life and their ability to engage in physical activity, further contributing to disease progression.^7,8

Comorbidities are common in patients with COPD, and can pose significant challenges to the diagnosis and management of the condition. Some of these comorbidities, such as lung cancer and ischemic heart disease, share a common etiologic pathway with COPD—smoking; while others, such as anxiety and depression, appear to be unrelated to COPD pathogenesis, although they may share a systemic inflammatory basis, and are highly prevalent in patients with COPD.⁹

Primary care physicians are the key point of contact for most patients with COPD,¹⁰ and play a critical role in diagnosis, drug and device selection, and long-term disease management of COPD and associated comorbidities. A number of pharmacologic and nonpharmacologic treatment options are available to manage COPD symptoms, which can confer considerable benefits to patients. Selection of pharmacologic treatment should be based on an individual patient’s symptom burden and their exacerbation history, and it is important that physicians are aware of when therapy should be escalated, and indeed stopped if no longer required.²

Proper device selection is an important part of choosing treatments for patients with COPD. A variety of inhaler devices are available for COPD medications, and it is important that devices are matched to patients’ needs and preferences based on device characteristics and individual patient capabilities.

The aim of this supplement is to provide readers with an introduction to 4 key topics critical to the effective management of COPD in primary care, highlighting best practices to optimize patient care and outcomes. In the first article, Dr. Marchetti and Dr. Kaplan review physical activity in COPD, discussing its inter-relationship with dyspnea and hyperinflation, and its importance in modifying disease progression.

The second article examines anxiety and depression in COPD. Prof. Yohannes, Dr. Kaplan, and Dr. Hanania review the prevalence, mechanisms, and impact of the 2 often overlooked and undertreated psychologic comorbidities in patients with COPD. The authors provide guidance on how anxiety and depression can be detected and managed in patients with COPD in a primary care setting.

The third article is authored by Dr. Dhand, Dr. Cavanaugh, and Dr. Skolnik, and reviews the device options available for COPD pharmacologic therapy. It summarizes the key features of each respective inhaler device, discusses considerations for patient-device matching, and emphasizes the importance of training in correct device use.

Finally, Dr. Victor Kim and I assess different COPD treatment options in the supplement’s fourth article. We review the latest updates in recommendations from both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the COPD Foundation, discuss the importance of personalized treatment goals for patients, and review how to address current unmet needs in patient management.

More than 13 million people in the United States have been diagnosed with chronic obstructive pulmonary disease (COPD),¹ a complex, heterogeneous respiratory condition characterized by persistent, and usually progressive, airflow limitation.^2,3 The prevalence of COPD is rising: It has been declared the third leading cause of death in the United States,⁴ and the World Health Organization has predicted that it will become the third leading cause of death worldwide by 2030.⁵ This increase is driven by an aging population, and tobacco smoking, which is the primary risk factor for COPD in high-income countries.⁶

Symptoms of COPD, as well as the severity of these symptoms, can vary, but patients typically present with dyspnea, chronic cough, and sputum production.² These symptoms are often underreported by patients with COPD,² but have a significant impact on patients’ day-to-day lives, adversely affecting their quality of life and their ability to engage in physical activity, further contributing to disease progression.^7,8

Comorbidities are common in patients with COPD, and can pose significant challenges to the diagnosis and management of the condition. Some of these comorbidities, such as lung cancer and ischemic heart disease, share a common etiologic pathway with COPD—smoking; while others, such as anxiety and depression, appear to be unrelated to COPD pathogenesis, although they may share a systemic inflammatory basis, and are highly prevalent in patients with COPD.⁹

Primary care physicians are the key point of contact for most patients with COPD,¹⁰ and play a critical role in diagnosis, drug and device selection, and long-term disease management of COPD and associated comorbidities. A number of pharmacologic and nonpharmacologic treatment options are available to manage COPD symptoms, which can confer considerable benefits to patients. Selection of pharmacologic treatment should be based on an individual patient’s symptom burden and their exacerbation history, and it is important that physicians are aware of when therapy should be escalated, and indeed stopped if no longer required.²

Proper device selection is an important part of choosing treatments for patients with COPD. A variety of inhaler devices are available for COPD medications, and it is important that devices are matched to patients’ needs and preferences based on device characteristics and individual patient capabilities.

The aim of this supplement is to provide readers with an introduction to 4 key topics critical to the effective management of COPD in primary care, highlighting best practices to optimize patient care and outcomes. In the first article, Dr. Marchetti and Dr. Kaplan review physical activity in COPD, discussing its inter-relationship with dyspnea and hyperinflation, and its importance in modifying disease progression.

The second article examines anxiety and depression in COPD. Prof. Yohannes, Dr. Kaplan, and Dr. Hanania review the prevalence, mechanisms, and impact of the 2 often overlooked and undertreated psychologic comorbidities in patients with COPD. The authors provide guidance on how anxiety and depression can be detected and managed in patients with COPD in a primary care setting.

The third article is authored by Dr. Dhand, Dr. Cavanaugh, and Dr. Skolnik, and reviews the device options available for COPD pharmacologic therapy. It summarizes the key features of each respective inhaler device, discusses considerations for patient-device matching, and emphasizes the importance of training in correct device use.

Finally, Dr. Victor Kim and I assess different COPD treatment options in the supplement’s fourth article. We review the latest updates in recommendations from both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the COPD Foundation, discuss the importance of personalized treatment goals for patients, and review how to address current unmet needs in patient management.

Introduction

Dyspnea, the sensation of difficult or labored breathing, is the most common symptom in chronic obstructive pulmonary disease (COPD) and the primary symptom that limits physical activity in more advanced disease.¹ According to the American Thoracic Society, dyspnea may be measured according to 3 domains²:

• what breathing feels like for the patient
• how distressed the patient feels when breathing
• how dyspnea affects functional ability, employment, health-related quality of life, or health status.

As disease severity increases, breathlessness becomes more disabling at lower activity levels. These changes further impact the quality of life of patients, and can lead to anxiety and depression.¹¹

Physical inactivity is often considered to be a major contributor to the progression of COPD,⁶ and is linked to hospitalizations and increased all-cause mortality.¹² There is therefore a need to recognize symptoms early and treat them accordingly.

CASE STUDY: 

KD, a 64-year-old woman, presented to her primary care physician’s office for a routine visit. Upon assessment, KD revealed that she used to enjoy going on walks with her neighbor, but she cannot walk up the hills in her neighborhood anymore without feeling “incredibly breathless.” She has become increasingly concerned that she is “having trouble getting a full breath.” KD informed her doctor that these symptoms had worsened since her last visit, and so she had stopped going on neighborhood walks. She was diagnosed with COPD 4 years ago, and is currently using a long-acting muscarinic antagonist (LAMA) bronchodilator. KD has a 40 pack-year smoking history, and has previously been advised to stop smoking, but has relapsed several times. She has a medical history of hypertension and depression, and a notable family history of emphysema, breast cancer, and diabetes.

The relationship between lung hyperinflation and dyspnea in COPD

In COPD, pathologic changes give rise to physiologic abnormalities such as mucus hypersecretion and ciliary dysfunction, gas exchange abnormalities, pulmonary hypertension, and airflow limitation and lung hyperinflation.¹³ Lung hyperinflation, an increase in resting functional residual volume above a normal level, represents a mechanical link between the characteristic expiratory airflow impairment, dyspnea, and physical activity limitation in COPD.¹

Although patients can compensate for several of the negative consequences of hyperinflation (eg, altering the chest wall due to overdistended lungs), such compensatory mechanisms are unable to cope with large increases in ventilation, such as those that occur during exercise.¹ Air trapping, together with ineffectiveness of respiratory muscle function, leads to increased ventilation requirements and dynamic pulmonary hyperinflation, resulting in dyspnea.¹

Patients with COPD describe a sensation of “air hunger,” reporting “unsatisfied” or “unrewarded” inhalation, “shallow breathing,” and a feeling that they “cannot get a deep breath,”¹⁸ whereas, in fact, they are limited in their ability to fully exhale. Verbal descriptors (eg, “air hunger” or “chest tightness”) are important tools in understanding a patient’s experience with dyspnea, and a patient’s choice of descriptor may be related to dyspnea severity, and the level of distress that dyspnea causes a given patient.¹⁹ Air hunger in turn encourages faster breathing, leading to further shortness of breath and more dynamic hyperinflation.^1,20

To deflate the lungs of patients with COPD, physiologic, pharmacologic, and possibly surgical interventions are required:

• Controlled breathing techniques (eg, purse-lipped breathing) that encourage slow and deep breathing can correct abnormal chest wall motion, decrease the work of breathing, increase breathing efficiency, and improve the distribution of ventilation to empty the lungs.²¹
• Bronchodilators can help to achieve lung deflation by improving ventilatory mechanics, as shown by increases in inspiratory capacity and vital capacity.²²
• Lung volume reduction surgery can also be considered to treat severe hyperinflation in emphysematous patients⁵; bronchoscopic interventions that lower lung volumes are also in development.²³ 

The impact of lung hyperinflation and dyspnea on physical activity in COPD

Dyspnea and hyperinflation are closely interrelated with physical activity limitation,^16,29,30 and so can be viewed as significant contributors to patient disability. During an acute exacerbation, patients with COPD will experience worsening airway obstruction, dynamic hyperinflation, and dyspnea.³¹ Patients with a greater number of comorbid conditions may also have greater shortness of breath.³² In addition, patients with COPD and hyperinflation perform less physical activity than individuals without hyperinflation, regardless of COPD severity, as assessed using the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe) and BODE (Body-mass index, airflow Obstruction, Dyspnea, and Exercise) index.³³ These patients also exhibit increases in dyspnea perception during commonly performed ADLs, which may limit physical activity and worsen lung hyperinflation.³³ More limited physical activity also contributes to higher dyspnea scores during ADLs.⁸

Furthermore, the ability to perform typical ADLs may be significantly altered or eliminated altogether in patients with COPD.¹¹ Leisure activities are often the first to be dropped by patients, as they generally require greater effort than simpler tasks, and are not critical to daily life.¹¹ Eventually, these activities become progressively more difficult, and most patients with moderate or severe COPD can struggle to complete even the most basic daily activities.¹¹

In addition to the morbidity burden and impact on ADLs, lower levels of physical activity in patients with COPD have also been shown to increase the risk of mortality and exacerbations, and elevate the risk of comorbidities such as heart disease and metabolic disease.³⁴ In light of these observations, improving exercise capacity should be a key goal in COPD management.

Assessment and measurement of dyspnea and hyperinflation

Reducing hyperinflation and dyspnea is essential for improving physical activity endurance and overall physical activity in patients with COPD; therefore, measuring the degree of impairment is important.²² Clinicians should be aware that some patients may have relief of dyspnea due to improvements in hyperinflation, despite relatively mild changes in FEV₁.³⁵ Lung volume measures, including total lung capacity, residual volume and functional residual capacity, are valuable tools in the assessment of lung hyperinflation in COPD, and therefore constitute a key component of pulmonary function testing.³⁶ However, expanded pulmonary function testing may be required for patients with severe dyspnea that does not correspond to spirometric findings, or cases in which diagnosis is uncertain.³⁷

Lung volumes are evaluated primarily by body plethysmography, during which a patient sits inside an airtight “body box” equipped to measure pressure and volume changes.^14,38 Helium dilution and nitrogen washing can also be used to measure functional residual capacity in patients with COPD,¹⁴ but body plethysmography is considered to be a more accurate method of lung volume evaluation in patients with severe airflow obstruction.^14,38 Radiographic techniques can also be used, but due to a lack of standardization, they are not typically utilized in clinical practice.¹⁴ Measurement of IC may complement other lung volume measures as part of assessment of hyperinflation.¹⁶ This can be measured using either spirometry or body plethysmography.^39,40

In addition to evaluating hyperinflation, ADLs, physical activity, exercise capacity, and dyspnea should all be assessed in patients with COPD in primary care. It is known that patients may self-limit ADLs to avoid symptoms of COPD; in doing so, worsening symptoms may be underappreciated, and subsequently underreported, by the patient. Thus, it is essential that physicians ask patients with COPD, as well as individuals at risk of COPD, questions about changes in their physical activity or ability to perform common tasks. There are a number of methods to measure functional performance, but for a simple assessment of ADLs, clinicians can ask the patient or caregiver questions related to basic daily tasks.¹¹ In early COPD, patients who experience mild dyspnea during exercise should be able to perform most productive activities. Patients with stable COPD and moderate dyspnea during exercise should be able to carry out most of the higher functioning ADLs, whereas patients with severe COPD may struggle to complete basic ADLs without assistance.¹¹ It should be noted, however, that patients may experience dyspnea with fairly routine activities, and even reduce physical activity at relatively early stages of airflow limitation.^41,42

Other tests may be useful in assessing the impact of an intervention, be it pharmacologic or nonpharmacologic, on dyspnea severity. For example, increases in the 6-minute-walk distance (6MWD) have been shown to correlate with improvements in dyspnea.⁴⁶ The 6MWD has also been shown to be an important predictor of hospitalization and mortality in patients with COPD.⁴⁷ However, it is important to note that improvements in 6MWD show only a very weak correlation with patient-reported outcomes,⁴⁸ and may be a less sensitive measure for patients with less disability than those with more profound functional limitation.⁴⁹ Moreover, 6MWD can be affected by a patient’s psychologic motivation,^6,50 as well as other comorbidities observed in patients with COPD, such as osteoporosis, heart failure, and peripheral vascular disease.^46,51 Although not used for COPD diagnosis or evaluation of dyspnea or physical activity limitation, a chest X-ray can also be a useful tool for excluding alternative diagnoses, as well as for detecting significant comorbidities in patients with COPD, such as concomitant respiratory, cardiac, and skeletal diseases.⁵

Pulmonary rehabilitation is a tailored intervention that encompasses exercise training, education, and self-management support for people with chronic respiratory disease, based on detailed assessment of their exercise capacity and symptoms.⁵² Pulmonary rehabilitation is as important as medication in COPD management, providing a cost-effective intervention with minimal adverse effects.⁵³ Moreover, pulmonary rehabilitation has been shown to benefit patients with mild to severe dyspnea (as classified according to the Medical Research Council dyspnea scale), demonstrating the value of successful execution of these programs in patients with COPD, irrespective of disease severity.⁵⁴ Although the most significant improvements in patient quality of life are observed when a multimodality approach is used, exercise and proper pulmonary rehabilitation programs have been shown to improve quality of life more than medication alone.^5,55 Notably, there are few supporting data for the use of supplemental oxygen in patients experiencing dyspnea without hypoxemia. Oxygen supplementation is only of minimal benefit to relieving the sensation of dyspnea.^56,57

The relationship between the impact of pulmonary rehabilitation in patients with COPD and frailty scores has also been evaluated. Frailty scores are calculated based on an individual’s level of physical activity, and other key criteria that are indicative of their ability to self-manage their medical condition.⁵⁸ These scores are particularly relevant in the context of COPD, given the high prevalence of the condition in older people.⁵⁸ Although frailty is a strong independent predictor of noncompletion of pulmonary rehabilitation, completion of a pulmonary rehabilitation program in patients who are frail has been shown to reverse their frailty in the short term.⁵⁸ It is therefore important that physicians guide and encourage these patients for the duration of a pulmonary rehabilitation program, from initiation through to completion, to ensure that those who are likely to derive the greatest benefit from pulmonary rehabilitation are supported to do so.

In addition to pulmonary rehabilitation, other nonpharmacologic interventions have emerged in recent years that may help to relieve dyspnea in patients with COPD. Airway clearance devices, such as acapella (Smiths Medical; Minneapolis, MN), Flutter (Allergan; Dublin, Ireland), Lung Flute (Medical Acoustics; Buffalo, NY), Quake (Thayer Medical; Tucson, AZ), and Aerobika (Monaghan Medical; Plattsburgh, NY) promote the clearance of sputum through the application of positive expiratory pressure, possibly allowing medicines to penetrate the lungs more effectively, and improving diffuse airflow obstruction.^59-61 Incorporating an airway clearance device into a bronchodilator therapy regimen has been shown to improve dyspnea scores, both before and after exercise, compared with bronchodilator therapy combined with a nonfunctional control device in patients with severe COPD.⁵⁹ In addition, noninvasive forms of ventilation, such as continuous positive airway pressure and bi-level positive airway pressure (BiPAP), have been shown to effectively reduce dyspnea in patients with COPD.^62,63 In a 24-month study in patients with severe COPD, resting dyspnea improved significantly in patients using the BiPAP Auto-Trak (Philips Respironics, Best, The Netherlands) in conjunction with their regular bronchodilator therapy, compared with those receiving long-term oxygen therapy in addition to their typical therapeutic regimen.⁶³ Further studies are required to establish the impact of these devices in the management of dyspnea and other symptoms of COPD.

These nonpharmacologic interventions can be supplemented with pharmacologic treatments to help patients achieve their treatment goals of improved dyspnea and increased exercise performance. Bronchodilators, which form the basis of various COPD treatment options, include⁵:

• short-acting muscarinic antagonists (SAMAs), such as ipratropium
• short-acting β₂-agonists (SABAs), such as albuterol, levalbuterol, and terbutaline
• SAMA/SABA combinations
• LAMAs, such as aclidinium, glycopyrrolate, tiotropium, and umeclidinium
• long-acting β ₂-agonists (LABAs), such as arformoterol, indacaterol, formoterol, olodaterol, salmeterol, and vilanterol
• LAMA/LABA combinations (umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, glycopyrrolate/indacaterol)

Inhaled corticosteroids can also be used in a fixed-dose combination with a LABA, which can be combined with a LAMA, in select patients⁵; however, these combination products may have minimal value in treating dyspnea unless asthma is concomitantly present.^5,64 Further discussion of the different treatment options available for patients with COPD can be found in the final article of this supplement.

In addition to improving quality of life, long-acting bronchodilators, such as LAMAs, LABAs, and LAMA/LABA combinations, increase expiratory flow, reduce dynamic hyperinflation, and improve exercise capacity of patients.^65-67 As disease severity worsens, physicians may opt for long-acting bronchodilator options that have twice-daily dosing, which may confer a benefit in improving night-time symptom control.⁶⁸

As well as active pharmacologic and nonpharmacologic interventions, physicians should always encourage smoking cessation in patients with COPD, as this has the greatest capacity to influence the natural course of the disease.⁵ It is essential that health care providers continually deliver smoking cessation messages to patients with COPD; patients can also be supported to stop smoking by using nicotine replacement therapy, pharmacologic interventions, attending smoking cessation programs, and counseling.⁵

Lung volume reduction surgery may also be considered as a strategy for the management of dyspnea in severe, refractory COPD.⁶⁹ Similarly, nonsurgical bronchoscopic interventions are being developed that look to achieve similar results to lung volume reduction surgery, including endobronchial one-way valves, lung volume reduction coils, airway bypasses, adhesives, and vapor therapy.²³ 

CASE STUDY:

The primary care physician assessed KD’s dyspnea using the CAT and ordered a chest X-ray to identify any significant comorbidities, such as concomitant respiratory, skeletal, or cardiac diseases. As KD’s CAT score was 17, and her symptoms were uncontrolled on LAMA monotherapy, her physician prescribed a long-acting LAMA/LABA combination, along with pulmonary rehabilitation. The physician also counseled KD on the importance of smoking cessation, and referred her to a local smoking cessation program.

Conclusions

Dyspnea, the most common symptom of COPD and the primary consequence of the condition’s characteristic lung hyperinflation, is a heavy burden on the lives of patients. The impact of dyspnea is perhaps most apparent in the context of physical activity, with activity limitation observed frequently in patients with COPD, regardless of disease stage. This can affect patients’ quality of life significantly, and has long-term consequences on disease progression. Improving dyspnea and increasing exercise endurance should therefore be a key goal for COPD management, which should encompass both nonpharmacologic interventions, such as pulmonary rehabilitation, and pharmacologic interventions, such as use of bronchodilator therapy.

Introduction

Dyspnea, the sensation of difficult or labored breathing, is the most common symptom in chronic obstructive pulmonary disease (COPD) and the primary symptom that limits physical activity in more advanced disease.¹ According to the American Thoracic Society, dyspnea may be measured according to 3 domains²:

• what breathing feels like for the patient
• how distressed the patient feels when breathing
• how dyspnea affects functional ability, employment, health-related quality of life, or health status.

As disease severity increases, breathlessness becomes more disabling at lower activity levels. These changes further impact the quality of life of patients, and can lead to anxiety and depression.¹¹

Physical inactivity is often considered to be a major contributor to the progression of COPD,⁶ and is linked to hospitalizations and increased all-cause mortality.¹² There is therefore a need to recognize symptoms early and treat them accordingly.

CASE STUDY: 

KD, a 64-year-old woman, presented to her primary care physician’s office for a routine visit. Upon assessment, KD revealed that she used to enjoy going on walks with her neighbor, but she cannot walk up the hills in her neighborhood anymore without feeling “incredibly breathless.” She has become increasingly concerned that she is “having trouble getting a full breath.” KD informed her doctor that these symptoms had worsened since her last visit, and so she had stopped going on neighborhood walks. She was diagnosed with COPD 4 years ago, and is currently using a long-acting muscarinic antagonist (LAMA) bronchodilator. KD has a 40 pack-year smoking history, and has previously been advised to stop smoking, but has relapsed several times. She has a medical history of hypertension and depression, and a notable family history of emphysema, breast cancer, and diabetes.

The relationship between lung hyperinflation and dyspnea in COPD

In COPD, pathologic changes give rise to physiologic abnormalities such as mucus hypersecretion and ciliary dysfunction, gas exchange abnormalities, pulmonary hypertension, and airflow limitation and lung hyperinflation.¹³ Lung hyperinflation, an increase in resting functional residual volume above a normal level, represents a mechanical link between the characteristic expiratory airflow impairment, dyspnea, and physical activity limitation in COPD.¹

Although patients can compensate for several of the negative consequences of hyperinflation (eg, altering the chest wall due to overdistended lungs), such compensatory mechanisms are unable to cope with large increases in ventilation, such as those that occur during exercise.¹ Air trapping, together with ineffectiveness of respiratory muscle function, leads to increased ventilation requirements and dynamic pulmonary hyperinflation, resulting in dyspnea.¹

Patients with COPD describe a sensation of “air hunger,” reporting “unsatisfied” or “unrewarded” inhalation, “shallow breathing,” and a feeling that they “cannot get a deep breath,”¹⁸ whereas, in fact, they are limited in their ability to fully exhale. Verbal descriptors (eg, “air hunger” or “chest tightness”) are important tools in understanding a patient’s experience with dyspnea, and a patient’s choice of descriptor may be related to dyspnea severity, and the level of distress that dyspnea causes a given patient.¹⁹ Air hunger in turn encourages faster breathing, leading to further shortness of breath and more dynamic hyperinflation.^1,20

To deflate the lungs of patients with COPD, physiologic, pharmacologic, and possibly surgical interventions are required:

• Controlled breathing techniques (eg, purse-lipped breathing) that encourage slow and deep breathing can correct abnormal chest wall motion, decrease the work of breathing, increase breathing efficiency, and improve the distribution of ventilation to empty the lungs.²¹
• Bronchodilators can help to achieve lung deflation by improving ventilatory mechanics, as shown by increases in inspiratory capacity and vital capacity.²²
• Lung volume reduction surgery can also be considered to treat severe hyperinflation in emphysematous patients⁵; bronchoscopic interventions that lower lung volumes are also in development.²³ 

The impact of lung hyperinflation and dyspnea on physical activity in COPD

Dyspnea and hyperinflation are closely interrelated with physical activity limitation,^16,29,30 and so can be viewed as significant contributors to patient disability. During an acute exacerbation, patients with COPD will experience worsening airway obstruction, dynamic hyperinflation, and dyspnea.³¹ Patients with a greater number of comorbid conditions may also have greater shortness of breath.³² In addition, patients with COPD and hyperinflation perform less physical activity than individuals without hyperinflation, regardless of COPD severity, as assessed using the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe) and BODE (Body-mass index, airflow Obstruction, Dyspnea, and Exercise) index.³³ These patients also exhibit increases in dyspnea perception during commonly performed ADLs, which may limit physical activity and worsen lung hyperinflation.³³ More limited physical activity also contributes to higher dyspnea scores during ADLs.⁸

Furthermore, the ability to perform typical ADLs may be significantly altered or eliminated altogether in patients with COPD.¹¹ Leisure activities are often the first to be dropped by patients, as they generally require greater effort than simpler tasks, and are not critical to daily life.¹¹ Eventually, these activities become progressively more difficult, and most patients with moderate or severe COPD can struggle to complete even the most basic daily activities.¹¹

In addition to the morbidity burden and impact on ADLs, lower levels of physical activity in patients with COPD have also been shown to increase the risk of mortality and exacerbations, and elevate the risk of comorbidities such as heart disease and metabolic disease.³⁴ In light of these observations, improving exercise capacity should be a key goal in COPD management.

Assessment and measurement of dyspnea and hyperinflation

Reducing hyperinflation and dyspnea is essential for improving physical activity endurance and overall physical activity in patients with COPD; therefore, measuring the degree of impairment is important.²² Clinicians should be aware that some patients may have relief of dyspnea due to improvements in hyperinflation, despite relatively mild changes in FEV₁.³⁵ Lung volume measures, including total lung capacity, residual volume and functional residual capacity, are valuable tools in the assessment of lung hyperinflation in COPD, and therefore constitute a key component of pulmonary function testing.³⁶ However, expanded pulmonary function testing may be required for patients with severe dyspnea that does not correspond to spirometric findings, or cases in which diagnosis is uncertain.³⁷

Lung volumes are evaluated primarily by body plethysmography, during which a patient sits inside an airtight “body box” equipped to measure pressure and volume changes.^14,38 Helium dilution and nitrogen washing can also be used to measure functional residual capacity in patients with COPD,¹⁴ but body plethysmography is considered to be a more accurate method of lung volume evaluation in patients with severe airflow obstruction.^14,38 Radiographic techniques can also be used, but due to a lack of standardization, they are not typically utilized in clinical practice.¹⁴ Measurement of IC may complement other lung volume measures as part of assessment of hyperinflation.¹⁶ This can be measured using either spirometry or body plethysmography.^39,40

In addition to evaluating hyperinflation, ADLs, physical activity, exercise capacity, and dyspnea should all be assessed in patients with COPD in primary care. It is known that patients may self-limit ADLs to avoid symptoms of COPD; in doing so, worsening symptoms may be underappreciated, and subsequently underreported, by the patient. Thus, it is essential that physicians ask patients with COPD, as well as individuals at risk of COPD, questions about changes in their physical activity or ability to perform common tasks. There are a number of methods to measure functional performance, but for a simple assessment of ADLs, clinicians can ask the patient or caregiver questions related to basic daily tasks.¹¹ In early COPD, patients who experience mild dyspnea during exercise should be able to perform most productive activities. Patients with stable COPD and moderate dyspnea during exercise should be able to carry out most of the higher functioning ADLs, whereas patients with severe COPD may struggle to complete basic ADLs without assistance.¹¹ It should be noted, however, that patients may experience dyspnea with fairly routine activities, and even reduce physical activity at relatively early stages of airflow limitation.^41,42

Other tests may be useful in assessing the impact of an intervention, be it pharmacologic or nonpharmacologic, on dyspnea severity. For example, increases in the 6-minute-walk distance (6MWD) have been shown to correlate with improvements in dyspnea.⁴⁶ The 6MWD has also been shown to be an important predictor of hospitalization and mortality in patients with COPD.⁴⁷ However, it is important to note that improvements in 6MWD show only a very weak correlation with patient-reported outcomes,⁴⁸ and may be a less sensitive measure for patients with less disability than those with more profound functional limitation.⁴⁹ Moreover, 6MWD can be affected by a patient’s psychologic motivation,^6,50 as well as other comorbidities observed in patients with COPD, such as osteoporosis, heart failure, and peripheral vascular disease.^46,51 Although not used for COPD diagnosis or evaluation of dyspnea or physical activity limitation, a chest X-ray can also be a useful tool for excluding alternative diagnoses, as well as for detecting significant comorbidities in patients with COPD, such as concomitant respiratory, cardiac, and skeletal diseases.⁵

Pulmonary rehabilitation is a tailored intervention that encompasses exercise training, education, and self-management support for people with chronic respiratory disease, based on detailed assessment of their exercise capacity and symptoms.⁵² Pulmonary rehabilitation is as important as medication in COPD management, providing a cost-effective intervention with minimal adverse effects.⁵³ Moreover, pulmonary rehabilitation has been shown to benefit patients with mild to severe dyspnea (as classified according to the Medical Research Council dyspnea scale), demonstrating the value of successful execution of these programs in patients with COPD, irrespective of disease severity.⁵⁴ Although the most significant improvements in patient quality of life are observed when a multimodality approach is used, exercise and proper pulmonary rehabilitation programs have been shown to improve quality of life more than medication alone.^5,55 Notably, there are few supporting data for the use of supplemental oxygen in patients experiencing dyspnea without hypoxemia. Oxygen supplementation is only of minimal benefit to relieving the sensation of dyspnea.^56,57

The relationship between the impact of pulmonary rehabilitation in patients with COPD and frailty scores has also been evaluated. Frailty scores are calculated based on an individual’s level of physical activity, and other key criteria that are indicative of their ability to self-manage their medical condition.⁵⁸ These scores are particularly relevant in the context of COPD, given the high prevalence of the condition in older people.⁵⁸ Although frailty is a strong independent predictor of noncompletion of pulmonary rehabilitation, completion of a pulmonary rehabilitation program in patients who are frail has been shown to reverse their frailty in the short term.⁵⁸ It is therefore important that physicians guide and encourage these patients for the duration of a pulmonary rehabilitation program, from initiation through to completion, to ensure that those who are likely to derive the greatest benefit from pulmonary rehabilitation are supported to do so.

