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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38626371
202402-0338VP
10.1164/rccm.202402-0338VP
Viewpoint: Turning the Air Blue
Optimizing Pharmacotherapy Management of Chronic Obstructive Pulmonary Disease: Don’t Miss the Forest for the Trees
Bourbeau Jean 1
Bhutani Mohit 2
Hernandez Paul 3
Penz Erika 4
Marciniuk Darcy D. 4
1 Department of Medicine, Respiratory Division, McGill University Health Centre, Montreal, Québec, Canada;
2 Department of Medicine, Division of Pulmonary Medicine, University of Alberta, Edmonton, Alberta, Canada;
3 Division of Respirology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; and
4 Division of Respirology, Critical Care and Sleep Medicine, and Respiratory Research Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Correspondence and requests for reprints should be addressed to Jean Bourbeau, M.D., Montreal Chest Institute, Centre for Outcomes Research and Evaluation, Research Institute, McGill University Health Centre, 5252 de Maisonneuve O, Third Floor, 3D.62, Montreal, Québec H4A 2J1, Canada. E-mail: jean.bourbeau@mcgill.ca.
16 4 2024
1 9 2024
16 4 2024
210 5 545547
25 3 2024
16 4 2024
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
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pmcDespite significant advancement in chronic obstructive pulmonary disease (COPD) therapeutics and management over the past decades, hospitalizations and mortality continue to increase. In Canada, hospital admissions for COPD continue to increase even after adjusting for population growth and aging, despite declining rates of all-cause hospital admissions (1). Risk of death in the 90 days after hospital admission for COPD ranges from 6.1 to 11.1% (2).

Considering the availability of effective evidence-based therapies, the persisting unmet needs are unacceptable. Global Initiative for Chronic Obstructive Lung Disease (GOLD) (3) guidelines over the years, in tandem with others such as the 2023 Canadian Thoracic Society (CTS) COPD pharmacotherapy guideline (4), have clearly identified a treatment pathway based on evidence, transforming the pharmacotherapy approach for clinicians.

This Viewpoint article highlights facets of COPD pharmacotherapy that could lead to an improvement of patient outcomes, and we discuss controversies in the context of the GOLD report. A summary of the highlights of COPD pharmacotherapy and key messages is given in Table 1.

Table 1. Summary of the Highlights of COPD Pharmacotherapy and Key Messages

Highlight of COPD Pharmacotherapy	Recommendations and Explanations for Patients with COPD	
LABA and LAMA dual therapy at the initiation of therapy	In symptomatic patients with a low risk of future exacerbation* • Evidence allows making a shift in the treatment paradigm for initial therapy with LABA and LAMA dual therapy.

• High value is placed on the treatment goal of alleviating dyspnea, known to be the most debilitating symptom in COPD.

	
Single-inhaler triple therapy as initial treatment	For patients with a high risk for exacerbations, SITT is superior to LABA and LAMA dual therapy according to the 2023 GOLD report and the 2023 CTS COPD guideline.
There is a debate on the initiation of triple therapy (the CTS guideline recommends adopting the best therapy) as opposed to “stepping up” therapy (GOLD recommends “stepping up,” i.e., accomplishing your goal after several tries with the risk of exacerbations, hospitalizations, or death).
A shared decision-making approach could be valuable, for example, by respecting “what matters most” to patients.	
Redefining the goal of treatment in COPD, reducing mortality	Many nonpharmacological interventions (e.g., smoking cessation, long-term oxygen therapy, noninvasive ventilation, and lung volume reduction surgery) are recognized and accepted for reducing mortality in specific subgroups of patients with COPD.
In symptomatic patients with a high risk of future exacerbation.† • Both the 2023 CTS COPD guideline and the GOLD report arrive at the same conclusion on the basis of evidence from two landmark RCTs, IMPACT and ETHOS.

There is not a clear understanding of the mechanisms that support SITT in preventing patients from having exacerbations and/or dying; this is not a reason to withhold prescription of SITT.	
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; CTS = Canadian Thoracic Society; GOLD = Global Initiative for Chronic Obstructive Lung Disease; LABA = long-acting β2 agonist; LAMA = long-acting muscarinic antagonist; RCTs = randomized clinical trials; SITT = single-inhaler triple therapy.

* Low risk of future exacerbations, defined as one or no moderate exacerbation and no severe exacerbation (requiring hospital admission) in the previous year.

† High risk of future exacerbations, defined as two or more moderate exacerbations or one or more severe exacerbations (requiring hospital admission) in the previous year.

In recent years, GOLD (3), the American Thoracic Society (5), and the CTS (4) have come to make the same recommendation of using inhaled long-acting β2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) dual bronchodilation at the initiation of therapy for symptomatic patients with COPD at low risk of exacerbation. This new “success approach” is supported by evidence from meta-analyses (6) that shows the clinical superiority of LABA and LAMA compared with monotherapy. Previously, “stepping up” from monotherapy to dual therapy, adjusting treatment regimens at visits, was the recommendation. One shortcoming of this approach is the inaccuracy and lack of a definitive way to define optimal therapy for a given individual. We now appreciate that a delay in optimizing bronchodilation contributes to long-standing negative consequences for patient-reported outcomes.

