Stable COPD: Follow-up pharmacologic management

INTRODUCTION — 

Chronic obstructive pulmonary disease (COPD) is a progressive obstructive lung disease with high morbidity and mortality. Current estimates suggest that approximately 10 percent of individuals aged 40 years or older have COPD, although the prevalence varies between countries and increases with age [1-3]. COPD is one of the leading causes of death among adults in the United States, resulting in over 140,000 deaths annually [4,5]. Prior to the onset of the COVID-19 (coronavirus disease 2019) pandemic, COPD was the third leading cause of death worldwide [6].

For the purposes of UpToDate topics, stable COPD refers to COPD in patients who are not currently experiencing an exacerbation of their disease. However, these patients may have experienced recent exacerbations with subsequent recovery to a new baseline or have ongoing COPD symptoms of varying intensity. Management of stable COPD typically occurs in the outpatient setting.

The pharmacologic management of patients with stable COPD who return in follow-up will be reviewed here. The clinical manifestations, diagnosis, comorbidities, and prognosis of COPD, as well as the management of refractory COPD, acute exacerbations, and alpha-1 antitrypsin deficiency are discussed separately.

●(See "Chronic obstructive pulmonary disease: Diagnosis and staging".)

●(See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions".)

●(See "Stable COPD: Overview of management".)

●(See "Stable COPD: Initial pharmacologic management".)

●(See "Management of refractory chronic obstructive pulmonary disease".)

●(See "COPD exacerbations: Management".)

●(See "Treatment of emphysema from alpha-1 antitrypsin deficiency".)

DISEASE METRICS — 

The Global Initiative Chronic Obstructive Lung Disease (GOLD) report uses the core metrics of dyspnea severity and frequency of exacerbations to categorize patients for pharmacologic management [7]. Initial management uses these metrics to divide patients into GOLD “ABE” groups for choice of initial therapy (algorithm 1). (See "Stable COPD: Initial pharmacologic management", section on 'Symptoms and risk of exacerbations'.)

Follow-up management for COPD uses the same core metrics of dyspnea and exacerbation history but differs from initial management in that it does not use GOLD groups for stratification. Importantly, follow-up management takes a similar approach to patients who have experienced exacerbations on therapy regardless of the degree of dyspnea.

ASSESSMENT

Symptoms and signs — For patients who return for follow-up management of COPD, we evaluate dyspnea and exercise tolerance using a validated instrument, such as the modified Medical Research Council (mMRC) dyspnea scale (calculator 1) or the COPD Assessment Test (CAT) (calculator 2) [7-10].

Physical examination focuses on changes associated with worsening airway obstruction and hyperinflation (hyperresonance, decreased breath sounds and diaphragmatic excursion, increased AP chest diameter, and wheezing). (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Physical examination'.)

We also monitor additional symptoms associated with COPD (eg, cough, sputum, activity limitations, sleep disturbance), medication use, lung function, and oxygenation to ascertain whether an adequate response to therapy has been achieved and whether complications or comorbidities have developed, as described separately. (See "Stable COPD: Overview of management", section on 'Monitoring' and "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Differential diagnosis' and "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions".)

Exacerbation history — We support risk stratification for follow-up COPD therapy based on the occurrence of and severity of COPD exacerbations requiring treatment in the previous year. As with other COPD manifestations, exacerbation history requires continuous reassessment. At each follow-up visit, we review both the frequency and severity of COPD exacerbations and hospitalizations since the last visit, as well as the last adjustments of pharmacologic therapy. This is especially important as patients often obtain healthcare for exacerbations from different healthcare providers and care centers. The proposed Rome severity criteria for exacerbations (figure 1) are more objective than previous classification schemes that depended on treatment choices but can be more difficult to determine afterwards without access to detailed medical records.

The Global Initiative Chronic Obstructive Lung Disease (GOLD) strategy have been less specific regarding the threshold number and severity of exacerbations required to qualify for changes in management due to exacerbations during follow-up. Nevertheless, GOLD cites evidence favoring ICS use during follow-up care in COPD patients with one moderate exacerbation in the prior year and strongly favor ICS use in patients with one COPD exacerbation leading to hospitalization or two moderate exacerbations in the prior year [7].

Long-term studies evaluating therapeutic interventions for patients at risk for exacerbations have focused on patients at greatest exacerbation risk with one hospitalization or two or more exacerbations requiring systemic antibiotics or glucocorticoids as criteria to define a need and show a benefit of escalating COPD therapy [11,12]. However, accumulating evidence suggests that a single exacerbation requiring systemic therapies in a patient on long-acting maintenance treatment increases the subsequent risk of exacerbations over the next 12 to 36 months by 1.5- to 3-fold [13-18].

Additional risk factors for future exacerbations are discussed elsewhere. (See "COPD exacerbations: Clinical manifestations and evaluation", section on 'Risk factors'.)

Inhaler technique and adherence — Suboptimal inhaler technique and/or adherence are potential (and common) causes of a failed treatment response and should be recurrently explored with every patient. Device education and re-education are essential to successful follow-up care and should always be considered before adding or changing therapy. (See "Stable COPD: Overview of management", section on 'Inhaler technique'.)

A prospective study followed patients after hospitalization for COPD exacerbations and found suboptimal adherence to technique and on-time use in two-thirds [19]. Similarly, a systematic review of studies on inhaler technique found that on average two-thirds of patients with asthma or COPD made one or more errors in device use [20]. These studies support the need for regimen simplicity and re-enforcement of inhaler technique. (See "Patient education: Inhaler techniques in adults (Beyond the Basics)" and "The use of inhaler devices in adults".)

