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 a leading cause of death among adults, both in the United States and 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: Diagnosis and staging".)
●(See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions".)
●(See "Chronic obstructive pulmonary disease: Risk factors and risk reduction".)
●(See "Stable COPD: Overview of management".)
●(See "Stable COPD: Follow-up pharmacologic management".)
●(See "Management of refractory chronic obstructive pulmonary disease".)
●(See "COPD exacerbations: Management".)
(Related Pathway(s): Chronic obstructive pulmonary disease: Severity assessment and selection of initial therapy in adults.)
ASSESSING DISEASE PATTERN AND SEVERITY — A multicomponent 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 primarily based on assessment of symptoms and risk of future exacerbations and hospitalizations. We support this approach to initial management. (Related Pathway(s): Chronic obstructive pulmonary disease: Severity assessment and selection of initial therapy in adults.)
Symptoms and risk of exacerbations — Patients with COPD may be classified according to symptoms and exacerbation history into three groups (A, B, and E) (algorithm 1) [6]. Symptoms should be assessed using a validated instrument, such as the modified Medical Research Council (mMRC) dyspnea scale (calculator 1) or the COPD assessment Test (CAT) (calculator 2) [6-9]. For patients newly initiating therapy, exacerbation risk should be determined based on the patient’s history of exacerbations and their severity in the past year; two or more exacerbations requiring systemic glucocorticoids or one or more COPD hospitalizations indicate a greater risk of future exacerbations [6,10,11]. After initiation of pharmacologic therapy, even less frequent exacerbations may make a significant impact on escalation of therapy, as described separately. (See "Stable COPD: Follow-up pharmacologic management", section on 'Exacerbation history'.)
The symptom and risk components are combined to categorize patients into one of three groups as follows:
●Group A: Less symptomatic, low risk of future exacerbations:
•mMRC grade 0 to 1 or CAT score <10
•Zero to one exacerbation per year without hospitalization
●Group B: More symptomatic, low risk of future exacerbations:
•mMRC grade ≥2 or CAT score ≥10
•Zero to one exacerbation per year without hospitalization
●Group E: High risk of future exacerbations:
•≥2 exacerbations per year or ≥1 hospitalization for exacerbation
Airflow limitation — Although the severity of the decrement in forced expiratory volume in one second (FEV1) is inversely associated with COPD exacerbation risk, FEV1 is inferior to exacerbation history in predicting risk of future exacerbations for individual patients [12]. For this reason, FEV1 is not included in the ABE groups [6].
We use spirometry to confirm the diagnosis of COPD, assess airflow limitation severity, and to calculate the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index (calculator 3), which remains a useful measure to assess risk of death or hospitalization due to COPD. As an objective measure of physiologic limitation, spirometry is also essential in other areas of COPD care, including disease progression, consideration of alternate diagnoses, surgical risk stratification and assessment for lung volume reduction, and other invasive interventions. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Assessment of severity and staging'.)
GENERAL PRINCIPLES — Pharmacologic therapy for COPD should always be employed along with nonpharmacologic 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 [6]. The initial selection of a pharmacologic agent is based on the severity of symptoms and risk of future exacerbations (algorithm 1); therapy is adjusted at follow-up visits based on the clinical response to current therapy. (See 'Symptoms and risk of exacerbations' above and "Stable COPD: Follow-up pharmacologic management".)
The mainstays of drug therapy for stable symptomatic COPD are inhaled bronchodilators (beta-agonists and muscarinic antagonists). These agents are most commonly given in combination with or without the addition of inhaled glucocorticoids; patients with less severe symptoms and low exacerbation risk may also receive inhaled bronchodilators individually (algorithm 1 and table 1). Inhaled bronchodilators are generally administered via handheld 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, revefenacin, budesonide).
While we believe the GOLD approach appropriately focuses on targeting therapies based on symptoms and exacerbation risk, the separation of patients into the "ABE" groups is based largely on post hoc analyses and we await rigorous prospective studies. Some patients with very severe disease may require initiation of multiple medications simultaneously to achieve symptom and exacerbation control rather than employing a stepwise approach. Additional study of specific COPD groups may yield better evidence to support initial treatment approaches.
