The Clopidogrel Conundrum

Joseph S. Bertino Jr., PharmD, FCP, FCCP

In this issue of the Journal, we feature a number of originalresearch articles and commentaries focusing onclopidogrel.

Clopidogrel was approved for use in the late 1990s. Asa prodrug, it is activated by a number of drugmetabolizingenzymes including enzymes showing genetic polymor-phism (CYP2C19, CYP2B6) and other enzymes showingsubstantial intersubject variability (CYP3A isozymes)and CYP1A2. Two major pharmacologic questionshave revolved around clopidogrel for years. First, doindividuals possessing CYP2C19 null alleles (primarilyCYP2C19 *2 and *3), resulting in reduced or lack ofCYP2C19 activity exhibit less pharmacologic effectdue to lack of prodrug conversion; secondly, do certainproton pump inhibitors (PPIs) such as omeprazole andesomeprazole, which auto-inhibit CYP2C19, reduce theconversion of the prodrug clopidogrel and result inreduced efficacy?

Unfortunately, the literature is not clear on either ofthese issues. In terms of the first issue, efficacy in the faceof CYP2C19 genotype, a recent review did not find strongevidence that CYP2C19 genotype makes a difference foreffect modification.1 These authors also noted that themajority of published studies which examined CYP2C19genotype and outcome were non-randomized substudieswhile the only randomized trial cited found no differencein adverse outcomes in patients regardless of CYP2C19genotype.1 While many Clinical Pharmacologists havewished and hoped for broad application of pharmacoge-nomics in drug use, clopidogrel may not be the benchmarkdrug in this regard.

Because clopidogrel is often coupled with aspirin use inpatients who have undergone percutaneous coronaryintervention (PCI), PPIsmay be administered concurrentlyto reduce the risk of GI bleeding, either as a prescription orover-the-counter drug. For this issue, whether or not asignificant reduction in efficacy is seenwhen clopidogrel isgiven with certain PPIs (omeprazole and esomeprazole),also shows inconclusive data concerning this drug–druginteraction. The study of Bhatt et al.2 suggested thatconcurrent omeprazole with clopidogrel did not reduceefficacy significantly, however, this study was terminatedearlyandby theauthor’sownconclusions, thestudywasnotpowered to show a difference in efficacy with concurrent

PPI use. A subsequent metaanalysis showed no effect ofPPIs on clopidogrel efficacy.3

The unclear nature of the literature has resulted inconfusion among clinicians. When examining the U.S.Food and Drug Administration (FDA) approved label forPlavix1 (clopidogrel) the label suggests that CYP2C19poor metabolizers (black box warning) may have reducedefficacy and alternative treatment strategies should beconsidered. Additionally, the FDA approved label statesthat doses of 80mg of omeprazole may result in reducedefficacy of clopidogrel and thus concurrent use should beavoided.4 Interestingly, the recommended doses ofPrilosec1 (omeprazole) for all indications except forpathological hypersecretory conditions is no more than40mg daily.5 The European Medicines Agency approvedlabel for Plavix1 (clopidogrel) suggests caution withconcurrent use of omeprazole and esomeprazole butsuggests that the data on the relationship of CYP2C19genotype and efficacy is still an unanswered question.6

Other alternatives to clopidogrel, such as prasugrel andticgrelor are available for use. Prasugrel and ticgrelor areavailable as brand name drugs only, at this time. A recentreport suggested that ticagrelor may be the most costeffective drug to use in some populations and settings, evenin the face of (CYP2C19) genotype directed therapy.7

However, given the fact that genotyping may not beavailable routinely in many parts of the world, and thatticagrelor and prasugrel are substantially more costly thanclopidogrel (which is available as a generic drug), a cleareridea ofwhichPCI patients should not receive clopidogrel isneeded. Many health care systems worldwide simplycannot bear the burden of using brand name antiplateletdrugs in the face of available generic agents.

The Journal of Clinical Pharmacology54(8) 841–842© 2014, The American College ofClinical PharmacologyDOI: 10.1002/jcph.344

Editor-in-Chief, Journal of Clinical Pharmacology, New WilliamsburgDrive, Schenectady, NY, USA

Submitted for publication 6 June 2014; accepted 9 June 2014.

