Placebo-controlled RCT: In critically ill adults at risk for GI bleeding, pantoprazole did not reduce 90-d mortality or clinically important events.
Krag M, Marker S, Perner A, et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. N Engl J Med. 2018 Oct 24. doi: 10.1056/NEJMoa1714919.

BACKGROUND: Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear.

METHODS: In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization.

RESULTS: A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P=0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.

CONCLUSIONS: Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621 .).

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Comments from MORE raters

Hemostasis and Thrombosis

While the findings are not overly surprising, this manuscript addresses a long-standing and important knowledge/data deficit.

An RCT comparing prophylactic pantoprazole vs placebo in ICU patients at risk for GI bleeding. No difference in mortality or rate of at least 1 clinically important event, although there was a modest reduction in the rate of GI bleeding (2.5 % pantoprazole; 4.2% placebo).

Hospital Doctor/Hospitalists

PPIs are used in the ICU for prophylaxis against GI bleeds. This randomized trial found a reduction in GI bleeding with PPI (2.5% vs 4.8%), which seems to confirm current practice, especially since there was no difference in any of the potential PPI-induced problems (pneumonia, C diff, myocardial ischemia). The authors' conclusions and the accompanying editorial, however, seem to call into question the use of PPI given the lack of improvement in all-cause mortality. The editorial title is "Proton Pump Inhibitor Prophylaxis in the ICU - Benefits Worth the Risks?" As best I can tell, the only "benefit" found in this trial is reduced clinically important GI bleeding, and there was no increased "risk" found at all. Thus, for at-risk patients, these data suggest the answer is "yes". If you are prescribing PPI for prophylaxis against GI bleeding, this trial supports that practice. If you are prescribing PPI to reduce all-cause mortality, this trial does not support that.

Internal Medicine

I'm not an intensivist, but was it ethical to use a placebo over an H2-blocker in this setting?

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