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  1. 1. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events Nicole Cullen Noon Conference February 4, 2009
  2. 2. Background <ul><li>Pharmacogenetics </li></ul><ul><ul><li>Tailoring drug therapy to genetic variants </li></ul></ul><ul><ul><li>Decreased adverse events and financial waste by not overdosing (coumadin) or underdosing (clopidogrel) </li></ul></ul><ul><li>Clopidogrel </li></ul><ul><ul><li>Lack of response (“resistance” to therapy) in 5-45% </li></ul></ul>
  3. 3. Study Background <ul><li>Currently, treatment with clopidogrel and aspirin is the recommended anti-platelet therapy after an MI to prevent further atherothrombotic event. Clopidogrel is part of the standard of care for after stent placement. </li></ul><ul><ul><li>Duration of 1 year is usual </li></ul></ul><ul><li>Known variation in clopidogrel’s biologic activity (antiplatelet effect) </li></ul><ul><li>Would these polymorphisms have an effect on clinical outcomes in patients post-MI? </li></ul>
  4. 4. Study Population <ul><li>Subset from the French Registry of Acute ST-Elevation and Non-ST Elevation Myocardial Infarction (FAST-MI) </li></ul><ul><ul><li>Patients diagnosed with acute MI, admitted to ICUs between Oct 1-Dec 24, 2005 and agreed to participate </li></ul></ul><ul><ul><li>Acute MI: defined by serum markers of myocardial necrosis (CK, CK-MB, troponin) >2x upper limit of normal, PLUS sx consistent with acute MI or EKG changes in at least two contiguous leads (Q waves, ST changes) </li></ul></ul><ul><ul><li>Time from onset of sx to admission to ICU <48hrs </li></ul></ul><ul><ul><li>Age >18 years </li></ul></ul><ul><ul><li>Total 3670 patients </li></ul></ul><ul><li>60% of centers in France that treated pts with acute MIs participated. </li></ul>
  5. 5. Population (con’t) <ul><li>Enrollment in the registry did not affect treatment decisions by physicians </li></ul><ul><li>Upon enrollment, 2430 (66%) agreed to give blood, and an extra 10cc’s were drawn for DNA banking in anticipation of future research </li></ul><ul><li>For our study, the subset who were placed on clopidogrel as part of their treatment were considered (n=2208) </li></ul>
  6. 6. Methods <ul><li>Polymorphisms already proven to modulate clopidogrel’s absorption, metabolic activation or biologic activity </li></ul><ul><ul><li>Some had been proven to decrease the platelet-inhibitory effect of clopidogrel ex vivo </li></ul></ul><ul><li>DNA analyzed for those specific allelic variants </li></ul><ul><ul><li>Genotyped for CYP2C19, CYP3A5, ABCB1, P2RY12 and ITGB3. </li></ul></ul><ul><li>Studied whether these were associated with death or ischemic events in a one year follow-up period </li></ul>
  7. 7. Absorption, mediated by intestinal efflux pump (ABCB1) Hepatic metabolization of prodrug by P450 (CYP3A5, CYP2C19) ADP receptor (P2RY12) GPIIb/IIIa receptor involved in platelet aggregation (ITGB3)
  8. 8. Methods (con’t) <ul><li>Primary outcome </li></ul><ul><ul><li>Composite of death from any causes, nonfatal MI, or stroke during 1-year of follow-up </li></ul></ul><ul><li>Follow-up results obtained from patients, family, physicians, registry offices </li></ul><ul><li>Follow-up at 1 year for 99.2% of patients initially enrolled </li></ul>
  9. 9. Statistical Analysis <ul><li>Χ 2 to test for polymorphism deviation from Hardy-Weinberg equilibrium </li></ul><ul><ul><li>Population did not deviate from those previously reported for white populations </li></ul></ul><ul><li>Univariate cox proportional-hazards model to compare baseline demographics, clinical characteristics and therapeutic management during hospitalization </li></ul><ul><ul><li>Variables considered to have important prognostic value were tested in a multivariable, stepwise, forward Cox proportional-hazards model for association with the primary outcome </li></ul></ul><ul><li>Results expressed as hazard ratios from these Cox models, using 95% CIs </li></ul>
