Re-EValuating the Inhibition of Stress Erosions: Prophylaxis Against Gastrointestinal Bleeding in the Critically Ill (The REVISE) Trial
Phase: PHASE3
Conditions: Gastrointestinal Hemorrhage (Clinically Important, Upper)
Sponsor: McMaster University

1 
 
COVER PAGE 
 
 
The main REVISE results were published in June 2024 as per this citation: 
  
Cook DJ, Deane A, Lauzier F, Zytaruk N, Guyatt G, Saunders L, Hardie M, Heels-Ansdell D, Alhazzani W, 
Marshall J, Muscedere J, Myburgh J, English S, Arabi Y, Ostermann M, Knowles S, Hammond N, Byrne 
K, Chapman M, Venkatesh B, Young P, Rajbhandari D, Poole A, Al Fares A, Reis G, Johnson D, Iqbal 
M, Hall R,   Meade M, Hand L, Duan E, Clarke F, Dionne JC, Tsang J, Rochwerg B, Karachi T, 
Lamontagne F, D’Aragon F,  St. Arnaud C, Reeve B, Geagea A, Niven D, Vazquez-Grande G, 
Zarychanski R, Ovakim D, Wood G, Burns K,  Goffi A, Wilcox E, Henderson W, Forrest D, Fowler R, 
Adhikari N, Ball I, Mele T, Binnie A, Trop S, Mehta S,   Morgan I, Loubani O, Vanstone M, Fiest K, 
Charbonney E, Cavayas A, Archambault P, Rewa O, Lau V, Kristof A, Khwaja K, Williamson D, Kanji 
S, Sy E, Dennis B, Reynolds S, Marquis F, Lellouche F, Rahman A, Hosek P, Barletta J, Cirone R, 
Tutschka M, Xie F, Billot L, Thabane L, Finfer S, for the REVISE Trial Investigators, the Canadian Critical 
Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials 
Group.  Stress Ulcer Prophylaxis for Invasively Ventilated Patients: A Randomized Trial. N Engl J Med 
2024;391(1):9-20. DOI: 10.1056/NEJMoa2404245. 
 NCT03374800 
 
 
 
 
  
This current upload on September 2024 is for a protocol and statistical analysis plan of a pre-
planned secondary analysis emerging from the REVISE database as per this citation, concurrently 
submitted for publication: 
  
Heels-Ansdell D, Lauzier F, Deane A, Lamontagne F, Adhikari N, Thabane L, Cook DJ. Risk Factors for 
Patient-Important Upper Gastrointestinal Bleeding: A Protocol and Statistical Analysis Plan for a 
Secondary Analysis of the REVISE (Re-Evaluating the Inhibition of Stress Erosions) Trial. 2024. 
Risk Factors for Patient-Important Upper Gastrointestinal Bleeding: 
NCT03374800 
Version Date: September 10, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A Protocol and Statistical Analysis Plan 
 
for a Secondary Analysis of the REVISE (Re-Evaluating the Inhibition of Stress Erosions) Trial 
 
Diane Heels-Ansdell, MSc 1 
François Lauzier, MD, MSc 2 
Adam Deane, MD, PhD 3 
François Lamontagne, MD, MSc 4 
Neill Adhikari, MD, MSc 5 
Lehana Thabane, PhD 6 
Deborah Cook, MD, MSc 7  
 
1 Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, 
Ontario, Canada 
2 Department of Medicine, Department of Anesthesiology and Critical Care, Université Laval, Québec, 
Canada 
3 Department of Critical Care, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, 
Australia 
4 Department of Critical Care, Université de Sherbrooke, Sherbrooke, Québec, Canada 
5 Interdepartmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada 
6 Department of Health Research Methods, Evidence and Impact, the Research Institute of St Joseph’s 
Healthcare, Hamilton, Ontario, Canada  
7 Departments of Medicine, Health Research Methods, Evidence and Impact, McMaster University, 
Hamilton, Ontario, Canada 
 