Review of smoking, comorbidities, and vaccination — Each follow-up visit is an opportunity to revisit smoking cessation, avoidance of exposure to inhalational particulates, fumes, or gases, vaccination against respiratory infections, contribution from potential comorbidities, and identification of patients for supplemental oxygen, pulmonary rehabilitation, and potential lung cancer screening. (See "Stable COPD: Overview of management" and "Screening for lung cancer".)

Blood eosinophils — For individuals in whom we are considering adding or discontinuing an inhaled corticosteroid (ICS), we evaluate the baseline eosinophil count to help guide this decision since the eosinophil count is associated with response to ICS. Although ICS therapy reduces exacerbation risk, it is also associated with several side effects, including lung infections, which highlights the need for judicious use and careful patient selection. (See "Stable COPD: Initial pharmacologic management", section on 'Assessing disease pattern and severity' and "Major side effects of inhaled glucocorticoids".)

When used as a biomarker to guide COPD therapy, blood eosinophil counts should be assessed during a period of disease stability and not during a course of systemic glucocorticoids or acute infection [21]. For patients who are already taking an ICS, eosinophil counts prior to ICS initiation are likely more predictive of a beneficial response compared with eosinophil counts while on ICS therapy [22].

Our approach to management based on blood eosinophil counts is discussed in detail elsewhere. (See 'Persistent exacerbations with or without dyspnea' below and 'Persistent dyspnea but no exacerbations in the past year' below and 'Dyspnea well controlled and no exacerbations in the past year' below.)

In general, higher levels of blood eosinophils are associated with a more robust response to ICS therapy. This may reasonably affect decision making regarding introduction of ICS therapy:

●Patients with ≥300 eosinophils/microL often have a favorable response to ICS. They are also more likely to have exacerbations following cessation of ICS therapy compared with those with lower eosinophil counts [23,24].

●Patients with ≥100 but <300 eosinophils/microL may have a favorable response to ICS therapy.

●Patients with <100 eosinophils/microL are less likely to respond to ICS treatment [25-28]; as the potential benefits may be limited, use is weighed against risks of ongoing therapy.

Several studies have reported an association between blood eosinophil count and risk of exacerbation with or without ICS [11,23-30]. As an example of exacerbation risk associated with ICS use and eosinophil levels, a post hoc analysis of the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial showed that among COPD patients with ≥1 exacerbation in the prior year, a blood eosinophil count ≥300 cells/microL identified patients at higher risk for exacerbations with discontinuation of steroids [23]. Among patients with ≥2 exacerbations per year, a blood eosinophil count ≥300 cells/microL was associated with roughly twice as many exacerbations after ICS discontinuation [24].

PHARMACOLOGIC ADJUSTMENT BASED ON ASSESSMENT — 

We agree with the Global Initiative Chronic Obstructive Lung Disease (GOLD) report strategy, which supports using quantified dyspnea and exacerbation frequency as the major metrics for adjustment of pharmacologic therapy in COPD (table 1) [7]. (See 'Disease metrics' above.)

Dyspnea well controlled and no exacerbations in the past year — In general, patients with good symptom control (ie, modified Medical Research Council [mMRC] grade <2 (calculator 1) or COPD Assessment Test [CAT] score <10 (calculator 2)) and no recent exacerbations should generally continue their current therapy [7]. Patients using only short-acting bronchodilators may benefit from the addition of a long-acting bronchodilator. (See "Stable COPD: Initial pharmacologic management", section on 'Less symptomatic patients at low risk of exacerbation (Group A)'.)

As an additional exception, if current therapy includes inhaled glucocorticoids (inhaled corticosteroids [ICS]), tapering or discontinuing ICS is reasonable, particularly for those who did not benefit from the addition of ICS, have a low eosinophil count (<100 cells/microL), or are experiencing adverse events related to ICS therapy. If ICS are withdrawn, close patient monitoring is required. Any worsening in symptoms, activity intolerance, or oxygenation following treatment reduction should lead to a return to the prior maintenance therapy. (See 'Blood eosinophils' above.)

Trials examining the effect of ICS withdrawal in well-controlled patients include the following:

●For patients with good control of symptoms and <2 exacerbations/year on triple therapy, a real-world study in 914 patients suggests that ICS can be safely withdrawn without significant risk of health status decline (CAT score) or exacerbations [31]. One concern about the broad applicability of this study is that the original indications for ICS therapy were unclear.

●In a 26-week trial, 527 patients with COPD on long-term triple therapy but infrequent exacerbations were randomly assigned to continue ICS (with tiotropium-salmeterol-fluticasone) or switch to dual therapy (glycopyrrolate-indacaterol) [32]. In the group without ICS, a small decrease was noted in forced expiratory volume in one second (FEV₁), but there was no increase in the annualized rate of moderate or severe exacerbations. Patients with blood eosinophils ≥300/microL at baseline experienced a greater decline in FEV₁ and a higher exacerbation risk.

Persistent dyspnea but no exacerbations in the past year

General approach to patients with dyspnea — For patients with persistent dyspnea or exercise limitation (ie, mMRC grade ≥2 (calculator 1) or CAT score ≥10 (calculator 2)) and no exacerbations in the past year, we generally agree with the pharmacologic approach recommended by the GOLD report (algorithm 2) [7]. The mainstay of therapy for this group of patients is the use of dual bronchodilator (long-acting muscarinic-antagonist [LAMA] and long-acting beta-agonist [LABA]) therapy. For persistent dyspnea despite dual LAMA-LABA therapy, or for those who do not tolerate one of the components of dual therapy, the nebulized agent ensifentrine may be helpful, where available.

