From Pages to Practice

By Robert Smyth, MD, MSc

Published November 16, 2022


Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). More than 3 million people worldwide die of COPD each year, accounting for approximately 6% of all deaths. COPD is a heterogenous condition with various phenotypes including emphysema and chronic bronchitis. Formal diagnosis of COPD involves detection of airflow limitation on spirometry (defined as a post-bronchodilator FEV1:FVC ratio <70%). COPD exacerbations are a common reason for inpatient admission.

Long acting beta2 agonists (LABA) typically improve airflow limitation and reduce dyspnea, exacerbation rates, and hospitalizations but they have no effect on mortality or the rate of decline of FEV1. Long-acting muscarinic antagonists (LAMA) improve symptoms and reduce exacerbations and hospitalizations. These anti-cholinergic drugs are particularly important in COPD treatment, as they exert the bronchodilatory effect by reducing vagal tone via airway muscarinic receptors. Results of clinical trials have shown a greater effect on rates of exacerbation for LAMA versus LABA treatment.

By the time spirometry detects airflow obstruction, substantial irreversible damage is present in the airways. Therefore, there is growing interest in using bronchodilators in a population that is at an earlier stage of the disease process, such as tobacco-exposed persons with respiratory symptoms and preserved lung function. The use of bronchodilators in this population is supported by observational data indicating that 50% of tobacco-exposed persons with respiratory symptoms and preserved lung function experience limitation of activity, exacerbations, and hospitalization. Some patients also have evidence of small airway disease, emphysema, or airway thickening on chest imaging.

In a multicenter, blinded, randomized-controlled trial (Redefining Therapy in COPD [RETHINC]), participants without concomitant respiratory disease and a COPD Assessment Test score of ≥10 were randomized in a stratified manner to receive indacaterol plus glycopyrrolate or placebo for 12 weeks. The primary outcome was a 4-point reduction (improvement) in the baseline St. George’s Respiratory Questionnaire after 12 weeks. The use of this fixed-dose combination did not significantly decrease symptoms. Furthermore, nearly 60% of placebo recipients had clinically significant improvement, highlighting the variability in symptoms over time in this cohort.

Given the lack of efficacy demonstrated in this study, inhaled bronchodilators do not appear to be appropriate in tobacco-exposed persons with respiratory symptoms without airflow obstruction, especially given the high costs associated with these therapies. A focus on smoking cessation where applicable is important as well as evaluation of therapies to reduce cough symptoms prevalent in this population.

The following NEJM Journal Watch summary provides more details on the RETHINC study.

Are Bronchodilators Effective in Symptomatic Smokers with Normal Spirometry?

David J. Amrol, MD, reviewing Han MK et al. N Engl J Med 2022 Sep 4 Sin DD. N Engl J Med 2022 Sep 4

The diagnosis of chronic obstructive pulmonary disease (COPD) requires a postbronchodilator forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio of <0.7. However, patients with normal spirometry can have small airway disease, classic emphysematous changes on imaging, or symptoms consistent with chronic bronchitis (i.e., presence of cough and sputum for >3 months for 2 consecutive years).

U.S. researchers enrolled 535 patients with respiratory symptoms (COPD Assessment Test score. opens in new tab, ≥10 on a 40-point scale) and at least a 10-year smoking history but no evidence of airflow obstruction. Patients were randomized to inhaled indacaterol (a long-acting β2-agonist) plus glycopyrrolate (a long-acting antimuscarinic agent) or to placebo. At 12 weeks, respiratory symptom scores were similar in the dual-bronchodilator group and the placebo group.

Comment: Every patient with COPD symptoms should undergo spirometry, because only those with true COPD are likely to benefit from inhaled therapy. Patients with COPD symptoms but normal spirometry are conundrums for clinicians, because standard COPD therapy clearly is not beneficial based on this study. For now, we can encourage smoking cessation and promote exercise for such patients. In an accompanying editorial, the author discusses more-sensitive tests that might be used in the future to diagnose and treat patients with early COPD, as more than 40% of terminal bronchioles can be lost by the time obstruction is apparent on spirometry.

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Robert Smyth, MD, MSc, is a 2022–2023 NEJM Editorial Fellow. He is currently an Assistant Professor of computational biomedicine at the Boston University School of Medicine.