Bronchodilators in Symptomatic Tobacco-exposed Persons with Preserved Spirometry for the RETHINC Study Group

Individuals with current or former smoking history who have respiratory symptoms despite lack of spirometric airflow obstruction experience significant morbidity. They are often treated with COPD medications without supporting evidence. We randomized 535 participants with ≥10 pack-years smoking history, respiratory symptoms defined by COPD Assessment Test (CAT) score ≥10, and preserved spirometry (post-bronchodilator FEV1 /FVC ≥0.70) to indacaterol/glycopyrrolate 27.5/15.6 mcg inhalation or blinded placebo twice daily for twelve weeks. The primary outcome was proportion with a ≥4-unit improvement in SGRQ score without treatment failure (defined as an increase in lower respiratory symptoms treated with long-acting inhaled bronchodilator, corticosteroids, or antibiotics). In the modified intention to treat analysis (n=471), 128 (56.4%) versus 144 participants (59.0%) in the intervention and control groups, respectively, achieved the primary outcome (difference, -2.6%; 95% confidence interval [CI], -11.6 to 6.3%; adjusted odds ratio 0.91; 95% CI, 0.60 to 1.37; p=0.65). The change in FEV1 (% predicted) was 2.48 (95% CI, 1.49 to 3.47) in the intervention group and -0.09 (95% CI, -1.06 to 0.89) in the placebo group; the change in inspiratory capacity (L) was 0.12 (95% CI, 0.07 to 0.18) in the intervention group and 0.02 (95% CI, -0.03 to 0.08) in the placebo group, respectively. Inhaled dual bronchodilator therapy did not improve respiratory symptoms in symptomatic, tobacco-exposed persons with preserved spirometry.