Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-05-03

AUTHORS

Shalini Santhakumaran, Anthony Gordon, A. Toby Prevost, Cecilia O’Kane, Daniel F. McAuley, Manu Shankar-Hari

ABSTRACT

BackgroundRandomised 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.MethodsWe 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.ResultsThe 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.ConclusionsWe 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. More... »

PAGES

156

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13054-019-2446-1

DOI

http://dx.doi.org/10.1186/s13054-019-2446-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113904984

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/31053084


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84 risk measurement
85 risk measures
86 risk of mortality
87 scale
88 scores
89 sepsis
90 sepsis trials
91 simvastatin
92 syndrome
93 terms
94 time
95 treatment differences
96 treatment effects
97 treatment risks
98 trial design
99 trial population
100 trial results
101 trials
102 variation
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