New analysis supports lack of association between alleged PPI-related adverse events and PPI exposure

The widespread use of proton pump inhibitors (PPIs; e.g., omeprazole, pantoprazole) has led to growing concerns regarding their long-term safety. Several studies have reported potential adverse associations with long-term PPI therapy, although the reported magnitudes of risk were generally low. Risks associated with long-term PPI use have included pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease and cancer. However, many of the studies identifying these risks relied on observational data, which are prone to bias from multiple sources.(1,2)A new 10-year, cross-sectional analysis of US national ambulatory healthcare data was undertaken to examine potential sources of bias in studies previously reporting adverse PPI associations. The primary outcome of interest was a clinical encounter for a diagnosis purportedly associated with continued PPI use (dementia, pneumonia, chronic kidney disease and intestinal infection). A secondary analysis examined four additional commonly prescribed drug classes (angiotensin-converting enzyme inhibitors [ACEIs], statins, calcium channel blockers [CCBs] and beta-blockers) and their relationship to these diagnoses.Over a 10-year period (2006 to 2015), more than 7.8 billion weighted observations were analyzed. PPI use was significantly associated with chronic kidney disease; however, no association was found between PPI use and dementia, pneumonia or intestinal infections, except for C. difficile. Significant associations with chronic kidney disease were also seen with statins, CCBs and beta-blockers.(1)The authors comment that, after they adjusted for patient demographics and comorbidities, many associations between PPIs and previously associated conditions became less or not significant compared with unadjusted estimates. In addition, although a significant association was seen between PPI use and chronic kidney disease, this association also existed for several other drug classes. They believe it is very unlikely that all these medications increase the risk of chronic kidney disease; therefore, these findings are likely due to residual confounding.(1)The authors conclude that their cross-sectional analysis supports a lack of association between purported PPI-related adverse events and PPI exposure. They note that previously reported disease associations are generally weak in magnitude and prone to retrospective biases.(1) In addition, a recent large placebo-controlled randomized trial found that pantoprazole was not associated with any adverse event when used for three years, with the possible exception of an increased risk of enteric infections.(2)Despite their findings, the authors recommend that PPIs be prescribed only for appropriate indications, at the lowest possible dose, and for the shortest possible duration.(1)ReferencesMa C, Shaheen AA, Congly SE, et al. Interpreting reported risks associated with use of proton pump inhibitors: residual confounding in a 10-year analysis of national ambulatory data. Gastroenterology 2020;158:780-2.Moayyedi P, Eikelboom JW, Bosch J, et al; COMPASS Investigators. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 2019;157:682-91.e2.

New analysis supports lack of association between alleged PPI-related adverse events and PPI exposure

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