Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function

Abstract

Background: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking.

Methods: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and 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) to receive either indacaterol (27.5 μg) plus glycopyrrolate (15.6 μg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) 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).

Results: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 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 mean change in the percent of predicted FEV₁ was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo.

Conclusions: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).

Figure 1.. Enrollment, Randomization, and Follow-up.

Participants were randomly assigned to receive indacaterol (27.5 μg) plus glycopyrrolate (15.6 μg) or placebo twice daily for 12 weeks. The modified intention-to-treat population excluded participants who had neither treatment failure nor week 12 data for the primary outcome. The per-protocol population excluded participants who had a protocol deviation or incorrect or unknown adherence. SGRQ denotes St. George’s Respiratory Questionnaire.

Figure 2. Primary and Secondary Binary Outcomes.

(facing page). The primary outcome was at least a 4-point decrease (i.e., improvement) in the SGRQ score after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms leading to treatment with a long-acting bronchodilator, glucocorticoid, or antibiotic agent). All odds ratios were based on generalized-estimating-equation models with adjustment for clinical center of recruitment, baseline smoking status, previous maintenance treatment for chronic obstructive pulmonary disease (COPD) warranting a washout period, body-mass index at baseline, and the baseline value of the outcome being evaluated. In sensitivity analysis 1, we reassigned 12 participants in the modified intention-to-treat analysis who had been incorrectly given treatment or placebo at randomization. In sensitivity analysis 2, we excluded 11 participants from the modified intention-to-treat population who actually had a ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) of less than 0.70 (meeting the definition of COPD). In sensitivity analysis 3, we excluded 56 participants from the modified intention-to-treat population who were enrolled after the start of the coronavirus disease 2019 (Covid-19) pandemic (March 30, 2020). In sensitivity analysis 4, we included 10 participants who had been excluded from the modified intention-to-treat population because they had the primary outcome measured more than 16 weeks after randomization. In the analysis shown, bronchodilator responsiveness was defined as an increase in either FEV₁ or FVC by at least 12% and at least 200 ml after bronchodilator use, in accordance with the American Thoracic Society and European Respiratory Society definition. SGRQ scores range from 0 to 100, with higher scores indicating worse health status. COPD Assessment Test (CAT) scores range from 0 to 40, with higher scores indicating worse symptoms. The Transition Dyspnea Index (TDI) score is a measure of the change in dyspnea severity from the baseline value established by the Baseline Dyspnea Index score; TDI scores range from −9 to 9, with higher scores indicating greater decreases in dyspnea severity. For all secondary and exploratory analyses, 95% confidence intervals have not been adjusted for multiplicity and therefore cannot be used in place of hypothesis tests.

Figure 3.. Lung Function and Symptom Scores.

Changes in lung-function measures were assessed as baseline prebronchodilator values as compared with those obtained 12 hours after the final dose of trial medication or placebo at 12 weeks. Heights of bars indicate the mean, and I bars indicate the 95% confidence interval based on linear mixed-effects model estimates. All changes were from baseline to the week 12 visit. AUC_0–3hr is the area under the curve, assessed hourly over the first 3 hours after a dose. For all analyses shown here, 95% confidence intervals have not been adjusted for multiplicity and therefore cannot be used in place of hypothesis tests.