The Peptic randomized clinical trial compared the effects of proton pump inhibitors (PPIs) and histamine-2 receptor blockers (H2RBs) on in-hospital mortality rates among ICU patients requiring invasive mechanical ventilation. Results demonstrated no statistically significant difference in 90-day all-cause mortality between the two medication classes, although PPIs were associated with a lower incidence of clinically significant upper gastrointestinal bleeding. The trial highlights the need for further research to evaluate the necessity of stress ulcer prophylaxis in mechanically ventilated ICU patients.

1. Effect of stress ulcer prophylaxis with proton pump inhibitors vs
histamine-2 receptor blockers on in-hospital mortality among ICU
patients receiving invasive mechanical ventilation
The PEPTIC Randomized Clinical Trial
JAMA. 2020
323(7):616-626
Holden Young, PharmD Candidate 2021
Roseman University of Health Sciences
College of Pharmacy
March 13th, 2020

2. Background
• Proton pump inhibitors (PPIs) and histamine-2 receptor blockers
(H2RBs) are commonly prescribed as stress ulcer prophylaxis for
mechanically ventilated patients in the intensive care unit (ICU).1
• 2014 data estimated 2.5% of adults admitted to ICU developed an
upper gastrointestinal (GI) bleed.2
• 70% received stress ulcer prophylaxis to prevent bleeding2
• High-income countries
• Estimated 2.5 million ICU patients per year are prescribed stress ulcer
prophylaxis5

3. Objective
• Compare mortality rates in mechanically ventilated ICU patients
receiving PPIs or H2RBs for stress ulcer prophylaxis

4. Methods
• Study Design
• Registry-embedded
• Cluster randomized crossover
• Multi-centered
• Multinational
• Open-label, unblinded trial

5. Methods
• 50 ICUs across 5 countries (Australia, Canada, England, Ireland, New
Zealand) were randomized and stratified by region and time period
• Each ICU was randomized into one of two groups:
• PPI group
• H2RBs group
• Each ICU was assigned a treatment approach (PPI or H2RB) for 6
months, then switched to the alternative for the following 6 months
• Prescribers were allowed to use either drug class for any specific
patient if they considered it preferable

6. Methods – Inclusion/Exclusion Criteria
Inclusion Criteria Exclusion Criteria
- Adults (18 year or older)
- Requiring invasive mechanical
ventilation within 24 hours of ICU
admission
- ICU admission diagnosis of upper GI
bleed

7. Outcomes
• Primary: In-hospital all-cause mortality up to 90 days from index ICU
admission
• Secondary: Clinically important upper gastrointestinal bleeding,
Clostridioides difficile infection, Days until discharged alive from the
ICU, days until discharged alive from the hospital
• Tertiary: Hours until removed alive from mechanical ventilation,
ventilator-associated conditions

8. Statistics
• Investigators determined the study would have:
• 80% power at a p-value of 0.05 using a two-tailed test
• To detect an absolute risk reduction of 2.4% for in-hospital mortality
from a baseline mortality of 15%,
• Corresponding to a relative risk reduction of 16% assuming a mean
cluster period size of 310 patients.
• Comparison of treatments are shown as risk ratios (RR) and 95% CI
• Due to potential of type I error, analysis of secondary endpoints
should be considered exploratory

9. Results
• 26,982 patients were randomized, 154 opted out, and 26,828 were analyzed
(PPIs: 13,436 patients, H2RBs: 13,392 patients)
• Baseline characteristics were similar between groups
• Mean age: PPI - 58.6 years | H2RBs - 58.2 years
• Male: PPI - 63.8% | H2RBs - 63.9%,
• Source of admission to ICU
a) Emergency department: PPI - 30% | H2RBs - 30.1%
b) After elective surgery: PPI - 32.4% | H2RBs - 33.3%
• For cardiac surgery patients, 90 day all-cause mortality relative risk (RR) was
1.27 (95% CI, 1.04-1.57).

10. Results
PPIs H2RBs Relative Risk (95% CI) P Value
90 day all-cause
mortality
No./total No. (%)
2459/13415 (18.3) 2333/13356 (17.5) 1.05 (1.00 to 1.10) 0.054
Upper GI bleed
No./total No. (%)
172/13436 (1.3) 239/13392 (1.8) 0.73 (0.57 to 0.92) 0.009

11. Conclusion/Discussion
• 90 day all-cause mortality is not statistically significant between PPI
and H2RBs as stress ulcer prophylaxis
• Clinically significant upper GI bleeding occurred less frequently in
the PPI patient group
• Risk of death in cardiac surgery patients who received PPIs is
statistically significantly higher than those who received H2RBs

12. Strengths
• Use of registries and a cluster crossover design provided a large
patient pool and sufficient power
• Provided generalizable findings
• 50 ICUs across 5 countries
• Prescribers allowed to choose any PPI or H2RB from drug class
and route of administration

13. Weaknesses
• Potential bias due to open-label trial
• Prescribers awareness of assigned treatment
• Prescribers’ ability to change treatment
• Variability in PPIs and H2RBs used
• Importance of primary outcome versus secondary outcome relative
to this trial

14. Clinical Implications
• Findings showed no statistically significant difference in 90 day all-
cause mortality when receiving PPIs or H2RBs
• Further randomized trials should be conducted to:
• Compare stress ulcer prophylaxis (PPIs or H2RBs) versus no stress
ulcer prophylaxis (enteral feeding only)
• Outcomes including upper GI bleed and all-cause mortality
• Provide insight as to whether stress ulcer prophylaxis is necessary
in mechanically-ventilated ICU patients

15. References
1. Young PJ, Bagshaw SM, Forbes AB, et al. Effect of Stress Ulcer Prophylaxis With Proton Pump
Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients
Receiving Invasive Mechanical Ventilation. JAMA. 2020;323(7):616-26.
2. Krag M, Perner A, Wetterslev J, et al. Prevalence and outcome of gastrointestinal bleeding and
use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Medicine.
2015;41(5):833-45.
3. Litton E, Eastwood GM, Bellomo R, et al. A multicentre feasibility study evaluating stress ulcer
prophylaxis using hospital-based registry data. Crit Care Resusc. 2014;16(3):158-63.
4. Eastwood GM, Litton E, Bellomo R, et al. Opinions and practice of stress ulcer prophylaxis in
Australian and New Zealand intensive care units. Crit Care Resusc. 2014;16(3):170-74.
5. Vincent J-L, Marshall JC, Ñamendys-Silva SA, et al. Assessment of the worldwide burden of
critical illness: the Intensive Care Over Nations (ICON) audit. The Lancet Respiratory Medicine.
2014;2(5):380-86.

16. Questions?
Thank you