Clinical trial NCT03374800: Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial
Official title: Re-EValuating the Inhibition of Stress Erosions: Prophylaxis Against Gastrointestinal Bleeding in the Critically Ill (The REVISE) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gastrointestinal Hemorrhage (Clinically Important, Upper)
Lead sponsor: McMaster University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Canadian Critical Care Trials Group
name: Australian and New Zealand Intensive Care Society Clinical Trials Group
name: National Health and Medical Research Council, Australia
First posted: 2017-12-15
Enrollment: 4800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A prospective, international, multicentre, parallel group, concealed, blinded, randomized trial in critically ill invasively mechanically ventilated adults
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Rate of clinically important upper gastro-intestinal bleeding
timeFrame: 90 days (In ICU or resulting in ICU readmission, censored at 90 days after randomization)
measure: Primary Safety Outcome: 90 Day Mortality
timeFrame: 90 days post randomization
Secondary outcomes:
measure: Rate of ventilator associated pneumonia (VAP) in ICU
timeFrame: 90 Days (while in ICU,censored at 90 days after randomization)
measure: Rate of Clostridioides difficile associated infection
timeFrame: 90 days (during the index hospital admission, censored at 90 days)
measure: New initiation of treatment with renal replacement therapy in ICU
timeFrame: 90 Days (In the ICU, censored at 90 days)
measure: Rate of all-cause-in-hospital mortality
timeFrame: While in hospital, censored at 90 days after randomization
measure: Rate of ICU mortality
timeFrame: While in the ICU, censored at 90 days after randomization
measure: Rate of patient important upper GI bleeding in ICU or resulting in ICU readmission, censored at 90 days after randomization
timeFrame: Censored at 90 days after randomization
Other outcomes:
measure: Total units of red blood cells transfused in the first 14 days of ICU stay
timeFrame: Censored at 14 days after randomization
measure: Peak serum creatinine concentration in ICU
timeFrame: Censored at 90 days after randomisation
measure: Duration of mechanical ventilation (days)
timeFrame: Censored at 90 days after randomisation
measure: ICU length of stay (days)
timeFrame: Censored at 90 days after randomisation
measure: Hospital length of stay (days)
timeFrame: Censored at 90 days after randomisation
Locations:
city: Omaha
country: United States
facility: University of Nebraska - Nebraska Medical Center
state: Nebraska
city: Bankstown
country: Australia
facility: Bankstown-Lidcombe Hospital
state: New South Wales
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Caringbah
country: Australia
facility: Sutherland Hospital
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane Womens Hospital
state: Queensland
city: Ipswich
country: Australia
facility: Ipswich Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bendigo
country: Australia
facility: Bendigo Health
state: Victoria
city: Geelong
country: Australia
facility: Geelong University Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Epworth Hospital
state: Victoria
city: Campina Grande Do Sul
country: Brazil
facility: Sociedade Hospitalar Angelina Caron
city: Governador Valadares
country: Brazil
facility: Beneficência Social Bom Samaritano
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Calgary
country: Canada
facility: Peter Lougheed Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Nanaimo
country: Canada
facility: Nanaimo Regional General Hospital
state: British Columbia
city: New Westminster
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: Health Science Center Winnipeg
state: Manitoba
city: Winnipeg
country: Canada
facility: Grace Hospital
state: Manitoba
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
state: Nova Scotia
city: Brampton
country: Canada
facility: William Osler Hospital, McKenzie Health, Brampton Civic Hospital
state: Ontario
city: Brantford
country: Canada
facility: Brantford General Hospital
state: Ontario
city: Cambridge
country: Canada
facility: Cambridge Memorial Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Center - General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Science Center - Juravinski Hospital
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Kitchener
country: Canada
facility: Grand River Hospital
state: Ontario
city: London
country: Canada
facility: London Health Science Center (LHSC) - University Hospital
state: Ontario
city: London
country: Canada
facility: London Health Science Center (LHSC) - Victoria Hospital
state: Ontario
city: North York
country: Canada
facility: North York General Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - OHRI (General and Civic Hospital)
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health Services - St. Catharine's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Science Center
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto Western Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre, Toronto
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital
state: Ontario
city: Lévis
country: Canada
facility: Centre de recherche de l'Hôtel-Dieu de Lévis
state: Quebec
city: Montréal
country: Canada
facility: Hôpital Maisonneuve Rosemont
state: Quebec
city: Montréal
country: Canada
facility: Center Hospital University Montreal (CHUM)
state: Quebec
city: Montréal
country: Canada
facility: Centre Universitaire de Santé McGill / McGill University Health Centre
state: Quebec
city: Montréal
country: Canada
facility: CIUSS du Nord de l'île de Montréal - Hôpital du Sacré-Cœur de Montréal
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre - Montreal General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Québec-Université Laval - Hôpital Enfant-Jésus
state: Quebec
city: Quebec City
country: Canada
facility: Institut Universitaire de cardiologie et de pneumologie de Québec Laval, Quebec
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Regina General Hospital
state: Saskatchewan
city: Kuwait City
country: Kuwait
facility: AL-Amiri Hospital
city: Islamabad
country: Pakistan
facility: Maroof International Hospital
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical Center
city: London
country: United Kingdom
facility: Guys & St. Thomas Hospital
state: New Westminster
Study officials:
affiliation: McMaster University
name: Deborah Cook, MD
role: PRINCIPAL_INVESTIGATOR
References: