Dangerous Interaction Between Heartburn Drugs and Clopidogrel (PLAVIX)

A new study, published online in Canadian Medical Association Journal January 28th, has found that people taking both clopidogrel (PLAVIX — a drug to prevent heart attacks in people who have just had a heart attack) and certain heartburn drugs, such as esomeprazole (NEXIUM — a PPI or proton pump inhibitor that inhibits stomach acid formation) had a 27 percent increased risk of subsequent heart attacks, compared with people who used only clopidogrel.

In the study, this dangerous interaction was only present in people who had used PPI drugs along with clopidogrel within the 30 days prior to their hospitalization with the recurrent heart attack. People who had used a PPI drug but stopped using it more than 30 days before the second heart attack did not have an increased risk of heart attacks compared to those who had never used PPI drugs with their clopidogrel.

The reason for this serious adverse interaction between these commonly used drugs is that clopidogrel is not effective until it has been converted to its active form by a drug-metabolizing enzyme in the liver. PPI drugs (such as esomeprazole) are often used by people who are taking clopidogrel because they are frequently taking aspirin as well and because clopidogrel can be irritating to the stomach.

When both drugs—clopidogrel and a PPI drug—are being used, the liver is stopped from converting clopidogrel into its active metabolic product. Much of the effectiveness of clopidogrel is therefore lost and its ability to prevent heart attacks is seriously impaired.

Large numbers of people are taking clopidogrel and/or an acid-suppressing PPI. In 2007, there were 22.3 million prescriptions for clopidogrel filled in the U.S. That same year, a total of 73 million prescriptions were filled for PPIs including esomeprazole, lansoprazole (PREVACID), rabeprazole (ACIPHEX) and the generically available omeprazole (PRILOSEC).

The enormous number of people taking both clopidogrel and a PPI can be seen in the data from the study in which well over one in five of those using clopidogrel were also using a PPI.

The study’s authors also found that there was also no evidence that other drugs that reduce stomach acid, such as H2 blockers (e.g., ZANTAC, PEPCID, TAGAMET and AXID) or antacids interfere with the antiplatelet activity of clopidogrel.

The authors of the Canadian study said:

Our findings have major implications for public health, given the number of patients exposed to this drug interaction. With annual sales of US$7.3 billion in 2007, clopidogrel is the drug with the second-largest sales volume worldwide. Millions of patients around the world receive a coronary stent or experience new or recurrent myocardial infarction each year. The majority of them will be prescribed clopidogrel in addition to ASA [aspirin].

Recent guidelines published by the American Heart Association, the American College of Gastroenterology and the American College of Cardiology advocate proton pump inhibitor therapy for the majority of patients receiving ASA after myocardial infarction, including all patients aged 60 years or older. Our findings suggest that indiscriminate treatment with a proton pump inhibitor could result in thousands of additional cases of recurrent myocardial infarction each year, all of which could potentially be avoided by preferentially using pantoprazole in patients taking clopidogrel who require treatment with a proton pump inhibitor.

The authors summarized that "Our findings highlight a widely unappreciated, common and completely avoidable drug interaction in a population at high risk of recurrent coronary events [heart attacks]." Last year, we reported to Worst Pills, Best Pills readers that a study investigating the effect of the heartburn drug omeprazole on the action of clopidogrel plus aspirin therapy found that omeprazole significantly decreased the effect of clopidogrel (meaning that it could be less effective in preventing strokes and heart attacks). Physicians should be aware of this association, since this drug combination is widely prescribed.

What You Can Do

Of the two drugs involved in this interaction, clopidogrel is clearly the more important one in terms of its heart attack prevention effects.

We therefore agree with the FDA’s recommendation that "healthcare providers […] continue prescribing clopidogrel and […] re-evaluate the need for starting or continuing treatment with a PPI in clopidogrel recipients. Clopidogrel recipients are advised to consult their healthcare providers if they are receiving or considering taking a PPI."

This recommendation, presumably made before knowledge of this new study, can be amplified by the authors’ findings and their recommendation that "concomitant treatment with clopidogrel and proton pump inhibitors other than pantoprazole should be minimized when possible. Pepcid, Zantac, Ranitidine or another H2-receptor antagonist may be an appropriate alternative for patients who require acid-lowering therapy. If a proton pump inhibitor is required, pantoprazole should be used preferentially in patients who are also receiving clopidogrel."