Canadian Thoracic Society Clinical Practice Guideline on pharmacotherapy in patients with COPD – 2019 update of evidence

Figures & data

Figure 1. Comprehensive management of COPD.

Integrated approach to care that includes confirming COPD diagnosis with spirometry, evaluation of symptom burden and risk of exacerbations with on-going monitoring, assessment for features of asthma, and comprehensive management, both non-pharmacologic and pharmacologic.

* = Self-Management Education includes appropriate inhaler device technique and review, breathing techniques and review, early recognition of AECOPD, written action plan development and implementation (if appropriate).

mMRC is a modified (0-4 scale) version of the MRC breathlessness scale which was used in previous CTS guidelines. The mMRC aligns with the Global Initiative for Chronic Obstructive Airways Disease (GOLD) 2019 report.

Abbreviations: CAT = COPD assessment test; mMRC = Modified Medical Research Council; prn = as-needed; AECOPD = acute exacerbation of COPD; Inhaled Long-Acting Therapies = long-acting muscarinic antagonist and/or long-acting ẞ2-agonist and/or inhaled corticosteroid; NIV = non-invasive ventilation.

Table

Healthcare	Nonhealthcare
Certified respiratory educators	Healthcare decision-makers
Internists	Patient advocates
Nurse practitioners	Patients
Pharmacists
Primary care physicians
Respirologists

Figure 2. COPD Pharmacotherapy.

COPD pharmacotherapy promoting an approach that aligns treatment decisions with symptom burden and risk of future exacerbations. To learn more about the Asthma-COPD Overlap (ACO) treatment algorithm, refer to the CTS position statement on the pharmacotherapy in patients with COPD in 2017.¹

mMRC is a modified (0-4 scale) version of the MRC breathlessness scale which was used in previous CTS guidelines. The mMRC aligns with the Global Initiative for Chronic Obstructive Airways Disease (GOLD) 2019 report.

SABD prn (as needed) should accompany all recommended therapies. Solid arrows indicate step up therapy to optimally manage symptoms of dyspnea and/or activity limitation, as well as prevention of AECOPD where appropriate. Dashed arrows indicate potential step down of therapy, with caution and with close monitoring of patient symptoms, exacerbations and lung function. Symbol “/” refers to combination products (in the same device) and combination regimens (in separate devices). ICS should ideally be administered in a combination inhaler.

†Patients are considered at Low Risk of AECOPD with ≤1 moderate AECOPD in the last year (moderate AECOPD is an event with prescribed antibiotic and/or oral corticosteroids), and did not require hospital admission/ED visit; or at High Risk of AECOPD with ≥2 moderate AECOPD or ≥1 severe exacerbation in the last year (severe AECOPD is an event requiring hospitalization or ED visit).

*Blood eosinophil ≥300/µL in patients with previous AECOPD may be useful to predict a favorable response to ICS combination inhaler.

‡Oral Therapies = Roflumilast, N-acetylcysteine, daily dose Azithromycin could be considered with patients with high risk AECOPD despite on optimal long-acting inhaled therapy. Oral corticosteroids as maintenance therapy are not indicated in COPD.

Abbreviations: CAT = COPD assessment test; mMRC = Modified Medical Research Council; SABD prn = short-acting bronchodilator as needed; AECOPD = acute exacerbation of COPD; LAMA = long-acting muscarinic antagonist; LABA = long-acting ẞ2-agonist; ICS = inhaled corticosteroid.

Table 1. 2019 Recommendations on improving symptoms, exercise tolerance, physical activity and health status in stable COPD patients.

