Spotlight on PPI safety

Recent studies came to differing conclusions in their assessments of the safety of proton-pump inhibitors (PPIs), with outcomes including mortality, hepatic encephalopathy, and infections.


A retrospective study and a meta-analysis found that use of proton-pump inhibitors (PPIs) was associated with adverse outcomes, while an industry-funded randomized trial found that PPI therapy was generally safe for up to a median of three years.

In the first study, researchers used data from the U.S. Department of Veterans Affairs to estimate all-cause and cause-specific mortality among new users of PPIs (n=157,625) or histamine H2-receptor antagonists (H2 blockers; n=56,842). Nearly 96% of participants were men, about 87% were white, and the average age was about 65 years. Results were published online on May 30 by The BMJ.

Over a median 10 years of follow-up, 80,062 (37.33%) patients died, and there were more deaths among patients taking PPIs than among those taking H2 blockers (37.92% vs. 35.69%). There were 45.20 excess deaths (95% CI, 28.20 to 61.40) per 1,000 patients taking PPIs. PPI use was associated with excess mortality due to cardiovascular disease (15.48 excess deaths; 95% CI, 5.02 to 25.19) and chronic kidney disease (4.19 excess deaths; 95% CI, 1.56 to 6.58). Among patients without a documented indication for acid-suppressing drugs (n=116,377), PPI use was associated with excess mortality due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. Longer duration of PPI exposure was associated with increased risk of all-cause mortality and death due to circulatory system diseases, neoplasms, and genitourinary system diseases.

Limitations of the study include its mostly older, white, male cohort, as well as the possibility of selection bias due to several inclusion and exclusion criteria, the study authors noted. “Because of the high prevalence of PPI use, the findings have public health implications and underscore the important message that PPIs should be used only when medically indicated and for the minimum duration necessary,” they concluded.

The second study, published online on June 7 by the World Journal of Gastroenterology, assessed the association of PPI use with the risk of hepatic encephalopathy in patients with advanced liver disease. The systematic review and meta-analysis included 188,053 patients from four cohort studies (including one conference abstract) and 4,342 patients from five case-control studies (including two conference abstracts).

In patients with advanced liver disease, PPI use was linked to an increased risk of developing hepatic encephalopathy compared to no PPI use. The pooled relative risk for cohort studies was 1.67 (95% CI, 1.30 to 2.14), and the pooled odds ratio for case-control studies was 2.58 (95% CI, 1.68 to 3.94). In a sensitivity analysis with conference abstracts excluded, the pooled results showed similar relative risk values and 95% CIs.

Limitations of the meta-analysis included the small number of studies and the fact that only one was a prospective cohort study (the rest were retrospective cohort studies or case-control studies), the authors noted. In addition, there was significant heterogeneity among the included studies, and the findings may have been affected by publication bias, they said. The results suggest that “clinicians need to strictly adhere to the indications for PPI use in patients with advanced liver disease,” the authors concluded.

Not all recent research linked PPI use to adverse outcomes, however. The final study, an industry-funded randomized trial, found that PPI use was associated with very few adverse events in 17,598 participants with stable cardiovascular disease and peripheral artery disease. The study was supported by Bayer AG, and results were published online on May 29 by Gastroenterology.

Researchers assessed the association of PPIs versus placebo with various adverse events, including all-cause mortality, gastric atrophy, and development of pneumonia, Clostridium difficile infection, or other enteric infections, over a median follow-up duration of three years. They randomly assigned participants to receive pantoprazole (40 mg/d; n=8,791) or placebo (n=8,807). Participants were also randomized to receive rivaroxaban (2.5 mg twice daily) with aspirin (100 mg/d), rivaroxaban (5 mg twice daily), or aspirin (100 mg/d) alone.

There was no significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs. 1.0%; odds ratio, 1.33; 95% CI, 1.01 to 1.75). The groups were similar on all other safety outcomes except for C. difficile infection, which was about twice as common in the pantoprazole versus the placebo group. However, there were only 13 C. difficile cases, so the difference was not statistically significant.

Limitations of the trial include a small number of events for some of the outcomes, as well as the fact that adverse events were mainly obtained by patient interview every six months, raising the possibility of misclassification, the authors noted. “As with all drugs, PPI therapy should only be used when the benefits are expected to outweigh the risks and should be used according to recommended dose and duration of treatment,” they concluded. “However, this trial suggests that limiting prescription of PPI therapy because of concerns of long-term harm is not appropriate.”