Gastrointestinal Hemorrhage (Clinically Important, Upper)Phase 3REVISENCT03374800
Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial
A Phase 3 study testing Pantoprazole in people with Gastrointestinal Hemorrhage (Clinically Important, Upper), run by McMaster University at 67 sites in 8 countries.
Trial summary
Patients who are critically ill in the in the Intensive Care Unit (ICU), especially those who need a breathing machine, can develop ulcers in the stomach that bleed. To prevent bleeding, many such patients around the world receive a drug called pantoprazole that decreases acid production. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gastrointestinal Hemorrhage (Clinically Important, Upper)
- What is being tested?
- Pantoprazole
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 4,800 participants
- Where
- 67 sitesin 8 countries
- Study dates
- 9 Jul 2018to 31 Jan 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 years or more.
- Receiving invasive mechanical ventilation in an ICU and in the opinion of the treating ICU physician mechanical ventilation will not be discontinued before the end of the day after tomorrow.
Who cannot join
- The treating clinician considers either Pantoprazole or placebo are indicated or contraindicated for this patient.
- Pantoprazole contraindicated for patient due to local product information;
- Australia/New Zealand;
- being treated with HIV protease inhibitors atazanavir or nelfinavir
- being treated with high dose methotrexate (i.e., greater than 300 mg as part of a chemotherapy regimen).
- documented cirrhosis or severe liver disease (for example as indicated by an INR greater than 5.0 due to underlying liver disease).
Show all 18Show fewer
- Canada;
- being treated with rilpivirine or atazanavir
- patients who are hypersensitive to pantoprazole, substituted benzimidazoles, or to any ingredient in the formulation
- Patients in whom a PPI or histamine 2 receptor antagonist (H2RA) is indicated due to active bleeding or increased bleeding risk, defined as patients with acute GI bleeding, severe oesophagitis or peptic ulcer disease within the previous 8 weeks, Zollinger Ellison syndrome, Barrett's oesophagus or any previous admission to hospital because of upper GI bleeding (patients receiving PPIs for mild dyspepsia or mild gastroesophageal reflux disease or an uncertain indication are not excluded).
- Received invasive mechanical ventilation during this ICU admission for 72 hours or more.
- Patients who have received more than 24 hours treatment (i.e., more than one daily dose equivalent) with a PPI or H2RA during this ICU admission.
- Being treated with or need for dual anti-platelet therapy.
- Admitted for palliative care or the ICU physician is not committed to continuing life-sustaining therapies at the time of enrolment.
- Known or suspected pregnancy.
- Physician, patient, or substitute decision maker (SDM) declines.
- Previously enrolled in the REVISE trial
- Enrolled in another trial for which co-enrolment is not approved.
Trial locations and contacts
67 sites in 8 countries.
67 sites in 8 countries
Canada41 sites
William Osler Hospital, McKenzie Health, Brampton Civic Hospital
Brampton, Ontario, L6R 3J7
Brantford General Hospital
Brantford, Ontario
Foothills Hospital
Calgary, Alberta
Peter Lougheed Hospital
Calgary, Alberta
Cambridge Memorial Hospital
Cambridge, Ontario, N1R 3G2
University of Alberta Hospital
Edmonton, Alberta, T6G 2B7
QEII Health Sciences Centre
Halifax, Nova Scotia, B3H 2Y9
St. Joseph's Healthcare Hamilton
Hamilton, Ontario, L9N 4A6
Hamilton Health Science Center - General Hospital
Hamilton, Ontario
Hamilton Health Science Center - Juravinski Hospital
Hamilton, Ontario
Kingston General Hospital
Kingston, Ontario
Grand River Hospital
Kitchener, Ontario, N2G 1G3
Centre de recherche de l'Hôtel-Dieu de Lévis
Lévis, Quebec
London Health Science Center (LHSC) - University Hospital
London, Ontario
London Health Science Center (LHSC) - Victoria Hospital
London, Ontario
Hôpital Maisonneuve Rosemont
Montreal, Quebec, H1T 2M4
Center Hospital University Montreal (CHUM)
Montreal, Quebec, H2X 0A9
Centre Universitaire de Santé McGill / McGill University Health Centre
Montreal, Quebec
CIUSS du Nord de l'île de Montréal - Hôpital du Sacré-Cœur de Montréal
Montreal, Quebec
McGill University Health Centre - Montreal General Hospital
Montreal, Quebec
Nanaimo Regional General Hospital
Nanaimo, British Columbia, V9S 2B7
Royal Columbian Hospital
New Westminster, British Columbia, V3L 3W7
North York General Hospital
North York, Ontario, M2K 1E1
Ottawa Health Research Institute - OHRI (General and Civic Hospital)
Ottawa, Ontario
CHU de Québec-Université Laval - Hôpital Enfant-Jésus
Québec, Quebec
Institut Universitaire de cardiologie et de pneumologie de Québec Laval, Quebec
Québec, Quebec
Regina General Hospital
Regina, Saskatchewan, S4P 0W5
Saint John Regional Hospital
Saint John, New Brunswick, E2L 4L2
