Inhaled dual bronchodilators did not reduce symptoms in adults with smoking history

Inhaled dual bronchodilator therapy did not decrease respiratory symptoms among individuals who were current or former smokers and had respiratory symptoms but preserved lung function without COPD, according to results of the RETHINC study.

“This stands in contrast to data on symptom abatement with dual long-acting bronchodilators in tobacco-exposed persons who meet criteria for COPD,” MeiLan K. Han, MD, professor of internal medicine in the division of pulmonary and critical care at the University of Michigan, and colleagues wrote.

The RETHINC study included 535 participants (mean age, 58.8 years; 48.6% men) with a history of at least 10 pack-years of smoking tobacco, respiratory symptoms (COPD Assessment Test score 10) and preserved lung function on spirometry. All participants were randomly assigned to indacaterol 27.5 µg plus glycopyrrolate 15.6 µg (n = 261) or placebo (n = 274) twice daily for 12 weeks.

The primary outcome was an improvement of at least 4 points in the St. George’s Respiratory Questionnaire (SGRQ) score after 12 weeks without treatment failure. Treatment failure was defined as an increase in lower respiratory symptoms requiring treatment with a long-acting bronchodilator, glucocorticoid or antibiotic medication.

The results were presented at the European Respiratory Society International Conference and simultaneously published in The New England Journal of Medicine.

Among 471 participants in the modified intention-to-treat population, 56.4% of the bronchodilator group and 59% of the placebo group experienced a 4-point decrease in their SGRQ score (adjusted OR = 0.91; 95% CI, 0.6-1.37; P = .65).

Researchers reported a mean change of 2.48 percentage points in percent predicted FEV₁ in the bronchodilator group compared with a mean change of –0.09 percentage points in the placebo group. In addition, mean change in inspiratory capacity was 0.12 L in the bronchodilator group compared with 0.02 L in the placebo group.

Four participants in the bronchodilator group reported four serious adverse events compared with eight participants who reported 11 adverse events in the placebo group. However, no adverse events were attributed to the treatment or placebo, according to the researchers.

In an accompanying editorial published in NEJM, Don D. Sin, MD, MPH, director of the Centre for Heart Lung Innovation at St. Paul’s Hospital and the division of respiratory medicine at the University of British Columbia, Vancouver, Canada, noted that, based on the findings of RETHINC and other studies, “it is clear” spirometry is not suitable for use to identify those with smoking history at high risk for disease progression. This is due to the test being too insensitive in detecting small airways disease, Sin wrote.

“Many tobacco-exposed symptomatic individuals are currently not being treated. We don't know if this is because physicians just aren't doing spirometry and assuming COPD or they strongly believe that there's benefit,” Han said during the presentation. “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 because there truly is pathogenesis and disease burden.”

References:

• Han MK, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2204752.
• Sin DD. N Engl J Med. 2022;doi:10.1056/NEJMe2210347.