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

  • Anders GranholmEmail author
  • Søren Marker
  • Mette Krag
  • Fernando G. Zampieri
  • Hans-Christian Thorsen-Meyer
  • Benjamin Skov Kaas-Hansen
  • Iwan C. C. van der Horst
  • Theis Lange
  • Jørn Wetterslev
  • Anders Perner
  • Morten Hylander Møller



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.


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.


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).


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. identifier



Stress ulcer prophylaxis Gastrointestinal bleeding Pantoprazole Heterogeneity of treatment effects Bayesian analysis Subgroup analysis 



The authors thank everybody involved in the SUP-ICU trial: research staff and investigators, clinical staff, patients and their relatives.

Author contributions

The idea for this project was conceived by AG, FGZ, AP and MHM. All authors contributed to the study protocol and statistical analysis plan. AG conducted all analyses and wrote the first draft of the article, which was critically revised by all authors. SM and MK were responsible for the SUP-ICU trial database. AG, SM, MK, ICCH, TL, JW, AP and MHM were all involved in the conduct of the SUP-ICU trial. All authors approved the final version.


The SUP-ICU trial was funded by Innovation Fund Denmark (4108-00011A) and supported by Rigshospitalet, the Capital Region of Denmark, the Regions of Denmark, the Scandinavian Society of Anaesthesiology and Intensive Care Medicine, Ehrenreich’s Foundation, Aase and Ejnar Danielsens Foundation, the Danish Society of Anaesthesiology and Intensive Care Medicine, the Danish Medical Association and the European Society of Intensive Care Medicine. The present substudy received no specific funding and none of the funders of the SUP-ICU trial had any influence on any aspects of this study. HCTM and BSKH received funding from Innovation Fund Denmark (5153-00002B).

Compliance with ethical standards

Conflicts of interest

None. The Department of Intensive Care at Rigshospitalet receives support for other research projects from Ferring Pharmaceuticals, Denmark and the Novo Nordisk Foundation, Denmark. FGZ received grants for other research projects from Bactiguard, Sweden and from the Brazilian Ministry of Health, both unrelated to this work.

Supplementary material

134_2019_5903_MOESM1_ESM.pdf (1.2 mb)
Supplementary file1 (PDF 1222 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  • Anders Granholm
    • 1
    Email author
  • Søren Marker
    • 1
    • 2
  • Mette Krag
    • 1
    • 2
  • Fernando G. Zampieri
    • 3
    • 4
  • Hans-Christian Thorsen-Meyer
    • 1
    • 5
  • Benjamin Skov Kaas-Hansen
    • 5
    • 6
  • Iwan C. C. van der Horst
    • 7
  • Theis Lange
    • 2
    • 8
    • 9
  • Jørn Wetterslev
    • 2
    • 10
  • Anders Perner
    • 1
    • 2
  • Morten Hylander Møller
    • 1
    • 2
  1. 1.Department of Intensive Care 4131Copenhagen University Hospital - RigshospitaletCopenhagenDenmark
  2. 2.Centre for Research in Intensive CareCopenhagenDenmark
  3. 3.Research InstituteHCor‐Hospital do CoraçãoSão PauloBrazil
  4. 4.D´Or Research and Education InstituteSão PauloBrazil
  5. 5.NNF Center for Protein ResearchUniversity of CopenhagenCopenhagenDenmark
  6. 6.Clinical Pharmacology UnitZealand University HospitalRoskildeDenmark
  7. 7.Department of Intensive Care, Maastricht University Medical Center+University MaastrichtMaastrichtThe Netherlands
  8. 8.Section of Biostatistics, Department of Public HealthUniversity of CopenhagenCopenhagenDenmark
  9. 9.Center for Statistical SciencePeking UniversityBeijingChina
  10. 10.Copenhagen Trial Unit, Centre for Clinical Intervention ResearchCopenhagen University Hospital - RigshospitaletCopenhagenDenmark

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