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, J1H 5N4
Niagara Health Services - St. Catharine's Hospital
St. Catharines, Ontario
Sunnybrook Health Science Center
Toronto, Ontario, M4N 3M5
Mount Sinai Hospital
Toronto, Ontario, M5G 1X5
University Health Network - Toronto Western Hospital
Toronto, Ontario, M5T 2S8
St. Joseph's Health Centre, Toronto
Toronto, Ontario, M6R 1B5
St. Michael's Hospital
Toronto, Ontario
Vancouver General Hospital
Vancouver, British Columbia
Vancouver Island Health Authority
Victoria, British Columbia
Windsor Regional Hospital
Windsor, Ontario, N8W 1L9
St. Boniface Hospital
Winnipeg, Manitoba, R2H 2A6
Health Science Center Winnipeg
Winnipeg, Manitoba, R3A 1R9
Grace Hospital
Winnipeg, Manitoba, R3J 3M7
Australia19 sites
Royal Adelaide Hospital
Adelaide, South Australia, 5000
Bankstown-Lidcombe Hospital
Bankstown, New South Wales, 2200
Bendigo Health
Bendigo, Victoria, 3550
Blacktown Hospital
Blacktown, New South Wales, 2148
Royal Brisbane Womens Hospital
Brisbane, Queensland, 4029
Sutherland Hospital
Caringbah, New South Wales, 2050
Geelong University Hospital
Geelong, Victoria, 3220
Gosford Hospital
Gosford, New South Wales, 2250
Austin Hospital
Heidelberg, Victoria, 3084
Ipswich Hospital
Ipswich, Queensland, 4305
Nepean Hospital
Kingswood, New South Wales, 2747
St George Hospital
Kogarah, New South Wales, 2217
Alfred Hospital
Melbourne, Victoria, 3004
Royal Melbourne Hospital
Melbourne, Victoria, 3050
Epworth Hospital
Melbourne, Victoria, 3121
Royal North Shore Hospital
Saint Leonards, New South Wales, 2050
Mater Hospital
South Brisbane, Queensland, 4101
Wollongong Hospital
Wollongong, New South Wales, 2500
Princess Alexandra Hospital
Woolloongabba, Queensland, 4102
Brazil2 sites
Sociedade Hospitalar Angelina Caron
Campina Grande do Sul
Beneficência Social Bom Samaritano
Governador Valadares, 35044-220
United States1 site
University of Nebraska - Nebraska Medical Center
Omaha, Nebraska, 987400
United Kingdom1 site
Guys & St. Thomas Hospital
London, New Westminster, SE1 7EH
About this study
Official title: Re-EValuating the Inhibition of Stress Erosions: Prophylaxis Against Gastrointestinal Bleeding in the Critically Ill (The REVISE) Trial
Patients who are critically ill in the in the Intensive Care Unit (ICU), especially those who need a breathing machine, can develop ulcers in the stomach that bleed. To prevent bleeding, many such patients around the world receive a drug called pantoprazole that decreases acid production. However, today, compared to decades ago, critically ill patients rarely develop upper gastrointestinal bleeding. This decrease is likely due to modern medicine, better resuscitation and earlier feeding. There may also be harms associated with pantoprazole and other drugs that reduce acid levels in the stomach including lung infections (pneumonia) and bowel infections (Clostridioides difficile). Studies in this area are old and of modest quality. Therefore, it is difficult to know whether pantoprazole does decrease stomach bleeding these days, or whether the possible harms of lung and bowel infections are actually more common and more serious problems. The goal of this international study is to determine if, in critically ill patients using breathing machines, the use of pantoprazole is effective in preventing bleeding from stomach ulcers or whether it causes more problems such as lung infection (pneumonia) and bowel infection (Clostridioides difficile), or whether pantoprazole has no effect at all. Whether the harms are worth the benefits, and whether the benefits are worth the costs, will be determined by an economic analysis to inform patients, families, clinicians, and healthcare systems globally.
Read the detailed description
Background: For 40 years, pharmacologic prevention of stress ulcer-related gastrointestinal (GI) bleeding with acid suppression has been the standard of care for invasively mechanically ventilated ICU patients. Worldwide, proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists. Observational studies and the latest network meta-analysis suggest that PPIs increase the risk of ventilator-associated pneumonia (VAP) and Clostridioides difficile infection (CDI). However, a recent large randomized trial showed that pantoprazole had no impact on the primary outcome of 90-day mortality. The secondary outcome (a composite of pneumonia, gastrointestinal bleeding, CDI and acute myocardial ischemia) was not different between the groups. Although pantoprazole was associated with a significantly lower rate of clinically important upper GI bleeding, some bleeding events required no blood transfusion, endoscopy or other diagnostic or therapeutic interventions, calling into question whether these bleeding events were truly patient-important. Further, patients with high illness severity on pantoprazole had a significant, unexplainable higher risk of death than those receiving placebo.
