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Participants were randomized to receive the anticoagulant rivaroxaban and/or aspirin to compare outcomes of cardiovascular death, stroke or heart attack. For the PPI arm, participants were randomized to receive either placebo or a 40-milligram dose of pantoprazole once daily. The researchers regularly collected data on participants for a median of three years. The researchers found no statistically significant evidence associating pantoprazole with cancer, heart attack, stroke, pneumonia, fracture, diabetes, chronic rena l disease, dementia, COPD, gastric atrophy or all-cause mortality when comparing individuals in the PPI group with those in the placebo group. The only adverse event for which pantoprazole showed statistically significant evidence of harm was enteric infections. The researchers' findings appeared in Gastroenterology. "To our knowledge, this is the largest PPI trial for any indication and the first prospective randomized trial to evaluate the many long-term safety concerns related to PPI therapy," the authors wrote. "It is reassuring that there was no evidence for harm for most of these events other than an excess of enteric infections." The results did not surprise Dr. Moayyedi, who points out that, when PPIs were created, no one worried they might cause certain adverse events, including dementia, fractures, renal disease and pneumonia, because that made little sense biologically. "[P]ost hoc, you could create any biological reason for why you found [an] association of harm, but if you're doing it after the fact, that is highly suspicious to me," he says. The evidence of harm for enteric infections — which barely rose to the level of statistical significance and was lower than estimations by systematic reviews of observational studies — carries the most biologic plausibility of any of the adverse events, Dr. Moayyedi says. It is reasonable to assume that acid suppression caused by PPI hampers the body's ability to kill bacteria that could cause enteric infections. CALLS FOR CONSCIENTIOUS PRESCRIBING Speaking on behalf of the American Gastroenterological Association, Gary Falk, MD, MS, Professor of Medicine in the Division of Gastroenterology at the University of Pennsylvania Perelman School of Medicine, says the study provides persuasive evidence that, used appropriately, PPIs are safe. When considering whether to prescribe a PPI, Dr. Falk — who was not involved with the study — advises clinicians to consider whether it is indicated for the patient, and, if so, what is the lowest dose that is likely to be effective. "[O]ur best level of evidence for clinical decision-making throughout the fields of medicine and surgery is randomized controlled trials," he says. "This is a randomized controlled trial that supports the safety ... of PPIs for at least three years, if not up to five years, and should put everybody's minds at ease about some of the adverse consequences that have been described in observational studies." Dr. Moayyedi agrees with Dr. Falk's call for careful prescribing. He adds that clinicians should discontinue PPI use in patients who have been taking them for years for undefined reasons or questionable indications, such as cough and sore throat. "I do hope that these data will stop some people who are on a PPI for appropriate reasons having their drug stopped or being scared into stopping the drug because ... as long as they truly need it and it's improving their quality of life, then the benefits should outweigh any possible harms," he says. n A Closer Look at Chronic Renal Disease and Dementia A RECENT R A NDOMIZED controlled trial that examined the long-term safety of proton pump inhibi- tors (PPIs) found no statistically significant evidence linking PPIs with a higher risk of chronic renal disease or dementia. However, the study included fewer chronic renal disease and dementia cases overall than other adverse events, leaving researchers with less robust data from which to draw conclusions for those conditions. Therefore, researchers were unable to say for cer tain that PPIs are not associated with chronic renal disease and dementia, although the benefits of the drugs are likely to outweigh any potential harms. "I think we've come as far as we can in saying [PPIs] are safe," says lead author Paul Moay yedi, BSc, MB ChB, PhD, MPH, FRCP, FRCPC, FACG, AGAF, Audrey Campbell Chair of Ulcerative Colitis Research and A ssistant Dean of Research at McMaster University in Ontario. "[T]he areas we need to focus more on are dementia and chronic renal disease. ... What we're hoping to do is interrogate the database fur- ther and see if we can pick out any signal of harm when we do a deeper dive of that data." M D N E W S . C O M /// M D N E W S S O U T H C E N T R A L P E N N S Y LVA N I A ■ 2 019 1 5