Increased risk of death seen even in lower-risk PPI users

Proton pump inhibitors are associated with a significantly higher risk of death than are H2 receptor antagonists, according to a five-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.

Doctors from St. Louise Health Care System and other 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, Jul 4:7:e015735. doi: 10.1136/bmjopen-2016-015735).

Researchers saw a 25 percent higher risk of death in the 275,977 participants treated with PPIs, compared with those who were treated with H2 receptors antagonists (95 percent 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 percent increase in the risk of death (95 percent CI, 1.14-1.15).  When compared with no known exposure to any acid suppression therapy, the increased risk of death was 23 percent (95 percent 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 condition 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 percent increase in the risk of death with PPIs, compared with that in H2-receptor antagonists (95 percent CI, 1.21-1.27) a 19 percent increase with PPIs, compared with no PPIs, and a 22 percent 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 had only a 5 percent increase in risk, while those taking them for 361-720 days has a 51 percent increased risk of death.

Although the 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.

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 oxigenase-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.

No conflict of interest were declared.