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Stable COPD: Initial pharmacologic management

Stable COPD: Initial pharmacologic management
Authors:
Gary T Ferguson, MD
Barry Make, MD
Section Editor:
James K Stoller, MD, MS
Deputy Editor:
Paul Dieffenbach, MD
Literature review current through: Dec 2022. | This topic last updated: Mar 18, 2022.

INTRODUCTION — Chronic obstructive pulmonary disease (COPD) is a common condition with high morbidity and mortality, affecting males and females equally. It is estimated 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 the fourth leading cause of death among adults in the United States and is the third leading cause of death worldwide [4,5].

The initial pharmacologic management of stable COPD will be reviewed here. The clinical manifestations, diagnosis, comorbidities, monitoring, and prognosis of COPD, an overview of COPD management, and the management of refractory COPD and acute exacerbations of COPD are discussed separately. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging" and "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions" and "Stable COPD: Overview of management" and "Chronic obstructive pulmonary disease: Risk factors and risk reduction" and "Stable COPD: Follow-up pharmacologic management" and "Management of refractory chronic obstructive pulmonary disease" and "COPD exacerbations: Management".) (Related Pathway(s): Chronic obstructive pulmonary disease: Initial diagnosis and Chronic obstructive pulmonary disease: Severity assessment and selection of initial therapy in adults.)

ASSESSING DISEASE PATTERN AND SEVERITY — A multi-component assessment system has been developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to guide initiation of therapy for COPD [6]. The GOLD system categorizes patients based on assessment of symptoms and risk of future exacerbations and hospitalizations. (Related Pathway(s): Chronic obstructive pulmonary disease: Severity assessment and selection of initial therapy in adults.)

Symptoms and risk of exacerbations — Each patient is classified as being in one of four groups (A,B,C,D), as described in the table (table 1) [6]. Symptoms are assessed using a validated instrument, the modified Medical Research Council (mMRC) dyspnea scale (table 2) or the COPD Assessment Test (CAT) [6-9]. Exacerbation risk is based on the patient’s history of exacerbations in the past year; two or more exacerbations requiring antibiotics and/or systemic glucocorticoids or one or more COPD hospitalizations indicate a greater risk of future exacerbations [6,10,11].

The symptom and risk components are combined into four groups as follows (table 3):

●Group A: Minimally symptomatic, low risk of future exacerbations: mMRC grade 0 to 1 or CAT score <10; 0 to 1 exacerbation per year and no prior hospitalization for exacerbation

●Group B: More symptomatic, low risk of future exacerbations: mMRC grade ≥2 or CAT score ≥10; 0 to 1 exacerbation per year and no prior hospitalization for exacerbation

●Group C: Minimally symptomatic, high risk of future exacerbations: mMRC grade 0 to 1 or CAT score <10; ≥2 exacerbations per year or ≥1 hospitalization for exacerbation

●Group D: More symptomatic, high risk of future exacerbations: mMRC grade ≥2 or CAT score ≥10; ≥2 exacerbations per year or ≥1 hospitalization for exacerbation

Spirometry — Although the severity of the decrement in forced expiratory volume in one second (FEV1) is inversely associated with COPD exacerbation risk, FEV1 alone does not predict risk of exacerbations for individual patients. For this reason, FEV1 is no longer included in the ABCD assessment categories [6].

Spirometry measurement of the presence and severity of airflow limitation (based on an FEV1 to forced vital capacity (FVC) ratio <0.7 and FEV1 percent predicted (table 3) are required to confirm the diagnosis of COPD and to calculate the BODE index. The multidimensional BODE index can be used to assess an individual's risk of death or hospitalization due to COPD (calculator 1), but is not recommended by GOLD as a guide to therapy [6]. Spirometry also remains important to monitor disease progression and to assess other areas of COPD care, including surgical risk and the potential role of surgical interventions for COPD. (See "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging", section on 'Assessment of severity and staging'.)

GENERAL PRINCIPLES — Pharmacologic therapy for COPD should not be employed alone. Rather, pharmacotherapy should be initiated along with non-pharmacologic management. (See "Stable COPD: Overview of management" and "Pulmonary rehabilitation".)

We share the philosophy of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) that the aim of therapy is to improve patient symptoms, decrease exacerbations, and improve patient function and quality of life and that therapy should be guided at least in part by disease severity [6]. The initial selection of a pharmacologic agent is based on the severity of symptoms and risk of exacerbations (table 1) (see 'Symptoms and risk of exacerbations' above); therapy is adjusted at follow-up visits based on the clinical response to current therapy. (See "Stable COPD: Follow-up pharmacologic management".).

In the following sections, initial pharmacologic therapy for COPD and the supportive clinical evidence are reviewed. Initial therapy is guided by the severity of symptoms and risk of future exacerbations (table 1). At follow-up visits, pharmacotherapy is adjusted depending upon the level of symptoms, risk of exacerbations, and response to therapy (table 4) (see "Stable COPD: Follow-up pharmacologic management"). However, for patients who present with more severe disease, a stepwise approach may not always be the best choice, as it may be appropriate to initiate more than one medication to achieve symptom and exacerbation control.

The mainstays of drug therapy for stable symptomatic COPD are inhaled bronchodilators (beta agonists and muscarinic antagonists) given alone, in combination, or with addition of inhaled glucocorticoids. These are generally administered via hand held inhalation in the form of metered dose, soft mist, or dry powder inhalers, although some patients may benefit from therapy administered by nebulization (eg, albuterol, formoterol, arformoterol, ipratropium, glycopyrronium, revefenacin, budesonide).

It is important to recognize that the GOLD therapeutic strategy attempts to create a graded approach to COPD management using the best available clinical information, although none of the recommendations for treatment advised for the GOLD “ABCD” groups has been rigorously studied within the context of the GOLD treatment groups. Indeed, most COPD treatment studies have tested therapeutic value of a given medication across a wide range of patients and the given treatment value and impact on a specific GOLD “ABCD” group has only, at best, been assessed with post-hoc study analysis.

MINIMALLY SYMPTOMATIC, LOW RISK OF EXACERBATION (GROUP A) — For all patients with COPD, we recommend that a short-acting bronchodilator be used as-needed for relief of intermittent increases in dyspnea [6]. If patients have minimally symptomatic COPD and are at low risk of exacerbation (ie, modified Medical Research Council [mMRC] grade 0 to 1 or COPD Assessment Test [CAT] score <10; and 0 to 1 exacerbation per year), this is usually the only medication needed (table 1) [6].

Bronchodilators have been consistently shown to induce long-term improvements in symptoms, exercise capacity, and airflow limitation. Spirometric improvement or lack thereof following a single dose of a short-acting bronchodilator does not predict long-term response to long-acting bronchodilators [12-16].

Short-acting bronchodilators — Short-acting beta agonists and short-acting muscarinic antagonists (anticholinergic) can be used alone or in combination for relief of intermittent symptoms of COPD. All of the short-acting bronchodilators improve symptoms and lung function. The advantage of short-acting bronchodilators is their rapid onset of action; the disadvantage for patients with more frequent symptoms is the relatively short duration of action, about four to six hours.

