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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.

Authors+Show Affiliations

Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. andersgran@gmail.com.Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. Centre for Research in Intensive Care, Copenhagen, Denmark.Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. Centre for Research in Intensive Care, Copenhagen, Denmark.Research Institute, HCor-Hospital do Coração, São Paulo, Brazil. D´Or Research and Education Institute, São Paulo, Brazil.Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. NNF Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.NNF Center for Protein Research, University of Copenhagen, Copenhagen, Denmark. Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Denmark.Department of Intensive Care, Maastricht University Medical Center+, University Maastricht, Maastricht, The Netherlands.Centre for Research in Intensive Care, Copenhagen, Denmark. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. Center for Statistical Science, Peking University, Beijing, China.Centre for Research in Intensive Care, Copenhagen, Denmark. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. Centre for Research in Intensive Care, Copenhagen, Denmark.Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. Centre for Research in Intensive Care, Copenhagen, Denmark.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31938829

Citation

Granholm, Anders, et al. "Heterogeneity of Treatment Effect of Prophylactic Pantoprazole in Adult ICU Patients: a Post Hoc Analysis of the SUP-ICU Trial." Intensive Care Medicine, 2020.
Granholm A, Marker S, Krag M, et al. Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial. Intensive Care Med. 2020.
Granholm, A., Marker, S., Krag, M., Zampieri, F. G., Thorsen-Meyer, H. C., Kaas-Hansen, B. S., ... Møller, M. H. (2020). Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial. Intensive Care Medicine, doi:10.1007/s00134-019-05903-8.
Granholm A, et al. Heterogeneity of Treatment Effect of Prophylactic Pantoprazole in Adult ICU Patients: a Post Hoc Analysis of the SUP-ICU Trial. Intensive Care Med. 2020 Jan 14; PubMed PMID: 31938829.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: 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, Y1 - 2020/01/14/ PY - 2019/10/12/received PY - 2019/12/16/accepted PY - 2020/1/16/entrez KW - Bayesian analysis KW - Gastrointestinal bleeding KW - Heterogeneity of treatment effects KW - Pantoprazole KW - Stress ulcer prophylaxis KW - Subgroup analysis JF - Intensive care medicine JO - Intensive Care Med 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. SN - 1432-1238 UR - https://www.unboundmedicine.com/medline/citation/31938829/Heterogeneity_of_treatment_effect_of_prophylactic_pantoprazole_in_adult_ICU_patients:_a_post_hoc_analysis_of_the_SUP-ICU_trial L2 - https://dx.doi.org/10.1007/s00134-019-05903-8 DB - PRIME DP - Unbound Medicine ER -