REVISE Pilot Trial: We completed the 91-patient REVISE Pilot Trial in Canada, Australia and Saudi Arabia, demonstrating a high consent rate (77.8%); recruitment rate (2.6 patients/month/center); and protocol adherence (96.8%), thereby successfully establishing the feasibility of a larger REVISE Trial.
Objectives of the REVISE Trial: To determine, among invasively mechanically ventilated patients, 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. Secondary outcomes are VAP, CDI, acute kidney injury, ICU mortality, hospital mortality and patient-important upper GI bleeding. Tertiary outcomes are transfused packed red blood cells, serum creatinine, duration of mechanical ventilation, duration of ICU stay and duration of hospital stay.
Methods: We will include 4,800 ICU patients >18 years old who have an anticipated duration of mechanical ventilation of ≥48 hours. Exclusion criteria are acute or recent GI bleeding, dual antiplatelet therapy, combined antiplatelet and anticoagulant therapy, hopeless prognosis or intent to withdraw advanced life support, and previous enrolment in this or a confounding trial. Patients will be randomized in a fixed 1:1 allocation, stratified by center and pre-ICU acid suppression ('start or no start' strata, and 'continue or discontinue' strata). Research Coordinators will obtain informed consent using a deferred or a priori consent model. Study Pharmacists will obtain concealed allocation from the REVISE website; all research team and clinical team members, patients and families will be blinded. Patients will receive pantoprazole 40 mg or identical placebo intravenously daily while in ICU up to 90 days or until: 1) successful discontinuation of mechanical ventilation for >48 hours; 2) development of clinically important upper GI bleeding, or 3) death in ICU. Analyses will be by intention-to-treat with a sensitivity analysis restricted to patients receiving study drug on ≥ 80% of study days while mechanically ventilated per protocol.
Collaborations: REVISE will be conducted in collaboration with the Canadian Critical Care Trials Group, the Australian and New Zealand Critical Care Trials Group, other consortia and interested international investigators.
Ethical Imperative: Many factors converge to underscore the ethical imperative for REVISE. Critical care has evolved, research standards have improved, epidemiology may have changed, the risk:benefit and cost:benefit ratios of prophylaxis may have shifted. Thus, stress ulcer prophylaxis may need to be REVISED.
Relevance: Most invasively mechanically ventilated patients around the world receive daily stress ulcer prophylaxis, although variation exists such that some centers do not use any. Many RCTs of stress ulcer prophylaxis were conducted 10-30 years ago, several are at moderate or high risk of bias, and cointerventions may not reflect current critical care. A recent large trial raised concerns about death associated with pantoprazole in the most severely ill patient subgroup. Although clinically important upper GI bleeding events were less frequent, they may not have been patient-important, and there were no other benefits observed. Consensus in the scientific and clinical community is that equipoise remains regarding whether routine use of pantoprazole should continue for stress ulcer prophylaxis during critical illness. The question is especially important for patients who are receiving acid suppression pre-ICU, those who are receiving enteral nutrition, and those at high risk of death. Today, infectious complications of PPIs have emerged as potentially more common and serious than upper GI bleeding. The number needed to prophylax to prevent 1 GI bleed and the cost per GI bleed averted may be very high; furthermore, the number needed to harm to cause 1 episode of VAP or CDI may be low. Recent practice guidelines are conflicting. Remaining doubts about the effectiveness and safety of PPIs urge re-examination of universal prophylaxis for possible de-adoption. Aligned with the 'Choosing Wisely' Campaign, REVISE and the companion economic evaluation (E-REVISE) will be incorporated into guidelines to inform global practice.
- Being tested
- Placebo (0.9% saline), Pantoprazole
- Medical subject headings
- Gastrointestinal Hemorrhage
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Placebo (0.9% saline)Drug
Also called normal saline; NaCl 0.9%
normal saline
PantoprazoleDrug
Also called Protonix
40 mg powder for injection reconstituted with 0.9% saline
| Study group | Role | What they receive |
|---|---|---|
| Placebo (0.9% saline) | Placebo comparator | Withholding Stress ulcer prophylaxis (intravenous 0.9% saline as placebo) Receives: Drug: Placebo (0.9% saline) |
| Stress Ulcer Prophylaxis (Pantoprazole) | Active comparator | pantoprazole 40mg powder for injection reconstituted with 0.9% saline Receives: Drug: Pantoprazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of clinically important upper gastro-intestinal bleeding
Clinically important upper GI bleeding requires the presence of overt GI bleeding which is defined as one of the following;
- Hematemesis
- Overt nasogastric bleeding
- Melena
- Hematochezia
PLUS (in the absence of another cause), at least one of the following in the 24 hours following overt GI bleeding:
- Haemodynamic change defined as a 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 haemoglobin 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 to maintain stable haemoglobin or haemodynamics, or
- Need for therapeutic intervention (e.g. angiography, surgery or endoscopic treatment of bleeding).
