Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial (REVISE)

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.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Hemorrhage (Clinically Important, Upper)
• Intervention / Treatment: Drug: Placebo (0.9% saline); Drug: Pantoprazole

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 Type: Interventional
• Enrollment (Actual): 4800
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Bankstown, New South Wales, Australia, 2200
      • Bankstown-Lidcombe Hospital
    • Blacktown, New South Wales, Australia, 2148
      • Blacktown Hospital
    • Caringbah, New South Wales, Australia, 2050
      • Sutherland Hospital
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • Kingswood, New South Wales, Australia, 2747
      • Nepean Hospital
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • Saint Leonards, New South Wales, Australia, 2050
      • Royal North Shore Hospital
    • Wollongong, New South Wales, Australia, 2500
      • Wollongong Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane Womens Hospital
    • Ipswich, Queensland, Australia, 4305
      • Ipswich Hospital
    • South Brisbane, Queensland, Australia, 4101
      • Mater Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Bendigo, Victoria, Australia, 3550
      • Bendigo Health
    • Geelong, Victoria, Australia, 3220
      • Geelong University Hospital
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
    • Melbourne, Victoria, Australia, 3121
      • Epworth Hospital
• Brazil
  • Campina Grande Do Sul, Brazil
    • Sociedade Hospitalar Angelina Caron
  • Governador Valadares, Brazil, 35044-220
    • Beneficência Social Bom Samaritano
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Hospital
    • Calgary, Alberta, Canada
      • Peter Lougheed Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Nanaimo, British Columbia, Canada, V9S 2B7
      • Nanaimo Regional General Hospital
    • New Westminster, British Columbia, Canada, V3L 3W7
      • Royal Columbian Hospital
    • Vancouver, British Columbia, Canada
      • Vancouver General Hospital
    • Victoria, British Columbia, Canada
      • Vancouver Island Health Authority
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3J 3M7
      • Grace Hospital
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St. Boniface Hospital
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Health Science Center Winnipeg
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Saint John Regional Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • QEII Health Sciences Centre
  • Ontario
    • Brampton, Ontario, Canada, L6R 3J7
      • William Osler Hospital, McKenzie Health, Brampton Civic Hospital
    • Brantford, Ontario, Canada
      • Brantford General Hospital
    • Cambridge, Ontario, Canada, N1R 3G2
      • Cambridge Memorial Hospital
    • Hamilton, Ontario, Canada, L9N 4A6
      • St. Joseph's Healthcare Hamilton
    • Hamilton, Ontario, Canada
      • Hamilton Health Science Center - General Hospital
    • Hamilton, Ontario, Canada
      • Hamilton Health Science Center - Juravinski Hospital
    • Kingston, Ontario, Canada
      • Kingston General Hospital
    • Kitchener, Ontario, Canada, N2G 1G3
      • Grand River Hospital
    • London, Ontario, Canada
      • London Health Science Center (LHSC) - University Hospital
    • London, Ontario, Canada
      • London Health Science Center (LHSC) - Victoria Hospital
    • North York, Ontario, Canada, M2K 1E1
      • North York General Hospital
    • Ottawa, Ontario, Canada
      • Ottawa Health Research Institute - OHRI (General and Civic Hospital)
    • St. Catharines, Ontario, Canada
      • Niagara Health Services - St. Catharine's Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5T 2S8
      • University Health Network - Toronto Western Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Science Center
    • Toronto, Ontario, Canada, M6R 1B5
      • St. Joseph's Health Centre, Toronto
    • Windsor, Ontario, Canada, N8W 1L9
      • Windsor Regional Hospital
  • Quebec
    • Lévis, Quebec, Canada
      • Centre de recherche de l'Hôtel-Dieu de Lévis
    • Montréal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve Rosemont
    • Montréal, Quebec, Canada, H2X 0A9
      • Center Hospital University Montreal (CHUM)
    • Montréal, Quebec, Canada
      • Centre Universitaire de Santé McGill / McGill University Health Centre
    • Montréal, Quebec, Canada
      • CIUSS du Nord de l'île de Montréal - Hôpital du Sacré-Cœur de Montréal
    • Montréal, Quebec, Canada
      • McGill University Health Centre - Montreal General Hospital
    • Quebec City, Quebec, Canada
      • CHU de Québec-Université Laval - Hôpital Enfant-Jésus
    • Quebec City, Quebec, Canada
      • Institut Universitaire de cardiologie et de pneumologie de Québec Laval, Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4P 0W5
      • Regina General Hospital
• Kuwait
  • Kuwait City, Kuwait
    • Al-Amiri Hospital
• Pakistan
  • Islamabad, Pakistan
    • Maroof International Hospital
• Saudi Arabia
  • Riyadh, Saudi Arabia, 11426
    • King Abdulaziz Medical Center
• United Kingdom
  • New Westminster
    • London, New Westminster, United Kingdom, SE1 7EH
      • Guys & St. Thomas Hospital
• United States
  • Nebraska
    • Omaha, Nebraska, United States, 987400
      • University of Nebraska - Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years or more.
2. 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.

