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1 Gladding PA, 1 Webster MW, 1 Zeng I, 1 Farrell H, 1 Stewart J, 1 Ruygrok P, 1 Ormiston J, 2 Gunes A, 3 Perry J

The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the Plavix Response in Coronary Intervention (PRINC) trial ACTRN12606000129583.

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1 Gladding PA, 1 Webster MW, 1 Zeng I, 1 Farrell H, 1 Stewart J, 1 Ruygrok P, 1 Ormiston J, 2 Gunes A, 3 Perry J

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  1. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the Plavix Response in Coronary Intervention (PRINC) trialACTRN12606000129583 1Gladding PA, 1Webster MW, 1Zeng I, 1Farrell H, 1Stewart J, 1Ruygrok P, 1Ormiston J, 2Gunes A, 3Perry J, Dahl M-L. 1Green Lane Cardiovascular Department 3Liggins Institute, Auckland, NZ 2Uppsala University, Sweden Funded by GLREF, NHF Support from Sanofi NZ

  2. Optimal Clopidogrel Dosing • Important for two reasons: • Antiplatelet effect at PCI corresponds with periprocedural infarction (ARMYDA-2) • Timing: Dosing <6-10hrs prior to PCI ineffective (CREDO) • Three recent studies have indicated that doses >600mg are notmore effective than 600mg

  3. Aims • To compare a higher split loading dose of clopidogrel (600mg + 600mg) with standard 600mg • Compare 150mg with 75mg once daily • Investigate the pharmacogenomics of clopidogrel

  4. Methods N=36 150mg/day Clopidogrel

  5. VerifyNow Platelet Function Analyser

  6. VerifyNow P2Y12 assay correlates well with Gold standard LTA van Werkum JW et al. J Thromb Haemost 2006;4(11):2516-8.

  7. Results of the PRINC (Plavix Response in Coronary Intervention) trial.

  8. Randomisation Effective Patients Well Matched in All Treatment Groups c.f age

  9. PRINCe study Non-responders

  10. Increase in Periprocedural MI (7hrs) in Clopidogrel Nonresponders

  11. Drug Response is Predictable Within the First Few Hours r = 0.72 p <0.0001 <2% platelet inhibition at 2 hrs predicts non-responder status at 7hrs (sensitivity 100%, specificity 88%) <2% platelet inhibition at 2 hrs predicts nonresponder status at 7hrs (sensitivity 100%, specificity 88%) r = 0.65 p <0.0001 r = 0.80 p <0.0001 r = 0.62 p <0.0001 r = 0.75 p <0.0001 r = 0.72 p <0.0001

  12. 1,200mg Split Dose of Clopidogrel is More Effective than Single LD Additional 600mg dose 1,200mg split dose n = 37 Standard 600mg dose 600mg dose n = 23 P = 0.03

  13. 150mg Clopidogrel OD has a Greater Antiplatelet Effect than 75mg OD P = 0.01 49.8% 28.8% 5.5% 3.7%

  14. Safety

  15. Clopidogrel Pharmacogenomics P2Y12 Receptor: H2 haplotype MDR1 C3435T genotype Biotransformation by CYP3A4, 3A5, C219, 2C9, 1A2 Polymorphic variants

  16. CYP2C19 Genetic Variants Influence Clopidogrel Response

  17. No benefit of higher dosing in normal *1 genotypes

  18. Loss of function carriers respond to higher doses

  19. Finding validated in higher maintenance dosing group

  20. Conclusion • Split loading with 600mg + 600mg (2hrs) clopidogrel increases the antiplatelet effect • 150mg OD > 75mg OD antiplatelet effect • Response can be measured robustly with a POC analyser & predicted early (2hrs) • Pharmacogenetics might predict response before Rx but phenotyping is still very effective

  21. Mark Webster Ralph Stewart Irene Zeng Helen Farrell Arzu Gunes M-L Dahl Jo Perry Auckland City Hospital Pharmacy Clinical Trials Unit

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