Measured: 90 days (In ICU or resulting in ICU readmission, censored at 90 days after randomization)
Primary Safety Outcome: 90 Day Mortality
Mortality status at day 90 post randomization
Measured: 90 days post randomization
Secondary outcomes (6)
Rate of ventilator associated pneumonia (VAP) in ICU
Diagnostic criteria for VAP include: previous mechanical ventilation for at least 48 hours, a new, progressive or persistent radiographic infiltrate on chest X-ray (without other obvious cause) plus at least 2 of the following 4 features:
- fever or hypothermia (temperature >38 °C or <36 °C)
- relative leukopenia or leukocytosis (WBC<4.0 or >12 x 10^9/L)
- purulent sputum
- gas exchange deterioration Using these uploaded data, the Clinical Pulmonary Infection Score is calculated. A score of 6 or greater is the primary definition of ventilator-associated pneumonia
Measured: 90 Days (while in ICU,censored at 90 days after randomization)
Rate of Clostridioides difficile associated infection
We will use clinical features (diarrhea, ileus, toxic megacolon) and either microbiological evidence of toxin producing Clostridioides difficile or Pseudomembranous colitis on colonoscopy.
Measured: 90 days (during the index hospital admission, censored at 90 days)
New initiation of treatment with renal replacement therapy in ICU
Rate of New initiation of treatment with renal replacement therapy in ICU
Measured: 90 Days (In the ICU, censored at 90 days)
Rate of all-cause-in-hospital mortality
hospital mortality
Measured: While in hospital, censored at 90 days after randomization
Rate of ICU mortality
ICU mortality
Measured: While in the ICU, censored at 90 days after randomization
Rate of patient important upper GI bleeding in ICU or resulting in ICU readmission, censored at 90 days after randomization
Patient important upper GI bleeding in ICU or resulting in ICU readmission, censored at 90 days after randomization
Measured: Censored at 90 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2017
- Study start9 Jul 2018
- Primary completion31 Oct 2023
- Study completion31 Jan 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Gastrointestinal Hemorrhage (Clinically Important, Upper)Studies of the same condition, open and under way.
- More trials run by McMaster UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A prospective, international, multicentre, parallel group, concealed, blinded, randomized trial in critically ill invasively mechanically ventilated adults
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 4,800 participants (actual)
Sponsor and investigators
- Lead sponsor
- McMaster University
- Sponsor type
- University, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR), Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group, National Health and Medical Research Council, Australia
- Responsible party
- Sponsor
- Investigators
- Deborah Cook, MD, Principal investigator, McMaster University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03374800
- Sponsor's protocol ID
- CCT38473
- Acronym
- REVISE
- Status last verified
- Sep 2024
- First submitted
- 21 Nov 2017
- Last updated
- 20 Sep 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Following the publication of REVISE, the dataset will be used for secondary observational studies addressing additional hypothesis-driven questions (e.g., predictors of gastrointestinal bleeding). Access by REVISE investigators will follow a submitted rationale, analysis plan and approval by the Management Committee. Requests for access to the dataset by external academic investigators will be considered following a submitted rationale, analysis plan and approval by the Management Committee and research ethics boards as relevant. Only de-identified data will be provided and will be transferred via a secure web portal. Requirements will be stipulated in a pre-specified data sharing agreement with investigators which aligns with each institution including the data sharing policy of The George Institute (https://www.georgeinstitute.org.au/data-sharing-policy.)
Publications
Dennis B, Heels-Ansdell D, Ibrahim Q, Basmaji J, Thabane L, Guyatt G, Saunders L, Hand L, Loy O, Zytaruk N, Hardie M, Deane AM, Marshall JC, Arabi Y, Lauzier F, Dionne JC, Burns KE, Alhazzani W, Vazquez-Grande G, Geagea A, Myburgh J, Muscedere J, English S, Binnie A, Tsang JL, Hunt M, Ostermann M, Al-Fares AA, Knowles S, Ahmed A, Cook DJ; REVISE Investigators and the Canadian Critical Care Trials Group. Proton pump inhibitors in invasively ventilated patients with SARS-CoV-2: a substudy of the re-evaluating the inhibition of stress erosions trial. BMJ Open. 2026 Aug 31;16(8):e119937. doi: 10.1136/bmjopen-2026-119937.
PubMed 42674788Kuriyama A, Heels-Ansdell D, Fernando SM, Adhikari NKJ, Lamontagne F, Teja B, Lewis KA, Rochwerg B, Carayannopoulos KL, Vazquez-Grande G, McIntyre L, Honarmand K, Chaudhuri D, Krag M, Zytaruk N, Cook D; Canadian Critical Care Trials Group. Pantoprazole Use in Invasively Ventilated Patients With Septic Shock: A Protocol and Statistical Analysis Plan. Acta Anaesthesiol Scand. 2026 Jul;70(6):e70267. doi: 10.1111/aas.70267.
PubMed 42186360Humphries B, Zytaruk N, Heels-Ansdell D, Lau V, Rochwerg B, Fowler R, Yao Y, Cook DJ, Xie F. Protocol for an economic evaluation alongside the Re-Evaluating the Inhibition of Stress Erosions (E-REVISE) trial. BMJ Open. 2025 Nov 9;15(11):e106841. doi: 10.1136/bmjopen-2025-106841.