In addition to pulmonary rehabilitation, other nonpharmacologic interventions have emerged in recent years that may help to relieve dyspnea in patients with COPD. Airway clearance devices, such as acapella (Smiths Medical; Minneapolis, MN), Flutter (Allergan; Dublin, Ireland), Lung Flute (Medical Acoustics; Buffalo, NY), Quake (Thayer Medical; Tucson, AZ), and Aerobika (Monaghan Medical; Plattsburgh, NY) promote the clearance of sputum through the application of positive expiratory pressure, possibly allowing medicines to penetrate the lungs more effectively, and improving diffuse airflow obstruction.^59-61 Incorporating an airway clearance device into a bronchodilator therapy regimen has been shown to improve dyspnea scores, both before and after exercise, compared with bronchodilator therapy combined with a nonfunctional control device in patients with severe COPD.⁵⁹ In addition, noninvasive forms of ventilation, such as continuous positive airway pressure and bi-level positive airway pressure (BiPAP), have been shown to effectively reduce dyspnea in patients with COPD.^62,63 In a 24-month study in patients with severe COPD, resting dyspnea improved significantly in patients using the BiPAP Auto-Trak (Philips Respironics, Best, The Netherlands) in conjunction with their regular bronchodilator therapy, compared with those receiving long-term oxygen therapy in addition to their typical therapeutic regimen.⁶³ Further studies are required to establish the impact of these devices in the management of dyspnea and other symptoms of COPD.

These nonpharmacologic interventions can be supplemented with pharmacologic treatments to help patients achieve their treatment goals of improved dyspnea and increased exercise performance. Bronchodilators, which form the basis of various COPD treatment options, include⁵:

• short-acting muscarinic antagonists (SAMAs), such as ipratropium
• short-acting β₂-agonists (SABAs), such as albuterol, levalbuterol, and terbutaline
• SAMA/SABA combinations
• LAMAs, such as aclidinium, glycopyrrolate, tiotropium, and umeclidinium
• long-acting β ₂-agonists (LABAs), such as arformoterol, indacaterol, formoterol, olodaterol, salmeterol, and vilanterol
• LAMA/LABA combinations (umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, glycopyrrolate/indacaterol)

Inhaled corticosteroids can also be used in a fixed-dose combination with a LABA, which can be combined with a LAMA, in select patients⁵; however, these combination products may have minimal value in treating dyspnea unless asthma is concomitantly present.^5,64 Further discussion of the different treatment options available for patients with COPD can be found in the final article of this supplement.

In addition to improving quality of life, long-acting bronchodilators, such as LAMAs, LABAs, and LAMA/LABA combinations, increase expiratory flow, reduce dynamic hyperinflation, and improve exercise capacity of patients.^65-67 As disease severity worsens, physicians may opt for long-acting bronchodilator options that have twice-daily dosing, which may confer a benefit in improving night-time symptom control.⁶⁸

As well as active pharmacologic and nonpharmacologic interventions, physicians should always encourage smoking cessation in patients with COPD, as this has the greatest capacity to influence the natural course of the disease.⁵ It is essential that health care providers continually deliver smoking cessation messages to patients with COPD; patients can also be supported to stop smoking by using nicotine replacement therapy, pharmacologic interventions, attending smoking cessation programs, and counseling.⁵

Lung volume reduction surgery may also be considered as a strategy for the management of dyspnea in severe, refractory COPD.⁶⁹ Similarly, nonsurgical bronchoscopic interventions are being developed that look to achieve similar results to lung volume reduction surgery, including endobronchial one-way valves, lung volume reduction coils, airway bypasses, adhesives, and vapor therapy.²³ 

CASE STUDY:

The primary care physician assessed KD’s dyspnea using the CAT and ordered a chest X-ray to identify any significant comorbidities, such as concomitant respiratory, skeletal, or cardiac diseases. As KD’s CAT score was 17, and her symptoms were uncontrolled on LAMA monotherapy, her physician prescribed a long-acting LAMA/LABA combination, along with pulmonary rehabilitation. The physician also counseled KD on the importance of smoking cessation, and referred her to a local smoking cessation program.

Conclusions

Dyspnea, the most common symptom of COPD and the primary consequence of the condition’s characteristic lung hyperinflation, is a heavy burden on the lives of patients. The impact of dyspnea is perhaps most apparent in the context of physical activity, with activity limitation observed frequently in patients with COPD, regardless of disease stage. This can affect patients’ quality of life significantly, and has long-term consequences on disease progression. Improving dyspnea and increasing exercise endurance should therefore be a key goal for COPD management, which should encompass both nonpharmacologic interventions, such as pulmonary rehabilitation, and pharmacologic interventions, such as use of bronchodilator therapy.

Introduction

Dyspnea, the sensation of difficult or labored breathing, is the most common symptom in chronic obstructive pulmonary disease (COPD) and the primary symptom that limits physical activity in more advanced disease.¹ According to the American Thoracic Society, dyspnea may be measured according to 3 domains²:

• what breathing feels like for the patient
• how distressed the patient feels when breathing
• how dyspnea affects functional ability, employment, health-related quality of life, or health status.

As disease severity increases, breathlessness becomes more disabling at lower activity levels. These changes further impact the quality of life of patients, and can lead to anxiety and depression.¹¹

Physical inactivity is often considered to be a major contributor to the progression of COPD,⁶ and is linked to hospitalizations and increased all-cause mortality.¹² There is therefore a need to recognize symptoms early and treat them accordingly.

CASE STUDY: 

KD, a 64-year-old woman, presented to her primary care physician’s office for a routine visit. Upon assessment, KD revealed that she used to enjoy going on walks with her neighbor, but she cannot walk up the hills in her neighborhood anymore without feeling “incredibly breathless.” She has become increasingly concerned that she is “having trouble getting a full breath.” KD informed her doctor that these symptoms had worsened since her last visit, and so she had stopped going on neighborhood walks. She was diagnosed with COPD 4 years ago, and is currently using a long-acting muscarinic antagonist (LAMA) bronchodilator. KD has a 40 pack-year smoking history, and has previously been advised to stop smoking, but has relapsed several times. She has a medical history of hypertension and depression, and a notable family history of emphysema, breast cancer, and diabetes.

The relationship between lung hyperinflation and dyspnea in COPD

In COPD, pathologic changes give rise to physiologic abnormalities such as mucus hypersecretion and ciliary dysfunction, gas exchange abnormalities, pulmonary hypertension, and airflow limitation and lung hyperinflation.¹³ Lung hyperinflation, an increase in resting functional residual volume above a normal level, represents a mechanical link between the characteristic expiratory airflow impairment, dyspnea, and physical activity limitation in COPD.¹

Although patients can compensate for several of the negative consequences of hyperinflation (eg, altering the chest wall due to overdistended lungs), such compensatory mechanisms are unable to cope with large increases in ventilation, such as those that occur during exercise.¹ Air trapping, together with ineffectiveness of respiratory muscle function, leads to increased ventilation requirements and dynamic pulmonary hyperinflation, resulting in dyspnea.¹

Patients with COPD describe a sensation of “air hunger,” reporting “unsatisfied” or “unrewarded” inhalation, “shallow breathing,” and a feeling that they “cannot get a deep breath,”¹⁸ whereas, in fact, they are limited in their ability to fully exhale. Verbal descriptors (eg, “air hunger” or “chest tightness”) are important tools in understanding a patient’s experience with dyspnea, and a patient’s choice of descriptor may be related to dyspnea severity, and the level of distress that dyspnea causes a given patient.¹⁹ Air hunger in turn encourages faster breathing, leading to further shortness of breath and more dynamic hyperinflation.^1,20

To deflate the lungs of patients with COPD, physiologic, pharmacologic, and possibly surgical interventions are required:

• Controlled breathing techniques (eg, purse-lipped breathing) that encourage slow and deep breathing can correct abnormal chest wall motion, decrease the work of breathing, increase breathing efficiency, and improve the distribution of ventilation to empty the lungs.²¹
• Bronchodilators can help to achieve lung deflation by improving ventilatory mechanics, as shown by increases in inspiratory capacity and vital capacity.²²
• Lung volume reduction surgery can also be considered to treat severe hyperinflation in emphysematous patients⁵; bronchoscopic interventions that lower lung volumes are also in development.²³ 

The impact of lung hyperinflation and dyspnea on physical activity in COPD

Dyspnea and hyperinflation are closely interrelated with physical activity limitation,^16,29,30 and so can be viewed as significant contributors to patient disability. During an acute exacerbation, patients with COPD will experience worsening airway obstruction, dynamic hyperinflation, and dyspnea.³¹ Patients with a greater number of comorbid conditions may also have greater shortness of breath.³² In addition, patients with COPD and hyperinflation perform less physical activity than individuals without hyperinflation, regardless of COPD severity, as assessed using the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe) and BODE (Body-mass index, airflow Obstruction, Dyspnea, and Exercise) index.³³ These patients also exhibit increases in dyspnea perception during commonly performed ADLs, which may limit physical activity and worsen lung hyperinflation.³³ More limited physical activity also contributes to higher dyspnea scores during ADLs.⁸

Furthermore, the ability to perform typical ADLs may be significantly altered or eliminated altogether in patients with COPD.¹¹ Leisure activities are often the first to be dropped by patients, as they generally require greater effort than simpler tasks, and are not critical to daily life.¹¹ Eventually, these activities become progressively more difficult, and most patients with moderate or severe COPD can struggle to complete even the most basic daily activities.¹¹

In addition to the morbidity burden and impact on ADLs, lower levels of physical activity in patients with COPD have also been shown to increase the risk of mortality and exacerbations, and elevate the risk of comorbidities such as heart disease and metabolic disease.³⁴ In light of these observations, improving exercise capacity should be a key goal in COPD management.

Assessment and measurement of dyspnea and hyperinflation

Reducing hyperinflation and dyspnea is essential for improving physical activity endurance and overall physical activity in patients with COPD; therefore, measuring the degree of impairment is important.²² Clinicians should be aware that some patients may have relief of dyspnea due to improvements in hyperinflation, despite relatively mild changes in FEV₁.³⁵ Lung volume measures, including total lung capacity, residual volume and functional residual capacity, are valuable tools in the assessment of lung hyperinflation in COPD, and therefore constitute a key component of pulmonary function testing.³⁶ However, expanded pulmonary function testing may be required for patients with severe dyspnea that does not correspond to spirometric findings, or cases in which diagnosis is uncertain.³⁷

Lung volumes are evaluated primarily by body plethysmography, during which a patient sits inside an airtight “body box” equipped to measure pressure and volume changes.^14,38 Helium dilution and nitrogen washing can also be used to measure functional residual capacity in patients with COPD,¹⁴ but body plethysmography is considered to be a more accurate method of lung volume evaluation in patients with severe airflow obstruction.^14,38 Radiographic techniques can also be used, but due to a lack of standardization, they are not typically utilized in clinical practice.¹⁴ Measurement of IC may complement other lung volume measures as part of assessment of hyperinflation.¹⁶ This can be measured using either spirometry or body plethysmography.^39,40

In addition to evaluating hyperinflation, ADLs, physical activity, exercise capacity, and dyspnea should all be assessed in patients with COPD in primary care. It is known that patients may self-limit ADLs to avoid symptoms of COPD; in doing so, worsening symptoms may be underappreciated, and subsequently underreported, by the patient. Thus, it is essential that physicians ask patients with COPD, as well as individuals at risk of COPD, questions about changes in their physical activity or ability to perform common tasks. There are a number of methods to measure functional performance, but for a simple assessment of ADLs, clinicians can ask the patient or caregiver questions related to basic daily tasks.¹¹ In early COPD, patients who experience mild dyspnea during exercise should be able to perform most productive activities. Patients with stable COPD and moderate dyspnea during exercise should be able to carry out most of the higher functioning ADLs, whereas patients with severe COPD may struggle to complete basic ADLs without assistance.¹¹ It should be noted, however, that patients may experience dyspnea with fairly routine activities, and even reduce physical activity at relatively early stages of airflow limitation.^41,42

Other tests may be useful in assessing the impact of an intervention, be it pharmacologic or nonpharmacologic, on dyspnea severity. For example, increases in the 6-minute-walk distance (6MWD) have been shown to correlate with improvements in dyspnea.⁴⁶ The 6MWD has also been shown to be an important predictor of hospitalization and mortality in patients with COPD.⁴⁷ However, it is important to note that improvements in 6MWD show only a very weak correlation with patient-reported outcomes,⁴⁸ and may be a less sensitive measure for patients with less disability than those with more profound functional limitation.⁴⁹ Moreover, 6MWD can be affected by a patient’s psychologic motivation,^6,50 as well as other comorbidities observed in patients with COPD, such as osteoporosis, heart failure, and peripheral vascular disease.^46,51 Although not used for COPD diagnosis or evaluation of dyspnea or physical activity limitation, a chest X-ray can also be a useful tool for excluding alternative diagnoses, as well as for detecting significant comorbidities in patients with COPD, such as concomitant respiratory, cardiac, and skeletal diseases.⁵

Pulmonary rehabilitation is a tailored intervention that encompasses exercise training, education, and self-management support for people with chronic respiratory disease, based on detailed assessment of their exercise capacity and symptoms.⁵² Pulmonary rehabilitation is as important as medication in COPD management, providing a cost-effective intervention with minimal adverse effects.⁵³ Moreover, pulmonary rehabilitation has been shown to benefit patients with mild to severe dyspnea (as classified according to the Medical Research Council dyspnea scale), demonstrating the value of successful execution of these programs in patients with COPD, irrespective of disease severity.⁵⁴ Although the most significant improvements in patient quality of life are observed when a multimodality approach is used, exercise and proper pulmonary rehabilitation programs have been shown to improve quality of life more than medication alone.^5,55 Notably, there are few supporting data for the use of supplemental oxygen in patients experiencing dyspnea without hypoxemia. Oxygen supplementation is only of minimal benefit to relieving the sensation of dyspnea.^56,57

The relationship between the impact of pulmonary rehabilitation in patients with COPD and frailty scores has also been evaluated. Frailty scores are calculated based on an individual’s level of physical activity, and other key criteria that are indicative of their ability to self-manage their medical condition.⁵⁸ These scores are particularly relevant in the context of COPD, given the high prevalence of the condition in older people.⁵⁸ Although frailty is a strong independent predictor of noncompletion of pulmonary rehabilitation, completion of a pulmonary rehabilitation program in patients who are frail has been shown to reverse their frailty in the short term.⁵⁸ It is therefore important that physicians guide and encourage these patients for the duration of a pulmonary rehabilitation program, from initiation through to completion, to ensure that those who are likely to derive the greatest benefit from pulmonary rehabilitation are supported to do so.

In addition to pulmonary rehabilitation, other nonpharmacologic interventions have emerged in recent years that may help to relieve dyspnea in patients with COPD. Airway clearance devices, such as acapella (Smiths Medical; Minneapolis, MN), Flutter (Allergan; Dublin, Ireland), Lung Flute (Medical Acoustics; Buffalo, NY), Quake (Thayer Medical; Tucson, AZ), and Aerobika (Monaghan Medical; Plattsburgh, NY) promote the clearance of sputum through the application of positive expiratory pressure, possibly allowing medicines to penetrate the lungs more effectively, and improving diffuse airflow obstruction.^59-61 Incorporating an airway clearance device into a bronchodilator therapy regimen has been shown to improve dyspnea scores, both before and after exercise, compared with bronchodilator therapy combined with a nonfunctional control device in patients with severe COPD.⁵⁹ In addition, noninvasive forms of ventilation, such as continuous positive airway pressure and bi-level positive airway pressure (BiPAP), have been shown to effectively reduce dyspnea in patients with COPD.^62,63 In a 24-month study in patients with severe COPD, resting dyspnea improved significantly in patients using the BiPAP Auto-Trak (Philips Respironics, Best, The Netherlands) in conjunction with their regular bronchodilator therapy, compared with those receiving long-term oxygen therapy in addition to their typical therapeutic regimen.⁶³ Further studies are required to establish the impact of these devices in the management of dyspnea and other symptoms of COPD.

These nonpharmacologic interventions can be supplemented with pharmacologic treatments to help patients achieve their treatment goals of improved dyspnea and increased exercise performance. Bronchodilators, which form the basis of various COPD treatment options, include⁵:

• short-acting muscarinic antagonists (SAMAs), such as ipratropium
• short-acting β₂-agonists (SABAs), such as albuterol, levalbuterol, and terbutaline
• SAMA/SABA combinations
• LAMAs, such as aclidinium, glycopyrrolate, tiotropium, and umeclidinium
• long-acting β ₂-agonists (LABAs), such as arformoterol, indacaterol, formoterol, olodaterol, salmeterol, and vilanterol
• LAMA/LABA combinations (umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, glycopyrrolate/indacaterol)

Inhaled corticosteroids can also be used in a fixed-dose combination with a LABA, which can be combined with a LAMA, in select patients⁵; however, these combination products may have minimal value in treating dyspnea unless asthma is concomitantly present.^5,64 Further discussion of the different treatment options available for patients with COPD can be found in the final article of this supplement.

In addition to improving quality of life, long-acting bronchodilators, such as LAMAs, LABAs, and LAMA/LABA combinations, increase expiratory flow, reduce dynamic hyperinflation, and improve exercise capacity of patients.^65-67 As disease severity worsens, physicians may opt for long-acting bronchodilator options that have twice-daily dosing, which may confer a benefit in improving night-time symptom control.⁶⁸

As well as active pharmacologic and nonpharmacologic interventions, physicians should always encourage smoking cessation in patients with COPD, as this has the greatest capacity to influence the natural course of the disease.⁵ It is essential that health care providers continually deliver smoking cessation messages to patients with COPD; patients can also be supported to stop smoking by using nicotine replacement therapy, pharmacologic interventions, attending smoking cessation programs, and counseling.⁵

Lung volume reduction surgery may also be considered as a strategy for the management of dyspnea in severe, refractory COPD.⁶⁹ Similarly, nonsurgical bronchoscopic interventions are being developed that look to achieve similar results to lung volume reduction surgery, including endobronchial one-way valves, lung volume reduction coils, airway bypasses, adhesives, and vapor therapy.²³ 

CASE STUDY:

The primary care physician assessed KD’s dyspnea using the CAT and ordered a chest X-ray to identify any significant comorbidities, such as concomitant respiratory, skeletal, or cardiac diseases. As KD’s CAT score was 17, and her symptoms were uncontrolled on LAMA monotherapy, her physician prescribed a long-acting LAMA/LABA combination, along with pulmonary rehabilitation. The physician also counseled KD on the importance of smoking cessation, and referred her to a local smoking cessation program.

Conclusions

Dyspnea, the most common symptom of COPD and the primary consequence of the condition’s characteristic lung hyperinflation, is a heavy burden on the lives of patients. The impact of dyspnea is perhaps most apparent in the context of physical activity, with activity limitation observed frequently in patients with COPD, regardless of disease stage. This can affect patients’ quality of life significantly, and has long-term consequences on disease progression. Improving dyspnea and increasing exercise endurance should therefore be a key goal for COPD management, which should encompass both nonpharmacologic interventions, such as pulmonary rehabilitation, and pharmacologic interventions, such as use of bronchodilator therapy.

Introduction

Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), occurring more frequently than in the general population^1-4 or patients with other chronic diseases such as hypertension, diabetes, cancer, or musculoskeletal disorders.^5,6 Their presence is associated with worse outcomes of COPD, and increased morbidity, mortality, disability, and health care expenditure.^6-8 In spite of this, both anxiety and depression are frequently overlooked and undertreated in patients with COPD,⁹ and symptoms of anxiety and depression can overlap significantly, as well as overlap with COPD symptoms.^7,10 

Comorbid depressive disorders that may occur in patients with COPD include major depressive disorder, dysthymias (chronic depressive symptoms of mild severity), and minor depression.¹¹ Depressive disorders are characterized by feelings of sadness, emptiness, and/or irritability, along with cognitive and somatic symptoms, which have a detrimental effect on the patient’s ability to function.¹¹ Anxiety disorders include generalized anxiety disorder (GAD), phobias, and panic disorders.¹¹ The main features of anxiety disorders, such as excessive fear and anxiety, may be accompanied by behavioral disturbances related to these symptoms, such as panic attacks and avoidance.^11,12

The reported prevalence of depression in COPD varies widely between studies, owing to differences in sampling methods and degrees of illness severity used in assessment of depression⁶; rates have been reported to range from 10% to 42% in patients with stable COPD,^6,13 and from 10% to 86% in patients with acute COPD exacerbation.¹⁴ Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD.¹⁰

Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients. GAD, panic disorders, and specific phobias are reported most frequently.¹⁵ Patients with COPD are 85% more likely to develop anxiety disorders compared with matched controls without COPD,⁴ and panic disorder is reported with a prevalence that is up to 10-fold higher than in the general population.¹⁶

Global prevalence rates of anxiety and depression are 1.8- and 1.4-fold higher in women than men, respectively¹⁷; the same gender difference is observed in patients with COPD.⁶ The higher prevalence rates of anxiety and depression in women are thought to be a result of sex differences in brain structure, function, and stress responses, as well as differences in exposure to reproductive hormones, social constraints, and experiences between women and men.¹⁸ However, psychologic comorbidity is an issue for both men and women with COPD, so it is important that clinicians are vigilant in recognizing anxiety and depression in both sexes, and are careful not to underestimate the burden in the male patient population.

It is also important to note that depression and anxiety often occur simultaneously in patients with COPD, with prevalence estimates of 26% to 43%.^9,19,20 COPD patients with both depression and anxiety are at a heightened risk of suicidal ideation, increased physical disability, and chronic depressive symptoms versus those with either disorder alone.^10,15 It is therefore important that comorbid anxiety and depression is not overlooked in patients with COPD.

Ensuring that anxiety and depression are recognized and treated effectively in patients with COPD is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD.

Potential mechanisms of anxiety and depression in COPD

Growing evidence suggests that the relationship between mood disorders—particularly depression—and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression.²¹ For example, in a study of
60 stable patients with COPD, elevated dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with the condition.²² In addition, the risk of new-onset depression was increased in COPD patients with moderate-to-severe dyspnea in a 3-year follow-up study.²³ Conversely, depression has been shown to be a significant risk factor for disabling dyspnea (modified Medical Research Council score ≥2) in patients with COPD.²⁴

COPD can lead to feelings of hopelessness, social isolation, reduced physical functioning, and sedentary lifestyle, all of which are associated with an increased level of depressive symptoms.²⁵ Similarly, inadequate social support increases the risk of anxiety in patients with COPD.²⁶ Therefore, ensuring that patients with COPD have high-quality support is very important for reducing anxiety and depressive symptoms.²⁷

The exact mechanisms for the association between mood disorders and COPD remain unclear.^7,10 Research to date indicates that the relationship between depression and impaired pulmonary function may be partly mediated by chronic inflammation^7,10; systemic inflammation has been associated with other comorbidities of COPD (eg, muscle wasting and osteoporosis),²⁸ and emerging data appear to show that proinflammatory cytokines partly mediate the association between depressive symptoms and pulmonary function.²⁹ Smoking and hypoxemia may also influence the prevalence of depression in COPD, but symptom severity and impaired quality of life remain the most important determinants.^6,30

Clinical studies have demonstrated that a number of patient-related factors, including female gender, younger age, current smoking, greater severity of airflow limitation, and lower socioeconomic status, are associated with a higher prevalence and/or increased risk of depression and/or anxiety in COPD.^3,4,30,31 Frequent episodes of rehospitalization, and comorbidities such as hypertension, arthritis, cancer, and heart disease, have been found to increase the risk of anxiety and depression in patients with COPD.^3,32 Risk of anxiety has been shown to increase with greater dyspnea severity.⁴ Pain, a frequently overlooked symptom in COPD, has been shown to be associated with symptoms of both anxiety and depression in patients with COPD.³³ This is driven by worsened quality of life and sleep quality, decreased physical activity, and an increased fear of movement that occur as a result of pain.³⁴

The impact of anxiety and depression in COPD

Comorbid anxiety and depression have a significant detrimental impact on morbidity and mortality in patients with COPD. Both disorders have been associated with an increased risk of death in COPD.^13,35-37 Indeed, of 12 comorbidities proposed to be predictors of mortality in a cohort of 187 female outpatients with COPD, anxiety was associated with the highest risk of death.^35,36

In addition, patients with COPD and anxiety and/or depression have a higher risk of COPD exacerbations,^{4,8,23,36,38-40} hospitalization,^41,42 rehospitalization,^14,36,43 longer hospital stays,^37,41,44 and mortality after exacerbations,^14,36,41 compared with patients without these comorbidities. Patients with COPD who have elevated anxiety symptoms also often experience their first hospitalization earlier in the natural course of COPD than those without anxiety.³⁶

Psychologic comorbidities are also associated with worse lung function, dyspnea, and respiratory symptom burden in patients with COPD.^37,40 Patients with COPD and anxiety are more likely to experience greater dyspnea at an earlier stage of disease than those without anxiety.³⁶ Persistent smoking at 6 months after hospitalization for an acute exacerbation of COPD is also more likely to be seen in patients with depression.³⁷

Patient-centered outcomes are worse in COPD patients with mood disorders. Both anxiety and depression have been shown to correlate with significantly reduced health-related quality of life (HRQoL), poorer physical health status, functional limitations, and reduced exercise capacity.^{4,23,37,40,45} The presence of either anxiety or depression at baseline has been shown to correlate with reduced HRQoL at 1-year follow-up, but depression appears to be the stronger predictor of low future HRQoL than anxiety.⁴⁵

Additionally, mood disorders—particularly depression—reduce physical activity in patients with COPD.^46,47 Emotional responses to COPD symptoms, such as dyspnea, can further decrease activity and worsen deconditioning, resulting in a downward spiral of reduced inactivity, social isolation, fear, anxiety, and depression.⁴⁸

COPD patients with any comorbidity exhibit lower rates of medication adherence than those without comorbidities.^49-51 Clinical studies have demonstrated that anxiety and depression are significant predictors of poor adherence to COPD interventions, including pulmonary rehabilitation (PR).^51-55 Nonadherence to COPD therapies is associated with poor clinical outcomes, including higher hospitalization rates and increased emergency department visits, and increased costs.^56,57 Health care expenditure, in terms of both specific COPD-related costs and general “all-cause” costs, is significantly higher in COPD patients with anxiety and/or depression than in those without.⁸

The underdiagnosis and undertreatment of anxiety and depression in this population is common and can adversely affect patient outcomes.^6,7,9,10,58 Hence, it is crucial that anxiety and depression are identified and more effectively managed in clinical practice.¹⁰

Primary care practitioners are the main point of contact for many patients with COPD,^6,59,60 and so can play a key role in screening for and early identification of anxiety and depression. However, detection of mood disorders by primary care practitioners is challenging for several reasons. These include the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),⁶ as well as factors associated with time constraints, such as competing agendas, duration of visits, and high patient load.^6,61 Furthermore, system-level barriers, such as lack of electronic medical records and adequate health insurance, as well as any communication gaps between primary care and mental health care, may hinder the detection and management of anxiety and depression.⁶ In addition, patients themselves may have a limited understanding of these comorbidities, or may be hesitant to discuss symptoms of anxiety or depression with their primary care practitioner owing to stigma around mental illness.⁶ 

Patients with COPD should be screened and assessed for anxiety and depression, and the United States Preventive Services Task Force recommends that clinicians screen for depression in all adults.^6,62 There are several validated screening tools suitable for clinical use:

• Anxiety Inventory for Respiratory (AIR) Disease scale: a brief, easy-to-use tool for screening and measuring anxiety in COPD.^63,64 It is a self-administered scale, and takes approximately 2 minutes to complete. The AIR scale is responsive to PR.⁶⁴
• COPD Anxiety Questionnaire (CAF): a reliable tool for early identification of COPD-related anxiety.⁶⁵
• Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ; available at: http://www.phqscreeners.com/select-screener/): the PRIME-MD comprises 26 yes/no questions on the 5 most common psychiatric disorders, including depression and anxiety.^66,67 This is not a diagnostic tool, but a high number of positive responses from a patient in any given module indicates that they require further clinical evaluation.
• PHQ-2 and PHQ-9 (Table 1; PHQ-9 available at http://www.phqscreeners.com/select-screener/): widely-used self-administered 2- and 9-item versions of the PRIME-MD, specific to depression; similarly, the 3-item PHQ-3 is available for anxiety assessment (Table 2).^6,67,68 In a study investigating tools used by family physicians in England to assess depression, over 75% used PHQ-9.⁶⁹
• 
  
  Generalized Anxiety Disorder 7-item (GAD-7) scale: an efficient, self-report scale that scores 7 common anxiety symptoms and can be used for screening and severity assessment of GAD in clinical practice.⁷⁰
• Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire-version 20 (GHQ-20): both can be used to screen for psychologic distress in patients with COPD.⁷¹
• The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI): two 21-item self-report questionnaires that are widely used in the United States to evaluate anxiety and depression.⁷²

In addition to specific anxiety and depression questionnaires (Tables 1 and 2), more general COPD assessments tools, such as the COPD Assessment Test and the COPD Clinical Questionnaire, also incorporate questions that may be indicative of symptoms of these comorbidities in patients with COPD.⁷³

Management of anxiety and depression in COPD

Even though anxiety and depression are among the most common and burdensome comorbid conditions in COPD, less than one-third of patients with these comorbidities receive effective intervention.^6,10 Primary care providers have an excellent opportunity to impact this care gap.

