In this guideline update, we highlight important and new findings related to pharmacological therapy of chronic obstructive pulmonary disease (COPD) that should change clinical practice and improve disease management. We present updated evidence, recommendations and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and nonpharmacological therapy of COPD are out-of-scope for this update. In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. In patients with high-risk exacerbations, LAMA/LABA is the preferred choice to ICS/LABA except in patients with previous exacerbations who have higher peripheral eosinophilia. There is no role for ICS monotherapy; when indicated, ICS should only be used in combination with bronchodilators. Treatment "step up" in COPD is proposed as a practical construct supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, "step down" may be considered for some patients (not at high risk for future exacerbations), but should be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist. The decision of changing a therapy should always occur after a complete evaluation of the patient and the potential benefit to a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and patient preferences. Pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and nonpharmacological therapies with the dual goals of reducing symptoms and preventing acute exacerbations of COPD (AECOPD).

# R ESUM E
La pr esente mise a jour des lignes directrices met de l'avant de nouveaux r esultats importants sur le traitement pharmacologique de la maladie pulmonaire obstructive chronique (MPOC) qui devraient modifier la pratique clinique et am eliorer la prise en charge de la maladie. Nous pr esentons une mise a jour des donn ees probantes et des recommandations, et des observations cliniques d'experts sur la pharmacoth erapie d'entretien pour les patients dont la MPOC est stable. La pr esente mise a jour ne porte pas sur le diagnostic et le traitement non pharmacologique de la MPOC. Chez les patients ayant une MPOC et dont l'essoufflement, l'intol erance a l'effort et la d et erioration de l' etat de sant e persistent malgr e une monoth erapie d'antimuscarinique a longue dur ee d'action (AMLA) ou de beta 2 -agoniste a longue dur ee d'action (BALA), nous recommandons une progression du traitement vers une bith erapie AMLA/BALA. Chez les patients pr esentant un risque elev e d'exacerbations, il faut privil egier une bith erapie AMLA/BALA plutot qu'une association de corticost eroide en inhalation (CSI)/BALA, sauf chez les patients ayant d ej a subi des exacerbations et dont le nombre d' eosinophiles de sang p eriph erique est elev e. Il n'y a pas lieu de recourir a la monoth erapie de CSI; lorsqu'ils sont indiqu es, les CSI doiventetre utilis es uniquement

