In this episode, I’ll discuss the three ongoing trials that will bring clarity to the question of when to use stress ulcer prophylaxis.
Many pharmacists have told me that getting and staying ahead of the vast critical care medical literature is one of our greatest challenges. There are so many journals to scan, let alone articles to read to see where they fit into practice.
That’s one of the reasons I’ve opened Pharmacy Joe’s Critical Care Pharmacy Academy.
Every week in the Academy, I scan the critical care literature and create a ~15 minute digest in video and audio formats of the most important articles. I include my opinion of where the articles fit in clinical practice.
To hear what current members have to say about the Academy, click here.
In episode 134 I discussed the delay in the publication of new ICU stress ulcer prophylaxis guidelines and some of the recent evidence that conflicts with the idea that large numbers of ICU patients require pharmacologic stress ulcer prophylaxis.
The best hope of clearing up the evidence are the completion of high-quality randomized, prospective, placebo-controlled trials.
Fortunately, 3 such trials are underway.
Enteral Nutrition as Stress Ulcer Prophylaxis in Critically Ill Patients
This is a two center randomized double blind, placebo-controlled trial at University of Louisville Hospital and Jewish Hospital
Sponsor: Abbott nutrition
Principle Investigator: Mohamed Saad
Purpose
The purpose of the study is to determine if proton pump inhibitors plus enteral nutrition is superior to enteral nutrition (EN) alone as a stress ulcer prophylaxis strategy in critically ill patients in terms of incidence of overt and significant GI bleeding related to stress gastropathy.
Notable inclusion criteria
- Expected need for mechanical ventilation > 48 hours
- No contraindication to EN within the first 24 hours after admission to the ICU
- Age 18 or greater
Notable exclusion criteria
- Evidence of active GI bleeding during current hospitalization prior to study entry
- Admission to ICU with primary diagnosis of burn injury
- Closed head injury or increased intracranial pressure
Intervention
Pantoprazole 40mg IV daily and tube feed vs. placebo and tube feed.
Estimated study completion date
October 2017
Primary outcome measures
- GI bleeding
- Incidence of overt GI bleeding (as defined by the presence of coffee ground emesis, hematemesis of bright red blood, melena, or hematochezia) seen with Proton Pump Inhibitor (PPI) and EN versus EN alone in critically ill patients
- Incidence of significant GI bleeding, defined by a 3-point decrease in hematocrit within 24 hours accompanied by signs of overt GI bleeding, or by an unexplained 6-point decrease in hematocrit during any 48 hour period
Secondary outcome measures
- Cost to the pharmacy for care related to stress ulcer prophylaxis and treatment of GI bleeding
- Incidence of ICU-acquired C. Difficile pseudomembranous colitis
- Cost to the pharmacy for care related to stress ulcer prophylaxis and treatment of GI bleeding (overt or significant) for patients receiving a PPI agent plus EN versus patients placed on EN alone
Anticipated clinical answer
This study should answer whether SUP needs to be given to critically ill patients who are receiving tube feeds. If no benefit to stress ulcer prophylaxis is found, the results of this study would be broadly generalizable to the large subpopulation of ICU patients that can tolerate tube feeds. This would also be a confirmatory study for the pop-up trial published October 2016 in Critical Care Medicine that I discussed in episode 134.
From a safety perspective, the study has only pre-specified ICU-acquired C. difficile as a relevant endpoint. It would be nice to also know the incidence of ICU-acquired pneumonia, but this will be an ad hoc analysis at this point.
Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU)
Principle investigator and sponsor: Morten Hylander Møller
The trial is multi-center randomized double blind, placebo-controlled.
Purpose
…to asses the overall benefits and harms of SUP with proton pump inhibitor in adult critically ill patients in the ICU.
Notable inclusion criteria
- One or more of the following risk factors:
- Shock (continuous infusion with vasopressors or inotropes, systolic blood pressure < 90 mmHg, mean arterial blood pressure < 70 mmHg or lactate > 4 mmol/l)
- Acute or chronic intermittent or continuous renal replacement therapy
- Invasive mechanical ventilation which is expected to last > 24 hours
- Coagulopathy (platelets < 50 x 10^9/l or international normalized ratio (INR) > 1.5 or prothrombin time (PT) > 20 seconds) documented within the last 24 hours
- Ongoing treatment with anticoagulant drugs (prophylaxis doses excluded)
- History of coagulopathy (platelets < 50 x 10^9/l or INR > 1.5 or PT > 20 seconds) within 6 months prior to hospital admission
- History of chronic liver disease (portal hypertension, cirrhosis proven by biopsy, computed tomography (CT) scan or ultrasound, history of variceal bleeding or hepatic encephalopathy in the past medical history)
Notable exclusion criteria
There are no notable exclusion criteria.
Intervention
Pantoprazole 40 mg IV daily vs. placebo
Estimated study completion date
August 2018
Primary outcome measures
- 90-day mortality
Secondary outcome measures
- Proportion of patients with clinically important GI bleeding, pneumonia, clostridium difficile infection or acute myocardial ischemia
- Proportion of patients with clinically important GI bleeding
- Proportion of patients with one or more infectious adverse events
- 1-year mortality
Anticipated clinical answer
This trial is anticipated to enroll over 3000 patients. If successful, it should provide a definitive answer on the benefits and risks of pantoprazole in preventing ICU stress ulcers. The alignment of the inclusion criteria to currently accepted risk factors for stress ulcer development is an excellent real-world study design. It is unfortunate that a second arm using famotidine is not included, but this is understandable given the increase in trial size that would be required.
Pre-specified subgroup analysis of the SUP-ICU trial data.
Principle Investigator: Jörg Schefold
Sponsor: University Hospital Inselspital, Berne Switzerland
Purpose
In the current prospective subanalysis “SIREN” of the randomized placebo-controlled clinical trial “SUP-ICU” (NCT02467621), the investigators seek to elucidate whether the subpopulation of critically ill patients with dialysis-dependent acute renal failure benefits from prophylactic treatment with a proton-pump-inhibitor such as pantoprazole.
Notable inclusion criteria
- Patients in the SUP-ICU trial data that also receive renal replacement therapy (RRT)
Notable exclusion criteria
- There are no notable exclusion criteria.
Intervention
Pantoprazole 40 mg IV daily vs. placebo
Estimated study completion date
December 2017
Primary Outcome measures
- Total number of patients with clinically important gastrointestinal (GI)-bleeding episodes undergoing RRT therapy within the first 3 days following ICU admission (“RRT group”) vs. in patients without need for RRT during ICU stay (“control group”).
Secondary outcome measures
- Number of patients receiving interventions to stop GI-bleeding
- Number of GI bleeding events
- Number of units of red blood cells (RBC) transfused
- Onset of pneumonia during ICU stay
- Days on treatment of Clostridium difficile enteritis
- ICU length of stay
- 90-day/360-day/ ICU mortality rate
Anticipated clinical answer
One of the highest risk ICU populations for stress ulcer prophylaxis is patients who undergo renal replacement therapy. Focusing prospectively on this subgroup will provide additional clarity on the exact benefits and risks of stress ulcer prophylaxis for this subgroup.
Expect 2018 to be a big year for stress ulcer prophylaxis data publication!
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