PICO 1: How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce symptom burden (notably dyspnea and exercise intolerance), increase physical activity, and improve health status?
#	Grade	Guidance	Clinical Remarks	References
1.1	1A	We recommend an inhaled long-acting bronchodilator, either LAMA or LABA monotherapy, to reduce dyspnea, improve exercise tolerance, and improve health status.	LAMA is preferred over LABA therapy to prevent AECOPD (see PICO 2).	^35–71
1.2	1A	We recommend an inhaled LAMA/LABA dual therapy in patients who experience persistent dyspnea, exercise intolerance, and/or poor health status despite the use of LAMA or LABA monotherapy.	Shortness of breath and exercise tolerance improve with LAMA/LABA dual therapy over monotherapy; health status has not been addressed as a primary outcome.	^30^,^40^,^72–90
1.3	2A	We suggest an inhaled long-acting bronchodilator, i.e., LAMA, LABA, or LAMA/LABA dual therapy, to increase physical activity.	A long-acting bronchodilator may improve exercise capacity but not improve physical activity unless a behavioral intervention is offered as well.	^30^,^38^,^51^,^91–94
1.4	2A	We suggest LAMA/LABA dual therapy rather than ICS/LABA dual therapy in COPD patients who have persistently poor health status despite the use of maintenance LABA.	ICS/LABA should be preferred to LAMA/LABA only in COPD patients with concomitant asthma.	^95^,^96
1.5	2A	We suggest LAMA/LABA/ICS triple therapy in COPD patients with persistent dyspnea and poor health status in the last year despite the use of inhaled LAMA/LABA dual therapy.	Dyspnea and exacerbation are often present in the same patient.	^33^,^34^,^97^,^98
1.6	Consensus	In stable COPD patients with no improvement in dyspnea, exercise tolerance or health status, despite the use of LAMA/LABA/ICS triple therapy or LAMA/LABA dual therapy, treatment “step down” may be considered. There is insufficient evidence to determine whether “step down” (LAMA/LABA/ICS triple therapy to LAMA/LABA dual therapy, or LAMA/LABA dual therapy to LAMA or LABA monotherapy) is safe and/or reduces patient benefit.	Withdrawing ICS may lower health status and lung function in some patients. Do not undertake “step down” in patients at high risk of AECOPD (see PICO 2).	^99
1.7	2C	There is insufficient or equivocal evidence to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4-inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines, or phosphodiesterase-5-inhibitors confers additional benefit to LAMA or LABA monotherapy, or LAMA/LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels, and/or improving health status.		^76^,^100–119
1.8	Consensus	We recommend against treatment with ICS monotherapy in stable COPD patients.	When indicated, ICS should ideally be administered in a combination therapy in COPD patients.

Stable COPD: Patients are considered to have “stable COPD” in all clinical states other than during the period of an acute exacerbation of COPD (AECOPD). However, patients with “stable COPD” may have progressive symptoms and/or have experienced an exacerbation. Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short- or long-acting. Different types of short- or long-acting bronchodilators work in different ways.

• Short-acting bronchodilators can be either SABAs (short-acting beta agonists) or SAMAs (short-acting muscarinic antagonists).

• Long-acting bronchodilators can be either LABAs (long-acting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).

Symbol “/” for combination therapy: The symbol “/” refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference.

Exacerbations: Exacerbations are “event-based” occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are:

• mild (worsening or new respiratory symptoms without a change in prescribed medications);

• moderate (prescribed antibiotic and/or oral corticosteroids); and

• severe (requiring a hospital admission or ED visit).

Low- and high-risk of future exacerbations: Patients are considered to be at:

• Low-risk of exacerbations if they had ≤1 moderate exacerbation in the last year and did not require an ED visit or hospitalization.

• High-risk of exacerbations if they had ≥ 2 moderate or ≥ 1 severe exacerbation in the last year requiring a hospital admission/ED visit.

Abbreviations: PICO, Patient/population - Intervention or interventions - Comparison groups - Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; ED, emergency department.

Table 2. 2019 Recommendations on preventing acute exacerbation in stable COPD.

