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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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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
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
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
Methods N=36 150mg/day Clopidogrel
VerifyNow P2Y12 assay correlates well with Gold standard LTA van Werkum JW et al. J Thromb Haemost 2006;4(11):2516-8.
Results of the PRINC (Plavix Response in Coronary Intervention) trial.
Randomisation Effective Patients Well Matched in All Treatment Groups c.f age
PRINCe study Non-responders
Increase in Periprocedural MI (7hrs) in Clopidogrel Nonresponders
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
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
150mg Clopidogrel OD has a Greater Antiplatelet Effect than 75mg OD P = 0.01 49.8% 28.8% 5.5% 3.7%
Clopidogrel Pharmacogenomics P2Y12 Receptor: H2 haplotype MDR1 C3435T genotype Biotransformation by CYP3A4, 3A5, C219, 2C9, 1A2 Polymorphic variants
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
Mark Webster Ralph Stewart Irene Zeng Helen Farrell Arzu Gunes M-L Dahl Jo Perry Auckland City Hospital Pharmacy Clinical Trials Unit