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

A. Granholm*, S. Marker, M. Krag, F.G. Zampieri, H.C. Thorsen-Meyer, B.S. Kaas-Hansen, I.C.C. van der Horst, T. Lange, J. Wetterslev, A. Perner, M.H. Moller

*Corresponding author for this work

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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
Original languageEnglish
Pages (from-to)717-726
Number of pages10
JournalIntensive Care Medicine
Issue number4
Publication statusPublished - 1 Apr 2020


  • bayesian analysis
  • bayesian-analysis
  • gastrointestinal bleeding
  • guidelines
  • heterogeneity of treatment effects
  • pantoprazole
  • proton-pump inhibitors
  • r package
  • score
  • sepsis
  • stress ulcer prophylaxis
  • stress-ulcer prophylaxis
  • subgroup analysis
  • Subgroup analysis
  • Stress ulcer prophylaxis
  • Heterogeneity of treatment effects
  • Pantoprazole
  • Gastrointestinal bleeding
  • Bayesian analysis

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