PICO 2. How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce the risk of AECOPD?
#	Grade	Guidance	Clinical Remarks	References
2.1	1A	We recommend either LAMA or LABA monotherapy over a SABD prn.	This is applicable to a patient at low risk of AECOPD.	^67^,^69^,^71^,^123^,^132–139
2.2	1A	We recommend LAMA monotherapy over LABA monotherapy.	This is applicable to a patient at low risk of AECOPD.	^69^,^123^,^124^,^138
2.3	1A 2C	We recommend LAMA monotherapy over a SAMA. AND We suggest LABA monotherapy over a SAMA.	This is applicable to a patient at low risk of AECOPD.	^59^,^123^,^136^,^138 ^123^,^138
2.4	1B	We recommend LAMA/LABA dual therapy for patients experiencing AECOPD despite use of LAMA or LABA monotherapy.		^85^,^123^,^140–148
2.5	1A 1A	We recommend ICS/LABA dual therapy over SABD prn to prevent AECOPD in patients at high risk of AECOPD. AND We recommend ICS/LABA dual therapy over LABA monotherapy to prevent AECOPD in patients at high risk of AECOPD.		^123^,^139^,^149–155 ^123^,^139^,^149–157
2.6	1B	We recommend either LAMA/LABA or ICS/LABA dual therapy for patients at high risk of AECOPD.		^33^,^123^,^130^,^145^,^146^,^158–162
2.7	1A	We recommend LAMA/LABA/ICS triple therapy for patients at high risk of AECOPD despite the use of LAMA monotherapy or dual therapy (ICS/LABA or LAMA/LABA).		^33^,^123^,^134^,^163–168
2.8	1A	We recommend oral Roflumilast for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.		^118^,^123^,^169–176
2.9	1B	We recommend oral N-acetylcysteine (600 mg po BID) for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.		^123^,^177–185
2.10	2A	We suggest macrolide maintenance therapy for patients with a high risk of AECOPD despite optimal long-acting inhaled therapy.	Weigh the benefits against the risks of potential microbial resistance, hearing impairment and QT-prolonging drug interactions.	^123^,^158^,^186–189
2.11	2B	We suggest that oral slow-release theophylline should not be used, as it does not prevent AECOPD in patients on optimal long-acting inhaled therapy.		^123^,^190

Stable COPD: Patients are considered to have “stable COPD” in all clinical states other than during the period of an acute exacerbation of COPD (AECOPD). However, patients with “stable COPD” may have progressive symptoms and/or have experienced an exacerbation. SABD prn (as needed) should accompany all recommended therapies. Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short- or long-acting. Different types of short- or long-acting bronchodilators work in different ways.

• Short-acting bronchodilators can be either SABAs (short-acting beta agonists) or SAMAs (short-acting muscarinic antagonists).

• Long-acting bronchodilators can be either LABAs (long-acting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).

Symbol “/” for combination therapy: The symbol “/” refers to: combination products (in the same device) and combination regimens (in separate devices). Single or multiple inhalers for combination therapy represent the clinical reality of different approaches to manage patients for a variety of considerations, such as access to medication, response to treatment, medical conditions other than COPD and patient preference.

Exacerbations: Exacerbations are “event-based” occurrences; that is, respiratory symptom(s) that worsen beyond the normal day-to-day variability and may require the use of antibiotics and/or systemic corticosteroids and/or healthcare services. The varying levels of exacerbation severity are:

• mild (worsening or new respiratory symptoms without a change in prescribed medications);

• moderate (prescribed antibiotic and/or oral corticosteroids); and

• severe (requiring a hospital admission or ED visit).

Low- and high-risk of future exacerbations: Patients are considered to be at:

• Low-risk of exacerbations if they had ≤1 moderate exacerbation in the last year and did not require an ED visit or hospitalization.

• High-risk of exacerbations if they had ≥2 moderate or ≥1 severe exacerbation in the last year requiring a hospital admission/ED visit.

Oral Therapies are Roflumilast, N-acetylcysteine or daily dose Azithromycin. Oral corticosteroids as maintenance therapy are not indicated in COPD. Optimal long-acting inhaled therapy is therapy that has been tailored to the patient’s exacerbation history, in accordance with Figure 2.

Abbreviations: PICO, Patient/population - Intervention or interventions - Comparison groups - Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; BID, bis in die (twice a day); ICS, inhaled corticosteroid; ED, emergency department; SABD prn, short-acting bronchodilator as needed.