PubMed 41213683Clarke F, Hand L, Deane A, Zytaruk N, Hardie M, Arabi Y, Al-Fares A, Heels-Ansdell D, Dechert W, Ostermann M, Watpool I, Millen T, Muscedere J, English S, Boyd G, Sibley S, Peck L, Eastwood G, Duan E, Soth M, Freitag A, Vazquez-Grande G, Slessarev M, Ball I, Geagea A, Burns K, Binnie A, Mehta S, Tsang J, Burry L, D'Aragon F, Cook D. Coenrollment in a critical care trial: Characteristics and consequences. Contemp Clin Trials. 2025 Jul;154:107938. doi: 10.1016/j.cct.2025.107938. Epub 2025 May 14.
PubMed 40379131Cook D, 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 YM, Ostermann M, Knowles S, Hammond N, Byrne KM, 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 JLY, 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 KEA, Goffi A, Wilcox ME, Henderson W, Forrest D, Fowler R, Adhikari NKJ, Ball I, Mele T, Binnie A, Trop S, Mehta S, Morgan I, Loubani O, Vanstone M, Fiest K, Charbonney E, Cavayas YA, Archambault P, Rewa OG, Lau V, Kristof AS, Khwaja K, Williamson D, Kanji S, Sy E, Dennis B, Reynolds S, Marquis F, Lellouche F, Rahman A, Hosek P, Barletta JF, Cirrone R, Tutschka M, Xie F, Billot L, Thabane L, Finfer S; REVISE Investigators. Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation. N Engl J Med. 2024 Jul 4;391(1):9-20. doi: 10.1056/NEJMoa2404245. Epub 2024 Jun 14.
PubMed 38875111Heels-Ansdell D, Billot L, Thabane L, Alhazzani W, Deane A, Guyatt G, Finfer S, Lauzier F, Myburgh J, Young P, Arabi Y, Marshall J, English S, Muscedere J, Ostermann M, Venkatesh B, Zytaruk N, Hardie M, Hammond N, Knowles S, Saunders L, Poole A, Al-Fares A, Xie F, Hall R, Cook D. REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial. Trials. 2023 Dec 6;24(1):796. doi: 10.1186/s13063-023-07794-z.
PubMed 38057875Deane AM, Alhazzani W, Guyatt G, Finfer S, Marshall JC, Myburgh J, Zytaruk N, Hardie M, Saunders L, Knowles S, Lauzier F, Chapman MJ, English S, Muscedere J, Arabi Y, Ostermann M, Venkatesh B, Young P, Thabane L, Billot L, Heels-Ansdell D, Al-Fares AA, Hammond NE, Hall R, Rajbhandari D, Poole A, Johnson D, Iqbal M, Reis G, Xie F, Cook DJ; Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol. BMJ Open. 2023 Nov 15;13(11):e075588. doi: 10.1136/bmjopen-2023-075588.
PubMed 37968012Dennis BB, Thabane L, Heels-Ansdell D, Dionne JC, Binnie A, Tsang J, Guyatt G, Ahmed A, Lauzier F, Deane A, Arabi Y, Marshall J, Zytaruk N, Saunders L, Finfer S, Myburgh J, Muscedere J, English S, Ostermann M, Hardie M, Knowles S, Cook D; REVISE Investigators the Canadian Critical Care Trials Group. Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial. Trials. 2023 Aug 30;24(1):561. doi: 10.1186/s13063-023-07589-2.
PubMed 37644556
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Re-EValuating the Inhibition of Stress Erosions: Prophylaxis Against Gastrointestinal Bleeding in the Critically Ill (The REVISE) Trial
- ClinicalTrials.gov ID
- NCT03374800
- Acronym / sponsor ID
- REVISE / CCT38473
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 4,800 participants (actual)
- Lead sponsor
- McMaster UniversityUniversity, hospital or other
- Collaborators
- Canadian Institutes of Health Research (CIHR), Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group, National Health and Medical Research Council, Australia
- Study start
- 9 Jul 2018 (actual)
- Primary completion
- 31 Oct 2023 (actual)
- Study completion
- 31 Jan 2024 (actual)
- First posted
- 15 Dec 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Patients who are critically ill in the in the Intensive Care Unit (ICU), especially those who need a breathing machine, can develop ulcers in the stomach that bleed. To prevent bleeding, many such patients around the world receive a drug called pantoprazole that decreases acid production. However, today, compared to decades ago, critically ill patients rarely develop upper gastrointestinal bleeding. This decrease is likely due to modern medicine, better resuscitation and earlier feeding. There may also be harms associated with pantoprazole and other drugs that reduce acid levels in the stomach including lung infections (pneumonia) and bowel infections (Clostridioides difficile). Studies in this area are old and of modest quality. Therefore, it is difficult to know whether pantoprazole does decrease stomach bleeding these days, or whether the possible harms of lung and bowel infections are actually more common and more serious problems. The goal of this international study is to determine if, in critically ill patients using breathing machines, the use of pantoprazole is effective in preventing bleeding from stomach ulcers or whether it causes more problems such as lung infection (pneumonia) and bowel infection (Clostridioides difficile), or whether pantoprazole has no effect at all. Whether the harms are worth the benefits, and whether the benefits are worth the costs, will be determined by an economic analysis to inform patients, families, clinicians, and healthcare systems globally.