 
Correspondence: DJ Cook, Departments of Medicine & Health Research Methods, Evidence and 
Impact, McMaster University Health Sciences Center, Room 2C11, 1200 Main Street West, Hamilton, 
Ontario, Canada, L8N 3Z5; debcook@mcmaster.ca 
 
Key Words: upper gastrointestinal bleeding, critically ill patient, risk factors, competing events 
 
Word Count: 2051 
 
Abstract Word Count: 262  
 
REVISE: Clinical Trial Registration: www.clinicaltrials.gov NCT03374800 
 
 

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Abstract 
Background: While studies have reported risk factors for clinically-important upper gastrointestinal 
bleeding among critically ill patients, the risk factors for patient-important upper gastrointestinal bleeding, 
as defined by ICU survivors and family members, are unknown. Further, although trials show that stress 
ulcer prophylaxis with pantoprazole decreases the risk of upper gastrointestinal bleeding, some research 
suggests that mortality may be increased among patients with high illness severity who are exposed to 
pantoprazole. The risk of death during critical illness is greater than the risk of upper gastrointestinal 
bleeding. 
Objective: To identify risk factors for patient-important upper gastrointestinal bleeding among invasively 
ventilated critically ill adults, taking into account illness severity and the competing risk of death. 
Materials and Methods:  This pre-planned secondary analysis of the REVISE trial database will be 
guided by this protocol. We will use Cox proportional hazards regression analysis to assess the effect of 
candidate risk factors on the hazard rate of the primary outcome of time to patient-important upper 
gastrointestinal bleeding, considering the competing risk of death. We propose 2 sensitivity analyses.  
Secondary analyses will evaluate risk factors for clinically-important upper gastrointestinal bleeding, and 
another model will evaluate whether enteral nutrition attenuates the effect of pantoprazole on bleeding 
prevention compared to placebo by including an interaction term between pantoprazole vs. placebo and 
amount of enteral nutrition received.  
Results: This study will identify conditions of critical illness which confer an increased risk of patient-
important upper gastrointestinal bleeding in critically ill patients, and factors that decrease the risk. 
Conclusions: The findings may inform bedside care, practice guidelines, and the design of future 
studies. 
 

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Introduction 
 
Patients and other members of the public infrequently have input into research priorities, protocol design 
and study conduct [1]. It has been suggested that patient input is inadequate for outcome selection in 
many trials conducted in general [2,3] and critical care medicine [4]. Historically, large multicenter trials 
evaluating upper gastrointestinal bleeding as a complication of critical illness have been focused on the 
outcome of clinically-important upper gastrointestinal bleeding - an endpoint defined by clinician-
researchers [5-9]. In collaboration with survivors of critical illness and family members of patients who 
were admitted to an intensive care unit (ICU), an outcome of patient-important upper gastrointestinal 
bleeding was recently developed [10]. 
 
This outcome of patient-important bleeding was a secondary endpoint for a recent stress ulcer 
prophylaxis trial [11]. REVISE (Re-Evaluating the Inhibition of Stress Erosions) was an international, parallel 
group randomized clinical trial that included 4,821 patients to test the effect of pantoprazole versus placebo on 
the primary efficacy outcome of clinically-important upper GI bleeding and the primary safety outcome of 90-
day mortality [12,13]. Pantoprazole reduced both patient-important and clinically-important upper 
gastrointestinal bleeding (hazard ratio [HR] 0.36; 95% CI 0.25 to 0.53; p<0.001, and HR 0.30; 95% 
CI 0.19 to 0.47; p<0.001, respectively), without affecting other endpoints [11]. 
 
In REVISE, patient-important upper gastrointestinal bleeding occurred more frequently than clinically-
important upper gastrointestinal bleeding. While studies have reported risk factors for clinically-important 
upper gastrointestinal bleeding [14], the risk factors for patient-important upper gastrointestinal bleeding, 
as defined by ICU survivors and family members, remain unknown. While some bleeding events confer 
an increased risk of death [15], most bleeding ICU patients do not die with or from gastrointestinal 
bleeding [11]. Dying is nonetheless a competing risk for bleeding, and dying is more common than 
bleeding. Thus, the primary objective of the current study is to identify risk factors for patient-important 
upper gastrointestinal bleeding among invasively ventilated critically ill adults, taking into account illness 
severity and the competing risk of death. 
 