Combination therapy is often preferred because the combination of a short-acting beta agonist plus a short-acting muscarinic antagonist achieves a greater bronchodilator response than either one alone [17]. However, monotherapy with either agent is acceptable.

Beta agonists — Short-acting beta agonists include albuterol and levalbuterol. They have been proven in randomized trials and meta-analyses to improve symptoms and lung function [18].

In general, short-acting beta agonists are prescribed on an as-needed basis, rather than regularly scheduled, in order to decrease sympathomimetic exposure in patients with less severe symptoms.

One trial randomly assigned 53 patients with COPD to receive regularly scheduled albuterol or placebo, while continuing ipratropium bromide, inhaled glucocorticoid, and as-needed albuterol [19]. Regularly scheduled albuterol doubled the total amount of albuterol received without a clinically significant impact on lung function, symptoms, or exercise capacity.

Inhaled short-acting beta agonists are generally felt to be safe when used at the recommended doses. However, a nested case control study of 76,661 patients with COPD found an increased rate of severe cardiac arrhythmia among those with new use of oral or inhaled short-acting beta agonist (RR 1.27, 95% CI 1.03-1.57) [20]. Unfortunately, the retrospective design does not allow assessment of confounders such as ongoing cigarette smoking, underlying cardiac disease, use of the oral or inhaled agent, and whether the arrhythmia occurred at a time of exacerbation or other excess use of the beta agonist, thus limiting the conclusions that can be drawn.

Most recommended doses of beta agonists (both short-acting and long-acting) result in less than the maximal bronchodilation that can be achieved with a higher dose of beta-agonists or a combination of beta-agonist and antimuscarinic agents. Risks of beta-agonist overuse are possible if an individual attempts to achieve maximal bronchodilation by using higher doses. These risks include tremor and reflex tachycardia due, in part, to peripheral arterial dilation. Hypokalemia can also occur in extreme cases and should be monitored in patients at risk. (See "Causes of hypokalemia in adults", section on 'Elevated beta-adrenergic activity' and "Management of the patient with COPD and cardiovascular disease" and "Arrhythmias in COPD".)

Oral beta-2 agonists are generally not prescribed because their incidence of side effects is particularly high and they are less effective bronchodilators.

Muscarinic antagonists — Short-acting muscarinic antagonist (SAMA; also known as anticholinergic) medications improve lung function and reduce symptoms. As an example, among 183 patients with moderate to severe COPD, ipratropium improved lung function and decreased dyspnea compared with placebo [21]. The usual dose of ipratropium MDI (17 mcg/actuation) is two inhalations (34 mcg) four to six times per day as needed. The usual dose of ipratropium solution for nebulization (0.5 mg/2.5 mL vial) is one vial every four to eight hours as needed. As-needed and regularly scheduled dosing regimens of short-acting muscarinic antagonists have not been compared. (See "Role of muscarinic antagonist therapy in COPD".)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy suggests the use of a short-acting bronchodilator (as needed) in less symptomatic, low risk COPD patients (group A), rather than a long-acting muscarinic antagonist (LAMA) [6]. However, in a multicenter randomized trial, 841 patents with minimally symptomatic COPD (forced expiratory volume in one second [FEV1] ≥50 percent predicted) were assigned to tiotropium 18 mcg or placebo once daily [22]. After 24 weeks, the FEV1 was higher in the tiotropium group (between group difference 157 mL [95% CI, 123-192]). Acute exacerbations of COPD were also improved with tiotropium (0.27 versus 0.50 events per patient-year; risk ratio, 0.53, 95% CI 0.39-0.73). Further study is needed to assess longer term outcomes before expanding the role of LAMAs in these patients.

Comparison — Albuterol and ipratropium have been compared in randomized trials [17,23,24]. On average, both medications improve lung function to a similar degree, although the effects may vary [25]. Side effects are unique to each medication class, but are minimal at commonly prescribed doses. (See "Role of muscarinic antagonist therapy in COPD", section on 'Potential risks'.)

Combination therapy — The combination of ipratropium-albuterol (20 mcg-100 mcg/actuation) in a soft mist inhaler (SMI) can be administered one inhalation every four to six hours as needed. The solution for nebulization (ipratropium 0.5 mg-albuterol 2.5 mg per 3 mL vial) can be administered as one vial every four to six hours as needed.

The degree of bronchodilation achieved by short-acting beta agonists and muscarinic antagonists is additive, especially when typically recommended (submaximal) doses of each agent are combined [6,17,24]. As an example, the largest trial randomly assigned 534 patients with COPD to receive albuterol alone, ipratropium alone, or combination therapy (albuterol plus ipratropium) [17]. Combination therapy increased the mean peak FEV1 more than either agent alone, but did not alter the frequency of exacerbations. A similar study reported that combination therapy decreased the frequency of exacerbation compared with albuterol, but not ipratropium [24].

MORE SYMPTOMATIC, LOW RISK OF EXACERBATION (GROUP B) — For patients who are more symptomatic, but at low risk of exacerbation based on their past history of exacerbations (ie, modified Medical Research Council [mMRC] grade ≥2 or COPD Assessment Test [CAT] score ≥10; 0 to 1 exacerbation per year), we recommend regular use of a long-acting bronchodilator, in addition to a short-acting bronchodilator (beta agonist or antimuscarinic agent) prescribed for as-needed relief of intermittent increases in dyspnea (table 1) [6,26]. Long-acting bronchodilators have been shown to be superior to short-acting bronchodilators taken on a regular basis.

Either a long-acting beta agonist (LABA) or a long-acting muscarinic antagonist (LAMA; also known as long-acting anticholinergic agent) is acceptable for patients with group B COPD [6]. Initial selection between a LAMA or LABA is often based on patient specific needs, comorbidities, and adverse effects. (See 'Selection of LAMA versus LABA' below.)

For patients taking a LAMA, we prescribe a short-acting beta agonist (SABA) for rescue use [27]; for those taking a LABA, we usually prescribe either a SABA or a combination short-acting muscarinic antagonist (SAMA)-SABA for rescue use.

Selection of LAMA versus LABA — The efficacy and safety of LABAs and LAMAs have been compared in meta-analyses and randomized trials [28-31]; most of the research has involved tiotropium as the LAMA. Overall efficacy and safety appear comparable in terms of symptom control. Both LAMAs and LABAs reduce exacerbations, but LAMAs have a greater effect. (See 'Initial therapy with a LAMA' below.)

Individual patients may prefer one bronchodilator over the other. As an example, some patients may experience a resting tachycardia or somatic tremor with LABA therapy and therefore prefer a LAMA. Alternatively, LAMAs are associated with dry mouth that can be bothersome; rinsing the mouth after use may reduce this effect. Symptoms of urinary retention have occasionally been reported with LAMA, so a LABA may be preferred for patients prone to urinary retention. (See "Arrhythmias in COPD", section on 'Beta-adrenergic agonists' and "Role of muscarinic antagonist therapy in COPD", section on 'Potential risks'.)