As in non-COPD patients, comorbid depression and anxiety may be treated with nonpharmacologic and/or pharmacologic interventions (Figure 1).⁷⁶

Evidence to date suggests that nonpharmacologic interventions such as behavioral therapy are as effective as antidepressants, and may be preferred by patients with mood disorders.¹²

Cognitive behavioral therapy (CBT), which is typically administered by psychologists/psychiatrists, may be effective in treating COPD-related anxiety and depression, especially in conjunction with exercise and education.^12,76,77 Individualized or group CBT is the treatment of choice for addressing thinking patterns that contribute to anxiety and depression to change a patient’s behavior and emotional state.⁷⁶ PR programs involve several components, including aerobic exercise, lung function training, and psycho-education.^62,76 PR is suitable for most patients with COPD, and provides multiple benefits, including reduced hospitalizations in patients who have had a recent exacerbation, and improved dyspnea, exercise tolerance, and health status in patients with stable disease,⁶² as well as clinically and statistically significant improvements in depression and anxiety, irrespective of age.^7,78,79 Exercise-based forms of PR appear to be the most effective for reducing mood symptoms,^12,76 and incorporating psychotherapy may also improve psychologic outcomes.⁸⁰ Stress reduction (relaxation) therapy aims to reduce anxiety-related physiologic changes, and includes a variety of techniques (eg, breathing exercises, sequential muscle relaxation, hypnosis, mindfulness meditation), some of which may be included in PR or used alongside other treatments (eg, CBT).⁷⁶ Limited data indicate that such therapy may be beneficial for reducing anxiety and depression, as well as respiratory symptoms and dyspnea, in patients with COPD.^12,76

Self-management techniques improve clinical outcomes in patients with COPD, but data on the management of depression or anxiety are inconclusive.^7,12 A minimal, home-based, nurse-led, psycho-educational intervention was designed to encourage more open-ended, descriptive discussions of thoughts, emotions, behaviors, and bodily sensations in patients with COPD.⁸¹ The intervention, which involved nurses attending a 1-hour face-to-face session in the patients’ homes with a 15-minute telephone “booster” session 2 weeks later, helped patients with advanced COPD to self-manage their condition and provide relief from anxiety.^81,82 However, it should be noted that there is currently a lack of high-quality data evaluating psychologic interventions in the COPD population.⁸³

In addition, it is important that caregivers are supported in the management of patients with COPD and comorbid anxiety and/or depression; areas in which caregivers can be assisted in their role may include disease education and counseling, where appropriate.⁸⁴

Given that smoking cessation is a key recommendation for patients with COPD,^44,62 practitioners should be aware that patients with comorbid depression and anxiety may experience greater difficulty in smoking cessation, and worsened mood during nicotine withdrawal.⁴⁴ Clinicians should therefore carefully monitor current smokers with COPD and comorbid depression/anxiety (using the tools described previously^63,68,70,71) when they are attempting to quit smoking.

Pharmacologic interventions

Pharmacologic therapy of anxiety and depression has so far only been investigated in patients with COPD in small studies.⁷⁶ However, the available evidence does not indicate that COPD patients with anxiety and depression should be managed any differently from individuals without COPD.⁶² As such, pharmacologic interventions are particularly important for patients with acute or severe anxiety or depression.

Antidepressant agents are categorized according to their mechanism of action, and most commonly include selective serotonin-reuptake inhibitors (SSRIs), selective norepinephrine-reuptake inhibitors, bupropion (a norepinephrine- and dopamine-reuptake inhibitor; also approved for smoking cessation⁸⁵), and mirtazapine (a norepinephrine and serotonin modulator), among others.⁸⁶ SSRIs are the current firstline drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date.⁷⁶ However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy.⁸⁷ In addition to antidepressants, atypical antipsychotics have also been shown to be useful for treating anxiety, either as monotherapy or combination therapy, and possibly as an adjunctive therapy for the management of depression.^88,89

Primary care practitioners can refer to existing guidelines on the management of anxiety and depression in patients with COPD,^86,90 while taking certain factors into consideration. Any pharmacologic management strategy for the treatment of COPD may increase the risk of drug–drug or drug–disease interactions.⁷⁶ For example, it is important to avoid medications that cause respiratory depression (eg, benzodiazepines [unless used with extreme caution], particularly in patients who are already CO₂ retainers) or sedation; chosen drugs should have minimal other adverse effects.⁷⁶ Moreover, SSRIs may also be associated with troublesome adverse effects during treatment initiation, such as gastrointestinal upset, headache, tremor, psychomotor activation, and sedation⁷⁶; in addition, dry mouth is an adverse effect associated with both SSRI treatment and several inhaled therapies, so may be particularly problematic in patients with COPD.^91,92 Currently, data are particularly scarce for the management of anxiety in patients with COPD, with inconclusive or contradictory findings reported for SSRIs, azapirones (including buspirone), and tricyclic antidepressants.⁷⁶

In addition to monitoring adherence to COPD therapies, primary care practitioners should carefully monitor patients treated with antidepressants and anxiolytics for adherence. A meta-analysis of 18,245 individuals with chronic diseases showed that depressed patients had a 76% significantly higher risk of nonadherence to medication compared with those without depressive symptoms.⁹³

Targeting dyspnea is key to the management of anxiety and depression in COPD, as breathlessness is frequently associated with the onset of both comorbidities.^21,22 Therapeutic approaches to alleviating dyspnea include PR, optimizing respiratory mechanics and muscle function (with bronchodilator therapy), and reducing central neural drive to respiratory muscles with supplemental oxygen or opioid medication.⁹⁴

Although bronchodilator therapy for COPD has not been shown to have significant direct effects on depression or anxiety,⁹⁵ it can be assumed that the beneficial effects on dyspnea are likely to alleviate associated emotional and mood symptoms.

Further research into effective screening, diagnosis, and management of comorbid anxiety and depressive disorders in COPD is warranted, including evaluation of a broad range of nonpharmacologic and drug-based interventions, alone and in combination.⁷⁶

Conclusions

Anxiety and depression are common, yet frequently overlooked, comorbidities in COPD. The impact of these psychologic comorbidities is significant; their consequences are evident in morbidity and mortality data, as well as in patient-reported outcomes. As key points of contact for patients with COPD, it is essential that primary care practitioners are vigilant in monitoring for anxiety and depression in their patients with COPD, making the most of the available tools that can support them in doing so, and maintain an ongoing line of communication with other members of the multidisciplinary team. Treatment of anxiety and depression in COPD should adopt a holistic approach that incorporates both nonpharmacologic and pharmacologic interventions. However, the impact of effective screening, diagnosis, and management of anxiety and depression on COPD burden in patients requires further investigation.

Introduction

Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), occurring more frequently than in the general population^1-4 or patients with other chronic diseases such as hypertension, diabetes, cancer, or musculoskeletal disorders.^5,6 Their presence is associated with worse outcomes of COPD, and increased morbidity, mortality, disability, and health care expenditure.^6-8 In spite of this, both anxiety and depression are frequently overlooked and undertreated in patients with COPD,⁹ and symptoms of anxiety and depression can overlap significantly, as well as overlap with COPD symptoms.^7,10 

Comorbid depressive disorders that may occur in patients with COPD include major depressive disorder, dysthymias (chronic depressive symptoms of mild severity), and minor depression.¹¹ Depressive disorders are characterized by feelings of sadness, emptiness, and/or irritability, along with cognitive and somatic symptoms, which have a detrimental effect on the patient’s ability to function.¹¹ Anxiety disorders include generalized anxiety disorder (GAD), phobias, and panic disorders.¹¹ The main features of anxiety disorders, such as excessive fear and anxiety, may be accompanied by behavioral disturbances related to these symptoms, such as panic attacks and avoidance.^11,12

The reported prevalence of depression in COPD varies widely between studies, owing to differences in sampling methods and degrees of illness severity used in assessment of depression⁶; rates have been reported to range from 10% to 42% in patients with stable COPD,^6,13 and from 10% to 86% in patients with acute COPD exacerbation.¹⁴ Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD.¹⁰

Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients. GAD, panic disorders, and specific phobias are reported most frequently.¹⁵ Patients with COPD are 85% more likely to develop anxiety disorders compared with matched controls without COPD,⁴ and panic disorder is reported with a prevalence that is up to 10-fold higher than in the general population.¹⁶

Global prevalence rates of anxiety and depression are 1.8- and 1.4-fold higher in women than men, respectively¹⁷; the same gender difference is observed in patients with COPD.⁶ The higher prevalence rates of anxiety and depression in women are thought to be a result of sex differences in brain structure, function, and stress responses, as well as differences in exposure to reproductive hormones, social constraints, and experiences between women and men.¹⁸ However, psychologic comorbidity is an issue for both men and women with COPD, so it is important that clinicians are vigilant in recognizing anxiety and depression in both sexes, and are careful not to underestimate the burden in the male patient population.

It is also important to note that depression and anxiety often occur simultaneously in patients with COPD, with prevalence estimates of 26% to 43%.^9,19,20 COPD patients with both depression and anxiety are at a heightened risk of suicidal ideation, increased physical disability, and chronic depressive symptoms versus those with either disorder alone.^10,15 It is therefore important that comorbid anxiety and depression is not overlooked in patients with COPD.

Ensuring that anxiety and depression are recognized and treated effectively in patients with COPD is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD.

Potential mechanisms of anxiety and depression in COPD

Growing evidence suggests that the relationship between mood disorders—particularly depression—and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression.²¹ For example, in a study of
60 stable patients with COPD, elevated dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with the condition.²² In addition, the risk of new-onset depression was increased in COPD patients with moderate-to-severe dyspnea in a 3-year follow-up study.²³ Conversely, depression has been shown to be a significant risk factor for disabling dyspnea (modified Medical Research Council score ≥2) in patients with COPD.²⁴

COPD can lead to feelings of hopelessness, social isolation, reduced physical functioning, and sedentary lifestyle, all of which are associated with an increased level of depressive symptoms.²⁵ Similarly, inadequate social support increases the risk of anxiety in patients with COPD.²⁶ Therefore, ensuring that patients with COPD have high-quality support is very important for reducing anxiety and depressive symptoms.²⁷

The exact mechanisms for the association between mood disorders and COPD remain unclear.^7,10 Research to date indicates that the relationship between depression and impaired pulmonary function may be partly mediated by chronic inflammation^7,10; systemic inflammation has been associated with other comorbidities of COPD (eg, muscle wasting and osteoporosis),²⁸ and emerging data appear to show that proinflammatory cytokines partly mediate the association between depressive symptoms and pulmonary function.²⁹ Smoking and hypoxemia may also influence the prevalence of depression in COPD, but symptom severity and impaired quality of life remain the most important determinants.^6,30

Clinical studies have demonstrated that a number of patient-related factors, including female gender, younger age, current smoking, greater severity of airflow limitation, and lower socioeconomic status, are associated with a higher prevalence and/or increased risk of depression and/or anxiety in COPD.^3,4,30,31 Frequent episodes of rehospitalization, and comorbidities such as hypertension, arthritis, cancer, and heart disease, have been found to increase the risk of anxiety and depression in patients with COPD.^3,32 Risk of anxiety has been shown to increase with greater dyspnea severity.⁴ Pain, a frequently overlooked symptom in COPD, has been shown to be associated with symptoms of both anxiety and depression in patients with COPD.³³ This is driven by worsened quality of life and sleep quality, decreased physical activity, and an increased fear of movement that occur as a result of pain.³⁴

The impact of anxiety and depression in COPD

Comorbid anxiety and depression have a significant detrimental impact on morbidity and mortality in patients with COPD. Both disorders have been associated with an increased risk of death in COPD.^13,35-37 Indeed, of 12 comorbidities proposed to be predictors of mortality in a cohort of 187 female outpatients with COPD, anxiety was associated with the highest risk of death.^35,36

In addition, patients with COPD and anxiety and/or depression have a higher risk of COPD exacerbations,^{4,8,23,36,38-40} hospitalization,^41,42 rehospitalization,^14,36,43 longer hospital stays,^37,41,44 and mortality after exacerbations,^14,36,41 compared with patients without these comorbidities. Patients with COPD who have elevated anxiety symptoms also often experience their first hospitalization earlier in the natural course of COPD than those without anxiety.³⁶

Psychologic comorbidities are also associated with worse lung function, dyspnea, and respiratory symptom burden in patients with COPD.^37,40 Patients with COPD and anxiety are more likely to experience greater dyspnea at an earlier stage of disease than those without anxiety.³⁶ Persistent smoking at 6 months after hospitalization for an acute exacerbation of COPD is also more likely to be seen in patients with depression.³⁷

Patient-centered outcomes are worse in COPD patients with mood disorders. Both anxiety and depression have been shown to correlate with significantly reduced health-related quality of life (HRQoL), poorer physical health status, functional limitations, and reduced exercise capacity.^{4,23,37,40,45} The presence of either anxiety or depression at baseline has been shown to correlate with reduced HRQoL at 1-year follow-up, but depression appears to be the stronger predictor of low future HRQoL than anxiety.⁴⁵

Additionally, mood disorders—particularly depression—reduce physical activity in patients with COPD.^46,47 Emotional responses to COPD symptoms, such as dyspnea, can further decrease activity and worsen deconditioning, resulting in a downward spiral of reduced inactivity, social isolation, fear, anxiety, and depression.⁴⁸

COPD patients with any comorbidity exhibit lower rates of medication adherence than those without comorbidities.^49-51 Clinical studies have demonstrated that anxiety and depression are significant predictors of poor adherence to COPD interventions, including pulmonary rehabilitation (PR).^51-55 Nonadherence to COPD therapies is associated with poor clinical outcomes, including higher hospitalization rates and increased emergency department visits, and increased costs.^56,57 Health care expenditure, in terms of both specific COPD-related costs and general “all-cause” costs, is significantly higher in COPD patients with anxiety and/or depression than in those without.⁸

The underdiagnosis and undertreatment of anxiety and depression in this population is common and can adversely affect patient outcomes.^6,7,9,10,58 Hence, it is crucial that anxiety and depression are identified and more effectively managed in clinical practice.¹⁰

Primary care practitioners are the main point of contact for many patients with COPD,^6,59,60 and so can play a key role in screening for and early identification of anxiety and depression. However, detection of mood disorders by primary care practitioners is challenging for several reasons. These include the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),⁶ as well as factors associated with time constraints, such as competing agendas, duration of visits, and high patient load.^6,61 Furthermore, system-level barriers, such as lack of electronic medical records and adequate health insurance, as well as any communication gaps between primary care and mental health care, may hinder the detection and management of anxiety and depression.⁶ In addition, patients themselves may have a limited understanding of these comorbidities, or may be hesitant to discuss symptoms of anxiety or depression with their primary care practitioner owing to stigma around mental illness.⁶ 

Patients with COPD should be screened and assessed for anxiety and depression, and the United States Preventive Services Task Force recommends that clinicians screen for depression in all adults.^6,62 There are several validated screening tools suitable for clinical use:

• Anxiety Inventory for Respiratory (AIR) Disease scale: a brief, easy-to-use tool for screening and measuring anxiety in COPD.^63,64 It is a self-administered scale, and takes approximately 2 minutes to complete. The AIR scale is responsive to PR.⁶⁴
• COPD Anxiety Questionnaire (CAF): a reliable tool for early identification of COPD-related anxiety.⁶⁵
• Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ; available at: http://www.phqscreeners.com/select-screener/): the PRIME-MD comprises 26 yes/no questions on the 5 most common psychiatric disorders, including depression and anxiety.^66,67 This is not a diagnostic tool, but a high number of positive responses from a patient in any given module indicates that they require further clinical evaluation.
• PHQ-2 and PHQ-9 (Table 1; PHQ-9 available at http://www.phqscreeners.com/select-screener/): widely-used self-administered 2- and 9-item versions of the PRIME-MD, specific to depression; similarly, the 3-item PHQ-3 is available for anxiety assessment (Table 2).^6,67,68 In a study investigating tools used by family physicians in England to assess depression, over 75% used PHQ-9.⁶⁹
• 
  
  Generalized Anxiety Disorder 7-item (GAD-7) scale: an efficient, self-report scale that scores 7 common anxiety symptoms and can be used for screening and severity assessment of GAD in clinical practice.⁷⁰
• Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire-version 20 (GHQ-20): both can be used to screen for psychologic distress in patients with COPD.⁷¹
• The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI): two 21-item self-report questionnaires that are widely used in the United States to evaluate anxiety and depression.⁷²

In addition to specific anxiety and depression questionnaires (Tables 1 and 2), more general COPD assessments tools, such as the COPD Assessment Test and the COPD Clinical Questionnaire, also incorporate questions that may be indicative of symptoms of these comorbidities in patients with COPD.⁷³

Management of anxiety and depression in COPD

Even though anxiety and depression are among the most common and burdensome comorbid conditions in COPD, less than one-third of patients with these comorbidities receive effective intervention.^6,10 Primary care providers have an excellent opportunity to impact this care gap.

As in non-COPD patients, comorbid depression and anxiety may be treated with nonpharmacologic and/or pharmacologic interventions (Figure 1).⁷⁶

Evidence to date suggests that nonpharmacologic interventions such as behavioral therapy are as effective as antidepressants, and may be preferred by patients with mood disorders.¹²

Cognitive behavioral therapy (CBT), which is typically administered by psychologists/psychiatrists, may be effective in treating COPD-related anxiety and depression, especially in conjunction with exercise and education.^12,76,77 Individualized or group CBT is the treatment of choice for addressing thinking patterns that contribute to anxiety and depression to change a patient’s behavior and emotional state.⁷⁶ PR programs involve several components, including aerobic exercise, lung function training, and psycho-education.^62,76 PR is suitable for most patients with COPD, and provides multiple benefits, including reduced hospitalizations in patients who have had a recent exacerbation, and improved dyspnea, exercise tolerance, and health status in patients with stable disease,⁶² as well as clinically and statistically significant improvements in depression and anxiety, irrespective of age.^7,78,79 Exercise-based forms of PR appear to be the most effective for reducing mood symptoms,^12,76 and incorporating psychotherapy may also improve psychologic outcomes.⁸⁰ Stress reduction (relaxation) therapy aims to reduce anxiety-related physiologic changes, and includes a variety of techniques (eg, breathing exercises, sequential muscle relaxation, hypnosis, mindfulness meditation), some of which may be included in PR or used alongside other treatments (eg, CBT).⁷⁶ Limited data indicate that such therapy may be beneficial for reducing anxiety and depression, as well as respiratory symptoms and dyspnea, in patients with COPD.^12,76

Self-management techniques improve clinical outcomes in patients with COPD, but data on the management of depression or anxiety are inconclusive.^7,12 A minimal, home-based, nurse-led, psycho-educational intervention was designed to encourage more open-ended, descriptive discussions of thoughts, emotions, behaviors, and bodily sensations in patients with COPD.⁸¹ The intervention, which involved nurses attending a 1-hour face-to-face session in the patients’ homes with a 15-minute telephone “booster” session 2 weeks later, helped patients with advanced COPD to self-manage their condition and provide relief from anxiety.^81,82 However, it should be noted that there is currently a lack of high-quality data evaluating psychologic interventions in the COPD population.⁸³

In addition, it is important that caregivers are supported in the management of patients with COPD and comorbid anxiety and/or depression; areas in which caregivers can be assisted in their role may include disease education and counseling, where appropriate.⁸⁴

Given that smoking cessation is a key recommendation for patients with COPD,^44,62 practitioners should be aware that patients with comorbid depression and anxiety may experience greater difficulty in smoking cessation, and worsened mood during nicotine withdrawal.⁴⁴ Clinicians should therefore carefully monitor current smokers with COPD and comorbid depression/anxiety (using the tools described previously^63,68,70,71) when they are attempting to quit smoking.

Pharmacologic interventions

Pharmacologic therapy of anxiety and depression has so far only been investigated in patients with COPD in small studies.⁷⁶ However, the available evidence does not indicate that COPD patients with anxiety and depression should be managed any differently from individuals without COPD.⁶² As such, pharmacologic interventions are particularly important for patients with acute or severe anxiety or depression.

Antidepressant agents are categorized according to their mechanism of action, and most commonly include selective serotonin-reuptake inhibitors (SSRIs), selective norepinephrine-reuptake inhibitors, bupropion (a norepinephrine- and dopamine-reuptake inhibitor; also approved for smoking cessation⁸⁵), and mirtazapine (a norepinephrine and serotonin modulator), among others.⁸⁶ SSRIs are the current firstline drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date.⁷⁶ However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy.⁸⁷ In addition to antidepressants, atypical antipsychotics have also been shown to be useful for treating anxiety, either as monotherapy or combination therapy, and possibly as an adjunctive therapy for the management of depression.^88,89

Primary care practitioners can refer to existing guidelines on the management of anxiety and depression in patients with COPD,^86,90 while taking certain factors into consideration. Any pharmacologic management strategy for the treatment of COPD may increase the risk of drug–drug or drug–disease interactions.⁷⁶ For example, it is important to avoid medications that cause respiratory depression (eg, benzodiazepines [unless used with extreme caution], particularly in patients who are already CO₂ retainers) or sedation; chosen drugs should have minimal other adverse effects.⁷⁶ Moreover, SSRIs may also be associated with troublesome adverse effects during treatment initiation, such as gastrointestinal upset, headache, tremor, psychomotor activation, and sedation⁷⁶; in addition, dry mouth is an adverse effect associated with both SSRI treatment and several inhaled therapies, so may be particularly problematic in patients with COPD.^91,92 Currently, data are particularly scarce for the management of anxiety in patients with COPD, with inconclusive or contradictory findings reported for SSRIs, azapirones (including buspirone), and tricyclic antidepressants.⁷⁶

In addition to monitoring adherence to COPD therapies, primary care practitioners should carefully monitor patients treated with antidepressants and anxiolytics for adherence. A meta-analysis of 18,245 individuals with chronic diseases showed that depressed patients had a 76% significantly higher risk of nonadherence to medication compared with those without depressive symptoms.⁹³

Targeting dyspnea is key to the management of anxiety and depression in COPD, as breathlessness is frequently associated with the onset of both comorbidities.^21,22 Therapeutic approaches to alleviating dyspnea include PR, optimizing respiratory mechanics and muscle function (with bronchodilator therapy), and reducing central neural drive to respiratory muscles with supplemental oxygen or opioid medication.⁹⁴

Although bronchodilator therapy for COPD has not been shown to have significant direct effects on depression or anxiety,⁹⁵ it can be assumed that the beneficial effects on dyspnea are likely to alleviate associated emotional and mood symptoms.

Further research into effective screening, diagnosis, and management of comorbid anxiety and depressive disorders in COPD is warranted, including evaluation of a broad range of nonpharmacologic and drug-based interventions, alone and in combination.⁷⁶

Conclusions

Anxiety and depression are common, yet frequently overlooked, comorbidities in COPD. The impact of these psychologic comorbidities is significant; their consequences are evident in morbidity and mortality data, as well as in patient-reported outcomes. As key points of contact for patients with COPD, it is essential that primary care practitioners are vigilant in monitoring for anxiety and depression in their patients with COPD, making the most of the available tools that can support them in doing so, and maintain an ongoing line of communication with other members of the multidisciplinary team. Treatment of anxiety and depression in COPD should adopt a holistic approach that incorporates both nonpharmacologic and pharmacologic interventions. However, the impact of effective screening, diagnosis, and management of anxiety and depression on COPD burden in patients requires further investigation.

Introduction

Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), occurring more frequently than in the general population^1-4 or patients with other chronic diseases such as hypertension, diabetes, cancer, or musculoskeletal disorders.^5,6 Their presence is associated with worse outcomes of COPD, and increased morbidity, mortality, disability, and health care expenditure.^6-8 In spite of this, both anxiety and depression are frequently overlooked and undertreated in patients with COPD,⁹ and symptoms of anxiety and depression can overlap significantly, as well as overlap with COPD symptoms.^7,10 

Comorbid depressive disorders that may occur in patients with COPD include major depressive disorder, dysthymias (chronic depressive symptoms of mild severity), and minor depression.¹¹ Depressive disorders are characterized by feelings of sadness, emptiness, and/or irritability, along with cognitive and somatic symptoms, which have a detrimental effect on the patient’s ability to function.¹¹ Anxiety disorders include generalized anxiety disorder (GAD), phobias, and panic disorders.¹¹ The main features of anxiety disorders, such as excessive fear and anxiety, may be accompanied by behavioral disturbances related to these symptoms, such as panic attacks and avoidance.^11,12

The reported prevalence of depression in COPD varies widely between studies, owing to differences in sampling methods and degrees of illness severity used in assessment of depression⁶; rates have been reported to range from 10% to 42% in patients with stable COPD,^6,13 and from 10% to 86% in patients with acute COPD exacerbation.¹⁴ Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD.¹⁰

Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients. GAD, panic disorders, and specific phobias are reported most frequently.¹⁵ Patients with COPD are 85% more likely to develop anxiety disorders compared with matched controls without COPD,⁴ and panic disorder is reported with a prevalence that is up to 10-fold higher than in the general population.¹⁶

Global prevalence rates of anxiety and depression are 1.8- and 1.4-fold higher in women than men, respectively¹⁷; the same gender difference is observed in patients with COPD.⁶ The higher prevalence rates of anxiety and depression in women are thought to be a result of sex differences in brain structure, function, and stress responses, as well as differences in exposure to reproductive hormones, social constraints, and experiences between women and men.¹⁸ However, psychologic comorbidity is an issue for both men and women with COPD, so it is important that clinicians are vigilant in recognizing anxiety and depression in both sexes, and are careful not to underestimate the burden in the male patient population.

It is also important to note that depression and anxiety often occur simultaneously in patients with COPD, with prevalence estimates of 26% to 43%.^9,19,20 COPD patients with both depression and anxiety are at a heightened risk of suicidal ideation, increased physical disability, and chronic depressive symptoms versus those with either disorder alone.^10,15 It is therefore important that comorbid anxiety and depression is not overlooked in patients with COPD.

Ensuring that anxiety and depression are recognized and treated effectively in patients with COPD is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD.

