Genes Predict Clopidogrel Response
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Physicians prescribe clopidogrel to prevent blood clots that can cause heart attacks and strokes. However, the drug is less effective for some patients. Up to 30% percent of patients have a genetic variant of the CYP2C19 allele that prevents them from metabolizing clopidogrel effectively.2,3
In 2009, Mega et al. published a retrospective analysis of the CYP2C19 alleles in 1477 subjects with acute coronary syndrome treated with clopidogrel in the TRITON-TIMI 38 trial. Patients with one variant in the CYP2C19 allele had an increased risk of serious cardiovascular events.2
The U.S. Food and Drug Administration (FDA) has recognized the effect of genetic variations on clinical outcomes. In March 2010, the FDA issued a Boxed Warning for clopidogrel.5
The ability of clopidogrel to inhibit platelet aggregation depends on the action of a key liver enzyme called cytochrome P450 2C19 (CYP2C19), which metabolizes the drug to its active form. Patients with reduced enzyme function (one or more loss of function gene variants of the CYP2C19 allele) have reduced conversion of clopidogrel to its active form.6
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Which CYP2C19 genotype do your patients have?
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CYP2C19 Phenotype & Genotype Frequencies
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Results of the Mega TRITON-TIMI 38 Study2
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Multiple studies, similar results
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A 2010 meta-analysis published in the Journal of the American Medical Association by Mega et al. included nine studies with 9685 patients. In eight of nine studies,3 patients with one or two variants of the CYP2C19 allele had an increased risk of cardiovascular death, heart attack and ischemic stroke. In this population, 91.3% of patients underwent PCI and 54.5% had ACS.3
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Carriers of 1 or 2 CYP2C19 reduced function alleles vs noncarriers3
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Risks to clopidogrel Ultra-Rapid Metabolizers7
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The genotypes of the CYP2C19 genes were analyzed in 1524 patients undergoing PCI who were pretreated with clopidogrel 600 mg.8 Patients metabolizing clopidogrel very effectively (Ultra-Rapid Metabolizers with one or two CYP2C19 *17 allele variants) had significantly increased drug response (P < 0.001) and significant bleeding increase (P = 0.006).
As shown to the right, patients with one *17 variant, associated with clopidogrel sensitivity, were more likely to have a bleeding event within 30 days of pretreatment with clopidogrel. People with two *17 variants were three times more likely to have a bleeding event within 30 days.8
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What about platelet function testing?
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Recent Recommendations for Clinical Practice
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1. In the recent recommendation from the American College of Cardiology on genotyping for clopidogrel it was suggested that for "moderate to high risk patients" genotyping may be considered to identify poor metabolizers. The ACC suggested this made sense, since as pointed out by the FDA, alternate therapies are available.9
2. In apparent agreement with the ACC recommendation, researchers from the Scripps Institute have recently pointed out that with stent thrombosis rates in carriers of CYP2C19 as high as 11%, mortality associated with such events close to 50%, and a near 2-fold increase in the risk of bleeding in CYP2C19*17 carriers, that rather than wait years for results from future prospective trials to be initiated, it makes clinical sense to implement all potential interventions to help prevent the catastrophic outcomes of stent thrombosis and death in the tens of thousands of patients currently at risk.11
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References
1. Plavix ® website. Available at: http://www.plavix.com/clopidogrel/blood-clots.aspx. Accessed: March 17, 2011.
2. Mega JL, Close SL, Wiviott SD. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354-362.
3. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304:1821-1830.
4. FDA Media Teleconference on Plavix at 5 (March 12, 2010). Dr. Robert Temple, Deputy Director for Clinical Science in the Center for Drug Evaluation and Research (CDER). Available at http://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/UCM204512.pdf.
5. Plavix ® (clopidogrel bisulfate) tablets [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; February 2011.
6. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119:2553–2560.
7. Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol. 2001;41:815-850.
8. Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121:512-518.
9. American College of Cardiology Task Force on Clinical Expert Consensus Documents, American Heart Association, Society for Cardiovascular Angiography and Interventions, et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2010;56:321-41.
10. Geisler T, Schaeffeler E, Dippon J, et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics. 2008;9:1251-1259.
11. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation [Internet]. 2011(published online at http://circ.ahajournals.org) on March 28, 2011);123:__.
Plavix ® is a registered trademark owned by Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals Partnership. There is no affiliation, sponsorship or endorsement by Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals and Iverson Genetic Diagnostics, Inc. Effient ® is a registered trademark owned by Eli Lilly and Company. There is no affiliation, sponsorship or endorsement by Eli Lilly and Company and Iverson Genetic Diagnostics, Inc .
Any other trademarks or service marks listed without identification of companies are the property of their respective owners. Quotations made by third parties represent their views only. The naming of a company is not a representation of the company interaction with the FDA, nor are any comments an endorsement or advertisement for such companies. No further reproductions, alterations or representations of this document by any third party are authorized or endorsed by Iverson Genetic Diagnostics, Inc.
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Iverson's Clopidogrel
GenoSTAT Panel tests
for the following gene:
• CYP2C19
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Does insurance
cover the test?
Many insurance carriers, as well as Medicare, may cover CYP2C19 testing when medically necessary and ordered by a physician.
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