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

NCT ID: NCT03374800

Last Updated: 2024-09-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 4800 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-09
• Study Completion Date: 2024-01-31

Brief 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. 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.

Conditions

Gastrointestinal Hemorrhage (Clinically Important, Upper)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo (0.9% saline)

Withholding Stress ulcer prophylaxis (intravenous 0.9% saline as placebo)

Group Type: PLACEBO_COMPARATOR

Placebo (0.9% saline)

Intervention Type: DRUG

normal saline

Stress Ulcer Prophylaxis (Pantoprazole)

pantoprazole 40mg powder for injection reconstituted with 0.9% saline

Group Type: ACTIVE_COMPARATOR

Pantoprazole

Intervention Type: DRUG

40 mg powder for injection reconstituted with 0.9% saline

Interventions

Placebo (0.9% saline)

normal saline

Intervention Type: DRUG

Pantoprazole

40 mg powder for injection reconstituted with 0.9% saline

Intervention Type: DRUG

Other Intervention Names

normal saline; NaCl 0.9%; Protonix

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

Canadian Critical Care Trials Group

OTHER

Sponsor Role: collaborator

Australian and New Zealand Intensive Care Society Clinical Trials Group

NETWORK

Sponsor Role: collaborator

National Health and Medical Research Council, Australia

OTHER

Sponsor Role: collaborator

McMaster University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Deborah Cook, MD

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Locations

University of Nebraska - Nebraska Medical Center

Omaha, Nebraska, United States

Bankstown-Lidcombe Hospital

Bankstown, New South Wales, Australia

Blacktown Hospital

Blacktown, New South Wales, Australia

Sutherland Hospital

Caringbah, New South Wales, Australia

Gosford Hospital

Gosford, New South Wales, Australia

Nepean Hospital

Kingswood, New South Wales, Australia

St George Hospital

Kogarah, New South Wales, Australia

Royal North Shore Hospital

Saint Leonards, New South Wales, Australia

Wollongong Hospital

Wollongong, New South Wales, Australia

Royal Brisbane Womens Hospital

Brisbane, Queensland, Australia

Ipswich Hospital

Ipswich, Queensland, Australia

Mater Hospital

South Brisbane, Queensland, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Bendigo Health

Bendigo, Victoria, Australia

Geelong University Hospital

Geelong, Victoria, Australia

Austin Hospital

Heidelberg, Victoria, Australia

Alfred Hospital

Melbourne, Victoria, Australia

Royal Melbourne Hospital

Melbourne, Victoria, Australia

Epworth Hospital

Melbourne, Victoria, Australia

Sociedade Hospitalar Angelina Caron

Campina Grande do Sul, , Brazil

Beneficência Social Bom Samaritano

Governador Valadares, , Brazil

Foothills Hospital

Calgary, Alberta, Canada

Peter Lougheed Hospital

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

Nanaimo Regional General Hospital

Nanaimo, British Columbia, Canada

Royal Columbian Hospital

New Westminster, British Columbia, Canada

Vancouver General Hospital

Vancouver, British Columbia, Canada

Vancouver Island Health Authority

Victoria, British Columbia, Canada

St. Boniface Hospital

Winnipeg, Manitoba, Canada

Health Science Center Winnipeg

Winnipeg, Manitoba, Canada

Grace Hospital

Winnipeg, Manitoba, Canada

Saint John Regional Hospital

Saint John, New Brunswick, Canada

QEII Health Sciences Centre

Halifax, Nova Scotia, Canada

William Osler Hospital, McKenzie Health, Brampton Civic Hospital

Brampton, Ontario, Canada

Brantford General Hospital

Brantford, Ontario, Canada

Cambridge Memorial Hospital

Cambridge, Ontario, Canada

St. Joseph's Healthcare Hamilton

Hamilton, Ontario, Canada

Hamilton Health Science Center - General Hospital

Hamilton, Ontario, Canada

Hamilton Health Science Center - Juravinski Hospital

Hamilton, Ontario, Canada

Kingston General Hospital

Kingston, Ontario, Canada

Grand River Hospital

Kitchener, Ontario, Canada

London Health Science Center (LHSC) - University Hospital

London, Ontario, Canada

London Health Science Center (LHSC) - Victoria Hospital

London, Ontario, Canada

North York General Hospital

North York, Ontario, Canada

Ottawa Health Research Institute - OHRI (General and Civic Hospital)

Ottawa, Ontario, Canada

Niagara Health Services - St. Catharine's Hospital

St. Catharines, Ontario, Canada

Sunnybrook Health Science Center

Toronto, Ontario, Canada

Mount Sinai Hospital

Toronto, Ontario, Canada

University Health Network - Toronto Western Hospital

Toronto, Ontario, Canada

St. Joseph's Health Centre, Toronto

Toronto, Ontario, Canada

St. Michael's Hospital

Toronto, Ontario, Canada

Windsor Regional Hospital

Windsor, Ontario, Canada

Centre de recherche de l'Hôtel-Dieu de Lévis

Lévis, Quebec, Canada

Hôpital Maisonneuve Rosemont

Montreal, Quebec, Canada

Center Hospital University Montreal (CHUM)

Montreal, Quebec, Canada

Centre Universitaire de Santé McGill / McGill University Health Centre

Montreal, Quebec, Canada

CIUSS du Nord de l'île de Montréal - Hôpital du Sacré-Cœur de Montréal

Montreal, Quebec, Canada

McGill University Health Centre - Montreal General Hospital

Montreal, Quebec, Canada

CHU de Québec-Université Laval - Hôpital Enfant-Jésus

Québec, Quebec, Canada

Institut Universitaire de cardiologie et de pneumologie de Québec Laval, Quebec

Québec, Quebec, Canada

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, Canada

Regina General Hospital

Regina, Saskatchewan, Canada

AL-Amiri Hospital

Kuwait City, , Kuwait

Maroof International Hospital

Islamabad, , Pakistan

King Abdulaziz Medical Center

Riyadh, , Saudi Arabia

Guys & St. Thomas Hospital

London, New Westminster, United Kingdom

Countries

United States; Australia; Brazil; Canada; Kuwait; Pakistan; Saudi Arabia; United Kingdom

References

Clarke 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.

Reference Type: DERIVED

PMID: 40379131 (View on PubMed)

Cook 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.

Reference Type: DERIVED

PMID: 38875111 (View on PubMed)

Heels-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.

Reference Type: DERIVED

PMID: 38057875 (View on PubMed)

Deane 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.

Reference Type: DERIVED

PMID: 37968012 (View on PubMed)

Dennis 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.

Reference Type: DERIVED

PMID: 37644556 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CCT38473

Identifier Type: -

Identifier Source: org_study_id