# Introduction
Since the last published Canadian Thoracic Society (CTS) position statement on the pharmacotherapy in patients with chronic obstructive pulmonary disease (COPD) in 2017, 1 several important publications have necessitated an update to the current approach. This document is intended to guide best practice in light of recent research.
In clinical practice, an integrated, comprehensive approach to care should include: a diagnosis of COPD confirmed with spirometry; clinical evaluation of the patient; and comprehensive management, which includes nonpharmacological and pharmacological interventions (Figure 1).
The diagnosis of COPD should be considered in patients at risk of developing this disease. Patients' smoking history should be the main focus as it remains the most important risk factor. However, clinicians should be aware of an increased risk of COPD in individuals reporting a past medical history of asthma and/or severe childhood respiratory disease. Additionally, patients who have been exposed to passive smoke and/or to indoor biomass fuel are also at increased risk for the development of COPD. 2 This includes individuals from developing countries where indoor biomass exposure is the leading cause of COPD. Physicians should also be attentive to patients presenting with "exacerbationlike respiratory events" in the office or emergency setting, which may be an initial presentation of previously undiagnosed COPD. These events are common in undiagnosed COPD (22% in undiagnosed compared to 40% in diagnosed COPD) and have substantial impact on health service utilization, such as emergency department (ED) visits and hospital admissions. 3 An exacerbation-like respiratory event can be a trigger (opportunity) for patients to come to the attention of the healthcare system and for clinicians to consider the diagnosis of COPD and/or to optimize disease management.
Recent robust population data have confirmed that many individuals with COPD remain undiagnosed, but symptomatic, with an increased risk of exacerbations, pneumonia and death. 4 However, undiagnosed COPD, but asymptomatic, can also have exacerbations and pneumonia. 4 These patients who are "asymptomatic" may have adapted their lives to the limitations associated with their disease and may not want to reflect upon changes that occur to them as being a problem, that is, denial. If the physician uses probing questions, then symptoms may be better determined. This reality calls into question the validity of current recommendations for diagnosis of COPD that suggest targeted testing with spirometry only for symptomatic individuals.
It is important to remind physicians that spirometry is essential for the diagnosis of COPD, that is, a fixed postbronchodilator ratio of the FEV 1 /FVC of <0.70 or < the lower limit of normal (LLN) ratio (i.e., less than the lower fifth percentile of the reference value from a healthy population). Recent results support the use of fixed ratio less than 0.70 as appropriate to identify individuals at risk of clinically significant COPD. 5,6 However, more than a single postbronchodilator spirometric assessment may be necessary for diagnosing COPD for patients with mild airway obstruction at baseline. 7 We suggest post-bronchodilator FEV 1 /FVC ratio should be confirmed by a repeat spirometry on a separate occasion if the value is between 0.6 and 0.8, because the ratio may change as a result of biological variation. Findings, however, indicate that if the initial post-bronchodilator FEV 1 /FVC ratio is less than 0.6 it is very unlikely to rise above 0.7 spontaneously. While the diagnosis of COPD is confirmed by a reduced FEV 1 /FVC ratio < 0.7, the severity of airflow obstruction in COPD should be assessed by the degree of reduction in the postbronchodilator FEV 1 (% predicted).
Non-pharmacological therapy is complementary to inhaled or oral medication and should be a foundational aspect of the comprehensive management of COPD. Physicians must ensure patients have the proper support to live in a smoke free environment, receive appropriate vaccinations, adhere to prescribed medication (including using proper inhaler technique), receive self-management education and coaching, remain physically active and be referred to and complete pulmonary rehabilitation. 1,8,9 In a recent survey by the COPD Foundation, 10 patients reported gaps such as not receiving information after diagnosis of COPD, and receiving almost no education on self-management skills. Patients wished they had mastered these skills sooner to recognize early signs of an exacerbation and what to do about it, to stay active, and to cope with episodes of anxiety and dyspnea.
In this guideline update, we highlight important and new findings related to pharmacological therapy that should change clinical practice and improve disease management. We present updated evidence and recommendations, and expert clinical remarks on maintenance pharmacotherapy in patients with stable COPD. The diagnosis and non-pharmacological therapy of COPD are out-of-scope for this update.

# Objectives
The overall objective of this CTS clinical practice guideline is to help clinicians to match their therapeutic decisions to the clinical status of each patient. This is a step toward personalizing therapy based on increasing individual characterization.
The specific objective is to provide clinical guidance with evidence-based recommendations and expert-informed clinical remarks to optimize maintenance pharmacological therapy for patients with COPD.

# Target patient population
The update applies to all individuals with stable COPD. 

# Key definitions
Bronchodilators open up the airways in the lungs by relaxing airway smooth muscle. They also reduce lung hyperinflation. Bronchodilator medications can be short-or longacting. Different types of short-or long-acting bronchodilators work in different ways.
Short-acting bronchodilators can be either SABAs (shortacting beta agonists) or SAMAs (short-acting muscarinic antagonists). Long-acting bronchodilators can be either LABAs (longacting beta2 agonists) or LAMAs (long-acting muscarinic antagonists).
Acute Exacerbations of COPD (AECOPD): 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).
We have chosen to reconsider the classification of exacerbations into low-and high-risk of future exacerbations to align with patients enrolled in recently published randomized clinical trials. This was a necessary decision considering that the recommendations made in the guideline are evidence based.
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.
Stable COPD: Patients are considered to have "stable COPD" in all clinical states other than during the period of an AECOPD. However, patients with "stable COPD" may have progressive symptoms and/or have experienced an exacerbation.
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.

# Methodology
This guideline was developed in accordance with the CTS guideline development process. 11 The panel used the AGREE II checklist to guide the development of the guideline. 12 

# Guideline panel composition
The COPD guideline panel comprised 12 experts: six respirologists with experience in COPD management, research and research methodology including three clinicians/epidemiologists; two primary care physicians appointed by the College of Family Physicians of Canada; and one pharmacist. All author conflicts of interests are available at https:// cts-sct.ca/guideline-library/.

