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.

Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR^® trial

“…An independent Mortality Adjudication Committee blinded to treatment reviewed the case report forms, medical documents, and witness reports and adjudicated the primary underlying cause of death using standardized criteria. 24 , 25 Generally, primary death cause was attributed to the underlying clinical condition for which the patient initially presented for treatment and not to the immediate cause of death (further details are provided in the Supplementary Appendix of Wise et al 23 ). Respiratory deaths were defined as those in the “Respiratory, thoracic, and mediastinal disorders” system organ classes, along with deaths from respiratory tract infections.…”

Adjudication of cardiovascular events in patients with chronic obstructive pulmonary disease: SUMMIT trial

“…Assessment of sudden or unwitnessed death is a particularly difficult problem in COPD populations since some of these deaths may be the result of respiratory events as well as cardiovascular death. 5 In line with previous adjudication committees, 1 – 3 , 14 we used arbitrary definitions of sudden death in the absence of a presenting acute illness and relied upon interviews with family or caretakers to help in this process. Among 320 deaths finally adjudicated as sudden death, only 189 (59%) were reported as such by site investigators.…”

“…The process for adjudicating the primary cause of death and assessing whether or not it was related to COPD was similar to that followed in recent large respiratory trials. 1 – 3 In brief, the adjudicated cause of death was classified based on the underlying cause of death defined as the presenting illness that preceded the terminal events, not the terminal events just preceding death. Adjudication of major adverse cardiovascular events generally followed the Food and Drug Administration guidance for cardiovascular outcomes.…”

“…Cause-specific mortality has become a routine adjudicated outcome in large COPD clinical trials, and the methods and experience of the adjudication process have been reported previously. 1 – 3 Although major adverse cardiovascular events are a common outcome measure in cardiovascular clinical trials, it has not been widely used as an adjudicated efficacy or safety outcome for COPD trials. The Study to Understand Mortality and Morbidity in COPD (SUMMIT) was a large COPD clinical trial that tested the secondary hypothesis that treatment of mild to moderate COPD with fluticasone furoate/vilanterol combination, in patients also with increased cardiovascular risk factors, would reduce the risk of major adverse cardiovascular events.…”

The Weight of Evidence From Electrophysiology, Observational, and Cardiovascular End Point Studies Demonstrates the Safety of Azithromycin

“…One key element: death certificates are known to be an imperfect means to establish cause of death in patients with chronic lung disease; CV death is often mistakenly assumed when patients die suddenly. 22,23…”