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Pharmacogenetics of Clopidogrel (Plavix) Resistance Alan R. Shuldiner, M.D.

Pharmacogenetics of Clopidogrel (Plavix) Resistance Alan R. Shuldiner, M.D. University of Maryland School of Medicine Baltimore, MD. Disclosures: None. Clopidogrel. Anti-platelet agent

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Pharmacogenetics of Clopidogrel (Plavix) Resistance Alan R. Shuldiner, M.D.

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  1. Pharmacogenetics of Clopidogrel (Plavix) Resistance Alan R. Shuldiner, M.D. University of Maryland School of Medicine Baltimore, MD Disclosures: None

  2. Clopidogrel • Anti-platelet agent • Effective (with aspirin) for secondary prevention of MI and stroke, and thrombosis prevention after percutaneous coronary interventions (e.g., stent placement, angioplasty) • In 2005, world’s 2nd highest selling drug • U.S. sales $5.9 billion • Acts by binding to ADP receptors on platelets, preventing platelet aggregation and thrombosis • Great variability in response to clopidogrel • 4 - 20% of individuals are resistant

  3. Distribution of Clopidogrel Response: The Amish Pharmacogenomics of Antiplatelet Intervention (PAPI ) Study • 600 healthy drug/vitamin/supplement naïve Amish individuals • Treated with clopidogrel for 7 days • Platelet aggregation studies pre-clopidogrel, post-clopidogrel Message: Clopidogrel works in the population, but not in all individuals Heritability of clopidogrel response = 0.7 Shuldiner et al (2009) JAMA

  4. Genome-Wide Search for Clopidogrel Response Genes • Do >500,000 genetic tests (genotypes) of common DNA variations throughout the genome in people given clopidogrel • Determine which of these common DNA variations associate with response to clopidogrel • Identify the gene(s) in which these clopidogrel response-associated DNA variations reside • Develop a diagnostic genetic test that predicts clopidogrel response • Use information to • Determine dose or choice of medication (personalized medicine) • Design new and more effective medications

  5. Genome-wide Association Study of Clopidogrel Response (ADP-stimulated platelet aggregation after clopidogrel treatment) Shuldiner et al (2009) JAMA

  6. Clopidogrel Metabolism: Role of CYP2C19 in Activation PharmGKB.org

  7. 33% CYP2C19*2 Loss of Function Variant Is a Major Determinant of Clopidogrel Response Shuldiner et al (2009) JAMA

  8. CYP2C19*2 Predicts Clopidogrel Response: Baltimore Sinai Hospital PCI Sample (n = 227) Shuldiner et al (2009) JAMA

  9. Event-Free Survival in Patients Treated With Clopidogrel Following PCI Stratified by CYP2C19*2 Genotype P = 0.004 HR 3.40; 95% CI 1.36-8.46 P = 0.60 HR 1.39; 95% CI 0.39-4.88 P = 0.02 HR 2.42; 95% CI 1.18-4.99 Shuldiner et al (2009) JAMA

  10. December 22, 2008 December 22, 2008 The Lancet, December 23, 2008

  11. REGIONAL: Scripps docs use genes to spot potential for clots PAUL SISSON - psisson@nctimes.com | Posted: Wednesday, October 14, 2009 8:05 pm Heart patients at Scripps Green Hospital in La Jolla are the first in the nation to have their genes screened before having heart-stent surgery, a step that doctors there say could potentially prevent life-threatening complications. Scripps announced last week that the hospital is offering genetic testing for a specific gene that a recent study, published by the Journal of the American Medical Association, says can determine whether or not a patient may respond to the blood thinner Plavix. October 14, 2009

  12. Implications of Clopidogrel Pharmacogenomics: The perfect storm for personalized medicine • Plavix (clopidogrel) soon to come off patent (inexpensive) • Son of clopidogrel, Prasagrel recently FDA approved (expensive) • Cyp2C19 *1*1  clopidogrel • Cyp2C19 -/*2  prasugrel • Prospective randomized trial - outcomes/pharmacoeconomics • Omeprazole (Prilosec) is a potent Cyp2C19 inhibitor (Ho et al JAMA, March 6, 2009) • Other genetic predictors: Clopidogrel Pharmacogenomics Consortium

  13. A HAPI/PAPI Platelet Thanks for your Attention!

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