REVISE is a global Canadian-led randomized clinical trial [NCT03374800] conducted by the Canadian Critical Care Trials Group, an ACT Partner. The Global Principal Investigator (Dr. D Cook) and Canadian Principal Investigator (Dr. G Guyatt) are Canadian. The Global Methods Center is in Hamilton, Canada. Randomization is ongoing. As of March 29, 2023, 3,992 of 4,800 patients have been recruited in 63 international centers; 808 patients remain to enrol. The manuscript submission is anticipated in September 2024.
Structured Abstract Summary
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 patients in the intensive care unit (ICU) [1]. Proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists (H2RAs). Observational studies and our recent networkmeta-analysis suggest that PPIs may increase the risk of ventilator-associated pneumonia (VAP) and Clostridioides difficile infection (CDI) [2,3]. Moreover, a recent large trial raised concerns about an increased risk of death associated with pantoprazole in the most severely ill patients [4]. Although in this trial GI bleeding events were less frequent in the pantoprazole group, the bleeds may not have been patient-important, and investigators identified no other benefits. Moreover, a cluster-crossover trial of 26,771 patients evaluating PPIs versus H2RAs also suggested an increased risk of death in the most severely ill patients receiving PPIs, raising further misgivings about PPIs in the ICU setting [5]. Given that the widespread use of PPIs may not be in the best interest of critically ill patients, successfully completing the REVISE trial is crucial from a clinical, ethical and policy perspective.
Objectives: To determine, in 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 patient-important GI bleeding, VAP and CDI, treatment with renal replacement therapy and hospital mortality. Tertiary outcomes are red blood cell transfusions, serum creatinine, duration of mechanical ventilation, duration of ICU stay and duration of hospital stay.
Methods: REVISE is a high-impact global randomized trial of 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, intent to withdraw advanced life support or hopeless prognosis, and previous enrolment in this or a confounding trial. The protocol allows either a priori informed consent or informed consent to continue with study drug. Patients are randomized in a fixed 1:1 allocation, stratified by center and whether or not they were using acid suppression prior to hospitalization. Stratification by pre-hospital acid suppression will allow evaluation of possible rebound gastric acid hypersecretion upon acid suppression termination [6] and possible microbiome and infection risk modification by long-term acid suppression [7]. Study Pharmacists obtain concealed allocation from a password-protected website; all researchers and clinicians, patients and families are blinded. With a priori or deferred consent, patients are randomized to pantoprazole 40 mg or placebo intravenously daily while in ICU up to 90days or until successful discontinuation of mechanical ventilation for >48 hours; development of clinically important GI bleeding; or 3) death in ICU.
International Collaboration: REVISE is conducted under the auspices of the International Forum for Acute Care Trialists in collaboration with the Canadian Critical Care Trials Group [www.ccctg.ca], the Australian and New Zealand Critical Care Trials Group [www.anzicsctg.com].