Detailed description
Background: For 40 years, pharmacologic prevention of stress ulcer-related gastrointestinal (GI) bleeding with acid suppression has been the standard of care for invasively mechanically ventilated ICU patients. Worldwide, proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists. Observational studies and the latest network meta-analysis suggest that PPIs increase the risk of ventilator-associated pneumonia (VAP) and Clostridioides difficile infection (CDI). However, a recent large randomized trial showed that pantoprazole had no impact on the primary outcome of 90-day mortality. The secondary outcome (a composite of pneumonia, gastrointestinal bleeding, CDI and acute myocardial ischemia) was not different between the groups. Although pantoprazole was associated with a significantly lower rate of clinically important upper GI bleeding, some bleeding events required no blood transfusion, endoscopy or other diagnostic or therapeutic interventions, calling into question whether these bleeding events were truly patient-important. Further, patients with high illness severity on pantoprazole had a significant, unexplainable higher risk of death than those receiving placebo.
REVISE Pilot Trial: We completed the 91-patient REVISE Pilot Trial in Canada, Australia and Saudi Arabia, demonstrating a high consent rate (77.8%); recruitment rate (2.6 patients/month/center); and protocol adherence (96.8%), thereby successfully establishing the feasibility of a larger REVISE Trial.
Objectives of the REVISE Trial: To determine, among invasively mechanically ventilated patients, 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. Secondary outcomes are VAP, CDI, acute kidney injury, ICU mortality, hospital mortality and patient-important upper GI bleeding. Tertiary outcomes are transfused packed red blood cells, serum creatinine, duration of mechanical ventilation, duration of ICU stay and duration of hospital stay.
Methods: We will include 4,800 ICU patients >18 years old who have an anticipated duration of mechanical ventilation of ≥48 hours. Exclusion criteria are acute or recent GI bleeding, dual antiplatelet therapy, combined antiplatelet and anticoagulant therapy, hopeless prognosis or intent to withdraw advanced life support, and previous enrolment in this or a confounding trial. Patients will be randomized in a fixed 1:1 allocation, stratified by center and pre-ICU acid suppression ('start or no start' strata, and 'continue or discontinue' strata). Research Coordinators will obtain informed consent using a deferred or a priori consent model. Study Pharmacists will obtain concealed allocation from the REVISE website; all research team and clinical team members, patients and families will be blinded. Patients will receive pantoprazole 40 mg or identical placebo intravenously daily while in ICU up to 90 days or until: 1) successful discontinuation of mechanical ventilation for >48 hours; 2) development of clinically important upper GI bleeding, or 3) death in ICU. Analyses will be by intention-to-treat with a sensitivity analysis restricted to patients receiving study drug on ≥ 80% of study days while mechanically ventilated per protocol.
Collaborations: REVISE will be conducted in collaboration with the Canadian Critical Care Trials Group, the Australian and New Zealand Critical Care Trials Group, other consortia and interested international investigators.
Ethical Imperative: Many factors converge to underscore the ethical imperative for REVISE. Critical care has evolved, research standards have improved, epidemiology may have changed, the risk:benefit and cost:benefit ratios of prophylaxis may have shifted. Thus, stress ulcer prophylaxis may need to be REVISED.
Relevance: Most invasively mechanically ventilated patients around the world receive daily stress ulcer prophylaxis, although variation exists such that some centers do not use any. Many RCTs of stress ulcer prophylaxis were conducted 10-30 years ago, several are at moderate or high risk of bias, and cointerventions may not reflect current critical care. A recent large trial raised concerns about death associated with pantoprazole in the most severely ill patient subgroup. Although clinically important upper GI bleeding events were less frequent, they may not have been patient-important, and there were no other benefits observed. Consensus in the scientific and clinical community is that equipoise remains regarding whether routine use of pantoprazole should continue for stress ulcer prophylaxis during critical illness. The question is especially important for patients who are receiving acid suppression pre-ICU, those who are receiving enteral nutrition, and those at high risk of death. Today, infectious complications of PPIs have emerged as potentially more common and serious than upper GI bleeding. The number needed to prophylax to prevent 1 GI bleed and the cost per GI bleed averted may be very high; furthermore, the number needed to harm to cause 1 episode of VAP or CDI may be low. Recent practice guidelines are conflicting. Remaining doubts about the effectiveness and safety of PPIs urge re-examination of universal prophylaxis for possible de-adoption. Aligned with the 'Choosing Wisely' Campaign, REVISE and the companion economic evaluation (E-REVISE) will be incorporated into guidelines to inform global practice.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- A prospective, international, multicentre, parallel group, concealed, blinded, randomized trial in critically ill invasively mechanically ventilated adults
| Arm | Type | Receives |
|---|---|---|
| Placebo (0.9% saline) | Placebo comparator | Drug: Placebo (0.9% saline)Withholding Stress ulcer prophylaxis (intravenous 0.9% saline as placebo) |
| Stress Ulcer Prophylaxis (Pantoprazole) | Active comparator | Drug: Pantoprazolepantoprazole 40mg powder for injection reconstituted with 0.9% saline |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Age 18 years or more.