●Efficacy – A meta-analysis included seven trials (12,223 participants) comparing tiotropium with various LABAs (salmeterol, formoterol, and indacaterol) [30]. No significant difference was noted in improvements in quality of life or dyspnea between tiotropium and the various LABAs. The meta-analysis concluded that the small number of studies and variability (heterogeneity) in the results prevented determination of which agent would lead to a greater long-term benefit. The effect on exacerbations is described below. (See 'Initial therapy with a LAMA' below.)

●Possible cardiovascular adverse effects – The possibility that LABAs or LAMAs might have different profiles for adverse cardiovascular effects has been examined. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial identified no significant safety issues with the use of tiotropium over four years [32], although other studies have reported conflicting data. (See 'Long-acting muscarinic antagonists' below and "Role of muscarinic antagonist therapy in COPD", section on 'Cardiovascular effects'.)

•In a nested case-control analysis, 26,628 patients age 66 or older with COPD who had a hospitalization or emergency room visit for a cardiovascular event were matched to controls with similar age and COPD severity who had no cardiovascular events [33]. Newly prescribed LABAs or LAMAs were associated with a greater likelihood of cardiovascular events compared with nonuse of these agents (adjusted odds ratios, 1.31 [95% CI 1.12-1.52] and 1.14 [1.01-1.28], respectively). However, confounding by susceptibility or disease severity is likely and cannot be excluded. No significant difference was noted between the two classes of bronchodilators.

•Indacaterol, a once daily LABA, was compared with tiotropium in a 26 week trial in which 1683 patients were randomly assigned to indacaterol 150 or 300 mcg, placebo, or open label tiotropium once daily [34]. Comparable results in forced expiratory volume in one second (FEV1), dyspnea, and quality of life were obtained in all of the active treatment arms. The incidence of adverse events, such as low serum potassium, high blood glucose, cardiac events, and prolonged QTc interval, was similar across treatments.

Both salmeterol alone and tiotropium alone have been compared with the combination of a long-acting bronchodilator plus a glucocorticoid. (See 'Alternative choice LABA-ICS' below.)

Long-acting beta agonists — LABAs include salmeterol, formoterol, arformoterol, indacaterol, vilanterol, and olodaterol; all are beta-2 selective (table 5). Arformoterol is only available as a solution for nebulization; vilanterol is only available as a component of a combination product. Multiple studies have demonstrated the benefit of LABAs in patients with stable COPD [13,35-42].

●Salmeterol – Salmeterol is the most studied of the LABAs and is administered by dry powder inhaler (50 mcg/actuation) one inhalation twice daily. The largest trial of salmeterol, Toward a Revolution in COPD Health (TORCH), randomly assigned 6112 patients with mostly severe COPD (mean FEV1 44 percent of predicted (table 3)) to one of four treatment arms for three years: salmeterol alone (50 mcg twice daily), fluticasone alone (500 mcg twice daily), combination therapy (salmeterol plus fluticasone), or placebo [38]. Salmeterol significantly decreased exacerbation rates, improved lung function, and improved health-related quality of life compared with placebo. Although not designed to evaluate survival, the study found no increase in mortality with salmeterol compared with placebo, supporting the safety of this LABA.

●Formoterol and arformoterol – Formoterol is a twice daily LABA with a rapid onset of action (median time to onset of bronchodilation 12 minutes) [42]. It is available as a single agent DPI in Canada and Europe. In the United States, it is available as a solution for nebulization (20 mcg/2 mL vial, 1 vial twice daily) and as a component in combination LAMA-LABA and LABA-glucocorticoid inhalers.

Arformoterol is available as a solution for nebulization, 15 mcg/2 mL vial, 1 vial twice daily [43].

●Indacaterol – Indacaterol is a once-daily LABA for the treatment of COPD; it has a rapid onset and long duration of action [34,44-52]. Indacaterol is approved by the US Food and Drug Administration (FDA), but is not currently available in the United States. The dose of indacaterol approved for use in the United States and Canada (75 mcg/capsule; once daily) is lower than the doses approved for Europe (150 and 300 mcg) [53]. The 75 mcg dose was selected in the United States after an analysis of studies of trough (24 hour) FEV1 at 12 weeks showed no significant difference between the 75 and 150 mcg doses of indacaterol, and doses higher than 75 mcg did not further improve quality of life measures [53]. In an analysis of 23 trials and 11,755 patients with COPD, no increase in adverse events was noted with the 75 mcg and 150 mcg doses of indacaterol relative to placebo, but a possible increase in asthma exacerbations and respiratory-related deaths was noted at 300 mcg [53].

Randomized trial data show that indacaterol improves lung function [34,44,51,54]. The largest trial randomly assigned 1683 patients with moderate-to-severe COPD to once daily indacaterol 150 or 300 mcg, placebo, or tiotropium [34]. Patients who were taking inhaled glucocorticoids at baseline (36 percent) continued on the same dose throughout the study. At week 12, the FEV1 at 24 hours post dose (ie, trough) increased by 180 mL over placebo with indacaterol (both 150 and 300 mcg) and by 140 mL over placebo with tiotropium. An extension of this study [34], which included 415 patients who continued to receive one of the two indacaterol doses or placebo, found that the increased trough FEV1 (≥170 mL) associated with indacaterol use persisted through week 52 [44]. In addition, both doses of indacaterol were associated with a decrease in the exacerbation rate relative to placebo and a modest decrease in the use of albuterol. Approximately 24 percent of those using indacaterol had a transient cough occurring within five minutes of inhalation.

Indacaterol is a substrate of CYP3A4 and the P-glycoprotein transporter; however, interactions with agents that inhibit these pathways are not felt to be clinically significant in the prescribed dose range.

●Olodaterol – Olodaterol, another once-daily LABA with a rapid onset and long duration of action, is delivered as two inhalations (2.5 mcg/actuation) via a soft mist inhaler and is approved for the treatment of COPD [55]. In two trials that included a total of 1838 subjects with moderate-to-severe COPD, 24 weeks of olodaterol therapy resulted in significant improvements in airflows, including peak and trough FEV1, and quality of life, compared with placebo [56]. Similar results were seen in a separate pair of trials of 48 weeks’ duration that included 1266 patients [57]. In all reports, adverse events with olodaterol were comparable to those of placebo [55-58]. (See "The use of inhaler devices in adults", section on 'Soft mist inhaler technique'.)

●Vilanterol – Vilanterol is a once-daily LABA with a rapid onset of action that has been developed for use in combination inhalers with umeclidinium or fluticasone furoate. Vilanterol is not available for use as a monotherapy [59,60]. Its use in combination inhalers with either umeclidinium or fluticasone is discussed below. (See 'LAMA-LABA for severe breathlessness' below and 'Alternative choice LABA-ICS' below.)

The potential association of LABA use with hospitalization or death due to a cardiac arrhythmia was examined in a nested case-control study of 76,661 patients aged ≥67 years with COPD [20]. The risk of an arrhythmia was increased among those with new use of a LABA (RR 1.27, 95% CI 1.03-1.57), but lost significance when patients with a history of arrhythmia or heart failure were excluded (RR 1.57, 95% CI 0.98-2.54). The observed effects waned with longer term use. As noted above, the study has methodologic flaws related to its retrospective design. (See 'Beta agonists' above.)

