RETHINC Takes Air Out of COPD-like Therapy for Smokers

Neil Osterweil

September 06, 2022

Current or former smokers who ha­ve clinically significant respiratory symptoms but no spirometric evidence of airway obstruction are often treated with dual bronchodilators commonly prescribed for patients with chronic obstructive pulmonary disease (COPD).

But as results of the randomized RETHINC trial showed, bronchodilator therapy was no better than placebo at reducing respiratory symptoms in smokers, reported MeiLan K. Han, MD, from the University of Michigan, Ann Arbor, on behalf of colleagues in the RETHINC (Redefining Therapy In Early COPD for the Pulmonary Trials Cooperative) study group.

"Many tobacco-exposed symptomatic individuals are currently 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 a benefit, but 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," Han said in an oral abstract presentation at the European Respiratory Society (ERS) 2022 Congress.

The study results were also published online in The New England Journal of Medicine (NEJM) to coincide with the presentation.

In an editorial accompanying the study in NEJM, Don D. Sin, MD, MPH, from the University of British Columbia in Vancouver, British Columbia, Canada, commented that the study shows that "long-acting bronchodilators do not appear to be effective for the treatment of symptomatic persons with a smoking history and preserved lung function on spirometry; these medications should most likely be reserved for patients with COPD who have clinically significant airflow limitation," and that "respiratory symptoms in tobacco-exposed persons are common but are highly variable over time."

Dave Singh, MD, from the University of Manchester, United Kingdom, the invited discussant, called it "a very important negative study."

Not Up to GOLD Standard

Current or former smokers who are symptomatic, with COPD Assessment Test (CAT) scores of at least 10 despite having preserved function on spirometry, have been shown to have higher prospective rates of respiratory disease exacerbations and increased sputum total mucin concentrations. Approximately 43% of such patients are treated with bronchodilators, and 23% are treated with inhaled corticosteroids (ICS), Han noted.

Her group hypothesized that ever-smokers with spirometric values that fall within the normal range — that is, a postbronchodilator FEV1/FVC ratio of 70 or greater — would still derive benefit from long-acting bronchodilator therapy, even though these patients are currently excluded from Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations.

To test this, they conducted a 12-week, multicenter, randomized, parallel-group study in which patients were assigned to receive either indacaterol (27.5 µg) and glycopyrrolate (15.6 µg) inhaled twice daily or placebo.

They enrolled adults aged 40-80 years with a minimum of 10 pack-years of smoking history, postbronchodilator FEV1/FVC ratio of 70 or greater, and CAT scores of 10 or greater. Patients with known concomitant lung disease, a primary diagnosis of asthma, or body mass index lower than 15 or higher than 40 and those being concomitantly treated with long-acting beta-2 agonists or muscarinic antagonists or a short-acting combination were excluded, although patients were allowed to be on a short-acting beta-agonist.

A total of 535 participants were randomized, but COVID-19 pandemic–imposed obstacles resulted in a modified intention-to-treat population of 277 patients assigned to receive the active treatment and 244 assigned to receive placebo.

There was no difference between the groups for the primary outcome of an at least 4-point decrease in St. George's Respiratory Questionnaire scores in patients who did not experience treatment failure, defined as an increase in respiratory symptoms requiring treatment with active long-acting bronchodilators or ICS.

The primary endpoint was seen in 56.4% of patients in the bronchodilator group, and 59% of controls.

Although there was greater improvement in pulmonary function from baseline in the treatment group compared with the placebo group, the improvements did not correlate with similar improvements in symptoms, Han said.

There were four serious adverse events in the bronchodilator group and 11 in the placebo group, but none of the events were deemed to be related to the assigned treatments.

Han acknowledged limitations of the study, which may have included symptoms driven by other factors such as cardiac disease, suggesting that if such patients had been identified and excluded, a stronger effect might have been seen for the active treatment.

In addition, the study was underpowered to look at the subgroup of participants with chronic bronchitis, and the 12 weeks of the study may have been too short to see improvements in symptoms.

In his NEJM editorial, Sin noted that the study showed that cough and sputum production rather than exertion dyspnea are the primary symptoms among ever-smokers.

"Although bronchodilators are effective in ameliorating breathlessness and improving exercise tolerance, they are generally ineffective for cough," he wrote. "Existing drugs for the treatment of COPD, such as inhaled glucocorticoids or phosphodiesterase-4 inhibitors, or new therapeutics such as P2X3 receptor antagonists may be more effective for the treatment of cough and sputum production related to smoking and could be considered for future evaluations in this patient population."

The study was supported by the National Heart, Lung, and Blood Institute, the National Center for Advancing Translational Sciences, and Sunovion Pharmaceuticals. Novartis Pharmaceuticals donated the trial medication and placebo. Han disclosed grant/research support and honoraria or consulting fees from various companies. Singh reported speaking fees, honoraria, and research grants from multiple companies. Sin reported having no conflicts of interest to disclosed,

European Respiratory Society Congress 2022. Presented September 4, 2022. Abstract

N Engl J Med. Published online September 4, 2022. Abstract; Editorial

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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