By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Adult Critical Care, Rush University Medical Center, Chicago

Dr. Hammond reports no financial relationships relevant to this field of study.

SYNOPSIS: Proton pump inhibitors reduce the risk of clinically important bleeding, but they may have no effect on the risk of 90-day mortality compared to histamine-2 receptor antagonists.

SOURCE: 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 ventilation: The PEPTIC Randomized Clinical Trial. JAMA 2020;323:616-626.

During the past 25 years, improved supportive care measures have reduced the risk of critically ill patients developing stress-related mucosal bleeding.1 Nevertheless, most of these patients are prescribed a proton pump inhibitor (PPI) or a histamine-2 receptor antagonist (H2RA) to reduce the risk of bleeding and ostensibly the risk of mortality.2 Although much of the data evaluating the safety and efficacy of these prophylactic agents compares each to placebo, a recent network meta-analysis suggested PPIs may reduce the development of clinically important upper gastrointestinal bleeding (GIB) vs. H2RAs, but this benefit did not translate into improved mortality.1 The PEPTIC trial was conducted to compare the risk of all-cause mortality during index hospitalization up to 90 days between PPIs and H2RAs.3

The PEPTIC investigators conducted an international, open-label, cluster crossover, registry-embedded, randomized clinical trial of 26,982 critically ill adults requiring at least one day of mechanical ventilation.3 Each study hospital was randomized to a standard approach for stress ulcer prophylaxis with either PPI or H2RA therapy for six months and then crossed over to the other therapy during its second six-month block. However, clinicians could preferentially provide PPI or H2RA therapy to an individual patient outside of the assigned strategy as desired, which occurred in 4.1% of patients in the PPI group and 20.1% of patients in the H2RA group.

The rate of 90-day in-hospital all-cause mortality approached significance but was similar between the PPI and H2RA groups (18.3% vs. 17.5%, risk ratio [RR] 1.05; 95% confidence interval [CI], 1.00-1.10; absolute risk difference [ARD] 0.93%, 95% CI, -0.01% to 1.88%, P = 0.054). This outcome remained fairly consistent in multiple sensitivity analyses, with P values ranging from 0.03-0.10. However, patients randomized to the PPI group experienced clinically significant GIB less frequently (1.3% vs. 1.8%, RR 0.73; 95% CI, 0.57-0.92; ARD -0.51%, 95% CI, -0.90% to -0.12%, P = 0.009).

Other outcomes, such as intensive care unit length of stay, duration of mechanical ventilation, and Clostridioides difficile infection, were similar between groups. Patients who had cardiac surgery and were in the PPI group more frequently expired (RR 1.27, 95% CI, 1.04-1.57). Additionally, patients with the highest severity of illness who were randomized to PPI had an increased risk of mortality (P = 0.004).

COMMENTARY

Although PPIs may prevent five fewer clinically significant GIB events per 1,000 patients compared to H2RAs, less than half of these patients appear to require an esophagogastroduodenoscopy. This benefit did not translate into improved mortality or differences in lengths of stay. This may have occurred because of potential deleterious effects from PPIs, including immunosuppressive effects such as inhibition of neutrophil chemotaxis and natural killer cell activity, and/or improved supportive care for clinically important GIBs.4,5 Additionally, PPIs are more effective at elevating and sustaining a raised gastric pH, which predisposes patients to pneumonia development from Gram-negative bacilli.6 Although the duration of mechanical ventilation was similar between groups, and pneumonia rates were not reported, previous literature has suggested a greater risk of pneumonia development with PPIs compared to H2RAs.1

The potential risks and benefits must be weighed by each clinician, and the individual patient’s risk of clinically important GIB, as well as severity of illness, must be considered. Patients who are not at an exceedingly high risk of developing clinically important GIB may not experience the potential benefit with PPI as opposed to H2RA therapy. This appears to be particularly relevant in the cardiac surgery and extremely ill cohorts, since both of these subpopulations experienced increased mortality with PPI vs. H2RA therapy. Until the post hoc analyses are published, including a per protocol evaluation of the trial, it appears that a conservative plan with H2RA for mechanically ventilated, critically ill adults is the safest strategy at this time.

REFERENCES

  1. Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: A network meta-analysis of randomized trials. Intensive Care Med 2018;44:1-11.
  2. Krag M, Perner A, Wetterslev J, et al; SUP-ICU coauthors. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med 2015;41:833-845.
  3. 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, Young PJ, Bagshaw SM, 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: The PEPTIC randomized clinical trial. JAMA 2020;10.1001/jama.2019.22190. [Online ahead of print].
  4. Aybay C, Imir T, Okur H. The effect of omeprazole on human natural killer cell activity. Gen Pharmacol 1995;26:1413-1418.
  5. Capodicasa E, De Bellis F, Pelli MA. Effect of lansoprazole on human leukocyte function. Immunopharmacol Immunotoxicol 1999;21:357-377.
  6. Bateman BT, Bykov K, Choudhry NK, et al. Type of stress ulcer prophylaxis and risk of nosocomial pneumonia in cardiac surgical patients: Cohort study. BMJ 2013;347:f5416.