Discussion about the long term side effects of Proton pump inhibitors (PPIs) continues, but almost all meaningful data to date have been derived from pharmacoepidemiological studies based upon naturalistic observational techniques. A large randomized trial has now examined the issue in detail. Using a 3×2 partial factorial double-blind design, 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n=8791) or placebo (n=8807). The subjects were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. The ADR endpoints included pneumonia, C difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality (assessed every 6 months). Patients were followed up for a median of 3.01 years, with 53,152 patient years of follow up.

There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% CI, 1.01–1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, twice as common with pantoprazole compared to the placebo group> The absolute number of events was small (13) calling into question the significance of this effect. Perhaps long term PPI treatment is not as unsafe as we might have been led to believe? Read more here