Table

PICO 1: How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce symptom burden (notably dyspnea and exercise intolerance), increase physical activity and improve health status?
PICO elements
Population	Intervention (s)	Comparator	Outcomes
Adults with stable COPD*, chronic bronchitis, emphysema	Maintenance inhaled therapy, alone or in combination: short-acting anticholinergic, short-acting beta-agonists, long-acting bronchodilators, long-acting beta-agonists, long-acting anticholinergic, long-acting muscarinic antagonists, inhaled corticosteroids, dual long-acting bronchodilators, combination ICS/LABA, triple therapy; oral therapy, alone or in combination(s): methylxanthines, theophylline, antibiotics, n-acetylcysteine, PDE-4 inhibitors, Roflumilast.	Placebo, combination therapies compared to single modality, head-to-head comparison	Dyspnea, exercise, exercise tolerance, exercise capacity, health-related quality of life
Search Terms		Inclusion/Exclusion Criteria
acute exacerbations, COPD, chronic obstructive lung disease, emphysema, chronic bronchitis, lung diseases (obstructive), chronic disease management, prevention, nonpharmacologic therapies, education, self-management, case management, action plans, in-home monitoring, tele-intervention, telehealth, tele-health, E-health, e-health, tele-healthcare, telecare, telemedicine, tele-monitoring, E-medicine, telecommunications and medicine, tele-consult, respiratory rehabilitation pulmonary rehabilitation, (exercise, exercise training, activity, physical activity, exercise movement techniques, muscle training, kinesiotherapy, strength, training, walking, ambulation, mobilization, mobility, fitness exercise)—only if exercise is included, immunizations, vaccination, influenza prevention, pneumococcal prevention, smoking cessation		English language studies, studies will be included based on population, intervention, comparison and outcome defined above. Include studies with follow-up duration of 3 months or greater and studies with follow-up duration of 6 months or greater. Primary and secondary outcomes will be included. If studies are included that examined an outcome of interest as a secondary outcome, the assessment of the secondary outcomes will be carefully examined and the body of evidence will be downgraded for risk of bias, if deemed necessary.
PICO 2: How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce the risk of AECOPD?
PICO Elements
Population	Intervention (s)	Comparator	Outcome
Adults with stable COPD,* chronic bronchitis, emphysema	Maintenance inhaled therapy, alone or in combination: short-acting anticholinergic, short-acting beta-agonists, long-acting bronchodilators, long-acting beta-agonists, long-acting anticholinergic, long-acting muscarinic antagonists, inhaled corticosteroids, dual long-acting bronchodilators, combination ICS/LABA, triple therapy; oral therapy, alone or in combination(s): methylxanthines, theophylline, antibiotics, n-acetylcysteine, PDE-4 inhibitors, Roflumilast.	Placebo, combination therapies compared to single modality, head-to-head comparison	Exacerbations requiring change in medication (antibiotic and/or prednisone), ER and hospital admissions/readmissions, time to first exacerbation, exacerbation rate
Search Terms		Inclusion/Exclusion Criteria
acute exacerbations, COPD, chronic obstructive lung disease, emphysema, chronic bronchitis, lung diseases (obstructive), chronic disease management, prevention, inhaled therapy, long acting beta agonists, long acting anticholinergics, short-acting anticholinergics, inhaled corticosteroids		English language studies, studies will be included based on population, intervention, comparison and outcome defined above. Include studies with follow-up duration of 3 months or greater and studies with follow-up duration of 6 months or greater. Primary and secondary outcomes will be included. If studies are included that examined an outcome of interest as a secondary outcome, the assessment of the secondary outcomes will be carefully examined and the body of evidence will be downgraded for risk of bias, if deemed necessary.

Abbreviations: PICO, Patient/population - Intervention or interventions - Comparison groups - Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; ICS/LABA, inhaled corticosteroid/long-acting beta agonists; AECOPD, acute exacerbation of COPD; ER, emergency room. Databases searched for both PICOs: MEDLINE (OVID), Embase (OVID), Cochrane Library, PubMed and National Guideline Clearinghouse.

*Patients are considered to have “stable COPD” in all clinical states other than during the period of an AECOPD.

