Re-evaluation of the Uplift Clinical Trial Using Age-Appropriate Spirometric Criteria.

Background: The clinical trial of tiotropium in COPD, UPLIFT, enrolled adults with a mean age of 65 years and moderate-to-severe airflow obstruction, based on criteria from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). For the UPLIFT cohort, however, GOLD-based criteria are not age-appropriate.

Research Question: Will the use of more age-appropriate criteria for airflow obstruction from the Global Lung Function Initiative (GLI) modify the spirometric classification of the UPLIFT cohort and, in turn, the mortality effect of tiotropium in COPD?

Study Design And Methods: Baseline spirometric classifications were first cross-tabulated by GLI- and GOLD-based criteria. Next, in GLI- and GOLD-based airflow obstruction, modified intention-to-treat analyses evaluated differences in time to death over 4 years, comparing tiotropium vs placebo. Because treatment response may differ by COPD severity, the mortality effect also was evaluated within stratum defined by GLI- and GOLD-based moderate and severe airflow obstruction.

Results: Of 5,898 participants with GOLD-based airflow-obstruction, staged as moderate in 2,739 (46.4%) and severe in 3,156 (53.5%), GLI-based criteria established airflow obstruction in 5,750 (97.5%), staged as moderate in 795 (13.5%) and severe in 4,947 (83.9%). Relative to placebo, tiotropium yielded statistically nonsignificant adjusted hazard ratios (adjHRs) (95% CI) for death of 0.91 (0.80-1.04) and 0.91 (0.79-1.03) in GLI- and GOLD-based airflow obstruction, respectively. However, statistically significant effect modification was observed, but only in GLI-based moderate and severe airflow-obstruction, with tiotropium yielding adjHRs for death of 0.53 (0.34-0.81) and 0.99 (0.86-1.13), respectively. The P value for interaction was .007.

Interpretation: Mortality reduction by tiotropium was only statistically significant in GLI-based moderate airflow-obstruction, a group that was underrepresented in UPLIFT because of severity misclassification by the original GOLD-based enrollment criteria.