Association of Guideline-recommended COPD Inhaler Regimens with Respiratory Exacerbations, Exercise Performance, and Quality of Life

Background: Although inhaled therapy reduces exacerbations among patients with COPD, the effectiveness of providing inhaled treatment according to recent risk-stratification models remains unclear. Research Question: Are inhaled regimens that align with the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy associated with clinically important outcomes? Study Design and Methods: We conducted secondary analyses of Long-term Oxygen Treatment Trial data. The trial enrolled COPD patients with moderate resting or exertional hypoxemia between 2009-2015. Our exposure was the patient-reported inhaled regimen at enrollment, categorized as either aligning with, undertreating, or potentially overtreating per the 2017 GOLD strategy. Our primary outcome was hospitalization for COPD. Additional outcomes included COPD exacerbation. We generated multivariable Cox proportional-hazard models across strata of GOLD-predicted exacerbation risk (high vs low) to estimate between-group hazard ratios for outcomes. We adjusted models a priori for potential confounders, clustered by site. Results: The trial enrolled 738 patients; 73.4% were male with mean age 68.8 years. 571 patients (77.4%) were judged to be at low risk for future exacerbations. 233 patients (31.6%) reported regimens aligning with GOLD recommendations; most regimens (54.1%) potentially overtreated. During 2.3-year median follow-up, 257 patients (34.8%) experienced hospitalization for COPD. Among high-risk patients (GOLD groups C/D), undertreatment was associated with a 49% lower risk of experiencing hospitalization for COPD than regimens that aligned with guideline recommendations (HR 0.51, 95% CI: 0.28, 0.91). Among low-risk patients (GOLD groups A/B), we found no difference in the incidence of hospitalization for COPD across categories of inhaled treatment regimens; however, potential overtreatment was associated with a 53% higher risk of COPD exacerbation (HR 1.53, 95% CI: 1.13, 2.07) and a 64% higher risk of pneumonia (IRR 1.64, 95% CI: 1.01, 2.66). Interpretation: Among COPD patients with moderate hypoxemia, those reporting inhaled regimens that aligned with the 2017 GOLD strategy did not experience improved clinical outcomes compared to those who were undertreated. The relatively narrow patient population and the observational nature of our study limit the interpretation of our findings. Additional studies are needed to establish the effectiveness of risk stratification model-based inhaled treatment strategies.