PPI use in the ICU associated with mortality risk

A systematic review and meta-analysis found that critically ill patients who received proton-pump inhibitors (PPIs) versus any comparator for stress ulcer prophylaxis had a higher risk for death, especially if they were more severely ill at baseline.

A recent systematic review and meta-analysis suggested that proton-pump inhibitors (PPIs) used to prevent stress ulcers in the ICU may be associated with an increased risk for death.

Researchers performed a systematic review and meta-analysis of 20 randomized controlled trials (RCTs) and 11 cohort studies of 78,009 critically ill adults receiving PPIs versus any comparator. The primary outcome was the association between PPI use for stress ulcer prophylaxis and death. Secondary outcomes included clinically important GI bleeding, which was defined as visualizable GI bleeding with at least one related symptom or additional procedure needed. Results were published May 26 by the Journal of Clinical Gastroenterology.

PPI use was significantly associated with an increased mortality risk versus comparators in all studies (19.6% vs. 17.5%; relative risk [RR], 1.10 [95% CI, 1.02 to 1.20]; P=0.01). The association remained significant for the subgroup of RCTs (19.4% vs. 18.7%; RR, 1.05 [95% CI, 1.0 to 1.09]; P=0.04), but not for the subgroup of cohort studies (19.9% vs. 16.7%; RR, 1.12 [95% CI, 0.98 to 1.28]; P=0.09). RCTs where patients were more severely ill at baseline demonstrated the highest mortality risk with PPI use (32.1% vs. 29.4%; RR, 1.09 [95% CI, 1.04 to 1.14]; P<0.001).

PPI use was associated with reduced clinically important bleeding in RCTs versus comparators (1.4% vs. 2.1%; RR, 0.67 [95% CI, 0.5 to 0.9]; P=0.009) but with increased bleeding in cohort studies (2.7% vs. 1.2%; RR, 2.05 [95% CI, 1.2 to 3.52]; P=0.009). It was also consistently associated with reduced clinically important bleeding when compared with enteral nutrition, control, or placebo (2.0% vs. 3.4%; RR, 0.62 [95% CI, 0.43 to 0.89]; P=0.01) but not when compared with histamine-2 receptor antagonists (H2RAs) or sucralfate. PPI use was consistently associated with a significant increase in pneumonia versus any other intervention (19.1% vs. 17.2%; RR, 1.13 [95% CI, 1.05 to 1.22]; P=0.002).

The researchers noted that while 22 of the 31 included studies revealed trends toward an increase in the relative risk for death, data came primarily from three studies, which accounted for 30% of the model weight. One of these studies (the PEPTIC trial) is limited by the fact that there was a high degree of crossover between H2RAs and PPIs, they said.

“The results of this study suggest that PPI use for SUP [stress ulcer prophylaxis] is associated with increased mortality, with stronger associations in patients with a higher severity of illness,” they wrote. “In an era where the indications of SUP are being debated, consideration should be made for the selection of an agent with the least associated harm while maintaining efficacy for the reduction of [clinically important bleeding]. The potent acid suppression of PPIs may contribute to unwarranted effects and SUP with these agents should be considered with caution.”