Table

Grade of Recommendation		Benefit vs. Risk and Burdens	Methodologic Strength of Supporting Evidence	Implications
Strong recommendation, high-quality evidence	1A	Benefits clearly outweigh risk and burdens or vice versa.	Consistent evidence from randomized controlled trials without important limitations, or exceptionally strong evidence from observational studies.	Recommendation can apply to most patients in most circumstances. Further research is unlikely to change our confidence in the estimate of effect.
Strong recommendation, moderate-quality evidence	1B	Benefits clearly outweigh risk and burdens or vice versa.	Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence from observational studies.	Recommendation can apply to most patients in most circumstances. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate.
Strong recommendation, low- or very-low- quality evidence	1C	Benefits clearly outweigh risk and burdens or vice versa.	Evidence for at least one critical outcome from observational studies, case series or randomized controlled trials, with serious flaws or indirect evidence.	Recommendation can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.
Weak recommendation, high-quality evidence	2A	Benefits closely balanced with risks and burden.	Consistent evidence from randomized controlled trials without important limitations, or exceptionally strong evidence from observational studies.	The best action may differ depending on circumstances or patient or societal values. Further research is unlikely to change our confidence in the estimate of effect.
Weak recommendation, moderate-quality evidence	2B	Benefits closely balanced with risks and burden.	Evidence from randomized controlled trials with important limitations (inconsistent results, methodologic flaws, indirect or imprecise), or very strong evidence from observational studies.	Best action may differ depending on circumstances or patient or societal values. Higher-quality research may well have an important impact on our confidence in the estimate of effect, and may change the estimate.
Weak recommendation, low- or very-low- quality evidence	2C	Uncertainty in the estimates of benefits, risks and burden; benefits, risk and burden may be closely balanced.	Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials, with serious flaws or indirect evidence.	Other alternatives may be equally reasonable. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect, and may well change the estimate.

Reference: Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines report from an American College of Chest Physicians task force. Chest. 2006;129(1):174–181.

Table

First round of voting	1. Wholeheartedly agree
	2. Agree
	3. Can support
	4. Reservations: would like more discussion
	5. Serious concerns: needs more discussion
	6. Cannot participate: block it
Second round of voting	1. Agree
	2. Can support
	3. Cannot support: block it

