Inhaled bronchodilators may not improve respiratory symptoms in tobacco-smoking patients with preserved lung function

A randomized controlled trial in patients with at least a 10 pack-year smoking history and respiratory symptoms but normal spirometry results found no difference in symptoms over 12 weeks between those who received indacaterol plus glycopyrrolate twice daily or placebo.

Bronchodilators do not appear to improve respiratory symptoms in patients who smoke tobacco and have preserved lung function, a recent study found.

Researchers in the Redefining Therapy in Early COPD (RETHINC) trial randomly assigned patients with a smoking history of at least 10 pack-years, respiratory symptoms, and preserved lung function on spirometry to receive indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. Patients were enrolled from 20 academic, Veterans Affairs, and community medical centers. Respiratory symptoms were defined as a COPD Assessment Test score of at least 10 (range, 0 to 40, with higher scores indicating worse symptoms), and preserved lung function was defined as an FEV1/FVC ratio of 0.70 or higher and an FVC of at least 70% of the predicted value after bronchodilator use. The primary outcome was a decrease of at least 4 points on the St. George's Respiratory Questionnaire (SGRQ) score (range, 1 to 100 where higher scores indicate worse health) after 12 weeks without treatment failure, defined as an increase in lower respiratory symptoms requiring treatment with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent.

The results of the trial were published Sept. 4 by the New England Journal of Medicine. It was supported by grants from the National Heart, Lung, and Blood Institute and the National Center for Advancing Translational Sciences and by financial support from Sunovion Pharmaceuticals to the centers conducting the trial through the COPD Foundation. The trial medication and placebo were donated by Novartis Pharmaceuticals.

Five hundred thirty-five patients were randomly assigned, and 471 were included in the intention-to-treat population. Of the latter, 128 of 227 in the treatment group and 144 of 244 in the placebo group had a 4-point decrease in the SGRQ score (56.4% vs. 59.0%; difference, −2.6 percentage points [95% CI, −11.6 to 6.3 percentage points]; adjusted odds ratio, 0.91 [95% CI, 0.60 to 1.37]; P=0.65). The mean change in the percent of predicted FEV1 and inspiratory capacity was 2.48 percentage points (95% CI, 1.49 to 3.47 percentage points) and 0.12 L (95% CI, 0.07 to 0.18 L) in the treatment group and −0.09 percentage point (95% CI, −1.06 to 0.89 percentage points) and 0.02 L (95% CI, −0.03 to 0.08 L) in the placebo group. There were four serious adverse events in the treatment group and 11 in the placebo group, none of which were considered study-related.

The researchers noted that some respiratory symptoms may have been due to conditions such as sleep apnea rather than pulmonary abnormalities and that only a few patients were taking bronchodilators before study enrollment. In addition, they pointed out that higher doses of the study drugs are available in countries other than the U.S., among other limitations. They concluded that long-acting bronchodilators do not appear to improve respiratory symptoms in patients without chronic obstructive pulmonary disease who smoke tobacco but have normal spirometry results. “Further research is urgently needed to better understand and treat the respiratory disease in these persons,” they wrote.

An accompanying editorial said the trial indicates that long-acting bronchodilators are not effective for treating respiratory symptoms in this population and that such symptoms, especially cough and sputum production, are common in patients who smoke tobacco but vary over time. The editorialist also noted that a history of bronchitis was present in 70% of patients included in the trial.

“Although bronchodilators are effective in ameliorating breathlessness and improving exercise tolerance, they are generally ineffective for cough,” the editorialist concluded. “Existing drugs for the treatment of COPD, such as inhaled glucocorticoids or phosphodiesterase-4 inhibitors, or new therapeutics such as P2X3 receptor antagonists may be more effective for the treatment of cough and sputum production related to smoking and could be considered for future evaluations in this patient population.”