Potential mechanisms of anxiety and depression in COPD

Growing evidence suggests that the relationship between mood disorders—particularly depression—and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression.²¹ For example, in a study of
60 stable patients with COPD, elevated dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with the condition.²² In addition, the risk of new-onset depression was increased in COPD patients with moderate-to-severe dyspnea in a 3-year follow-up study.²³ Conversely, depression has been shown to be a significant risk factor for disabling dyspnea (modified Medical Research Council score ≥2) in patients with COPD.²⁴

COPD can lead to feelings of hopelessness, social isolation, reduced physical functioning, and sedentary lifestyle, all of which are associated with an increased level of depressive symptoms.²⁵ Similarly, inadequate social support increases the risk of anxiety in patients with COPD.²⁶ Therefore, ensuring that patients with COPD have high-quality support is very important for reducing anxiety and depressive symptoms.²⁷

The exact mechanisms for the association between mood disorders and COPD remain unclear.^7,10 Research to date indicates that the relationship between depression and impaired pulmonary function may be partly mediated by chronic inflammation^7,10; systemic inflammation has been associated with other comorbidities of COPD (eg, muscle wasting and osteoporosis),²⁸ and emerging data appear to show that proinflammatory cytokines partly mediate the association between depressive symptoms and pulmonary function.²⁹ Smoking and hypoxemia may also influence the prevalence of depression in COPD, but symptom severity and impaired quality of life remain the most important determinants.^6,30

Clinical studies have demonstrated that a number of patient-related factors, including female gender, younger age, current smoking, greater severity of airflow limitation, and lower socioeconomic status, are associated with a higher prevalence and/or increased risk of depression and/or anxiety in COPD.^3,4,30,31 Frequent episodes of rehospitalization, and comorbidities such as hypertension, arthritis, cancer, and heart disease, have been found to increase the risk of anxiety and depression in patients with COPD.^3,32 Risk of anxiety has been shown to increase with greater dyspnea severity.⁴ Pain, a frequently overlooked symptom in COPD, has been shown to be associated with symptoms of both anxiety and depression in patients with COPD.³³ This is driven by worsened quality of life and sleep quality, decreased physical activity, and an increased fear of movement that occur as a result of pain.³⁴

The impact of anxiety and depression in COPD

Comorbid anxiety and depression have a significant detrimental impact on morbidity and mortality in patients with COPD. Both disorders have been associated with an increased risk of death in COPD.^13,35-37 Indeed, of 12 comorbidities proposed to be predictors of mortality in a cohort of 187 female outpatients with COPD, anxiety was associated with the highest risk of death.^35,36

In addition, patients with COPD and anxiety and/or depression have a higher risk of COPD exacerbations,^{4,8,23,36,38-40} hospitalization,^41,42 rehospitalization,^14,36,43 longer hospital stays,^37,41,44 and mortality after exacerbations,^14,36,41 compared with patients without these comorbidities. Patients with COPD who have elevated anxiety symptoms also often experience their first hospitalization earlier in the natural course of COPD than those without anxiety.³⁶

Psychologic comorbidities are also associated with worse lung function, dyspnea, and respiratory symptom burden in patients with COPD.^37,40 Patients with COPD and anxiety are more likely to experience greater dyspnea at an earlier stage of disease than those without anxiety.³⁶ Persistent smoking at 6 months after hospitalization for an acute exacerbation of COPD is also more likely to be seen in patients with depression.³⁷

Patient-centered outcomes are worse in COPD patients with mood disorders. Both anxiety and depression have been shown to correlate with significantly reduced health-related quality of life (HRQoL), poorer physical health status, functional limitations, and reduced exercise capacity.^{4,23,37,40,45} The presence of either anxiety or depression at baseline has been shown to correlate with reduced HRQoL at 1-year follow-up, but depression appears to be the stronger predictor of low future HRQoL than anxiety.⁴⁵

Additionally, mood disorders—particularly depression—reduce physical activity in patients with COPD.^46,47 Emotional responses to COPD symptoms, such as dyspnea, can further decrease activity and worsen deconditioning, resulting in a downward spiral of reduced inactivity, social isolation, fear, anxiety, and depression.⁴⁸

COPD patients with any comorbidity exhibit lower rates of medication adherence than those without comorbidities.^49-51 Clinical studies have demonstrated that anxiety and depression are significant predictors of poor adherence to COPD interventions, including pulmonary rehabilitation (PR).^51-55 Nonadherence to COPD therapies is associated with poor clinical outcomes, including higher hospitalization rates and increased emergency department visits, and increased costs.^56,57 Health care expenditure, in terms of both specific COPD-related costs and general “all-cause” costs, is significantly higher in COPD patients with anxiety and/or depression than in those without.⁸

The underdiagnosis and undertreatment of anxiety and depression in this population is common and can adversely affect patient outcomes.^6,7,9,10,58 Hence, it is crucial that anxiety and depression are identified and more effectively managed in clinical practice.¹⁰

Primary care practitioners are the main point of contact for many patients with COPD,^6,59,60 and so can play a key role in screening for and early identification of anxiety and depression. However, detection of mood disorders by primary care practitioners is challenging for several reasons. These include the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),⁶ as well as factors associated with time constraints, such as competing agendas, duration of visits, and high patient load.^6,61 Furthermore, system-level barriers, such as lack of electronic medical records and adequate health insurance, as well as any communication gaps between primary care and mental health care, may hinder the detection and management of anxiety and depression.⁶ In addition, patients themselves may have a limited understanding of these comorbidities, or may be hesitant to discuss symptoms of anxiety or depression with their primary care practitioner owing to stigma around mental illness.⁶ 

Patients with COPD should be screened and assessed for anxiety and depression, and the United States Preventive Services Task Force recommends that clinicians screen for depression in all adults.^6,62 There are several validated screening tools suitable for clinical use:

• Anxiety Inventory for Respiratory (AIR) Disease scale: a brief, easy-to-use tool for screening and measuring anxiety in COPD.^63,64 It is a self-administered scale, and takes approximately 2 minutes to complete. The AIR scale is responsive to PR.⁶⁴
• COPD Anxiety Questionnaire (CAF): a reliable tool for early identification of COPD-related anxiety.⁶⁵
• Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ; available at: http://www.phqscreeners.com/select-screener/): the PRIME-MD comprises 26 yes/no questions on the 5 most common psychiatric disorders, including depression and anxiety.^66,67 This is not a diagnostic tool, but a high number of positive responses from a patient in any given module indicates that they require further clinical evaluation.
• PHQ-2 and PHQ-9 (Table 1; PHQ-9 available at http://www.phqscreeners.com/select-screener/): widely-used self-administered 2- and 9-item versions of the PRIME-MD, specific to depression; similarly, the 3-item PHQ-3 is available for anxiety assessment (Table 2).^6,67,68 In a study investigating tools used by family physicians in England to assess depression, over 75% used PHQ-9.⁶⁹
• 
  
  Generalized Anxiety Disorder 7-item (GAD-7) scale: an efficient, self-report scale that scores 7 common anxiety symptoms and can be used for screening and severity assessment of GAD in clinical practice.⁷⁰
• Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire-version 20 (GHQ-20): both can be used to screen for psychologic distress in patients with COPD.⁷¹
• The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI): two 21-item self-report questionnaires that are widely used in the United States to evaluate anxiety and depression.⁷²

In addition to specific anxiety and depression questionnaires (Tables 1 and 2), more general COPD assessments tools, such as the COPD Assessment Test and the COPD Clinical Questionnaire, also incorporate questions that may be indicative of symptoms of these comorbidities in patients with COPD.⁷³

Management of anxiety and depression in COPD

Even though anxiety and depression are among the most common and burdensome comorbid conditions in COPD, less than one-third of patients with these comorbidities receive effective intervention.^6,10 Primary care providers have an excellent opportunity to impact this care gap.

As in non-COPD patients, comorbid depression and anxiety may be treated with nonpharmacologic and/or pharmacologic interventions (Figure 1).⁷⁶

Evidence to date suggests that nonpharmacologic interventions such as behavioral therapy are as effective as antidepressants, and may be preferred by patients with mood disorders.¹²

Cognitive behavioral therapy (CBT), which is typically administered by psychologists/psychiatrists, may be effective in treating COPD-related anxiety and depression, especially in conjunction with exercise and education.^12,76,77 Individualized or group CBT is the treatment of choice for addressing thinking patterns that contribute to anxiety and depression to change a patient’s behavior and emotional state.⁷⁶ PR programs involve several components, including aerobic exercise, lung function training, and psycho-education.^62,76 PR is suitable for most patients with COPD, and provides multiple benefits, including reduced hospitalizations in patients who have had a recent exacerbation, and improved dyspnea, exercise tolerance, and health status in patients with stable disease,⁶² as well as clinically and statistically significant improvements in depression and anxiety, irrespective of age.^7,78,79 Exercise-based forms of PR appear to be the most effective for reducing mood symptoms,^12,76 and incorporating psychotherapy may also improve psychologic outcomes.⁸⁰ Stress reduction (relaxation) therapy aims to reduce anxiety-related physiologic changes, and includes a variety of techniques (eg, breathing exercises, sequential muscle relaxation, hypnosis, mindfulness meditation), some of which may be included in PR or used alongside other treatments (eg, CBT).⁷⁶ Limited data indicate that such therapy may be beneficial for reducing anxiety and depression, as well as respiratory symptoms and dyspnea, in patients with COPD.^12,76

Self-management techniques improve clinical outcomes in patients with COPD, but data on the management of depression or anxiety are inconclusive.^7,12 A minimal, home-based, nurse-led, psycho-educational intervention was designed to encourage more open-ended, descriptive discussions of thoughts, emotions, behaviors, and bodily sensations in patients with COPD.⁸¹ The intervention, which involved nurses attending a 1-hour face-to-face session in the patients’ homes with a 15-minute telephone “booster” session 2 weeks later, helped patients with advanced COPD to self-manage their condition and provide relief from anxiety.^81,82 However, it should be noted that there is currently a lack of high-quality data evaluating psychologic interventions in the COPD population.⁸³

In addition, it is important that caregivers are supported in the management of patients with COPD and comorbid anxiety and/or depression; areas in which caregivers can be assisted in their role may include disease education and counseling, where appropriate.⁸⁴

Given that smoking cessation is a key recommendation for patients with COPD,^44,62 practitioners should be aware that patients with comorbid depression and anxiety may experience greater difficulty in smoking cessation, and worsened mood during nicotine withdrawal.⁴⁴ Clinicians should therefore carefully monitor current smokers with COPD and comorbid depression/anxiety (using the tools described previously^63,68,70,71) when they are attempting to quit smoking.

Pharmacologic interventions

Pharmacologic therapy of anxiety and depression has so far only been investigated in patients with COPD in small studies.⁷⁶ However, the available evidence does not indicate that COPD patients with anxiety and depression should be managed any differently from individuals without COPD.⁶² As such, pharmacologic interventions are particularly important for patients with acute or severe anxiety or depression.

Antidepressant agents are categorized according to their mechanism of action, and most commonly include selective serotonin-reuptake inhibitors (SSRIs), selective norepinephrine-reuptake inhibitors, bupropion (a norepinephrine- and dopamine-reuptake inhibitor; also approved for smoking cessation⁸⁵), and mirtazapine (a norepinephrine and serotonin modulator), among others.⁸⁶ SSRIs are the current firstline drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date.⁷⁶ However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy.⁸⁷ In addition to antidepressants, atypical antipsychotics have also been shown to be useful for treating anxiety, either as monotherapy or combination therapy, and possibly as an adjunctive therapy for the management of depression.^88,89

Primary care practitioners can refer to existing guidelines on the management of anxiety and depression in patients with COPD,^86,90 while taking certain factors into consideration. Any pharmacologic management strategy for the treatment of COPD may increase the risk of drug–drug or drug–disease interactions.⁷⁶ For example, it is important to avoid medications that cause respiratory depression (eg, benzodiazepines [unless used with extreme caution], particularly in patients who are already CO₂ retainers) or sedation; chosen drugs should have minimal other adverse effects.⁷⁶ Moreover, SSRIs may also be associated with troublesome adverse effects during treatment initiation, such as gastrointestinal upset, headache, tremor, psychomotor activation, and sedation⁷⁶; in addition, dry mouth is an adverse effect associated with both SSRI treatment and several inhaled therapies, so may be particularly problematic in patients with COPD.^91,92 Currently, data are particularly scarce for the management of anxiety in patients with COPD, with inconclusive or contradictory findings reported for SSRIs, azapirones (including buspirone), and tricyclic antidepressants.⁷⁶

In addition to monitoring adherence to COPD therapies, primary care practitioners should carefully monitor patients treated with antidepressants and anxiolytics for adherence. A meta-analysis of 18,245 individuals with chronic diseases showed that depressed patients had a 76% significantly higher risk of nonadherence to medication compared with those without depressive symptoms.⁹³

Targeting dyspnea is key to the management of anxiety and depression in COPD, as breathlessness is frequently associated with the onset of both comorbidities.^21,22 Therapeutic approaches to alleviating dyspnea include PR, optimizing respiratory mechanics and muscle function (with bronchodilator therapy), and reducing central neural drive to respiratory muscles with supplemental oxygen or opioid medication.⁹⁴

Although bronchodilator therapy for COPD has not been shown to have significant direct effects on depression or anxiety,⁹⁵ it can be assumed that the beneficial effects on dyspnea are likely to alleviate associated emotional and mood symptoms.

Further research into effective screening, diagnosis, and management of comorbid anxiety and depressive disorders in COPD is warranted, including evaluation of a broad range of nonpharmacologic and drug-based interventions, alone and in combination.⁷⁶

Conclusions

Anxiety and depression are common, yet frequently overlooked, comorbidities in COPD. The impact of these psychologic comorbidities is significant; their consequences are evident in morbidity and mortality data, as well as in patient-reported outcomes. As key points of contact for patients with COPD, it is essential that primary care practitioners are vigilant in monitoring for anxiety and depression in their patients with COPD, making the most of the available tools that can support them in doing so, and maintain an ongoing line of communication with other members of the multidisciplinary team. Treatment of anxiety and depression in COPD should adopt a holistic approach that incorporates both nonpharmacologic and pharmacologic interventions. However, the impact of effective screening, diagnosis, and management of anxiety and depression on COPD burden in patients requires further investigation.

Device considerations

The SMI delivers the aerosol as a fine mist with slow velocity lasting >1 second, which is considerably slower than spray delivery with pMDIs.¹⁴ The aim of this design is to make it easier for patients to coordinate actuation with inhalation, but it is important to note that some coordination is still required for SMI devices to function correctly.¹⁴ In addition, the SMI is not dependent on a patient’s ability to generate sufficient PIF for effective drug delivery. A limitation of the SMI is the need to assemble the device, as patients with poor manual dexterity may encounter difficulty when attempting to load the drug cartridge.¹⁵

Nebulizers deliver aerosolized drug in a fine mist. Newer-generation portable vibrating mesh nebulizers can deliver a dose over a period of ~2 minutes, compared with 10 minutes for conventional pneumatic devices.¹⁶ Patients find them effective and easy to use, and the newer generation devices overcome problems with portability and length of treatment, which may be an issue during the daytime for ambulatory patients, along with the requirement for cleaning after each dose.^4,8 However, drug delivery may be somewhat compromised with nebulizers compared with other inhalation devices, as medication can be dispersed into the atmosphere and lost, rather than inhaled.⁷ An additional point to consider is medication availability; some medications, particularly fixed-dose combination maintenance therapies, are currently unavailable in a nebulized format.¹⁶

The most important device-related factors influencing the site of deposition within the lungs are aerosol velocity and particle size of the inhaled drug.^3,7,17 To maximize clinical effectiveness, adequate distribution throughout the lung is required to reach target sites of action for β₂-agonists, anticholinergics, and corticosteroids.¹⁷ Particle size differs between inhaler device types, but all available devices generate drug particles sufficient for deposition throughout the lower airways and lung periphery, ie, within the range of 1–5 microns.^3,18-21 Extra fine particles of <1 micron (or “submicron particles”) can be deposited deeper in the pulmonary acinus, but a higher fraction of such particles may be exhaled compared with particles 1–5 microns in size.^3,20,22 In contrast, particles >5 microns deposit in the oropharynx and may be swallowed, potentially leading to systemic adverse effects.^3,20,22

When more than one drug is required, it may be preferable to deliver them via a single device where possible to facilitate patient compliance with correct technique, and decrease confusion about how to use different inhalers.²³ The inhaler device ideally serves as a platform on which many treatments are available; the greater the number of devices employed by the patient, the greater the likelihood of making an error with the usage of each device.²⁴

Errors relating to device handling are common in patients with COPD. The results of a meta-analysis by Chrystyn et al reported that overall error rates were high across all devices in patients with COPD and asthma, ranging from 50%–100%²⁵; the reported frequencies of patients with at least one error were 86.8% and 60.9% for pMDIs and DPIs, respectively. However, the authors note that heterogeneity between the studies used in the analysis was high, and suggest that future investigations should look to use a more standardized approach in assessment of inhaler device errors.²⁵ Moreover, further studies to investigate the frequency of errors in SMI devices, and to establish the relationship between critical errors in device handling and device efficacy, are warranted.

Handling errors are directly linked to compromised drug delivery and reduced treatment efficacy.³ This may lead to more frequent or inappropriate medication use that, in turn, could result in unnecessary dose increases by the physician due to perceived lack of efficacy, and subsequently more adverse effects.^3,26-28 However, these errors can be addressed through proper training and demonstration.^29-32

Common device-handling errors include^{4,26,27,32,33}:

• pMDIs: not shaking the inhaler (for suspensions), not exhaling fully before actuation, inhaling too forcefully, and not holding their breath for long enough after inhalation.
• DPIs: exhaling into the device mouthpiece, not exhaling fully before inhalation, not inhaling deeply or forcefully enough, and not holding their breath after inhalation.
• SMIs: not rotating the inhaler with mouth cap facing upwards, rotating the inhaler while looking into the spray nozzle with the cap open (before inhalation), and not maintaining inhalation with drug spray.

Incorrect inhaler use is a common cause of secondary nonadherence (ie, relating to incorrect medication use) among patients with COPD.^4,34 Compromised inhaler technique and medication nonadherence jeopardize health outcomes and add to the economic burden of COPD.^8,12,26
A 2005 study estimated that over 20% of the $25 billion spent on inhalers annually in the United States is wasted as a direct consequence of incorrect device handling.³⁵

Failing to inhale correctly to achieve the optimal inspiratory flow for the specific device being used—deep and slow for pMDIs, or forceful, quick and deep for DPIs—is a critical handling error for inhaler devices.²⁶ Significant associations between critical errors and clinical outcomes (hospitalization, emergency department visits, antibiotic courses, and corticosteroid courses) have been reported in COPD patients.26 In a retrospective analysis of COPD inpatients, suboptimal PIF rates with DPIs were associated with worse scores on the COPD Assessment Test, higher COPD and all-cause readmission rates, and shorter time to next COPD exacerbation.12

Patient considerations

Poor inhaler technique is frequently reported in patients with COPD or asthma, irrespective of the device used and with considerable variability in handling error rates for each individual device.^25,26,35,45 Although clinical evidence is limited,²⁵ research to date indicates that some DPIs may require less training than pMDIs.^23,29,45,46 Therefore, DPI devices may be viewed as a more appropriate option for patients who encounter difficulty in coordinating the inhalation and actuation required for effective operation of a pMDI device. Alternatively, use of a spacer with pMDIs appears to reduce handling errors compared with pMDIs alone, but whether a pMDI plus spacer improves technique versus DPIs remains unclear.^25,46,47 Lack of device training appears to be a key reason for inhaler handling errors across device types.²⁶ 

Elderly patients need special consideration when selecting an inhaler and ensuring it is used correctly.⁴⁸ Reduced physical ability and cognitive function due to age-related conditions (eg, dementia, depression, neuromuscular and cerebrovascular diseases) are the main reasons for suboptimal inhaler use in older patients, but other factors may also contribute (eg, multiple comorbid conditions, consequent complicated medication regimens).¹⁵ Older age is strongly associated with inhaler misuse,²⁶ and has also been shown to have a negative correlation with PIF, independent of COPD severity.⁴¹ When compared with younger patients, older patients make more attempts before mastering the inhalation technique for a specific device, and need longer instruction time from trained health care professionals to correct inhaler mishandling.^49,50 In elderly patients with adequate cognitive and manual ability, the most important factors in selecting a device are availability, convenience, ease of use, patient preference, and cost.^8,23

Device continuity is a key consideration when multiple inhaled medications are needed.²³ Lack of continuity of device type for different clinical needs means that patients may need to master the different techniques for each device.³ For instance, a patient may have a pMDI rescue medication, one or more DPIs for their maintenance therapy, and a nebulizer for additional bronchodilation, which may lead to confusion and incorrect device usage. Device continuity has been shown to improve disease control compared with using multiple inhalers in patients with asthma.⁵¹

A full summary of patient- and physician-related considerations for device selection, along with suggestions for how these can be addressed, is provided in Table 5.

Comprehensive instruction, including practical demonstration, is important for ensuring patients with COPD use the correct inhaler technique, with regular review and repeated instruction generally needed for continued correct use.^1,23,32,42 Lack of instruction is significantly associated with inhaler misuse in patients with COPD or asthma.²⁶ Verbal training on inhalation technique increased the number of patients achieving the minimum inhalation flow rate required for a range of different DPIs.³⁹ Similarly, training helped patients using a pMDI to slow their inhalation rate to <90 L/min, as recommended for this type of device.³⁹ The ‘teach-back’ method, where patients are asked to demonstrate correct usage of their inhaler after instruction from a health care professional,⁵² has shown to be particularly effective in pharmacist-led patient device training.⁵³ Educational interventions that incorporated a physical demonstration significantly improved inhaler technique in patients with COPD and asthma compared with patients receiving written and verbal information alone.⁵³ Proper device training in primary care settings should also include education about why the inhaler is needed.³

Face-to-face instruction from trained caregivers for approximately 5 to 10 minutes improves the use of MDIs and DPIs by patients.⁴⁹ However, clinical research indicates that learning correct handling and use may be easier and quicker for some devices than for others.^31,49 For example, patients naïve to the PulmoJet (a DPI device not currently available in the United States) were found to have fewer serious errors after training than those using Diskus or Turbuhaler devices.²⁴ In another study, it took less time to correct errors in inhaler use with the Diskus compared with the HandiHaler.⁴⁴ Health care professionals themselves may lack training or knowledge on correct use of inhaler devices,^35,36,54 with 1 study finding that up to 67% of nurses, doctors, and respiratory therapists were unable to describe or perform critical steps for using inhalers.³⁵

A range of resources is available to aid in training patients and health care professionals in inhaler techniques:

• Tools such as the In-Check DIAL inspiratory flow meter (Clement Clarke International Ltd, Harlow, UK), TurbuHaler Trainer (AstraZeneca, Lund, Sweden), Diskus/Accuhaler Training Device (Vitalograph, Ennis, Ireland), and 2Tone Trainer (Canday Medical Ltd, Newmarket, UK) can be used to evaluate a patient’s physical ability to use a specific inhaler.⁵⁵
• The emergence of electronic monitoring devices, such as SmartTrack, SmartTurbo, and SmartMat (all developed by Adherium Ltd, Auckland New Zealand), can provide objective and detailed adherence data to support clinical decision-making.⁵⁶
• It is essential that patients and physicians alike utilize the instructions and video demonstrations available online to understand how to use a device correctly, and avoid errors. These resources can be found on a number of organizations’ websites (eg, COPD Foundation, Allergy and Asthma Network, Centers for Disease Control and Prevention, National Jewish Health, Asthma UK, Centre for Pharmacy Postgraduate Education) and on manufacturers’ websites for individual inhalers or treatments (eg, https://www.advair.com/how-to-use-advair.html, https://www.incruse.com/how-to-use-incruse.html, https://www.mysymbicort.com/copd/taking-symbicort/how-to-use-the-inhaler.html, https://www.tudorzahcp.com/tudorza-instructions-dosing.html, www.us.respimat.com (“How to Use the RESPIMAT Inhaler”), https://www.utibron.com/how-to-use.html).

Conclusions

A number of inhalation devices are available for the treatment of COPD. However, incorrect usage or a poor match between the patient and the device may lead to confusion, suboptimal treatment, and increased cost to the patient and health care system. Considering both patient- and health care system-related factors can ensure that appropriate inhaler section and usage can be optimized.

Device considerations

The SMI delivers the aerosol as a fine mist with slow velocity lasting >1 second, which is considerably slower than spray delivery with pMDIs.¹⁴ The aim of this design is to make it easier for patients to coordinate actuation with inhalation, but it is important to note that some coordination is still required for SMI devices to function correctly.¹⁴ In addition, the SMI is not dependent on a patient’s ability to generate sufficient PIF for effective drug delivery. A limitation of the SMI is the need to assemble the device, as patients with poor manual dexterity may encounter difficulty when attempting to load the drug cartridge.¹⁵

Nebulizers deliver aerosolized drug in a fine mist. Newer-generation portable vibrating mesh nebulizers can deliver a dose over a period of ~2 minutes, compared with 10 minutes for conventional pneumatic devices.¹⁶ Patients find them effective and easy to use, and the newer generation devices overcome problems with portability and length of treatment, which may be an issue during the daytime for ambulatory patients, along with the requirement for cleaning after each dose.^4,8 However, drug delivery may be somewhat compromised with nebulizers compared with other inhalation devices, as medication can be dispersed into the atmosphere and lost, rather than inhaled.⁷ An additional point to consider is medication availability; some medications, particularly fixed-dose combination maintenance therapies, are currently unavailable in a nebulized format.¹⁶

The most important device-related factors influencing the site of deposition within the lungs are aerosol velocity and particle size of the inhaled drug.^3,7,17 To maximize clinical effectiveness, adequate distribution throughout the lung is required to reach target sites of action for β₂-agonists, anticholinergics, and corticosteroids.¹⁷ Particle size differs between inhaler device types, but all available devices generate drug particles sufficient for deposition throughout the lower airways and lung periphery, ie, within the range of 1–5 microns.^3,18-21 Extra fine particles of <1 micron (or “submicron particles”) can be deposited deeper in the pulmonary acinus, but a higher fraction of such particles may be exhaled compared with particles 1–5 microns in size.^3,20,22 In contrast, particles >5 microns deposit in the oropharynx and may be swallowed, potentially leading to systemic adverse effects.^3,20,22

When more than one drug is required, it may be preferable to deliver them via a single device where possible to facilitate patient compliance with correct technique, and decrease confusion about how to use different inhalers.²³ The inhaler device ideally serves as a platform on which many treatments are available; the greater the number of devices employed by the patient, the greater the likelihood of making an error with the usage of each device.²⁴

Errors relating to device handling are common in patients with COPD. The results of a meta-analysis by Chrystyn et al reported that overall error rates were high across all devices in patients with COPD and asthma, ranging from 50%–100%²⁵; the reported frequencies of patients with at least one error were 86.8% and 60.9% for pMDIs and DPIs, respectively. However, the authors note that heterogeneity between the studies used in the analysis was high, and suggest that future investigations should look to use a more standardized approach in assessment of inhaler device errors.²⁵ Moreover, further studies to investigate the frequency of errors in SMI devices, and to establish the relationship between critical errors in device handling and device efficacy, are warranted.

Handling errors are directly linked to compromised drug delivery and reduced treatment efficacy.³ This may lead to more frequent or inappropriate medication use that, in turn, could result in unnecessary dose increases by the physician due to perceived lack of efficacy, and subsequently more adverse effects.^3,26-28 However, these errors can be addressed through proper training and demonstration.^29-32

Common device-handling errors include^{4,26,27,32,33}:

• pMDIs: not shaking the inhaler (for suspensions), not exhaling fully before actuation, inhaling too forcefully, and not holding their breath for long enough after inhalation.
• DPIs: exhaling into the device mouthpiece, not exhaling fully before inhalation, not inhaling deeply or forcefully enough, and not holding their breath after inhalation.
• SMIs: not rotating the inhaler with mouth cap facing upwards, rotating the inhaler while looking into the spray nozzle with the cap open (before inhalation), and not maintaining inhalation with drug spray.

Incorrect inhaler use is a common cause of secondary nonadherence (ie, relating to incorrect medication use) among patients with COPD.^4,34 Compromised inhaler technique and medication nonadherence jeopardize health outcomes and add to the economic burden of COPD.^8,12,26
A 2005 study estimated that over 20% of the $25 billion spent on inhalers annually in the United States is wasted as a direct consequence of incorrect device handling.³⁵

Failing to inhale correctly to achieve the optimal inspiratory flow for the specific device being used—deep and slow for pMDIs, or forceful, quick and deep for DPIs—is a critical handling error for inhaler devices.²⁶ Significant associations between critical errors and clinical outcomes (hospitalization, emergency department visits, antibiotic courses, and corticosteroid courses) have been reported in COPD patients.26 In a retrospective analysis of COPD inpatients, suboptimal PIF rates with DPIs were associated with worse scores on the COPD Assessment Test, higher COPD and all-cause readmission rates, and shorter time to next COPD exacerbation.12

Patient considerations

Poor inhaler technique is frequently reported in patients with COPD or asthma, irrespective of the device used and with considerable variability in handling error rates for each individual device.^25,26,35,45 Although clinical evidence is limited,²⁵ research to date indicates that some DPIs may require less training than pMDIs.^23,29,45,46 Therefore, DPI devices may be viewed as a more appropriate option for patients who encounter difficulty in coordinating the inhalation and actuation required for effective operation of a pMDI device. Alternatively, use of a spacer with pMDIs appears to reduce handling errors compared with pMDIs alone, but whether a pMDI plus spacer improves technique versus DPIs remains unclear.^25,46,47 Lack of device training appears to be a key reason for inhaler handling errors across device types.²⁶ 

Elderly patients need special consideration when selecting an inhaler and ensuring it is used correctly.⁴⁸ Reduced physical ability and cognitive function due to age-related conditions (eg, dementia, depression, neuromuscular and cerebrovascular diseases) are the main reasons for suboptimal inhaler use in older patients, but other factors may also contribute (eg, multiple comorbid conditions, consequent complicated medication regimens).¹⁵ Older age is strongly associated with inhaler misuse,²⁶ and has also been shown to have a negative correlation with PIF, independent of COPD severity.⁴¹ When compared with younger patients, older patients make more attempts before mastering the inhalation technique for a specific device, and need longer instruction time from trained health care professionals to correct inhaler mishandling.^49,50 In elderly patients with adequate cognitive and manual ability, the most important factors in selecting a device are availability, convenience, ease of use, patient preference, and cost.^8,23

Device continuity is a key consideration when multiple inhaled medications are needed.²³ Lack of continuity of device type for different clinical needs means that patients may need to master the different techniques for each device.³ For instance, a patient may have a pMDI rescue medication, one or more DPIs for their maintenance therapy, and a nebulizer for additional bronchodilation, which may lead to confusion and incorrect device usage. Device continuity has been shown to improve disease control compared with using multiple inhalers in patients with asthma.⁵¹

A full summary of patient- and physician-related considerations for device selection, along with suggestions for how these can be addressed, is provided in Table 5.