# Key clinical questions
The key clinical questions were developed using the Patient/ population; Intervention or interventions; Comparison groups; Outcome or outcomes of interest (PICO) method. The PICO questions were based on the last published CTS position statement on the pharmacotherapy in patients with COPD in 2017. 1 We identified new evidence for PICO questions 1 and 2 but no new evidence to support an update of PICO 3 on Asthma COPD overlap (ACO). We did not include new interventions or de novo clinical questions in this review.

# Literature search and screening of abstracts
This update includes all new research publications from the end-date of the literature search for the 2017 CTS position statement on pharmacotherapy in patients with chronic obstructive pulmonary disease. 1 An initial search was conducted through the CTS/McMaster Plus database with selected relevant manuscripts included with publication dates through October 31, 2018. A dedicated literature search and additional articles were found by reviewing the references in included articles and based on authors' knowledge of other relevant publications. See Appendix 1 for details of the search strategy and a flow chart of search results and articles reviewed. We indexed the studies according to the PICO questions and made them available to the guideline panel on a dedicated software platform for manual assignment to individual reviewers.
For each PICO question, two panel members scrutinized titles and abstracts to decide whether the article was relevant (JB/PH-PICO 1; MB/DM-PICO 2). Where opinions differed, the two panel members resolved the conflict by discussion. Upon reaching consensus on the list of relevant abstracts, we obtained and reviewed copies of the full articles of all relevant and possibly relevant articles. The chosen inclusion and exclusion criteria (Appendix 1) were documented at both the abstract and full-text review stages.

# Study selection criteria
We excluded studies if they were not related to maintenance pharmacotherapy in patients with stable, moderate to very-severe COPD. We included only randomized clinical trials and systematic reviews for further review and inclusion. The same pairs of reviewers who scrutinized titles and abstracts also assessed inclusion/exclusion criteria (Appendix 1) for full-text articles. The Cochrane Risk of Bias Tool for randomized clinical trials was used to assess the risk of bias in individual studies. The Documentation and Appraisal Review (DART) tool was used to assess the quality of systematic reviews addressing a variety of research designs.

# Critical appraisal of identified studies
We compiled data from all articles relevant to each PICO question into evidence tables (available at: / guideline-library/). The entire panel discussed each PICO question via webinars in June 2019, at which time, all evidence tables were reviewed. Accordingly, we established group consensus on the quality and strength of the evidence addressing each clinical question according to the GRADE criteria (Appendix 1). 13 In instances where there was insufficient evidence but a recommendation was still warranted, a suggestion was developed and "consensus-based (CB)" replaced the grade.

# Synthesis of evidence-base and clinical judgment of risk-versus-benefit
For each clinical question, we considered the strength and directness of the evidence supporting an intervention or treatment approach. For each therapeutic approach, we also considered: the potential health benefit to the patient; the morbidity and mortality impact on the overall COPD population; risks/harms; the burden placed on the patient; and the cost-effectiveness (these are the factors categorized under the "Contextualization and Deliberations" domain of the guidelines). 14 We also included informed clinical remarks with PICO clinical questions and recommendations, in an effort to compliment recommendations with practical clinical advice. Some of these remarks are not based on strong evidence, but represent the consensus opinions of panel members based on expertise.

# Update of recommendations and classification
We used recommendations in the 2015 Prevention of Acute Exacerbations of COPD -American College of Chest Physicians, the Canadian Thoracic Society Guideline document 15  Following open and extensive discussions and evidence review for each PICO question, the entire panel proposed wording updates to each prior recommendation pertaining to that PICO question, and where applicable, a change to the strength of the recommendation to reflect newly published literature. We based strength of the recommendation on the GRADE quality of evidence 13 (Appendix 1), and our synthesis of clinical judgment. The CTS Canadian Respiratory Guidelines Committee (CRGC) Chair then vetted the recommendations to optimize language with a view to improving likelihood of uptake. 16,17 Recommendations were then voted upon by electronic survey using a six-point voting scale, whereby it was defined a priori that a recommendation would only be accepted if each panel member voted for option 1, 2 or 3 (wholeheartedly agree, agree or can support). For a recommendation to be accepted, it had to be voted on by 75% of the eligible panel members and achieve ratings 1, 2 or 3 by 80% of the voting panelists. In the event of a failure to reach 80% of votes with ratings 1, 2 or 3, another period of discussion ensued, whereby dissenting opinions were heard and considered. The recommendation was revised and followed by a second round of voting by electronic survey using a three-point scale, for which acceptance of a recommendation required a majority (80%) of panelists to choose option 1 or 2 (Appendix 1). Throughout this process all recommendations achieved acceptance, with no recommendation requiring a second round of voting.