RESCUE BRONCHODILATOR THERAPY FOR ALL PATIENTS — For all patients with COPD, we prescribe a short-acting bronchodilator to use as needed for relief of episodic dyspnea and early treatment of exacerbations. We typically use a short-acting beta-agonist (SABA) in most patients because short-acting muscarinic antagonists (SAMAs) are generally not recommended to be used in those also prescribed long-acting muscarinic antagonist (LAMA) therapy. For patients receiving long-acting beta-agonists (LABAs) without LAMA coadministration or who only use short-acting agents, we prefer combination SABA-SAMA therapy because this achieves a greater bronchodilator response than either agent alone [13].
●Rescue therapy in patients taking long-acting muscarinic antagonists – SAMAs are generally not recommended to be used routinely in conjunction with LAMAs due to cumulative anticholinergic side effects and theoretical blockage of LAMA effects by the SAMA. For the majority of patients with COPD who are also on LAMA therapy, SABAs are prescribed for relief of episodic worsening of dyspnea, such as associated with triggers and exacerbations.
Short-acting inhaled beta-agonists include albuterol and levalbuterol. They have been proven in randomized trials and meta-analyses to improve symptoms and lung function acutely in stable COPD [14]. However, SABA therapy is prescribed only on an as-needed basis for those with intermittent symptoms, rather than regularly scheduled, to decrease sympathomimetic exposure. Patients requiring frequent use should transition to long-acting agents.
One trial randomly assigned 53 patients with COPD to receive regularly scheduled albuterol or placebo, while continuing regular SAMA therapy, inhaled glucocorticoid, and as-needed albuterol [15]. Regularly scheduled albuterol doubled the total amount of albuterol received without a clinically significant impact on lung function, symptoms, or exercise capacity.
Although inhaled SABAs are generally felt to be safe when used at the recommended doses, side effects and toxicity can occur. Because most recommended doses of SABAs result in less than maximal achievable bronchodilation, patients frequently use multiple doses in the setting of severe breathlessness. Symptoms of SABA overuse include tremor and tachycardia, which is due to a combination of chronotropism and peripheral arterial dilation. Hypokalemia can also occur in extreme cases and should be monitored in patients at risk. Large trials have not demonstrated an increase in serious cardiac arrhythmias with typical use. (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", section on 'Beta-adrenergic agonists'.)
Oral SABAs are generally avoided when possible because of a higher incidence of side effects and reduced efficacy as bronchodilators.
●Rescue therapy for patients not taking long-acting muscarinic antagonists – In patients not coadministered LAMAs, we prefer SABA-SAMA therapy for rescue because of increased bronchodilator effectiveness compared with either short-acting agent alone. In addition, using low doses of both agents avoids side effects associated with use of a high-dose single agent.
Like SABAs, SAMAs are inhaled bronchodilators that result in a relatively short-term, pharmacologically mediated improvement in lung function due to inhibition of smooth muscle activation (figure 1). Inhaled muscarinic antagonists (eg, ipratropium, tiotropium) are typically synthetic quaternary ammonium derivatives of older naturally occurring tertiary ammonium compounds (eg, atropine, scopolamine) (figure 2); the additional ammonium structure reduces systemic absorption and side effects.
When used alone as a rescue therapy, the usual dose of the SAMA ipratropium is two inhalations (17 mcg/actuation via metered dose inhaler [MDI]) four to six times per day as needed. Ipratropium can also be prescribed via nebulization (0.5 mg/2.5 mL vial) at a dose of one vial every four to eight hours as needed. As-needed and regularly scheduled dosing regimens of SAMAs have not been compared; regular use produces a sustained and reversible improvement in lung function (forced expiratory volume in one second [FEV1]) [16].
Individually, albuterol and ipratropium have been compared in several randomized trials [13,17,18]. On average, both medications improve lung function to a similar degree, although the effects may vary [19]. Side effects are unique to each medication class but are minimal at commonly prescribed doses.
The combination of ipratropium-albuterol (20 mcg/100 mcg per 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 SABAs and muscarinic antagonists is larger than either agent alone when typically recommended (submaximal) doses of each agent are combined [6,13,18,20]. As an example, one trial randomly assigned 534 patients with COPD to receive albuterol alone, ipratropium alone, or combination therapy (albuterol plus ipratropium) [13]. Combination therapy increased the mean peak forced expiratory volume in one second (FEV1) more than either agent alone but did not alter exacerbation frequency. A similar study reported that combination therapy decreased exacerbation rates compared with albuterol, but not ipratropium [18].
