In the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, tiotropium therapy for patients with chronic obstructive pulmonary disease (COPD) was associated with long-term improvements in lung function, quality of life, and COPD exacerbations. The therapy did not, however, significantly reduce the rate of decline in forced expiratory volume in 1 second (FEV1) compared with placebo.
In the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, tiotropium therapy for patients with chronic obstructive pulmonary disease (COPD) was associated with long-term improvements in lung function, quality of life, and COPD exacerbations. The therapy did not, however, significantly reduce the rate of decline in forced expiratory volume in 1 second (FEV1) compared with placebo. These results were reported in the New England Journal of Medicine.
This 4-year, randomized, double-blind, placebo-controlled, parallel-group trial recruited patients from 490 investigational centers in 37 countries. Patients were included if they were aged at least 40 years and had a diagnosis of COPD, a smoking history of at least 10 pack-years, postbronchodilator FEV1 of 70% or less of the predicted value, and postbronchodilator FEV1 of 70% or less of the forced vital capacity (FVC). Patients were randomized to receive either tiotropium 18 mcg or placebo once daily. All other respiratory medications (excluding other inhaled anticholinergics) were permitted throughout the trial. The coprimary end points were the yearly rate of decline in mean FEV1 before and after bronchodilation from Day 30 (steady state) until the end of treatment. Secondary end points included rate of decline in FVC and slow vital capacity (SVC); health-related quality of life (as measured by the St. George’s Respiratory Questionnaire [SGRQ]); exacerbations of COPD; and rate of death.
A total of 5,993 patients underwent randomization (tiotropium, 2,987; placebo, 3,006). The median treatment duration was 1,436 days for tiotropium-treated patients and 1,435 for placebo-treated patients. Concomitant medication use and baseline characteristics were similar between the 2 groups.
No significant difference was observed between the groups in the rate of decline in mean values of FEV1 and FVC before or after bronchodilation from Day 30 until study end. Tiotropium-treated patients did, however, demonstrate significant improvements in mean FEV1 values versus placebo both before and after bronchodilation (P<.001). Patients treated with tiotropium had a significantly improved SGRQ score compared with placebo-treated patients at all time points (P<.001). Tiotropium-treated patients also demonstrated a significant delay in the time to first COPD exacerbation and the time to first hospitalization for an exacerbation compared with placebo-treated patients. An analysis of mortality rates demonstrated that over the 4-year, protocol-defined study period, 14.4% of tiotropium-treated and 16.3% of placebo-treated patients died (HR=0.87; 95% CI, 0.76–0.99).
The authors pointed out that the rate of decline in FEV1 observed in this study was lower than the rates previously reported. They suggested that this lower rate could be explained in part by the ability of patients to use other respiratory therapies throughout the study or by the higher proportion of patients who abstained from smoking during the study compared with previous studies.
In an accompanying editorial, John J. Reilly, MD, suggests that the results of this study may demonstrate a problem with how COPD is defined. He states, “In our efforts to simplify and clarify our definition of COPD, we have promulgated an inclusive definition that relies primarily on spirometric measures to establish the diagnosis. There is increasing recognition that FEV1 alone, while important, does not capture and communicate the heterogeneity of COPD.”
Tashkin DP, Celli B, Senn S, et al; for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–1554.
Reilly JJ. COPD and declining FEV1-time to divide and conquer [editorial]? N Engl J Med. 2008;359:1616–1618.