According to a new study published in BMJ-Open, patients taking proton pump inhibitors (PPIs) may be at increased risk of death, compared to those not taking these medications or those taking other acid-suppressing drugs.

Prior observational studies have linked PPI use with an increase in adverse health outcomes, including an increase in acute interstitial nephritis and kidney disease progression. Use of PPIs has also been associated with hypomagnesemia, dementia, recurrent Clostridium difficile infections, and an increase in the risk of fractures in patients with osteoporosis. 

The study authors based their findings on longitudinal data found in the U.S. Department of Veterans Affairs databases, identifying patients who had received outpatient acid suppressive therapy during a 2-year period between October 1, 2006 and September 30, 2008. The selected patients were then followed until September 30, 2013 or until patient death. 

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Patients with prior history of PPI or histamine H2 receptor antagonist (H2RA) therapy were excluded from the study. The primary cohort consisted of new PPI or H2RA users (n=349,312); other cohorts included PPI vs. no PPI use (n=3,288,092) and PPI vs. no H2RA use (n=2,887,030). 

The authors found that compared to the use of H2RA therapy, patients initiated on PPI therapy had a 25% increased risk of death (hazard ratio [HR] 1.25, 95% CI: 1.23–1.28). This increase was also seen when PPI treatment was compared to no PPI use (HR 1.15 (95% CI: 1.14–1.15) and no PPI and no H2RA use (HR 1.23 (95% CI: 1.23, 1.22–1.24).  

An analysis excluding patients with documented medical conditions for PPI therapy, including GERD, upper GI bleed, ulcer disease, H. pylori infection, Barrett’s esophagus, and other GI diseases was also conducted. The risk of death in patients without these conditions increased with PPI use by 24% vs. H2RAs (HR 1.24, 95% CI: 1.21–1.27). The risk was 19% higher when compared to no PPI use and 22% higher when compared to no PPI and H2RA use.  

Moreover, the authors observed that the mortality risk increased with longer exposure to PPI therapy. 

Currently, the mechanism by which PPIs increase mortality risk remains unclear; more studies are needed to clarify the biological link. Some studies have shown that the drug’s mechanism of action may play a part in increasing oxidative stress and endothelial dysfunction, leading to adverse health events and a potential increase in death risk. 

Given the results of the study, the authors suggest limiting PPI use and the length of exposure to circumstances where therapy is clinically appropriate.

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