This study is a post hoc analysis of the SUP-ICU trial . The trial protocol, statistical analysis plan and primary results have been published elsewhere [1, 7, 8]. The SUP-ICU trial was approved by all relevant institutions prior to randomisation of the first patient. No additional approvals were required for this study. We have prepared this manuscript according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement , and the filled-in checklist is available in the Electronic Supplementary Material (ESM).
The SUP-ICU trial
The SUP-ICU trial was a randomised, multicenter, stratified, parallel-group, placebo-controlled, blinded clinical trial recruiting 3350 patients (3291 were available for data analyses) at risk for GI bleeding in 33 ICUs in Denmark, Finland, Norway, Switzerland, the Netherlands and UK from 4 January 2016 to 22 October 2017 . Eligible subjects were patients aged 18 years or older, who were acutely admitted to the ICU and had at least one risk factor for clinically important GI bleeding, including any history of liver disease, any history of or ongoing coagulopathy, shock, or use of anticoagulant agents, renal replacement therapy, or mechanical ventilation expected to last > 24 h .
We excluded patients with GI bleeding during current hospital admission, ongoing daily treatment with acid suppressants, patients who were withdrawn from active treatment or brain dead, had organ transplantation during current hospital admission, had peptic ulcer confirmed by endoscopy or other method during current hospital admission, had a contraindication to pantoprazole, were pregnant or where consent for enrolment could not be obtained. The full definitions of the inclusion and exclusion criteria are presented in the ESM.
Patients were randomly assigned to daily intravenous pantoprazole 40 mg or a matching placebo during the ICU stay. Randomisation was stratified according to the presence or absence of hematological malignancy and trial site. The intervention period lasted until discharge from the ICU to a maximum of 90 days. The protocol was reinitiated in case of readmissions to trial ICUs within this period. Apart from the use of stress ulcer prophylaxis, all other parts of patient care were at the discretion of the clinicians.
At baseline we collected data on demographics and clinical characteristics. Daily recordings during the entire admission to the ICU included GI bleeding events, infectious adverse events (pneumonia and Clostridium difficile infection) and data on the usage of life support modalities. Time of death was registered for all patients at a maximum follow-up of 90 days. Observations for GI bleeding and infectious adverse events stopped at the time of discharge from the ICU.
Informed consent was obtained prior to randomisation from all participants or their legal substitutes according to national legislation.
The primary outcome was 90-day mortality. Secondary outcomes were the proportion of patients with clinically important events (a composite outcome of clinically significant GI bleeding, pneumonia, Clostridium difficile infection and myocardial ischemia), clinically important GI bleeding, infectious adverse events (pneumonia or Clostridium difficile infection) and serious adverse reactions (SARs) and the percentage of days alive without the use of life support (mechanical ventilation, renal replacement therapy or inotropes/vasopressor) .
Clinically important GI bleeding was defined as overt GI bleeding and at least one of the following four features within 24 h of the bleeding episode, in the absence of other causes, in the ICU: (1) a spontaneous drop of systolic blood pressure, mean arterial pressure or diastolic blood pressure of 20 mmHg or more, (2) start of a vasopressor or a 20% increase in vasopressor dose, (3) decrease in hemoglobin of at least 2 g/dl (1.24 mmol/l), or (4) transfusion of two or more units of packed red blood cells . The full definitions of the other outcomes are presented in the ESM.
We repeated all predefined analyses on all outcomes and in all predefined subgroups according to the published SUP-ICU trial statistical analysis plan  in this subgroup of patients with baseline SAPS II > 53. The SAPS II score is calculated from 17 variables with a total range from 0 to 163 points; higher scores indicating greater severity of disease (Table S7 in the ESM). Fifty-three points was chosen a priori as the cut-off for the subgroup analysis, as it was found to predict a 50% mortality rate in the original model  and similar cut-offs have been used previously .
In brief, we conducted the primary analyses in the intention-to-treat population. In the primary analyses, we compared data in the two treatment groups by binary logistic regression analysis adjusted for the stratification variables (trial site and active hematological malignancy); relative risks with 95% confidence intervals were computed from odds ratios . In a sensitivity analysis, we compared the primary outcome in the per-protocol population (excluding patients having one or more major protocol violations—definition in ESM), and in the originally pre-specified subgroups, defined by the presence or absence of any history of liver disease, the presence or absence of any history of or ongoing coagulopathy, the type of ICU admission (medical versus surgical), the presence or absence of shock and the use or not of mechanical ventilation .
In the secondary analyses, we compared all dichotomous outcomes using binary logistic regression analyses adjusted for stratification variables and predefined risk factors at baseline (age, type of admission (medical, elective surgery or emergency surgery) and the Sepsis-related Organ Failure Assessment (SOFA) score (Table S8 in the ESM) assessed in the 24 h before randomisation). We analysed percentages of days alive without life support in the 90-day period by use of the van Elteren test (adjusted for site only), as the assumptions for Poisson or negative binomial distributions were not met . We performed no adjustment for multiple comparisons and reported results as point estimates with 95% confidence intervals.
To account for the between-group imbalance in coagulopathy, we conducted a post hoc sensitivity analysis in which we included coagulopathy in the adjusted (secondary) binary logistic regression model.
As the proportion of patients with incomplete SAPS II could be of importance, we conducted the following two post hoc sensitivity analyses (of all outcomes): (1) patients with missing SAPS II who could potentially have had SAPS II > 53 were included (assigning the worst possible SAPS II sub-score, when missing, and then re-calculating the total SAPS II). An additional 169/249 patients with missing SAPS II were included in this sensitivity analysis; and (2) patients with missing SAPS II who after computer-generated single-imputation of missing SAPS II sub-scores had a SAPS II > 53 were included. The single-imputation approach was repeated three times to assess random variation and showed consistency. An additional 106/249 patients with missing SAPS II were included in this sensitivity analysis.
In the complete-case population, nine patients were lost to 90-day follow-up in the full trial population, of which three had a SAPS II > 53. Accordingly, complete-case analysis was the main primary outcome analysis. Additional details on handling of missing data, including sensitivity analyses with imputation of SAPS II values are provided in the ESM.
All analyses were performed using SAS software, version 9.4, and R software, version 3.4.3.