Proton Pump Inhibitor Therapy Deemed Safe at 3 Years

Hand with green latex glove holds a capsule of pantoprazole, chemical composition, conceptual image
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In the United States, proton pump inhibitors (PPIs) are one of the most widely used classes of drugs and are the most effective drugs for treating Gastroesophageal reflux disease (GERD). Given their high usage, it is crucial to ensure their safety.

Researchers discovered that long-term adverse events (AE) were similar in patients receiving pantoprazole compared with those receiving placebo, according to a study published in Gastroenterology.

In this 3 X 2 partial factorial, multicenter, double-blind, randomized, placebo-controlled trial, researchers analyzed the outcomes of participants with stable cardiovascular (CV) disease and peripheral artery disease (N=17,598) who were not already taking a PPI at baseline. Study participants were randomly assigned to groups receiving pantoprazole 40 mg daily (n=8791) or matching placebo daily (n=8807), between March 2013 and May 2016. They had also been randomly assigned to receive rivaroxaban 2.5 mg daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg once daily alone to compare the primary outcomes of CV death, stroke, or myocardial infarction (MI).

There was no significant difference in the primary efficacy outcome when comparing combinations of rivaroxaban and aspirin for the composite outcome of MI, stroke, or CV death (hazard ratio [HR] 1.04; 95% confidence interval [CI], 0.93-1.15) with pantoprazole compared with placebo. No significant difference in the secondary CV efficacy outcomes of the rivaroxaban/aspirin trial and no difference between pantoprazole and placebo was found separately for MI (HR 0.94; 95% CI, 0.79-1.12), stroke (HR 1.16; 95% CI, 0.94-1.44), or acute limb ischemia (HR 1.13; 95% CI, 0.73-1.75).

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The rates of hospitalization (HR 1.04; 95% CI, 0.99-1.09) and all-cause mortality (HR 1.03; 95% CI, 0.92-1.15) were similar between the pantoprazole and placebo groups, as well as the non-CV events of interest, including pneumonia, fracture, new diagnosis of diabetes mellitus, chronic kidney disease, dementia, chronic obstructive lung disease, and gastric atrophy. However, enteric infections were more frequent in the pantoprazole group compared with the placebo group (odds ratio [OR] 1.33; 95% CI, 1.01-1.75).

This trial was potentially limited by underestimation of the incidence of gastric atrophy because the researchers relied on participants being referred for endoscopy and having a gastric biopsy. While the proportion of gastric atrophy cases was similar between the 2 groups, the number of participants was small and may have biased the results toward the null. The associations of proton pump inhibitor therapy with B-12 deficiency and gastric cancer are not supported by these randomized data, although a small effect cannot be excluded. The low numbers of apparent excess of C difficile-associated diarrhea need to be interpreted cautiously. There is possible misclassification regarding this and other enteric infections because these AEs were obtained mainly by patient interview every 6 months.

In conclusion, the researchers suggested that proton pump inhibitors are not associated with any long-term harm other than possible enteric infections for up to a median of 3 years. Moreover, the benefits are likely to outweigh the risks for these medications when clinically indicated.


Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirinGastroenterology. 2019;157(3):682-691.e2.