Several physiologic reasons exist for the potential benefit of combination therapy with ipratropium and a beta-agonist:
•Muscarinic antagonists act predominantly on the proximal large airways, while sympathomimetics act on the more distal small airways.
•The two classes of medications cause bronchodilation via different mechanisms: Beta-agonists are thought to cause bronchodilation by directly acting on muscle, and ipratropium causes bronchodilation by reducing cholinergic tone.
•Coadministration of adrenergic and muscarinic antagonists provides the rapid onset of action of the former and the sustained activity of the latter; their combined effect is present at intermediate times.
LESS SYMPTOMATIC PATIENTS AT LOW RISK OF EXACERBATION (GROUP A)
Choice of long-acting bronchodilator agent — In addition to short-acting bronchodilator rescue therapy, we suggest that Group A patients use a long-acting bronchodilator (algorithm 1). Long-acting bronchodilators have been shown to be effective even in patients with mild symptoms and low baseline exacerbation rates.
For example, in a placebo-controlled trial of 841 patents with minimally symptomatic COPD (forced expiratory volume in one second [FEV1] ≥50 percent predicted) patients receiving tiotropium daily demonstrated a decrease in yearly exacerbation rates (0.27 versus 0.50 events per patient-year; risk ratio 0.53, 95% CI 0.39-0.73) and an increase in FEV1 (between group difference 157 mL [95% CI, 123-192]) [21].
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 A COPD [6]. In our clinical practice, we prefer a LAMA to a LABA based on evidence of modestly increased efficacy in preventing exacerbations [22-26]. However, a once daily LABA is a reasonable alternative depending on the patient’s symptoms, comorbidities, and potential medication adverse effects.
The efficacy and safety of LABAs and LAMAs have been compared in meta-analyses and randomized trials [22,23,27,28]; 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 [22-24].
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 can be 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 at high risk for urinary retention. (See "Arrhythmias in COPD", section on 'Beta-adrenergic agonists' and 'Long-acting muscarinic antagonists' below.)
●Comparative efficacy – A meta-analysis that included seven trials (12,223 participants) compared tiotropium with various LABAs (salmeterol, formoterol, and indacaterol) [23]. No significant difference was noted in improvements in quality of life or dyspnea between tiotropium and the various LABAs. Tiotropium was more effective at reducing exacerbations (odds ratio [OR] 0.86, 95% CI 0.79-0.93). However, no statistically significant differences were noted in overall hospitalizations or mortality. 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.
In a subsequent trial of 3444 patients with severe COPD and at least one exacerbation in the previous year, tiotropium and indacaterol yielded similar improvements in FEV1, but tiotropium provided better protection against exacerbations over the next year than indacaterol (0.61 versus 0.79 exacerbations, rate ratio 0.76, 95% CI 0.68-0.87) [24].
●Comparison of adverse cardiovascular effects – LABAs and LAMAs are associated with similar rates of adverse cardiovascular events. The data on cardiovascular side effects of individual agents are covered elsewhere. (See "Arrhythmias in COPD", section on 'Beta-adrenergic agonists' and "Management of the patient with COPD and cardiovascular disease", section on 'Beta-2 agonists' and "Management of the patient with COPD and cardiovascular disease", section on 'Inhaled anticholinergic medications'.)
The best comparative data come from a trial of 1683 patients with COPD randomly assigned to receive indacaterol 150 or 300 mcg, placebo, or open-label tiotropium once daily [29]. The incidence of adverse events, such as low serum potassium, high blood glucose, cardiac events, and prolonged QTc interval was similar across treatments.
In addition, a large case-control analysis found similar small increases in the likelihood of hospitalizations or emergency department visits for cardiovascular events associated with new LABA or LAMA prescriptions compared with those not prescribed these agents (adjusted odds ratios 1.31 [95% CI 1.12-1.52] and 1.14 [1.01-1.28], respectively) [30]. No significant differences were noted between the two classes of bronchodilators. The noted increased short-term risk of bronchodilator prescriptions, however, must be interpreted in the context of likely confounding by susceptibility or disease severity. The cardiovascular safety of individual long-acting bronchodilators is largely reassuring based on postapproval monitoring and clinical trials, which are discussed in detail separately. (See "Management of the patient with COPD and cardiovascular disease", section on 'Long-acting beta-agonists'.)