Materials and Methods 
 
Risk Factor Analysis 
This pre-planned secondary analysis of the REVISE trial data will be guided by this protocol. The 
inception cohort will comprise the 4,821 participants in the REVISE trial. These were critically ill patients 
who were receiving invasive mechanical ventilation patients in the ICU, who were expected to remain 
ventilated beyond the calendar day after randomization, and were without a clear indication or 
contraindication to pantoprazole [12,13].  
   
We will use Cox proportional hazards regression analysis to assess the effect of candidate risk factors on 
the hazard rate of the primary outcome of time to patient-important upper gastrointestinal bleeding, 
considering the competing risk of death [16,17]. In REVISE, approximately 10 times as many patients 
died at 90-days than experienced upper gastrointestinal bleeding. The main analysis will then be a 
competing risk analysis for the competing risk of death [18]. The proportional hazards assumption (which 
states that the effects of the time-dependent variables remain stable over time) will be assessed and 
handled appropriately using time-varying effects [19]; alternative methods will be used if this is not 
satisfactory [20]. We will also assess collinearity of the independent variables (e.g., therapeutic 
anticoagulation and coagulopathy).   
 
We will include both baseline variables and time-dependent variables, described further below. All time-
dependent risk factors will be defined as existing any time in the preceding 3 days, but not including the 
day of bleed. For bleeds that occur on day 1 of the study, we will use day 1 data to define the time-
dependent covariates. We will consider ICU discharge and consent withdrawal as censoring events. 
 
 
 
 

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Dependent Variables: 
Primary Outcome 
The primary dependent variable will be patient-important upper gastrointestinal bleeding. This was 
defined in a mixed-methods study of ICU survivors and families [21], with gastrointestinal bleeding judged 
as important if bleeding resulted in a blood transfusion, vasopressor treatment, diagnostic endoscopy, CT-
angiography, surgery, or if it resulted in death, disability, or prolonged hospitalization [10]. These criteria 
were applied to the REVISE database up to 90 days after randomization [11]. Our main analysis will 
include all patient-important upper gastrointestinal bleeds that occurred in the ICU.  
 
Among 4,821 patients, 136 (2.8%) had patient-important upper gastrointestinal bleeding, 5 of whom bled 
on the ward prompting ICU readmission. These 5 patients will be censored at ICU discharge, as daily 
data for the time-dependent risk factors were not collected beyond the index ICU admission. 
 
Secondary Outcome 
A secondary analysis will be to determine risk factors for the secondary outcome of clinically-important 
upper gastrointestinal bleeding. We defined clinically-important upper gastrointestinal bleeding as the 
presence of overt bleeding (hematemesis, overt nasogastric bleeding, melena, or hematochezia) and at 
least one of the following within 24 hours in the absence of another cause: spontaneous decrease in 
invasively monitored mean arterial pressure or non-invasive systolic or diastolic blood pressure of 20 
mmHg or more or an orthostatic increase in pulse rate of 20 beats/minute and a decrease in systolic 
blood pressure of 10 mmHg, with or without vasopressor initiation or increase; vasopressor initiation; a 
decrease in hemoglobin of ≥ 20 g/L in a 24-hour period or less; transfusion of ≥2 units of packed red 
blood cells within 24 hours of bleeding, or therapeutic intervention (e.g., angio-embolization, surgery or 
endoscopic treatment of bleeding) [12]. Each bleed was reviewed in duplicate by an adjudication 
committee, blinded to study drug, to determine whether the clinically-important upper gastrointestinal 
bleeding criteria were fulfilled [22]. 
 
Among 4,821 patients, 109 (2.2%) had an event which were adjudicated as clinically-important upper 
gastrointestinal bleeding, 5 of whom bled on the ward prompting ICU readmission. These 5 patients will 
be censored at ICU discharge, as daily data for the time-dependent risk factors were not collected beyond 
the index ICU admission.  
 