Long-acting muscarinic antagonists — The LAMAs (also known as long-acting anticholinergic medications) include tiotropium, aclidinium, umeclidinium, and glycopyrrolate (also called glycopyrronium) (table 6). These agents are discussed in greater detail separately. (See "Role of muscarinic antagonist therapy in COPD".)

●Tiotropium – Tiotropium, the most studied LAMA, is available as a dry powder inhaler (18 mcg/capsule; inhale contents of one capsule once daily) and as a soft mist inhaler (2.5 mcg/actuation; two inhalations once daily). It improves lung function and decreases dynamic hyperinflation (an effect also seen with other medications), while also decreasing dyspnea and exacerbations [28,37,61-65]. In addition, it improves trough lung function (ie, 24 hours after the last dose) and reduces hyperinflation, indicating that its effects are long-lasting [66]. Tiotropium may slow the rate of decline in FEV1 over time [66-69]. Tiotropium is largely excreted by the kidneys; patients with kidney impairment should be monitored for anticholinergic adverse effects, although data on safety are reassuring [70]. (See "Role of muscarinic antagonist therapy in COPD", section on 'Tiotropium'.)

●Aclidinium – Aclidinium is available as a dry powder inhaler (400 mcg/actuation, one inhalation twice a day). (See "Role of muscarinic antagonist therapy in COPD", section on 'Aclidinium'.)

●Umeclidinium – Umeclidinium (62.5 mcg/actuation) is available as a dry powder inhaler, administered one inhalation, once daily. (See "Role of muscarinic antagonist therapy in COPD", section on 'Umeclidinium'.)

●Glycopyrrolate – Glycopyrrolate (also known as glycopyrronium) is available outside the United States as a dry powder inhaler (eg, 50 mcg/capsule used once daily or 25 mcg/capsule used twice daily) (table 7), depending on the region of approval. It is available in the United States as a solution for nebulization (25 mcg/1 mL vial) one vial twice daily, but requires a specialized nebulizer. (See "Role of muscarinic antagonist therapy in COPD", section on 'Glycopyrronium'.)

●Revefenacin – Revefenacin is available as a solution for nebulization. It is administered once daily (175 mcg/3 mL vial, 1 vial once daily via a standard jet nebulizer). (See "Role of muscarinic antagonist therapy in COPD", section on 'Revefenacin'.)

Conflicting evidence has suggested possible adverse cardiovascular effects of inhaled muscarinic antagonist therapy in patients with COPD. However, data from a long-term, randomized trial (UPLIFT) identified no significant safety issues with the use of tiotropium over four years [32]. Reassuring data also come from the ASCENT-COPD trial, which was performed in 3589 subjects with moderate to very severe COPD and increased risk of cardiovascular events and did not find an increased risk of cardiovascular events with aclidinium compared with placebo [71]. (See "Role of muscarinic antagonist therapy in COPD", section on 'Cardiovascular effects'.)

Concern has also been raised about a potential increase in cardiovascular adverse effects associated with the Respimat soft mist inhaler compared with the Handihaler dry powder inhaler, both containing tiotropium. However, a large randomized trial, the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial, revealed no safety issues with the device and is reassuring about the safety of the Respimat device [72]. These issues are discussed in greater detail separately. (See "Role of muscarinic antagonist therapy in COPD", section on 'Potential risks'.)

Alternate choices — For patients with more severe breathlessness (eg, CAT ≥20) at the time of presentation, initial therapy with a LAMA-LABA combination may provide greater relief of breathlessness (table 8) (see 'LAMA-LABA for severe breathlessness' below) [6]. In contrast, occasional patients with less severe breathlessness may prefer regular use of short-acting bronchodilators despite needing to use them several times a day to relieve symptoms. However, frequent short-acting bronchodilator use has not been shown to have the same patient efficacies as long-acting bronchodilators. (See 'Combination therapy' above.)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy includes theophylline as an inexpensive, but not recommended, alternative to the above described long-acting inhaled bronchodilators [6]. We do not recommend regular use of short-acting bronchodilators or theophylline, unless the preferred alternatives are unavailable. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Theophylline'.)

For patients with ACO, symptoms may be better controlled with a combination long-acting beta agonist plus inhaled glucocorticoid, than with dual bronchodilator therapy. Features that can be used to identify patients with ACO are discussed separately [73]. (See 'Alternative choice LABA-ICS' below and "Asthma and COPD overlap (ACO)".)

MINIMALLY SYMPTOMATIC, HIGH RISK OF EXACERBATION (GROUP C)

Initial therapy with a LAMA — For the uncommon patients who are minimally symptomatic on a day-to-day basis (ie, modified Medical Research Council [mMRC] grade 0 to 1 or COPD Assessment Test [CAT] score <10), but are at high risk of an exacerbation due to their history of exacerbations in the past year (ie, ≥2 exacerbations per year with one or more leading to hospitalization), we suggest initial treatment with a long-acting muscarinic antagonist (LAMA) due to the reduced exacerbation rate associated with LAMAs (table 1 and table 6) [6].

The effect of LAMAs on reducing exacerbations is illustrated in the following analyses:

●A meta-analysis included seven trials (12,223 participants) comparing tiotropium with salmeterol, formoterol, or indacaterol [30]. Tiotropium was more effective at reducing exacerbations (OR 0.86, 95% CI 0.79-0.93). However, no statistically significant differences were noted in overall hospitalizations or mortality.

●In the largest comparison trial, 7376 patients with moderate to severe COPD were randomly assigned to tiotropium or salmeterol with or without concomitant inhaled glucocorticoids [29]. Tiotropium increased the time to the first exacerbation of COPD and reduced the risk of developing an exacerbation by 17 percent (hazard ratio 0.83, 95% CI 0.77-0.90).

●Among 3444 patients with severe COPD and at least one exacerbation in the previous year, tiotropium provided better protection against exacerbations over the next year than indacaterol (ratio 1.29 [one-sided 97.5% CI upper limit 1.44]) [74].

The various LAMAs and their dosing are described above (table 6). (See 'Long-acting muscarinic antagonists' above.)

MORE SYMPTOMATIC, HIGH RISK OF EXACERBATION (GROUP D)

Initial therapy with LAMA — For patients with a higher symptom burden (ie, modified Medical Research Council [mMRC] grade ≥2 or COPD Assessment Test [CAT] score ≥10) and a high risk of exacerbation (ie, ≥2 exacerbations per year with one or more leading to hospitalization), we suggest initial treatment with a long-acting muscarinic antagonist (LAMA), as a LAMA alone will reduce dyspnea and exacerbations in most such patients; a LAMA-long-acting beta agonist (LABA) combination is a reasonable alternative for patients with severe dyspnea (eg, CAT ≥20) (table 1) [6]. (See 'Long-acting muscarinic antagonists' above and 'Initial therapy with a LAMA' above and 'LAMA-LABA for severe breathlessness' below.)