Dosing and efficacy of individual agents
Long-acting beta-agonists — LABAs include salmeterol, formoterol, arformoterol, indacaterol, vilanterol, and olodaterol; all are beta-2 selective (table 2). Arformoterol is only available as a solution for nebulization; vilanterol is only available as a component of a combination product with a LAMA. Multiple studies have demonstrated the benefit of LABAs in patients with stable COPD [31-39].
●Salmeterol – Salmeterol is the most commonly used and well-studied stand-alone LABA and is administered by dry powder inhaler (50 mcg/actuation) one inhalation twice daily. It has a slow onset (120 minutes) with intermediate duration [40]. The largest trial of salmeterol, Toward a Revolution in COPD Health (TORCH), randomly assigned 6112 patients with mostly severe airflow limitation (mean FEV1 44 percent of predicted) 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 [35]. Salmeterol significantly decreased exacerbation rates and improved lung function 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 in COPD.
●Formoterol and arformoterol – Formoterol is a twice daily LABA with a rapid onset (time to onset of bronchodilation within three minutes) and intermediate duration of action [39,41]. It is available as a single agent dry powder inhaler in Canada and Europe. In the United States, it is available as a solution for nebulization (20 mcg/2 mL vial, one 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, one vial twice daily [42].
●Indacaterol – Indacaterol is a once-daily LABA for the treatment of COPD; it has a rapid onset and long duration of action [29,43-51]. 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) based on data showing no improvement in efficacy and a possible increase in asthma exacerbations and respiratory-related deaths at the highest doses [52]. 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. Indacaterol has been shown to improve lung function and reduce exacerbation rates in patients with COPD [29,43,50,53].
●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 (SMI) and is approved for the treatment of COPD [54]. It has been shown to improve lung function and quality of life compared with placebo in patients with moderate to severe COPD [54-57]. The soft mist inhaler device can be helpful for certain patients with very poor inspiratory flow or poor hand-breath coordination, typically the elderly or those with advanced COPD. (See "The use of inhaler devices in adults", section on 'Soft mist inhaler technique'.)
●Vilanterol – Vilanterol is a once-daily LABA with an intermediate onset of action (15 minutes) that has been developed for use in combination inhalers with umeclidinium or fluticasone furoate [58]. 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 'Comparison with single long-acting bronchodilator' below.)
The potential association of LABA use with cardiac arrhythmias has been closely examined after retrospective studies suggested a possible risk; the data have been generally reassuring regarding LABA safety in patients with COPD. These data are covered in detail elsewhere. (See "Arrhythmias in COPD", section on 'Beta-adrenergic agonists' and "Management of the patient with COPD and cardiovascular disease", section on 'Beta-2 agonists'.)
Long-acting muscarinic antagonists — The LAMAs include tiotropium, aclidinium, umeclidinium, and glycopyrrolate (also called glycopyrronium) (table 3).
●Tiotropium – Tiotropium, the most studied LAMA, is available as a dry powder inhaler (18 mcg/capsule, the contents of which are inhaled once daily) and as an SMI (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 [27,34,61-65]. In addition, it improves trough lung function (ie, FEV1 24 hours after the last dose) and reduces hyperinflation, indicating that its effects are long-lasting [66]. Tiotropium may also 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].
●Aclidinium – Aclidinium is available as a dry powder inhaler (400 mcg/actuation, one inhalation twice a day). In a 24-week placebo-controlled trial, trough and peak FEV1 as well as dyspnea improved in the group receiving twice daily aclidinium [71]. The effect on lung function has been found to be similar to tiotropium or formoterol in small trials [72,73]. Aclidinium has very low bioavailability (less than 5 percent) [74], which may reduce the risk of systemic side effects.
●Umeclidinium – Umeclidinium (62.5 mcg/actuation) is available as a dry powder inhaler, administered one inhalation, once daily. Bronchodilation peaks at three hours after a dose and is sustained for 24 hours [75]. In a 28-day randomized trial, three higher once-daily doses of umeclidinium (125 mcg, 250 mcg, 500 mcg) significantly increased trough FEV1 (by 150 to 160 mL) at 24 hours after the last dose on days 2, 14, 28, and 29, and also reduced rescue albuterol use compared with placebo in patients with COPD [75].
●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 4), depending on the region of approval. In a 26-week trial, 822 subjects with moderate to severe chronic obstructive pulmonary disease (COPD) were randomly assigned to glycopyrrolate 50 mcg by oral inhalation once daily or placebo [76]. The trough forced expiratory volume in one second (FEV1), assessed at 12 weeks, was significantly higher (least squares mean treatment difference of 108 mL) in the glycopyrrolate group. In a separate trial, glycopyrrolate had similar effects on lung function, dyspnea, and use of rescue medication compared with tiotropium [77].