ICS should be continued if it has been helping to reduce exacerbations and has been otherwise well tolerated. Patients with eosinophilia (blood eosinophil count >100 cells/microL) or possible concomitant asthma are also more likely to benefit from the use of ICS.

Specific adjustments based on current regimens are detailed in the sections below.

Dyspnea on LAMA, LABA, or short-acting bronchodilators alone — For patients with COPD on a single long-acting bronchodilator or short-acting bronchodilators experiencing ongoing dyspnea without exacerbations, we recommend use of a LAMA and LABA dual bronchodilator (available as a combination in a single inhaler). Ensifentrine is an alternative that may be particularly useful in those who do not tolerate one of the other agents or for those in whom nebulized treatment is preferred.

●Efficacy of LAMA-LABA compared with either agent alone – A systematic review and meta-analysis of 10 trials (10,894 participants) compared combination LAMA (tiotropium) plus LABA (salmeterol, formoterol, or indacaterol) to LAMA (tiotropium) alone and found slightly better quality-of-life and a small increase in the postbronchodilator FEV₁ with the combination [33].

Another systematic review and meta-analysis of 10 studies (9609 participants) found that LAMA/LABA (umeclidinium-vilanterol) combination therapy improved lung function compared with umeclidinium (LAMA), vilanterol (LABA), tiotropium (LAMA), and fluticasone-salmeterol (LABA-ICS; mean improvement in trough FEV₁ 60, 110, 90, and 90 mL, respectively) [34]. Umeclidinium-vilanterol combination therapy also demonstrated a greater likelihood of a clinically significant improvement in dyspnea compared with either single-agent umeclidinium (56 versus 49 percent; risk ratio [RR] 1.14, 95% CI 1.05-1.24) or vilanterol (58 versus 48 percent; RR 1.21, 95% CI 1.12-1.31).

●Ensifentrine as an add-on agent – Ensifentrine is an inhaled selective dual phosphodiesterase-3 (PDE3) and phosphodiesterase-4 (PDE4) inhibitor that is a novel class of combined inhaled bronchodilator and anti-inflammatory agents. Acting through regulation of cyclic adenosine monophosphate (cAMP), PDE3 increases airway smooth muscle tone, and PDE4 promotes inflammatory cell activation [35,36]. Dual inhibition of PDE3 and PDE4 has been suggested to enhance or have synergistic effects on both responses [37,38], prompting clinical development of a combined selective inhibitor [39,40]. Ensifentrine has been approved in the United States for the treatment of stable COPD at a dose of 3 mg by nebulizer twice daily [41]. The role of this therapy in COPD management is still evolving given minimal real-world experience with its use.

In two concomitant phase 3 trials (ENHANCE-1 and ENHANCE-2), 760 and 789 patients with COPD, dyspnea (modified Medical Research Council [mMRC] scale ≥2 (calculator 1)), and moderate to severe airway obstruction (postbronchodilator forced expiratory volume in one second [FEV₁] 30 to 70 percent predicted) received ensifentrine 3 mg or placebo twice daily via nebulizer [42]. Patients were receiving either no maintenance therapy, LABA±ICS, or LAMA±ICS at baseline, with these baseline therapies continued throughout the trials. No enrolled patients were receiving either dual LAMA-LABA or LAMA-LABA-ICS therapy. Ensifentrine demonstrated efficacy as a bronchodilator, leading to significant improvements in peak and trough FEV₁. Patients using ensifentrine experienced potentially meaningful improvements in dyspnea (1.0- and 0.9-point increase in the Transition Dyspnea Index compared with placebo). There were no major differences in efficacy based on baseline bronchodilator therapy. Adverse events, including gastrointestinal side effects often seen with oral PDE4 inhibitors, were minimal and similar to placebo.

Dyspnea on LABA-ICS — LABA-ICS therapy is no longer recommended for most patients as initial treatment for COPD [7]. However, many patients use this combination based on its wide availability and endorsement in previous guideline recommendations. For patients without exacerbations but experiencing dyspnea on a LABA-ICS, we suggest addition of LAMA therapy either with or without continuation of the ICS. Ensifentrine is a reasonable alternative to LAMA therapy and has shown similar efficacy in this group compared with those on LAMA or LABA alone. (See 'Dyspnea on LAMA, LABA, or short-acting bronchodilators alone' above.)

A recent history of frequent exacerbations that has improved with addition of ICS or a diagnosis of COPD and asthma (aka, COPD-A or ACO) argue in favor of changing LABA-ICS to LAMA-LABA-ICS triple therapy. Alternatively, if the initial indication for ICS is unclear, there has been no response to ICS treatment, or there have been significant ICS side effects, LABA-ICS can be changed to LAMA-LABA therapy.

Close monitoring is required for patients withdrawing from ICS to minimize any potential deterioration. Patients with blood eosinophils ≥300 cells/microL are more likely to experience an exacerbation after ICS withdrawal. (See 'Blood eosinophils' above.)

Very few studies focus on this group of patients, so this strategy is based primarily on evidence of beneficial addition of LAMA for dyspnea in patients on single bronchodilator therapy or improvement in dyspnea measures in trials examining patients with frequent exacerbations. (See 'Persistent exacerbations with or without dyspnea' below.)

