Observational studies have linked proton pump inhibitors (PPIs) to a litany of health conditions. A recent randomized controlled trial undermines many of those associations, finding PPIs to be largely safe to use for at least three years.
Commonly used to treat GERD and other acid-related conditions, PPIs have long been linked with a variety of complications. A 2004 study by Dutch researchers found that individuals who used PPIs had a higher risk of pneumonia. A 2016 study in Germany linked PPIs with a significant increase in dementia risk. In a study published earlier this year, American researchers found PPIs were associated with an uptick in deaths due to cardiovascular disease, chronic renal disease and upper GI cancer.
“[T]he concern with observational data is that these results could always be due to residual confounding, and so you can never be sure that the effect is real,” says Paul Moayyedi, BSc, MB ChB, PhD, MPH, FRCP, FRCPC, FACG, AGAF, Audrey Campbell Chair of Ulcerative Colitis Research and Assistant Dean of Research at McMaster University in Ontario. “It may just be that patients who are on PPI are sicker than people who are not on PPI, and therefore at risk of pneumonia and fracture and other things.”
Strong Evidence of Safety
To obtain more definitive answers about the safety of PPIs, Dr. Moayyedi led the PPI arm of a large, international trial evaluating 17,598 individuals with stable atherosclerotic vascular disease. 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 renal 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.