Mortality with two stress ulcer prophylaxis treatments did not differ in critically ill patients

Among critically ill patients requiring mechanical ventilation, 90-day in-hospital mortality rates did not differ significantly between those who received proton pump inhibitors and those who received histamine-2 receptor blockers for stress ulcer prophylaxis, new data published in JAMA indicate.

Proton pump inhibitors (PPIs) are associated with various immunosuppressive effects that could lead to an increased risk for death from infections that commonly occur in the ICU, such as nosocomial pneumonia or Clostridioides difficile, according to the researchers.

“The relative effect of different classes of stress ulcer prophylaxis drugs on mortality rates is unknown because adequately powered clinical trials including patients in the ICU and comparing proton pump inhibitors and histamine-2 receptor blockers have not been performed,” they wrote.

To learn more, the researchers conducted the international, open-label, cluster crossover, registry-embedded randomized PEPTIC trial comparing preferential use with PPIs vs. histamine-2 receptor blockers for stress ulcer prophylaxis. Each prophylaxis strategy was used for 6 months before switching to the other strategy for 6 months.

The study was conducted at 50 ICUs in five countries from 2016 to 2019. A total of 26,771 critically ill adults requiring mechanical ventilation were included in the analysis.

No significant mortality difference

Of those included in the mortality analysis, 18.3% assigned the PPI strategy died in the hospital by 90 days and 17.5% assigned histamine-2 receptor blockers died in the hospital by 90 days, yielding a nonsignificant 0.93 percentage point difference in absolute risk (RR = 1.05; 95% CI, 1-1.1).

However, clinically important upper gastrointestinal bleeding occurred in fewer patients in the PPI group vs. the histamine-2 receptor blocker group (1.3% vs. 1.8%; RR = 0.73; 95% CI, 0.57-0.92; absolute risk difference, –0.51 percentage points; 95% CI, –0.9 to –0.12).

No significant differences were noted in C. difficile infection and ICU or hospital lengths of stay.

Importantly, the researchers noted that an estimated 4.1% of patients assigned PPIs actually received histamine-2 receptor blockers, and an estimated 20.1% of those assigned histamine-2 receptor blockers actually received PPIs.

Cautious interpretation

In an accompanying editorial, Todd W. Rice, MD, MSc, from the division of allergy, pulmonary and critical care medicine and the department of medicine at Vanderbilt University Medical Center; Sunil Kripalani, MD, MSc, from the division of general internal medicine and public health, the department of medicine and the Center for Clinical Quality and Implementation Research at Vanderbilt University Medical Center; and Christopher J. Lindsell, PhD, from the Center for Clinical Quality and Implementation Research and the department of biostatistics at Vanderbilt University Medical Center, noted that the study protocol allowing clinicians to override the study treatment in this open-label trial could be problematic.

“Although this may be presumed to bias the results toward finding no between-group differences, the likely nonrandom override of the recommended prevention strategy could have several effects,” they wrote. “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.”

Consequently, the editorialists lauded the researchers’ efforts but recommended that the study results be interpreted with caution.

“Overall, the results do not preclude the possibility of a small increase in hospital mortality with the proton pump inhibitor prophylaxis strategy despite showing a small, statistically significant reduction in clinically important gastrointestinal bleeding,” they wrote. “Moreover, in the PEPTIC trial, the large pragmatic open-label luster 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 individually critically ill patients.” – by Melissa Foster

Disclosures: One of the study authors reports receiving grants and personal fees from Baxter and personal fees from Spectral Medical and CNA Diagnostics. Another study author reports receiving grants and personal fees from AstraZeneca and GlaxoSmithKline. Lindsell reports receiving grants from the NIH, CDC and Marcus Foundation and personal fees from Endpoint Health. Rice reports receiving personal fees from Cumberland Pharmaceuticals.