Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials

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Title: Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials
Authors: Santhakumaran, S
Gordon, AC
Prevost, A
O'Kane, C
McAuley, DF
Shankar-Hari, M
Item Type: Journal Article
Abstract: Background Randomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design. Methods We assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term. Results The ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p < 0.001). The HTE patterns were inconsistent across the secondary risk measures. The sensitivity analyses of HTE effects for vasopressin, hydrocortisone and levosimendan were consistent with the main analyses and attenuated for simvastatin. Conclusions We assessed HTE in three recent ICU RCTs, using multivariable baseline risk of death models. There was considerable within-trial variation in the baseline risk of death. We observed potential HTE for simvastatin in ARDS, but no evidence of HTE for vasopressin, hydrocortisone or levosimendan in the two sepsis trials. Our findings could be explained either by true lack of HTE (no benefit of vasopressin, hydrocortisone or levosimendan vs comparator for any patient subgroups) or by lack of power to detect HTE. Our results require validation using similar trial databases.
Issue Date: 3-May-2019
Date of Acceptance: 14-Apr-2019
ISSN: 1364-8535
Publisher: BMC
Journal / Book Title: Critical Care
Volume: 23
Copyright Statement: © The Author(s). 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0International License (, which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver( applies to the data made available in this article, unless otherwise stated.
Sponsor/Funder: National Institute for Health Research
National Institute for Health Research
Imperial College Healthcare NHS Trust
Guys & St Thomas NHS Foundation Trust
Funder's Grant Number: NIHR/CS/009/007
NIHR Fellowship
RDB17 79560
Keywords: Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
General & Internal Medicine
acute respiratory distress syndrome
Study design
Models, statistical
Sepsis, acute respiratory distress syndrome
Study design
11 Medical and Health Sciences
Emergency & Critical Care Medicine
Publication Status: Published
Article Number: ARTN 156
Appears in Collections:Division of Surgery
Epidemiology, Public Health and Primary Care

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