Comprehensive instruction, including practical demonstration, is important for ensuring patients with COPD use the correct inhaler technique, with regular review and repeated instruction generally needed for continued correct use.^1,23,32,42 Lack of instruction is significantly associated with inhaler misuse in patients with COPD or asthma.²⁶ Verbal training on inhalation technique increased the number of patients achieving the minimum inhalation flow rate required for a range of different DPIs.³⁹ Similarly, training helped patients using a pMDI to slow their inhalation rate to <90 L/min, as recommended for this type of device.³⁹ The ‘teach-back’ method, where patients are asked to demonstrate correct usage of their inhaler after instruction from a health care professional,⁵² has shown to be particularly effective in pharmacist-led patient device training.⁵³ Educational interventions that incorporated a physical demonstration significantly improved inhaler technique in patients with COPD and asthma compared with patients receiving written and verbal information alone.⁵³ Proper device training in primary care settings should also include education about why the inhaler is needed.³

Face-to-face instruction from trained caregivers for approximately 5 to 10 minutes improves the use of MDIs and DPIs by patients.⁴⁹ However, clinical research indicates that learning correct handling and use may be easier and quicker for some devices than for others.^31,49 For example, patients naïve to the PulmoJet (a DPI device not currently available in the United States) were found to have fewer serious errors after training than those using Diskus or Turbuhaler devices.²⁴ In another study, it took less time to correct errors in inhaler use with the Diskus compared with the HandiHaler.⁴⁴ Health care professionals themselves may lack training or knowledge on correct use of inhaler devices,^35,36,54 with 1 study finding that up to 67% of nurses, doctors, and respiratory therapists were unable to describe or perform critical steps for using inhalers.³⁵

A range of resources is available to aid in training patients and health care professionals in inhaler techniques:

• Tools such as the In-Check DIAL inspiratory flow meter (Clement Clarke International Ltd, Harlow, UK), TurbuHaler Trainer (AstraZeneca, Lund, Sweden), Diskus/Accuhaler Training Device (Vitalograph, Ennis, Ireland), and 2Tone Trainer (Canday Medical Ltd, Newmarket, UK) can be used to evaluate a patient’s physical ability to use a specific inhaler.⁵⁵
• The emergence of electronic monitoring devices, such as SmartTrack, SmartTurbo, and SmartMat (all developed by Adherium Ltd, Auckland New Zealand), can provide objective and detailed adherence data to support clinical decision-making.⁵⁶
• It is essential that patients and physicians alike utilize the instructions and video demonstrations available online to understand how to use a device correctly, and avoid errors. These resources can be found on a number of organizations’ websites (eg, COPD Foundation, Allergy and Asthma Network, Centers for Disease Control and Prevention, National Jewish Health, Asthma UK, Centre for Pharmacy Postgraduate Education) and on manufacturers’ websites for individual inhalers or treatments (eg, https://www.advair.com/how-to-use-advair.html, https://www.incruse.com/how-to-use-incruse.html, https://www.mysymbicort.com/copd/taking-symbicort/how-to-use-the-inhaler.html, https://www.tudorzahcp.com/tudorza-instructions-dosing.html, www.us.respimat.com (“How to Use the RESPIMAT Inhaler”), https://www.utibron.com/how-to-use.html).

Conclusions

A number of inhalation devices are available for the treatment of COPD. However, incorrect usage or a poor match between the patient and the device may lead to confusion, suboptimal treatment, and increased cost to the patient and health care system. Considering both patient- and health care system-related factors can ensure that appropriate inhaler section and usage can be optimized.

Device considerations

The SMI delivers the aerosol as a fine mist with slow velocity lasting >1 second, which is considerably slower than spray delivery with pMDIs.¹⁴ The aim of this design is to make it easier for patients to coordinate actuation with inhalation, but it is important to note that some coordination is still required for SMI devices to function correctly.¹⁴ In addition, the SMI is not dependent on a patient’s ability to generate sufficient PIF for effective drug delivery. A limitation of the SMI is the need to assemble the device, as patients with poor manual dexterity may encounter difficulty when attempting to load the drug cartridge.¹⁵

Nebulizers deliver aerosolized drug in a fine mist. Newer-generation portable vibrating mesh nebulizers can deliver a dose over a period of ~2 minutes, compared with 10 minutes for conventional pneumatic devices.¹⁶ Patients find them effective and easy to use, and the newer generation devices overcome problems with portability and length of treatment, which may be an issue during the daytime for ambulatory patients, along with the requirement for cleaning after each dose.^4,8 However, drug delivery may be somewhat compromised with nebulizers compared with other inhalation devices, as medication can be dispersed into the atmosphere and lost, rather than inhaled.⁷ An additional point to consider is medication availability; some medications, particularly fixed-dose combination maintenance therapies, are currently unavailable in a nebulized format.¹⁶

The most important device-related factors influencing the site of deposition within the lungs are aerosol velocity and particle size of the inhaled drug.^3,7,17 To maximize clinical effectiveness, adequate distribution throughout the lung is required to reach target sites of action for β₂-agonists, anticholinergics, and corticosteroids.¹⁷ Particle size differs between inhaler device types, but all available devices generate drug particles sufficient for deposition throughout the lower airways and lung periphery, ie, within the range of 1–5 microns.^3,18-21 Extra fine particles of <1 micron (or “submicron particles”) can be deposited deeper in the pulmonary acinus, but a higher fraction of such particles may be exhaled compared with particles 1–5 microns in size.^3,20,22 In contrast, particles >5 microns deposit in the oropharynx and may be swallowed, potentially leading to systemic adverse effects.^3,20,22

When more than one drug is required, it may be preferable to deliver them via a single device where possible to facilitate patient compliance with correct technique, and decrease confusion about how to use different inhalers.²³ The inhaler device ideally serves as a platform on which many treatments are available; the greater the number of devices employed by the patient, the greater the likelihood of making an error with the usage of each device.²⁴

Errors relating to device handling are common in patients with COPD. The results of a meta-analysis by Chrystyn et al reported that overall error rates were high across all devices in patients with COPD and asthma, ranging from 50%–100%²⁵; the reported frequencies of patients with at least one error were 86.8% and 60.9% for pMDIs and DPIs, respectively. However, the authors note that heterogeneity between the studies used in the analysis was high, and suggest that future investigations should look to use a more standardized approach in assessment of inhaler device errors.²⁵ Moreover, further studies to investigate the frequency of errors in SMI devices, and to establish the relationship between critical errors in device handling and device efficacy, are warranted.

Handling errors are directly linked to compromised drug delivery and reduced treatment efficacy.³ This may lead to more frequent or inappropriate medication use that, in turn, could result in unnecessary dose increases by the physician due to perceived lack of efficacy, and subsequently more adverse effects.^3,26-28 However, these errors can be addressed through proper training and demonstration.^29-32

Common device-handling errors include^{4,26,27,32,33}:

• pMDIs: not shaking the inhaler (for suspensions), not exhaling fully before actuation, inhaling too forcefully, and not holding their breath for long enough after inhalation.
• DPIs: exhaling into the device mouthpiece, not exhaling fully before inhalation, not inhaling deeply or forcefully enough, and not holding their breath after inhalation.
• SMIs: not rotating the inhaler with mouth cap facing upwards, rotating the inhaler while looking into the spray nozzle with the cap open (before inhalation), and not maintaining inhalation with drug spray.

Incorrect inhaler use is a common cause of secondary nonadherence (ie, relating to incorrect medication use) among patients with COPD.^4,34 Compromised inhaler technique and medication nonadherence jeopardize health outcomes and add to the economic burden of COPD.^8,12,26
A 2005 study estimated that over 20% of the $25 billion spent on inhalers annually in the United States is wasted as a direct consequence of incorrect device handling.³⁵

Failing to inhale correctly to achieve the optimal inspiratory flow for the specific device being used—deep and slow for pMDIs, or forceful, quick and deep for DPIs—is a critical handling error for inhaler devices.²⁶ Significant associations between critical errors and clinical outcomes (hospitalization, emergency department visits, antibiotic courses, and corticosteroid courses) have been reported in COPD patients.26 In a retrospective analysis of COPD inpatients, suboptimal PIF rates with DPIs were associated with worse scores on the COPD Assessment Test, higher COPD and all-cause readmission rates, and shorter time to next COPD exacerbation.12

Patient considerations

Poor inhaler technique is frequently reported in patients with COPD or asthma, irrespective of the device used and with considerable variability in handling error rates for each individual device.^25,26,35,45 Although clinical evidence is limited,²⁵ research to date indicates that some DPIs may require less training than pMDIs.^23,29,45,46 Therefore, DPI devices may be viewed as a more appropriate option for patients who encounter difficulty in coordinating the inhalation and actuation required for effective operation of a pMDI device. Alternatively, use of a spacer with pMDIs appears to reduce handling errors compared with pMDIs alone, but whether a pMDI plus spacer improves technique versus DPIs remains unclear.^25,46,47 Lack of device training appears to be a key reason for inhaler handling errors across device types.²⁶ 

Elderly patients need special consideration when selecting an inhaler and ensuring it is used correctly.⁴⁸ Reduced physical ability and cognitive function due to age-related conditions (eg, dementia, depression, neuromuscular and cerebrovascular diseases) are the main reasons for suboptimal inhaler use in older patients, but other factors may also contribute (eg, multiple comorbid conditions, consequent complicated medication regimens).¹⁵ Older age is strongly associated with inhaler misuse,²⁶ and has also been shown to have a negative correlation with PIF, independent of COPD severity.⁴¹ When compared with younger patients, older patients make more attempts before mastering the inhalation technique for a specific device, and need longer instruction time from trained health care professionals to correct inhaler mishandling.^49,50 In elderly patients with adequate cognitive and manual ability, the most important factors in selecting a device are availability, convenience, ease of use, patient preference, and cost.^8,23

Device continuity is a key consideration when multiple inhaled medications are needed.²³ Lack of continuity of device type for different clinical needs means that patients may need to master the different techniques for each device.³ For instance, a patient may have a pMDI rescue medication, one or more DPIs for their maintenance therapy, and a nebulizer for additional bronchodilation, which may lead to confusion and incorrect device usage. Device continuity has been shown to improve disease control compared with using multiple inhalers in patients with asthma.⁵¹

A full summary of patient- and physician-related considerations for device selection, along with suggestions for how these can be addressed, is provided in Table 5.

Comprehensive instruction, including practical demonstration, is important for ensuring patients with COPD use the correct inhaler technique, with regular review and repeated instruction generally needed for continued correct use.^1,23,32,42 Lack of instruction is significantly associated with inhaler misuse in patients with COPD or asthma.²⁶ Verbal training on inhalation technique increased the number of patients achieving the minimum inhalation flow rate required for a range of different DPIs.³⁹ Similarly, training helped patients using a pMDI to slow their inhalation rate to <90 L/min, as recommended for this type of device.³⁹ The ‘teach-back’ method, where patients are asked to demonstrate correct usage of their inhaler after instruction from a health care professional,⁵² has shown to be particularly effective in pharmacist-led patient device training.⁵³ Educational interventions that incorporated a physical demonstration significantly improved inhaler technique in patients with COPD and asthma compared with patients receiving written and verbal information alone.⁵³ Proper device training in primary care settings should also include education about why the inhaler is needed.³

Face-to-face instruction from trained caregivers for approximately 5 to 10 minutes improves the use of MDIs and DPIs by patients.⁴⁹ However, clinical research indicates that learning correct handling and use may be easier and quicker for some devices than for others.^31,49 For example, patients naïve to the PulmoJet (a DPI device not currently available in the United States) were found to have fewer serious errors after training than those using Diskus or Turbuhaler devices.²⁴ In another study, it took less time to correct errors in inhaler use with the Diskus compared with the HandiHaler.⁴⁴ Health care professionals themselves may lack training or knowledge on correct use of inhaler devices,^35,36,54 with 1 study finding that up to 67% of nurses, doctors, and respiratory therapists were unable to describe or perform critical steps for using inhalers.³⁵

A range of resources is available to aid in training patients and health care professionals in inhaler techniques:

• Tools such as the In-Check DIAL inspiratory flow meter (Clement Clarke International Ltd, Harlow, UK), TurbuHaler Trainer (AstraZeneca, Lund, Sweden), Diskus/Accuhaler Training Device (Vitalograph, Ennis, Ireland), and 2Tone Trainer (Canday Medical Ltd, Newmarket, UK) can be used to evaluate a patient’s physical ability to use a specific inhaler.⁵⁵
• The emergence of electronic monitoring devices, such as SmartTrack, SmartTurbo, and SmartMat (all developed by Adherium Ltd, Auckland New Zealand), can provide objective and detailed adherence data to support clinical decision-making.⁵⁶
• It is essential that patients and physicians alike utilize the instructions and video demonstrations available online to understand how to use a device correctly, and avoid errors. These resources can be found on a number of organizations’ websites (eg, COPD Foundation, Allergy and Asthma Network, Centers for Disease Control and Prevention, National Jewish Health, Asthma UK, Centre for Pharmacy Postgraduate Education) and on manufacturers’ websites for individual inhalers or treatments (eg, https://www.advair.com/how-to-use-advair.html, https://www.incruse.com/how-to-use-incruse.html, https://www.mysymbicort.com/copd/taking-symbicort/how-to-use-the-inhaler.html, https://www.tudorzahcp.com/tudorza-instructions-dosing.html, www.us.respimat.com (“How to Use the RESPIMAT Inhaler”), https://www.utibron.com/how-to-use.html).

Conclusions

A number of inhalation devices are available for the treatment of COPD. However, incorrect usage or a poor match between the patient and the device may lead to confusion, suboptimal treatment, and increased cost to the patient and health care system. Considering both patient- and health care system-related factors can ensure that appropriate inhaler section and usage can be optimized.

Introduction

Chronic obstructive pulmonary disease (COPD) is common, often seen in primary care daily practice, and places a substantial burden on patients, their families, and society.^1-4 Although dyspnea, cough, wheezing, chest tightness, and/or sputum production are typical symptoms of COPD, some patients present with less obvious issues, such as a highly sedentary lifestyle, adjusted to match their limitations and fatigue.^5-7

Both pharmacologic and nonpharmacologic treatment options can reduce symptoms, treat comorbidities, prevent exacerbation, and improve quality of life, exercise tolerance,  and health status in patients with COPD.³ Patients require initial therapy based on symptoms, history, and their own treatment goals, with regular monitoring to determine when to enhance or discontinue unnecessary therapy, and when to refer to a pulmonologist.

Primary care physicians manage the care of approximately 80% of patients with COPD.⁸ This provides the opportunity to engage patients in management goal-setting that facilitates more tailored treatments, and can improve adherence to therapy, which is historically poor in patients with COPD, thereby improving outcomes.^9-11

Current COPD management guidelines

Both the Global Initiative for Obstructive Lung Disease (GOLD) and COPD Foundation guidelines recommend individualized care for patients with COPD.^3,12 This individualized care is based on comprehensive assessment of symptoms (including assessment of whether symptoms are persistent or worsening) and/or continuation of exacerbations to escalate therapy. COPD phenotypes, such as individuals with frequent exacerbations, chronic bronchitis, and asthma–COPD overlap syndrome (ACO) can also guide treatment.^13-15

GOLD 2017 strategy: key updates

• GOLD A – low symptoms, low exacerbation frequency
• GOLD B – high symptoms, low exacerbation frequency
• GOLD C – low symptoms, high exacerbation frequency
• GOLD D – high symptoms, high exacerbation frequency.

Postbronchodilator spirometry confirms the diagnosis of COPD by a forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) ratio of less than 0.7, and denotes levels of airflow limitation severity based on the postbronchodilator FEV₁ percentage predicted (Figure 1). Repeated spirometry assessment can identify individuals with rapidly declining lung function who are appropriate for referral to a pulmonologist.

Nonpharmacologic treatment approaches

Smoking cessation and pulmonary rehabilitation are central to effective COPD disease management.³ Smoking cessation has the greatest capacity to influence the natural history of COPD.³ Nicotine replacement products, as well as varenicline and bupropion, have been shown to increase long-term smoking cessation rates.¹⁶

Pulmonary rehabilitation (which includes exercise training, education, and self-management interventions aimed at behavior change) should be considered a fundamental part of COPD care.³ Pulmonary rehabilitation is recommended for any COPD patient of GOLD grades B–D (postbronchodilator FEV₁/FVC ratio <0.70 and FEV₁ <80% of predicted).³ The 2015 Cochrane Review of pulmonary rehabilitation for COPD assessed 65 randomized controlled trials involving 3822 participants, and concluded that pulmonary rehabilitation relieved dyspnea and fatigue, resulting in statistically improved functional exercise, maximal exercise capacity, and quality of life.¹⁷ Inclusion of pulmonary rehabilitation in treatment regimens may provide greater benefit than other more commonly used therapies alone.¹⁷

Long-term oxygen therapy has been shown to improve survival in COPD patients with severe resting hypoxemia (defined as a partial pressure of arterial oxygen [PaO₂] of ≤55 mm Hg, or an oxyhemoglobin saturation level [SpO₂] of ≤88%¹⁸), and is recommended in the current GOLD guidelines for selected patients.³ However, there is no clinical evidence demonstrating a mortality benefit with oxygen therapy in patients with stable COPD who have only moderate arterial oxygen desaturation (PaO₂ of 56–59 mm Hg or SpO₂ between 88%–90%¹⁸) at rest or with exercise.³ The Long-Term Oxygen Treatment Trial (LOTT) investigated the impact of the prescription of long-term supplemental oxygen in 738 patients with COPD and moderate resting (SpO₂ between 89%–93%) or exercise-induced (SpO₂ ≥80% for ≥5 min and <90% for ≥10 seconds during exercise) desaturation. Long-term oxygen supplementation did not result in either a longer time to death or first hospitalization.¹⁹ In a Cochrane Review published in 2016, Ekström et al conclude with moderate confidence that oxygen can relieve breathlessness when given during exercise to mildly hypoxemic and nonhypoxemic individuals with COPD, but does not improve health-related quality of life.²⁰ Consultation with a pulmonologist is appropriate if when and how to prescribe oxygen therapy is not clear.

Recent updates of the GOLD recommendations acknowledge the discordance between lung function and symptoms in patients with COPD. The 2017 recommendations use symptoms and exacerbation risk to define the ABCD categories that guide therapy selection. However, the GOLD authors still acknowledge the importance of spirometry in diagnosis, prognostic evaluation, and treatment with nonpharmacologic interventions in patients with COPD.³ 

• GOLD A patients: initial treatment with a short- or long-acting bronchodilator
• GOLD B patients: initial treatment with a single long-acting muscarinic receptor antagonist (LAMA) or long-acting β₂-agonist (LABA). If symptoms (such as dyspnea) are severe at initiation of therapy, or persistent with use of 1 long-acting bronchodilator, LAMA/LABA combination is recommended
• GOLD C patients: initial treatment with a LAMA (LAMA is the preferred treatment due to superior exacerbation prevention versus LABA), with preferred escalation to LAMA/LABA if further exacerbations occur. Escalation to ICS/LABA combination may be considered (although is not preferred due to possible risk of pneumonia²¹)
• GOLD D patients: initial treatment with LAMA/LABA; initial treatment with ICS/LABA may be preferred in patients with a history and/or findings suggestive of asthma–COPD overlap or high blood eosinophil counts (but consider the risk of pneumonia). Escalation to ICS/LAMA/LABA triple therapy may be considered if symptoms persist or further exacerbations occur.

GOLD grades provide a valuable guide for initiating therapy and continuing assessment and care. Initial therapy may provide sufficient disease control in some patients, but disease progression and persistent symptoms despite therapy often require treatment escalation. Assessing and escalating therapy should be based on changes in functional status and symptom burden, which can be identified by asking appropriate questions, or performing tests to evaluate functional capacity, such as the 6-minute walk test.³ The modified Medical Research Council (mMRC) dyspnea scale is also a good example of a quick tool for baseline assessment of the patient’s functional status. This assessment must be coupled with appropriate follow-up. During follow-up visits, it is important to ask patients about their typical daily activities, and assess how these compare to what has been reported previously. Follow-up visits can also be an opportunity to check that a patient is using their inhaler device correctly.   

Regular assessment of patients’ health status is important for optimal disease management.²² The COPD Assessment Test (CAT) is a short, simple, COPD patient-completed questionnaire, designed to inform the clinician about the severity and impact of a patient’s disease. Changes in patients’ functional abilities and symptoms over time can be monitored with regular use of the CAT at COPD visits.²³ Although the CAT test facilitates prediction of COPD exacerbations,²⁴ it is not intended to identify comorbidities; for example, the mental health comorbidities of COPD (including anxiety, sleep disturbances, and depression) are often unreported by patients and so can be difficult for clinicians to detect.²⁵ Awareness of possible comorbid conditions, and appropriate screening for conditions such as depression (PHQ-2), anxiety (GAD-7), or osteoporosis (BMD) is recommended.²⁶ Further details of PHQ-2 and GAD-7 are provided in the second article (Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management) of this supplement.

Physicians need to make decisions about whether (and how) treatment should be escalated using parameters in addition to frequency of exacerbations, such as a lack of improvement or worsening of symptoms or functional status.³ For example, the addition of a second bronchodilator is recommended for a GOLD B patient with continued breathlessness on a single bronchodilator, and escalating from 1 to 2 long-acting bronchodilators is recommended for GOLD C patients with persistent exacerbations despite monotherapy with a LABA or LAMA. LAMA/LABA combinations that are currently approved for the treatment of COPD by the US Food and Drug Administration are umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, and glycopyrrolate/indacaterol.^27-30

For patients with high symptom burden (mMRC ≥2, CAT ≥10) experiencing frequent exacerbations, defined as 2 or more exacerbations per year, or 1 or more exacerbations per year that lead to a hospitalization (ie, GOLD D patients), LAMA/LABA is recommended as first-choice treatment. A recent study showed LAMA/LABA to be superior to ICS/LABA for preventing exacerbations; while it should be noted that the majority of exacerbations in this study were mild, LAMA/LABA was also found to be significantly more effective at reducing exacerbations classed as moderate or severe than ICS/LABA.³¹ However, these findings may not be broadly generalizable, owing to limitations associated with the study’s exclusion criteria and the high discontinuation rate reported during the study’s run-in phase, which may have introduced a selection bias.³¹

ICS/LABA may be considered for treating persistent exacerbations in some GOLD C patients, and may be first choice in GOLD D patients with asthma-like features, or possibly high blood eosinophil counts.³ Patients who remain symptomatic on LAMA/LABA may also be considered for triple therapy (ICS/LAMA/LABA), as per the GOLD recommendations.³ Care must be taken to use ICS appropriately, as ICS treatment may increase a patient’s risk of developing pneumonia, although risk profiles for pneumonia vary depending on the ICS treatment selected.³² Increased risk of other adverse effects associated with ICS treatment should also be considered, including oral candidiasis (odds ratio [OR], 2.65; 95% confidence interval [CI], 2.03–3.46 [note, oral candidiasis can be avoided by mouth-rinsing³³]), hoarse voice (OR, 1.95; 95% CI, 1.41–2.70), and skin bruising (OR, 1.63; 95% CI, 1.31–2.03) compared with placebo in patients with COPD.²¹ Nonetheless, use of ICS is not associated with a mortality risk,³⁴ and a 2017 study by Crim et al reported that the risk of pneumonia was not increased with ICS compared with placebo in patients with moderate airflow limitation who had/were at high risk of cardiovascular disease.³⁵ Physicians should therefore consider both the potential risks and benefits of ICS before prescribing them to patients with COPD.

While careful consideration of ICS is warranted, ICS/LABA combinations are often prescribed inappropriately in many patients with COPD in clinical practice, including those at low exacerbation risk.¹⁵ Treatment de-escalation by stopping ICS may be appropriate in patients receiving ICS/LAMA/LABA who suffer from fewer than 2 exacerbations per year (ie, receiving ICS inappropriately),³⁶ or in those who continue to experience persistent exacerbations despite ICS.³ The use of systemic steroids in stable COPD is not recommended.³⁷

At any stage of disease, patients may benefit from a referral by primary care to a pulmonologist for further evaluation.³⁸ Reasons include uncertain diagnosis, severe COPD, assessment for oxygen therapy, trouble finding or referring to pulmonary rehabilitation, and COPD in patients younger than 40 years of age (who may be suffering from α₁-antitrypsin deficiency).³⁸ Referring patients with significant emphysema or other co-existing lung diseases also allows evaluation for surgical interventions such as lung transplantation, lung volume reduction surgery (LVRS), or other therapies.

Patients with COPD may gain particular benefit from comanagement by primary care physicians and pulmonologists.³⁹ For example, primary care physicians may require guidance from pulmonologists regarding the management of patients with severe disease whose therapy requirements are becoming more complex. Similarly, pulmonologists may not be comfortable managing the comorbidities often encountered in COPD (eg, anxiety and depression), so would require support from the primary care physician to provide the patients with effective, holistic management.

Surgical and bronchoscopic interventions have the potential to significantly benefit carefully selected patient groups with emphysema.³ LVRS resects parts of the lungs to reduce hyperinflation, and improves lung function and reduces exacerbations in patients with advanced emphysema.³ It can prolong mortality in selected patients,⁴⁰ but can increase the risk of death in those with low FEV₁ and either homogenous emphysema or very low carbon monoxide diffusing capacity.⁴¹

Nonsurgical bronchoscopic interventions continue to improve; they have been designed to achieve similar results to LVRS (but with less morbidity), and provide a possible intervention for patients with heterogenous or homogenous emphysema, and significant hyperinflation refractory to optimized medical care.³ Use of endobronchial one-way valves and lung volume reduction coils has resulted in significant improvements in patients’ quality of life, exercise capacity, and pulmonary function for select patients with severe emphysema.^42,43 Other therapies, such as adhesives (where a biologic sealant collapses targeted areas of the lung to induce the formation of scar tissue, thus reducing lung tissue volume), and vapor therapy (where heated water vapor is used to deliver thermal energy to the lungs, inducing an inflammatory response that causes contraction fibrosis and atelectasis, and subsequently lung volume reduction) are also in development.⁴⁴ Consideration of surgical or nonsurgical interventions require referral to a pulmonologist.

Lung transplantation may be an option for patients with very severe COPD without significant comorbidities. Lung transplantation improves quality of life, but does not prolong survival.^3,45,46 The procedure is limited by donor availability, high cost, and potential complications.³ 

COPD Foundation guidelines

The COPD Foundation guidelines note that some spirometry results are normal, but do not rule out the presence of chronic bronchitis, emphysema, or other lung disease; or are neither normal nor consistent with COPD or other lung disease. The guidelines therefore define 2 additional spirometric grades, referred to as SG 0 (representing patients with normal spirometry) and SG U (representing patients who have a FEV₁/FVC ratio >0.7 but FEV₁ <80% predicted). At present, neither SG 0 nor SG U are associated with therapeutic options distinct from other spirometric grades, but this may change as we learn more from clinical studies.^47,48

Importance of managing COPD comorbidities

Comorbidities are common among patients with COPD, and COPD itself may increase the risk of developing other diseases.^3,49-52 It can be difficult to recognize the many comorbidities in patients with COPD, due to the diverse nature of these comorbidities, a lack of understanding of their underlying causes, patients’ failure to recognize or share symptoms, or misdiagnosing them as adverse effects associated with COPD medication.⁵³ Failure to recognize and treat comorbidities can increase risk of hospitalizations or exacerbations, worsen prognosis, increase morbidity, lower the chances of treatment adherence, and place a greater burden on the patient, family, and health care resources.^51,52,54-56 Common comorbidities include cardiovascular disease, musculoskeletal dysfunction, metabolic syndrome, anxiety/depression, osteoporosis, lung cancer, and heart failure.^3,51,52

The value of effectively managing comorbidities in improving outcomes and adherence to therapy is well documented. For example, personalized management of patients with COPD and comorbid anxiety and/or depression has been shown to reduce both the mental health symptoms and COPD-related outcomes (eg, exercise tolerance, disability).^57-59

Comorbidity burden may impact adherence to COPD medication. Depression, for instance, is a known risk factor for nonadherence to treatment. Patients with multiple untreated or uncontrolled comorbid conditions may also be less likely to benefit from pulmonary rehabilitation.⁶⁰ It is therefore important that comorbidities are managed effectively to improve adherence to therapy, and enhance the benefits of pulmonary rehabilitation.

Patient monitoring

Routine follow-up of patients with COPD is essential as lung function may worsen over time, even with the best available care.³ Worsening of symptoms, activity limitation, and disease progression should be monitored closely to determine when to modify management/pharmacotherapy, and to identify any complications and/or comorbidities that may develop.³ When patients with COPD do not receive the appropriate level of treatment or monitoring, it can be due to:  under-reporting of disease severity, symptoms, and exacerbations during consultation; lack of information on the impact of the disease on the patient’s quality of life; and failure to recognize comorbidities.^23,25,53 Continued use of the patient questionnaires described previously is recommended, and the GOLD strategy advises that symptoms are assessed at each visit. These follow-up visits also provide an opportunity to monitor patients with COPD for key comorbidities, including heart failure, ischemic heart disease, arrhythmias, osteoporosis, depression/anxiety, and lung cancer, as well as to determine a patient’s current smoking status, taking appropriate action as needed.³

COPD remains underdiagnosed in the United States, with only 50% of individuals with impaired lung function reported to receive a formal diagnosis of COPD.^61,62 Opportunities for diagnosing COPD earlier in its course are being missed; 85% of patients consult primary care for lower respiratory symptoms in the 5 years before diagnosis of COPD, and might have been candidates for further evaluation of those symptoms, including spirometry testing.⁶³ Initiating treatment at early stages of COPD has the potential to improve patients’ health-related quality of life, and may provide opportunities to slow disease progression through interventions such as smoking cessation.⁶⁴ Practical approaches to improving early diagnosis in primary care involve the use of questionnaires and clinical suspicion to identify those appropriate for spirometry, the most reliable method for identifying patients with COPD.^3,9,65 Such methodology is currently under investigation, with early studies demonstrating the potential benefit of the COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE) questionnaire in conjunction with peak expiratory flow to gauge whether a patient requires further diagnostic evaluation.⁶⁶

In addition, the GOLD strategy and COPD Foundation guidelines emphasize that correct assessment of symptoms is of paramount importance in determining the most appropriate therapy (both pharmacologic and nonpharmacologic) for patients with COPD, but traditionally has not been used to inform management choices. Both guidelines therefore highlight the importance of symptom assessment ahead of therapeutic decision-making.

