• MeiLan K Han, Wen Ye, Di Wang, Emily White, Mehrdad Arjomandi, Igor Z Barjaktarevic, Stacey-Ann Brown, Russell G Buhr, Alejandro P Comellas, Christopher B Cooper, Gerard J Criner, Mark T Dransfield, Frank Drescher, Rodney J Folz, Nadia N Hansel, Ravi Kalhan, Robert J Kaner, Richard E Kanner, Jerry A Krishnan, Stephen C Lazarus, Veeranna Maddipati, Fernando J Martinez, Anne Mathews, Catherine Meldrum, Charlene McEvoy, Toru Nyunoya, Linda Rogers, William W Stringer, Christine H Wendt, Robert A Wise, Stephen R Wisniewski, Frank C Sciurba, Prescott G Woodruff, and RETHINC Study Group.
• From the Division of Pulmonary and Critical Care (M.K.H., C. Meldrum) and the School of Public Health (W.Y., D.W., E.W.), University of Michigan, Ann Arbor; the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine (M.A., S.C.L., P.G.W.) and the Cardiovascular Research Institute (S.C.L., P.G.W.), University of California San Francisco, and the San Francisco Veterans Affairs (VA) Healthcare System (M.A.) - both in San Francisco; the Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA (I.Z.B., R.G.B., C.B.C.), and the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (W.W.S.) - both in Los Angeles; the Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore (S.-A.B., N.N.H., R.A.W.); the Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa, Iowa City (A.P.C.); the Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia (G.J.C.); the Division of Pulmonary, Allergy, and Critical Care Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham (M.T.D.); Geisel School of Medicine at Dartmouth and Pulmonary and Critical Care Medicine, VA Medical Center, White River Junction, VT (F.D.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Houston Methodist Academic Medicine Associates, Houston (R.J.F.); the Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine (R.K.), and the Breathe Chicago Center, Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois Chicago (J.A.K.) - both in Chicago; the Department of Genetic Medicine (R.J.K.) and Joan and Sanford I. Weill Department of Medicine (R.J.K., F.J.M.), Weill Cornell Medicine and New York-Presbyterian Hospital, and the Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai (L.R.) - both in New York; the Division of Respiratory, Critical Care, and Occupational Pulmonary Medicine, University of Utah School of Medicine, Salt Lake City (R.E.K.); East Carolina University, Greenville (V.M.), and Duke University School of Medicine, Durham (A.M.) - both in North Carolina; HealthPartners Institute, Bloomington (C. McEvoy), and Minneapolis VA Healthcare System, Minneapolis (C.H.W.) - both in Minnesota; and the Division of Pulmonary, Allergy, and Critical Care Medicine (T.N., F.C.S.) and Epidemiology Data Center (S.R.W.), University of Pittsburgh, Pittsburgh.
• N. Engl. J. Med. 2022 Sep 29; 387 (13): 117311841173-1184.

BackgroundMany 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.MethodsWe 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).ResultsA 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.ConclusionsInhaled 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.).Copyright © 2022 Massachusetts Medical Society.

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