●Revefenacin – Revefenacin is available as a solution for nebulization. It is administered once daily (175 mcg/3 mL vial, one vial once daily via a standard jet nebulizer). Given the time needed for a nebulizer treatment (>8 minutes), this medication is typically reserved for patients who have difficulty with the technique of soft mist or dry powder formulations of the other LAMAs.
In two randomized trials that included 395 patients with moderate to severe COPD (mean forced expiratory volume in one second [FEV1] 55 percent of predicted), revefenacin 175 mcg increased mean FEV1 from baseline to trough at day 85 by 146 mL (95% CI 103.7-188.8 mL) and 147 mL (95% CI 97.0-197.1 mL) [78-80]. In the placebo groups, approximately 37 percent were also taking a long-acting beta-agonist (LABA) or inhaled glucocorticoid/LABA.
Use of revefenacin should be avoided in patients with hepatic impairment and has not been studied in patients with endstage kidney disease. Revefenacin can exacerbate narrow angle glaucoma and worsen urinary retention.
Older systematic reviews and a case-cohort study suggested possible adverse cardiovascular effects of inhaled muscarinic antagonist therapy [81,82]. However, data from long-term, placebo-controlled randomized trials have not identified any significant safety issues or increased risk of cardiovascular events in patients with COPD [83-87]. Similarly, after an initial concerning safety signal [88,89], a large randomized trial of over 17,000 patients demonstrated no difference in mortality between those receiving tiotropium by SMI compared with DPI [85]. (See "Management of the patient with COPD and cardiovascular disease", section on 'Inhaled anticholinergic medications'.)
Systemic absorption of inhaled muscarinic antagonists has the potential to increase the risk of acute urinary retention in susceptible patients such as those with benign prostatic hypertrophy (BPH) or lower urinary tract symptoms [90-93]. For example, in a pooled analysis of 19 randomized trials, the relative risk of symptoms of urinary retention was 10.93 (95% CI 1.26-94.88) [90]. However, the severity of the urinary symptoms was not delineated. A separate case-control study also suggested an increased risk of acute urinary retention among men with BPH in users of inhaled muscarinic agonists compared with nonusers (OR 1.81, 95% CI 1.46-2.24) [91]. Aclidinium has not been shown to demonstrate similar urinary retention risk in clinical trials [71,73], perhaps due to its low bioavailability [74].
Alternate approaches in patients with minimal intermittent symptoms — For patients with infrequent symptoms, it is reasonable to continue only short-acting rescue therapy, as described above.
Although some patients may employ regular use of short-acting bronchodilators to relieve symptoms, frequent short-acting bronchodilator use has not been shown to yield the same quality-of-life improvements or reduction in exacerbation rates as long-acting bronchodilators, so it is not a preferred approach.
MORE SYMPTOMATIC PATIENTS AT LOW RISK OF EXACERBATION (GROUP B)
Use of dual bronchodilator therapy — For patients with more severe symptoms but low risk for exacerbations, we suggest the use of dual bronchodilator (long-acting beta-agonist/long-acting muscarinic antagonist [LABA-LAMA]) therapy over short-acting bronchodilators or either long-acting bronchodilator alone (table 5).
For patients with more severe symptoms, long-acting bronchodilators improve breathlessness and lung function compared with short-acting therapy alone. For example, in one trial comparing the use of ipratropium (a short-acting muscarinic antagonist) four times daily to daily tiotropium (a LAMA), tiotropium meaningfully improved dyspnea (31 versus 18 percent) and quality of life (52 versus 35 percent) after one year of therapy, as well as airflow limitation (forced expiratory volume in one second [FEV1] +120 mL versus +30 mL) [62]. Similarly, compared with placebo, patients using the LABAs indacaterol and salmeterol were more likely to have meaningful improvement in quality of life (53 and 49 percent versus 38 percent) and lung function (FEV1 +150 mL and +90 mL versus -30 mL) after 26 weeks of therapy [53]. Additional placebo-controlled trials of individual agents have generally established the efficacy of long-acting bronchodilators in terms of both pulmonary function and symptomatic improvement. These data are discussed separately. (See 'Dosing and efficacy of individual agents' above.)
