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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 - PowerPoint PPT Presentation


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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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slide1

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
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
slide3
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
Methods

N=36

150mg/day

Clopidogrel

verifynow p2y12 assay correlates well with gold standard lta
VerifyNow P2Y12 assay correlates well with Gold standard LTA

van Werkum JW et al. J Thromb Haemost 2006;4(11):2516-8.

randomisation effective

Randomisation Effective

Patients Well Matched in All Treatment Groups c.f age

prince study
PRINCe study

Non-responders

drug response is predictable within the first few hours
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
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

slide15

Clopidogrel Pharmacogenomics

P2Y12 Receptor:

H2 haplotype

MDR1 C3435T genotype

Biotransformation by CYP3A4, 3A5, C219, 2C9, 1A2

Polymorphic variants

conclusion
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
slide21

Mark Webster

Ralph Stewart

Irene Zeng

Helen Farrell

Arzu Gunes

M-L Dahl

Jo Perry

Auckland City Hospital Pharmacy

Clinical Trials Unit