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

Gastrointestinal Hemorrhage (Clinically Important, Upper) Clinical Trial

— REVISE  

Official title:

Re-EValuating the Inhibition of Stress Erosions: Prophylaxis Against Gastrointestinal Bleeding in the Critically Ill (The REVISE) Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03374800
• Other study ID #: CCT38473
• Status: Completed
• Phase: Phase 3
• Start date: July 9, 2018
• Est. completion date: January 31, 2024

Study information

• Verified date: April 2024
• Source: McMaster University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4800
• Est. completion date: January 31, 2024
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Gastrointestinal Hemorrhage
• Gastrointestinal Hemorrhage (Clinically Important, Upper)
• Hemorrhage

Intervention

Drug:
• Placebo (0.9% saline)
normal saline
• Pantoprazole
40 mg powder for injection reconstituted with 0.9% saline

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Bankstown-Lidcombe Hospital	Bankstown	New South Wales
Australia	Bendigo Health	Bendigo	Victoria
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Royal Brisbane Womens Hospital	Brisbane	Queensland
Australia	Sutherland Hospital	Caringbah	New South Wales
Australia	Geelong University Hospital	Geelong	Victoria
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Ipswich Hospital	Ipswich	Queensland
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	St George Hospital	Kogarah	New South Wales
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Epworth Hospital	Melbourne	Victoria
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Australia	Mater Hospital	South Brisbane	Queensland
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Brazil	Sociedade Hospitalar Angelina Caron	Campina Grande Do Sul
Brazil	Beneficência Social Bom Samaritano	Governador Valadares
Canada	William Osler Hospital, McKenzie Health, Brampton Civic Hospital	Brampton	Ontario
Canada	Brantford General Hospital	Brantford	Ontario
Canada	Foothills Hospital	Calgary	Alberta
Canada	Peter Lougheed Hospital	Calgary	Alberta
Canada	Cambridge Memorial Hospital	Cambridge	Ontario
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	QEII Health Sciences Centre	Halifax	Nova Scotia
Canada	Hamilton Health Science Center - General Hospital	Hamilton	Ontario
Canada	Hamilton Health Science Center - Juravinski Hospital	Hamilton	Ontario
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston	Ontario
Canada	Grand River Hospital	Kitchener	Ontario
Canada	Centre de recherche de l'Hôtel-Dieu de Lévis	Lévis	Quebec
Canada	London Health Science Center (LHSC) - University Hospital	London	Ontario
Canada	London Health Science Center (LHSC) - Victoria Hospital	London	Ontario
Canada	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	Hôpital Maisonneuve Rosemont	Montréal	Quebec
Canada	McGill University Health Centre - Montreal General Hospital	Montréal	Quebec
Canada	Nanaimo Regional General Hospital	Nanaimo	British Columbia
Canada	Royal Columbian Hospital	New Westminster	British Columbia
Canada	North York General Hospital	North York	Ontario
Canada	Ottawa Health Research Institute - OHRI (General and Civic Hospital)	Ottawa	Ontario
Canada	CHU de Québec-Université Laval - Hôpital Enfant-Jésus	Quebec City	Quebec
Canada	Institut Universitaire de cardiologie et de pneumologie de Québec Laval, Quebec	Quebec City	Quebec
Canada	Regina General Hospital	Regina	Saskatchewan
Canada	Saint John Regional Hospital	Saint John	New Brunswick
Canada	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec
Canada	Niagara Health Services - St. Catharine's Hospital	St. Catharines	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St. Joseph's Health Centre, Toronto	Toronto	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Science Center	Toronto	Ontario
Canada	University Health Network - Toronto Western Hospital	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Vancouver Island Health Authority	Victoria	British Columbia
Canada	Windsor Regional Hospital	Windsor	Ontario
Canada	Grace Hospital	Winnipeg	Manitoba
Canada	Health Science Center Winnipeg	Winnipeg	Manitoba
Canada	St. Boniface Hospital	Winnipeg	Manitoba
Kuwait	AL-Amiri Hospital	Kuwait City
Pakistan	Maroof International Hospital	Islamabad
Saudi Arabia	King Abdulaziz Medical Center	Riyadh
United Kingdom	Guys & St. Thomas Hospital	London	New Westminster
United States	University of Nebraska - Nebraska Medical Center	Omaha	Nebraska

Sponsors (5)

Lead Sponsor	Collaborator
McMaster University	Australian and New Zealand Intensive Care Society Clinical Trials Group, Canadian Critical Care Trials Group, Canadian Institutes of Health Research (CIHR), National Health and Medical Research Council, Australia

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Peak serum creatinine concentration in ICU	Peak serum creatinine concentration in ICU	Censored at 90 days after randomisation
Other	Duration of mechanical ventilation (days)	Duration of mechanical ventilation (days)	Censored at 90 days after randomisation
Other	ICU length of stay (days)	ICU length of stay (days)	Censored at 90 days after randomisation
Other	Hospital length of stay (days)	Hospital length of stay (days)	Censored at 90 days after randomisation
Primary	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)
Primary	Primary Safety Outcome: 90 Day Mortality	Mortality status at day 90 post randomization	90 days post randomization
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Rate of all-cause-in-hospital mortality	hospital mortality	While in hospital, censored at 90 days after randomization
Secondary	Rate of ICU mortality	ICU mortality	While in the ICU, censored at 90 days after randomization
Secondary	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