title: Implications of Heterogeneity of Treatment Effect for Reporting and Analysis of Randomized Trials in Critical Care.
abstract: Randomized clinical trials (RCTs) are conducted to guide clinicians' selection of therapies for individual patients. Currently, RCTs in critical care often report an overall mean effect and selected individual subgroups. Yet work in other fields suggests that such reporting practices can be improved. Specifically, this Critical Care Perspective reviews recent work on so-called "heterogeneity of treatment effect" (HTE) by baseline risk and extends that work to examine its applicability to trials of acute respiratory failure and severe sepsis. Because patients in RCTs in critical care medicine-and patients in intensive care units-have wide variability in their risk of death, these patients will have wide variability in the absolute benefit that they can derive from a given therapy. If the side effects of the therapy are not perfectly collinear with the treatment benefits, this will result in HTE, where different patients experience quite different expected benefits of a therapy. We use simulations of RCTs to demonstrate that such HTE could result in apparent paradoxes, including: (1) positive trials of therapies that are beneficial overall but consistently harm or have little benefit to low-risk patients who met enrollment criteria, and (2) overall negative trials of therapies that still consistently benefit high-risk patients. We further show that these results persist even in the presence of causes of death unmodified by the treatment under study. These results have implications for reporting and analyzing RCT data, both to better understand how our therapies work and to improve the bedside applicability of RCTs. We suggest a plan for measurement in future RCTs in the critically ill.
authors.affiliation: 1 Department of Internal Medicine and.|2 Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.|3 Center for Clinical Management Research, Department of Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan; and.
authors.forename: Theodore J
authors.identifier: http://orcid.org/0000-0002-4226-9310
authors.initials: TJ
authors.lastname: Iwashyna
authors.affiliation: 4 Department of Neurology, University of Michigan, Ann Arbor, Michigan.
authors.forename: James F
authors.initials: JF
authors.lastname: Burke
authors.affiliation: 1 Department of Internal Medicine and.|3 Center for Clinical Management Research, Department of Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan; and.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Sussman
authors.affiliation: 1 Department of Internal Medicine and.
authors.forename: Hallie C
authors.initials: HC
authors.lastname: Prescott
authors.affiliation: 1 Department of Internal Medicine and.|3 Center for Clinical Management Research, Department of Veterans Affairs Ann Arbor Health System, Ann Arbor, Michigan; and.
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Hayward
authors.affiliation: 5 Clinical Research, Investigation, and Systems Modeling of Acute Illness Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
mesh_terms: D000368:Aged; D003422:Critical Care / Q000379:methods* / Q000706:statistics & numerical data*; D005260:Female; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012131:Respiratory Insufficiency / Q000628:therapy*; D018805:Sepsis / Q000628:therapy*
keywords: acute respiratory failure; heterogeneity of treatment effect; precision medicine; randomized clinical trials; sepsis