Some heartburn drugs may not be as safe as we think

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Researchers have claimed through a large data-mining study that a popular class of heartburn drugs might not be as safe as we think as they have been linked to an elevated risk of heart attack.

Though researchers at the Sanford University School of Medicine have found an association between PPI (Proton-pump inhibitors) use and increased chances of a subsequent heart attack, it doesn’t in and of itself prove causation. According to Nigam Shah, Ph.D., MBBS, an assistant professor of biomedical informatics and assistant director of the Stanford Center for Biomedical Informatics Research said that they combed through electronic health records of nearly three million people and crunched trillions of pieces of medical data, raising concerns that should be taken seriously, especially now that PPIs are available over the counter.

Proton-pump inhibitors, or PPIs, are among the world’s most widely prescribed drugs and are effective at lowering the acidity of the stomach, in turn preventing heartburn, a burning sensation in the chest that occurs when stomach acid rises up into the esophagus.

In the US alone, more than 100 million prescriptions are filled every year for PPIs, a class of drugs long considered benign except for people concurrently taking the blood thinner clopidogrel (Plavix). However, the new study upends this view: it indicates that PPI use was associated with a roughly 20 percent increase in the rate of subsequent heart-attack risk among all adult PPI users, even when excluding those also taking clopidogrel.

Nicholas Leeper, M.D., the study’s senior author and an assistant professor of vascular surgery and of cardiovascular medicine says: ‘These drugs may not be as safe as we think.’

The researchers found that another commonly prescribed heartburn drug class called H2 blockers showed no association with elevated heart-attack risk. H2 blockers, which have been around longer than PPIs, are reasonably effective against heartburn and are the second-largest-selling class of drugs used to treat it.

Research say that their findings lend support to an explanation for an untoward effect of PPIs on heart-disease risk proposed by Stanford scientists a few years ago. At the time it was shown that PPIs impede the production of an important substance, nitric oxide, in the endothelial cells that line all of the nearly 100,000 miles of blood vessels in an average adult’s body.

Researchers, through their data mining study, found that there is a 16-21 per cent increase in the rate of heart attacks, depending on which statistical approach they used, among members of the PPI group. This higher heart-attack frequency could be seen even in otherwise healthy PPI users under age 45.

In a bid to further validate their findings, researchers turned to an ongoing prospective, longitudinal study of 1,500 patients with chest pain, shortness of breath or abnormal stress-test results, conducted by Stanford in collaboration with Mount Sinai Medical Center in New York City. As a routine part of this study, patients are asked whether they are using PPIs.

To ensure that they would spot adverse drug effects if there were any, Shah, Leeper and their colleagues looked for not only heart attacks but cardiac arrest, stroke and other bad outcomes. They found that in this study population, PPI use more than doubled the risk of a patient’s suffering a subsequent major adverse cardiovascular event.

Several hypotheses have been advanced to explain the increased cardiovascular risk attributable to PPI use among clopidogrel users, who in the past were often placed on PPIs because clopidogrel can increase gastric distress. But those hypotheses haven’t held up well under scrutiny.

A new hypothesis was born in 2013, when a study in Circulation by John Cooke, M.D., Ph.D., then a professor of cardiovascular medicine at Stanford, and his colleagues, including Yohannes Ghebremariam, Ph.D., implicated PPIs in igniting a cascade of biochemical reactions that led to diminished nitric oxide levels in endothelial tissue. (Cooke and Ghebremariam, both now at Houston Methodist Research Center, are co-authors of the new study.)

‘That study implied that PPIs’ cardiovascular-risk effect had nothing to do with clopidogrel but was, instead, a direct effect on blood vessels themselves,’ Leeper said. ‘That could mean everybody on PPIs, not just people with coronary disease, is at increased risk from these drugs.’

Those findings inspired Shah and Leeper to undertake the new study. ‘We looked at cardiovascular risk for different PPI drugs,’ said Shah. ‘And we found that the degree to which the use of any particular PPI was associated with a subsequent heart attack mirrors the degree to which the drug inhibits nitric oxide in the vasculature.’

A small pilot trial led by Leeper and recently published in Vascular Medicine showed a trend between PPI use and increases in a chemical known to impair the function of an enzyme that produces nitric oxide. But the study population of 21 subjects was too small to show a conclusive link.

‘This association needs to be tested in a large, prospective, randomized trial,’ said Leeper. ‘The truth will come out when we randomize several hundred people, give half of them PPIs and put the other half on H2 blockers, and see what happens.’

Neither Shah nor Leeper recommends that people now on PPIs simply stop taking them without first talking to their doctors about alternatives.

Meanwhile, they both said, the study results should give clinicians and patients pause when deciding whether to take these medications — particularly because they’re so often taken for far longer time periods than the label recommends.