●KRONOS trial – The KRONOS trial compared the use of LAMA-LABA-ICS (budesonide-glycopyrrolate-formoterol 320/18/9.6 mcg) with LAMA-LABA therapy (glycopyrrolate-formoterol 18/9.6 mcg) and LABA-ICS (budesonide-formoterol 320/9.6 mcg or 400/12 mcg) in COPD patients who were symptomatic on two inhaled therapies [43]. Seventy-five percent of these patients had not had exacerbations within the past year. The groups using LAMA had much larger improvements in air movement (various FEV₁-related measures) than patients on LABA-ICS. For example, change in predose trough FEV₁ compared with baseline was 137 mL with LAMA-LABA-ICS, 110 mL with LAMA-LABA therapy, and 63 and 80 mL on the LABA-ICS combinations. Peak change in FEV₁ postdosing was 381 mL with LAMA-LABA-ICS, 364 mL with LAMA-LABA therapy, and 275 or 291 mL with LABA-ICS. The small improvement with LAMA-LABA-ICS compared with LAMA-LABA was driven by patients with blood eosinophil counts >150 cells/microL. There were no consistent effects on dyspnea indices or rescue medication use. Regimens containing ICS reduced estimated exacerbation rates (approximately 0.5 exacerbations per year compared with 0.95 per year).

●Other trials – Results from other studies of LAMA-LABA-ICS were all performed in patients with frequent exacerbations. They show a similar moderate to large improvement in predose FEV₁ compared with LABA-ICS (63 to 170 mL), as well as modest improvements in symptomatic dyspnea (6 to 11 percent absolute increase in the number of patients reporting a clinically significant improvement in dyspnea by St. George’s respiratory questionnaire [SGRQ]) [12,44-47]. Trials that compared LAMA-LABA-ICS with LAMA-LABA showed a much smaller change in spirometry measures (eg, 30 to 40 mL difference in trough FEV₁) but similar improvements in respiratory symptoms by SGRQ, as well as fewer exacerbations [12,46-48]. (See 'Persistent exacerbations with or without dyspnea' below.)

Dyspnea on LAMA-LABA — For patients with low risk for exacerbations but significant dyspnea despite LAMA-LABA therapy, we add-on either inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) or ensifentrine (if available) depending on clinical features. For those with possible concomitant asthma or eosinophils >100 cells/microL, we suggest the addition of ICS prior to ensifentrine or other options. For those without these features or those who do not improve despite ICS, we suggest the addition of ensifentrine, if available. Despite extremely limited data regarding the additional efficacy of triple inhaled bronchodilator therapy, the distinct mechanisms and favorable safety profiles of these three agents prompt this approach until more data are available. Availability, cost, and insurance coverage of ensifentrine may be additional practical barriers to instituting this regimen.

●Measures prior to add-on therapy – Given that these patients are experiencing dyspnea despite powerful bronchodilating agents, we spend extra effort ensuring their current management is optimal prior to adding additional agents. This includes determining whether inhaler adherence or technique require reinforcement or if they would benefit from a change to an alternative inhaler device (eg, dry powder inhaler versus soft mist inhaler, or trial of nebulized therapy). (See "The use of inhaler devices in adults" and "Delivery of inhaled medication in adults".)

Pulmonary rehabilitation can be very helpful for patients with dyspnea despite bronchodilator therapies, and tobacco cessation is critical. Additional work-up directed at other potential causes of dyspnea is also appropriate. (See "Pulmonary rehabilitation" and "Stable COPD: Overview of management", section on 'General measures for all patients'.)

●Add-on ICS, for patients with possible concomitant asthma or peripheral eosinophilia – Patients with clinical or spirometric features of asthma and COPD (variability of symptoms, history of atopy/allergies, strong bronchodilator response) likely benefit from the addition of ICS therapy. (See "Concomitant asthma and COPD".)

Trials comparing LAMA-LABA and LAMA-LABA-ICS suggest that ICS is most likely to improve lung function in patients with blood eosinophilia (≥100 to ≥150 cells/microL) [43,46]. We suggest a trial of LAMA-LABA-ICS in patients with ≥100 eosinophils/microL before moving to other interventions. Changing to LAMA-LABA-ICS conveniently consolidates therapy into a single once or twice daily inhaler and is often effective at improving dyspnea in this population.

Patients using combination therapy with ICS who have not benefited or have experienced adverse effects should stop ICS therapy. ICS withdrawal requires close patient monitoring to avoid potential deterioration, particularly in patients who have elevated peripheral blood eosinophils ≥300 cells/microL. (See 'Blood eosinophils' above.)

●Add-on ensifentrine – For patients still experiencing dyspnea despite the above interventions, we proceed with the addition of nebulized ensifentrine, if available. The typical dose is 3 mg (one vial) by nebulizer twice daily. There are extremely limited data regarding the additional efficacy of triple inhaled therapy with LAMA, LABA, and ensifentrine over dual therapy with two of these agents. However, each class of agent acts via a different mechanism, and each are well-tolerated. Forthcoming studies and real-world experience with this combination of agents will be helpful in determining its role in COPD management.

●Other options – For those without access to ensifentrine, evidence of concomitant asthma, or peripheral eosinophilia, either a switch to LAMA-LABA-ICS or the addition of low-dose theophylline can be attempted; however, these interventions usually do not have a major effect. Invasive approaches (eg, bronchoscopic or surgical lung volume reduction or lung transplant) should be discussed with patients who meet criteria for these interventions. (See "Management of refractory chronic obstructive pulmonary disease".)

Dyspnea despite optimized inhaled therapies — For patients with dyspnea despite optimized inhaled therapies as described above, other potential causes of dyspnea should be explored. Pulmonary rehabilitation often helps reduce dyspnea in this setting, particularly in more sedentary patients. (See "Pulmonary rehabilitation".)

Patients using combination therapy with ICS who have not benefited from or have experienced adverse effects should stop ICS therapy with close monitoring. (See 'Dyspnea on LAMA-LABA' above.)

Invasive approaches (eg, bronchoscopic or surgical lung volume reduction or lung transplant) or low-dose theophylline may be of benefit in carefully selected patients. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Persistent dyspnea without recurrent exacerbations'.)

