Ascertainment of Cause-Specific Mortality in COPD -- Operations of the TORCH Clinical Endpoint Committee

Abstract

Background: TORCH (Towards a Revolution in COPD Health) is an international multicentre randomised placebo-controlled clinical trial of inhaled fluticasone propionate /salmeterol combination therapy and its monotherapy components for maintenance therapy of moderately to severely impaired patients with chronic obstructive pulmonary disease (COPD). The primary outcome is all-cause mortality. Cause-specific mortality and deaths related to COPD are additional outcome measures, but systematic methods for ascertainment of these outcomes have not been previously described. Methods: A clinical end-point committee (CEC) was tasked with categorization of cause of death and relationship of deaths to COPD in a systematic, unbiased, and independent manner. The key elements of the operation of the committee were the use of pre-defined principles of operation and definitions of cause of death and COPD-relatedness; the independent review of cases by all members with development of a consensus opinion; and a substantial infrastructure to collect medical information. Results: 911 deaths were reviewed and consensus was reached in all. Cause-specific mortality was: Cardiovascular 27%, Respiratory 35%, Cancer 21%, Other 10% and Unknown 8%. 40% of deaths were definitely or probably related to COPD. Adjudications were identical in 83% of blindly re-adjudicated cases (Kappa=0.80) COPD-relatedness was reproduced 84% of the time. (Kappa = 0.73). The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52% of cases. Conclusion: A CEC can provide standardized, reliable, and informative adjudication of COPD mortality that provides information that frequently differs from data collected from site investigators assessment.