Bronchodilators fail in symptomatic smokers with preserved lung function

According to clinical trial results recently published in The New England Journal of Medicine.

Since dual inhaled bronchodilator therapy is effective in controlling symptoms in patients with COPD, it is assumed that such treatment will also work with current or former smokers with significant respiratory symptoms. However, data proving the effectiveness of this approach is lacking. The researchers therefore sought to determine whether inhaled bronchodilator therapy would benefit people who smoked (currently or formerly, with a 10-pack-year history) and had clinically significant respiratory symptoms, despite preserved lung function as assessed by spirometry.

The researchers conducted Redefining Therapy in Early COPD (RETHINC), a randomized, multicenter, blinded controlled trial (ClinicalTrials.gov Identifier: NCT02867761) that included 471 intention-to-treat participants randomized to treatment (n=227) or the placebo group (n=244). All participants had a smoking history of at least 10 pack-years, preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] with forced vital capacity [FVC] ≥ 0.70 and FVC ≥ 70% predicted after bronchodilator use) and respiratory symptoms defined by a COPD assessment test score of at least 10 (range 0 to 40, higher scores indicating more severe symptoms).


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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 an improvement (decrease) of at least 4 points in the St. George’s Respiratory Questionnaire (SGRQ) score after 12 weeks without treatment failure (defined as an increase in lower respiratory tract symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). The researchers found that adherence was 88% of the doses taken in both groups.

Investigators found that 56.4% of participants in the treatment group and 59.0% of those in the placebo group had a 4-point improvement in 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) versus 0.02 liters (95% CI, -0.03 to 0. 08) in the placebo group. The mean change in predicted FEV percentage1 in the treatment group was 2.48 percentage points (95% CI, 1.49 to 3.47) versus -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.

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

“We found that long-acting bibronchodilator treatment did not decrease respiratory symptoms in people who were current or former cigarette smokers and had significant respiratory symptoms despite preservation of lung function, as assessed by the spirometry. This contrasts with data on symptom reduction with long-acting dual bronchodilators in tobacco-exposed individuals who meet criteria for COPD,” the study authors said. “The therapy of Smoking cessation remains a primary goal for this patient population,” they noted, adding that further research into treatment for this patient population is needed.

Reference

Han MK, YeW, Wang D, et al. ; RETHINC Study Group. Bronchodilators in people exposed to tobacco with symptoms and preserved lung function. N English J med. Published online September 4, 2022. doi:10.1056/NEJMoa2204752

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