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Study Finds Dangerous Interaction Between PLAVIX and Heartburn MedicationsFeb 1, 2009
On January 28, a study published online in the Canadian Medical Association Journal announced the finding that people taking PLAVIX (clopidogrel), who had already suffered a recent heart attack, as well as certain heartburn medications, had a 27% increased risk of subsequent heart attacks, compared with people taking only PLAVIX.
PLAVIX is a drug designed to prevent heart attacks in people who have just suffered a heart attack, while medications such as esomeprazole (NEXIUM) are known as proton pump inhibitors (PPI) and retard stomach acid formation.
The research revealed that this dangerous interaction occurred only in people who had used PPIs along with PLAVIX within the 30 days prior to their hospitalization with the subsequent heart attack. Subjects who had used a PPI medication 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 a PPI with clopidogrel.
The explanation for this adverse interaction is that PLAVIX is not effective until it is converted to its active form by a drug-metabolizing enzyme in the liver. PPI s are frequently taken by people who are taking PLAVIX because they are often taking aspirin as well and because PLAVIX can irritate the stomach.
When the two medications are used together, the liver is stopped from converting PLAVIX into its active metabolic product. As a result, the effectiveness of the PLAVIX is lost and its ability to prevent heart attacks is seriously impaired. The problem is a significant one due to the extensive use of the two types of medications. In 2007 alone, there were some 22.3 million prescriptions for clopidogrel in the United States along with a total of 73 million prescriptions for PPIs, which include NEXIUM (esomeprazole), PREVACID (lansoprazole, ACIPHEX (rabeprazole) and PRILOSEC (the generically available omeprazole). An analysis of the data indicates that some 20% of those taking PLAVIX also take a PPI.
The researchers found no evidence that other drugs that reduce stomach acid, such as H2 blockers (including ZANTAC, PEPCID, TAGAMET and AXID) or antacids have a negative effect on the antiplatelet activity of PLAVIX. According to the study authors, "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 researchers concluded 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]."
In 2008, the team reported to Worst Pills, Best Pills 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.
Clearly, of the two drugs involved, PLAVIX is unquestionably the more important in terms of heart attack prevention. The FDA recommends 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, which was presumably issued before knowledge of the new study, should now be amplified by the researchers' findings and their suggestion 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."
The study found over-the-counter anti-acid drugs and an alternative PPI, pantoprazole (PROTONIX), do not cause this dangerous interaction and there was no increase in repeat heart attacks. PROTONIX, unlike the other PPIs, does not inhibit the liver enzyme that converts PLAVIX into its active form thereby permitting it to be metabolized properly and help prevent subsequent heart attacks.