  10. 10. Baseline Characteristics/ In-hospital treatment <ul><li>Event group </li></ul><ul><ul><li>Older, HTN, DM, MI, stroke, PCI, CHF </li></ul></ul><ul><ul><li>Less frequently reperfusion therapy (PCI or fibrinolysis) </li></ul></ul><ul><ul><li>Less likely receive statins, BB, ACEIs, IIb/IIIa inhibitors, heparin while in hospital </li></ul></ul>
  11. 11. Results – Allelic Frequencies <ul><li>Rates of CYP3A5, P2RY12, ITGB3, and individual CYP2C19 variants did not differ significantly between groups </li></ul><ul><li>Frequency of ABCB1 variant allele and combined CYP2C19 loss of function alleles DID differ significantly between the two groups. </li></ul><ul><ul><li>ABCB1 variants (TT 29 vs. 26%, CT 51 vs. 48%. p=0.04) </li></ul></ul><ul><ul><li>CYP2C19 with two variant LOF alleles (4% vs. 2%, p=0.045) </li></ul></ul>
  12. 12. Results – Predictors Starting at the beginning of the study, the ABCB1 variant and two CYP2C19 LOF variants carried a significant increase in risk for an outcome event during the year (p=0.007 and p=0.003, respectively) -Remained significant after adjusting for the risk factors and treatments listed in original table ABCB1: Event rate 15.5% vs 10.7%, adjusted hazard ratio 1.72, 95% CI 1.20-2.47 For CYP2C19: Event rate 21.5% vs 13.3%, adjusted hazard ratio 1.98, 95% CI 1.10-3.58 (After propensity-score matching, risk of outcome was even higher – HR 2.14, 95% CI 1.09-4.17)
  13. 13. Results - Interactions <ul><li>Addition of omeprazole or other PPIs (known to be CYP2C19 inhibitors) had no significant effect on the clinical response to clopidogrel, as evaluated by CV events </li></ul><ul><li>CYP2C19*17 (associated with very rapid CYP2C19 activity) also had no effect </li></ul><ul><li>The presence of ABCB1 variant along with two CYP2C19 LOF alleles had the highest risk of events (adjusted hazard ratio 5.31, 95% CI 2.13-13.20, p=0.009) </li></ul><ul><li>In the subset who underwent PCI during hospitalization, the adjusted risk of an outcome was significantly different only for CYP2C19 two LOF alleles – 3.58x those of wild-type. 95% CI 1.71-7.51, p=0.005. </li></ul>
  14. 14. Author Conclusions <ul><li>Two of the candidate genes were linked to an increased rate of CV events </li></ul><ul><ul><li>ABCB1 (absorption) </li></ul></ul><ul><ul><li>CYP2C19 (metabolism) </li></ul></ul><ul><li>This effect was particularly marked in the subgroup of pts who underwent PCI during hospitalization (for two CYP2C19 variant alleles only) </li></ul><ul><li>Significantly worse risk profile at admission for those who had an event, but no significant difference in the risk profile or treatment given between those with and without allelic variants </li></ul>
  15. 15. Flaws? <ul><li>Relation between ABCB1 gene and actual P-glycoprotein expression (the drug-efflux transporter encoded by that gene) still controversial </li></ul><ul><li>Clinical factors such as obesity, insulin resistance, and the nature of the coronary event also contribute to the variability of the clopidogrel response (BMI and DM were considered in baseline characteristics of this study, but not specifics of MI) </li></ul><ul><li>Different doses in the study (could loss of effect in the genetic variants be overcome by increasing the dose?) </li></ul><ul><ul><li>Mean loading dose 300mg PO qday, mean discharge dose 75mg PO qday </li></ul></ul><ul><li>Observational study – can’t tell cause and effect </li></ul><ul><li>Could ABCB1 and CYP2C19 polymorphisms affect artherothrombosis directly rather than acting through modulation of clopidogrel response? No effect seen in subgroup of pts who contributed blood but did not receive clopidogrel </li></ul><ul><li>Could genetic response to clopidogrel have been different in the absence of these other medications? </li></ul>