Persistent exacerbations with or without dyspnea

General approach to patients with exacerbations — For patients with one or more exacerbations in the past year on their current regimen with or without associated persistent dyspnea, our approach is largely similar to the strategies outlined in the GOLD report (algorithm 3) [7]. We generally ensure these patients are on a baseline of LAMA-LABA therapy, as there are benefits in terms of dyspnea and possible benefits in exacerbation risk with only rare adverse effects. For patients with exacerbations on this regimen, we then recommend a trial of ICS to reduce exacerbation risk; lack of efficacy or development of adverse effects from ICS should merit discontinuation. Escalation of pharmacologic therapy may occur as part of exacerbation management or when the patient is seen at follow-up. Patients with ongoing exacerbations despite triple therapy are considered refractory; further management is described elsewhere. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Recurrent exacerbations'.)

Occasionally, patients who have been stable for many years have an exacerbation associated with an unusual exposure or respiratory infection. It is reasonable to eschew pharmacologic escalation in this setting.

Typical pharmacologic adjustments based on current therapies are outlined below:

Exacerbations on LAMA, LABA, or short-acting bronchodilators alone — For patients with exacerbations on a LAMA, LABA, or short-acting bronchodilators alone and peripheral eosinophils ≤300 cells/microL, GOLD suggests a change to LAMA-LABA prior to instituting LAMA-LABA-ICS therapy, as dual bronchodilator therapy reduces dyspnea and may reduce exacerbations compared with single bronchodilator therapy [7,33,34]. However, the evidence for a reduction in exacerbations when a LABA is added to a LAMA is not consistent between trials [33,34,49]. (See "Stable COPD: Initial pharmacologic management", section on 'Use of dual bronchodilator therapy'.)

For patients on a long-acting agent with frequent exacerbations and a blood eosinophil count ≥300 cells/microL, we support increasing therapy to a LAMA-LABA-ICS, as advised by GOLD [7]. These patients have been found more likely to respond to ICS (LABA-ICS or LAMA-LABA-ICS) and are likely the main beneficiaries of the mortality gains seen with ICS therapy [25-28,50]. We also escalate to triple therapy in patients with severe exacerbations who require hospitalization, as these patients are at the highest risk for future COPD-associated hospitalizations and mortality. (See 'Exacerbations on LAMA-LABA therapy' below and "Concomitant asthma and COPD" and "Stable COPD: Initial pharmacologic management", section on 'Group E patients presenting with elevated eosinophil counts or hospitalization' and 'Blood eosinophils' above.)

Although multiple studies have shown the benefit of dual therapy with LABA-ICS versus monotherapy with LABA, we only use LABA-ICS in patients who are unable to take a LAMA or have asthma and COPD. Our preference for dual bronchodilator therapy is based largely on the low rate of adverse effects with LAMA therapy compared with ICS as well as the evidence in favor of triple therapy LAMA-LABA-ICS over LABA-ICS. The GOLD recommendations also endorse this approach [7]. LABA-ICS is an alternative in patients with eosinophil counts ≥100 cells/microL who do not tolerate LAMA therapy (table 1).

Exacerbations on LAMA-LABA therapy — For most patients with exacerbations despite dual therapy with LAMA-LABA, we suggest a change to LAMA-LABA-ICS, which is likely to reduce the frequency of exacerbations, improve lung function, and possibly improve mortality. Patients with higher levels of blood eosinophils (≥300 cells/microL) have the greatest likelihood of benefit, while those with very low baseline blood eosinophilia (<100 cells/microL) are least likely to benefit [11,12,28,48,51].

The primary rationale for conversion of patients on LAMA-LABA to LAMA-LABA-ICS triple therapy is to achieve an improvement in respiratory symptoms and a decrease in exacerbations. A meta-analysis of four clinical trials totaling over 15,000 patients demonstrated that compared with LAMA-LABA therapy, triple therapy led to decreased rates of moderate to severe exacerbations (RR 0.74, 95% CI 0.67-0.81) and an increased proportion of patients demonstrating significantly improved respiratory quality of life or dyspnea [52]. These benefits came at the cost of increased risk of pneumonia (3.3 versus 1.9 percent incidence, OR 1.74, 95% CI 1.4-2.2).

The above results are derived from several key clinical trials, which are reviewed in more detail below:

●IMPACT – This trial compared a single, once-daily inhaler containing three agents (fluticasone furoate-umeclidinium-vilanterol) with a once-daily LAMA-LABA inhaler (umeclidinium-vilanterol) or a once-daily glucocorticoid-LABA inhaler (fluticasone furoate-vilanterol) in 10,355 patients with COPD who were at increased risk of exacerbations due to a combination of disease severity and exacerbation history [11]. The rate of moderate-to-severe exacerbations was lower with the triple inhaler compared with umeclidinium-vilanterol (annual rate of exacerbations 0.91 versus 1.21; RR 0.75, 95% CI 0.70-0.81). Additionally, lung function was better with triple therapy and hospitalizations were less frequent. However, the incidence of pneumonia was higher with triple therapy (95.8/1000 patient years) than with umeclidinium-vilanterol (61.2/1000 patient years; time-to-event hazard ratio [HR] 1.53, 95% CI 1.22-1.92). Questions have been raised about the role of withdrawal of ICS just prior to study onset as a factor in the findings from IMPACT [51], although this concept has also been contested.

Post hoc analysis suggests that the impact on exacerbation reduction, as well as lung function and dyspnea measures, was driven primarily by patients with peripheral blood eosinophils >100/microL [28].