- Receiving invasive mechanical ventilation in an ICU and in the opinion of the treating ICU physician mechanical ventilation will not be discontinued before the end of the day after tomorrow.
Key exclusion criteria (18 listed)
- The treating clinician considers either Pantoprazole or placebo are indicated or contraindicated for this patient.
- Pantoprazole contraindicated for patient due to local product information;
- Australia/New Zealand;
- Canada;
- Patients in whom a PPI or histamine 2 receptor antagonist (H2RA) is indicated due to active bleeding or increased bleeding risk, defined as patients with acute GI bleeding, severe oesophagitis or peptic ulcer disease within the previous 8 weeks, Zollinger Ellison syndrome, Barrett's oesophagus or any previous admission to hospital because of upper GI bleeding (patients receiving PPIs for mild dyspepsia or mild gastroesophageal reflux disease or an uncertain indication are not excluded).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Placebo (0.9% saline)Also: normal saline; NaCl 0.9%normal saline | Drug | Placebo (0.9% saline) |
| PantoprazoleAlso: Protonix40 mg powder for injection reconstituted with 0.9% saline | Drug | Stress Ulcer Prophylaxis (Pantoprazole) |
Primary outcome
Rate of clinically important upper gastro-intestinal bleeding
Time frame: 90 days (In ICU or resulting in ICU readmission, censored at 90 days after randomization)
Clinically important upper GI bleeding requires the presence of overt GI bleeding which is defined as one of the following; * Hematemesis * Overt nasogastric bleeding * Melena * Hematochezia PLUS (in the absence of another cause), at least one of the following in the 24 hours following overt GI bleeding: * Haemodynamic change defined as a 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 haemoglobin 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 to maintain stable haemoglobin or haemodynamics, or * Need for therapeutic intervention (e.g. angiography, surgery or endoscopic treatment of bleeding).
Primary Safety Outcome: 90 Day Mortality
Time frame: 90 days post randomization
Mortality status at day 90 post randomization
6 secondary outcomes
Rate of ventilator associated pneumonia (VAP) in ICU
Time frame: 90 Days (while in ICU,censored at 90 days after randomization)
Rate of Clostridioides difficile associated infection
Time frame: 90 days (during the index hospital admission, censored at 90 days)
New initiation of treatment with renal replacement therapy in ICU
Time frame: 90 Days (In the ICU, censored at 90 days)
Rate of all-cause-in-hospital mortality
Time frame: While in hospital, censored at 90 days after randomization
Rate of ICU mortality
Time frame: While in the ICU, censored at 90 days after randomization
Rate of patient important upper GI bleeding in ICU or resulting in ICU readmission, censored at 90 days after randomization
Time frame: Censored at 90 days after randomization
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2024.
- Derived from this study: PubMed 42674788Dennis B, Heels-Ansdell D, Ibrahim Q, Basmaji J, Thabane L, Guyatt G, Saunders L, Hand L, Loy O, Zytaruk N, Hardie M, Deane AM, Marshall JC, Arabi Y, Lauzier F, Dionne JC, Burns KE, Alhazzani W, Vazquez-Grande G, Geagea A, Myburgh J, Muscedere J, English S, Binnie A, Tsang JL, Hunt M, Ostermann M, Al-Fares AA, Knowles S, Ahmed A, Cook DJ; REVISE Investigators and the Canadian Critical Care Trials Group. Proton pump inhibitors in invasively ventilated patients with SARS-CoV-2: a substudy of the re-evaluating the inhibition of stress erosions trial. BMJ Open. 2026 Aug 31;16(8):e119937. doi: 10.1136/bmjopen-2026-119937.
- Derived from this study: PubMed 42186360Kuriyama A, Heels-Ansdell D, Fernando SM, Adhikari NKJ, Lamontagne F, Teja B, Lewis KA, Rochwerg B, Carayannopoulos KL, Vazquez-Grande G, McIntyre L, Honarmand K, Chaudhuri D, Krag M, Zytaruk N, Cook D; Canadian Critical Care Trials Group. Pantoprazole Use in Invasively Ventilated Patients With Septic Shock: A Protocol and Statistical Analysis Plan. Acta Anaesthesiol Scand. 2026 Jul;70(6):e70267. doi: 10.1111/aas.70267.
- Derived from this study: PubMed 41213683Humphries B, Zytaruk N, Heels-Ansdell D, Lau V, Rochwerg B, Fowler R, Yao Y, Cook DJ, Xie F. Protocol for an economic evaluation alongside the Re-Evaluating the Inhibition of Stress Erosions (E-REVISE) trial. BMJ Open. 2025 Nov 9;15(11):e106841. doi: 10.1136/bmjopen-2025-106841.