Alternatively, for patients with a blood eosinophil count ≥300 cells/microL or features of asthma-COPD overlap, a LABA-inhaled glucocorticoid (ICS) may be selected [6]. (See 'Initial therapy with a LAMA' above and "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, in patients on inhaled corticosteroids or with exacerbations'.)

LAMA-LABA for severe breathlessness — Clinical trials in support of combined LAMA-LABA therapy for patients with severe breathlessness generally show added value to dual bronchodilation for relief of dyspnea, although results vary depending on the specific agents and end-points (table 8) [6,75-85].

Use of fixed dose LAMA-LABA combinations, rather than two separate inhalers, may be preferred due to a potential for improved adherence, which may lead to improved outcomes and reduced costs (table 8) [86,87]. In general, dual bronchodilator therapies do not show any additional risks in their safety profiles as compared with their monotherapies.

Comparison with single bronchodilator — A systematic review and meta-analysis of 10 trials (10,894 participants) that assessed combination bronchodilator therapy with tiotropium (LAMA) plus a LABA (salmeterol, formoterol, or indacaterol) found a slightly better quality of life and a small increase in the post-bronchodilator FEV1 with the combination compared with tiotropium alone [75]. Adding tiotropium to a LABA reduced exacerbations, while adding a LABA to tiotropium did not. No difference was noted in other end-points, such as hospital admissions, mortality, symptom scores, and serious adverse events.

Studies of various other combinations include the following:

●Tiotropium-olodaterol – A combination tiotropium-olodaterol (2.5 mcg-2.5 mcg/actuation) two inhalations once daily delivered via soft mist inhaler is approved for use in COPD, in the United States. The efficacy of tiotropium-olodaterol was compared with the individual agents in two replicate 24 week trials with a total of 5162 patients with moderate to very severe COPD [78]. The combination inhaler achieved greater increases in trough forced expiratory volume in one second (FEV1) and FEV1 area under the curve over 0 to 3 hours compared with its mono-components. In two other replicate trials (1621 participants; 12 weeks), tiotropium-olodaterol (5 mcg-5 mcg) improved health status, measured by St George's Respiratory Questionnaire, by a clinically meaningful difference (4.89 and 4.56 units), compared with placebo [88].

●Umeclidinium-vilanterol – A combination umeclidinium-vilanterol (62.5 mcg-25 mcg/actuation) dry powder inhaler has been approved for use in COPD in the United States, at a dose of one inhalation once daily [81,89-91]. The efficacy of umeclidinium-vilanterol (62.5 mcg-25 mcg) was compared with the individual agents and with placebo in a 24 week trial [89]. The combination inhaler achieved greater increases in trough FEV1 and mean peak FEV1 (over the six hours after dosing) compared with its monocomponents and placebo. A meta-analysis of umeclidinium-vilanterol reported that the number of patients with at least one COPD exacerbation was less in the combination group compared with the monocomponents (vilanterol [RR 0.72, 95% CI 0.54-0.95] and umeclidinium [RR 0.74, 95% CI 0.54-0.98]), but is not different compared with tiotropium or fluticasone-salmeterol [81].

●Glycopyrronium-indacaterol – A once-daily, dry powder inhaler, containing the combination of glycopyrronium-indacaterol (43 mcg-85 mcg/capsule), is approved for use in Europe and Japan [92]. The glycopyrronium-indacaterol combination inhaler was found to be superior to monotherapy with glycopyrronium, indacaterol, or tiotropium in terms of trough FEV1 and decreased use of rescue medication [79].

A twice daily, dry powder inhaler containing glycopyrrolate-indacaterol (15.6 mcg-27.5 mcg) is approved by the US Food and Drug Administration (FDA) for the treatment of COPD, but is not available [93]. By United States labeling convention, the "glycopyrrolate" dose includes the molecular weight of the bromide base, so 15.6 mcg equals approximately 12.5 mcg of glycopyrrolate, the active drug (table 7). In contrast, labels in Europe and Canada express the dose in mcg of glycopyrronium. In all countries, the inhalation powder is formulated as a bromide salt. The glycopyrrolate-indacaterol (15.6 mcg-27.5 mcg) preparation, which contains lower medication doses than the product approved in Europe and Japan, was examined in 2038 patients with moderate-to-severe COPD in parallel randomized trials [94]. Significant benefits were noted in lung function, health-related quality of life, and dyspnea compared with the individual components or placebo.

A trial comparing the effect of glycopyrronium-indacaterol versus fluticasone-salmeterol is described below. (See 'Comparison with LABA-ICS' below.)

As with tiotropium, glycopyrronium containing therapies are excreted by the kidney and their use in patients with severe kidney impairment should be based on expected benefits versus potential risks [95]. Patients with kidney impairment should be monitored for anticholinergic adverse effects. (See 'Long-acting muscarinic antagonists' above.)

●Glycopyrrolate-formoterol – A combination metered dose inhaler containing glycopyrrolate and formoterol (9 mcg-4.8 mcg/actuation) is approved by the FDA for the treatment of COPD at a dose of 2 inhalations twice daily [96]. In parallel randomized trials, glycopyrrolate-formoterol was compared with placebo and the individual components [97]. The mean peak increases from baseline in FEV1 over 24 weeks compared with placebo were 291 mL (95% CI, 252-331) and 267 mL (95% CI, 226-308) in trials 1 and 2, respectively.

●Aclidinium-formoterol – A combination, dry powder inhaler containing aclidinium-formoterol (400 mcg-12 mcg/actuation; one inhalation twice daily) is approved for use in the United States, Europe, the United Kingdom, and Canada. In clinical trials, aclidinium-formoterol improved airflows and dyspnea compared with either of the individual agents alone or placebo [80,83,98,99]. The combination also decreased the rate of moderate-severe exacerbations relative to placebo [80].

Fixed-dose LAMA-LABA combinations (FDC) reduce exacerbations in some studies, but not all are FDA approved for the indication of reducing the risk of exacerbations in patients with a history of COPD exacerbations.

Comparison with LABA-ICS — The preference for using LAMA-LABA therapy over a LABA-ICS combination is largely based on evidence of improved lung function, better control of mild exacerbations, and fewer episodes of pneumonia (and other ICS adverse effects), although improvement in symptoms varies among studies [6,100,101]. However, LABA-ICS combinations have demonstrated reductions in mortality and exacerbations compared with single bronchodilator therapy. (See 'Efficacy and adverse effects' below.).

In a multicenter trial, glycopyrronium-indacaterol (50 microg/110 microg, once daily) was compared with fluticasone-salmeterol (500 microg/50 microg, twice daily) in 3362 patients with moderate-to-severe COPD characterized by higher dyspnea scores and a history of at least one moderate-severe exacerbation in the previous year [100]. Over the 52 week trial, glycopyrronium-indacaterol reduced the rate of mild-severe COPD exacerbations by 11 percent compared with fluticasone-salmeterol (rate ratio 0.89 [95% CI, 0.83-0.96]). Importantly, patients with a history of two or more moderate exacerbations or one hospitalization in the previous year had similar exacerbation rates between the two treatment arms. Glycopyrronium-indacaterol was associated with slightly fewer episodes of pneumonia (3.2 percent) compared with fluticasone-salmeterol (4.8 percent).