●ETHOS – This trial compared a twice-daily inhaler containing three agents (budesonide-glycopyrrolate-formoterol) at two different ICS doses (320 mcg and 160 mcg budesonide) with a twice-daily LAMA-LABA inhaler (glycopyrrolate-formoterol) or a twice-daily ICS-LABA inhaler (budesonide-formoterol) in 8509 patients with COPD who were at increased risk for exacerbations [12]. The rate of moderate-to-severe exacerbations was nearly identically lower with either dose of the triple inhaler compared with LAMA-LABA (glycopyrrolate-formoterol; annual rate of exacerbations for the 320 mcg budesonide dose was 1.08 versus 1.42; RR 0.76, 95% CI 0.69-0.83). The incidence of pneumonia was higher with triple therapy (53.3/1000 patient years) than with glycopyrrolate-formoterol (37.3/1000 patient years).

●TRIBUTE – This trial compared the single-inhaler triple therapy beclomethasone-formoterol-glycopyrrolate with glycopyrrolate-indacaterol in 1532 patients with severe to very severe COPD and increased exacerbation risk [48]. Over 52 weeks, triple therapy reduced exacerbation rates by approximately 15 percent (0.50 versus 0.59 exacerbations/patient per year for triple therapy and dual therapy, respectively). The effect was most pronounced in patients with blood eosinophil counts ≥2 percent. Overall adverse events were similar between the two study groups.

In addition to the impact of triple therapy on exacerbation rates, these trials demonstrated an improvement in mortality in high-risk patients with triple therapy compared with dual therapies. Although the magnitude of benefit appears small, the effect of these changes over time could become an important indication for LAMA-LABA-ICS therapy in the future. Meta-analysis of multiple trials has increased confidence in this result [50,52].

●In a meta-analysis of eight trials (including those discussed above) and over 25,000 patients with moderate-severe COPD, those assigned to LAMA-LABA-ICS compared with LAMA-LABA experienced a modest one-year mortality benefit (1.4 percent versus 2 percent, respectively, odds ratio 0.72, 95% CI 0.57-0.89) [50]. Subgroup analyses suggest that this benefit is likely driven by patients with ≥2 exacerbations per year and higher levels of blood eosinophils (≥200 cells / microL).

●Post hoc analysis of mortality data from IMPACT demonstrated a likely benefit from triple therapy compared to LAMA-LABA (2.4 versus 3.2 percent one-year mortality, HR 0.72, 95% CI 0.53-0.99) [53]. Similar one-year mortality results were seen in ETHOS, although only improvements with standard-dose budesonide were statistically significant (high-dose budesonide-containing triple therapy versus. LAMA-LABA 1.4 versus 2.6 percent, HR 0.51, 95% CI 0.33-0.80; low-dose budesonide-containing triple therapy versus LAMA-LABA 2.1 versus 2.6 percent, HR 0.78, 95% CI 0.52-1.16) [54]. Other smaller trials, including TRIBUTE, were generally consistent with these findings.  

Exacerbations on LABA-ICS — LABA-ICS therapy is no longer recommended for most patients as initial treatment for COPD [7]. However, many patients use this combination based on its wide availability and endorsement in previous guideline recommendations. For COPD patients with recurrent exacerbations on LABA-ICS, we suggest step-up therapy to LAMA-LABA-ICS. These therapies have been directly compared in several randomized trials as outlined below.

For occasional patients with recurrent pneumonia, adverse side effects from ICS, or a clear lack of response to ICS, a switch to a LAMA-LABA is a reasonable alternative option. However, patients with a peripheral blood eosinophil count ≥300 cells/microL are more likely to experience an exacerbation if ICS therapy is discontinued. (See 'Blood eosinophils' above.)

Rare patients who cannot tolerate LAMA therapy may reasonably substitute ensifentrine instead.

The evidence favoring the conversion of patients on LABA-ICS to LAMA-LABA-ICS triple therapy comes from several large clinical trials, which are reviewed in more detail below:

●IMPACT and ETHOS – In the IMPACT trial, the rate of moderate-to-severe exacerbations was lower with the triple inhaler compared with fluticasone furoate-vilanterol (annual rate of exacerbations 0.91 versus 1.07; RR 0.85, 95% CI 0.80-0.90). There were also lung function and dyspnea improvements with triple therapy compared with LABA-ICS. In ETHOS, the change in annual rate of exacerbations was similar (1.08 versus 1.24; RR 0.87, 95% CI 0.79-0.95). These trials also evaluated triple therapy versus LAMA-LABA, as discussed in detail above. (See 'Dyspnea on LAMA, LABA, or short-acting bronchodilators alone' above.)

●TRILOGY – This trial compared single-inhaler triple therapy with beclomethasone-glycopyrrolate-formoterol with beclomethasone-formoterol in 1368 patients with severe to very severe COPD and increased exacerbation risk [44]. Triple therapy reduced exacerbation rates by 23 percent (0.41 versus 0.53 annualized exacerbations; RR 0.77, 95% CI 0.65-0.92). The addition of the LAMA to the LABA-inhaled glucocorticoid increased trough FEV₁ by 81 mL and reduced dyspnea. Overall, adverse events were similar between the two study arms.

●FULFIL – This trial compared a once-daily single inhaler with fluticasone furoate-umeclidinium-vilanterol with twice-daily budesonide-formoterol in 1810 patients with moderate to severe COPD or with mild COPD at increased exacerbation risk [45]. At 26 weeks, triple therapy resulted in a mean increase in FEV₁ (142 mL; 95% CI 126 to 158 mL), while dual therapy caused a decrease (-29 mL; 95% CI, -46 to -13 mL). A greater percentage of patients in the LAMA-LABA-ICS group had improvement in dyspnea compared with LABA-ICS (50 versus 41 percent). The annualized rate of moderate-to-severe exacerbations was reduced by 35 percent (0.22 versus 0.34; RR 0.65, 95% CI 0.49-0.86) with triple versus dual therapy.

