Comparison of the effects of dual bronchodilators with single bronchodilators in group B COPD patients according to the FEV1 level: patient-level pooled analysis of phase-3 RCTs

Abstract

Rationale: Global initiative for Obstructive Pulmonary Disease (GOLD) consensus document serves as an important reference for clinicians in assessment and management of patients with chronic obstructive pulmonary disease (COPD). The 2017 revised version of the document removed forced expiratory volume at 1 s (FEV1) from the criteria used in patient grouping, leaving only the severity of symptoms and exacerbation history. To test the hypothesis that lower FEV1 level (<50%pred.) identifies a population more likely to benefit from dual bronchodilators than single bronchodilator treatment, this study compared the effects of dual and single bronchodilators in group B COPD patients according to the FEV1 level. Methods: This study was a patient-level pooled analysis of the phase-3 randomized controlled trials of dual bronchodilators. Individual patient level data were obtained from the available trials provided by sponsor companies. Glycopyrronium/indacaterol, umeclidinium/vilanterol, or tiotropium/olodaterol were the dual bronchodilators of interest. Studies with a parallel-design and duration longer than 8 weeks were included. Data were obtained from ClinicalStudyDataRequest.com. Study outcomes were changes in trough FEV1, St. George’s Respiratory Questionnaire (SGRQ) score, proportion of SGRQ responders, rate of acute exacerbation, time to first exacerbation, and a risk of adverse events. Results: A total of 12 studies were included in this pooled analysis. Among patients in the 2017 GOLD group B, 8043 had FEV1 less than 50% of the predicted value (%pred.) and 6406 had FEV1 ≥50%pred. Dual bronchodilator treatment was significantly effective than long-acting beta-2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) in improving trough FEV1, regardless of the baseline FEV1 level. In patients with FEV1 <50%pred., dual bronchodilator treatment consistently showed a significant association with a greater reduction in SGRQ scores and proportion of SGRQ responder regardless of the comparator; however, in patients with FEV1 ≥50%pred., dual bronchodilator treatment was only better than LAMA, not LABA. Time to first exacerbation was significantly longer with dual bronchodilators compared with LABA in patients with FEV1 <50%pred.; but there was no difference between dual bronchodilators and single bronchodilators in patients with FEV1 ≥50%pred. The risk of adverse events was similar between dual and single bronchodilator treatment. Conclusions: In conclusion, the benefit of dual bronchodilators over single bronchodilators were consistently significant in improving FEV1 and health-related quality of life without increasing the risk of adverse events in GOLD group B COPD patients with FEV1 <50%pred. Patients with lower FEV1 may be the population who are likely to benefit from more intensive treatment.