2023 Canadian Thoracic Society Guideline on Pharmacotherapy in Patients with Stable COPD

Figures & data

Figure 1. Integrated Comprehensive Management of COPD.Integrated comprehensive management of COPD includes confirming COPD diagnosis with postbronchodilator spirometry, evaluation and on-going monitoring of dyspnea/symptom burden and risk of exacerbations and use of both pharmacologic and nonpharmacologic interventions (see Figure 3) to alleviate dyspnea/symptoms, improve health status, prevent AECOPD and reduce mortality. The approach should not be viewed as “stepwise” and may not necessarily occur in the order they appear for all patients. Self-Management Education includes optimizing inhaler device technique and [re-]review, assessment and review of medication adherence, breathing and cough techniques, early recognition of AECOPD, written AECOPD action plan and implementation (when appropriate), promoting physical activity and/or exercise, and other healthy habits including diet and smoking cessation.**Inhaled Maintenance/Preventative Pharmacotherapies are long-acting muscarinic antagonists (LAMA) and/or long-acting ẞ2-agonists (LABA) with or without inhaled corticosteroids (ICS). ICS monotherapy should NOT be used in COPD management.*Other pharmacotherapies include oral therapies (prophylactic macrolide, and PDE-4 inhibitor, mucolytic agents for patients with chronic bronchitis), alpha-1-antitrypsin augmentation therapy for documented severe A1AT deficiency, and opioids for severe refractory dyspnea (see prior CTS Guideline).^13ǂSurgical therapies may include lung transplantation and lung volume reduction (including with endoscopic valves).Abbreviations. A1AT, alpha-1 antitrypsin; AECOPD, acute exacerbation of COPD; CAT, COPD assessment test; COPD, chronic obstructive pulmonary disease; CTS, Canadian Thoracic Society; mMRC, modified Medical Research Council; prn, as-needed; NIV, noninvasive ventilation.

Table

Health Care Providers	Nonhealth Care Providers
Certified Respiratory Educators	Healthcare decision-makers (i.e., national, provincial and local policy makers)
Internists	Patient advocates
Nurse Practitioners/Physician Assistants	Patients
Pharmacists	Healthcare researchers
	Knowledge translation specialists
Primary Care Physicians Respirologists

Figure 2. PRISMA Diagram.

Table 1. 2023 recommendations for PICO 1

How does a clinician choose appropriate maintenance pharmacotherapies in individuals with stable COPD to reduce symptom burden, for example, dyspnea and exercise intolerance, and improve health status?