Alternative choice LABA-ICS — For patients who have frequent COPD exacerbations (eg ≥2/year) and/or blood eosinophils ≥300 cells/microL, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy suggests regular treatment with a LABA-ICS combination as an alternative (table 1 and table 9) [6,26,102]. It is reasonable to add the ICS component for a trial period (eg one to three months) and discontinue it, if symptoms, frequency of exacerbations, and/or lung function fail to improve. (See "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, in patients on inhaled corticosteroids or with exacerbations'.)

Efficacy and adverse effects — Combination LABA-ICS therapy significantly improves outcomes compared with placebo, LABA alone, or ICS alone [38,103-106]. Support for these conclusions comes from the two largest trials of combination therapy [38,105]. In the Toward a Revolution in COPD Health (TORCH) trial described above (6112 patients with moderate to severe COPD), salmeterol plus fluticasone significantly improved the secondary end points of lung function, health status, and the rate of exacerbations compared with placebo, salmeterol alone, or fluticasone alone [38]. (See 'LAMA-LABA for severe breathlessness' above.)

With respect to the primary end point of the TORCH trial, a reduction in mortality rate over three years, salmeterol plus fluticasone minimally decreased mortality compared with placebo (10.3 versus 12.6 percent, hazard ratio 0.81, 95% CI 0.67-0.98). While this is only of borderline statistical significance, the actual effect on mortality may be larger than reported; in the intention to treat analysis, sicker patients in the placebo group may have left the trial, seeking active treatment. The risk of death in the combination group did not differ from that in the salmeterol alone group (hazard ratio 0.95), but was significantly lower than the fluticasone alone group (hazard ratio 0.77, 95% CI 0.64-0.93).

The second large trial of combination LABA-ICS therapy (Investigating New Standards for Prophylaxis in Reduction of Exacerbations [INSPIRE]) included 1323 patients with stable, mostly severe COPD (mean forced expiratory volume in one second [FEV1] 39 percent of predicted (table 3)) who were randomly assigned to receive salmeterol plus fluticasone (50 and 500 mcg/puff, respectively) or tiotropium alone for two years [105]. There was no difference in the frequency of exacerbations, which was the primary endpoint, although salmeterol plus fluticasone improved several secondary endpoints, including mortality (HR for time to death 0.48, 95% CI 0.27-0.85) and health status. On the other hand, a subsequent analysis of this trial found that pneumonia was substantially more frequent in the salmeterol plus fluticasone group (HR for time to first pneumonia 1.94, 95% CI 1.19-3.17), despite the lower mortality [107]. Whether a lower strength preparation of fluticasone would have a similarly beneficial effect on mortality without the adverse effect on pneumonia is not known, although a prior study using the 250 mcg strength of fluticasone in combination with salmeterol reported a similar increase in the number of pneumonias compared with salmeterol alone [102]. These data are insufficient to warrant a change in the current guidelines in which the first step is initiation of a long-acting bronchodilator alone rather than the combination of a LABA plus an ICS [108]. (See 'Initial therapy with LAMA' above.)

Adverse effects associated with ICS (eg, pneumonia, oropharyngeal candidiasis, cataracts, and increased risk of osteoporosis) are discussed in greater detail separately. (See "Major side effects of inhaled glucocorticoids".)

LABA-ICS preparations versus LABA — In addition to fluticasone-salmeterol, other twice-daily combination inhalers include budesonide-formoterol and mometasone-formoterol (off-label for COPD) [109,110]. A once daily dry powder inhaler, containing fluticasone furoate and vilanterol, 100/25 mcg per inhalation, is also available [111-113].

●A multicenter controlled effectiveness trial randomly assigned 2799 patients with COPD to once daily fluticasone furoate-vilanterol (FF-V, 100 mcg-25 mcg) or usual care for one year [113]. The rate of moderate-to-severe exacerbations was lower in the FF-V group by 8 percent (95% CI 1.1-15.2). No significant excess in pneumonia (incidence ratio 1.1, 95% CI 0.9-1.5) or other serious adverse events was noted with FF-V.

●In a multicenter, 24-week trial, 1224 subjects with stable moderate-to-severe COPD were randomly assigned to fluticasone furoate-vilanterol (200/25 mcg, 100/25 mcg), fluticasone furoate (200 mcg, 100 mcg), vilanterol (25 mcg), or placebo inhalation once daily in the morning [114]. Vilanterol-fluticasone (200/25) resulted in a sustained improvement in lung function with a statistically significant increase in trough FEV1 of 131 mL over placebo at 24 weeks. A similar increase was noted for vilanterol-fluticasone (100/25). Subjects reported modest improvements in symptoms.

●In a pooled analysis of two trials that compared combinations of vilanterol-fluticasone with vilanterol alone in 3255 patients with COPD, vilanterol 25 mcg with fluticasone 100 mcg or 200 mcg modestly reduced the yearly moderate and severe exacerbation rates more than vilanterol alone (RR 0.79, 95% CI 0.64-0.97, RR 0.69, 95% CI 0.56-0.85, respectively) [115]. The rate of pneumonia was increased in the vilanterol-fluticasone combination groups, although the absolute number of patients affected was small.

The combination of a LAMA plus an ICS has not been compared with LAMA monotherapy.

Lack of role for monotherapy with inhaled glucocorticoids — COPD is characterized by both airway and systemic inflammation [116]. ICS may reduce this inflammation [117-122]. The available data, which are presented in detail separately, suggest that ICS decrease exacerbations and modestly slow the progression of respiratory symptoms, but appear to have little impact on lung function and mortality. In COPD, ICS are used as part of a combined regimen, but should NOT be used as sole therapy for COPD (ie, without long-acting bronchodilators) [6]. (See "Role of inhaled glucocorticoid therapy in stable COPD".)

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".)

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 5th to 6th 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 10th to 12th 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: Chronic obstructive pulmonary disease (COPD) (The Basics)" and "Patient education: Shortness of breath (dyspnea) (The Basics)" and "Patient education: How to use your metered dose inhaler (adults) (The Basics)" and "Patient education: How to use your dry powder inhaler (adults) (The Basics)" and "Patient education: How to use your soft mist inhaler (adults) (The Basics)" and "Patient education: Coping with high drug prices (The Basics)" and "Patient education: Medicines for chronic obstructive pulmonary disease (COPD) (The Basics)" and "Patient education: Inhaled corticosteroid medicines (The Basics)")

●Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD) (Beyond the Basics)" and "Patient education: Chronic obstructive pulmonary disease (COPD) treatments (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Assessing symptoms and exacerbation risk to guide therapy – A categorization system for chronic obstructive pulmonary disease (COPD) that defines disease severity according to the frequency and severity of symptoms and the risk of exacerbations and hospitalization can be used as a guide for the initial management of patients with stable COPD (table 1). Symptoms are assessed using a validated instrument such as the modified Medical Research Council (mMRC) dyspnea scale (table 2) or the COPD Assessment Test (CAT). Exacerbation risk is based on the patient’s history of exacerbations in the past year; two or more exacerbations and one or more hospitalizations indicate a greater risk of future exacerbations. (See 'Assessing disease pattern and severity' above.) (Related Pathway(s): Chronic obstructive pulmonary disease: Severity assessment and selection of initial therapy in adults.)