The morbidity and mortality associated with COPD are driven largely by patients with recurrent exacerbations and hospital admissions. Recent evidence has emerged, predominately from two large randomized clinical trials (RCTs), IMPACT (7) and ETHOS (8), which recruited patients with an impaired health status (COPD assessment test score ⩾10) and a high risk of exacerbations (i.e., two or more moderate and/or severe exacerbations, defined as one or more hospital admissions). These studies demonstrated that single-inhaler triple therapy (SITT) significantly reduces exacerbations (primary outcome) and mortality (secondary outcome) compared with LABA and LAMA therapy. The robustness of the mortality findings was further assessed and maintained after additional data retrieval for more than 99% of the intention-to-treat population (9, 10). These findings are supported by GOLD (4), and with detailed meta-analysis by CTS (5), that patients with symptom burden and high risk of exacerbations can have a greater benefit of survival when comparing SITT with LABA/LAMA dual therapy.

There has been discussion as to whether these trials demonstrated a true reduction in all-cause mortality with SITT or whether the abrupt discontinuation of inhaled corticosteroid (ICS)–based therapy before randomization led to worse outcomes. Alternatively, one might infer that these high-risk patients were on the right treatment in the first place. To test this hypothesis, a trial of ICS-naive patients with COPD would need to be conducted, which is neither feasible nor ethical. Arguments have been provided with subgroup analyses from the IMPACT (7) and ETHOS (8) RCTs among ICS-naive patients showing that the hazard ratios of mortality comparing SITT with LABA and LAMA dual therapy—1.25 (95% confidence interval [CI], 0.60–2.59) and 1.49 (95% CI, 0.49–4.55), respectively—no longer demonstrate a reduction in mortality (11). Despite the apparent lack of treatment effect, the very large confidence intervals in this post hoc analysis indicates that the sample size was too small, preventing a definitive conclusion. Although further research may provide additional clarification, we should not withhold prescription of SITT in symptomatic patients who are at high risk of exacerbation. Questions regarding these important findings have been addressed, but ongoing debate leads one to miss the forest because of the trees.

Clinical approaches to the patient with COPD at high risk of exacerbations may also involve stepped care if prior treatment is unsuccessful. As such, GOLD (4) recommends triple therapy as the initial treatment in patients who have a high risk of exacerbations and a blood eosinophil count (BEC) of 300 or more cells per microliter and “stepping up” in those with BECs of 100–300 cells per microliter who still have exacerbations despite LABA and LAMA dual therapy. The 2023 CTS COPD Pharmacotherapy Guideline (7), which is based exclusively on reported data obtained from a systematic review of RCTs, recommends initiating triple therapy in all symptomatic patients who are at high risk of exacerbations.

Why does the CTS COPD guideline (4) differ from GOLD recommendations (3)? The recommendations relating to BECs are based on post hoc analysis of RCTs or retrospective studies and, although potentially informative, are more likely to be impacted by the existence of unmeasured confounders. This is not to say that using BECs in clinical practice cannot inform clinical decisions; however, we should avoid any misinterpretation that only patients with BECs of 300 or more cells per microliter will experience the benefit of a reduction in exacerbations with SITT.

Although there is no definitive answer, “stepping up” to SITT requires that we (and our patients) must wait and see whether exacerbations occur with the lag time to recurrence that is often more than a year, making it difficult to conclude when we have reached “optimal therapy.” The ideal conditions for following patients are rarely met in clinical practice. This may explain why patients are often undertreated and readmitted to hospital. Even if a physician would be able to follow accurately what is recommended for “stepping up,” a delay of a year is far from acceptable, because every passing visit can result in unnecessary, and preventable, hospitalizations and death.

It deserves emphasis that there are no RCT data for treatment-naive patients. This is an area where real-world evidence (RWE) is complementary and helps fill the evidence gap. One RWE study of ICS-naive patients with COPD with two or more prior exacerbations confirmed the benefit from SITT as initial treatment versus LABA and LAMA dual therapy; hazard ratio, 0.83 (95% CI, 0.74–0.92) (12). This information is well aligned with high-risk patients enrolled in the IMPACT (7) and ETHOS (8) trials.

In this Viewpoint, we advocate that, considering the totality of the evidence and the consistency of the results gleaned from RCT and consolidated in RWE, this should inform our clinical judgment to make a better choice of therapy improving outcomes for patients with COPD. At the very least, we could engage in a shared decision-making approach in which patients are supported to consider all their options, resulting in informed decisions.

Originally Published in Press as DOI: 10.1164/rccm.202402-0338VP on April 16, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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