Use of PPIs associated with higher risk of death than use of H2 blockers

Study results should not deter prescription and use of proton pump inhibitors (PPIs) where medically indicated, but rather emphasize the need to be judicious about use of PPIs and duration of therapy, the authors said.


Patients who use proton-pump inhibitors (PPIs) may have a 25% higher risk of death than those who use histamine H2 receptor antagonists (H2 blockers), according to a recent study.

Using inpatient and outpatient data from the U.S. Department of Veterans Affairs, researchers assessed risk of all-cause mortality in a primary cohort of new users of PPIs or H2 blockers (n=349,312), as well as in cohorts of PPI users versus non-PPI users (n=3,288,092) and PPI users versus users of neither PPIs nor H2 blockers (n=2,887,030). Median follow-up was 5.71 years.

Results were published online on July 4 by BMJ Open.

Compared with use of H2 blockers, use of PPIs was associated with increased risk of death (adjusted hazard ratio [HR], 1.25; 95% CI, 1.23 to 1.28). Mortality risk was also higher with PPI use versus no PPI use (adjusted HR, 1.15; 95% CI, 1.14 to 1.15) and with PPI use versus use of neither PPIs nor H2 blockers (adjusted HR, 1.23; 95% CI, 1.22 to 1.24).

The risk of death associated with PPI use was also examined in those without a clear indication for treatment with a PPI (such as gastroesophageal reflux disease, gastrointestinal bleeding, or Barrett's esophagus). Mortality risk was also higher in these patients in all three cohorts: PPI versus H2 blockers (adjusted HR, 1.24; 95% CI, 1.21 to 1.27), PPI use versus no PPI use (adjusted HR, 1.19; 95% CI, 1.18 to 1.20), and PPI use versus no use of PPIs or H2 blockers (adjusted HR, 1.22; 95% CI, 1.21 to 1.23).

Among 166,098 new users of PPIs, mortality risk increased with duration of PPI use. Compared to participants exposed to PPIs for 30 days or fewer, those exposed to PPIs for longer durations had a higher risk of death: 31 to 90 days (adjusted HR, 1.05; 95% CI, 1.02 to 1.08), 91 to 180 days (adjusted HR, 1.17; 95% CI, 1.13 to 1.20), 181 to 360 days (adjusted HR, 1.31; 95% CI, 1.27 to 1.34), and 361 to 720 days (adjusted HR, 1.51; 95% CI, 1.47 to 1.56).

The authors noted limitations to their study, such as its observational design, the possibility of residual confounding, and its population of mostly older, white male veterans. In addition, they defined drug exposure as having a prescription for PPIs or H2 blockers but noted that some participants' exposure may have gone undetected if they obtained the medications over the counter.

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