  16. 16. Where to go from here? <ul><li>Is genotyping rather than repeated platelet monitoring (or no platelet monitoring) a realistic, affordable way to identify patients at high frisk for recurrent atherothrombotic events? </li></ul><ul><li>How many people are we talking? </li></ul><ul><ul><li>30% of population carriers for a CYP2C19 LOF allele </li></ul></ul><ul><ul><li>Based on this study, CYP2C19 for two variant alleles, 0.03% </li></ul></ul><ul><li>Implications for other drugs, such as coumadin </li></ul><ul><li>Prasugrel (another P2RY12 inhibitor) on the horizon, although not yet approved by the FDA. </li></ul><ul><ul><li>Skips the need for hepatic metabolism </li></ul></ul><ul><li>The million dollar question: </li></ul>
  17. 17. What our clients say... &quot;I just wanted to call and tell you that my physician switched my medications based on my test results, and I cannot describe how much better I feel. You have made a believer out of me, my family, and my physician. I hope this testing becomes routine before anyone is placed on long term medication.&quot; - PY, Eirie , CO
  18. 18. Cost <ul><li>Costs $260 for a “single pathway” test, looking at CYP2C19 </li></ul><ul><li>Insurance reimbursement forms provided </li></ul><ul><ul><li>Patient and/or doctor have to fight with the insurance company </li></ul></ul>
  19. 19. Interesting related info <ul><li>In another study published in the same issue of NEJM, Mega et al. studied the association between CYP genetic variants and CV outcomes in pts presenting with ACS who were treated with clopidogrel (TRIJTON-TIMI trial) </li></ul><ul><ul><li>Found that in healthy subjects, carriers of at least one CYP2C19 LOF allele had decreased levels of the active clopidogrel metabolite </li></ul></ul><ul><ul><li>Less reduction in platelet aggregation </li></ul></ul><ul><ul><li>Risk of stent thrombosis 3x higher </li></ul></ul><ul><ul><li>Increased risk of death from CV causes, MI or stroke </li></ul></ul><ul><li>Both this study and Mega showed increased level of CV events particularly marked in pts undergoing PCI </li></ul>
  20. 22. References <ul><li>Simon T, Verstuyft C, Mary-Krause M, et al. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. N Engl J Med 2009;360:363-375. </li></ul><ul><li>Angiolillo D, Fernandez-Ortiz A, Bernardo E, et al. PIA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation. Blood Coagul Fibrinolysis 2004;15:89-93. </li></ul><ul><li>Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphage-induced platelet aggregation is associated with P2Y12 gene sequence variastions in healthy subjects. Circulation 2003;108:989-995. </li></ul><ul><li>Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006;108:2244-2247. </li></ul><ul><li>Taubert D, von Beckerath N, Grimberg G, et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006;80:486-501. </li></ul><ul><li>Trenk D, Hocholzer W, Fromm MF, et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008;51:1925-1934. </li></ul><ul><li>Suh J, Koo B, Zhang S, et al. Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel. CMAJ 2006;174:1715-1722. </li></ul><ul><li>Sim S, Risinger C Dahl M, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006;79:103-113. </li></ul><ul><li>Mason P, Jacobs A, Freedman J. Aspirin resistance and atherothrombotic disease. J Am Coll Cardiol 2005;46:986-993. </li></ul><ul><li>Mega J, Close S, Wiviott S, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362. </li></ul><ul><li>Eckman M, Rosand J, Greenberg S et al. Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients with Nonvalvular Atrial Fibrillation. Ann of Int Med 2009;150:73-83 </li></ul><ul><li>Genelex Laboratries website - </li></ul>
  21. 23. http:// =826