title: Discordance in investigator-reported and adjudicated sudden death in TIOSPIR.
abstract: Accurate and consistent determination of cause of death is challenging in chronic obstructive pulmonary disease (COPD) patients. TIOSPIR (N=17 135) compared the safety and efficacy of tiotropium Respimat 5/2.5 µg with HandiHaler 18 µg in COPD patients. All-cause mortality was a primary end-point. A mortality adjudication committee (MAC) assessed all deaths. We aimed to investigate causes of discordance in investigator-reported and MAC-adjudicated causes of death and their impact on results, especially cardiac and sudden death. The MAC provided independent, blinded assessment of investigator-reported deaths (n=1302) and assigned underlying cause of death. Discordance between causes of death was assessed descriptively (shift tables). There was agreement between investigator-reported and MAC-adjudicated deaths in 69.4% of cases at the system organ class level. Differences were mainly observed for cardiac deaths (16.4% investigator, 5.1% MAC) and deaths assigned to general disorders including sudden death (17.4% investigator, 24.6% MAC). Reasons for discrepancies included investigator attribution to the immediate (e.g.myocardial infarction (MI)) over the underlying cause of death (e.g.COPD) and insufficient information for a definitive cause. Cause-specific mortality varies in COPD, depending on the method of assignment. Sudden death, witnessed and unwitnessed, is common in COPD and often attributed to MI without supporting evidence.
authors.affiliation: Dept of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wise
authors.affiliation: Division of Cardiology, Lankenau Heart Institute and Jefferson Medical College, Wynnewood, PA, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Kowey
authors.affiliation: Global Biostatistics and Data Sciences, Boehringer Ingelheim Ltd, Bracknell, UK.
authors.forename: George
authors.initials: G
authors.lastname: Austen
authors.affiliation: Global Biostatistics and Data Sciences, Boehringer Ingelheim Pharma GmbH Co & KG, Biberach, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Mueller
authors.affiliation: Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH Co & KG, Ingelheim am Rhein, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Metzdorf
authors.affiliation: Dept of Medical Affairs, Boehringer Ingelheim Pharma Ltd, Bracknell, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Fowler
authors.affiliation: Centre for Infection and Immunity, Queen's University Belfast, Belfast, UK.
authors.forename: Lorcan P
authors.initials: LP
authors.lastname: McGarvey