The Association Between Proton Pump Inhibitor Exposure and Key Liver-Related Outcomes in Patients With Cirrhosis: A Veterans Affairs Cohort Study

Gastroenterology. 2022 Jul;163(1):257-269.e6. doi: 10.1053/j.gastro.2022.03.052. Epub 2022 Apr 6.


Background & aims: The impact of proton pump inhibitory (PPI) medications on adverse outcomes in cirrhosis remains controversial. We aimed to evaluate the association between PPI exposure and all-cause mortality, infection, and decompensation in a large national cohort.

Methods: This was a retrospective study of patients with cirrhosis in the Veterans Health Administration. PPI exposure was classified as a time-updating variable from the index time of the cirrhosis diagnosis. Inverse probability treatment weighting-adjusted Cox regression was performed with additional adjustment for key time-varying covariates, including cardiovascular comorbidities, gastrointestinal bleeding (GIB), and statin exposure.

Results: The study included 76,251 patients, 23,628 of whom were on a PPI at baseline. In adjusted models, binary (yes/no) PPI exposure was associated with reduced hazard of all-cause mortality in patients with hospitalization for GIB (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.84-0.91; P < .001) but had no significant association in all others (HR, 0.99; 95% CI, 0.97-1.02; P = .58). However, cumulative PPI exposure was associated with increased mortality in patients without hospitalization for GIB (HR, 1.07 per 320 mg-months [omeprazole equivalents]; 95% CI, 1.06-1.08; P < .001). PPI exposure was significantly associated with severe infection (HR, 1.21; 95% CI, 1.18-1.24; P < .001) and decompensation (HR, 1.64; 95% CI, 1.61-1.68; P < .001). In a cause-specific mortality analysis, PPI exposure was associated with increased liver-related mortality (HR, 1.23; 95% CI, 1.19-1.28) but with decreased nonliver-related mortality (HR, 0.88; 95% CI, 0.85-0.91).

Conclusions: PPI exposure is associated with increased risk of infection and decompensation in cirrhosis, which may mediate liver-related mortality. However, PPI use was associated with reduced all-cause mortality in those with prior GIB, suggesting benefit in the presence of an appropriate indication.

Keywords: Cirrhosis; Deprescribing; Gastrointestinal Bleed; Proton Pump Inhibitor; Veterans Affairs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cohort Studies
  • Gastrointestinal Hemorrhage / chemically induced
  • Gastrointestinal Hemorrhage / complications
  • Gastrointestinal Hemorrhage / epidemiology
  • Humans
  • Liver Cirrhosis / complications
  • Proton Pump Inhibitors* / adverse effects
  • Retrospective Studies
  • Risk Factors
  • Veterans*


  • Proton Pump Inhibitors