Table

RECOMMENDATIONS — Improving Symptom, Exercise Tolerance and Health Status in Stable COPD
PICO 1: How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce symptom burden (notably dyspnea and exercise intolerance), increase physical activity, and improve health status?
2017	2019
Rec 1 – We recommend the use of an inhaled long-acting bronchodilator, either LAMA or LABA monotherapy, to reduce dyspnea, improve exercise tolerance and improve health status in stable COPD patients. (Grade 1A)	We recommend an inhaled long-acting bronchodilator, either LAMA or LABA monotherapy, to reduce dyspnea, improve exercise tolerance, and improve health status. Clinical remark: LAMA is preferred over LABA therapy to prevent AECOPD (see PICO 2).	GRADE 1A unchanged	Recommendation not updated New clinical remark
Rec 2 - We suggest that in stable COPD patients who experience persistent dyspnea, exercise intolerance, and/or poor health status despite use of inhaled LAMA or LABA monotherapy that they are considered for treatment “step up” with LAMA plus LABA dual therapy. (Grade 2A)	We recommend an inhaled LAMA/LABA dual therapy in patients who experience persistent dyspnea, exercise intolerance, and/or poor health status despite the use of LAMA or LABA monotherapy. Clinical remark: Shortness of breath and exercise tolerance improve with LAMA/LABA dual therapy over monotherapy; health status has not been addressed as a primary outcome.	GRADE 1A From 2A	Recommendation updated New clinical remark
Rec 3 - We suggest the use of a treatment with an inhaled long-acting bronchodilator, i.e., LAMA, LABA or LAMA plus LABA dual therapy, to improve physical activity levels in stable COPD patients. (Grade 2A)	We suggest an inhaled long-acting bronchodilator, i.e., LAMA, LABA, or LAMA/LABA dual therapy, to increase physical activity. Clinical remark: A long-acting bronchodilator may improve exercise capacity but not improve physical activity unless a behavioral intervention is offered as well.	GRADE 2A unchanged	Recommendation not updated New clinical remark
Rec 4 - We suggest in stable COPD patients without ACO who have persistently poor health status despite the regular use of a LABA, to “step up” therapy to an inhaled LAMA plus LABA dual therapy rather than to inhaled ICS/LABA combination. (Grade 2B)	We suggest LAMA/LABA dual therapy rather than ICS/LABA dual therapy in COPD patients who have persistently poor health status despite the use of maintenance LABA. Clinical remark: ICS/LABA should be preferred to LAMA/LABA only in COPD patients with concomitant asthma.	GRADE 2A From 2B	Recommendation not updated
Rec 5 - There is insufficient evidence in stable COPD patients to determine whether inhaled LAMA plus ICS/LABA triple therapy confers additional benefit to inhaled LAMA plus LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels, or improving health status. However, in stable COPD patients with high symptom burden and poor health status despite the use of inhaled LAMA plus LABA dual therapy, “step up” of treatment to LAMA plus ICS/LABA triple therapy may be considered. (Consensus-based).	We suggest LAMA/LABA/ICS triple therapy in COPD patients with persistent dyspnea and poor health status in the last year despite the use of inhaled LAMA/LABA dual therapy. Clinical remark: Dyspnea and exacerbation are often present in the same patient.	GRADE 2A From consensus-based	Recommendation updated
Rec 6 - There is insufficient evidence in stable COPD patients to determine whether treatment “step down,” i.e., inhaled triple therapy to inhaled LAMA plus LABA dual therapy or inhaled LAMA plus LABA dual therapy to LAMA or LABA monotherapy can be safe and/or without reducing patient benefits (i.e., dyspnea, exercise tolerance and health status). However, in stable COPD patients with no improvement of dyspnea, exercise tolerance or health status despite the use of triple inhaled therapy or inhaled LAMA plus LABA dual therapy, treatment “step down” may be considered (Consensus-based).	In stable COPD patients with no improvement in dyspnea, exercise tolerance or health status, despite the use of LAMA/LABA/ICS triple therapy or LAMA/LABA dual therapy, treatment “step down” may be considered. There is insufficient evidence to determine whether “step down” (LAMA/LABA/ICS triple therapy to LAMA/LABA dual therapy, or LAMA/LABA dual therapy to LAMA or LABA monotherapy) is safe and/or reduces patient benefit. Clinical remark: Withdrawing ICS may lower health status and lung function in some patients. Do not undertake “step down” in patients at high risk of AECOPD (see PICO 2).	Consensus-based unchanged	Recommendation revised New clinical remark
Rec 7 - There is insufficient or equivocal evidence in stable COPD patients to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4-inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitors, confers additional benefit to inhaled LAMA or LABA monotherapy, or LAMA plus LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels or improving health status. (Grade 2C).	There is insufficient or equivocal evidence to determine whether the addition of an oral therapy, such as theophyllines, phosphodiesterase-4-inhibitors, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitors confers additional benefit to LAMA or LABA monotherapy, or LAMA/LABA dual therapy in reducing dyspnea, improving exercise tolerance and activity levels and/or improving health status.	GRADE 2C unchanged	Recommendation not updated
