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

Abstract

IMPORTANCE Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H 2 RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. OBJECTIVE To compare in-hospital mortality rates using PPIs vs H 2 RBs for stress ulcer prophylaxis.DESIGN, SETTING, AND PARTICIPANTS Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital.INTERVENTIONS Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H 2 RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H 2 RBs and 25 ICUs were randomized to the sequence with use of H 2 RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H 2 RBs). MAIN OUTCOMES AND MEASURESThe primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. RESULTS Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H 2 RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, −0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H 2 RBs and an estimated 20.1% of patients randomized by ICU site to H 2 RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H 2 RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, −0.51 percentage points [95% CI, −0.90 to −0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group.CONCLUSIONS AND RELEVANCE Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication.

Proton pump inhibitors versus histamine-2 receptor antagonists for stress ulcer prophylaxis during extracorporeal membrane oxygenation: a propensity score-matched analysis

“…23 Our results showed no significant differences for in-hospital mortality or the proportions of patients requiring endoscopic haemostasis, similar to results in previous randomised controlled trials. [24][25][26] Some previous studies have shown conflicting results regarding the efficacy of PPIs and H 2 RAs for stress ulcer prophylaxis. 7 27 In the present study, we found no significant difference in C. difficile infection rates between patients receiving PPIs versus H 2 RAs for stress ulcer prophylaxis.…”

Using Bayesian Methods to Augment the Interpretation of Critical Care Trials. An Overview of Theory and Example Reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial

“…In other scenarios, different combinations may be acceptable. Some hypothetical scenarios are shown in Table 2 ( 14 , 25 , 27 – 29 ). Consider previous trials and or other valid external evidence.…”

Could stress ulcer prophylaxis increase mortality in high-acuity patients?

“…Based on the available evidence, we surmise that, although considerable uncertainty remains, the inferences from SUP-ICU and PEPTIC are consistent with the hypothesis that PPIs increase the risk of death in patients with higher illness severity. While, the overall evidence that PPIs reduce upper GI bleeding in the critically ill is unequivocal [5,15], it appears that most upper GI bleeds are not fatal, and the attributable mortality from such bleeds appears to be low [16]. Therefore, we suspect that most patients would exchange the small increased risk of upper GI bleeding to avoid a therapy that might increase their risk of death, despite the uncertainty.…”

“…The results of the analysis by Granholm and colleagues [13] are particularly compelling when viewed together with the recently published Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) study [15]. The PEPTIC trial was a randomized, open-label, cluster-crossover trial that compared PPIs and histamine 2 receptor blockers (H 2 RBs) for stress ulcer prophylaxis in 26,982 mechanically ventilated adults.…”

“…The PEPTIC trial was a randomized, open-label, cluster-crossover trial that compared PPIs and histamine 2 receptor blockers (H 2 RBs) for stress ulcer prophylaxis in 26,982 mechanically ventilated adults. In the PEP-TIC trial [15], similar to the SUP-ICU trial [7], patients with high illness severity who were assigned to PPIs had higher mortality than comparator patients.…”