"For Plavix to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug do not effectively convert Plavix to its active form. In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death.¹" —FDA 2010

The FDA warning regarding Plavix^® (clopidogrel bisulfate) tablets:

Many publications have verified the association between CYP2C19 nonfunctional alleles and Plavix metabolism. A recent publication in the New England Journal of Medicine reported the following:^‡2

• In healthy subjects treated with clopidogrel, 2C19 reduced-function allele carriers had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (p<0.001)
• Carriers also had 9% less reduction in maximal platelet aggregation in response to clopidogrel than that seen in noncarriers (p<0.001)
• Among ACS patients treated with clopidogrel, the rate of the primary efficacy outcome (a composite of death from cardiovascular causes, MI, or stroke) was 12.1% among carriers, as compared with 8.0% among noncarriers (hazard ratio for carriers, 1.53; 95% confidence interval (CI), 1.07 to 2.19; p= 0.01) (Figure 1)
• Among patients treated with clopidogrel who underwent PCI with stenting, the rate of definite or probable stent thrombosis was 2.6% among carriers and 0.8% among noncarriers (hazard ratio 3.09; 95% CI, 1.19 to 8.00; p = 0.02) (Figure 2)

Carriers were defined as subjects with at least one CYP2C19 reduced-function allele and were approximately 30% of the study population.

• Study conclusions were: Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

Berkeley HeartLab CYP2C19 Genotype Test Results

For more information about CYP2C19, call Berkeley HeartLab Customer Support at 1-800-432-7889, option 3 or fill out our contact form.

*The clinical impact of the CYP2C19 genotype on the metabolism of specific drugs will vary based on non-genetic factors, such as hepatic and renal status, other medications used (including over-the-counter medications, herbals, and other supplements), alcohol or illegal drug use, race, age, weight, diet, and diseases present in an individual patient.

‡Pharmacokinetic and pharmacodynamic analysis was performed on healthy individuals. Clinical outcomes data was performed in Caucasian patients with known coronary syndrome undergoing dual antiplatelet treatment.

#The Berkley HeartLab CYP2C19 Genotype Test detects the non-functional alleles *2, *3,*4, *5, *6, *7 and *8 and the ultra rapid allele *17. Other rare alleles are not detected by this assay. Metabolism of drugs including clopidogrel may also be influenced by race, ethnicity, diet and/or other medications.

^Detection of CYP2C19 genetic variants does not replace the need for assessment of antiplatelet effectiveness and clinical monitoring.

†Ultra-rapid metabolizers are defined as patients with two *17 alleles. Clinical outcome data performed on patients with coronary artery syndrome and planned drug eluting stent replacement.

This test was developed and its performance characteristics were determined by Berkeley HeartLab, a CLIA-certified and CAP-accredited laboratory. It has not been reviewed or approved by the FDA.

Plavix is a registered trademark of Sanofi-Aventis Corp.

References:

1. US Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed July 7, 2010.

2. Mega et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel, NEJM 2009; 360:354-62

3. Sofi et al. Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics Journal. 2010, 1-8.

4. Sibbing 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.

5. Mega et al. Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes. Circulation 2009; 119; 2553-2560

6. http://products.sanofi-aventis.us/plavix/plavix.html#section-2. Accessed July 7, 2010.

7. http://ghr.nlm.nih.gov/glossary=cytochromep450. Accessed July 7, 2010.

8. US Food and Drug Administration. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm190848.htm. Accessed July 7, 2010.

9. Simon et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. NEJM. 2009; 360; 363-375

10. Li-Wan-Po et al. Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. British Journal of Clinical Pharmacology; 2009. 69:3; 222-230

11. Desta et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002; 41: 913-958.