Maintenance Proton Pump Inhibitor Use Associated with Increased All-Cause and Cause-Specific Mortality in Sweden

BACKGROUND: Proton pump inhibitor (PPI) use has increased over the last decades and has been associated with multiple adverse events and potentially even overall survival. AIMS: We aimed to investigate the association between proton pump inhibitor maintenance use and all-cause and cause-specific mortality, addressing confounding by indication and duration of use. METHODS: This Swedish population-based cohort study included all adult (N = 935,236) PPI and histamine-2 receptor antagonist maintenance users (≥ 180 days use) during 2005–2014. Standardised mortality ratios (SMRs) and 95% confidence intervals were calculated for all-cause and cause-specific mortality comparing the risk among PPI/H2RA users to that of the Swedish background population, stratified by age, sex, calendar period, indication and duration of use. Multivariable Poisson regression models were used to compare PPI use to H2RA use, expressed as incidence rate ratios and 95% confidence intervals. RESULTS: PPI and histamine-2 receptor antagonist use were associated with an increased risk of all-cause mortality (SMR = 1.35; 1.34–1.36; SMR = 1.31; 1.27–1.36, respectively). The highest SMRs were found in the youngest age groups. In direct comparison, PPI use showed a higher mortality risk than histamine-2 receptor antagonist use (incidence rate ratios = 1.42; 1.38–1.46). PPIs were related to increased cancer (SMR = 1.21; 1.20–1.22), and cardiovascular mortality (SMR = 1.36; 1.35–1.37). Increased SMRs were observed for most indications. Longer duration of use was associated with a higher mortality among PPI users but not among histamine-2 receptor antagonist users. CONCLUSION: Maintenance PPI use was associated with an increased risk of all-cause and cause-specific mortality, and the risk increased with prolonged duration. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10620-023-07820-9.