Independent Variables: 
Bleeding risk factors will include both baseline and time-dependent variables. Factors will draw on 
pathophysiologic rationale and prior literature. Given the number of patient-important upper 
gastrointestinal bleeds, we have taken into account the suitable number of independent variables to avoid 
an over-fitted model [23]. The same risk factors will be analyzed for the secondary outcome of clinically-
important upper gastrointestinal bleeding as for the primary outcome of patient-important upper 
gastrointestinal bleeding.  
 
Baseline Variables  
1) APACHE II score (considered as a continuous variable) 
2) Medical vs. surgical/trauma (considered as 2 categories) 
3) Pantoprazole versus placebo as randomized (considered as 2 categories) 
 
Time-dependent Variables  
1) Respiratory failure, defined as receiving invasive mechanical ventilation (considered as 2 
categories) 
2) Circulatory failure, defined as receiving inotropes or vasopressors (any dose of any of 
norepinephrine, epinephrine, phenylephrine, vasopressin, dopamine, dobutamine or milrinone) 
(considered as 2 categories) 
3) Renal failure including acute kidney injury or end-stage renal disease, defined as receiving renal 
replacement therapy (any of intermittent hemodialysis [IHD], continuous renal replacement 
therapy [CRRT], sustained low efficiency dialysis [SLED] or peritoneal dialysis) (considered as 2 
categories) 
4) Enteral nutrition in mL/day (considered as a continuous variable) 

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5) Therapeutic anticoagulation, defined as therapeutic unfractionated heparin or low molecular 
weight heparin, fondaparinux, warfarin, non-vitamin K antagonist oral anticoagulants including 
anti-Xa inhibitors and direct thrombin inhibitors, and thrombolytic therapy (considered as 2 
categories) 
6) Coagulopathy, defined as international normalized ratio (INR) > 3.0 or prothrombin time (PTT) 
>70 seconds (considered as 2 categories) 
7) Severe thrombocytopenia, defined as platelet count <50 × 109/L (considered as 2 categories) 
8) Platelet aggregation inhibitors, defined as receipt of any of acetyl salicylic acid, clopidogrel, 
dipyridamole, ticlopidine, tirofiban, P2Y12 inhibitors, or non-steroidal anti-inflammatory drugs 
(considered as 2 categories) 
9) Corticosteroids, defined as any corticosteroid drug or dose, either enteral or intravenous 
administration (considered as 2 categories) 
 
Sensitivity Analyses 
1) To evaluate the effect of the competing risk of death, we will conduct an analysis that does not 
consider the competing risk of death. 
2) To evaluate the influence of risk factors more proximate to the bleed, we will evaluate all time-
dependent risk factors defined as any time in the preceding 2 days, instead of the preceding 3 
days. 
 
Secondary Analyses  
1) To evaluate risk factors for clinically-important upper gastrointestinal bleeding, we will repeat the 
same analysis [11].  
2) To evaluate whether enteral nutrition attenuates the effect of pantoprazole on bleeding prevention 
compared to placebo, we will include an interaction term between pantoprazole vs. placebo and 
amount of enteral nutrition received [24,25]. 
3) To evaluate whether certain baseline conditions are associated with patient-important upper 
gastrointestinal bleeding, we will include these variables in the main model one at a time: acute 
hepatic failure [26], traumatic brain injury [27] and female sex [28]. 
 
Missing Data 
We anticipate little missing data except for 2 risk factors in patients with length of ICU stay greater than 2 
weeks. Platelet aggregation inhibitors and corticosteroids were not collected from day 15 onwards 14 on 
the abbreviated trial case report form. For the primary analysis, if there are any patients remaining in the 
ICU after 2 weeks who received a platelet aggregation inhibitor on day 14, we will impute that it was 
continued until ICU discharge, except in the event of bleeding, assuming that the indication persisted over 
time (e.g., coronary artery disease). For the primary analysis, we will impute that if there are any patients 
receiving corticosteroid treatment on day 14, it was continued only to day 21, assuming the indication 
resolved (e.g., septic shock). 
 
