PEPTIC (Holden Young - Roseman University College of Pharmacy)
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 (PEPTIC).
JAMA . 2020; 323(7):616-626
PEPTIC (Holden Young - Roseman University College of Pharmacy)
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
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.
