Ann Arbor, MI—For long-term smokers, it is not uncommon to have clinically significant respiratory symptoms without airflow obstruction as assessed by spirometry, according to a new study.

University of Michigan authors and colleagues pointed out that the patients often are treated with medications for chronic obstructive pulmonary disease (COPD), even though supporting evidence for the therapy remained inconclusive.

For the study, reported in the New England Journal of Medicine, the team randomly assigned a cohort of 535 tobacco smokers to receive either indacaterol (27.5 mcg) plus glycopyrrolate (15.6 mcg) or a placebo twice daily for 12 weeks. The participants had smoked at least 10 pack-years; had respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (the scores range from 0 to 40, with higher scores indicating worse symptoms); and had preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use).

The primary outcome was defined as at least a 4-point decrease (i.e., improvement) in the St. George’s Respiratory Questionnaire (SGRQ) score (the scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure. For purposes of the study, treatment failure was defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent.

After randomization, in the modified intention-to-treat population of 471 participants, 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, –2.6 percentage points; 95% CI, –11.6-6.3; adjusted odds ratio, 0.91; 95% CI, 0.60-1.37; P = 0.65), according to the study.

Researchers calculated the mean change in the percent of predicted FEV1 as 2.48 percentage points (95% CI, 1.49-3.47) in the treatment group and –0.09 percentage points (95% CI, –1.06-0.89) in the placebo group. The mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07-0.18) in the treatment group and 0.02 liters (95% CI, –0.03-0.08) in the placebo group. They note that four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group, although none were deemed potentially related to the treatment or placebo.

“Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry,” the authors concluded.

Background information in the article pointed out that COPD is defined by a reduced ratio of FEV1 to FVC after bronchodilator use. “However, we previously found that some tobacco-exposed persons who have preserved lung function as assessed by spirometry report having substantial respiratory symptoms, activity limitation, and exacerbations, similar to those in persons with airflow obstruction measured on spirometry,” the authors explained. “These tobacco-exposed persons with preserved lung function on spirometry who have respiratory symptoms as defined by a COPD Assessment Test (CAT) score of 10 or greater (scores range from 0 to 40, with higher scores indicating worse symptoms) also have airway-wall thickening and higher sputum mucin concentrations than non-symptomatic persons.”

Other studies, they added, have shown that those with tobacco exposure sometimes have respiratory impairments and abnormalities on CT, such as emphysema and air trapping.

“Many symptomatic tobacco-exposed persons with preserved lung function on spirometry are treated with COPD medications, including inhaled bronchodilators and glucocorticoids,” the researchers noted. “Because spirometry is infrequently performed in primary care, it is unclear whether physicians believe they are treating COPD or whether they believe COPD medications are effective for these patients. Regardless, randomized trials to guide treatment in this patient population are lacking. In response to this evidence gap, we hypothesized that persons who currently or formerly smoked cigarettes with at least a 10-pack-year history and who have clinically spirometry (i.e., FEV1:FVC ≥0.70 and FVC ≥70% of the predicted value) would benefit from treatment with inhaled bronchodilators.”

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