Bronchodilators ineffective in symptomatic, tobacco-exposed patients without COPD

Bronchodilators, used in the treatment of chronic obstructive pulmonary disease (COPD), did not appear to benefit individuals with a history of smoking and respiratory symptoms who did not have airflow obstruction, results of the US-based RETHINC* study showed.

“We found that dual long-acting bronchodilator treatment did not decrease respiratory symptoms [in this population],” said the investigators. “This stands in contrast to data on symptom abatement with dual long-acting bronchodilators in tobacco-exposed persons who meet criteria for COPD,” they said.

Participants were 535 patients aged 40–80 years (mean age 58.8 years, 48.6 percent male, 56.4 percent White, mean BMI 29.5 kg/m²) with ≥10 pack-years smoking history, respiratory symptoms (COPD Assessment Test [CAT] score ≥10 [mean 17.6]), and preserved lung function on spirometry (post-bronchodilator FEV₁:FVC** ≥0.70 [mean 0.78] and FVC ≥70 percent of the predicted value [mean 93.6 percent]). They were randomized to receive inhaled indacaterol/glycopyrrolate 27.5/15.6 µg or placebo BID for 12 weeks.

At baseline, mean St. George’s Respiratory Questionnaire (SGRQ) score was 38.2. Twenty-eight percent were already on inhaled COPD therapy. Sixty-four percent were current smokers. Seventeen percent had diabetes (the most common comorbidity). Chronic bronchitis prevalence differed according to definition (36.5 percent based on Medical Research Council definition, 70.3 percent based on CAT).

At 12 weeks, the primary outcome, a ≥4-unit reduction (improvement) in SGRQ score without treatment failure (ie, increase in lower respiratory symptoms requiring long-acting inhaled bronchodilator, glucocorticoid, or antibiotic treatment), was achieved by a comparable proportion of patients in the indacaterol/glycopyrrolate and placebo groups in the mITT*** population (56.4 percent vs 59.0 percent; adjusted odds ratio, 0.91, 95 percent confidence interval [CI], 0.60–1.37; p=0.65). [ERS 2022, session ALERT 1: COPD and hospital management; N Engl J Med 2022;doi:10.1056/NEJMoa2204752]

The incidence of treatment failure was low, affecting only five and nine patients in the indacaterol/glycopyrrolate and placebo groups, respectively (2.2 percent vs 3.7 percent), while adherence was high (88 percent in both groups).

Percent predicted change in FEV₁ was a mean 2.48 percentage points (95 percent CI, 1.49–3.47) in the indacaterol/glycopyrrolate group and a mean –0.09 percentage points (95 percent CI, –1.06 to 0.89) in the placebo group. Inspiratory capacity changed by a mean 0.12 L (95 percent CI, 0.07–0.18) in the indacaterol/glycopyrrolate group and 0.02 L (95 percent CI, –0.03 to 0.08) in the placebo group.

Four and 11 serious adverse events (AEs) were documented in the indacaterol/glycopyrrolate and placebo groups, respectively (1.5 percent vs 2.9 percent), none of which led to death or were considered treatment related. The most frequent non-serious AEs were cough (3.4 percent vs 4.4 percent) and headache (3.4 percent vs 4.4 percent).

A different population requires a different treatment

According to the investigators, many patients with a history of tobacco smoking who have respiratory symptoms but no airflow obstruction on spirometry are treated with COPD medications despite the lack of evidence on the effectiveness of these treatments in this population.

“We’ve assumed these medications worked in patients who don’t meet lung function criteria for COPD, but we never checked,” remarked principal investigator Dr MeiLan K. Han from the University of Michigan, Ann Arbor, Michigan, US. “We now know these existing medications don’t work for these patients.”

“Our results have important implications for clinical practice. Preserved lung function on spirometry (FEV₁:FVC ≥0.70) in a person with current or former exposure to smoked tobacco and respiratory symptoms should generally discourage the prescription of bronchodilators for symptom control,” said Han and co-investigators.

They highlighted the importance of using spirometry in primary care to distinguish between patients with and without COPD, as the former generally derive benefit from bronchodilators. They also called for research into identifying other treatments that may benefit this non-COPD group.

“Because cough and mucus production show up prominently among these patients, we believe therapies that target mucus production in the airways may be effective,” said senior author Professor Prescott Woodruff from the University of California San Francisco, California, US.

The investigators acknowledged that the short follow-up period was insufficient to assess whether the treatment affected exacerbations. Additionally, the FDA-approved dose of indacaterol/glycopyrrolate used in this trial is lower than that used in other countries, which could have impacted the results.