# Review and approval process
The CTS independently invited formal review of the update by an external (non-CTS) content expert. The lead author responded to the comments and made corresponding changes. Two members of the CRGC then completed their own review and provided further feedback for consideration. Upon acceptance, the Committee recommended approval of the guideline to the CTS Executive Committee.

# Living guideline/future updates
The guideline will be formally reviewed every three years or sooner to determine the need for and nature of any updates, in accordance with the CTS Living Guideline Model (details available at /). Authors and/or the CTS COPD Assembly Steering Committee members will also use the continuously updated McMaster Plus database, whereby they will receive alerts when new articles pertaining to these PICO questions are published (starting from the last date of the literature search conducted for this guideline). This will serve to prompt members to consider timely guideline updates with evolving evidence and will facilitate formal literature reviews.
Summary PICO 1: Improving symptoms, exercise tolerance, physical activity and health status in stable COPD patients Among respiratory symptoms, shortness of breath (dyspnea) on exertion is the most debilitating symptom COPD patients experience. 18 Since disease progression reduces patients' capacity to exercise and, therefore, affects the ability to perform the activities of daily life, 19,20 they consider relief of this symptom to be one of the most important outcomes in the management of their disease. 21 Shortness of breath also contributes to the established extra-pulmonary manifestations of COPD, including anxiety, depression, 22 cardiovascular disease 23 and peripheral locomotor muscle deconditioning. 24 Importantly, it is strongly associated with increased morbidity and mortality in adults with COPD. 25,26 Persistent shortness of breath is associated with increased exacerbation risk. 26,27 Dyspnea and exacerbation are not independent or dichotomous outcomes and they are often present in the same patient. Alleviating shortness of breath is a key goal of COPD management.
Inhaled bronchodilators are the mainstay medications in the pharmacologic management of COPD. There are two main classes of bronchodilators: B 2 -adrenoreceptor agonists and muscarinic antagonists, both in long-and short-acting forms. They can be used as monotherapy, combined as dual bronchodilators or combined with ICS for maintenance treatment. Bronchodilators enhance the neuromechanical coupling of the respiratory system and delay the onset of mechanical constraints, providing relief from exertional shortness of breath with concomitant improvement in exercise tolerance in patients with COPD. 28 This section discusses the optimal use of inhaled and oral pharmacologic maintenance therapies shown to improve shortness of breath, exercise tolerance, physical activity and health status in stable COPD patients.

