CMAJ: PPIs increase risk of heart attacks for patients on clopidogrel

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Patients taking clopidogrel following a heart attack are at a significantly higher risk of a recurrence if they are also taking acid-lowering medications such as proton pump inhibitors (PPIs), according to a study published online in January in the Canadian Medical Association Journal.

Previous research indicates that PPIs other than pantoprazole can block the liver's ability to convert clopidogrel to its active form, required for clopidogrel's anti-platelet effect. Due to questions raised by these studies, the FDA launched further studies, seeking a better understanding and characterization of the effects of genetic factors and other drugs, especially PPIs, on the effectiveness of clopidogrel.

Recent guidelines from the American Heart Association (AHA), the American College of Gastroenterology (ACG) and the American College of Cardiology (ACC) recommend PPI therapy for many patients following a MI to prevent bleeding from the stomach, including all patients aged 60 years or older receiving ASA. Because clopidogrel and aspirin are often prescribed together following a heart attack, the authors said that it is probable that millions of patients worldwide will take a PPI with clopidogrel.

The study found a significantly increased risk of readmission for heart attacks patients, aged 66 years and older, if they were taking one of several PPIs, including omeprazole (Prilosec, AstraZeneca) lansoprazole (Prevacid, TAP Pharmaceuticals) or rabeprazole (Aciphex, Ortho-McNeil-Janssen Pharmaceuticals). The investigators found no such association with the PPI pantoprazole (Protonix, Wyeth) or with other acid-lowering medications, called H2 receptor antagonists.

The researchers conducted a population-based, nested-case control study among patients age 66 years or older, who commenced clopidogrel between April 1, 2002, and Dec. 31, 2007, following hospital discharge after treatment of acute MI. The cases were those readmitted with acute myocardial infarction within 90 days after discharge. The investigators performed a secondary analysis considering events within one year.

Among 13,636 patients prescribed clopidogrel following acute MI, the researchers identified 734 cases re-admitted with myocardial infarction and 2,057 controls.  After extensive multivariable adjustment, current use of PPI was associated with an increased risk of reinfarction. They found no association with more distant exposure to PPIs or in multiple sensitivity analyses. In a stratified analysis, pantoprazole, which does not inhibit cytochrome P450 2C19, had no association with readmission for MI.

“Depending on the exposure to these drugs following a heart attack, we estimate that 5 to 15 percent of early readmissions for MI among patients taking clopidogrel could be the result of this drug interaction," wrote the study’s lead author David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto. "These findings highlight a widely unappreciated, extremely common and completely avoidable drug interaction in a population of patient at very high risk of reinfarction.”

“Our findings suggest that indiscriminate treatment with a PPI could result in thousands of additional cases of recurrent MI each year, all of which could be avoided simply by selectively prescribing pantoprazole in patients receiving clopidogrel who require treatment with a PPI,” the authors wrote.