Clinical trials in support of combined LAMA-LABA therapy for patients with severe breathlessness generally show added value to dual bronchodilation over single-agents for relief of dyspnea, although results vary depending on the specific agents and end-points [6,25,26,94-103]. Nearly all trials demonstrate improvements in forced expiratory volume in one second (FEV1) with dual compared with individual long-acting bronchodilator therapy, but not always with clinically significant changes in breathlessness or quality of life.
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 [104,105]. In general, dual bronchodilator therapies do not show any additional risks in their safety profiles as compared with their monotherapies.
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 postbronchodilator FEV1 with the combination compared with either LAMA or LABA alone [25]. No difference was noted in hospital admissions, mortality, and serious adverse events.
Each of the following single-inhaler combinations improve FEV1 compared with their single-agent components [96-99,101,106-114]:
●Tiotropium-olodaterol – Combination tiotropium-olodaterol (2.5 mcg/2.5 mcg per actuation, two inhalations once daily) is delivered via soft mist inhaler (SMI).
●Umeclidinium-vilanterol – Umeclidinium-vilanterol (62.5 mcg/25 mcg per actuation) is a dry powder inhaler used at a dose of one inhalation daily for COPD.
●Glycopyrronium-indacaterol – A once-daily dry powder inhaler containing the combination of glycopyrronium-indacaterol (50 mcg/110 mcg per capsule) is available in Canada, Europe, and elsewhere [110]. A lower dose preparation is approved for use in the United States based on evidence of efficacy compared with its components [111], but is not being manufactured [115].
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 [116]. 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-formoterol (9 mcg/4.8 mcg per actuation) is available for the treatment of COPD at a dose of two inhalations twice daily [117].
●Aclidinium-formoterol – Aclidinium-formoterol (400 mcg/12 mcg per actuation) is available as a combination dry powder inhaler administered as one inhalation twice daily.
Alternative approaches
Group B patients who cannot use LAMA-LABA — For Group B patients with COPD who are unable to take a LAMA-LABA combination therapy due to cost, availability, or side effects, either a LAMA or a LABA alone are reasonable alternatives. (See 'Dosing and efficacy of individual agents' above.)
Patients with possible concomitant asthma — For patients with COPD and asthma (also known as COPD-A or asthma-COPD overlap [ACO]), symptoms and exacerbations may be better controlled with the addition of an inhaled glucocorticoid (ie, inhaled corticosteroids [ICS]) to their therapy. Although combination therapy with a LABA plus ICS may be used in these patients, we prefer LABA-LAMA-ICS therapy due to the added benefits of dual bronchodilation for COPD along with the ICS for asthma control. Features that can be used to identify patients with ACO are discussed separately. (See "Asthma and COPD overlap (ACO)".)
PATIENTS AT HIGH RISK OF EXACERBATION (GROUP E) — Among the Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups, patients with frequent exacerbations (Group E) are at the highest risk for hospitalization and death due to COPD. Because of this, they require the use of potent combination therapies upfront to reduce the risk of these adverse outcomes. Many patients will improve with dual bronchodilator therapy, which avoids potential adverse effects from inhaled glucocorticoids (ie, inhaled corticosteroids [ICS]).
Dual bronchodilator therapy, in most cases — In general, for patients initiating COPD therapy with a high risk of future exacerbations, we suggest initial treatment with combination long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) therapy rather than using either agent alone or automatic initiation of inhaled glucocorticoids (table 5) [6].
Comparison with single long-acting bronchodilator — Specific data in support of dual bronchodilator therapy over single bronchodilators in patients with exacerbations include:
●A meta-analysis of 10 trials assessing combination bronchodilator therapy with tiotropium found small symptomatic improvements with combination therapy compared with individual therapy (described above), as well as an improvement in exacerbations with tiotropium-LABA therapy compared with LABA alone (odds ratio [OR] 0.80, 95% CI 0.69-0.93) [25].
●A meta-analysis including indirect comparisons (ie, network analysis) of 26 studies and over 30,000 participants with a history of recent exacerbation suggested a reduction in moderate to severe exacerbations compared with LAMA (hazard ratio [HR] 0.87, 95% CI 0.78-0.99) or LABA alone (HR 0.70, 95% CI 0.61-0.8) [26]. There was also a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared with monotherapies.
●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 individual agents (vilanterol [RR 0.72, 95% CI 0.54-0.95] and umeclidinium [RR 0.74, 95% CI 0.54-0.98]); however, umeclidinium-vilanterol was not different compared with tiotropium or fluticasone-salmeterol [99].