A number of smaller trials and retrospective studies further support adding a LAMA to dual LABA-ICS therapy in patients with moderate to severe COPD [55-59].

Exacerbations on LAMA-LABA-ICS — For patients with COPD on LAMA-LABA-ICS who continue to have exacerbations, further pharmacologic management may include addition of dupilumab, a macrolide (ie, azithromycin), roflumilast, or ensifentrine. Choice between these agents is driven by disease phenotype and severity, drug interactions, patient comorbidities, and side effect profile (algorithm 4). (See "Management of refractory chronic obstructive pulmonary disease", section on 'Recurrent exacerbations'.)

REFRACTORY DISEASE — 

Some patients have severe COPD and are still symptomatic or continue to have exacerbations despite smoking cessation, an optimal regimen of inhaled medications, education about inhaler technique, pulmonary rehabilitation, and supplemental oxygen for severe hypoxemia. The management of these patients is discussed separately. (See "Management of refractory chronic obstructive pulmonary disease".)

FUTURE DIRECTIONS — 

Several novel therapies for COPD are being investigated. The success of biologics in severe eosinophilic asthma has led to investigational use of these agents in COPD and regulatory approval of dupilumab for those with refractory exacerbations and peripheral eosinophilia ≥300 cells/microL. Identification of the most effective agents and the subgroups of COPD patients who are most likely to benefit from these costly injectable therapies remains a challenge. (See "Concomitant asthma and COPD", section on 'Biologic agents' and "Management of refractory chronic obstructive pulmonary disease", section on 'Patients with peripheral eosinophilia'.)

Investigational biologic therapies for subgroups of patients with COPD include:

●Mepolizumab – Mepolizumab is a monoclonal antibody against interleukin (IL)-5 that is approved for use in eosinophilic asthma. In two parallel, randomized trials, 1138 patients with COPD, a blood eosinophil count ≥150 cells/microL, and moderate or severe exacerbations of COPD despite triple inhaler therapy were assigned to mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) or placebo, administered subcutaneously every four weeks [60]. After one year, mepolizumab slightly reduced the rate of exacerbations compared with placebo (rate ratio 0.82, 95% CI 0.68-0.98 in METREX; RR 0.80, 95% CI 0.65-0.98 for mepolizumab 100 mg; and RR 0.86, 95% CI 0.70-1.05 for mepolizumab 300 mg in METREO). In a post hoc analysis, point estimates of outcomes were slightly better in those with a screening blood eosinophil count ≥300 cells/microL [61]. A follow-up placebo-controlled trial (MATINEE) using this higher eosinophilia threshold reportedly demonstrated a reduction in annualized exacerbation rates [62].

●Benralizumab – Benralizumab is an IL-5 receptor alpha monoclonal antibody that is used as add-on therapy for patients with severe asthma and an eosinophilic phenotype. Mixed results have been reported with benralizumab in COPD [63]. In two parallel randomized trials, a total of 3910 patients with moderate to very severe COPD and a history of frequent exacerbations were assigned to take benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) or placebo subcutaneously every four weeks for two doses, then every eight weeks for a year [64]. None of the benralizumab doses achieved a significant reduction in annualized exacerbations relative to placebo among patients with a blood eosinophil count ≥220 cells/microL. In a subsequent post hoc subgroup analysis, patients with certain clinical characteristics (ie, ≥3 exacerbations in the previous year, on LAMA-LABA-ICS, and with blood eosinophil count ≥220 cells/microL) experienced a 30 percent reduction in exacerbations (RR 0.70, 95% CI 0.56-0.88) with benralizumab at the highest dose (100 mg every eight weeks) compared with placebo [65]. Limited evidence also indicates benralizumab may be beneficial in the management of acute exacerbations [66]. Further prospective study is needed to determine the optimal role of benralizumab in COPD patients.

●Tezepelumab – Tezepelumab is a human monoclonal antibody against thymic stromal lymphopoietin that has been found to be effective for patients with severe asthma with both eosinophilic and noneosinophilic phenotypes. In one randomized trial of approximately 330 patients with moderate to severe COPD without evidence of asthma and ≥2 moderate to severe exacerbations despite triple therapy, there were numerically lower rates of subsequent moderate to severe exacerbations at 52 weeks with tezepelumab 420 mg subcutaneously every four weeks compared with placebo, but the difference was not statistically significant (rate ratio [RR] 0.8, 95% CI 0.6-1.1) [67]. Benefit was more likely with increasing blood eosinophil counts, with a post hoc analysis demonstrating a 37 percent reduction in exacerbation risk in those with blood eosinophil counts ≥150 cells/microL (RR 0.63, 95% CI 0.43-0.93). Serious adverse events were similar between the two arms.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease" and "Society guideline links: Pulmonary rehabilitation".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pulmonary rehabilitation (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Disease metrics – At follow-up visits for COPD, titration for therapy is guided by a patient-centered evaluation of symptoms (dyspnea and exercise tolerance) and exacerbation history. The Global Initiative Chronic Obstructive Lung Disease (GOLD) “ABE” groups that are used to guide initial therapy are not used for follow-up adjustments of medication. Although a progressive decline in lung function is common in patients with worsening disease, pharmacotherapy decisions are also not made based on lung function parameters. (See 'Disease metrics' above.)

●Assessment – Dyspnea should be determined using validated instruments. Physical examination may assist in evaluation of worsening hyperinflation and airflow obstruction. Exacerbation history and severity in the prior year should also be reassessed. We concomitantly evaluate inhaler technique and adherence, review tobacco use and comorbidities, administer vaccines against respiratory pathogens, and measure blood eosinophil levels in selected patients. (See 'Assessment' above.)

