Anders Granholm1, Søren Marker1,2, Mette Krag1,2, Fernando G Zampieri3, Hans-Christian Thorsen-Meyer1,4, Benjamin S Kaas-Hansen4,5, Iwan C C van der Horst6, Theis Lange2,7,8, Jørn Wetterslev2,9, Anders Perner1,2, Morten H Møller1,2. 1. Department of Intensive Care, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark. 2. Centre for Research in Intensive Care, Copenhagen, Denmark. 3. Research Institute, HCor-Hospital do Coração, São Paulo, Brazil. 4. NNF Center for Protein Research, University of Copenhagen, Copenhagen, Denmark. 5. Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Denmark. 6. Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 7. Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark. 8. Center for Statistical Science, Peking University, Beijing, China. 9. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Abstract
BACKGROUND: In the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, 3291 adult ICU patients at risk for gastrointestinal (GI) bleeding were randomly allocated to intravenous pantoprazole 40 mg or placebo once daily in the ICU. No difference was observed between the groups in the primary outcome 90-day mortality or the secondary outcomes, except for clinically important gastrointestinal bleeding. However, heterogeneity of treatment effect (HTE) not detected by conventional subgroup analyses could be present. METHODS: This is a protocol and statistical analysis plan for a secondary, post hoc, exploratory analysis of the SUP-ICU trial. We will explore HTE in one set of subgroups based on severity of illness (using the Simplified Acute Physiology Score [SAPS] II) and another set of subgroups based on the total number of risk factors for GI bleeding in each patient using Bayesian hierarchical models. We will summarise posterior probability distributions using medians and 95% credible intervals and present probabilities for different levels of benefit and harm of the intervention in each subgroup. Finally, we will assess if the treatment effect interacts with SAPS II and the number of risk factors separately on the continuous scale using marginal effects plots. CONCLUSIONS: The outlined post hoc analysis will explore whether HTE was present in the SUP-ICU trial and may help answer some of the remaining questions regarding the balance between benefits and harms of pantoprazole in ICU patients at risk of GI bleeding. CLINICALTRIALS. GOV REGISTRATION: NCT02467621.
RCT Entities:
BACKGROUND: In the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, 3291 adult ICU patients at risk for gastrointestinal (GI) bleeding were randomly allocated to intravenous pantoprazole 40 mg or placebo once daily in the ICU. No difference was observed between the groups in the primary outcome 90-day mortality or the secondary outcomes, except for clinically important gastrointestinal bleeding. However, heterogeneity of treatment effect (HTE) not detected by conventional subgroup analyses could be present. METHODS: This is a protocol and statistical analysis plan for a secondary, post hoc, exploratory analysis of the SUP-ICU trial. We will explore HTE in one set of subgroups based on severity of illness (using the Simplified Acute Physiology Score [SAPS] II) and another set of subgroups based on the total number of risk factors for GI bleeding in each patient using Bayesian hierarchical models. We will summarise posterior probability distributions using medians and 95% credible intervals and present probabilities for different levels of benefit and harm of the intervention in each subgroup. Finally, we will assess if the treatment effect interacts with SAPS II and the number of risk factors separately on the continuous scale using marginal effects plots. CONCLUSIONS: The outlined post hoc analysis will explore whether HTE was present in the SUP-ICU trial and may help answer some of the remaining questions regarding the balance between benefits and harms of pantoprazole in ICU patients at risk of GI bleeding. CLINICALTRIALS. GOV REGISTRATION: NCT02467621.
Authors: Anders Granholm; 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 Journal: Intensive Care Med Date: 2020-01-14 Impact factor: 17.440
Authors: Thomas L Klitgaard; Olav L Schjørring; Theis Lange; Morten H Møller; Anders Perner; Bodil S Rasmussen; Anders Granholm Journal: Br J Anaesth Date: 2021-10-19 Impact factor: 9.166
Authors: Nina Andersen-Ranberg; Lone M Poulsen; Anders Perner; Johanna Hästbacka; Matthew P G Morgan; Giuseppe Citerio; Marie Oxenbøll-Collet; Sven-Olaf Weber; Anne Sofie Andreasen; Morten H Bestle; Bülent Uslu; Helle B S Pedersen; Louise G Nielsen; Kjeld Damgaard; Troels B Jensen; Trine Sommer; Nilanjan Dey; Ole Mathiesen; Anders Granholm Journal: Acta Anaesthesiol Scand Date: 2022-05-31 Impact factor: 2.274