2023 Recommendations to reduce symptom burden and improve health status	Strength of recommendation	Certainty of evidence	Evidence from meta-analysis
			Online Supplement Table 1	Online Supplement 2
P.1.A. In individuals with stable COPD, at low risk of exacerbations§, with low symptom burden and health status impairment (CAT <10, mMRC 1), and only mildly impaired lung function (FEV1 ≥ 80% predicted), we recommend starting initial monotherapy with either LAMA or LABA. Clinical remark: All studies have characterized individuals with spirometry-based COPD although not all have classified disease severity by FEV1, mMRC and/or CAT exactly as we have in order to compare either LAMA or LABA monotherapy to placebo; however, the panel valued the importance of providing a precise consensus working definition of COPD with mild symptom burden for recommending regular long-acting bronchodilator therapy.	Strong	Moderate to high certainty of greater improvements in dyspnea, exercise tolerance, and health status with LAMA or LABA compared to placebo. Low certainty of greater improvements in dyspnea, exercise tolerance, and health status with LAMA monotherapy compared to LABA monotherapy. Low certainty of greater improvement in physical activity with LAMA or LABA compared to placebo.	1.1 a, b 1.1 c 1.1 d	Tables 16, 17; Pages 127, 128. Table 1; Figures: 1-13; Pages 5-23. n/a
P.1.B. In individuals with stable COPD, at low risk of exacerbations^§, with a moderate to high symptom burden/health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted), we recommend starting LAMA/LABA dual therapy as initial maintenance therapy. Clinical remarks: This recommendation reflects the strength and quality of evidence and high importance to patients and clinicians of alleviating dyspnea and improving health status as key treatment goals of COPD, particularly in individuals with moderate to high symptom burden/health status impairment. Note that improvement in exercise capacity may not lead to improvement in physical activity without adding a behavioral intervention. LAMA/LABA dual therapy is preferred to ICS/LABA combination therapy due to significant improvement in lung function and lower rates of pneumonia. However, ICS/LABA combination therapy is preferred to LAMA/LABA dual therapy in individuals who have COPD with concomitant asthma.	Strong	Moderate to high certainty of greater improvements in dyspnea, exercise intolerance, and health status with LAMA/LABA compared to LAMA monotherapy. Moderate certainty of greater improvements in dyspnea, exercise intolerance, and health status with LAMA/LABA compared to LABA monotherapy. Low certainty of greater improvement in physical activity with LAMA/LABA compared to placebo. Low certainty of greater improvements in dyspnea, exercise intolerance, and health status with LAMA/LABA compared to ICS/LABA combination therapy.	1.2 a 1.2 b 1.3 1.5	Table 2; Figures: 14-23; Pages 24-40. Table 3; Figures: 24-34; Pages 41-50. Table 18; Page 129. Table 4; Figures: 35-46; Pages 51-62.
P.1.C. In individuals with stable COPD, at low risk of exacerbations^§, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted) despite LAMA/LABA dual therapy or ICS/LABA combination therapy, we recommend step-up to a LAMA/LABA/ICS triple combination therapy. Clinical remark: The best option to alleviate dyspnea and other symptoms as well as to improve health status is to combine optimal pharmacotherapy with pulmonary rehabilitation.	Strong	Moderate certainty of greater improvements in dyspnea and health status with LAMA/LABA/ICS compared to LAMA/LABA dual therapy or ICS/LABA combination therapy.	1.6 a, b	Tables 7, 8; Figures: 71-92; Pages 90-107.
P.1.D. In individuals with stable COPD, at low risk of exacerbations^§, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted) despite LAMA/LABA/ICS triple combination therapy, we suggest not stepping down to LAMA/LABA dual therapy. For patients taking LAMA/LABA dual therapy, we suggest not stepping down to LAMA or LABA monotherapy. Clinical Remark: This recommendation reflects the high importance that both patients and clinicians ascribe to alleviating dyspnea and improving health status, particularly in individuals with moderate to high symptom burden/health status impairment. Withdrawing ICS may result in worsening of health status and lung function in some patients. Therefore, we prioritized these outcomes over the risk of adverse events including pneumonia with use of LAMA/LABA/ICS triple combination therapy. However, stepping down may be considered in patients in whom the step up did not result in improved symptoms or health status or because of adverse effects that are of significant importance. No studies of step-down have assessed the impact on dyspnea.	Weak Weak	Low to moderate certainty of lack of harm from step down from LAMA/LABA/ICS to LAMA/LABA dual therapy. Insufficient evidence.	1.7	Table 10; Figures: 101-103; Pages 115-117.
P.1.E. In individuals with stable COPD, at low risk of exacerbations^§, currently on LAMA monotherapy, LABA monotherapy or LAMA/LABA dual therapy, we do not suggest adding any of the following oral medications: - Phosphodiesterase-4-inhibitors - Mucolytics - Statins - Anabolic steroids - Oral Chinese herbal medicines - Theophylline Clinical remark: There are limited studies assessing theophylline, which showed equivocal changes in health status. Although there is evidence of a modest improvement in FEV1 with theophylline, the panel placed greater weight on the risk of adverse events and drug interactions.	Weak	Low certainty of no improvements in dyspnea, exercise tolerance, physical activity levels, and/or health status with oral therapies compared to placebo.	1.8	Tables 12-20; Pages 118-131.
P.1.F. In all individuals with stable COPD and at a low risk of exacerbations^§, we recommend against treatment with ICS monotherapy. Clinical Remark: When indicated in patients with COPD, ICS should only be administered as part of combination therapy (see above). The panel placed greater weight on the increased risk of adverse events (e.g., pneumonia).	Strong	Low certainty of no improvements in dyspnea, exercise tolerance, physical activity levels, and/or health status with ICS monotherapy compared to placebo.	1.9	Table 19; Page 130.

^§Patients are considered at “Low Risk of AECOPD” if ≤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.

Abbreviations. CAT, COPD assessment test; mMRC, Modified Medical Research Council; FEV₁, Forced expiratory volume in the first second; AECOPD, acute exacerbation of COPD; ED, emergency department; LAMA, long-acting muscarinic antagonist; LABA, long-acting ẞ2-agonist; ICS, inhaled corticosteroid; P.1., Patients/population (P); Intervention(s) (I), Comparison/comparator (C); and Outcome (O), (PICO)1.

Table 2. 2023 Recommendations for PICO 2

How does a clinician choose appropriate maintenance pharmacotherapies in individuals with stable COPD to reduce the risk of AECOPD?

