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

Abstract

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 causespecific 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. KeywordsProton pump inhibitors (PPI) • Histamine-2 receptor antagonists (H2RA) • Mortality Abbreviations ATC Anatomical therapeutic chemical CI Confidence interval H2RA Histamine-2 receptor antagonist ICD-10 International classification of diseases 10th edition IRR/aIRR Incidence rate ratio/adjusted incidence rate ratio NSAIDS Nonsteroidal anti-inflammatory drugs PPI Proton pump inhibitor SMR Standardised mortality ratio * Nele Brusselaers

Timely Cessation of Proton Pump Inhibitors in Critically Ill Patients Impacts Morbidity and Mortality: A Propensity Score-Matched Cohort Study*

“…Consideration of the second year after discharge appears to be of importance, as the mortality differences were particularly presented here. This finding lines up with observational studies showing an increasing risk of mortality with an increasing duration of a PPI therapy ( 32 ).…”

“…Greater risk of clostridium difficile infection (15)(16)(17)(18), gastritis (17), pneumonia (15), cardiovascular events (19,20), chronic renal failure (21,22), greater frequency of various neoplasms (23)(24)(25)(26)(27), possibly malabsorption disorders evoking vitamin B12 deficiency (28,29), hypocalcemia (30), and hypomagnesemia (30) are specific predescribed side effects of a long-term PPI therapy. Even an increased risk of mortality has been observed in retrospective studies (31)(32)(33)(34).…”

The association between drugs and repeated treatment with budesonide in patients with microscopic colitis: a retrospective observational study

“…However, the tax-financed medical system in Sweden, which includes cost support for prescribed drugs, leads to most long-term PPI users getting their PPIs from doctor prescriptions. 33 In our study, one can assume that patients with clinical relapse as well as patients without clinical relapse in our study to some extent take NSAIDs bought ‘over the counter’. However, we also assume that a patient who is prescribed NSAIDs uses more of the drug than patients who are not on prescription.…”