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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    4800
  • sponsor
    McMaster University
Updated on 24 January 2021
resuscitation

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 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 (clostridium 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 (Clostridium 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 mechanically ventilated critically ill patients. Worldwide, proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists. Pantoprazole is the dominant PPI prescribed in the ICU. However, recent observational studies and a recent network meta-analysis suggest that PPIs increase the risk of ventilator-associated pneumonia (VAP) and Clostridium difficile infection (CDI). Further, the incidence of bleeding from stress ulceration appears to be lower than in the past, perhaps related to earlier resuscitation and enteral nutrition. Given the apparent decline in GI bleeding, and concern about infectious complications, a large randomized trial is needed to test the efficacy and safety of withholding PPIs in the ICU. We successfully 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 establishing the feasibility of a larger trial.

Objectives of the REVISE Trial: To determine, among mechanically ventilated patients, the effect of withholding (placebo) vs administering (active study drug) pantoprazole on clinically important upper GI bleeding, VAP, CDI, acute kidney injury, and mortality.

Methods: We will include 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 60 days. Patients will receive the trial intervention from the first administration until 60 days or: 1) successful discontinuation of mechanical ventilation for >48 hours; 2) development of clinically important GI bleeding, or 3) death in ICU. Analyses will be by intention-to-treat and per protocol. The sample size is based on the logic of a non-inferiority trial; if the absolute increase in bleeding as a result of withholding pantoprazole is sufficiently low (in this case, 1.5% or less), we will conclude that withholding a PPI is non-inferior to administering a PPI. This non-inferiority threshold was selected on the basis that avoiding the risk of VAP and CDI with pantoprazole would warrant accepting an absolute increase in bleeding of up to 1.5%. REVISE will enrol 4,800 patients, conducted in collaboration with the Canadian Critical Care Trials Group, the Australian and New Zealand Intensive Care Society Critical Care Trials Group, other consortia and collaborators under the auspices of the International Forum for Acute Care Trialists.

Ethical Imperative: Many factors converge to underscore the ethical imperative for this trial: critical care has evolved, epidemiology may have changed, the risk:benefit and cost:benefit ratios of prophylaxis have shifted, and our research standards have improved. Thus, stress ulcer prophylaxis may need to be REVISED.

Relevance: Most mechanically ventilated patients around the world receive daily stress ulcer prophylaxis, although international variation exists such that some centers do not use any. Many of the RCTs of stress ulcer prophylaxis were conducted 10-30 years ago, several are at moderate or high risk of bias, and cointerventions in those trials do not reflect current ancillary critical care management. 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. The apparent decline in the incidence of upper GI bleeding, and doubts about the effectiveness and safety of PPIs, demand re- examining 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.

Details
Condition Hemorrhage, Gastrointestinal Hemorrhage, GASTROINTESTINAL DISORDER, Gastrointestinal Diseases and Disorders, gastrointestinal bleeding, gi bleeding, gi hemorrhage
Treatment Pantoprazole, Placebo (0.9% saline)
Clinical Study IdentifierNCT03374800
SponsorMcMaster University
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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

Exclusion Criteria

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)
Canada
being treated with rilpivirine or atazanavir 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
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