Bronchodilators Fail in Symptomatic Smokers With Preserved Lung Function

man smoking a cigarette
man smoking a cigarette
A clinical trial assessed the benefit of inhaled bronchodilator therapy for symptomatic individuals with a 10-pack-year smoking history, preserved lung function, and no COPD.

In symptomatic, tobacco-exposed individuals with preserved lung function, respiratory symptoms did not decrease with inhaled dual bronchodilator therapy, according to clinical trial findings published recently in The New England Journal of Medicine.

Because inhaled dual bronchodilator therapy is effective for controlling symptoms in patients with COPD, there is speculation that such treatment will also work with current or former smokers with significant respiratory symptoms. However, data proving the effectiveness of this approach have been lacking. Researchers therefore sought to determine if inhaled bronchodilator treatment would benefit individuals who smoked (currently or formerly, with a 10-pack-year history) and had clinically significant respiratory symptoms, despite having preserved lung function as assessed via spirometry.

The investigators conducted Redefining Therapy in Early COPD (RETHINC), a randomized, multicenter, blinded, controlled trial ( Identifier: NCT02867761) that included 471 intention-to-treat participants randomized into either the treatment group (n=227) or the placebo group (n=244). All participants had a tobacco-smoking history of at least 10 pack-years, 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), and respiratory symptoms defined by a COPD Assessment Test score of at least 10 (range 0-40, with higher scores indicating worse symptoms).

The treatment group received indacaterol (27.5 μg) plus glycopyrrolate (15.6 μg) and the control group received placebo twice daily for 12 weeks. The primary endpoint was at least a 4-point improvement (decrease) in the St. George’s Respiratory Questionnaire (SGRQ) score after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). Researchers found adherence to be 88% of doses taken in both groups.

The investigators found that 56.4% of treatment group participants and 59.0% of those in the placebo group had a 4-point improvement in the SGRQ score (difference, -2.6 percentage points; 95% CI, -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60-1.37; P =.65). The mean change in inspiratory capacity in the treatment group was 0.12 liters (95% CI, 0.07-0.18) vs 0.02 liters (95% CI, −0.03 to 0.08) in the placebo group. The mean change in the percent of predicted FEV1 in the treatment group was 2.48 percentage points (95% CI, 1.49-3.47) vs -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group.

The researchers observed 11 serious adverse events in the placebo group and 4 serious adverse events in the treatment group; none were found to be related to placebo or treatment.

Trial limitations include an overly broad definition of the patient population, an underpowered level of study participants with chronic bronchitis, selection bias, a strong placebo effect, a short follow-up period, and the use of FDA-approved drug doses that are lower than dosage levels approved in other countries.

“We found that dual long-acting bronchodilator treatment did not decrease respiratory symptoms in persons who currently or formerly smoked cigarettes and had substantial respiratory symptoms despite also having preserved lung function as assessed by spirometry. This stands in contrast to data on symptom abatement with dual long-acting bronchodilators in tobacco exposed persons who meet criteria for COPD,” said study authors. “Smoking-cessation therapy remains a primary goal for this patient population,” they noted, adding that further research into treating this patient population is needed.


Han MK, Ye W, Wang D, et al.; RETHINC Study Group. Bronchodilators in tobacco-exposed persons with symptoms and preserved lung function. N Engl J Med. Published online September 4, 2022. doi:10.1056/NEJMoa2204752