Composite Endpoints in Critical Care Delirium Trials

Delirium is an abnormal mental status, commonly occurring among critically ill patients, in which a person's attention and awareness change acutely. Delirium is associated with negative outcomes, including death. Furthermore, a longer duration of delirium is associated with long-term cognitive impairment in survivors of critical illness. Hence, there is a need for novel interventions that reduce the duration of delirium; however, measuring and analyzing "duration of delirium" as an endpoint in randomized trials is challenging due to the episodic nature of delirium and the competing events of coma and death, which can bias analyses of duration of delirium. Given these challenges, delirium trials have adopted one of two composite endpoints: delirium- and coma-free days, defined as the number of days alive without delirium or coma for both survivors and nonsurvivors, and an alternative composite that ranks death as the worst state and orders days alive without delirium or coma among survivors. To date, these composite endpoints have not been rigorously evaluated. Hence, herein we use data from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction (MENDS) trial to motivate the use of composite endpoints in critical care delirium trials, discuss how to define the effect of treatment on each composite endpoint and their clinical interpretability, and present a method for visualizing how the treatment effects accrue over the course of follow-up. Based on these analyses, we provide practical recommendations for the use of composite endpoints in critical care delirium trials, which could be extended to other randomized trials that rely on similar composite endpoints.