2023 Recommendations to reduce the risk of acute exacerbations	Strength of recommendation	Certainty of evidence	Evidence from meta-analysis
			Supplement Table 1	Supplement 2
P.2.A. In individuals with stable COPD, at low risk of exacerbations^§, a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted), we recommend starting LAMA/LABA dual therapy as initial maintenance therapy. Clinical Remark: LAMA/LABA dual therapy is preferred to ICS/LABA combination therapy due to significant improvement in lung function and lower rates of pneumonia. However, ICS/LABA combination therapy is preferred to LAMA/LABA dual therapy in individuals who have COPD with concomitant asthma.	Strong	Moderate certainty of greater reduction in rate of exacerbation with LAMA/LABA dual therapy compared to LAMA monotherapy. Low to moderate certainty of greater reduction in rate of exacerbation with LAMA/LABA dual therapy compared to LABA monotherapy. Low to moderate certainty of greater reduction in rate of exacerbation with LAMA/LABA dual therapy compared to ICS/LABA combination therapy.	2.4 a 2.4 b 2.6	Table 22; Figures: 118-122; Pages 137-14. Table 23; Figures: 123-126; Pages 142-144. Table 24; Figures: 127-129; Pages 145-148.
P.2.B. In individuals with stable COPD, at high risk of exacerbations*, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted), we recommend the use of LAMA/LABA/ICS triple combination therapy. Clinical Remark: The panel placed high value on the reduction of exacerbations and mortality as demonstrated in several studies when LAMA/LABA/ICS triple combination therapy was used in this high-risk population compared to LAMA/LABA dual therapy or ICS/LABA combination therapy.	Strong	Low to moderate certainty of greater reduction in rate of exacerbation with LAMA/LABA/ICS triple combination therapy compared to LAMA monotherapy. Moderate certainty of greater reduction in rate of exacerbation with LAMA/LABA/ICS triple combination therapy compared to ICS/LABA combination therapy. Moderate certainty of greater reduction in rate of exacerbation with LAMA/LABA/ICS triple combination therapy compared to LAMA/LABA dual therapy.	2.7 a 2.7 b 2.7 c	Table 29; Figures: 147-151; Pages 164-167. Table 28; Figures: 142-146; Pages 160-163. Table 27; Figures: 137-141; Pages 157-159.
P.2.C. In individuals with stable COPD, at a high risk of exacerbations*, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted), we do not suggest step down from LAMA/LABA/ICS triple combination therapy to LAMA/LABA dual therapy. Clinical Remark: Withdrawing ICS may lower health status and lung function. Withdrawing ICS may also be associated with an increased risk of moderate-severe AECOPD, especially in patients with blood eosinophils counts ≥300 cells/µL.	Weak	Low certainty of benefit of stepdown from LAMA/LABA/ICS to LAMA/LABA	2.8	Table 30; Figure: 152-154; Pages 168-170.
P.2.D. In individuals with stable COPD, at a high risk of exacerbations*, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted) who continue to exacerbate (either moderate or severe) despite being on LAMA/LABA/ICS triple combination therapy, we recommend the addition of macrolide maintenance therapy. Clinical Remark: the benefits of macrolide maintenance therapy studied over one-year should be weighed against the risks of microbial resistance, hearing impairment and cardiac arrhythmia related to QT prolongation/drug interactions.	Strong	Moderate certainty of greater reduction in rate of exacerbation with addition of oral macrolide to LAMA/LABA/ICS	2.11	Table 35; Page 179.
P.2.E. In individuals with stable COPD, with a Chronic Bronchitic Phenotype at a high risk of exacerbations*, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 < 80% predicted) who continue to exacerbate despite being on LAMA/LABA/ICS triple combination therapy, we suggest the addition of either Roflumilast or N-Acetylcysteine.	Weak	Low certainty of greater reduction in rate of exacerbation with the addition of Roflumilast compared to placebo? Moderate certainty of the addition of N-Acetylcysteine.	2.9 2.10	Table 40; Page 184. Table 32; Figures: 157; Page 173.

^§Patients are considered at “Low Risk of AECOPD” if ≤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/Emergency Department visit.

*Patients are considered at “High Risk of AECOPD” if ≥2 moderate AECOPD or ≥1 severe AECOPD in the last year (severe AECOPD is an event requiring hospitalization or ED visit).

Abbreviations. CAT, COPD assessment test; mMRC, Modified Medical Research Council; FEV₁, Forced expiratory volume in the first second; AECOPD, acute exacerbation of COPD; ED, emergency department; LAMA, long-acting muscarinic antagonist; LABA, long-acting ẞ2-agonist; ICS, inhaled corticosteroid; P.2., Patients/population (P); Intervention(s) (I); Comparison/comparator (C); and Outcome (O), (PICO) 2.

Table 3. 2023 Recommendations for PICO 3

How does a clinician choose appropriate maintenance pharmacotherapies in individuals with stable COPD to reduce mortality?