# Key evidence
Based on this review for PICO 1, recommendations 1, 3, 7 and 8 remain unchanged, while recommendations 2, 4 and 5 have a change in GRADE assessment due to new research findings, and 2, 5 and 6 are revised based on evidence from published literature. See Appendix 2 detailing the upgrades and revisions from 2017.
As stated in the previous position statement, use of LAMA or LABA monotherapy is endorsed to reduce shortness of breath, improve exercise tolerance and improve health status in patients with stable COPD. Although LAMA is often preferred to LABA in monotherapy, the evidence of its superiority comes primarily from studies in which the main outcome was to prevent COPD exacerbations. In patients with COPD who have persistent shortness of breath, exercise intolerance and/or poor health status despite using inhaled LAMA or LABA monotherapy, we recommend augmenting treatment to LAMA/LABA dual therapy. Patients should be routinely monitored and evaluated for their response after any change in their therapy, as many have persisting symptoms with an impact on their well-being. 29 In terms of improving physical activity, the evidence suggests that combining a self-management behavioral intervention with exercise and pharmacologic interventions has the largest effect on physical activity and symptom improvement. A self-management behavioral intervention is more likely to help patients change their behavior and can lead to long-term adoption of a more physically active lifestyle. 30,31 For patients who remain symptomatic and have poor exercise tolerance or health status despite being on LAMA/ LABA combination therapy, the evidence supports patients enrolling in a pulmonary rehabilitation program. 32 For patients who remain symptomatic and have poor health status despite these interventions, a clinician should consider "step up" to triple therapy (LAMA/LABA/ICS), although each individual should be evaluated for risk/benefit of adding ICS in these circumstances. Evidence for its benefit has been demonstrated primarily in patients who have a high risk of exacerbations. 33,34 For PICO 1, data is lacking with respect to withdrawal or "step down" from LAMA/LABA/ICS to LAMA/LABA dual therapy or from dual therapy to monotherapy. We continue to support guidance from the previous position statement. 1 The consensus was that, in patients with COPD with no improvement in shortness of breath, exercise tolerance or health status despite the use of triple inhaled therapy or inhaled LAMA/LABA dual therapy, clinicians may cautiously consider "step down" treatment for some patients. These patients need to be monitored carefully with close clinical follow-ups to detect any signs of clinical deterioration after medication "step down."
As per previous guidelines, oral therapies such as theophylline, phosphodiesterase-4-inhibitor, mucolytics, statins, anabolic steroids, oral Chinese herbal medicines or phosphodiesterase-5-inhibitor demonstrate no evidence of conferring additional benefit in patients already on combination longacting bronchodilators. We reiterate that ICS monotherapy, as a lone intervention, has no place in treating COPD patients. If there is an indication for ICS therapy or the patient has asthma in addition to COPD, then ICS should be prescribed in a combination inhaler with long-acting bronchodilator(s). 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 shortor 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 Summary PICO 2: Preventing acute exacerbations in stable COPD patients
In Canada, AECOPD continues to be the most frequent cause of acute hospitalization in adults, 120 and is associated with the highest total hospital cost of care (2016)(2017). The cost of hospitalizations related to COPD is more than 30% higher than that of the next most expensive health condition (heart failure). 121 AECOPDs are a gateway to poor outcomes and adverse consequences.  They accelerate lung function decline, dramatically reduce quality of life, and are strong predictors of future AECOPDs. They are acute, trajectory-changing manifestations of a chronic disease associated with increased mortality. COPD is the third leading cause of death worldwide. 125,126 A fundamental and achievable goal of therapy in managing stable COPD is to reduce the occurrence and severity of AECOPDs. Furthermore, providing appropriate preventive therapy for patients at increased risk of exacerbation increases the likelihood of reducing and preventing ED visits and hospital admissions. In patients with severe COPD, reducing AECOPD may also reduce mortality. 33 This section discusses the optimal use of inhaled and oral pharmacologic maintenance therapies shown to prevent AECOPD in patients with stable COPD, not the treatment of acute exacerbations.

