Re-EValuating the Inhibition of Stress Erosions (REVISE) - COVID-19 Cohort Study

Study Overview
=================
Brief Summary
-----------------
Commonly employed medications used in critically ill patients requiring life support include proton pump inhibitors (PPIs). These medications are thought to prevent gastrointestinal (GI) bleeding from stress-induced ulceration. Despite their widespread use, they do hold some risks which include infection in the form of pneumonia and diarrheal illnesses such as Clostridioides difficile infection (C. difficile). Emerging high-quality studies suggest PPI usage does not influence susceptibility to COVID-19 infection, however some studies suggest PPI use leads to poor outcomes in this population, including prolonged time on life-support and death. While we can appreciate the negative effects of PPI may be magnified in the sickest of patients, namely hospitalized patients with COVID-19, the beneficial or potentially harmful role they play in this population remains unclear. We aim to build a clinical profile to further describe critically ill patients with COVID-19 in Ontario using the infrastructure of an ongoing multicenter clinical trial of acid suppression. We will identify characteristics that predict poor outcomes among sick COVID patients, examining the impact of PPIs on this population.

Detailed Description
-----------------
The overall aims are to further characterize the high-risk population of COVID-19 patients nested within the multicenter REVISE trial. Specifically, we plan 1) to explore the impact of PPIs on mechanically ventilated critically ill COVID-19 patients, 2) describe the clinical course for patients with COVID-19 and identify characteristics that predict poor prognosis, and 3) compare outcomes to patients without COVID-19. The overall research questions are as follows: Do critically ill patients projected to receive mechanical ventilation for >48 hours with COVID-19 have different clinical outcomes without PPIs? Are there prognostically relevant demographic, biomarker and clinical data to characterize critically ill patients with COVID-19? Do critically ill patients with COVID-19 have significant higher rates of clinically important GI bleeding, 90-day mortality, and rates of infection when compared to a propensity-matched non-COVID REVISE cohort? To accomplish this, the investigators propose to gather information in patients' medical charts including biomarkers drawn by the ICU team, venous thromboembolism (VTE) and tracheostomy timing, to link with extensive baseline characteristics and outcomes already collected in the REVISE trial (NCT03374800)

Official Title
-----------------
Re-EValuating the Inhibition of Stress Erosions (REVISE) - COVID-19 Cohort Study

Conditions
-----------------
COVID-19, GastroIntestinal Bleeding

Intervention / Treatment
-----------------
* Other: Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial (NCT03374800)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ≥18 years old projected to receive invasive mechanical ventilation for ≥48 hours according to the treating physician Exclusion Criteria: Already received invasive mechanical ventilation >72 hours during this hospital admission Acid suppression for active gastrointestinal bleeding or high risk of bleeding (e.g., current bleeding, peptic ulcer bleeding within 8 weeks, recent severe esophagitis, Barrett's esophagus, Zollinger-Ellison syndrome); [dyspepsia or gastroesophageal reflux is not an exclusion criterion] Acid suppression in the intensive care unit for >1 daily dose equivalent of a proton pump inhibitor or histamine-2-receptor antagonist Dual antiplatelet therapy Combined antiplatelet and therapeutic anticoagulation Pantoprazole contraindication per local product information Palliative care or anticipated withdrawal of advanced life support Pregnancy Previous enrolment in REVISE, or a related trial, or trial for which co-enrolment is prohibited Patient, proxy or physician declines

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with COVID-19<br> | Other: Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial (NCT03374800)<br>* Following the intervention of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial (NCT03374800)<br>|
| Patients without COVID-19<br> | Other: Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial (NCT03374800)<br>* Following the intervention of the Re-EValuating the Inhibition of Stress Erosions (REVISE) Trial (NCT03374800)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinically important gastro-intestinal bleeding | The primary efficacy outcome is clinically important GI bleeding occurring in the ICU or resulting in ICU readmission during the index hospital stay. The definition of clinically important GI bleeding is overt GI bleeding (i.e., hematemesis, frank blood or coffee ground nasogastric aspirate, melena or hematochezia) plus 1 of the following in the absence of other causes: Hemodynamic change defined as a spontaneous decrease in invasively monitored mean arterial pressure or non-invasive systolic or diastolic blood pressure of >20 mmHg, 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; hemoglobin decrease of >2 g/dl (20 g/L) within 24 h of bleeding; transfusion of >2 units red blood cells within 24 h of bleeding; or therapeutic intervention (e.g., therapeutic endoscopy, angiography, surgery). | 90 days | 
| Primary Safety Outcome: 90 Day Mortality | Mortality status at day 90 post randomization | 90 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-associated pneumonia | VAP is diagnosed in patients who received invasive mechanical ventilation for >48 hours when there is a new, progressive or persistent radiographic infiltrate plus at least 2 of the following without other obvious cause: 1) fever (temperature>38 °C) or hypothermia (temperature <36 °C); 2) leukopenia (<4.0x106/L) or leukocytosis (>12x106/L); 3) purulent sputum; or 4) gas exchange deterioration. | 90 Days (while in ICU,censored at 90 days after randomization) | 
| C. difficile infection | Defined as clinical features (diarrhea [>3 episodes of unformed stools or Bristol type 6 or 7), ileus, or toxic megacolon) and either microbiological evidence of toxin-producing C. difficile or pseudomembranous colitis on colonoscopy in hospital. | 90 days (during the index hospital admission, censored at 90 days) | 
| Renal replacement therapy | Defined as initiation of new renal replacement therapy in the ICU. | While in ICU,censored at 90 days after randomization | 
| Hospital mortality | Defined as all-cause mortality in hospital. | While in hospital, censored at 90 days after randomization | 
| Patient important GI bleeding | Defined as overt GI bleeding, plus an invasive intervention (e.g., therapeutic endoscopy, angiography, surgery), acknowledging how some clinically important GI bleeds in prior studies did not actually require any tests or treatments, and thus may not be important to patients. This outcome will be refined by an ongoing mixed methods study with an overarching instrument-building aim. | Censored at 90 days after randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, pandemic, gastrointestinal bleeding, pneumonia, Clostridioides difficile