●Pharmacologic adjustment – For patients who have persistent symptoms or recurrent exacerbations, pharmacologic therapy should be adjusted based on the patient’s current medications . Other causes of dyspnea and recurrent exacerbations should be explored and treated as indicated. (See "Stable COPD: Initial pharmacologic management".)

•Patients without dyspnea or exacerbations – Patients with good symptom control (ie, modified Medical Research Council [mMRC] grade 0 or 1 (calculator 1) or COPD Assessment Test [CAT] score <10 (calculator 2)) and low exacerbation risk should continue their current therapy. As an exception, if current therapy includes inhaled glucocorticoid (inhaled corticosteroid [ICS]), tapering or discontinuing the ICS is often well tolerated, particularly in those with low blood eosinophil counts. (See 'Dyspnea well controlled and no exacerbations in the past year' above.)

•Patients with persistent dyspnea but without exacerbations – The mainstay of therapy for COPD patients with persistent dyspnea is the use of dual bronchodilator (long-acting muscarinic-antagonist/long-acting beta-agonist [LAMA-LABA]) therapy. ICS should be continued if it has been helping reduce exacerbations and has otherwise been well tolerated. (See 'General approach to patients with dyspnea' above.)

For patients with COPD and persistent dyspnea (ie, mMRC grade ≥2 (calculator 1) or CAT score ≥10 (calculator 2)), inhaled therapy can be adjusted step-wise depending on current therapy and baseline eosinophil count, as follows (algorithm 2):

-For patients on monotherapy with a LAMA or LABA or short-acting bronchodilators alone with dyspnea, we suggest changing to dual LAMA-LABA therapy rather than switching to an alternative single agent (Grade 2B). Most trials show additional modest improvement in quality of life and lung function with dual bronchodilator rather than single bronchodilator therapy. Ensifentrine, where available, is a reasonable alternative for those who do not tolerate one of the components of dual therapy. (See 'Dyspnea on LAMA, LABA, or short-acting bronchodilators alone' above.)

-For patients previously using a LABA-ICS combination with dyspnea, we suggest adding a LAMA rather than other options (Grade 2C). For occasional patients with intolerable adverse effects from LAMAs, the addition of nebulized ensifentrine is a reasonable alternative. Patients without concomitant asthma or peripheral eosinophilia (eg, blood eosinophils < 100 per microL) are reasonable candidates for transition to LAMA-LABA (or LABA plus ensifentrine) and dropping ICS. (See 'Dyspnea on LABA-ICS' above.)

-For patients with dyspnea despite LAMA-LABA therapy and eosinophils >100 cells/microL, we suggest the addition of ICS therapy prior to ensifentrine or other options (Grade 2C). Trials comparing LAMA-LABA and LAMA-LABA-ICS suggest that ICS is most likely to improve lung function in patients with blood eosinophilia ≥100 to ≥150 cells/microL. For those with eosinophils < 100 cells/microL or those who do not improve despite inhaled glucocorticoids, we suggest the addition of ensifentrine, if available (Grade 2C). Despite extremely limited data regarding the additional efficacy of triple inhaled bronchodilator therapy, the distinct mechanisms and favorable safety profiles of these three agents prompt this approach until there are additional data. When ensifentrine is unavailable, these patients should be considered to have refractory disease. (See 'Dyspnea on LAMA-LABA' above.)

-For patients with continued dyspnea despite maximal inhaled therapies, low-dose theophylline and/or nonpharmacologic options, such as pulmonary rehabilitation, bronchoscopic or surgical lung volume reduction, or lung transplantation, may be of benefit. (See 'Dyspnea despite optimized inhaled therapies' above and "Management of refractory chronic obstructive pulmonary disease".)

•Patients with exacerbations – For patients with one or more exacerbations in the past year with or without persistent dyspnea, our step-wise approach depends on current therapy and baseline eosinophil count, as follows (algorithm 3):

-For patients on LAMA or LABA monotherapy or short-acting bronchodilators alone, we suggest initiation of dual bronchodilator therapy with a LAMA-LABA rather than an alternative single agent or initiation of ICS (Grade 2C). As exceptions, patients who have had a severe exacerbation requiring hospitalization and those on a long-acting bronchodilator with a blood eosinophil count ≥300 cells/microL may be more likely to benefit from LAMA-LABA-ICS. (See 'Exacerbations on LAMA, LABA, or short-acting bronchodilators alone' above.)

-For patients already using dual therapy (LAMA-LABA or LABA-ICS), we suggest changing to triple therapy (LAMA-LABA-ICS) rather than other options (Grade 2B). The beneficial effects of inhaled glucocorticoids appear to be most robust in those with higher levels of blood eosinophils (eg, ≥300 cells/microL); those with very low baseline blood eosinophilia (<100 cells/microL) are least likely to benefit. (See 'Exacerbations on LAMA-LABA therapy' above and 'Exacerbations on LABA-ICS' above.)

-Additional treatment options for refractory exacerbations include dupilumab, a macrolide (ie, azithromycin), roflumilast, or ensifentrine, with the choice guided by disease phenotype and severity, patient comorbidities and tolerance of side effects (algorithm 4). (See 'Exacerbations on LAMA-LABA-ICS' above and "Management of refractory chronic obstructive pulmonary disease", section on 'Recurrent exacerbations'.)

ACKNOWLEDGEMENTS — 

The UpToDate editorial staff acknowledges Gary T Ferguson, MD, and Barry Make, MD, who contributed to earlier versions of this topic review.