1. Aschenbrenner, Diane S. MS, APRN,BC

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* In patients taking both clopidogrel and a proton pump inhibitor, the drug interaction that may occur through the cytochrome P-450 isoenzyme system can diminish the effectiveness of clopidogrel. * A genetic variation in the same isoenzyme system may impair the metabolism of clopidogrel, thereby also diminishing the effectiveness of the drug.


Recent research indicates that either a drug interaction or a genetic variation affecting metabolism can alter the effectiveness of the antiplatelet drug clopidogrel (Plavix), posing the risk of possibly life-threatening cardiovascular complications. Clopidogrel, which inhibits platelet aggregation and therefore can prevent blood clots and cardiovascular events, is prescribed after recent myocardial infarction or stroke, after acute coronary syndromes, and as prophylaxis in patients with peripheral arterial disease.


But clopidogrel can also cause dyspepsia (gastric distress, including pain, burning, and nausea) as well as gastric ulceration and gastrointestinal bleeding, especially when used with aspirin in the dual antiplatelet therapy commonly prescribed after acute coronary syndromes. Because proton pump inhibitors (including omeprazole [Prilosec, Zegerid], lansoprazole [Prevacid], pantoprazole [Protonix], rabeprazole [Aciphex], and esomeprazole [Nexium]) decrease gastric acidity and are useful in the treatment of gastroesophageal reflux disease and stomach ulcers, they are commonly prescribed to treat or prevent gastric adverse effects in patients taking clopidogrel. However, studies noted by the Food and Drug Administration (FDA; see for more information) describe the possibility of an interaction between clopidogrel and omeprazole via the cytochrome P-450 (CYP) isoenzyme system that appears to significantly diminish clopidogrel's antiplatelet effect.


Clopidogrel is a "prodrug," meaning it's not therapeutically active in its natural state but must first be metabolized. CYP 2C19 is one of the principal enzymes in the liver through which clopidogrel is extensively metabolized. Therefore, coadministration of clopidogrel and a drug that alters the level of CYP 2C19 will change the amount of clopidogrel that can be metabolized into the therapeutically active form. If the other drug decreases the available CYP 2C19, less clopidogrel will be converted to its therapeutically active form. Conversely, if the other drug increases the amount of CYP 2C19, more than the expected amount of clopidogrel will become active. Proton pump inhibitors exert an effect on CYP 2C19 in two ways: they inhibit it and can also be metabolized by it (that is, it is a "substrate" of the enzyme). Both actions diminish the amount of CYP 2C19 available to metabolize clopidogrel. If significantly less therapeutically active clopidogrel is formed, its effectiveness is diminished or may even be lost.


Current studies also suggest that some patients may have a genetic variation in their CYP isoenzyme system that predisposes them to poorly metabolize clopidogrel. Such patients receive less therapeutically active drug and experience worse clinical outcomes. When patients with this genetic variation concurrently take clopidogrel and a proton pump inhibitor, the problem is compounded.


The FDA is conducting a safety review of these recent findings and has asked the manufacturers of clopidogrel (Sanofi-Aventis and Bristol-Myers Squibb) to conduct additional clinical trials to learn more about the genetic variation that can alter its effectiveness, as well as additional research into possible drug interactions, especially in the use of proton pump inhibitors. As more becomes known, it's possible that the FDA will request revisions to the clopidogrel labeling, but so far none are proposed.


In the meantime, patients likely to have such drug interactions, rather than discontinue clopidogrel, should discontinue use of the proton pump inhibitor and change to another class of drug to diminish gastric acidity, such as the histamine H2 blockers ranitidine (Zantac), famotidine (Pepcid), cimetidine (Tagamet), and nizatidine (Axid), and take antacids that don't interfere with clopidogrel's effectiveness. Because not all patients taking clopidogrel develop gastric distress, it may be prudent in light of the new findings not to use proton pump inhibitors prophylactically, but instead restrict their use to patients who can't use other drug therapy.


To assess for possible drug interactions, nurses should review all other prescribed medications in patients taking clopidogrel, especially the concomitant use of a proton pump inhibitor. If an interaction is likely, the prescriber should be notified to discuss with the patient a safe substitution for the other drug. If use of that drug must be continued, the nurse should monitor laboratory data to assess clopidogrel's therapeutic effectiveness. The patient should be instructed not to use the over-the-counter proton pump inhibitor omeprazole (Prilosec OTC) concurrently with clopidogrel. Until there's more information on genetic variations in CYP 2C19 and how to identify people with it, nurses should carefully monitor laboratory data on all patients taking clopidogrel to verify that platelet aggregation and bleeding time are within therapeutic range-diminished aggregation and lengthened bleeding time are the expected findings.