2023 Recommendations to reduce mortality	Strength of recommendation	Certainty of evidence	Evidence from meta-analysis
			Supplement Table 1	Supplement 2
P.3.A. In individuals with stable COPD, at a high risk of exacerbations*, with a moderate to high symptom burden and/or health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 <80% predicted), we recommend the use of LAMA/LABA/ICS triple combination therapy over LABA/LAMA dual therapy. Clinical remark: Triple combination therapy is preferred to LABA/LAMA dual therapy because of the greater benefit in reducing mortality (secondary or other outcome) and also the additional benefits of preventing moderate-severe AECOPD (primary outcomes in these RCTs) and improving dyspnea, health status, lung function (secondary outcomes), in this well-defined population of patients.	Strong	Moderate certainty for greater reduction in mortality with LAMA/LABA/ICS triple combination compared to LABA/LAMA dual therapy.	3.2	Table 41; Figures 162-164; Pages 186-188.
P.3.B. In individuals with stable COPD, at a high risk of exacerbations*, with a moderate to high symptom burden/health status impairment (CAT ≥10, mMRC ≥2) and impaired lung function (FEV1 <80% predicted) we recommend the use of LAMA/LABA/ICS triple combination therapy over ICS/LABA combination therapy. Clinical remark: Although triple therapy has not shown superiority in reducing mortality (secondary or other outcome) compared to ICS/LABA, it has shown greater benefit on other important outcomes such as preventing moderate-severe AECOPD (primary outcomes in these RCTs) and improving dyspnea, health status, lung function (secondary outcomes), in this well-defined population of patients.	Weak	Moderate certainty for greater reduction in mortality with LAMA/LABA/ICS triple combination therapy compared to ICS/LABA combination therapy.	3.3	Table 42; Figures: 165-167; Pages 189-192.

*Patients are considered at “High Risk of AECOPD” if ≥2 moderate AECOPD or ≥ 1 severe exacerbation in the last year (severe AECOPD is an event requiring hospitalization or ED visit).

Abbreviations. CAT, COPD assessment test; mMRC, Modified Medical Research Council; FEV1, Forced expiratory volume in the first second; AECOPD, acute exacerbation of COPD; ED, emergency department; LAMA, long-acting muscarinic antagonist; LABA, long-acting ẞ2-agonist; ICS, inhaled corticosteroid; P.3., Patients/population (P); Intervention(s) (I); Comparison/comparator (C); and Outcome (O), (PICO) 3; RCTs, randomized controlled trials.

Figure 3. COPD Pharmacotherapy.This figure promotes an evidence-informed approach that aligns proven effective treatments with spirometry, symptom burden, risk of future exacerbations and mortality risk. Because of the clinical heterogeneity in COPD, spirometry should not be used in isolation to assess disease severity and this is why it is also important to perform a thorough clinical evaluation of the patient, including symptom burden and risk of exacerbations that permits the implementation of treatments that are specific for subpopulations. SABD prn (as needed) should accompany all recommended therapies across the spectrum of COPD.^†Symptom burden encompasses shortness of breath, activity limitation, and impaired health status.^††Individuals are considered at “Low Risk of AECOPD” if ≤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. Individuals are considered at “High Risk of AECOPD” if ≥2 moderate AECOPD or  ≥1 severe exacerbation in the last year (severe AECOPD is an event requiring hospitalization or ED visit).*LAMA/LABA single inhaled dual therapy is preferred over ICS/LABA inhaled combination therapy considering the additional improvements in lung function and the lower rates of adverse events such as pneumonia. ICS/LABA combination therapy should be used in individuals with concomitant asthma. There is no universally accepted definition of concomitant asthma. The 2017 CTS Position Statement on COPD Pharmacotherapy provides guidance on the assessment of patients who may have concomitant asthma.**Triple inhaled ICS/LAMA/LABA combination therapy should preferably be administered in a single inhaler triple therapy (SITT), and not in multiple inhalers (see text), although we acknowledge that some patients continue to prefer separate inhalers. ⁺Oral pharmacotherapies in this group include prophylactic macrolide, and PDE-4 inhibitor and mucolytic agents for patients with chronic bronchitis.Abbreviations. CAT, COPD assessment test; mMRC, Modified Medical Research Council; SABD prn, short-acting bronchodilator as needed; AECOPD, acute exacerbation of COPD; ED, emergency department; LAMA, long-acting muscarinic antagonist; LABA, long-acting ẞ2-agonist; ICS, inhaled corticosteroid.

Bourbeau J, Bhutani M, Hernandez P, et al. Canadian Thoracic Society Clinical Practice Guideline on pharmacotherapy in patients with COPD – 2019 update of evidence. Canadian Journal of Respiratory, Critical Care, and Sleep Medicine. 2019;3(4):210–232. doi:10.1080/24745332.2019.1668652.

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