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

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. 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. 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. 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). 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.