PIC QUESTION OF THE WEEK: 2/09/09

Q: What is the significance of the possible drug interaction between clopidogrel and proton pump inhibitors?

A: The FDA has recently distributed preliminary information regarding a potential drug interaction between

clopidogrel (Plavix) and proton pump inhibitors (PPIs). Clopidogrel is an antiplatelet medication used

extensively to prevent arterial thromboembolism in patients at risk for myocardial infarction and stroke as

well as in individuals undergoing percutaneous coronary intervention (PCI) or receiving coronary artery by-

pass grafting (CABG). It is considered a “pro-drug” and must be converted to an intermediary metabolite,

then subsequently hydrolyzed to its active moiety. The hepatic isoenzyme responsible for conversion of

clopidogrel is CYP2C19. PPIs are often prescribed with clopidogrel because of its association with gastric

irritation and possible hemorrhage. PPIs can inhibit various CYP isoenzymes and may prevent the conversion

of clopidogrel to its active derivative. A recently completed double-blind trial involving 124 patients

receiving aspirin and clopidogrel after coronary stent implantation compared the effects of omeprazole or

placebo on the ability of clopidogrel to inhibit platelet activation. After one week of therapy, platelet

reactivity was significantly higher in the omeprazole arm of the study. Another trial evaluated the effects of

PPIs in nearly 14,000 patients taking clopidogrel for one year after stent placement. Approximately 9,000

study patients took clopidogrel alone while over 4,000 took a PPI along with clopidogrel. This study

concluded that patients taking both drugs were at a higher risk for major cardiac events than those taking

clopidogrel alone. It has not been established whether other PPIs similarly affect clopidogrel. Thus far, only

omeprazole has been implicated in this possible interaction; however, other PPIs would be expected to

behave similarly. The FDA currently has no evidence that acid suppressants such as histamine H2 antagonists

or antacids interfere with the antiplatelet activity of clopidogrel. Healthcare providers should re-evaluate the

need to place patients receiving clopidogrel on concurrent PPI therapy. Further study is necessary to more

clearly identify the risk of combined treatment with clopidogrel and PPIs.

References:

Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel sulfate

(marketed as Plavix). Available at http://www.fda.gov/cder/drug/early_comm/clopidogrel_bisulfate.htm

PPI interactions with clopidogrel. Med Lett Drugs Ther 2009; 51:2-3.

Gilard M, Amaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel

associated with aspirin: the randomized, double blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am

Coll Cardiol 2008; 51:256-60.

Brandon J. Lawatsch and Sarah G. Stramat, Pharm.D. Candidates

The PIC Question of the Week is a publication of the Pharmaceutical Information Center, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282 (412.396.4600).

Dick LeBeau – Defensive Coordinator, Super Bowl Steelers-2009

  

PIC QUESTION OF THE WEEK: 2/09/09 

Q: What is the significance of the possible drug interaction between clopidogrel and proton pump inhibitors?

Update

This Update is provided because of some recent literature suggesting the potential drug interaction between Clopidogrel - PPIs discussed in the 2/09/2009 PIC Question of the Week may be more significant than initially suggested. A number of studies published in 2009 have directly or indirectly evaluated P-450 2C19 enzyme activity and patient response to clopidogrel and PPIs. It appears that patients receiving clopidogrel have a greater tendency toward cardiovascular (CV) events if they possess a less active genetic variant of 2C19. In one of the studies, concomitant use of PPIs had no effect on CV events. In another, there was an increase in the number of CV events in those receiving PPIs, but not among patients treated with pantoprazole. The Medical Letter on Drugs and Therapeutics has recently published an addendum to its earlier review of the topic and also advised that the interaction may be important. It appears that histamine H2-antagonists might be preferable to PPIs in patients receiving clopidogrel. The significance of the interaction between PPIs and clopidogrel does require further study. Supportive references are included below. References:

• Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-62.

• Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;360:363-75.

• PPI interactions with clopidogrel – revisited. Med Lett Drugs Ther 2009;51:13. • Juurlink DN, Gomes T, Ko D, et al. A population-based study of the drug interaction between proton pump

inhibitors and clopidogrel. CMAJ 2009;180(7). DOI:10.1503/cmaj.o82001 John G. Lech, Pharm.D. The PIC Question of the Week is a publication of the Pharmaceutical Information Center, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282 (412.396.4600).

Dick LeBeau – Defensive Coordinator, Super Bowl Steelers-2009