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Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial

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@article{5a0fc228d4f14ce59310d1bc4d9b8f88,
title = "Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial",
abstract = "PURPOSE: The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present.METHODS: We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots.RESULTS: We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63).CONCLUSIONS: In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT02467621.",
keywords = "Bayesian analysis, Gastrointestinal bleeding, Heterogeneity of treatment effects, Pantoprazole, Stress ulcer prophylaxis, Subgroup analysis",
author = "Anders Granholm and S{\o}ren Marker and Mette Krag and Zampieri, {Fernando G} and Hans-Christian Thorsen-Meyer and Kaas-Hansen, {Benjamin Skov} and {van der Horst}, {Iwan C C} and Theis Lange and J{\o}rn Wetterslev and Anders Perner and M{\o}ller, {Morten Hylander}",
year = "2020",
month = "4",
doi = "10.1007/s00134-019-05903-8",
language = "English",
volume = "46",
pages = "717--726",
journal = "Intensive Care Medicine",
issn = "0342-4642",
publisher = "Springer",
number = "4",

}

RIS

TY - JOUR

T1 - Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients

T2 - a post hoc analysis of the SUP-ICU trial

AU - Granholm, Anders

AU - Marker, Søren

AU - Krag, Mette

AU - Zampieri, Fernando G

AU - Thorsen-Meyer, Hans-Christian

AU - Kaas-Hansen, Benjamin Skov

AU - van der Horst, Iwan C C

AU - Lange, Theis

AU - Wetterslev, Jørn

AU - Perner, Anders

AU - Møller, Morten Hylander

PY - 2020/4

Y1 - 2020/4

N2 - PURPOSE: The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present.METHODS: We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots.RESULTS: We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63).CONCLUSIONS: In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT02467621.

AB - PURPOSE: The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present.METHODS: We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots.RESULTS: We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63).CONCLUSIONS: In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT02467621.

KW - Bayesian analysis

KW - Gastrointestinal bleeding

KW - Heterogeneity of treatment effects

KW - Pantoprazole

KW - Stress ulcer prophylaxis

KW - Subgroup analysis

U2 - 10.1007/s00134-019-05903-8

DO - 10.1007/s00134-019-05903-8

M3 - Journal article

VL - 46

SP - 717

EP - 726

JO - Intensive Care Medicine

JF - Intensive Care Medicine

SN - 0342-4642

IS - 4

ER -

ID: 59134835