Relative Timing of Clinically Important Deterioration and Related Long-Term Outcomes in COPD: A Post Hoc Analysis of the UPLIFT Study

Rationale:

Lung function, health status, and exacerbations are important measures of chronic obstructive pulmonary disease (COPD) progression. So far, treatments in COPD have failed to demonstrate a reduction in rate of decline of trough forced expiratory volume in 1 second (FEV1) or mortality, which may be related to the multicomponent nature of COPD. This post hoc analysis assessed the suitability to predict long-term outcomes using a composite endpoint in patients with moderate to very severe COPD in the UPLIFT trial that may better reflect the multifactorial disease progression in COPD.

Methods:

In the 4 year UPLIFT study (NCT00144339) Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage 2 – 4 COPD patients were randomized to receive tiotropium 18 µg once daily (via Handihaler®) or placebo. A composite endpoint of clinically important deterioration (CID: first confirmed ≥100mL decrease in FEV1, confirmed increase in St. George's Respiratory Questionnaire (SGRQ) total score of ≥4units, or time to first moderate/severe exacerbation) was tested and treatment arms were pooled.

Results:

CID events were highly variable across patients. Confirmed FEV1 deterioration and confirmed SGRQ deterioration were observed at the same assessment in only 18% of patients. Time intervals between a first event and subsequent, different, event type were also highly variable. CID events at 6 and 12 months were a good predictor of moderate/severe and severe exacerbation, but a weaker, predictor for death [CID at 6 months HR: 1.21,95% CI: 1.06, 1.39; CID at 12 months HR 1.31, 95% CI: 1.13, 1.53]. When CID events were analyzed as time-varying covariate to predict death, it was associated with a HR of 1.69 [95% CI 1.42, 2.01]. Importantly, tiotropium significantly lowered Hazard ratios for time to first CID in GOLD 2 [HR: 0.70, 95% CI: 0.65, 0.77] and GOLD 3 patients [HR: 0.69, 95% CI: 0.63, 0.75].

Conclusions:

Here we show that CID is a clinically meaningful parameter in order to predict long-term outcome in COPD, including mortality. CID may therefore have a significant impact on future clinical trial designs, e.g. by reducing the optimal number of participants to show a clinically relevant effect of therapeutic intervention. CID may also change future treatment strategies by taking into account the multicomponent nature of COPD.