Spirometric Z-Score Reappraisal of the UPLIFT Trial: A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

Spirometric Z-Score Reappraisal of the UPLIFT Trial: A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a breathing disorder that is defined by reduced airflow in the lungs (termed airway obstruction), most often resulting from tobacco smoking and most often affecting aging populations (middle-aged or older persons). COPD is projected to be a leading cause of disability (5th) and death (3rd) worldwide by 2030. Hence, establishing effective therapies in COPD is a high clinical priority.The UPLIFT trial previously evaluated the benefits of tiotropium, over a 4-year period, in 5993 participants with COPD and mean age of 65 years. Tiotropium is an inhaled medication that opens the airways in the lung. In the UPLIFT trial, however, tiotropium did not improve survival but we note that the criteria used to establish a diagnosis of COPD were not age-appropriate. In particular, the test that established airway obstruction (COPD), namely a breathing test called spirometry, used diagnostic criteria (termed GOLD criteria) that cannot adequately distinguish changes in lung function (spirometry) which are due to normal aging from those which are due to disease (as in COPD).As an alternative approach, we have shown that COPD is best established by diagnostic criteria which are based on a statistical method called spirometric Z-scores, as these rigorously account for the effects of normal aging. Accordingly, using data that was already collected in the UPLIFT trial, we propose the following research objectives:First, we will re-interpret spirometry from the UPLIFT cohort, using Z-scores. Based on our prior work, we hypothesize that at least 20% of the UPLIFT cohort will have been misidentified as having COPD. Second, we will evaluate all-cause mortality, comparing tiotropium with placebo. We hypothesize that tiotropium will improve survival, when COPD is defined by spirometric Z-scores. Lastly, we propose to evaluate the other outcomes of the UPLIFT trial, including lung function (spirometry), respiratory-related quality of life, exacerbations of COPD, and adverse events, each over the 4-year study period. We hypothesize that tiotropium will improve these outcomes, when COPD is defined by spirometric Z-scores.If subsequent results support the hypotheses, our proposed research may show that tiotropium has greater clinical efficacy in aging populations when COPD is established by age-appropriate spirometric Z-scores.

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