When Clopidogrel Fails…

March 10, 2010

imagesMarisa Mizus

Faculty peer reviewed

Clopidogrel (Plavix) has been the standard of care for patients with coronary artery disease following percutaneous coronary intervention (PCI) for the past decade.  Although it is a successful antiplatelet treatment in many patients, like any hero, it has a weakness: formation of its active metabolite depends on two hepatic cytochrome P450 (CYP450)-dependent steps.  Clopidogrel resistance, or non-response, is correlated with an increased risk of major adverse cardiovascular events, including reinfarction and stent thrombosis.(1)  It is often unclear why a patient does not respond to clopidogrel, although there is speculation that clopidogrel resistance results from the attenuating effects of proton pump inhibitors (PPIs) and CYP450 reduced function polymorphisms.(2)

Patients showing inadequate platelet response to clopidogrel have been treated with varying success with either a larger dose of clopidogrel or the addition of a glycoprotein IIb/IIIa inhibitor. Prasugrel (Effient), another thienopyridine, has been shown to be a more potent inhibitor of platelet aggregation than clopidogrel. (3) In fact, some studies have shown prasugrel’s superior efficacy even in combination with PPIs or in patients with CYP450 reduced function alleles, thus making it a second-line therapy in patients exhibiting clopidogrel resistance, with the potential of replacing clopidogrel as the drug of choice in certain types of patients.

PPIs are typically prescribed prophylactically with anti-platelet therapy in order to reduce the risk of gastrointestinal bleeding.  PPIs have been shown to inhibit CYP450 enzymes, thereby reducing the efficacy of drugs like thienopyridines.  Clopidogrel activation specifically depends on CYP2C19 activity.  The extent to which PPIs, especially omeprazole, actually affect clinical outcomes in patients taking thienopyridines is controversial. (4)  However, it has been shown that administration of certain PPIs significantly decreases clopidogrel’s inhibitory effect on platelet reactivity (5) and that current use of PPIs in patients also on clopidogrel status-post MI is associated with an increased risk of reinfarction and readmission for MI. (6)  Similarly, patients with reduced function polymorphisms in CYP450 alleles show decreased anti-platelet activity and are at greater risk for re-infarction and stent thrombosis.  This effect is thought to be even more pronounced in patients taking clopidogrel with a PPI. (7) In contrast, it has been shown that prasugrel, which depends on the enzyme CYP3A, retains anti-platelet activity even with PPI co-administration.(8)  Prasugrel also maintains anti-platelet efficacy in the face of reduced function polymorphisms of hepatic CYP450 alleles.(9)  However, prasugrel has been shown to increase the risk of major bleeding compared with clopidogrel and, at this point, its use is suggested for patients who are at low risk for bleeding and for patients who do not respond to clopidogrel therapy.

The FDA approved prasugrel to prevent thrombotic events in patients undergoing angioplasty in July of 2009.  It is suggested that clinicians weigh the risks of major bleeds against the benefits of superior anti-platelet activity, keeping in mind the limitations of applying data from a study population to individual patients in the community. 

Marisa Mizus is a 3rd year medical student at NYU School of Medicine.

Faculty peer reviewed by Dr. Robert Donnino, NYU Division of Cardiology.


1)  Simon DI, Jozic J.  Drug-eluting stents and antiplatelet resistance.  Am J Cardiol. 2008;102 (9 Suppl):29J-37J. Accessed October 12, 2009.

 2) Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.  JAMA. 2009;301(9):937-944.  http://jama.ama-assn.org/cgi/content/full/301/9/937.  Accessed October 21, 2009.

 3) Wiviott SD, Braunwald E, McCabe CH, et al.  Prasugrel versus clopidogrel in patients with acute coronary syndromes.  N  Engl J Med. 2007:357(20):2001-2015.  http://content.nejm.org/cgi/content/full/NEJMoa0706482.  Accessed on October 19, 2009.

 4) Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet. 2009;374(9694):952-954.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961562-2/fulltext.  Accessed October 19, 2009.

 5) Roden D, Stein C.  Clopidogrel and the concept of high-risk pharmacokinetics.   Circulation. 2009;119(16):2127-2130.  http://circ.ahajournals.org/cgi/content/full/119/16/2127.  Accessed on October 21, 2009.

 6) Li XQ, Andersson TB, Ahlstrom M, Weidolf L.  Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole, on human cytochrome P450 activities.  Drug Metab Dispos. 2004;32(8):821-827.  http://dmd.aspetjournals.org/cgi/reprint/32/8/821.  Accessed October 12, 2009.

 7) Mega  JL, Close SL, Wiviott S, et al. Cytochrome p-450 polymorphisms and response to clopidogrel.  N Eng J Med. 2009;360(4):354-362. http://content.nejm.org/cgi/content/full/NEJMoa0809171.  Accessed October 12, 2009.

 8) Small DS, Farid NA, Payne CD, et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel.  J Clin Pharmacol. 2008; 48(4):475-484.  http://jcp.sagepub.com/cgi/content/short/48/4/475.  Accessed October 21, 2009.

 9) O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomized trials.  Lancet. 2009;374(9694):989-997.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961525-7/fulltext.  Accessed October 21, 2009.

 

 

One Response to When Clopidogrel Fails…

  1. Charles Maltz, MD on March 14, 2010 at 5:23 pm

    As you note, the data regarding the clinical significance of the interaction of PPI’s and clopidogrel is mixed. The only double blind, prospective study I am aware of is the Cogent study comparing the combination of ASA, clopiodgrel, and omeprazole versus ASA and clopidogrel. Although this study was terminated early due to financial difficulty of the sponsor, the date obtained showed no significant difference in cardiac events in the two arms. The number of GI events was signficantly greater in the arm without the omeprazole

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