PPI, H2RB as stress ulcer prophylaxis in ICU yield similar mortality rate

The choice of stress ulcer prophylaxis strategy – proton pump inhibitor (PPI) or histamine-2 receptor blocker (H₂RB) – did not affect mortality within 90 days of admission to the intensive care unit (ICU), according to results of the PEPTIC* trial presented at the recent Critical Care Reviews Meeting (CCR20).

“Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of PPIs vs H₂RBs resulted in [a difference in] hospital mortality rates … that did not reach the significance threshold,” said the researchers.

Fifty ICUs in five countries participated in the trial; twenty-five were randomized to use a PPI stress ulcer prophylaxis strategy for 6 months then switch to a H₂RB strategy for 6 months, and the other 25 vice-versa. Participants were 26,828 adults who required invasive mechanical ventilation within 24 hours of ICU admission (mean age 58 years, 36.1 percent female). Median exposure to prophylaxis was 2.8 and 2.7 days in the PPI and H₂RB groups, respectively.

The in-hospital all-cause mortality rate within 90 days of the index hospitalization did not significantly differ between patients who were assigned to the PPI and H₂RB groups (18.3 percent vs 17.5 percent; risk ratio [RR], 1.05, 95 percent confidence interval [CI], 1.00–1.10, absolute risk difference, 0.93 percentage points; p=0.054). [JAMA 2020;doi:10.1001/jama.2019.22190]

There was a lower incidence of clinically important upper gastrointestinal (GI) bleeding in the PPI vs the H₂RB group (1.3 percent vs 1.8 percent; RR, 0.73, 95 percent CI, 0.57–0.92, absolute risk difference, -0.51 percentage points; p=0.009).

However, the researchers suggested that the potential use of PPIs prior to ICU admission with rebound acid secretion occurring upon switching to H₂RBs may have resulted in a higher risk of upper GI bleeding in the H₂RB group. Additionally, some patients may have already had upper GI bleeding at ICU admission.

The incidence of new-onset Clostridioides difficile infection in the ICU did not significantly differ between patients in the PPI and H₂RB groups (0.30 percent vs 0.43 percent; RR, 0.74, absolute risk difference, -0.11 percentage points; p=0.13), nor did duration of hospitalization or ICU stay.

In a post hoc analysis, greater illness severity was associated with a higher in-hospital mortality risk in the PPI than the H₂RB group.

Preferred strategy remains unclear

The researchers recommended caution when interpreting the results as crossover use of medication may have influenced the findings. In the PPI group, an estimated 4.1 percent of patients received H₂RBs, while an estimated 20.1 percent of patients in the H₂RB group received PPIs.

With physician preference taken into account regardless of randomized therapy, the researchers suggested that physicians who chose to use PPIs in the H₂RB group may have done so due to “expected benefit” from the former option. The use of the alternative strategy as opposed to the randomized one may have attenuated the results, they said.

“If patients at greatest risk of benefit or harm from one strategy had the recommended approach overridden in such a way that they all ended up receiving the same drug, any signal of either benefit or harm of the drug would be attenuated,” pointed out Associate Professor Todd Rice and colleagues from the Vanderbilt University Medical Center, Nashville, Tennessee, US, in an editorial. [JAMA 2020;doi:10.1001/jama.2019.22436]

“[The results] preclude the possibility of benefit of recommending PPIs as the default stress ulcer prophylaxis strategy for reducing mortality,” they added.

The editorialists also noted that the use of a pragmatic effectiveness trial such as this one may have “introduced complexity in the understanding of the drug effects of PPIs vs H₂RBs, as opposed to the understanding of the effects of deploying a strategy of recommending one drug instead of the other.”

“[T]he large pragmatic open-label cluster crossover design with incomplete data on which patients in the trial received which drug confounds interpretation of the results and leaves the clinician unsure of the best way to optimize benefit and avoid harm when deciding on stress ulcer prophylaxis for individual critically ill patients,” they said.