1. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the Plavix Response in Coronary Intervention (PRINC) trial ACTRN12606000129583 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, Dahl M-L. 1 Green Lane Cardiovascular Department 3 Liggins Institute, Auckland, NZ 2 Uppsala University, Sweden Funded by GLREF, NHF Support from Sanofi NZ

2. Optimal Clopidogrel Dosing Important for two reasons:Important for two reasons: 1.Antiplatelet effect at PCI corresponds with periprocedural infarction (ARMYDA-2) 2.Timing: Dosing <6-10hrs prior to PCI ineffective (CREDO) Three recent studies have indicated that doses >600mg are not more effective than 600mgThree recent studies have indicated that doses >600mg are not more effective than 600mg

3. Aims To compare a higher split loading dose of clopidogrel (600mg + 600mg) with standard 600mgTo compare a higher split loading dose of clopidogrel (600mg + 600mg) with standard 600mg Compare 150mg with 75mg once dailyCompare 150mg with 75mg once daily Investigate the pharmacogenomics of clopidogrelInvestigate 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 data presented are median (interquartile) 7 hours %inhibition > 10% 7 hours %inhibition ≤ 10% p value* N=52N=8 Troponin at 7 hours 0.01(0.01,0.03)0.05(0.01,0.29)0.05 *Mann Whitney U test

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

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

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

14. Safety Adverse Event: 600mg1,200mg GIVomitingDiarrhoea0011 Rash00 BleedingMinorMajor1001

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

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 effectSplit loading with 600mg + 600mg (2hrs) clopidogrel increases the antiplatelet effect 150mg OD > 75mg OD antiplatelet effect150mg OD > 75mg OD antiplatelet effect Response can be measured robustly with a POC analyser & predicted early (2hrs)Response can be measured robustly with a POC analyser & predicted early (2hrs) Pharmacogenetics might predict response before Rx but phenotyping is still very effectivePharmacogenetics might predict response before Rx but phenotyping is still very effective

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