Dr. Paul Young

Risks and Benefits of Proton Pump Inhibitors To Prevent GI Bleeds in Intensive Care Patients

MedicalResearch.com Interview with:

Dr. Paul Young

Dr. Paul Young

Dr. Paul Young MBChB, BSc (Hons), FCICM
Medical Director of the Wakefield Hospital ICU
Head of the Intensive Care Research Unit
Wellington Hospital

MedicalResearch.com: What is the background for this study?

Response: Proton pump inhibitors (PPIs) are among the most widely prescribed drugs in the intensive care unit (ICU) in the world.   Many, if not most, prescriptions of PPIs in the ICU are for stress ulcer prophylaxis.  Although PPIs are used most widely for this indication, histamine-2 receptor blockers (H2RBs) are used in preference to PPIs in some ICUs.  This practice variation, which appears to be largely dependent on clinician preference rather than based on patient-specific factors, has continued for decades.  The PPIs vs. H2RBs for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial results raise the possibility that PPIs, the most commonly used medicines for stress ulcer prophylaxis, may be responsible for a clinically important increase in the risk of death that, in global health terms could equate to many tens of 1000s of deaths per year.

MedicalResearch.com: What are the main findings? 

Response: The PEPTIC trial was an international, randomised, open-label, cluster crossover, registry-embedded trial which compared strategies of stress ulcer prophylaxis in mechanically ventilated adults implemented at the level of the ICU.  One approach was to use PPIs as the default treatment and the other was to use H2RBs as the default treatment when stress ulcer prophylaxis was prescribed.  Irrespective of the treatment being implemented in the ICU, clinicians could use either a PPI or an H2RB for individual patients where they considered this indicated.  The primary outcome was in-hospital all-cause mortality up to 90 days.

The rate of clinically important upper GI bleeding was a key secondary end point.  With 26 828 participants, the PEPTIC trial is the largest clinical trial ever conducted in intensive care medicine.  For the first time, we now have clinically-directive data on the comparative efficacy and safety of using these classes of drugs for stress ulcer prophylaxis in the ICU.  A total of 18.3% of patients admitted to the ICU when PPIs were used as the default stress ulcer prophylaxis and 17.5% of patients admitted when H2RBs were used died in hospital by day 90 (risk ratio; 1.05 95% CI 1.00 to 1.10; P=0.05).  In other words the data are consistent with an effect that from no effect to a 10% relative increase in mortality using PPIs instead of H2RBS.  On the other hand, for every 1000 mechanically ventilated patients admitted when PPIs were the default stress ulcer prophylaxis, five fewer patients had a clinically significant upper GI bleed compared to when H2RBs were the default.

MedicalResearch.com: What should readers take away from your report?

Response: Weighing a potential increased risk of death with PPIs against what is essentially, on the basis of the entirety of the evidence, an unequivocal reduction in the risk of clinically significant upper GI bleeding is not simple and clinicians will not necessarily all come to the same conclusion about how to do this.  However, the PEPTIC study suggests that the number needed to treat with a default PPI strategy to prevent clinically significant upper GI bleeding compared to a default H2RB strategy is 200.

My view is that mortality is the most important outcome and, although there is still uncertainty about whether PPIs do in fact increase mortality risk, most patients would rather not be exposed to a therapy that might kill them in order to have a 1 in 200 chance of being prevented from having an upper GI bleed that probably will not be fatal.  

MedicalResearch.com: What recommendations do you have for future research as a result of this work? 

Response: The PEPTIC trial is so large that the opportunities to undertake exploratory analyses to evaluate the role of stress ulcer prophylaxis is various important clinical subgroups is unprecedented.  There are many interesting subgroups where is it plausible that the risks and benefits of PPIs vs. H2RBs may vary.  These include patients with traumatic injuries, sepsis, and coagulopathy.  We plan to evaluate such subgroups in the near future.

I have no disclosures.


The PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group. Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical VentilationThe PEPTIC Randomized Clinical TrialJAMA. Published online January 17, 2020. doi:10.1001/jama.2019.22190


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Last Updated on January 17, 2020 by Marie Benz MD FAAD