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Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in former or current smokers with preserved lung function, the trial showed.

Among 535 symptomatic smokers with a 10 pack-year history and preserved lung function assessed by spirometry, 56.4% in the treatment group and 59.0% in the placebo group had a least a 4-point decrease in (SGRQ) scores, a 100-point scale with higher scores indicating worse health.

The between-group difference was -2.6 percentage points (95% CI -11.6 to 6.3) and the adjusted OR was 0.91 (95% CI 0.60-1.37, P=0.65), reported MeiLan Han, MD, of the University of Michigan in Ann Arbor, at the meeting.

Findings from the study were published simultaneously in the (NEJM).

Mean change in the percent of predicted forced expiratory volume in 1 second (FEV₁) was 2.48 percentage points (95% CI 1.49-3.47) among people on dual bronchodilator treatment and -0.09 percentage points (95% CI -1.06 to 0.89) in the placebo group. Mean change in inspiratory capacity was 0.12 liters (95% CI 0.07-0.18) for the treatment group and 0.02 liters (95% CI -0.03 to 0.08) for placebo. Serious adverse events were rare and deemed not likely to be related to treatment.

Many people with a history of smoking go on to develop clinically significant respiratory symptoms despite not displaying airflow obstructions on spirometry and are often treated with chronic obstructive pulmonary disease (COPD) medication.

"Physicians essentially often treat them as if they have COPD, with a significant proportion being treated with bronchodilators as well as inhaled corticosteroids," Han said during her presentation.

RETHINC highlights why clinicians cannot keep giving these patients COPD medications without spirometry testing and expect improvement, Han noted.

"The bottom line is that we really need to do spirometry to understand who benefits from bronchodilators, and we need further research to understand how to treat this specific group of patients," she said.

COPD develops in a small subgroup of persons who smoke but there are no biomarkers to guide early intervention, observed Don Sin, MD, of the University of British Columbia in Vancouver, in an .

"A clinical approach to this conundrum is to empirically treat tobacco-exposed persons who are symptomatic, regardless of spirometric measures," Sin noted.

But RETHINC findings suggest that long-acting bronchodilators may not be effective for symptomatic patients with a smoking history and preserved lung function on spirometry, Sin pointed out. "These medications should most likely be reserved for patients with COPD who have clinically significant airflow limitation," he suggested.

"On the basis of this trial and other studies, it is clear that spirometry cannot be used to identify persons with a history of smoking who are at high risk for disease progression because the test is too insensitive in detecting small airway disease," Sin added.

"Forced oscillometry, the lung clearance index (also known as the multiple breath washout test), and imaging-based methods such as parametric response mapping with the use of computed tomography and functional and microstructural magnetic resonance imaging show promise for the detection of small-airway disease before the onset of airflow limitation on spirometry," he wrote.

The (RETHINC) study was a multicenter, blinded, randomized controlled trial with data collected from 20 enrolling centers, including academic, Veterans Affairs, and community medical centers.

To be included, participants were required to have a tobacco-smoking history of at least 10 pack-years, respiratory symptoms defined by a score of at least 10, and preserved lung function on spirometry (ratio of FEV₁ to forced vital capacity ≥0.70, and FVC ≥70% of the predicted value after bronchodilator use). Potential participants were excluded if they had a primary diagnosis of asthma, other known concomitant lung disease, or if they used certain maintenance inhalers commonly prescribed for COPD (unless they underwent a 30-day washout period).

Between July 2017 and March 2021, participants 40 to 80 years old were randomly assigned to receive inhaled indacaterol plus glycopyrrolate (27.5 μg/15.6 μg, the FDA-approved doses for the treatment of COPD) or placebo twice daily for 12 weeks. Mean age of participants was 58.6 and 48.7% were men. Mean baseline SGRQ score was 37.9.

The symptoms seen in some participants may have been driven by other variables such as cardiac disease or sleep apnea. Since there was improvement in both groups, a strong placebo effect may have been a factor, according to the researchers.

It is also possible a 12-week treatment period was not long enough to observe symptomatic improvement, the researchers acknowledged. Drug doses also differ by country and may yield different results.