Corresponding Author:Joseph S. Bertino Jr., PharmD, FCP, FCCP, Editor-in-Chief, Journal ofClinical Pharmacology, 3078 New Williamsburg Drive, Schenectady,NY 12303, USAEmail: sbertino@ix.netcom.com

Special Section: ClopidogrelCommentary

A planned investigation, the POPular-Genetics Studywill attempt to enroll 2700 CYP2C19 genotyped patientsundergoing PCI and randomize them to clopidogrel(CYP2C19 *1 homozygotes) or ticagrelor or prasugrel(CYP2C19 carriers of one or two *2 or *3 alleles).8

Unfortunately, this study will not answer the question asto whether or not standard doses of clopidogrel are usefulin carriers of the null activity alleles of CYP2C19.

This issue of the Journal attempts to address some ofthe questions discussed above. The article of Martínez-Quintana et al.9 suggests that CYP2C19 genotype orconcurrent omeprazole use does not affect outcome inPCI patients receiving clopidogrel. Uotani et al.10

investigated the use of famotidine (which does notinhibit CYP2C19 or CYP3A isozymes) to prevent gastricmucosal injury by antiplatelet agents, suggesting thatalternatives to PPIs may be useful to reduce the risk ofGI bleed when using aspirin þ clopidogrel. Horensteinet al. notes that larger doses of clopidogrel may beindicated in patients with reduced CYP2C19 activity.11

In addition this issue of the Journal has other excellentoriginal research articles presenting useful informationand some opposing points of view.

It is clear that for a drug that has been available for over15 years, substantial questions still are left unanswered. Arecent review of clinicaltrials.gov revealed that there areover 400 ongoing studies with clopidogrel. While thearticles in this month’s issue of The Journal of ClinicalPharmacology do not provide all the answers, hopefullythese articles will provide clinicians with food for thoughton the use of clopidogrel and in what circumstancesalternative therapies may be appropriate.

Declaration of Conflicting Interests

None.

References1. Agency for Healthcare Quality and Research. Executive Summary:

Testing of CYP2C19 Variants and Platelet Reactivity for GuidingAntiplatelet Treatment. Effective Health Care Program; 2013.Accessed at http://effectivehealthcare. ahrq.gov/search-for-guides-reviews-and-reports/?pageaction[1]displayproduct &productID =1725 on 6 June 2014.

2. Bhatt DL, Cryer BL, Contant CF. Clopidogrel with or withoutomeprazole in coronary artery disease. New Engl J Med.2010;363(20):1909–1917.

3. Kwok CS, Loke YK. Meta-analysis: effects of proton pumpinhibitors on cardiovascular events and mortality in patientsreceiving clopidogrel. Aliment Pharmacol Therapeut. 2010;31-(5):810–823.

4. Kazi DS, Garber AM, Shah RU, et al. Cost-effectiveness ofgenotype-guided and dual antiplatelet therapies in acute coronarysyndrome. Ann Int Med. 2014;160(2):221–232.

5. Plavix Package Insert. United States Food andDrugAdministration,December 2013.

6. Prilosec Package insert. United States Food and Drug Administra-tion. March 2014.

7. Plavix Package Insert. European Medicines Agency. March 2014.8. Bergmeijer TO, Janssen PWA, Schipper JC, et al. CYP 2C19

genotype guided antiplatelet therapy in STEMI patients – rationaleand design of the POPular Genetics-study. Am Heart J. 2014.DOI: 10.1016/j.ahj.2014.03.006.

9. Martínez-Quintana E,Medina-Gil JM, Rodríguez-González F, et al.Positive clinical response to clopidogrel is independent ofparaoxonase 1 Q192R and CYP 2C19 genetic variants. J ClinPharmacol. Article first published online: 14 FEB 2014 | DOI:10.1002/jcph.275.

10. Uotani T, Sugimoto M, Nishino JM, et al. Prevention of Gastricmucosal injury induced by anti-platelet drugs by famotidine. J ClinPharmacol. Article first published online: 21 MAR 2014 DOI:10.1002/jcph.284.

11. Horenstein RB, Madabushi R, Zineh I, et al. Effectiveness ofclopidogrel dose escalation to normalize active metabolite exposureand antiplatelet effects in CYP2C19 poor metabolizers. J ClinPharmacol. Article first published online: 7 APR 2014 | DOI:10.1002/jcph.293.

842 The Journal of Clinical Pharmacology / Vol 54 No 8 (2014)