●General principles – The mainstays of therapy for stable COPD are inhaled bronchodilators (beta agonists and muscarinic antagonists) given alone, in combination, or with addition of inhaled glucocorticoids. Nonpharmacologic therapies (eg, smoking cessation, pulmonary rehabilitation, vaccination, nutrition) should be initiated along with pharmacotherapy. (See 'General principles' above and "Stable COPD: Overview of management".)

●Short-acting bronchodilator for quick relief – For all patients with COPD, we recommend that a short-acting bronchodilator (eg, beta-agonist, muscarinic antagonist, or combination) be prescribed for use as-needed for relief of intermittent increases in dyspnea (Grade 1B). For patients on a long-acting muscarinic antagonist (LAMA), a short-acting beta agonist (SABA) is generally used for quick relief of COPD symptoms. For patients not on a LAMA, a SABA or a combination SABA plus a short-acting muscarinic antagonist (SAMA) is prescribed for rescue use. (See 'Short-acting bronchodilators' above.)

●Initial pharmacologic therapy – Initial therapy is guided by the severity of symptoms and risk of future exacerbations (table 1):

•Group A – For group A patients who are minimally symptomatic (ie, mMRC grade <2) and at low risk of exacerbation (ie, 0 to 1 exacerbation per year), either a SABA or a combination SABA-SAMA can be used for relief of symptoms. (See 'Minimally symptomatic, low risk of exacerbation (Group A)' above.)

•Group B – For group B patients who are more symptomatic (ie, mMRC grade ≥2 or CAT score ≥10) (table 2), but at low risk of exacerbation based on their past history of exacerbations (ie, 0 to 1 exacerbation per year), we recommend regular use of a long-acting inhaled bronchodilator (Grade 1B). In our clinical practice, we prefer a LAMA to a long-acting beta agonist (LABA). However, a once daily LABA is a reasonable alternative depending on the patient’s symptoms and potential medication adverse effects. (See 'More symptomatic, low risk of exacerbation (Group B)' above.)

•Group C – For group C patients who are minimally symptomatic on a day-to-day basis (ie, mMRC grade 0 to 1 or CAT score <10), but are at high risk of an exacerbation due to their history of exacerbations in the past year (ie, ≥2 exacerbations per year with one or more leading to hospitalization), we suggest initial treatment with a LAMA, rather than a LABA, due to the reduced exacerbation rate associated with LAMA therapy (table 6) (Grade 2B). (See 'Selection of LAMA versus LABA' above and 'Minimally symptomatic, high risk of exacerbation (Group C)' above.)

•Group D – For group D patients with a higher symptom burden (ie, mMRC grade ≥2 or CAT score ≥10) and a high risk of exacerbation (ie, ≥2 exacerbations per year with one or more leading to hospitalization), we suggest initial treatment with a LAMA (table 6) (Grade 2B), although a LAMA-LABA combination may be preferred for patients with severe breathlessness (eg, CAT ≥20) (table 8). A possible exception would be patients with a clinical presentation or findings that suggest asthma-COPD overlap in whom a LABA-inhaled glucocorticoid combination might be preferred (table 9). (See 'More symptomatic, high risk of exacerbation (Group D)' above.)

●Follow-up adjustment – Pharmacologic therapy is adjusted at follow-up visits based on the response to therapy (table 4). (See "Stable COPD: Follow-up pharmacologic management".)

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  68. Decramer M, Celli B, Tashkin DP, et al. Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial. COPD 2004; 1:303.
  69. Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009; 374:1171.
  70. LaForce C, Derom E, Bothner U, et al. Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies. Int J Chron Obstruct Pulmon Dis 2018; 13:1819.
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  75. Farne HA, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2015; :CD008989.
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  77. Tashkin DP, Pearle J, Iezzoni D, Varghese ST. Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD 2009; 6:17.
  78. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J 2015; 45:969.
  79. Rodrigo GJ, Plaza V. Efficacy and safety of a fixed-dose combination of indacaterol and Glycopyrronium for the treatment of COPD: a systematic review. Chest 2014; 146:309.
  80. Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res 2015; 16:92.
  81. Rodrigo GJ, Neffen H. A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPD. Chest 2015; 148:397.
  82. Horita N, Nagashima A, Kaneko T. Long-Acting β-Agonists (LABA) Combined With Long-Acting Muscarinic Antagonists or LABA Combined With Inhaled Corticosteroids for Patients With Stable COPD. JAMA 2017; 318:1274.
  83. Ni H, Moe S, Soe Z, et al. Combined aclidinium bromide and long-acting beta2-agonist for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2018; 12:CD011594.
  84. Oba Y, Keeney E, Ghatehorde N, Dias S. Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis. Cochrane Database Syst Rev 2018; 12:CD012620.
  85. Maltais F, Aumann JL, Kirsten AM, et al. Dual bronchodilation with tiotropium/olodaterol further reduces activity-related breathlessness versus tiotropium alone in COPD. Eur Respir J 2019; 53.
  86. Yu AP, Guérin A, de Leon DP, et al. Clinical and economic outcomes of multiple versus single long-acting inhalers in COPD. Respir Med 2011; 105:1861.
  87. Yu AP, Guérin A, Ponce de Leon D, et al. Therapy persistence and adherence in patients with chronic obstructive pulmonary disease: multiple versus single long-acting maintenance inhalers. J Med Econ 2011; 14:486.
  88. Singh D, Ferguson GT, Bolitschek J, et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir Med 2015; 109:1312.
  89. Donohue JF, Maleki-Yazdi MR, Kilbride S, et al. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013; 107:1538.
  90. Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study. Chest 2014; 145:981.
  91. Maleki-Yazdi MR, Kaelin T, Richard N, et al. Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir Med 2014; 108:1752.
  92. Frampton JE. QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease. Drugs 2014; 74:465.
  93. Utibron neohaler prescribing information. http://www.pharma.us.novartis.com/product/pi/pdf/utibron.pdf (Accessed on November 02, 2015).
  94. Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 192:1068.
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  96. Bevespi aerosphere prescribing information. http://www.azpicentral.com/bevespi/bevespi_pi.pdf (Accessed on April 28, 2016).
  97. Martinez FJ, Rabe KF, Rodriquez-Roisin R, et al.. Pooled Analyses from PINNACLE-1 and -2: The Novel LAMA/LABA Co-Suspension Technology Glycopyrrolate/Formoterol Fixed-Dose Combination Delivered by MDI Shows Improvement Versus Monocomponents in Patients with COPD. American Thoracic Society International Conference Abstracts 2016; :A6782.
  98. Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med 2014; 14:178.
  99. D'Urzo AD, Rennard SI, Kerwin EM, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res 2014; 15:123.
  100. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med 2016; 374:2222.
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  102. Ferguson GT, Anzueto A, Fei R, et al. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med 2008; 102:1099.
  103. Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175:144.
  104. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; :CD006829.
  105. Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008; 177:19.
  106. Celli BR, Thomas NE, Anderson JA, et al. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med 2008; 178:332.
  107. Calverley PMA, Stockley RA, Seemungal TAR, et al. Reported pneumonia in patients with COPD: findings from the INSPIRE study. Chest 2011; 139:505.
  108. Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013; :CD007891.
  109. Sharafkhaneh A, Southard JG, Goldman M, et al. Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir Med 2012; 106:257.
  110. Doherty DE, Tashkin DP, Kerwin E, et al. Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD. Int J Chron Obstruct Pulmon Dis 2012; 7:57.
  111. FDA approves Breo Ellipta to treat chronic obstructive pulmonary disease http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm351664.htm (Accessed on May 20, 2013).
  112. Breo Ellipta: An Inhaled Fluticasone/Vilanterol Combination for COPD. Med Lett Drugs Ther 2013; 55:69.
  113. Vestbo J, Leather D, Diar Bakerly N, et al. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice. N Engl J Med 2016; 375:1253.
  114. Martinez FJ, Boscia J, Feldman G, et al. Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial. Respir Med 2013; 107:550.
  115. Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013; 1:210.
  116. Sin DD, Paul Man SF. Cooling the fire within: inhaled corticosteroids and cardiovascular mortality in COPD. Chest 2006; 130:629.
  117. Pinto-Plata VM, Müllerova H, Toso JF, et al. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax 2006; 61:23.
  118. Gan WQ, Man SF, Sin DD. Effects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease: a systematic review and a meta-analysis. BMC Pulm Med 2005; 5:3.
  119. Ozol D, Aysan T, Solak ZA, et al. The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients. Respir Med 2005; 99:1494.
  120. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170:760.
  121. Siva R, Green RH, Brightling CE, et al. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J 2007; 29:906.
  122. Bart G. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Ann Intern Med 2009; 151:218; author reply 218.
Topic 1447 Version 78.0