# Key evidence
Based on this review for PICO 2, recommendations 3 and 10 remain unchanged, while recommendations 1, 2, 4, 5, 6, 7, 8 and 9 have a change in GRADE assessment due to new research findings. Recommendations 5, 6, 7, 9 and 11 are revised based on evidence from published literature. See Appendix 2 detailing the upgrades and revisions from 2017.
A significant change is the use of either an ICS/LABA or LAMA/LABA as a first step in patients with high risk of AECOPD. Although ICS/LABA or LAMA/LABA is a viable inhaled therapeutic option in this setting, LAMA/LABA is the preferred choice except in patients with previous exacerbations who have higher peripheral eosinophilia (Figure 2). In this case, ICS/LABA could be the favored therapy as stated by the evidence described in the Discussion section of this guideline. Monotherapy with either LAMA or LABA is not the optimal initial maintenance treatment for patients who experience or are at high risk of AECOPD. Acknowledging the significant adverse consequences of AECOPD, consider inhaled therapy with either ICS/LABA or LAMA/LABA as the acceptable minimum maintenance therapy for this high risk population. It is important to remember that in real life practice, it is the exception to treat a patient only to prevent exacerbations; the vast majority of time we optimize bronchodilator therapy to improve a patient's dyspnea.
Similar to our analysis in PICO 1, we conclude that there is no role for ICS monotherapy and ICS should only be used in combination with bronchodilators. ICS/LABA and LAMA/ LABA/ICS are the only current single inhaler options. Health Canada has not approved an inhaled ICS for monotherapy use in COPD. Furthermore, in prior studies, the monotherapy ICS arm underperformed compared to combination ICS/ LABA, and post-hoc analysis suggested increased mortality in the ICS monotherapy participants. 127 Administering ICS with LAMA/LABA in separate inhalers has not been studied in COPD. 120,122,123 When combination ICS/LABA or LAMA/ LABA/ICS is used, high doses of ICS 122 are not typically necessary to achieve optimum benefit in COPD, as shown by a relatively flat dose-response curve 128 and greater incidence of adverse effect with higher inhaled ICS doses. 129 There remains clinical uncertainty regarding potential "step down" of therapy 90,123 in patients with a history of a high risk of future AECOPD. Evidence from a randomized clinical trial involving participants with COPD receiving combination ICS/LABA with LAMA in separate inhalers who underwent stepwise ICS withdrawal suggests the intervention is not associated with a significantly increased risk of exacerbation over a short term of follow up. 130 However, in this study the initial baseline exacerbation rate was low, about one-third of participants had not previously required inhaled triple therapy before recruitment, there was a statistically significant reduction in FEV 1 (43 mL, p 14 0.001) after ICS withdrawal, and the number of deaths was numerically small but higher in the ICS withdrawal group (n 14 40) compared to the ICS continuation group (n 14 34). More recently, another randomized clinical trial of patients with COPD with low risk of AECOPD on long-term triple inhaled therapy with direct de-escalation to LAMA/LABA led to a small decrease in lung function as a primary endpoint, with no difference in exacerbation rate. However, the primary study endpoint was not met, with confidence limits for trough FEV 1 exceeding the non-inferiority margin of A50 mL. Further analysis of these studies revealed a higher rate of exacerbation in patients with !300 blood eosinophils/lL, suggesting that, as a biomarker, blood eosinophil at !300/lL in patients with previous AECOPD could be useful to predict a favorable response to ICS when combined with long-acting bronchodilator(s). However, no RCT has compared ICS/LABA versus LABA/LAMA in patients with high risk of and blood eosinophil at !300/lL, with exacerbation as a primary endpoint.
Given these findings and acknowledging the negative impact of AECOPD, reductions in lung function and the potential adverse consequences of therapy, we continue to support guidance from the previous CTS guidance document 123 that the clinical phenotype should drive pharmacotherapy for patients with COPD. If therapy was started without a clear indication (such as the use of an ICS in a patient with no history of exacerbations), you may consider initiating a "step down." However, if therapy was started according to recommendations (such as the use of LAMA/LABA/ICS in a patient with moderate-severe COPD with poor quality of life and history of frequent and/or severe AECOPD) and treatment has been effective, a "step down" is NOT recommended. Given the potential for serious negative consequences of AECOPD, including hospitalization and death, we believe that de-escalation should only be considered in patients at low risk of morbidity and mortality, and this after a period of considerable stability. Moreover, while awaiting objective documentation supporting the safety of this approach, if you decide to "step down," we highly recommend monitoring your patients carefully with regular clinical assessments that includes the monitoring of lung function and re-occurrence of AECOPD.
As noted, the incidence of pneumonia is higher with maintenance therapy of ICS-containing inhaled medicines, especially in COPD patients with severe and very severe disease. However, these are also the patients who benefit most from an ICS-containing regimen. Debate still ensues as to an intra-class difference between fixed combinations of inhaled corticosteroid/long acting b 2 agonist regarding the risk of pneumonia and pneumonia-related events in treating patients with COPD. 131 However, the clinical significance of increased pneumonia in COPD patients who use ICS remains unclear, since there is no concurrent documented increase risk of mortality in this group. 131 Results from a large clinical trial 33 confirmed a higher incidence of pneumonia with ICS-combination therapy, but this was accompanied by significant improvements in lung function and quality of life and significant reductions in exacerbations and mortality, which are endpoints of significant importance.
As stated in the previous position statement, if patients with COPD continue to experience exacerbations despite being on optimal long-acting inhaled therapy, consider adding a daily macrolide (e.g. Azithromycin) as maintenance therapy in appropriate patients who have normal QT interval on ECG and no evidence of either colonization or acute infection with atypical mycobacterium. Also consider oral Roflumilast or oral N-acetylcysteine (600 mg po BID) in those having a clinical phenotype by history in keeping with chronic bronchitis. In recommendation 2.11 in this update, recent evidence supports not using theophylline in patients who are on long-acting inhaled therapy. We reiterate that systemic corticosteroids should not be used for maintenance pharmacotherapy in stable COPD. 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). A Blood eosinophil !300/mL in patients with previous AECOPD may be useful to predict a favorable response to ICS combination inhaler. Oral Therapies 14 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.  