Additional evidence supports benefit for dual bronchodilator therapy for the improvement of dyspnea in patients with severe symptoms. (See 'Use of dual bronchodilator therapy' above.)
Comparison with LABA-ICS — Both LABA-LAMA therapy and LABA-ICS combinations have demonstrated reductions in exacerbations compared with single bronchodilator therapy. 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 [6,26,118-120]. Although there is a small signal towards improved mortality in patients receiving LABA-ICS, this effect was driven by patients with frequent exacerbations and eosinophilia despite dual therapy [121]. We believe this group is more appropriate for LABA-LAMA-ICS treatment, rather than either LABA-LAMA or LABA-ICS. (See 'Alternative approaches' below and "Stable COPD: Follow-up pharmacologic management", section on 'Exacerbations on LAMA-LABA therapy' and "Stable COPD: Follow-up pharmacologic management", section on 'Exacerbations on LABA-ICS'.)
In one 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 to severe exacerbation in the previous year [118]. Over the 52-week trial, glycopyrronium-indacaterol reduced the rate of mild to 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 in 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 approaches — Selected patients with COPD and a high risk of exacerbations may benefit from alternative therapeutic approaches.
Group E patients presenting with elevated eosinophil counts or hospitalization — For patients who have frequent COPD exacerbations (ie, ≥2/year) and blood eosinophils ≥300 cells/microL, we agree with the GOLD that initial treatment with dual bronchodilator therapy plus an ICS is reasonable initial therapy based on potential benefits of ICS in this population. Additional information on the use of eosinophils to guide use of ICS is detailed elsewhere. (See "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, inhaled corticosteroids, and exacerbations'.)
Although not as well-studied, LAMA-LABA-ICS therapy may also be appropriate in patients hospitalized for a COPD exacerbation needing initial medical management, as these patients are at high risk for additional COPD-associated hospitalizations and mortality.
Patients with greater numbers of exacerbations, severe exacerbations leading to hospitalization, and higher blood eosinophil levels demonstrate greater reductions in exacerbations and improvement in lung function plus a likely small improvement in mortality in trials of LAMA-LABA-ICS versus other therapeutic approaches, including LAMA-LABA therapy [121-129]. However, LAMA-LABA-ICS therapy has not been studied specifically as an initial treatment option in clinical trials. Data supporting the use of LAMA-LABA-ICS as follow-up therapy in patients with frequent exacerbations are detailed separately. (See "Stable COPD: Follow-up pharmacologic management", section on 'Persistent exacerbations with or without dyspnea'.)
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".)
Group E patients who cannot use LAMA-LABA — For Group E patients with COPD who are unable to use a LAMA-LABA combination therapy due to cost, availability, or side effects, either single bronchodilator therapy or LABA-ICS therapy may be of benefit. Combined LAMA and ICS therapy has not been investigated.
Either a LAMA or a LABA alone has been shown to improve symptoms and reduce exacerbation rates compared with placebo. (See 'Dosing and efficacy of individual agents' above.)
For those who cannot use a LAMA, combination LABA-ICS therapy (table 6) is frequently more effective than LABA alone. In patients with moderate to severe airflow limitation and frequent exacerbations, combination LABA-ICS therapy significantly improves outcomes compared with placebo, LABA alone, or ICS alone [35,130-138].
●For example, in the Toward a Revolution in COPD Health (TORCH) trial of 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 [35].
●Similarly, 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 or 200 mcg modestly reduced the yearly 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) [138].
Multiple analyses have shown that blood eosinophil counts strongly correlate with the effectiveness of ICS when added to LABA therapy in preventing future COPD exacerbations [124,125,139]. Minimal effects of ICS are seen in patients with lower eosinophil counts, with incrementally increasing effects at higher levels [126]. Although precise cutoffs by their nature are arbitrary, patients with ≥300 cells/microL have consistent benefits from ICS, whereas patients with lower eosinophil counts (<100 cells/microL) may be at increased risk for pneumonia compared with other COPD patients on ICS therapy [127,128]. The role of eosinophil counts in managing therapy is discussed in more detail separately. (See "Stable COPD: Follow-up pharmacologic management", section on 'Blood eosinophils, inhaled corticosteroids, and exacerbations'.)
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".)
