Clopidogrel: Some Drugs May Reduce Its Effectiveness

In October 2003, this column discussedthe potential interactionbetween clopidogrel (Plavix) andatorvastatin. At that time, it was concludedthat this interaction was unlikelyto cause a risk to patients. Multiplestudies in the past few years have confirmedthat view.

Clopidogrel represents a ratherunique risk for drug interactions, however.It is a prodrug that requires metabolicconversion to a thiol metabolitethat binds to the platelet adenosinediphosphate receptor and reduces theability of platelets to aggregate. Theantiplatelet effect is useful to preventblood clots in the arterial system and inpatients with coronary artery stents.

CYP3A4 Inhibitors

It is believed that cytochrome P(CYP) enzymes CYP3A4 and CYP2C19are involved in the conversion of clopidogrelto its active metabolite. Previously,CYP3A4 inhibitors such as erythromycinand ketoconazole (Nizoral)have been demonstrated to reduceclopidogrel antiplatelet activity. Alldrugs that possess at least modestCYP3A4 inhibitory activity should beconsidered to interact with clopidogreland may reduce its therapeutic effectiveness.

Thus, it is very important for pharmaciststo review the drug therapy ofpatients prescribed clopidogrel. Oneshould look for any concomitant drugknown to be an inhibitor of CYP3A4.Other common CYP3A4 inhibitors includeclarithromycin (Biaxin), fluconazole(Diflucan), itraconazole (Sporanox),posaconazole (Noxafil), voriconazole(Vfend), diltiazem (Cardizem), verapamil(Calan), and the chronic consumptionof grapefruit juice.

CYP2C19 Inhibitors

Recently, omeprazole (Prilosec), aninhibitor of CYP2C19, has been reportedto reduce the activity of clopidogrel.^1,2 In both observational and placebo-controlled trials, patients receivingomeprazole with clopidogrel had agreater likelihood of inadequateantiplatelet response. Theodds ratio of being a poorresponder to clopidogrelwhen taking concomitantomeprazole was estimatedto be 4.3.²

The mechanism of omeprazole-induced reductionin antiplatelet activity ofclopidogrel has not beendefined. It may be due toomeprazole's inhibition ofCYP2C19. If this is true, esomeprazole(Nexium) wouldbe expected to interact in asimilar manner.

It is important to note that none ofthe other proton pump inhibitors (eg,lansoprazole [Prevacid], rabeprazole[Aciphex], pantoprazole [Protonix])inhibit CYP2C19 and may not interactwith clopidogrel. In addition to omeprazoleand esomeprazole, fluvoxamine(Luvox), voriconazole, and cimetidine(Tagamet) have been noted to inhibitCYP2C19 activity. Until data are availableshowing a lack of interaction withthese drugs, patients taking clopidogrelshould avoid drugs that inhibit CYP2C19activity.

CYP2C19 metabolic activity is geneticallydetermined, with 10% to 30% ofpatients having reduced CYP2C19activity. Patients who are geneticallypoor metabolizers (PMs) for CYP2C19may not have an adequate response toclopidogrel treatment. Patients ofAsian descent are more commonlyfound to be PMs for CYP2C19.

The antiplatelet activity of clopidogrelhas been reported to predict theability of clopidogrel to prevent cardiovascularevents. Reduced antiplateletactivity has been associated with theoccurrence of recurrent coronaryevents and stent thrombosis.³ Severalstudies have reported resistance toclopidogrel's effects in up to30% of patients treated withthe drug. Unfortunately,these studies did not controlfor the patient's CYP2C19phenotype or for concurrentdrug therapy that mightaffect clopidogrel's conversionto its active metabolitevia CYP3A4 or CYP2C19.

Rifampin (Rifadin), rifapentine(Priftin), carbamazepine(Tegretal), barbiturates, andSt. John's wort are known toinduce the activity of CYP3A4and will enhance the antiplatelet effectof clopidogrel. For that reason, patientstaking clopidogrel should be advised toavoid St. John's wort, and clopidogreldoses may need to be reduced if aCYP3A4 inducer is coadministered.

By careful monitoring of patientsprescribed clopidogrel, drugs likely toreduce its effectiveness can be avoided,and perhaps fewer patients will beresistant to its beneficial therapeuticeffects.

References

• Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J Thromb Haemost. 2006;4:2508-2509.
• Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. J Am Coll Cardiol. 2008;51:256-260.
• Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109:3171-3175.