# 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.

# 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. 

# 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.

# Discussion
Since the 2017 CTS pharmacotherapy position statement, there have been several important clinical trials that have necessitated an update. In this guideline we have incorporated new evidence from published large multicenter clinical trials and systematic reviews that have an impact on clinicians' approach to the medical management of patients living with COPD. We have summarized our updated recommendations in Tables 1 and 2 and included a comparison of 2017 and 2019 recommendations in Appendix 2.
An updated COPD pharmacologic algorithm (Figure 2) that reflects these updates was also derived.
The treatment propositions presented in this updated Guideline, in particular the approach of a treatment "step up" and "step down" are pragmatic and intended to provide meaningful guidance for clinicians. Most research trials were not strictly designed to assess such a therapeutic approach. However, treatment "step up" in COPD is a practical construct with wide appeal that is supported by evidence that inhaled combined therapy is superior to monotherapy and triple therapy to dual therapy in certain patient populations. Because the superiority of inhaled triple or dual bronchodilator therapy may not be achieved in every patient, "step down" may be considered for some patients, but should only be done with close medical supervision, as the risk of clinical deterioration is real and continues to exist.
There are several important considerations in the management of COPD that are not addressed by the PICO questions in this guideline document. We have therefore provided a commentary of selected topics in this discussion. A full review of these clinical issues may be undertaken in subsequent guideline development.

# Choice of inhaler device
The choice of the inhaler device and/or the decision to use single or multiple devices for combination therapy remains a subject of clinical interest and controversy. Very few studies have compared combination products in the same device compared to separate devices. In the only randomized clinical trial examining this issue, a single-inhaler LAMA/ LABA/ICS was compared to an ICS/LABA and LAMA in separate devices; this study demonstrated non-inferiority between the two treatment strategies. 191 There is no study that has been performed in COPD comparing LABA or combined LAMA/LABA with ICS in single and separate devices. Although the use of single or multiple devices for combination therapy is a clinical reality, properly designed trials or real-life data are lacking in COPD.

# Choice of bronchodilator combination
Another topic is the question clinicians may have with respect to the equivalence or superiority of the various combined long-acting bronchodilators (LAMA/LABA). Few comparative efficacy trials compared combination long-acting bronchodilator therapy; those that did showed between-treatment differences in FEV 1 that were small and of uncertain clinical significance. 192,193 Interval for changing inhaler therapy
The decision to change a therapy should always occur after a complete evaluation of the patient and the potential benefit of a change in therapy; as well as an assessment of any adverse effects of the therapy, and with a review of patient adherence, inhaler technique and preferences. Although there is no absolute interval time at which the evaluation should be performed following a change in therapy, 6 months after initiating a long acting bronchodilator and 12 months after initiating a combination regimen with an ICS are suggested timeframes.

# Peripheral blood eosinophils in COPD
While peripheral blood eosinophil counts have demonstrated reasonable repeatability over a year in a population-based cohort of COPD patients in primary care, 194 practical uncertainty remains regarding the exact cut-off level of sputum or blood eosinophils for predicting therapeutic response in COPD. Despite this uncertainty, peripheral blood eosinophil counts may play a role in certain clinical settings. New information is incorporated into this update with respect to blood eosinophils as a potential biomarker for use in COPD patients known to have exacerbations to prevent future exacerbations. A consistent pattern of results from randomized clinical trials conducted in COPD patients at risk of exacerbations has emerged. Lower eosinophil counts (<100 eosinophils/mL) predict a lower or no response to ICS containing regimens in terms of preventing exacerbation. ICS containing regimens will benefit in reducing the likelihood of exacerbations in the magnitude of effect being greater at higher eosinophil counts, particularly !300 eosinophils/lL. 156 This provides a measure of probability of response to ICS containing regimen in patients who had previous exacerbations, aligning with a more personalized approach.