References

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35 : Salmeterol reduces dyspnea and improves lung function in patients with COPD.

36 : Long-acting beta2 agonists in the management of stable chronic obstructive pulmonary disease.

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38 : Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.

39 : Use of a long-acting inhaled beta2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease.

40 : Quality of life changes in COPD patients treated with salmeterol.

41 : Addition of salmeterol to existing treatment in patients with COPD: a 12 month study.

42 : Long-acting beta2-agonists for chronic obstructive pulmonary disease.

43 : One-year safety and efficacy study of arformoterol tartrate in patients with moderate to severe COPD.

44 : Long-term safety and efficacy of indacaterol, a long-actingβ₂-agonist, in subjects with COPD: a randomized, placebo-controlled study.

45 : Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol, tiotropium and placebo in COPD.

46 : Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study.

47 : Efficacy and tolerability of indacaterol 75μg once daily in patients aged≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies.

48 : Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD.

49 : Indacterol (Arcapta Neohaler) for COPD.

50 : Safety and efficacy of 12-week or longer indacaterol treatment in moderate-to-severe COPD patients: a systematic review.

51 : Indacaterol, a once-daily beta2-agonist, versus twice-daily beta₂-agonists or placebo for chronic obstructive pulmonary disease.

52 : Role of indacaterol, a once-daily bronchodilator, in chronic obstructive pulmonary disease.

53 : The risks and benefits of indacaterol--the FDA's review.

54 : Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison.

55 : A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV1 profile for once-daily versus twice-daily treatment with olodaterol, a novel long-actingβ2-agonist, in patients with chronic obstructive pulmonary disease.

56 : Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat®versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.

57 : Efficacy and safety of olodaterol once daily delivered via Respimat®in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.

58 : A randomised, placebo-controlled, Phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-actingβ2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease.

59 : Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD.

60 : The efficacy and safety of the novel long-actingβ2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial.

61 : A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.

62 : Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium.

63 : The effect of tiotropium on exacerbations and airflow in patients with COPD.

64 : The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group.

65 : Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial.

66 : Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD.

67 : One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium.

68 : Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial.

69 : Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial.

70 : Long-term safety of tiotropium/olodaterol Respimat®in patients with moderate-to-very severe COPD and renal impairment in the TONADO®studies.

71 : Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease: The ASCENT-COPD Randomized Clinical Trial.

72 : Tiotropium Respimat inhaler and the risk of death in COPD.

73 : Tiotropium Respimat inhaler and the risk of death in COPD.

74 : Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.

75 : Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease.

76 : Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.

77 : Formoterol and tiotropium compared with tiotropium alone for treatment of COPD.

78 : Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4).

79 : Efficacy and safety of a fixed-dose combination of indacaterol and Glycopyrronium for the treatment of COPD: a systematic review.

80 : Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT).

81 : A Systematic Review of the Efficacy and Safety of a Fixed-Dose Combination of Umeclidinium and Vilanterol for the Treatment of COPD.

82 : Long-Actingβ-Agonists (LABA) Combined With Long-Acting Muscarinic Antagonists or LABA Combined With Inhaled Corticosteroids for Patients With Stable COPD.

83 : Combined aclidinium bromide and long-acting beta2-agonist for chronic obstructive pulmonary disease (COPD).

84 : Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta-analysis.

85 : Dual bronchodilation with tiotropium/olodaterol further reduces activity-related breathlessness versus tiotropium alone in COPD.

86 : Clinical and economic outcomes of multiple versus single long-acting inhalers in COPD.

87 : Therapy persistence and adherence in patients with chronic obstructive pulmonary disease: multiple versus single long-acting maintenance inhalers.

88 : Tiotropium + olodaterol shows clinically meaningful improvements in quality of life.

89 : Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD.

90 : Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study.

91 : Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial.

92 : QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease.

93 : QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease.

94 : FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

95 : FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

96 : FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

97 : Pooled Analyses from PINNACLE-1 and -2: The Novel LAMA/LABA Co-Suspension Technology Glycopyrrolate/Formoterol Fixed-Dose Combination Delivered by MDI Shows Improvement Versus Monocomponents in Patients with COPD

98 : Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study.

99 : Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study.

100 : Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.

101 : Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD.

102 : Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations.

103 : Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease.

104 : Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease.

105 : The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.

106 : Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study.

107 : Reported pneumonia in patients with COPD: findings from the INSPIRE study.

108 : Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease.

109 : Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study.

110 : Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD.

111 : Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD.

112 : Breo Ellipta: An Inhaled Fluticasone/Vilanterol Combination for COPD

113 : Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice.

114 : Fluticasone furoate/vilanterol (100/25; 200/25μg) improves lung function in COPD: a randomised trial.

115 : Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials.

116 : Cooling the fire within: inhaled corticosteroids and cardiovascular mortality in COPD.

117 : C-reactive protein in patients with COPD, control smokers and non-smokers.

118 : Effects of inhaled corticosteroids on sputum cell counts in stable chronic obstructive pulmonary disease: a systematic review and a meta-analysis.

119 : The effect of inhaled corticosteroids on bronchoalveolar lavage cells and IL-8 levels in stable COPD patients.

120 : Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease.

121 : Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial.

122 : Concerns about consensus guidelines for QTc interval screening in methadone treatment.