Study links common heartburn drug to increased heart attack risk

One in every 14 Americans uses a proton pump inhibitor (PPI)— the most common type of heartburn drug— in any given year, but new research that links them to an increased risk of heart attack has prompted scientists to re-evaluate their safety.

A study by Stanford University researchers, published Wednesday in the journal PLOS One, linked PPI use to an about 20 percent increased chance of heart attack in patients diagnosed with heartburn. PPIs like omeprazole, sold as Prilosec, are offered over the counter, racking up $14 billion in annual sales worldwide, and are prescribed to more than 20 million Americans each year. They are used to treat gastroesophageal reflux disease (GERD), also called heartburn or acid reflux.

“The AHA (American Heart Association) estimates a heart attack happens every 34 seconds in America. If we’re estimating this risk is increasing by 20 percent [with PPI use], the public health impact is substantial,” senior study author Nick Leeper, assistant vascular surgery and cardiovascular medicine professor at Stanford University, told

Researchers’ findings, drawn from a study group of nearly 3 million American adults, support previous research— by current study co-authors John Cooke and Yohannes Ghebremariam, and published in 2013 in the journal Circulation— that suggests that PPIs signal a biochemical reaction that decreases levels of nitric oxide in endothelial cells. Maintaining nitric oxide levels is crucial for dilating blood vessel walls and maintaining cardiovascular health. When nitric oxide levels are low, the chance of adverse cardiovascular events like heart attack is higher.

Their study also suggests that not only people on blood thinners like clopidogrel, sold as Plavix, may be more vulnerable to heart attack with PPI use, but that anyone on the drug and diagnosed with heartburn— regardless of predisposed cardiovascular risk or other medication use— may be at risk.

Lead study author Nigam Shah, assistant professor of medicine and biomedical informatics at Stanford, used a data-mining method to scan electronic health records gathered between 1994 and 2012— consisting of 1.8 million patients seen at Stanford and 1.1 million patients through Practice Fusion Inc., a web-based electronic health record system for clinicians. Among those groups, respectively, researchers identified 70,000 and 227,000 adults diagnosed with heartburn. They compared heart attack rates among those patients who reported using PPIs, either over the counter or by prescription, to patients who didn’t report taking the drugs.

After using a false-positive estimation method similar to one meant to adjust for confounding variables in a traditional study, the data-mining results suggested a 16 to 21 percent increase in the rate of heart attacks among PPI users— a trend that held true even among otherwise healthy participants under age 45.

Stanford researchers further validated their findings by looking at an ongoing progressive, longitudinal genetics study of 1,500 people they are conducting with Mount Sinai Medical Center in New York City. As part of the study, participants had to record medication usage, including other prescriptions and over-the-counter medications, so researchers were able to identify PPI users. Researchers sought potential links between PPI use and any adverse cardiovascular event, including not only heart attack but also cardiac arrest, stroke and the like. They observed that taking a PPI was associated with a twofold increased risk of any of these events.

Although researchers observed a link between PPI use and a higher heart attack risk in all three data sets, they noted that a larger randomized, blinded study needs to be done to confirm whether that relationship is definitely causal. Study authors’ related research, published April in the online edition of Vascular Medicine, marks the next step in their future analysis. For that pilot study, about half of the 21 adult participants diagnosed with heartburn received a PPI and the other half received a placebo.

“In the Vascular Medicine journal paper, we’re seeing a trend towards worse levels of vascular biomarkers in people on the PPIs,” Leeper said. “All together, we’re painting a picture that this may be associated with risk, and we want to validate that moving forward.”

When those preliminary results are released in August in the print edition of the journal, researchers will present them to pharmaceutical companies and the National Institutes of Health (NIH) to seek funding of a larger prospective trial, Shah told

Researchers noted that, in the PLOS One study, while they observed an increased heart attack risk among PPI users, they did not among people who took H2 blockers, the second most commonly prescribed heartburn drug in the United States. Both drugs work to balance acid in the stomach, but while H2 blockers block the histamine receptor, PPIs block the proton pump. PPIs are thought to be more effective at reducing heartburn symptoms, and historically have been thought to have fewer side effects compared to H2 blockers, Leeper said.

“We don’t recommend anyone change their practice— what we’re really recommending at this time is a prospective study,” explained Leeper, who said his team’s findings do suggest patients who are taking PPIs over the counter consult their doctors and evaluate their personal heart attack risk as a precaution.

“This really speaks to the power of big data,” he added, “and this is tangible data that machine learning can be used to identify big risks that haven’t been on anyone’s radar.”