# Mortality
Reducing mortality has been a long-standing goal of therapy in COPD. Older studies have revealed mortality-reducing trends with inhaled therapy 127,195 but statistical significance was not achieved. Although there is still no definitive answer, more recent evidence from a large randomized controlled trial study demonstrated significant relative reduction in all-cause mortality during treatment with regimens that included inhaled ICS/LABA or triple therapy (LAMA/ LABA/ICS) compared to LAMA/LABA for COPD patients with high risk of exacerbations. Despite a higher incidence of study-reported pneumonia in the ICS-containing treatment regimens, mortality was reduced by 42% in favor of LAMA/LABA/ICS vs. LAMA/LABA (unadjusted p 14 0.01), and 39% in favor of ICS/LABA vs LAMA/LABA (unadjusted p 14 0.02). An analysis of adjudicated cause-specific death during treatment demonstrated fewer deaths from both respiratory and cardiovascular etiologies in the ICS-containing regimens. This topic requires further attention, but mortality is an important outcome that should have our consideration in clinical decision.

# Dissemination and implementation
Our guideline will be disseminated through traditional channels including this publication, through the CTS website and social media channels, and through an accompanying slide deck that will be used to present this content to various target groups across the country. It is also anticipated that we will produce a separate implementation document that will include key indicators of appropriate care and practical guidance for healthcare system change. Our goal is to monitor the impact of these actionable recommendations through their ability to correct knowledge gaps and improve actual behaviors within the target user groups. On a population level, we also believe that monitoring the frequency of COPD ED visits, hospital admissions and re-admissions would be relevant metrics to assess the success of this guideline. For messages targeting nonexperts, we will seek to tailor messages and produce corresponding educational content, in collaboration with key stakeholders such as provincial lung associations, RESPIPLUS and RESPTREC.

# Conclusion
This update is an important step toward optimizing the pharmacologic management of COPD. Recommendations enable better-personalized therapy based on more specific individual characteristics. The update further highlights the intent and benefit of therapy in both improving symptoms and activity limitations, and reducing the risk of AECOPD. Areas of debate still require further study, including approach to treatment "step down" targeting specific group of patients, blood eosinophil use and its cut off, and use of single or multiple inhalers for combination therapy, but recent evidence has strengthened many recommendations to optimize management of COPD. In summary, pharmacological therapy plays a foundational role in therapy, but it should never be the sole treatment in managing COPD patients. Clinicians should always combine and optimize pharmacological and non-pharmacological therapies with the dual goals of reducing symptoms and preventing AECOPD. bers of the CTS CRGC for their input and guidance. We would like to acknowledge with sincere appreciation our expert reviewer, Marc Miravitlles from the Pneumonlogy Department, University Hospital Vall d'Hebron, Ciber de Enfermedales Respiratorias (CIBERES), Barcelona, Spain.

# Editorial independence
The CTS COPD guideline panel is accountable to the CTS Canadian Respiratory Guidelines Committee and the CTS Board of Directors. The CTS COPD guideline panel is functionally and editorially independent from any funding sources of the CTS and does not receive any direct funding from external sources. The CTS receives unrestricted grants that are combined into a central operating account to facilitate the knowledge translation activities of the CTS Assemblies and its guideline panels. No funders played a role in the collection, review, analysis or interpretation of the scientific literature or in any decisions regarding the key messages presented in this document.

# Disclosures
Members of the CTS COPD Guideline Panel declared potential conflicts of interest at the time of appointment and these were updated throughout the process in accordance with the CTS Conflict of Interest Disclosure Policy. Individual member conflict of interest statements are posted at /. Evidence for at least one critical outcome from observational studies, case series or randomized controlled trials, with serious flaws or indirect evidence.

# ORCID
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-lowquality 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. 

# 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-5inhibitors, 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-4inhibitors, 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 (continued)