- Derived from this study: PubMed 40379131Clarke F, Hand L, Deane A, Zytaruk N, Hardie M, Arabi Y, Al-Fares A, Heels-Ansdell D, Dechert W, Ostermann M, Watpool I, Millen T, Muscedere J, English S, Boyd G, Sibley S, Peck L, Eastwood G, Duan E, Soth M, Freitag A, Vazquez-Grande G, Slessarev M, Ball I, Geagea A, Burns K, Binnie A, Mehta S, Tsang J, Burry L, D'Aragon F, Cook D. Coenrollment in a critical care trial: Characteristics and consequences. Contemp Clin Trials. 2025 Jul;154:107938. doi: 10.1016/j.cct.2025.107938. Epub 2025 May 14.
- Derived from this study: PubMed 38875111Cook D, 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 YM, Ostermann M, Knowles S, Hammond N, Byrne KM, 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 JLY, 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 KEA, Goffi A, Wilcox ME, Henderson W, Forrest D, Fowler R, Adhikari NKJ, Ball I, Mele T, Binnie A, Trop S, Mehta S, Morgan I, Loubani O, Vanstone M, Fiest K, Charbonney E, Cavayas YA, Archambault P, Rewa OG, Lau V, Kristof AS, Khwaja K, Williamson D, Kanji S, Sy E, Dennis B, Reynolds S, Marquis F, Lellouche F, Rahman A, Hosek P, Barletta JF, Cirrone R, Tutschka M, Xie F, Billot L, Thabane L, Finfer S; REVISE Investigators. Stress Ulcer Prophylaxis during Invasive Mechanical Ventilation. N Engl J Med. 2024 Jul 4;391(1):9-20. doi: 10.1056/NEJMoa2404245. Epub 2024 Jun 14.
- Derived from this study: PubMed 38057875Heels-Ansdell D, Billot L, Thabane L, Alhazzani W, Deane A, Guyatt G, Finfer S, Lauzier F, Myburgh J, Young P, Arabi Y, Marshall J, English S, Muscedere J, Ostermann M, Venkatesh B, Zytaruk N, Hardie M, Hammond N, Knowles S, Saunders L, Poole A, Al-Fares A, Xie F, Hall R, Cook D. REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial. Trials. 2023 Dec 6;24(1):796. doi: 10.1186/s13063-023-07794-z.
- Derived from this study: PubMed 37968012Deane AM, Alhazzani W, Guyatt G, Finfer S, Marshall JC, Myburgh J, Zytaruk N, Hardie M, Saunders L, Knowles S, Lauzier F, Chapman MJ, English S, Muscedere J, Arabi Y, Ostermann M, Venkatesh B, Young P, Thabane L, Billot L, Heels-Ansdell D, Al-Fares AA, Hammond NE, Hall R, Rajbhandari D, Poole A, Johnson D, Iqbal M, Reis G, Xie F, Cook DJ; Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol. BMJ Open. 2023 Nov 15;13(11):e075588. doi: 10.1136/bmjopen-2023-075588.
- Derived from this study: PubMed 37644556Dennis BB, Thabane L, Heels-Ansdell D, Dionne JC, Binnie A, Tsang J, Guyatt G, Ahmed A, Lauzier F, Deane A, Arabi Y, Marshall J, Zytaruk N, Saunders L, Finfer S, Myburgh J, Muscedere J, English S, Ostermann M, Hardie M, Knowles S, Cook D; REVISE Investigators the Canadian Critical Care Trials Group. Proton pump inhibitors in critically ill mechanically ventilated patients with COVID-19: protocol for a substudy of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial. Trials. 2023 Aug 30;24(1):561. doi: 10.1186/s13063-023-07589-2.
- Individual participant dataSharing planned: Yes. Following the publication of REVISE, the dataset will be used for secondary observational studies addressing additional hypothesis-driven questions (e.g., predictors of gastrointestinal bleeding). Access by REVISE investigators will follow a submitted rationale, analysis plan and approval by the Management Committee. Requests for access to the dataset by external academic investigators will be considered following a submitted rationale, analysis plan and approval by the Management Committee and research ethics boards as relevant. Only de-identified data will be provided and will be transferred via a secure web portal. Requirements will be stipulated in a pre-specified data sharing agreement with investigators which aligns with each institution including the data sharing policy of The George Institute (https://www.georgeinstitute.org.au/data-sharing-policy.)
Related trials for Gastrointestinal Hemorrhage (Clinically Important, Upper)
Not yet recruiting
FENOX Trial (Comparative Effectiveness of Fexuprazan Co-therapy in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants)
Atrial Fibrillation (AF), Upper Gastrointestinal Bleeding (UGIB)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Deborah Cook, MD principal investigator
McMaster University
67 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Pantoprazole in people with Gastrointestinal Hemorrhage (Clinically Important, Upper), run by McMaster University at 67 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 67 sites in Canada, Australia, Brazil, United States, Kuwait and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of clinically important upper gastro-intestinal bleeding (time frame: 90 days (In ICU or resulting in ICU readmission, censored at 90 days after randomization)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03374800, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2024.