Rec 8 - We recommend against treatment with ICS monotherapy in stable COPD patients. (Consensus-based)	We recommend against treatment with ICS monotherapy in stable COPD patients. Clinical remark: When indicated, ICS should ideally be administered in a combination therapy in COPD patients.	Consensus-based unchanged	Recommendation not updated New clinical remark
RECOMMENDATIONS – Preventing acute exacerbation in stable COPD
PICO 2. How does a clinician choose appropriate maintenance pharmacotherapies in patients with stable COPD to reduce the risk of AECOPD?
2017	2019
Rec 1 - We recommend the use of an inhaled LAMA (Grade 1A) or an inhaled LABA (Grade 1B) compared with placebo (i.e., SABD prn) to prevent AECOPD.	We recommend either LAMA or LABA monotherapy over a SABD prn. Clinical remark: This is applicable to a patient at low risk of AECOPD.	GRADE 1A From 1B (for LABA only)	Recommendation not updated
Rec 2 - We recommend the use of an inhaled LAMA as a preferred choice compared with an inhaled LABA to prevent AECOPD (Grade 1B).	We recommend LAMA monotherapy over LABA monotherapy. Clinical remark: This is applicable to a patient at low risk of AECOPD.	GRADE 1A From 1B	Recommendation not updated
Rec 3 - We recommend an inhaled LAMA (Grade 1A) or suggest an inhaled LABA (Grade 2C) compared with an inhaled short-acting muscarinic antagonist to prevent AECOPD.	We recommend LAMA monotherapy over SAMA. AND We suggest LABA monotherapy over a SAMA. Clinical remark: This is applicable to a patient at low risk of AECOPD.	GRADE 1A unchanged GRADE 2C unchanged	Recommendation not updated
Rec 4 - We recommend inhaled LAMA plus LABA dual therapy for patients experiencing AECOPD despite the use of inhaled LAMA or LABA monotherapy (Grade 1C).	We recommend LAMA/LABA dual therapy for patients experiencing AECOPD despite use of LAMA or LABA monotherapy.	GRADE 1B From 1C	Recommendation not updated
Rec 5 - We recommend combination ICS/LABA compared to placebo (Grade 1B) or an inhaled LABA (Grade 1C) to prevent AECOPD.	We recommend ICS/LABA dual therapy over SABD prn to prevent AECOPD in patients at high risk of AECOPD. AND We recommend ICS/LABA dual therapy over LABA monotherapy to prevent AECOPD in patients at high risk of AECOPD.	GRADE 1A From 1B GRADE 1A From 1C	Recommendation updated
Rec 6 - We recommend inhaled LAMA plus LABA dual therapy as a preferred choice compared with ICS/LABA combination therapy to prevent AECOPD (Grade 1C).	We recommend either LAMA/LABA or ICS/LABA dual therapy for patients at high risk of AECOPD.	GRADE 1B From 1C	Recommendation updated
Rec 7 - We recommend LAMA plus LABA/ICS triple therapy to prevent AECOPD for patients experiencing AECOPD despite the use of inhaled LAMA (Grade 1B) or ICS/LABA (Grade 1C).	We recommend LAMA/LABA/ICS triple therapy for patients at high risk of AECOPD despite the use of LAMA monotherapy or dual therapy (ICS/LABA or LAMA/LABA).	GRADE 1A From 1C	Recommendation updated
Rec 8 - We recommend the use of oral Roflumilast to prevent AECOPD for patients with chronic bronchitis and a history of at least one exacerbation in the previous year despite long-acting inhaled therapy (Grade 1B).	We recommend oral Roflumilast for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.	GRADE 1A From 1B	Recommendation not updated
Rec 9 - We suggest treatment with oral N-acetylcysteine (600 mg po BID) to prevent AECOPD for patients with chronic bronchitis, a history of at least one exacerbation in the previous year, and on long-acting inhaled therapy (Grade 2B).	We recommend oral N-acetylcysteine (600 mg po BID) for patients with chronic bronchitis and a high risk of AECOPD despite optimal long-acting inhaled therapy.	GRADE 1B From 2B	Recommendation updated
Rec 10 - We suggest a macrolide as maintenance therapy to prevent AECOPD for patients with a history of recurrent moderate or severe COPD exacerbations in the previous year despite long-acting inhaled therapy (Grade 2A).	We suggest macrolide maintenance therapy for patients with a high risk of AECOPD despite optimal long-acting inhaled therapy. Clinical remark: Weigh the benefits against the risks of potential microbial resistance, hearing impairment and QT-prolonging drug interactions.	GRADE 2A unchanged	Recommendation not updated New clinical remark
Rec 11 - We suggest treatment with oral slow-release theophylline to prevent AECOPD for patients on long-acting inhaled therapy (Grade 2B).	We suggest that oral slow-release theophylline should not be used, as it does not prevent AECOPD in patients on optimal long-acting inhaled therapy.	GRADE 2B unchanged	Recommendation updated

Abbreviations: PICO, Patient/population ‐ Intervention or interventions ‐ Comparison groups ‐ Outcome or outcomes of interest; COPD, chronic obstructive pulmonary disease; ICS/LABA, inhaled corticosteroid/long‐acting beta agonists; AECOPD, acute exacerbation of COPD; LAMA, long‐acting muscarinic antagonists; SABD, SABD prn, short‐acting bronchodilator as needed; SAMA, short‐acting muscarinic antagonists; BID, bis in die (twice a day).

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