Proton pump inhibitors (PPIs) are associated with a significantly higher risk of death than are H2 receptor antagonists, according to a 5-year longitudinal cohort study.

The study, published online in BMJ Open, found that increased risk of death was evident even in people without gastrointestinal conditions, and it increased with longer duration of use.

Yan Xie, PhD, of the VA Saint Louis Health Care System and coauthors, wrote that PPIs are linked to a range of serious adverse outcomes – such as acute interstitial nephritis, chronic kidney disease, incident dementia, and Clostridium difficile infection – each of which is associated with higher risk of mortality.

“Whether PPI use is associated with excess risk of death is not known and has not been examined in large epidemiological studies spanning a sufficiently long duration of follow-up.”

In this study, a cohort of 349,312 veterans initiated on acid-suppression therapy was followed for a mean duration of 5.71 years (BMJ Open 2017. July 4;7:e015735. doi: 10.1136/bmjopen-2016-015735 ).

Researchers saw a 25% higher risk of death in the 275,977 participants treated with PPIs, compared with that in those who were treated with H2 receptor antagonists (95% confidence interval, 1.23-1.28), after adjusting for factors such as estimated glomerular filtration rate, age, hospitalizations, and a range of comorbidities, including gastrointestinal disorders.

When PPI use was compared with no PPI use, there was a 15% increase in the risk of death (95% CI, 1.14-1.15). When compared with no known exposure to any acid suppression therapy, the increased risk of death was 23% (95% CI, 1.22-1.24).

In an attempt to look at the risk of death in a lower-risk cohort, the researchers analyzed a subgroup of participants who did not have the conditions for which PPIs are normally prescribed, such as gastroesophageal reflux disease, upper gastrointestinal tract bleeding, ulcer disease, Helicobacter pylori infection, and Barrett’s esophagus.

However, even in this lower-risk cohort, the study still showed a 24% increase in the risk of death with PPIs, compared with that in H2 receptor antagonists (95% CI, 1.21-1.27); a 19% increase with PPIs, compared with no PPIs; and a 22% increase with PPIs, compared with no acid suppression.

Duration of exposure to PPIs was also associated with increasing risk of death. Participants who had taken PPIs for fewer than 90 days in total only had a 5% increase in risk, while those taking them for 361-720 days had a 51% increased risk of death.

“Although our results should not deter prescription and use of PPIs where medically indicated, they may be used to encourage and promote pharmacovigilance and emphasize the need to exercise judicious use of PPIs and limit use and duration of therapy to instances where there is a clear medical indication and where benefit outweighs potential risk,” the authors wrote.

“Standardized guidelines for initiating PPI prescription may lead to reduced overuse [and] regular review of prescription and over-the-counter medications, and deprescription, where a medical indication for PPI treatment ceases to exist, may be a meritorious approach.”

Examining possible physiologic mechanisms to explain the increased risk of death, the authors noted that animal studies suggested PPIs may limit the liver’s capacity to regenerate.

PPIs are also associated with increased activity of the heme oxygenase-1 enzyme in gastric and endothelial cells and impairment of lysosomal acidification and proteostasis and may alter gene expression in the cellular retinol metabolism pathway and the complement and coagulation cascades pathway.

However, the clinical mediator of the heightened risk of death was likely one of the adverse events linked to PPI use, they said.

No conflicts of interest were declared.