Poor adherence to prescribed therapies and inad­equate patient monitoring also need addressing. Two studies analyzing refill adherence data in patients with COPD and asthma in Sweden reported that only 28%–29% of prescribed treatments were dispensed with refill adherence that covered more than 80% of prescribed treatment time^67,68; a study in 5504 patients in the United States with a prescription of fluticasone propionate/salmeterol combination therapy found that more than half of patients only refilled their prescription once over the course of the 1-year study.⁶⁹ With studies showing incorrect use of inhalers in more than 50% of patients with COPD, incorrect inhaler technique is a significant contributor to poor treatment adherence.^70,71 Inhaler technique should be reviewed regularly with direct observation of patients’ technique. Assessment of the patients’ ability to use their current prescribed inhaler(s) is recommended before considering a change in treatment.⁷⁰ Errors in inhaler use are also associated with an increased rate of severe COPD exacerbations, increased risk of hospitalization, and poor disease control.^71,72 Important factors affecting inhaler use include age, education, product design, costs (copays and deductibles) for medications, and instruction and inhaler technique education from the health care providers.^70,72,73 Recent data support improvements in product design, training by the health care provider, and “self-training” by the patient (assisted by instructional video or other digital media) to increase adherence and reduce the frequency of handling errors.^10,70,74 Electronic monitoring devices, messaging systems, and cell phone applications are also being considered as ways to increase adherence.⁷⁵

Maintenance medication is an essential component of COPD management. However, patients with COPD often report that their preference is for medication that they can “feel” working, which may be implicated in their motivation to adhere to therapy.⁷⁶ Conversely, while maintenance medication may reduce exacerbations, and lessen a patient’s decline in lung function,⁷⁷ it may not have a significant impact on how they “feel.” As a result, patients may not take it as prescribed, contributing to poor adherence. It is therefore important for primary care physicians to acknowledge that the impact of taking the maintenance medication may not be felt immediately, and articulate the importance of maintenance therapy to their patients, as failure to adhere to treatment can have significant implications for longer-term outcomes such as symptom burden, quality of life, and exacerbation risk.¹¹

Regular patient follow-up is necessary to reinforce such information: patients with milder or stable COPD may be followed at 6-month intervals, while patients with severe or frequent exacerbations, or patients who have recently been hospitalized, require follow-up at 2- to 4-week intervals.⁷⁸

Conclusions

Defining personal treatment goals for patients with COPD can enhance patient and physician communication and encourage continued collaboration to improve adherence and outcomes. Regularly monitoring symptoms, exacerbations, and comorbidities via patient-focused questionnaires, and closely examining patient adherence and technique, form a fundamental part of care for patients with COPD. Recent updates to the GOLD and the COPD Foundation guidelines have emphasized the importance of symptom assessment in initiating COPD therapy, and continued assessment to appropriately escalate treatment. Nonpharmacologic therapies such as smoking cessation and pulmonary rehabilitation are recommended at all stages of COPD alongside pharmacologic treatment.

Introduction

Chronic obstructive pulmonary disease (COPD) is common, often seen in primary care daily practice, and places a substantial burden on patients, their families, and society.^1-4 Although dyspnea, cough, wheezing, chest tightness, and/or sputum production are typical symptoms of COPD, some patients present with less obvious issues, such as a highly sedentary lifestyle, adjusted to match their limitations and fatigue.^5-7

Both pharmacologic and nonpharmacologic treatment options can reduce symptoms, treat comorbidities, prevent exacerbation, and improve quality of life, exercise tolerance,  and health status in patients with COPD.³ Patients require initial therapy based on symptoms, history, and their own treatment goals, with regular monitoring to determine when to enhance or discontinue unnecessary therapy, and when to refer to a pulmonologist.

Primary care physicians manage the care of approximately 80% of patients with COPD.⁸ This provides the opportunity to engage patients in management goal-setting that facilitates more tailored treatments, and can improve adherence to therapy, which is historically poor in patients with COPD, thereby improving outcomes.^9-11

Current COPD management guidelines

Both the Global Initiative for Obstructive Lung Disease (GOLD) and COPD Foundation guidelines recommend individualized care for patients with COPD.^3,12 This individualized care is based on comprehensive assessment of symptoms (including assessment of whether symptoms are persistent or worsening) and/or continuation of exacerbations to escalate therapy. COPD phenotypes, such as individuals with frequent exacerbations, chronic bronchitis, and asthma–COPD overlap syndrome (ACO) can also guide treatment.^13-15

GOLD 2017 strategy: key updates

• GOLD A – low symptoms, low exacerbation frequency
• GOLD B – high symptoms, low exacerbation frequency
• GOLD C – low symptoms, high exacerbation frequency
• GOLD D – high symptoms, high exacerbation frequency.

Postbronchodilator spirometry confirms the diagnosis of COPD by a forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) ratio of less than 0.7, and denotes levels of airflow limitation severity based on the postbronchodilator FEV₁ percentage predicted (Figure 1). Repeated spirometry assessment can identify individuals with rapidly declining lung function who are appropriate for referral to a pulmonologist.

Nonpharmacologic treatment approaches

Smoking cessation and pulmonary rehabilitation are central to effective COPD disease management.³ Smoking cessation has the greatest capacity to influence the natural history of COPD.³ Nicotine replacement products, as well as varenicline and bupropion, have been shown to increase long-term smoking cessation rates.¹⁶

Pulmonary rehabilitation (which includes exercise training, education, and self-management interventions aimed at behavior change) should be considered a fundamental part of COPD care.³ Pulmonary rehabilitation is recommended for any COPD patient of GOLD grades B–D (postbronchodilator FEV₁/FVC ratio <0.70 and FEV₁ <80% of predicted).³ The 2015 Cochrane Review of pulmonary rehabilitation for COPD assessed 65 randomized controlled trials involving 3822 participants, and concluded that pulmonary rehabilitation relieved dyspnea and fatigue, resulting in statistically improved functional exercise, maximal exercise capacity, and quality of life.¹⁷ Inclusion of pulmonary rehabilitation in treatment regimens may provide greater benefit than other more commonly used therapies alone.¹⁷

Long-term oxygen therapy has been shown to improve survival in COPD patients with severe resting hypoxemia (defined as a partial pressure of arterial oxygen [PaO₂] of ≤55 mm Hg, or an oxyhemoglobin saturation level [SpO₂] of ≤88%¹⁸), and is recommended in the current GOLD guidelines for selected patients.³ However, there is no clinical evidence demonstrating a mortality benefit with oxygen therapy in patients with stable COPD who have only moderate arterial oxygen desaturation (PaO₂ of 56–59 mm Hg or SpO₂ between 88%–90%¹⁸) at rest or with exercise.³ The Long-Term Oxygen Treatment Trial (LOTT) investigated the impact of the prescription of long-term supplemental oxygen in 738 patients with COPD and moderate resting (SpO₂ between 89%–93%) or exercise-induced (SpO₂ ≥80% for ≥5 min and <90% for ≥10 seconds during exercise) desaturation. Long-term oxygen supplementation did not result in either a longer time to death or first hospitalization.¹⁹ In a Cochrane Review published in 2016, Ekström et al conclude with moderate confidence that oxygen can relieve breathlessness when given during exercise to mildly hypoxemic and nonhypoxemic individuals with COPD, but does not improve health-related quality of life.²⁰ Consultation with a pulmonologist is appropriate if when and how to prescribe oxygen therapy is not clear.

Recent updates of the GOLD recommendations acknowledge the discordance between lung function and symptoms in patients with COPD. The 2017 recommendations use symptoms and exacerbation risk to define the ABCD categories that guide therapy selection. However, the GOLD authors still acknowledge the importance of spirometry in diagnosis, prognostic evaluation, and treatment with nonpharmacologic interventions in patients with COPD.³ 

• GOLD A patients: initial treatment with a short- or long-acting bronchodilator
• GOLD B patients: initial treatment with a single long-acting muscarinic receptor antagonist (LAMA) or long-acting β₂-agonist (LABA). If symptoms (such as dyspnea) are severe at initiation of therapy, or persistent with use of 1 long-acting bronchodilator, LAMA/LABA combination is recommended
• GOLD C patients: initial treatment with a LAMA (LAMA is the preferred treatment due to superior exacerbation prevention versus LABA), with preferred escalation to LAMA/LABA if further exacerbations occur. Escalation to ICS/LABA combination may be considered (although is not preferred due to possible risk of pneumonia²¹)
• GOLD D patients: initial treatment with LAMA/LABA; initial treatment with ICS/LABA may be preferred in patients with a history and/or findings suggestive of asthma–COPD overlap or high blood eosinophil counts (but consider the risk of pneumonia). Escalation to ICS/LAMA/LABA triple therapy may be considered if symptoms persist or further exacerbations occur.

GOLD grades provide a valuable guide for initiating therapy and continuing assessment and care. Initial therapy may provide sufficient disease control in some patients, but disease progression and persistent symptoms despite therapy often require treatment escalation. Assessing and escalating therapy should be based on changes in functional status and symptom burden, which can be identified by asking appropriate questions, or performing tests to evaluate functional capacity, such as the 6-minute walk test.³ The modified Medical Research Council (mMRC) dyspnea scale is also a good example of a quick tool for baseline assessment of the patient’s functional status. This assessment must be coupled with appropriate follow-up. During follow-up visits, it is important to ask patients about their typical daily activities, and assess how these compare to what has been reported previously. Follow-up visits can also be an opportunity to check that a patient is using their inhaler device correctly.   

Regular assessment of patients’ health status is important for optimal disease management.²² The COPD Assessment Test (CAT) is a short, simple, COPD patient-completed questionnaire, designed to inform the clinician about the severity and impact of a patient’s disease. Changes in patients’ functional abilities and symptoms over time can be monitored with regular use of the CAT at COPD visits.²³ Although the CAT test facilitates prediction of COPD exacerbations,²⁴ it is not intended to identify comorbidities; for example, the mental health comorbidities of COPD (including anxiety, sleep disturbances, and depression) are often unreported by patients and so can be difficult for clinicians to detect.²⁵ Awareness of possible comorbid conditions, and appropriate screening for conditions such as depression (PHQ-2), anxiety (GAD-7), or osteoporosis (BMD) is recommended.²⁶ Further details of PHQ-2 and GAD-7 are provided in the second article (Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management) of this supplement.

Physicians need to make decisions about whether (and how) treatment should be escalated using parameters in addition to frequency of exacerbations, such as a lack of improvement or worsening of symptoms or functional status.³ For example, the addition of a second bronchodilator is recommended for a GOLD B patient with continued breathlessness on a single bronchodilator, and escalating from 1 to 2 long-acting bronchodilators is recommended for GOLD C patients with persistent exacerbations despite monotherapy with a LABA or LAMA. LAMA/LABA combinations that are currently approved for the treatment of COPD by the US Food and Drug Administration are umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, and glycopyrrolate/indacaterol.^27-30

For patients with high symptom burden (mMRC ≥2, CAT ≥10) experiencing frequent exacerbations, defined as 2 or more exacerbations per year, or 1 or more exacerbations per year that lead to a hospitalization (ie, GOLD D patients), LAMA/LABA is recommended as first-choice treatment. A recent study showed LAMA/LABA to be superior to ICS/LABA for preventing exacerbations; while it should be noted that the majority of exacerbations in this study were mild, LAMA/LABA was also found to be significantly more effective at reducing exacerbations classed as moderate or severe than ICS/LABA.³¹ However, these findings may not be broadly generalizable, owing to limitations associated with the study’s exclusion criteria and the high discontinuation rate reported during the study’s run-in phase, which may have introduced a selection bias.³¹

ICS/LABA may be considered for treating persistent exacerbations in some GOLD C patients, and may be first choice in GOLD D patients with asthma-like features, or possibly high blood eosinophil counts.³ Patients who remain symptomatic on LAMA/LABA may also be considered for triple therapy (ICS/LAMA/LABA), as per the GOLD recommendations.³ Care must be taken to use ICS appropriately, as ICS treatment may increase a patient’s risk of developing pneumonia, although risk profiles for pneumonia vary depending on the ICS treatment selected.³² Increased risk of other adverse effects associated with ICS treatment should also be considered, including oral candidiasis (odds ratio [OR], 2.65; 95% confidence interval [CI], 2.03–3.46 [note, oral candidiasis can be avoided by mouth-rinsing³³]), hoarse voice (OR, 1.95; 95% CI, 1.41–2.70), and skin bruising (OR, 1.63; 95% CI, 1.31–2.03) compared with placebo in patients with COPD.²¹ Nonetheless, use of ICS is not associated with a mortality risk,³⁴ and a 2017 study by Crim et al reported that the risk of pneumonia was not increased with ICS compared with placebo in patients with moderate airflow limitation who had/were at high risk of cardiovascular disease.³⁵ Physicians should therefore consider both the potential risks and benefits of ICS before prescribing them to patients with COPD.

While careful consideration of ICS is warranted, ICS/LABA combinations are often prescribed inappropriately in many patients with COPD in clinical practice, including those at low exacerbation risk.¹⁵ Treatment de-escalation by stopping ICS may be appropriate in patients receiving ICS/LAMA/LABA who suffer from fewer than 2 exacerbations per year (ie, receiving ICS inappropriately),³⁶ or in those who continue to experience persistent exacerbations despite ICS.³ The use of systemic steroids in stable COPD is not recommended.³⁷

At any stage of disease, patients may benefit from a referral by primary care to a pulmonologist for further evaluation.³⁸ Reasons include uncertain diagnosis, severe COPD, assessment for oxygen therapy, trouble finding or referring to pulmonary rehabilitation, and COPD in patients younger than 40 years of age (who may be suffering from α₁-antitrypsin deficiency).³⁸ Referring patients with significant emphysema or other co-existing lung diseases also allows evaluation for surgical interventions such as lung transplantation, lung volume reduction surgery (LVRS), or other therapies.

Patients with COPD may gain particular benefit from comanagement by primary care physicians and pulmonologists.³⁹ For example, primary care physicians may require guidance from pulmonologists regarding the management of patients with severe disease whose therapy requirements are becoming more complex. Similarly, pulmonologists may not be comfortable managing the comorbidities often encountered in COPD (eg, anxiety and depression), so would require support from the primary care physician to provide the patients with effective, holistic management.

Surgical and bronchoscopic interventions have the potential to significantly benefit carefully selected patient groups with emphysema.³ LVRS resects parts of the lungs to reduce hyperinflation, and improves lung function and reduces exacerbations in patients with advanced emphysema.³ It can prolong mortality in selected patients,⁴⁰ but can increase the risk of death in those with low FEV₁ and either homogenous emphysema or very low carbon monoxide diffusing capacity.⁴¹

Nonsurgical bronchoscopic interventions continue to improve; they have been designed to achieve similar results to LVRS (but with less morbidity), and provide a possible intervention for patients with heterogenous or homogenous emphysema, and significant hyperinflation refractory to optimized medical care.³ Use of endobronchial one-way valves and lung volume reduction coils has resulted in significant improvements in patients’ quality of life, exercise capacity, and pulmonary function for select patients with severe emphysema.^42,43 Other therapies, such as adhesives (where a biologic sealant collapses targeted areas of the lung to induce the formation of scar tissue, thus reducing lung tissue volume), and vapor therapy (where heated water vapor is used to deliver thermal energy to the lungs, inducing an inflammatory response that causes contraction fibrosis and atelectasis, and subsequently lung volume reduction) are also in development.⁴⁴ Consideration of surgical or nonsurgical interventions require referral to a pulmonologist.

Lung transplantation may be an option for patients with very severe COPD without significant comorbidities. Lung transplantation improves quality of life, but does not prolong survival.^3,45,46 The procedure is limited by donor availability, high cost, and potential complications.³ 

COPD Foundation guidelines

The COPD Foundation guidelines note that some spirometry results are normal, but do not rule out the presence of chronic bronchitis, emphysema, or other lung disease; or are neither normal nor consistent with COPD or other lung disease. The guidelines therefore define 2 additional spirometric grades, referred to as SG 0 (representing patients with normal spirometry) and SG U (representing patients who have a FEV₁/FVC ratio >0.7 but FEV₁ <80% predicted). At present, neither SG 0 nor SG U are associated with therapeutic options distinct from other spirometric grades, but this may change as we learn more from clinical studies.^47,48

Importance of managing COPD comorbidities

Comorbidities are common among patients with COPD, and COPD itself may increase the risk of developing other diseases.^3,49-52 It can be difficult to recognize the many comorbidities in patients with COPD, due to the diverse nature of these comorbidities, a lack of understanding of their underlying causes, patients’ failure to recognize or share symptoms, or misdiagnosing them as adverse effects associated with COPD medication.⁵³ Failure to recognize and treat comorbidities can increase risk of hospitalizations or exacerbations, worsen prognosis, increase morbidity, lower the chances of treatment adherence, and place a greater burden on the patient, family, and health care resources.^51,52,54-56 Common comorbidities include cardiovascular disease, musculoskeletal dysfunction, metabolic syndrome, anxiety/depression, osteoporosis, lung cancer, and heart failure.^3,51,52

The value of effectively managing comorbidities in improving outcomes and adherence to therapy is well documented. For example, personalized management of patients with COPD and comorbid anxiety and/or depression has been shown to reduce both the mental health symptoms and COPD-related outcomes (eg, exercise tolerance, disability).^57-59

Comorbidity burden may impact adherence to COPD medication. Depression, for instance, is a known risk factor for nonadherence to treatment. Patients with multiple untreated or uncontrolled comorbid conditions may also be less likely to benefit from pulmonary rehabilitation.⁶⁰ It is therefore important that comorbidities are managed effectively to improve adherence to therapy, and enhance the benefits of pulmonary rehabilitation.

Patient monitoring

Routine follow-up of patients with COPD is essential as lung function may worsen over time, even with the best available care.³ Worsening of symptoms, activity limitation, and disease progression should be monitored closely to determine when to modify management/pharmacotherapy, and to identify any complications and/or comorbidities that may develop.³ When patients with COPD do not receive the appropriate level of treatment or monitoring, it can be due to:  under-reporting of disease severity, symptoms, and exacerbations during consultation; lack of information on the impact of the disease on the patient’s quality of life; and failure to recognize comorbidities.^23,25,53 Continued use of the patient questionnaires described previously is recommended, and the GOLD strategy advises that symptoms are assessed at each visit. These follow-up visits also provide an opportunity to monitor patients with COPD for key comorbidities, including heart failure, ischemic heart disease, arrhythmias, osteoporosis, depression/anxiety, and lung cancer, as well as to determine a patient’s current smoking status, taking appropriate action as needed.³

COPD remains underdiagnosed in the United States, with only 50% of individuals with impaired lung function reported to receive a formal diagnosis of COPD.^61,62 Opportunities for diagnosing COPD earlier in its course are being missed; 85% of patients consult primary care for lower respiratory symptoms in the 5 years before diagnosis of COPD, and might have been candidates for further evaluation of those symptoms, including spirometry testing.⁶³ Initiating treatment at early stages of COPD has the potential to improve patients’ health-related quality of life, and may provide opportunities to slow disease progression through interventions such as smoking cessation.⁶⁴ Practical approaches to improving early diagnosis in primary care involve the use of questionnaires and clinical suspicion to identify those appropriate for spirometry, the most reliable method for identifying patients with COPD.^3,9,65 Such methodology is currently under investigation, with early studies demonstrating the potential benefit of the COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE) questionnaire in conjunction with peak expiratory flow to gauge whether a patient requires further diagnostic evaluation.⁶⁶

In addition, the GOLD strategy and COPD Foundation guidelines emphasize that correct assessment of symptoms is of paramount importance in determining the most appropriate therapy (both pharmacologic and nonpharmacologic) for patients with COPD, but traditionally has not been used to inform management choices. Both guidelines therefore highlight the importance of symptom assessment ahead of therapeutic decision-making.

Poor adherence to prescribed therapies and inad­equate patient monitoring also need addressing. Two studies analyzing refill adherence data in patients with COPD and asthma in Sweden reported that only 28%–29% of prescribed treatments were dispensed with refill adherence that covered more than 80% of prescribed treatment time^67,68; a study in 5504 patients in the United States with a prescription of fluticasone propionate/salmeterol combination therapy found that more than half of patients only refilled their prescription once over the course of the 1-year study.⁶⁹ With studies showing incorrect use of inhalers in more than 50% of patients with COPD, incorrect inhaler technique is a significant contributor to poor treatment adherence.^70,71 Inhaler technique should be reviewed regularly with direct observation of patients’ technique. Assessment of the patients’ ability to use their current prescribed inhaler(s) is recommended before considering a change in treatment.⁷⁰ Errors in inhaler use are also associated with an increased rate of severe COPD exacerbations, increased risk of hospitalization, and poor disease control.^71,72 Important factors affecting inhaler use include age, education, product design, costs (copays and deductibles) for medications, and instruction and inhaler technique education from the health care providers.^70,72,73 Recent data support improvements in product design, training by the health care provider, and “self-training” by the patient (assisted by instructional video or other digital media) to increase adherence and reduce the frequency of handling errors.^10,70,74 Electronic monitoring devices, messaging systems, and cell phone applications are also being considered as ways to increase adherence.⁷⁵

Maintenance medication is an essential component of COPD management. However, patients with COPD often report that their preference is for medication that they can “feel” working, which may be implicated in their motivation to adhere to therapy.⁷⁶ Conversely, while maintenance medication may reduce exacerbations, and lessen a patient’s decline in lung function,⁷⁷ it may not have a significant impact on how they “feel.” As a result, patients may not take it as prescribed, contributing to poor adherence. It is therefore important for primary care physicians to acknowledge that the impact of taking the maintenance medication may not be felt immediately, and articulate the importance of maintenance therapy to their patients, as failure to adhere to treatment can have significant implications for longer-term outcomes such as symptom burden, quality of life, and exacerbation risk.¹¹

Regular patient follow-up is necessary to reinforce such information: patients with milder or stable COPD may be followed at 6-month intervals, while patients with severe or frequent exacerbations, or patients who have recently been hospitalized, require follow-up at 2- to 4-week intervals.⁷⁸

Conclusions

Defining personal treatment goals for patients with COPD can enhance patient and physician communication and encourage continued collaboration to improve adherence and outcomes. Regularly monitoring symptoms, exacerbations, and comorbidities via patient-focused questionnaires, and closely examining patient adherence and technique, form a fundamental part of care for patients with COPD. Recent updates to the GOLD and the COPD Foundation guidelines have emphasized the importance of symptom assessment in initiating COPD therapy, and continued assessment to appropriately escalate treatment. Nonpharmacologic therapies such as smoking cessation and pulmonary rehabilitation are recommended at all stages of COPD alongside pharmacologic treatment.

Introduction

Chronic obstructive pulmonary disease (COPD) is common, often seen in primary care daily practice, and places a substantial burden on patients, their families, and society.^1-4 Although dyspnea, cough, wheezing, chest tightness, and/or sputum production are typical symptoms of COPD, some patients present with less obvious issues, such as a highly sedentary lifestyle, adjusted to match their limitations and fatigue.^5-7

Both pharmacologic and nonpharmacologic treatment options can reduce symptoms, treat comorbidities, prevent exacerbation, and improve quality of life, exercise tolerance,  and health status in patients with COPD.³ Patients require initial therapy based on symptoms, history, and their own treatment goals, with regular monitoring to determine when to enhance or discontinue unnecessary therapy, and when to refer to a pulmonologist.

Primary care physicians manage the care of approximately 80% of patients with COPD.⁸ This provides the opportunity to engage patients in management goal-setting that facilitates more tailored treatments, and can improve adherence to therapy, which is historically poor in patients with COPD, thereby improving outcomes.^9-11

Current COPD management guidelines

Both the Global Initiative for Obstructive Lung Disease (GOLD) and COPD Foundation guidelines recommend individualized care for patients with COPD.^3,12 This individualized care is based on comprehensive assessment of symptoms (including assessment of whether symptoms are persistent or worsening) and/or continuation of exacerbations to escalate therapy. COPD phenotypes, such as individuals with frequent exacerbations, chronic bronchitis, and asthma–COPD overlap syndrome (ACO) can also guide treatment.^13-15

GOLD 2017 strategy: key updates

• GOLD A – low symptoms, low exacerbation frequency
• GOLD B – high symptoms, low exacerbation frequency
• GOLD C – low symptoms, high exacerbation frequency
• GOLD D – high symptoms, high exacerbation frequency.

Postbronchodilator spirometry confirms the diagnosis of COPD by a forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) ratio of less than 0.7, and denotes levels of airflow limitation severity based on the postbronchodilator FEV₁ percentage predicted (Figure 1). Repeated spirometry assessment can identify individuals with rapidly declining lung function who are appropriate for referral to a pulmonologist.

Nonpharmacologic treatment approaches

Smoking cessation and pulmonary rehabilitation are central to effective COPD disease management.³ Smoking cessation has the greatest capacity to influence the natural history of COPD.³ Nicotine replacement products, as well as varenicline and bupropion, have been shown to increase long-term smoking cessation rates.¹⁶

Pulmonary rehabilitation (which includes exercise training, education, and self-management interventions aimed at behavior change) should be considered a fundamental part of COPD care.³ Pulmonary rehabilitation is recommended for any COPD patient of GOLD grades B–D (postbronchodilator FEV₁/FVC ratio <0.70 and FEV₁ <80% of predicted).³ The 2015 Cochrane Review of pulmonary rehabilitation for COPD assessed 65 randomized controlled trials involving 3822 participants, and concluded that pulmonary rehabilitation relieved dyspnea and fatigue, resulting in statistically improved functional exercise, maximal exercise capacity, and quality of life.¹⁷ Inclusion of pulmonary rehabilitation in treatment regimens may provide greater benefit than other more commonly used therapies alone.¹⁷

Long-term oxygen therapy has been shown to improve survival in COPD patients with severe resting hypoxemia (defined as a partial pressure of arterial oxygen [PaO₂] of ≤55 mm Hg, or an oxyhemoglobin saturation level [SpO₂] of ≤88%¹⁸), and is recommended in the current GOLD guidelines for selected patients.³ However, there is no clinical evidence demonstrating a mortality benefit with oxygen therapy in patients with stable COPD who have only moderate arterial oxygen desaturation (PaO₂ of 56–59 mm Hg or SpO₂ between 88%–90%¹⁸) at rest or with exercise.³ The Long-Term Oxygen Treatment Trial (LOTT) investigated the impact of the prescription of long-term supplemental oxygen in 738 patients with COPD and moderate resting (SpO₂ between 89%–93%) or exercise-induced (SpO₂ ≥80% for ≥5 min and <90% for ≥10 seconds during exercise) desaturation. Long-term oxygen supplementation did not result in either a longer time to death or first hospitalization.¹⁹ In a Cochrane Review published in 2016, Ekström et al conclude with moderate confidence that oxygen can relieve breathlessness when given during exercise to mildly hypoxemic and nonhypoxemic individuals with COPD, but does not improve health-related quality of life.²⁰ Consultation with a pulmonologist is appropriate if when and how to prescribe oxygen therapy is not clear.

Recent updates of the GOLD recommendations acknowledge the discordance between lung function and symptoms in patients with COPD. The 2017 recommendations use symptoms and exacerbation risk to define the ABCD categories that guide therapy selection. However, the GOLD authors still acknowledge the importance of spirometry in diagnosis, prognostic evaluation, and treatment with nonpharmacologic interventions in patients with COPD.³ 

• GOLD A patients: initial treatment with a short- or long-acting bronchodilator
• GOLD B patients: initial treatment with a single long-acting muscarinic receptor antagonist (LAMA) or long-acting β₂-agonist (LABA). If symptoms (such as dyspnea) are severe at initiation of therapy, or persistent with use of 1 long-acting bronchodilator, LAMA/LABA combination is recommended
• GOLD C patients: initial treatment with a LAMA (LAMA is the preferred treatment due to superior exacerbation prevention versus LABA), with preferred escalation to LAMA/LABA if further exacerbations occur. Escalation to ICS/LABA combination may be considered (although is not preferred due to possible risk of pneumonia²¹)
• GOLD D patients: initial treatment with LAMA/LABA; initial treatment with ICS/LABA may be preferred in patients with a history and/or findings suggestive of asthma–COPD overlap or high blood eosinophil counts (but consider the risk of pneumonia). Escalation to ICS/LAMA/LABA triple therapy may be considered if symptoms persist or further exacerbations occur.

GOLD grades provide a valuable guide for initiating therapy and continuing assessment and care. Initial therapy may provide sufficient disease control in some patients, but disease progression and persistent symptoms despite therapy often require treatment escalation. Assessing and escalating therapy should be based on changes in functional status and symptom burden, which can be identified by asking appropriate questions, or performing tests to evaluate functional capacity, such as the 6-minute walk test.³ The modified Medical Research Council (mMRC) dyspnea scale is also a good example of a quick tool for baseline assessment of the patient’s functional status. This assessment must be coupled with appropriate follow-up. During follow-up visits, it is important to ask patients about their typical daily activities, and assess how these compare to what has been reported previously. Follow-up visits can also be an opportunity to check that a patient is using their inhaler device correctly.   