Exclusion Criteria:

1. The treating clinician considers either Pantoprazole or placebo are indicated or contraindicated for this patient.

2. 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).

   Canada;

   • being treated with rilpivirine or atazanavir
   • patients who are hypersensitive to pantoprazole, substituted benzimidazoles, or to any ingredient in the formulation
3. 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).
4. Received invasive mechanical ventilation during this ICU admission for 72 hours or more.
5. 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.
6. Being treated with or need for dual anti-platelet therapy.
7. Admitted for palliative care or the ICU physician is not committed to continuing life-sustaining therapies at the time of enrolment.
8. Known or suspected pregnancy.
9. Physician, patient, or substitute decision maker (SDM) declines.
10. Previously enrolled in the REVISE trial
11. Enrolled in another trial for which co-enrolment is not approved.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (0.9% saline); Withholding Stress ulcer prophylaxis (intravenous 0.9% saline as placebo)	Drug: Placebo (0.9% saline); normal saline; Other Names: normal saline; NaCl 0.9%
Active Comparator: Stress Ulcer Prophylaxis (Pantoprazole); pantoprazole 40mg powder for injection reconstituted with 0.9% saline	Drug: Pantoprazole; 40 mg powder for injection reconstituted with 0.9% saline; Other Names: Protonix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Safety Outcome: 90 Day Mortality	Mortality status at day 90 post randomization	90 days post randomization
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).	90 days (In ICU or resulting in ICU readmission, censored at 90 days after randomization)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of all-cause-in-hospital mortality	hospital mortality	While in hospital, censored at 90 days after randomization
New initiation of treatment with renal replacement therapy in ICU	Rate of New initiation of treatment with renal replacement therapy in ICU	90 Days (In the ICU, censored at 90 days)
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	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.	90 days (during the index hospital admission, censored at 90 days)
Rate of ICU mortality	ICU mortality	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	Censored at 90 days after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak serum creatinine concentration in ICU	Peak serum creatinine concentration in ICU	Censored at 90 days after randomisation
Duration of mechanical ventilation (days)	Duration of mechanical ventilation (days)	Censored at 90 days after randomisation
ICU length of stay (days)	ICU length of stay (days)	Censored at 90 days after randomisation
Hospital length of stay (days)	Hospital length of stay (days)	Censored at 90 days after randomisation
Total units of red blood cells transfused in the first 14 days of ICU stay	Total units of red blood cells transfused in the ICU in the first 14 days	Censored at 14 days after randomization

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: National Health and Medical Research Council, Australia; Canadian Institutes of Health Research (CIHR); Australian and New Zealand Intensive Care Society Clinical Trials Group; Canadian Critical Care Trials Group
• Investigators: Principal Investigator: Deborah Cook, MD, McMaster University

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2018
• Primary Completion (Actual): October 31, 2023
• Study Completion (Actual): January 31, 2024

Study Registration Dates

• First Submitted: November 21, 2017
• First Submitted That Met QC Criteria: December 14, 2017
• First Posted (Actual): December 15, 2017

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: September 18, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Hemorrhage; Gastrointestinal Hemorrhage; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Pantoprazole
• Other Study ID Numbers: CCT38473

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.)
• IPD Sharing Time Frame: Anticipated availability 2025 for up to 15 years.
• IPD Sharing Access Criteria: 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.)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No