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Mortality in the 4-Year Trial of Tiotropium (UPLIFT) in Patients with Chronic Obstructive Pulmonary Disease

¹ Brigham and Women's Hospital and St. Elizabeth's Medical Center, Boston, Massachusetts; ² University of Leuven, Leuven, Belgium; ³ Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut; ⁴ Pfizer Pharmaceuticals, New York, New York; and ⁵ David Geffen School of Medicine at UCLA, Los Angeles, California

Correspondence and requests for reprints should be addressed to Bartolome Celli, M.D., Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: bcelli{at}copdnet.org

Rationale: In the 4-year UPLIFT trial, tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease (COPD). Mortality and its causes was a secondary endpoint in UPLIFT.

Objectives: We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients.

Methods: This study involved a randomized, double-blind trial comparing tiotropium with placebo in patients with COPD (40 yr of age; postbronchodilator FEV₁ 70%; FEV₁/FVC 70%). Mortality was evaluated during treatment and with follow-up of discontinued patients. Cause of death was adjudicated by an endpoint committee.

Measurements and Main Results: A total of 5,993 patients were randomized, 3,006 to placebo and 2,987 to tiotropium. While patients were receiving treatment, there were 792 deaths, with a lower risk in the tiotropium group (hazard ratio, 0.84; 95% confidence interval [CI], 0.73–0.97). Statistical significance was observed at the end of the protocol-defined treatment period (P = 0.034) but not 30 days thereafter (P = 0.086). Adjustment by GOLD stage, sex, age, baseline smoking behavior, and baseline respiratory medications subgroups did not alter the results of the analysis. The most common causes of death adjudicated by an independent end-point committee were lower respiratory, cancer, general disorders, and cardiac disorders. The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 (95% CI, 0.68–1.09) and 0.86 (95% CI, 0.75–0.99), respectively.

Conclusions: Treatment with tiotropium over 4 years is associated with decreased mortality, with the effect being most prominent in the cardiac and respiratory systems.

Key Words: COPD • tiotropium • mortality

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject There is limited knowledge on the effect of pharmacotherapy on mortality in patients with chronic obstructive pulmonary disease, although the results of the TORCH study support a benefit in patients receiving the combination of inhaled fluticasone and salmeterol. What This Study Adds to the Field This study shows that pharmacotherapy with tiotropium reduces mortality compared with usual care while patients are receiving treatment. These results provide support that disease progression can be affected by pharmacotherapy.