Regular assessment of patients’ health status is important for optimal disease management.²² The COPD Assessment Test (CAT) is a short, simple, COPD patient-completed questionnaire, designed to inform the clinician about the severity and impact of a patient’s disease. Changes in patients’ functional abilities and symptoms over time can be monitored with regular use of the CAT at COPD visits.²³ Although the CAT test facilitates prediction of COPD exacerbations,²⁴ it is not intended to identify comorbidities; for example, the mental health comorbidities of COPD (including anxiety, sleep disturbances, and depression) are often unreported by patients and so can be difficult for clinicians to detect.²⁵ Awareness of possible comorbid conditions, and appropriate screening for conditions such as depression (PHQ-2), anxiety (GAD-7), or osteoporosis (BMD) is recommended.²⁶ Further details of PHQ-2 and GAD-7 are provided in the second article (Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management) of this supplement.

Physicians need to make decisions about whether (and how) treatment should be escalated using parameters in addition to frequency of exacerbations, such as a lack of improvement or worsening of symptoms or functional status.³ For example, the addition of a second bronchodilator is recommended for a GOLD B patient with continued breathlessness on a single bronchodilator, and escalating from 1 to 2 long-acting bronchodilators is recommended for GOLD C patients with persistent exacerbations despite monotherapy with a LABA or LAMA. LAMA/LABA combinations that are currently approved for the treatment of COPD by the US Food and Drug Administration are umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, and glycopyrrolate/indacaterol.^27-30

For patients with high symptom burden (mMRC ≥2, CAT ≥10) experiencing frequent exacerbations, defined as 2 or more exacerbations per year, or 1 or more exacerbations per year that lead to a hospitalization (ie, GOLD D patients), LAMA/LABA is recommended as first-choice treatment. A recent study showed LAMA/LABA to be superior to ICS/LABA for preventing exacerbations; while it should be noted that the majority of exacerbations in this study were mild, LAMA/LABA was also found to be significantly more effective at reducing exacerbations classed as moderate or severe than ICS/LABA.³¹ However, these findings may not be broadly generalizable, owing to limitations associated with the study’s exclusion criteria and the high discontinuation rate reported during the study’s run-in phase, which may have introduced a selection bias.³¹

ICS/LABA may be considered for treating persistent exacerbations in some GOLD C patients, and may be first choice in GOLD D patients with asthma-like features, or possibly high blood eosinophil counts.³ Patients who remain symptomatic on LAMA/LABA may also be considered for triple therapy (ICS/LAMA/LABA), as per the GOLD recommendations.³ Care must be taken to use ICS appropriately, as ICS treatment may increase a patient’s risk of developing pneumonia, although risk profiles for pneumonia vary depending on the ICS treatment selected.³² Increased risk of other adverse effects associated with ICS treatment should also be considered, including oral candidiasis (odds ratio [OR], 2.65; 95% confidence interval [CI], 2.03–3.46 [note, oral candidiasis can be avoided by mouth-rinsing³³]), hoarse voice (OR, 1.95; 95% CI, 1.41–2.70), and skin bruising (OR, 1.63; 95% CI, 1.31–2.03) compared with placebo in patients with COPD.²¹ Nonetheless, use of ICS is not associated with a mortality risk,³⁴ and a 2017 study by Crim et al reported that the risk of pneumonia was not increased with ICS compared with placebo in patients with moderate airflow limitation who had/were at high risk of cardiovascular disease.³⁵ Physicians should therefore consider both the potential risks and benefits of ICS before prescribing them to patients with COPD.

While careful consideration of ICS is warranted, ICS/LABA combinations are often prescribed inappropriately in many patients with COPD in clinical practice, including those at low exacerbation risk.¹⁵ Treatment de-escalation by stopping ICS may be appropriate in patients receiving ICS/LAMA/LABA who suffer from fewer than 2 exacerbations per year (ie, receiving ICS inappropriately),³⁶ or in those who continue to experience persistent exacerbations despite ICS.³ The use of systemic steroids in stable COPD is not recommended.³⁷

At any stage of disease, patients may benefit from a referral by primary care to a pulmonologist for further evaluation.³⁸ Reasons include uncertain diagnosis, severe COPD, assessment for oxygen therapy, trouble finding or referring to pulmonary rehabilitation, and COPD in patients younger than 40 years of age (who may be suffering from α₁-antitrypsin deficiency).³⁸ Referring patients with significant emphysema or other co-existing lung diseases also allows evaluation for surgical interventions such as lung transplantation, lung volume reduction surgery (LVRS), or other therapies.

Patients with COPD may gain particular benefit from comanagement by primary care physicians and pulmonologists.³⁹ For example, primary care physicians may require guidance from pulmonologists regarding the management of patients with severe disease whose therapy requirements are becoming more complex. Similarly, pulmonologists may not be comfortable managing the comorbidities often encountered in COPD (eg, anxiety and depression), so would require support from the primary care physician to provide the patients with effective, holistic management.

Surgical and bronchoscopic interventions have the potential to significantly benefit carefully selected patient groups with emphysema.³ LVRS resects parts of the lungs to reduce hyperinflation, and improves lung function and reduces exacerbations in patients with advanced emphysema.³ It can prolong mortality in selected patients,⁴⁰ but can increase the risk of death in those with low FEV₁ and either homogenous emphysema or very low carbon monoxide diffusing capacity.⁴¹

Nonsurgical bronchoscopic interventions continue to improve; they have been designed to achieve similar results to LVRS (but with less morbidity), and provide a possible intervention for patients with heterogenous or homogenous emphysema, and significant hyperinflation refractory to optimized medical care.³ Use of endobronchial one-way valves and lung volume reduction coils has resulted in significant improvements in patients’ quality of life, exercise capacity, and pulmonary function for select patients with severe emphysema.^42,43 Other therapies, such as adhesives (where a biologic sealant collapses targeted areas of the lung to induce the formation of scar tissue, thus reducing lung tissue volume), and vapor therapy (where heated water vapor is used to deliver thermal energy to the lungs, inducing an inflammatory response that causes contraction fibrosis and atelectasis, and subsequently lung volume reduction) are also in development.⁴⁴ Consideration of surgical or nonsurgical interventions require referral to a pulmonologist.

Lung transplantation may be an option for patients with very severe COPD without significant comorbidities. Lung transplantation improves quality of life, but does not prolong survival.^3,45,46 The procedure is limited by donor availability, high cost, and potential complications.³ 

COPD Foundation guidelines

The COPD Foundation guidelines note that some spirometry results are normal, but do not rule out the presence of chronic bronchitis, emphysema, or other lung disease; or are neither normal nor consistent with COPD or other lung disease. The guidelines therefore define 2 additional spirometric grades, referred to as SG 0 (representing patients with normal spirometry) and SG U (representing patients who have a FEV₁/FVC ratio >0.7 but FEV₁ <80% predicted). At present, neither SG 0 nor SG U are associated with therapeutic options distinct from other spirometric grades, but this may change as we learn more from clinical studies.^47,48

Importance of managing COPD comorbidities

Comorbidities are common among patients with COPD, and COPD itself may increase the risk of developing other diseases.^3,49-52 It can be difficult to recognize the many comorbidities in patients with COPD, due to the diverse nature of these comorbidities, a lack of understanding of their underlying causes, patients’ failure to recognize or share symptoms, or misdiagnosing them as adverse effects associated with COPD medication.⁵³ Failure to recognize and treat comorbidities can increase risk of hospitalizations or exacerbations, worsen prognosis, increase morbidity, lower the chances of treatment adherence, and place a greater burden on the patient, family, and health care resources.^51,52,54-56 Common comorbidities include cardiovascular disease, musculoskeletal dysfunction, metabolic syndrome, anxiety/depression, osteoporosis, lung cancer, and heart failure.^3,51,52

The value of effectively managing comorbidities in improving outcomes and adherence to therapy is well documented. For example, personalized management of patients with COPD and comorbid anxiety and/or depression has been shown to reduce both the mental health symptoms and COPD-related outcomes (eg, exercise tolerance, disability).^57-59

Comorbidity burden may impact adherence to COPD medication. Depression, for instance, is a known risk factor for nonadherence to treatment. Patients with multiple untreated or uncontrolled comorbid conditions may also be less likely to benefit from pulmonary rehabilitation.⁶⁰ It is therefore important that comorbidities are managed effectively to improve adherence to therapy, and enhance the benefits of pulmonary rehabilitation.

Patient monitoring

Routine follow-up of patients with COPD is essential as lung function may worsen over time, even with the best available care.³ Worsening of symptoms, activity limitation, and disease progression should be monitored closely to determine when to modify management/pharmacotherapy, and to identify any complications and/or comorbidities that may develop.³ When patients with COPD do not receive the appropriate level of treatment or monitoring, it can be due to:  under-reporting of disease severity, symptoms, and exacerbations during consultation; lack of information on the impact of the disease on the patient’s quality of life; and failure to recognize comorbidities.^23,25,53 Continued use of the patient questionnaires described previously is recommended, and the GOLD strategy advises that symptoms are assessed at each visit. These follow-up visits also provide an opportunity to monitor patients with COPD for key comorbidities, including heart failure, ischemic heart disease, arrhythmias, osteoporosis, depression/anxiety, and lung cancer, as well as to determine a patient’s current smoking status, taking appropriate action as needed.³

COPD remains underdiagnosed in the United States, with only 50% of individuals with impaired lung function reported to receive a formal diagnosis of COPD.^61,62 Opportunities for diagnosing COPD earlier in its course are being missed; 85% of patients consult primary care for lower respiratory symptoms in the 5 years before diagnosis of COPD, and might have been candidates for further evaluation of those symptoms, including spirometry testing.⁶³ Initiating treatment at early stages of COPD has the potential to improve patients’ health-related quality of life, and may provide opportunities to slow disease progression through interventions such as smoking cessation.⁶⁴ Practical approaches to improving early diagnosis in primary care involve the use of questionnaires and clinical suspicion to identify those appropriate for spirometry, the most reliable method for identifying patients with COPD.^3,9,65 Such methodology is currently under investigation, with early studies demonstrating the potential benefit of the COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk (CAPTURE) questionnaire in conjunction with peak expiratory flow to gauge whether a patient requires further diagnostic evaluation.⁶⁶

In addition, the GOLD strategy and COPD Foundation guidelines emphasize that correct assessment of symptoms is of paramount importance in determining the most appropriate therapy (both pharmacologic and nonpharmacologic) for patients with COPD, but traditionally has not been used to inform management choices. Both guidelines therefore highlight the importance of symptom assessment ahead of therapeutic decision-making.

Poor adherence to prescribed therapies and inad­equate patient monitoring also need addressing. Two studies analyzing refill adherence data in patients with COPD and asthma in Sweden reported that only 28%–29% of prescribed treatments were dispensed with refill adherence that covered more than 80% of prescribed treatment time^67,68; a study in 5504 patients in the United States with a prescription of fluticasone propionate/salmeterol combination therapy found that more than half of patients only refilled their prescription once over the course of the 1-year study.⁶⁹ With studies showing incorrect use of inhalers in more than 50% of patients with COPD, incorrect inhaler technique is a significant contributor to poor treatment adherence.^70,71 Inhaler technique should be reviewed regularly with direct observation of patients’ technique. Assessment of the patients’ ability to use their current prescribed inhaler(s) is recommended before considering a change in treatment.⁷⁰ Errors in inhaler use are also associated with an increased rate of severe COPD exacerbations, increased risk of hospitalization, and poor disease control.^71,72 Important factors affecting inhaler use include age, education, product design, costs (copays and deductibles) for medications, and instruction and inhaler technique education from the health care providers.^70,72,73 Recent data support improvements in product design, training by the health care provider, and “self-training” by the patient (assisted by instructional video or other digital media) to increase adherence and reduce the frequency of handling errors.^10,70,74 Electronic monitoring devices, messaging systems, and cell phone applications are also being considered as ways to increase adherence.⁷⁵

Maintenance medication is an essential component of COPD management. However, patients with COPD often report that their preference is for medication that they can “feel” working, which may be implicated in their motivation to adhere to therapy.⁷⁶ Conversely, while maintenance medication may reduce exacerbations, and lessen a patient’s decline in lung function,⁷⁷ it may not have a significant impact on how they “feel.” As a result, patients may not take it as prescribed, contributing to poor adherence. It is therefore important for primary care physicians to acknowledge that the impact of taking the maintenance medication may not be felt immediately, and articulate the importance of maintenance therapy to their patients, as failure to adhere to treatment can have significant implications for longer-term outcomes such as symptom burden, quality of life, and exacerbation risk.¹¹

Regular patient follow-up is necessary to reinforce such information: patients with milder or stable COPD may be followed at 6-month intervals, while patients with severe or frequent exacerbations, or patients who have recently been hospitalized, require follow-up at 2- to 4-week intervals.⁷⁸

Conclusions

Defining personal treatment goals for patients with COPD can enhance patient and physician communication and encourage continued collaboration to improve adherence and outcomes. Regularly monitoring symptoms, exacerbations, and comorbidities via patient-focused questionnaires, and closely examining patient adherence and technique, form a fundamental part of care for patients with COPD. Recent updates to the GOLD and the COPD Foundation guidelines have emphasized the importance of symptom assessment in initiating COPD therapy, and continued assessment to appropriately escalate treatment. Nonpharmacologic therapies such as smoking cessation and pulmonary rehabilitation are recommended at all stages of COPD alongside pharmacologic treatment.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Realistic prospective performance data are needed to quantify the additional benefit of the cytology component of cotesting on top of what is already known to be highly sensitive molecular HPV testing. While the addition of cytology to HPV testing can add performance, it also can add further costs and the potential for unnecessary colposcopies for what are merely cytomorphologic manifestations of an active HPV infection. Frequent invasive procedures such as colposcopy, which can be costly and lead to anxiety and distress in generally young women and the potential for overtreatment of likely regressive lesions, has been defined as a harm of screening by the US Preventive Services Task Force (USPSTF).

Details of the study

In a cohort from Kaiser Permanente Northern California, 1,208,710 women aged 30 years or older were screened with cotesting from 2003 to 2015. Those who cotested HPV negative and cytology negative were offered triennial screening. Positive cotest results were managed according to Kaiser protocol. Women with cytologic abnormalities were referred for colposcopy. Those with HPV positive/cytology negative results or HPV negative/cytology equivocal results underwent accelerated testing at 1 year. A total of 623 cervical cancers were identified and included in the analyses.

Using multiple analyses, Schiffman and colleagues demonstrated the sensitivity advantage of HPV testing. They clearly showed that the cytology component to cotesting performance over many years is very limited for detecting precancers and early curable cancers. For example, prediagnostic HPV testing (76.7%) was more likely to be positive than cytology (59.1%; P<.001 for paired comparison); 82.6% of all prediagnostic cotests were positive by HPV and/or cytology; and only 5.9% of the cotests were positive by cytology alone (HPV negative.)

Primary HPV testing is recommended as a potential screening strategy by an interim guidance group led by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and it is the primary cervical cancer screening recommendation of USPSTF draft guidelines.¹ There have been reports that reliance on primary HPV testing would encourage cervical cancer mortality; Schiffman and colleagues point out, however, that according to their study data, such reports are overstated.

Despite these data, practically speaking, shifting away from standard cotesting poses numerous challenges for clinicians and laboratories alike; however, these data clearly show the limited value of cytology and, due to the overtreatment of likely regressive cervical intraepithelial neoplasia grade 2, the possible increased risk of preterm birth and its subsequent harm as well.

Study strengths and weaknesses

The authors examined the long-term relative history of HPV testing and cytology prior to cancer diagnosis in a large, prospectively followed US cohort where hundreds of women in this cohort developed cancer. There will not be a validation study of this size and scale in the near future. Further, the authors showed that the relative value of cytology to cotesting is minimal. Multiple subsequent rounds of cotesting after negative results also can be questioned. 

One weakness of the study is that the data were collected from only one health care system and therefore may not be representative of all populations. Additionally, cotesting was performed on 2 separately collected specimens, which may have reduced HPV testing performance.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For many years, the approach to the diagnosis of hypertension was straight-forward—multiple blood pressure (BP) measurements ≥140/90 mm Hg established the diagnosis of hypertension, a disease associated with an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. For more than a decade, hypertension experts have argued that a BP ≥130/80 mm Hg should establish the diagnosis of hypertension. Many clinicians resisted the change because it would markedly increase the number of asymptomatic adults with the diagnosis, increasing the number needing treatment. However, the findings of the Systolic Blood Pressure Intervention Trial (SPRINT) and other observational studies have catalyzed the American College of Cardiology (ACC) and the American Heart Association (AHA) to redefine normal BP as <120/80 mm Hg.¹ This change will expand the diagnosis of hypertension to include up to 50% of American adults.¹ In addition, the new definition of normal BP will result in the greater use of lifestyle interventions and antihypertensive medications to achieve the new normal, a BP of <120/80 mm Hg.

The new definition of hypertension

The new definition of hypertension is of particular importance for people at risk for developing cardiovascular disease (CVD) ^1,2 and is summarized here.

• Normal BP: systolic BP (SBP) <120 mm Hg and diastolic BP (DBP) <80 mm Hg
• Elevated BP: SBP 120–129 mm Hg and DBP <80 mm Hg
• Stage 1 hypertension: SBP 130–139 mm Hg or DBP 80–89 mm Hg.
• Stage 2 hypertension: SBP ≥140 mm Hg or DBP ≥90 mm Hg.

The new definition of hypertension will markedly increase the number of mid-life adults eligible to be treated for hypertension. I summarize the approach to treating hypertension in this article.

For mid-life adults, a SBP of <120 mm Hg is better for the heart
The heart is a pump, and not surprisingly, if a pump can achieve its job at a lower rather than a higher pressure, it is likely to last longer. The SPRINT study clearly demonstrated that in elderly hypertensive adults, an SBP target of <120 mm Hg is associated with fewer deaths than a SBP in the range of 130 to 140 mm Hg.³

In the SPRINT trial, 9,361 people with a mean age, body mass index, and BP of 68 years, 30 kg/m² and 140/78 mm Hg, respectively, were randomly assigned to intensive treatment of SBP to a goal of <120 mm Hg or to a target of <140 mm Hg. After 1 year of treatment, the intensive treatment group had a mean SBP of 121 mm Hg and the standard treatment group had a mean SBP of 136 mm Hg. To achieve a SBP <120 mm Hg, most patients required 3 antihypertensive medications, in contrast to the 2 antihypertensive medications typically needed to achieve a SBP in the range of 130 to 140 mm Hg.

After a median of 3.3 years of follow-up, significantly fewer deaths occurred in the intensive treatment group than in the standard treatment group, including deaths from all causes (3.3% vs 4.5%, P = .003) and deaths from CVD (0.8% vs 1.4%; P = .005). In addition, the risk of developing heart failure was lower in the intensive treatment than in the standard treatment group (1.3% vs 2.1%, P = .002). There was no difference between the 2 groups in the risk of stroke (1.3% vs 1.5%, P = .50) or myocardial infarction (2.1% vs 2.5%, P = .19). The rate of syncope was higher in the intensive treatment group (2.3% vs 1.7% in the standard treatment group, P = .05).³ Self-reported mental and physical health and satisfaction with treatment was similar in both groups.⁴

The investigators concluded that among people at risk for CVD, targeting a SBP of <120 mm Hg as compared to <140 mm Hg resulted in lower rates of heart failure and death, two clinically meaningful endpoints.

Read about nonpharmacologic interventions and antihypertensive medications to treat hypertension.

Diet and exercise

Nonpharmacologic interventions, including diet and exercise, are recommended for all people with a BP >120/80 mm Hg. In most situations, antihypertensive medications are not necessary if the patient has elevated BP (SBP 120–129 mm Hg and DBP <80 mm Hg) or Stage 1 hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg) and a 10-year CVD risk of less than 10% using the ACC/AHA cardiovascular risk calculator⁵ (see http://www.cvriskcalcula tor.com/). For people at low risk for CVD, nonpharmacologic interventions, including diet and exercise, are often sufficient treatment.

The Dietary Approaches to Stop Hypertension (DASH) diet emphasizes increasing consumption of fruits, vegetables, low-fat dairy, whole-grains, fish, poultry, and nuts and decreasing the consumption of red meats, sugary drinks, sweets, sodium, and saturated and trans-fats. In randomized trials, the DASH diet is associated with a reduction in BP of approximately 5 mm Hg systolic and 3 mm Hg diastolic.⁶ The DASH trial monitored weight changes and adjusted calorie intake to ensure a stabilized weight throughout the study. Hence, the positive effect of the DASH diet was observed in the absence of any weight loss. Weight loss also can decrease BP with every 1- to 2-lb weight loss, reducing SBP by approximately 1 mm Hg.⁷ Combining the DASH diet with a low-sodium diet is especially important in people with high sodium intake, and is reported to reduce SBP by 5 to 20 mm Hg.⁸ Reducing the consumption of alcohol can result in a reduction of SBP and DBP in the range of 3 and 2 mm Hg, respectively.⁹

Exercising for 40 minutes, 3 to 4 times per week is associated with a reduction of SBP and DBP of approximately 5 and 3 mm Hg, respectively.¹⁰ Although the studies are of low quality, meditation is reported to decrease SBP and DBP by 4 and 2 mm Hg, respectively.¹¹

Antihypertensive medications

For all mid-life adults with Stage 2hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg) or with both clinical CVD and Stage 1 hypertension, antihypertensive medications are recommended.¹ For people with Stage 1 hypertension and a 10-year CVD risk of ≥10%, antihypertensive medications are recommended. The target BP is <130/80 mm Hg for most people.

The recommended antihypertensive medications include thiazide diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). Many patients with Stage 2 hypertension will need treatment with 2 agents of different classes to achieve a BP <130/80 mm Hg. Some experts believe that an optimal 2-agent regimen includes an ACE or ARB plus a CCB based on the results of the ACCOMPLISH trial.¹² In this trial, 11,506 adults with hypertension and at very high risk for CVD, were randomly assigned to treatment with an ACE inhibitor plus CCB or with an ACE inhibitor plus hydrochlorothiazide. The BP achieved in both groups was approximately 132/73 mm Hg. The study was stopped after 3 years because participants in the ACE/thiazide group had a higher rate of adverse cardiovascular events (myocardial infarction, stroke, or death) than those in the ACE/CCB group (11.8% vs 9.6%; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72–0.90; P<.001). Compared to the ACE/thiazide group, the ACE/CCB group had a significantly lower rate of fatal and nonfatal myocardial infarction (2.2% vs 2.8%; HR, 0.78; 95% CI, 0.62–0.99; P = .04) and a lower rate of death from cardiovascular causes (1.9% vs 2.3%; HR, 0.80; 95% CI, 0.62–1.03, P = .08).

Worldwide, approximately 1 billion adults have a SBP ≥140 mm Hg.¹³ In the United States, 32% of adult women have Stage 2 hypertension or are taking an antihypertensive medication (TABLE).¹ There is a generally linear relationship between increasing SBP and DBP and an increased risk of a cardiovascular event, including heart failure, myocardial infarction, and stroke. An increase of SBP of 20 mm Hg or DBP of 10 mm Hg above a baseline BP of 115/75 mm Hg doubles the risk of death from CVD.¹⁴ For adults at risk for CVD, intensive treatment of hypertension clearly reduces the risk of a life-changing cardiovascular event.

It will probably take many years for the new SBP target of <120 mm Hg to be fully accepted by clinicians and patients because, although achieving a SBP of <120 mm Hg will decrease cardiovascular events, it is a very difficult target to achieve, requiring treatment with 3 antihypertensive medications for most patients. The early diagnosis and intensive treatment of hypertension is challenging because it requires clinicians to initiate a multi-decade course of treatment of asymptomatic people with the goal of preventing a life-altering cardiovascular event, including stroke and myocardial infarction.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For many years, the approach to the diagnosis of hypertension was straight-forward—multiple blood pressure (BP) measurements ≥140/90 mm Hg established the diagnosis of hypertension, a disease associated with an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. For more than a decade, hypertension experts have argued that a BP ≥130/80 mm Hg should establish the diagnosis of hypertension. Many clinicians resisted the change because it would markedly increase the number of asymptomatic adults with the diagnosis, increasing the number needing treatment. However, the findings of the Systolic Blood Pressure Intervention Trial (SPRINT) and other observational studies have catalyzed the American College of Cardiology (ACC) and the American Heart Association (AHA) to redefine normal BP as <120/80 mm Hg.¹ This change will expand the diagnosis of hypertension to include up to 50% of American adults.¹ In addition, the new definition of normal BP will result in the greater use of lifestyle interventions and antihypertensive medications to achieve the new normal, a BP of <120/80 mm Hg.

The new definition of hypertension

The new definition of hypertension is of particular importance for people at risk for developing cardiovascular disease (CVD) ^1,2 and is summarized here.

• Normal BP: systolic BP (SBP) <120 mm Hg and diastolic BP (DBP) <80 mm Hg
• Elevated BP: SBP 120–129 mm Hg and DBP <80 mm Hg
• Stage 1 hypertension: SBP 130–139 mm Hg or DBP 80–89 mm Hg.
• Stage 2 hypertension: SBP ≥140 mm Hg or DBP ≥90 mm Hg.

The new definition of hypertension will markedly increase the number of mid-life adults eligible to be treated for hypertension. I summarize the approach to treating hypertension in this article.

For mid-life adults, a SBP of <120 mm Hg is better for the heart
The heart is a pump, and not surprisingly, if a pump can achieve its job at a lower rather than a higher pressure, it is likely to last longer. The SPRINT study clearly demonstrated that in elderly hypertensive adults, an SBP target of <120 mm Hg is associated with fewer deaths than a SBP in the range of 130 to 140 mm Hg.³

In the SPRINT trial, 9,361 people with a mean age, body mass index, and BP of 68 years, 30 kg/m² and 140/78 mm Hg, respectively, were randomly assigned to intensive treatment of SBP to a goal of <120 mm Hg or to a target of <140 mm Hg. After 1 year of treatment, the intensive treatment group had a mean SBP of 121 mm Hg and the standard treatment group had a mean SBP of 136 mm Hg. To achieve a SBP <120 mm Hg, most patients required 3 antihypertensive medications, in contrast to the 2 antihypertensive medications typically needed to achieve a SBP in the range of 130 to 140 mm Hg.

After a median of 3.3 years of follow-up, significantly fewer deaths occurred in the intensive treatment group than in the standard treatment group, including deaths from all causes (3.3% vs 4.5%, P = .003) and deaths from CVD (0.8% vs 1.4%; P = .005). In addition, the risk of developing heart failure was lower in the intensive treatment than in the standard treatment group (1.3% vs 2.1%, P = .002). There was no difference between the 2 groups in the risk of stroke (1.3% vs 1.5%, P = .50) or myocardial infarction (2.1% vs 2.5%, P = .19). The rate of syncope was higher in the intensive treatment group (2.3% vs 1.7% in the standard treatment group, P = .05).³ Self-reported mental and physical health and satisfaction with treatment was similar in both groups.⁴

The investigators concluded that among people at risk for CVD, targeting a SBP of <120 mm Hg as compared to <140 mm Hg resulted in lower rates of heart failure and death, two clinically meaningful endpoints.

Read about nonpharmacologic interventions and antihypertensive medications to treat hypertension.

Diet and exercise

Nonpharmacologic interventions, including diet and exercise, are recommended for all people with a BP >120/80 mm Hg. In most situations, antihypertensive medications are not necessary if the patient has elevated BP (SBP 120–129 mm Hg and DBP <80 mm Hg) or Stage 1 hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg) and a 10-year CVD risk of less than 10% using the ACC/AHA cardiovascular risk calculator⁵ (see http://www.cvriskcalcula tor.com/). For people at low risk for CVD, nonpharmacologic interventions, including diet and exercise, are often sufficient treatment.

The Dietary Approaches to Stop Hypertension (DASH) diet emphasizes increasing consumption of fruits, vegetables, low-fat dairy, whole-grains, fish, poultry, and nuts and decreasing the consumption of red meats, sugary drinks, sweets, sodium, and saturated and trans-fats. In randomized trials, the DASH diet is associated with a reduction in BP of approximately 5 mm Hg systolic and 3 mm Hg diastolic.⁶ The DASH trial monitored weight changes and adjusted calorie intake to ensure a stabilized weight throughout the study. Hence, the positive effect of the DASH diet was observed in the absence of any weight loss. Weight loss also can decrease BP with every 1- to 2-lb weight loss, reducing SBP by approximately 1 mm Hg.⁷ Combining the DASH diet with a low-sodium diet is especially important in people with high sodium intake, and is reported to reduce SBP by 5 to 20 mm Hg.⁸ Reducing the consumption of alcohol can result in a reduction of SBP and DBP in the range of 3 and 2 mm Hg, respectively.⁹

Exercising for 40 minutes, 3 to 4 times per week is associated with a reduction of SBP and DBP of approximately 5 and 3 mm Hg, respectively.¹⁰ Although the studies are of low quality, meditation is reported to decrease SBP and DBP by 4 and 2 mm Hg, respectively.¹¹

Antihypertensive medications

For all mid-life adults with Stage 2hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg) or with both clinical CVD and Stage 1 hypertension, antihypertensive medications are recommended.¹ For people with Stage 1 hypertension and a 10-year CVD risk of ≥10%, antihypertensive medications are recommended. The target BP is <130/80 mm Hg for most people.