Patients with possible concomitant asthma — Patients with exacerbations and both COPD and asthma (also known as COPD-A and asthma-COPD overlap [ACO]) may also benefit from LABA plus ICS rather than with dual bronchodilator therapy. In patients with more severe symptoms or hospitalizations due to exacerbation, we prefer LAMA-LABA-ICS therapy due to the added benefits of dual bronchodilation for COPD. Features that can be used to identify patients with COPD and asthma are discussed separately. (See "Asthma and COPD overlap (ACO)".)
OBSOLETE APPROACHES — Inhaled glucocorticoids have been used for decades as part of COPD therapy based on their efficacy in treating airway and systemic inflammation [140-145]; however, they are no longer recommended for use without accompanying long-acting bronchodilator therapy. (See "Role of inhaled glucocorticoid therapy in stable COPD".)
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 also do not recommend the substitution of theophylline for long-acting bronchodilator therapies unless these agents are unavailable. Use of theophylline in refractory COPD is discussed separately. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Theophylline, monitored by drug levels'.)
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 (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 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 – As a guide for initial pharmacologic management, patients with stable COPD can be categorized according to the severity of symptoms and the risk of future exacerbations (algorithm 1). Symptoms should be assessed using a validated instrument; the modified Medical Research Council (mMRC) dyspnea scale (calculator 1) or the COPD Assessment Test (CAT) (calculator 2) are preferred. Exacerbation risk is based on the patient’s history of exacerbations in the past year; two or more exacerbations requiring systemic glucocorticoids or any hospitalization for COPD exacerbation 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, usually long-acting) given alone, in combination, or with the 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 provide a short-acting bronchodilator (eg, beta-agonist, muscarinic antagonist, or combination) for use as needed for relief of intermittent increases in dyspnea. 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) should be prescribed for rescue use. (See 'Rescue bronchodilator therapy for all patients' above and "COPD exacerbations: Management", section on 'Home or office management of COPD exacerbations'.)
●Initial pharmacologic therapy – Initial therapy is guided by the severity of symptoms and risk of future exacerbations (algorithm 1):
•Group A – For patients who are less symptomatic (mMRC grade <2 (calculator 1) or CAT score <10 (calculator 2)) and at low risk of exacerbation (zero to one exacerbation per year), we suggest the use of a long-acting bronchodilator rather than short-acting bronchodilators alone (Grade 2B). We suggest using a LAMA (table 3) rather than a long-acting beta-agonist (LABA) (Grade 2C); however, a once daily LABA is an appropriate alternative depending on the patient’s symptoms and risks for medication adverse effects (table 2). Short-acting therapies alone are also reasonable in patients with only infrequent intermittent dyspnea. (See 'Less symptomatic patients at low risk of exacerbation (Group A)' above.)
•Group B – For patients who are more symptomatic (mMRC grade ≥2 (calculator 1) or CAT score ≥10 (calculator 2)), but at low risk of exacerbation based on their past history of exacerbations (zero to one exacerbation per year), we suggest regular use of long-acting inhaled bronchodilators rather than short-acting agents (Grade 2B), preferably dual bronchodilator (LAMA-LABA) therapy (Grade 2C). 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 5). (See 'Dosing and efficacy of individual agents' above and 'More symptomatic patients at low risk of exacerbation (Group B)' above.)
•Group E – For patients with a high risk of exacerbation (ie, ≥2 exacerbations per year or one or more exacerbation leading to hospitalization), we suggest initial treatment with LAMA-LABA therapy rather than either bronchodilator alone (Grade 2C). For patients with hospitalization due to exacerbation or highly elevated blood eosinophils (≥300 cells/microL), we suggest upfront LAMA-LABA-ICS therapy (Grade 2C). (See 'Patients at high risk of exacerbation (Group E)' above.)
●Possible asthma-COPD overlap – Patients with asthma-COPD overlap (ACO, also known as COPD-A) may benefit from earlier initiation of inhaled glucocorticoids than recommended for typical patients with COPD. The diagnosis and management of ACO is discussed separately. (See "Asthma and COPD overlap (ACO)".)
●Follow-up adjustment – Pharmacologic therapy is adjusted at follow-up visits based on the response to therapy (table 1). (See "Stable COPD: Follow-up pharmacologic management".)
ACKNOWLEDGEMENTS — The UpToDate editorial staff acknowledges Gary T Ferguson, MD, and Barry Make, MD, who contributed to earlier versions of this topic review.
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