Results  
 
We will report independent variables and other characteristics of participants with and without patient-
important upper gastrointestinal bleeding using descriptive statistics, including means and standard 
deviations (or medians with interquartile ranges, if appropriate) for continuous data, and numbers with 
percentages for categorical data.  
 
Figures we will present include the day of each bleed in the ICU, the concordance between patient-
important gastrointestinal bleeding and clinically-important upper gastrointestinal bleeding, and the daily 
use of invasive ventilation and any enteral nutrition.  
 
Regression results will be presented as adjusted hazard ratios with 95% confidence intervals and 
corresponding two-tailed p-values for the associations of each independent variable with the primary and 
secondary outcomes. The criterion for statistical significance will be set at alpha = 0.05. No corrections for 
multiple testing will be performed because of the exploratory nature of the analyses, but findings will be 
interpreted in light of confidence intervals and cautiously interpreted. 

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Discussion 
 
In this study, we will examine baseline and time-dependent risk factors for patient-important upper 
gastrointestinal bleeding, including the effect of pantoprazole versus placebo. Use of the REVISE trial 
database will build on risk factor analyses of clinically-important upper gastrointestinal bleeding from prior 
large trials [25,29]. 
 
Strengths of this study include the focus on an outcome developed by ICU survivors and relatives of ICU 
survivors or decedents. We will minimize the risk of over-fitted regression models caused by evaluation of 
many admitting diagnoses. Beyond assessing baseline characteristics, we will use Cox models to assess 
interventions and key laboratory values reflecting events and exposures over the ICU stay.  Although 
proton-pump inhibitors for bleeding prophylaxis do not affect 90-day mortality overall as shown in a recent 
meta-analysis (RR 0.99 [95% CI, 0.93 to 1.05]) [30], within-trial subgroup analysis suggests a possible 
heterogeneity of treatment effect based on disease severity. Accordingly, the main analysis will address 
the competing risk of death and a sensitivity analysis will evaluate whether this impacts the results. In this 
contemporary database, half of the patients were randomized to no stress ulcer prophylaxis, enabling the 
evaluation of risk factors with and without stress ulcer prophylaxis. This study will address some issues 
proposed for future research on this topic [31], including evaluating the volume of enteral nutrition (e.g., 
trophic versus full feeding) and special populations (e.g., acute hepatic failure). Heterogeneous patients 
from 68 international centers will increase the generalizability of the results. 
 
Limitations of this study include no information on some uncommon exposures in the REVISE trial (e.g., 
non-invasive ventilation) and on some rare conditions (e.g., admitting diagnosis of organ transplantation). 
To focus on events that consume healthcare resources, we will not address overt bleeding, which often 
resolves; if it evolves into patient-important or clinically-important upper gastrointestinal bleeding, these 
events will be included in this analysis. This study is not designed to construct or both construct and 
validate a prediction model, which requires a different design. All analyses such as these are subject to 
confounding, yielding information on association rather than causation, needing cautious interpretation.  
 
Conclusions 
 
This study will identify conditions of critical illness which confer an increased risk of patient-important 
upper gastrointestinal bleeding. The findings may inform bedside care, practice guidelines, and the 
design of future studies. 
 
 
 
 

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Acknowledgements 
We thank the many patients and families who participated in this trial, as well as participating clinicians 
and Methods Center staff at McMaster University and The George Institute. We appreciate the CLARITY 
Biostatistics team for guidance on our approach and Ms. Nicole Zytaruk for her assistance with this 
document. 
 
 
Funding: This study received peer-review funding from the Canadian Institutes for Health Research and 
the Accelerating Clinical Trials Fund as well as the National Health and Medical Research Council of 
Australia.   
 
 
Career Support 
Dr. F Lauzier and F Lamontagne are recipients of a Research Career Award from the Fonds de la 
recherche du Québec-Santé. D Cook is supported by a Canada Research Chair in Critical Care 
Knowledge Translation. 
 

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