The recommended antihypertensive medications include thiazide diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). Many patients with Stage 2 hypertension will need treatment with 2 agents of different classes to achieve a BP <130/80 mm Hg. Some experts believe that an optimal 2-agent regimen includes an ACE or ARB plus a CCB based on the results of the ACCOMPLISH trial.¹² In this trial, 11,506 adults with hypertension and at very high risk for CVD, were randomly assigned to treatment with an ACE inhibitor plus CCB or with an ACE inhibitor plus hydrochlorothiazide. The BP achieved in both groups was approximately 132/73 mm Hg. The study was stopped after 3 years because participants in the ACE/thiazide group had a higher rate of adverse cardiovascular events (myocardial infarction, stroke, or death) than those in the ACE/CCB group (11.8% vs 9.6%; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72–0.90; P<.001). Compared to the ACE/thiazide group, the ACE/CCB group had a significantly lower rate of fatal and nonfatal myocardial infarction (2.2% vs 2.8%; HR, 0.78; 95% CI, 0.62–0.99; P = .04) and a lower rate of death from cardiovascular causes (1.9% vs 2.3%; HR, 0.80; 95% CI, 0.62–1.03, P = .08).

Worldwide, approximately 1 billion adults have a SBP ≥140 mm Hg.¹³ In the United States, 32% of adult women have Stage 2 hypertension or are taking an antihypertensive medication (TABLE).¹ There is a generally linear relationship between increasing SBP and DBP and an increased risk of a cardiovascular event, including heart failure, myocardial infarction, and stroke. An increase of SBP of 20 mm Hg or DBP of 10 mm Hg above a baseline BP of 115/75 mm Hg doubles the risk of death from CVD.¹⁴ For adults at risk for CVD, intensive treatment of hypertension clearly reduces the risk of a life-changing cardiovascular event.

It will probably take many years for the new SBP target of <120 mm Hg to be fully accepted by clinicians and patients because, although achieving a SBP of <120 mm Hg will decrease cardiovascular events, it is a very difficult target to achieve, requiring treatment with 3 antihypertensive medications for most patients. The early diagnosis and intensive treatment of hypertension is challenging because it requires clinicians to initiate a multi-decade course of treatment of asymptomatic people with the goal of preventing a life-altering cardiovascular event, including stroke and myocardial infarction.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

For many years, the approach to the diagnosis of hypertension was straight-forward—multiple blood pressure (BP) measurements ≥140/90 mm Hg established the diagnosis of hypertension, a disease associated with an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. For more than a decade, hypertension experts have argued that a BP ≥130/80 mm Hg should establish the diagnosis of hypertension. Many clinicians resisted the change because it would markedly increase the number of asymptomatic adults with the diagnosis, increasing the number needing treatment. However, the findings of the Systolic Blood Pressure Intervention Trial (SPRINT) and other observational studies have catalyzed the American College of Cardiology (ACC) and the American Heart Association (AHA) to redefine normal BP as <120/80 mm Hg.¹ This change will expand the diagnosis of hypertension to include up to 50% of American adults.¹ In addition, the new definition of normal BP will result in the greater use of lifestyle interventions and antihypertensive medications to achieve the new normal, a BP of <120/80 mm Hg.

The new definition of hypertension

The new definition of hypertension is of particular importance for people at risk for developing cardiovascular disease (CVD) ^1,2 and is summarized here.

• Normal BP: systolic BP (SBP) <120 mm Hg and diastolic BP (DBP) <80 mm Hg
• Elevated BP: SBP 120–129 mm Hg and DBP <80 mm Hg
• Stage 1 hypertension: SBP 130–139 mm Hg or DBP 80–89 mm Hg.
• Stage 2 hypertension: SBP ≥140 mm Hg or DBP ≥90 mm Hg.

The new definition of hypertension will markedly increase the number of mid-life adults eligible to be treated for hypertension. I summarize the approach to treating hypertension in this article.

For mid-life adults, a SBP of <120 mm Hg is better for the heart
The heart is a pump, and not surprisingly, if a pump can achieve its job at a lower rather than a higher pressure, it is likely to last longer. The SPRINT study clearly demonstrated that in elderly hypertensive adults, an SBP target of <120 mm Hg is associated with fewer deaths than a SBP in the range of 130 to 140 mm Hg.³

In the SPRINT trial, 9,361 people with a mean age, body mass index, and BP of 68 years, 30 kg/m² and 140/78 mm Hg, respectively, were randomly assigned to intensive treatment of SBP to a goal of <120 mm Hg or to a target of <140 mm Hg. After 1 year of treatment, the intensive treatment group had a mean SBP of 121 mm Hg and the standard treatment group had a mean SBP of 136 mm Hg. To achieve a SBP <120 mm Hg, most patients required 3 antihypertensive medications, in contrast to the 2 antihypertensive medications typically needed to achieve a SBP in the range of 130 to 140 mm Hg.

After a median of 3.3 years of follow-up, significantly fewer deaths occurred in the intensive treatment group than in the standard treatment group, including deaths from all causes (3.3% vs 4.5%, P = .003) and deaths from CVD (0.8% vs 1.4%; P = .005). In addition, the risk of developing heart failure was lower in the intensive treatment than in the standard treatment group (1.3% vs 2.1%, P = .002). There was no difference between the 2 groups in the risk of stroke (1.3% vs 1.5%, P = .50) or myocardial infarction (2.1% vs 2.5%, P = .19). The rate of syncope was higher in the intensive treatment group (2.3% vs 1.7% in the standard treatment group, P = .05).³ Self-reported mental and physical health and satisfaction with treatment was similar in both groups.⁴

The investigators concluded that among people at risk for CVD, targeting a SBP of <120 mm Hg as compared to <140 mm Hg resulted in lower rates of heart failure and death, two clinically meaningful endpoints.

Read about nonpharmacologic interventions and antihypertensive medications to treat hypertension.

Diet and exercise

Nonpharmacologic interventions, including diet and exercise, are recommended for all people with a BP >120/80 mm Hg. In most situations, antihypertensive medications are not necessary if the patient has elevated BP (SBP 120–129 mm Hg and DBP <80 mm Hg) or Stage 1 hypertension (SBP 130–139 mm Hg or DBP 80–89 mm Hg) and a 10-year CVD risk of less than 10% using the ACC/AHA cardiovascular risk calculator⁵ (see http://www.cvriskcalcula tor.com/). For people at low risk for CVD, nonpharmacologic interventions, including diet and exercise, are often sufficient treatment.

The Dietary Approaches to Stop Hypertension (DASH) diet emphasizes increasing consumption of fruits, vegetables, low-fat dairy, whole-grains, fish, poultry, and nuts and decreasing the consumption of red meats, sugary drinks, sweets, sodium, and saturated and trans-fats. In randomized trials, the DASH diet is associated with a reduction in BP of approximately 5 mm Hg systolic and 3 mm Hg diastolic.⁶ The DASH trial monitored weight changes and adjusted calorie intake to ensure a stabilized weight throughout the study. Hence, the positive effect of the DASH diet was observed in the absence of any weight loss. Weight loss also can decrease BP with every 1- to 2-lb weight loss, reducing SBP by approximately 1 mm Hg.⁷ Combining the DASH diet with a low-sodium diet is especially important in people with high sodium intake, and is reported to reduce SBP by 5 to 20 mm Hg.⁸ Reducing the consumption of alcohol can result in a reduction of SBP and DBP in the range of 3 and 2 mm Hg, respectively.⁹

Exercising for 40 minutes, 3 to 4 times per week is associated with a reduction of SBP and DBP of approximately 5 and 3 mm Hg, respectively.¹⁰ Although the studies are of low quality, meditation is reported to decrease SBP and DBP by 4 and 2 mm Hg, respectively.¹¹

Antihypertensive medications

For all mid-life adults with Stage 2hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg) or with both clinical CVD and Stage 1 hypertension, antihypertensive medications are recommended.¹ For people with Stage 1 hypertension and a 10-year CVD risk of ≥10%, antihypertensive medications are recommended. The target BP is <130/80 mm Hg for most people.

The recommended antihypertensive medications include thiazide diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). Many patients with Stage 2 hypertension will need treatment with 2 agents of different classes to achieve a BP <130/80 mm Hg. Some experts believe that an optimal 2-agent regimen includes an ACE or ARB plus a CCB based on the results of the ACCOMPLISH trial.¹² In this trial, 11,506 adults with hypertension and at very high risk for CVD, were randomly assigned to treatment with an ACE inhibitor plus CCB or with an ACE inhibitor plus hydrochlorothiazide. The BP achieved in both groups was approximately 132/73 mm Hg. The study was stopped after 3 years because participants in the ACE/thiazide group had a higher rate of adverse cardiovascular events (myocardial infarction, stroke, or death) than those in the ACE/CCB group (11.8% vs 9.6%; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72–0.90; P<.001). Compared to the ACE/thiazide group, the ACE/CCB group had a significantly lower rate of fatal and nonfatal myocardial infarction (2.2% vs 2.8%; HR, 0.78; 95% CI, 0.62–0.99; P = .04) and a lower rate of death from cardiovascular causes (1.9% vs 2.3%; HR, 0.80; 95% CI, 0.62–1.03, P = .08).

Worldwide, approximately 1 billion adults have a SBP ≥140 mm Hg.¹³ In the United States, 32% of adult women have Stage 2 hypertension or are taking an antihypertensive medication (TABLE).¹ There is a generally linear relationship between increasing SBP and DBP and an increased risk of a cardiovascular event, including heart failure, myocardial infarction, and stroke. An increase of SBP of 20 mm Hg or DBP of 10 mm Hg above a baseline BP of 115/75 mm Hg doubles the risk of death from CVD.¹⁴ For adults at risk for CVD, intensive treatment of hypertension clearly reduces the risk of a life-changing cardiovascular event.

It will probably take many years for the new SBP target of <120 mm Hg to be fully accepted by clinicians and patients because, although achieving a SBP of <120 mm Hg will decrease cardiovascular events, it is a very difficult target to achieve, requiring treatment with 3 antihypertensive medications for most patients. The early diagnosis and intensive treatment of hypertension is challenging because it requires clinicians to initiate a multi-decade course of treatment of asymptomatic people with the goal of preventing a life-altering cardiovascular event, including stroke and myocardial infarction.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Atrial fibrosis could be a key trigger for arrhythmia and stroke, how walnuts and the microbiome may cut cardiovascular risk, why some inflammatory bowel disease patients benefit by lighting up, and specialists warn Congress to protect Medicare Part B drug payments.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Atrial fibrosis could be a key trigger for arrhythmia and stroke, how walnuts and the microbiome may cut cardiovascular risk, why some inflammatory bowel disease patients benefit by lighting up, and specialists warn Congress to protect Medicare Part B drug payments.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

Atrial fibrosis could be a key trigger for arrhythmia and stroke, how walnuts and the microbiome may cut cardiovascular risk, why some inflammatory bowel disease patients benefit by lighting up, and specialists warn Congress to protect Medicare Part B drug payments.

Listen to the MDedge Daily News podcast for all the details on today’s top news.

A series of National Institute of Health (NIH) clinical trials are bringing Zika virus vaccines closer to the public.

According to preliminary findings from 3 phase 1 clinical trials, an investigational Zika purified inactivated virus (ZPIV) vaccine was well tolerated and induced an immune response. Scientists from Walter Reed Army Institute of Research are developing the vaccine and leading 1 of the trials.

Of 67 adult participants, 55 received the investigational vaccine; 12 received placebo. All participants received 2 intramuscular injections 4 weeks apart. The researchers detected antibodies in > 90% of those who received the vaccine, 4 weeks after the last dose.

In phase 2 clinical trials, 2 versions of an experimental gene-based Zika vaccine, developed by scientists at the National Institute of Allergy and Infectious Diseases, were both found to be safe and to induce an immune response. One candidate showed “the most promise,” paving the way for an international phase 2/2b safety and efficacy trial, which began in 2017 and will last for 2 years.

“This trial marks a significant milestone in our efforts to develop countermeasures for a pandemic in progress,” said Anthony Fauci, MD, NIAID director

A series of National Institute of Health (NIH) clinical trials are bringing Zika virus vaccines closer to the public.

According to preliminary findings from 3 phase 1 clinical trials, an investigational Zika purified inactivated virus (ZPIV) vaccine was well tolerated and induced an immune response. Scientists from Walter Reed Army Institute of Research are developing the vaccine and leading 1 of the trials.

Of 67 adult participants, 55 received the investigational vaccine; 12 received placebo. All participants received 2 intramuscular injections 4 weeks apart. The researchers detected antibodies in > 90% of those who received the vaccine, 4 weeks after the last dose.

In phase 2 clinical trials, 2 versions of an experimental gene-based Zika vaccine, developed by scientists at the National Institute of Allergy and Infectious Diseases, were both found to be safe and to induce an immune response. One candidate showed “the most promise,” paving the way for an international phase 2/2b safety and efficacy trial, which began in 2017 and will last for 2 years.

“This trial marks a significant milestone in our efforts to develop countermeasures for a pandemic in progress,” said Anthony Fauci, MD, NIAID director

A series of National Institute of Health (NIH) clinical trials are bringing Zika virus vaccines closer to the public.

According to preliminary findings from 3 phase 1 clinical trials, an investigational Zika purified inactivated virus (ZPIV) vaccine was well tolerated and induced an immune response. Scientists from Walter Reed Army Institute of Research are developing the vaccine and leading 1 of the trials.

Of 67 adult participants, 55 received the investigational vaccine; 12 received placebo. All participants received 2 intramuscular injections 4 weeks apart. The researchers detected antibodies in > 90% of those who received the vaccine, 4 weeks after the last dose.

In phase 2 clinical trials, 2 versions of an experimental gene-based Zika vaccine, developed by scientists at the National Institute of Allergy and Infectious Diseases, were both found to be safe and to induce an immune response. One candidate showed “the most promise,” paving the way for an international phase 2/2b safety and efficacy trial, which began in 2017 and will last for 2 years.

“This trial marks a significant milestone in our efforts to develop countermeasures for a pandemic in progress,” said Anthony Fauci, MD, NIAID director

Mayo Clinic Proceedings

Intravenous (IV) bevacizumab “dramatically” improves severe bleeding associated with hereditary hemorrhagic telangiectasia (HHT), according to researchers.

In a retrospective study, HHT patients with severe bleeding had a substantial reduction in nose bleeds and gastrointestinal (GI) bleeding after treatment with IV bevacizumab.

In addition, patients were able to stop or considerably reduce red blood cell (RBC) transfusions.

The researchers therefore believe that IV bevacizumab should be considered as a first-line therapy for the treatment of refractory bleeding in patients with severe HHT.

The team detailed this research and in Mayo Clinic Proceedings alongside a related editorial.

“Some HHT patients suffer from severe epistaxis and gastrointestinal bleeding, which can result in severe anemia and years of blood transfusions,” said study author Vivek N. Iyer, MD, of the Mayo Clinic in Rochester, Minnesota.

“Both problems also appear to sometimes worsen with age. In some patients, both epistaxis and GI bleeding can become refractory/resistant to existing treatment options, leaving patients severely anemic and dependent on iron infusions or blood transfusions. Quality of life is very poor in these cases.”

With this in mind, Dr Iyer and his colleagues analyzed the records of 34 patients who were treated with IV bevacizumab for severe HHT-related bleeding from June 2013 through January 2017.

Patient characteristics

Patients had a median age of 63 (range, 57 to 72). Sixty-two percent of patients were female.

The primary source of bleeding was epistaxis in 15 patients, GI bleeding in 4 patients, and combined epistaxis and GI bleeding in 15 patients.

Prior epistaxis treatments included potassium-titanyl-phosphate/other laser procedures (62%), sclerotherapy (26%), endovascular angiographic embolization (21%), septodermoplasty (24%), subcutaneous bevacizumab injections (21%), and bevacizumab nasal spray (29%).

Seventy-one percent of patients underwent upper endoscopy (100% of these with telangiectasias), and 53% underwent colonoscopy (56% of these with telangiectasias).

Forty-one percent of patients had IV iron supplementation in the past 6 months.

Twenty-eight patients had received RBC transfusions. Sixteen patients were transfusion-dependent and had received a median of 75 transfusions before starting treatment with bevacizumab. The median duration of transfusion dependence was 6 years.

Treatment

The typical initial dosing cycle of bevacizumab consisted of 8 doses (4 doses each administered 2 weeks apart, followed by 4 doses each administered 1 month apart) over a period of around 22 weeks.

Further maintenance doses after the initial dosing cycle were individualized in each patient.

At last follow-up, 3 patients were still receiving bevacizumab from the initial dosing protocol. For the 31 patients who had completed the first dosing cycle, the median duration of follow-up was 13.6 months.

Eighteen patients required at least 1 top-up dose of IV bevacizumab because of worsening bleeding and/or anemia.

Efficacy

The median follow-up was 17.6 months (range, 3 to 42.5 months).

An Epistaxis Severity Score (ESS) questionnaire was used to assess the severity of nose bleeds both at the beginning of the study and after starting bevacizumab.

One month after starting treatment, there was a significant reduction in ESS scores (P<0.001). This improvement was maintained after patients completed the initial treatment cycle.

The median ESS score was 6.5 at baseline, 3.3 at 1 month, 4.0 at 3 months, 2.3 at the end of the first cycle, 2.0 at 1 to 3 months after the first cycle, 3.2 at 4 to 6 months, and 2.8 at 7 to 12 months.

GI bleeding also improved, with resolution or improvement of anemia in all 19 patients with this condition.

There was a reduction in RBC transfusions as well. The proportion of patients receiving transfusions was 53% in the 6 months before IV bevacizumab, 15% in the 1 to 3 months after starting IV bevacizumab, 14% at 4 to 6 months, 8% at 7 to 9 months, and 9% at 9 to 12 months.

Eighty-eight percent (n=14) of the transfusion-dependent patients had received a transfusion in the 6 months prior to starting IV bevacizumab. This compares to 31% (n=5) of patients in the 1 to 3 months after the start of treatment, 29% (n=4) at 4 to 6 months, 14% (n=2) at 7 to 9 months, and 8% (n=1) at 9 to 12 months.

Safety

Four patients had hypertension (HTN). One had pre-existing HTN and had to double the daily dose of lisinopril from 10 mg to 20 mg.

Two HTN patients had to start antihypertensive medications. The fourth patient experienced hypertensive urgency with a temporary decline in renal function. However, the patient was able to resume bevacizumab.

Two patients had infusion-related chills and fever, but premedication with acetaminophen and diphenhydramine prevented these events from recurring.

Three patients died during follow-up. Causes of death were stroke, infective endocarditis (methicillin-sensitive Staphylococcus aureus) with multiple cerebral infarcts, and postoperative respiratory failure (after left atrial appendectomy for paroxysmal atrial fibrillation).

None of these deaths were directly linked to bevacizumab.

“This study provides good-quality evidence for the excellent efficacy and safety of intravenous bevacizumab in the treatment of these patients,” Dr Iyer said. “Intravenous bevacizumab should be considered as a standard, first-line treatment option for HHT patients with severe bleeding and transfusion-dependent anemia.”

Mayo Clinic Proceedings

Intravenous (IV) bevacizumab “dramatically” improves severe bleeding associated with hereditary hemorrhagic telangiectasia (HHT), according to researchers.

In a retrospective study, HHT patients with severe bleeding had a substantial reduction in nose bleeds and gastrointestinal (GI) bleeding after treatment with IV bevacizumab.

In addition, patients were able to stop or considerably reduce red blood cell (RBC) transfusions.

The researchers therefore believe that IV bevacizumab should be considered as a first-line therapy for the treatment of refractory bleeding in patients with severe HHT.

The team detailed this research and in Mayo Clinic Proceedings alongside a related editorial.

“Some HHT patients suffer from severe epistaxis and gastrointestinal bleeding, which can result in severe anemia and years of blood transfusions,” said study author Vivek N. Iyer, MD, of the Mayo Clinic in Rochester, Minnesota.

“Both problems also appear to sometimes worsen with age. In some patients, both epistaxis and GI bleeding can become refractory/resistant to existing treatment options, leaving patients severely anemic and dependent on iron infusions or blood transfusions. Quality of life is very poor in these cases.”

With this in mind, Dr Iyer and his colleagues analyzed the records of 34 patients who were treated with IV bevacizumab for severe HHT-related bleeding from June 2013 through January 2017.

Patient characteristics

Patients had a median age of 63 (range, 57 to 72). Sixty-two percent of patients were female.

The primary source of bleeding was epistaxis in 15 patients, GI bleeding in 4 patients, and combined epistaxis and GI bleeding in 15 patients.

Prior epistaxis treatments included potassium-titanyl-phosphate/other laser procedures (62%), sclerotherapy (26%), endovascular angiographic embolization (21%), septodermoplasty (24%), subcutaneous bevacizumab injections (21%), and bevacizumab nasal spray (29%).

Seventy-one percent of patients underwent upper endoscopy (100% of these with telangiectasias), and 53% underwent colonoscopy (56% of these with telangiectasias).

Forty-one percent of patients had IV iron supplementation in the past 6 months.

Twenty-eight patients had received RBC transfusions. Sixteen patients were transfusion-dependent and had received a median of 75 transfusions before starting treatment with bevacizumab. The median duration of transfusion dependence was 6 years.

Treatment

The typical initial dosing cycle of bevacizumab consisted of 8 doses (4 doses each administered 2 weeks apart, followed by 4 doses each administered 1 month apart) over a period of around 22 weeks.

Further maintenance doses after the initial dosing cycle were individualized in each patient.

At last follow-up, 3 patients were still receiving bevacizumab from the initial dosing protocol. For the 31 patients who had completed the first dosing cycle, the median duration of follow-up was 13.6 months.

Eighteen patients required at least 1 top-up dose of IV bevacizumab because of worsening bleeding and/or anemia.

Efficacy

The median follow-up was 17.6 months (range, 3 to 42.5 months).

An Epistaxis Severity Score (ESS) questionnaire was used to assess the severity of nose bleeds both at the beginning of the study and after starting bevacizumab.

One month after starting treatment, there was a significant reduction in ESS scores (P<0.001). This improvement was maintained after patients completed the initial treatment cycle.

The median ESS score was 6.5 at baseline, 3.3 at 1 month, 4.0 at 3 months, 2.3 at the end of the first cycle, 2.0 at 1 to 3 months after the first cycle, 3.2 at 4 to 6 months, and 2.8 at 7 to 12 months.

GI bleeding also improved, with resolution or improvement of anemia in all 19 patients with this condition.

There was a reduction in RBC transfusions as well. The proportion of patients receiving transfusions was 53% in the 6 months before IV bevacizumab, 15% in the 1 to 3 months after starting IV bevacizumab, 14% at 4 to 6 months, 8% at 7 to 9 months, and 9% at 9 to 12 months.

Eighty-eight percent (n=14) of the transfusion-dependent patients had received a transfusion in the 6 months prior to starting IV bevacizumab. This compares to 31% (n=5) of patients in the 1 to 3 months after the start of treatment, 29% (n=4) at 4 to 6 months, 14% (n=2) at 7 to 9 months, and 8% (n=1) at 9 to 12 months.

Safety

Four patients had hypertension (HTN). One had pre-existing HTN and had to double the daily dose of lisinopril from 10 mg to 20 mg.

Two HTN patients had to start antihypertensive medications. The fourth patient experienced hypertensive urgency with a temporary decline in renal function. However, the patient was able to resume bevacizumab.

Two patients had infusion-related chills and fever, but premedication with acetaminophen and diphenhydramine prevented these events from recurring.

Three patients died during follow-up. Causes of death were stroke, infective endocarditis (methicillin-sensitive Staphylococcus aureus) with multiple cerebral infarcts, and postoperative respiratory failure (after left atrial appendectomy for paroxysmal atrial fibrillation).

None of these deaths were directly linked to bevacizumab.

“This study provides good-quality evidence for the excellent efficacy and safety of intravenous bevacizumab in the treatment of these patients,” Dr Iyer said. “Intravenous bevacizumab should be considered as a standard, first-line treatment option for HHT patients with severe bleeding and transfusion-dependent anemia.”

Mayo Clinic Proceedings

Intravenous (IV) bevacizumab “dramatically” improves severe bleeding associated with hereditary hemorrhagic telangiectasia (HHT), according to researchers.

In a retrospective study, HHT patients with severe bleeding had a substantial reduction in nose bleeds and gastrointestinal (GI) bleeding after treatment with IV bevacizumab.

In addition, patients were able to stop or considerably reduce red blood cell (RBC) transfusions.

The researchers therefore believe that IV bevacizumab should be considered as a first-line therapy for the treatment of refractory bleeding in patients with severe HHT.

The team detailed this research and in Mayo Clinic Proceedings alongside a related editorial.

“Some HHT patients suffer from severe epistaxis and gastrointestinal bleeding, which can result in severe anemia and years of blood transfusions,” said study author Vivek N. Iyer, MD, of the Mayo Clinic in Rochester, Minnesota.

“Both problems also appear to sometimes worsen with age. In some patients, both epistaxis and GI bleeding can become refractory/resistant to existing treatment options, leaving patients severely anemic and dependent on iron infusions or blood transfusions. Quality of life is very poor in these cases.”

With this in mind, Dr Iyer and his colleagues analyzed the records of 34 patients who were treated with IV bevacizumab for severe HHT-related bleeding from June 2013 through January 2017.

Patient characteristics

Patients had a median age of 63 (range, 57 to 72). Sixty-two percent of patients were female.

The primary source of bleeding was epistaxis in 15 patients, GI bleeding in 4 patients, and combined epistaxis and GI bleeding in 15 patients.

Prior epistaxis treatments included potassium-titanyl-phosphate/other laser procedures (62%), sclerotherapy (26%), endovascular angiographic embolization (21%), septodermoplasty (24%), subcutaneous bevacizumab injections (21%), and bevacizumab nasal spray (29%).

Seventy-one percent of patients underwent upper endoscopy (100% of these with telangiectasias), and 53% underwent colonoscopy (56% of these with telangiectasias).

Forty-one percent of patients had IV iron supplementation in the past 6 months.

Twenty-eight patients had received RBC transfusions. Sixteen patients were transfusion-dependent and had received a median of 75 transfusions before starting treatment with bevacizumab. The median duration of transfusion dependence was 6 years.

Treatment

The typical initial dosing cycle of bevacizumab consisted of 8 doses (4 doses each administered 2 weeks apart, followed by 4 doses each administered 1 month apart) over a period of around 22 weeks.

Further maintenance doses after the initial dosing cycle were individualized in each patient.

At last follow-up, 3 patients were still receiving bevacizumab from the initial dosing protocol. For the 31 patients who had completed the first dosing cycle, the median duration of follow-up was 13.6 months.

Eighteen patients required at least 1 top-up dose of IV bevacizumab because of worsening bleeding and/or anemia.

Efficacy

The median follow-up was 17.6 months (range, 3 to 42.5 months).

An Epistaxis Severity Score (ESS) questionnaire was used to assess the severity of nose bleeds both at the beginning of the study and after starting bevacizumab.

One month after starting treatment, there was a significant reduction in ESS scores (P<0.001). This improvement was maintained after patients completed the initial treatment cycle.

The median ESS score was 6.5 at baseline, 3.3 at 1 month, 4.0 at 3 months, 2.3 at the end of the first cycle, 2.0 at 1 to 3 months after the first cycle, 3.2 at 4 to 6 months, and 2.8 at 7 to 12 months.

GI bleeding also improved, with resolution or improvement of anemia in all 19 patients with this condition.

There was a reduction in RBC transfusions as well. The proportion of patients receiving transfusions was 53% in the 6 months before IV bevacizumab, 15% in the 1 to 3 months after starting IV bevacizumab, 14% at 4 to 6 months, 8% at 7 to 9 months, and 9% at 9 to 12 months.

Eighty-eight percent (n=14) of the transfusion-dependent patients had received a transfusion in the 6 months prior to starting IV bevacizumab. This compares to 31% (n=5) of patients in the 1 to 3 months after the start of treatment, 29% (n=4) at 4 to 6 months, 14% (n=2) at 7 to 9 months, and 8% (n=1) at 9 to 12 months.

Safety

Four patients had hypertension (HTN). One had pre-existing HTN and had to double the daily dose of lisinopril from 10 mg to 20 mg.

Two HTN patients had to start antihypertensive medications. The fourth patient experienced hypertensive urgency with a temporary decline in renal function. However, the patient was able to resume bevacizumab.

Two patients had infusion-related chills and fever, but premedication with acetaminophen and diphenhydramine prevented these events from recurring.

Three patients died during follow-up. Causes of death were stroke, infective endocarditis (methicillin-sensitive Staphylococcus aureus) with multiple cerebral infarcts, and postoperative respiratory failure (after left atrial appendectomy for paroxysmal atrial fibrillation).

None of these deaths were directly linked to bevacizumab.

“This study provides good-quality evidence for the excellent efficacy and safety of intravenous bevacizumab in the treatment of these patients,” Dr Iyer said. “Intravenous bevacizumab should be considered as a standard, first-line treatment option for HHT patients with severe bleeding and transfusion-dependent anemia.”