The antiplatelet effect of The antiplatelet effect of higher loading and higher loading and maintenance dose regimens maintenance dose regimens of clopidogrel: the Plavix of clopidogrel: the Plavix Response in Coronary Response in Coronary Intervention (PRINC) trial Intervention (PRINC) trial ACTRN12606000129583 ACTRN12606000129583 1 Gladding PA, Gladding PA, 1 Webster MW, Webster MW, 1 Zeng I, Zeng I, 1 Farrell H, Farrell H, 1 Stewart J, Stewart J, 1 Ruygrok P, Ruygrok P, 1 Ormiston J, Ormiston J, 2 Gunes A, Gunes A, 3 Perry J, Dahl M-L. Perry J, Dahl M-L. 1 Green Lane Cardiovascular Department Green Lane Cardiovascular Department 3 Liggins Institute, Auckland, NZ Liggins Institute, Auckland, NZ 2 Uppsala University, Sweden Uppsala University, Sweden Funded by GLREF, NHF Funded by GLREF, NHF Support from Sanofi NZ Support from Sanofi NZ
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The antiplatelet effect of higher The antiplatelet effect of higher loading and maintenance dose loading and maintenance dose
regimens of clopidogrel: the Plavix regimens of clopidogrel: the Plavix Response in Coronary Intervention Response in Coronary Intervention
2.2. Timing: Dosing <6-10hrs prior to PCI Timing: Dosing <6-10hrs prior to PCI ineffective (CREDO)ineffective (CREDO)
• Three recent studies have indicated that Three recent studies have indicated that doses >600mg are doses >600mg are notnot more effective more effective than 600mgthan 600mg
AimsAims
• To compare a higher split loading dose of To compare a higher split loading dose of clopidogrel (600mg + 600mg) with clopidogrel (600mg + 600mg) with standard 600mgstandard 600mg
• Compare 150mg with 75mg once dailyCompare 150mg with 75mg once daily
• Investigate the pharmacogenomics of Investigate the pharmacogenomics of clopidogrelclopidogrel
No benefit of higher dosing in No benefit of higher dosing in normal *1 genotypesnormal *1 genotypes
4 hr 1200 vs 600 mg in CYP2C19 *1*1 carriers
1200 mg 600 mg0
25
50
75
100
*1*1 carriers
4 h
r %
inh
ibit
ion
Loss of function carriers respond to Loss of function carriers respond to higher doseshigher doses
4 hr 1200 vs 600 mg in CYP2C19*2 or*4 carriers
1200 mg 600 mg0
10
20
30
40
50
60
70
80
90
*p=0.002
CYP2C19*2or*4 carriers
4 h
r %
in
hib
itio
n
Finding validated in higher Finding validated in higher maintenance dosing groupmaintenance dosing group
7 day 150 mg vs 75 mg in CYP2C19 *2 or *4 carriers
150 mg 75 mg0
10
20
30
40
50
60
70
80
90
p=0.042
CYP2C19 *2 or *4 carriers
7 d
ay %
in
hib
itio
n
ConclusionConclusion
• Split loading with 600mg + 600mg (2hrs) Split loading with 600mg + 600mg (2hrs) clopidogrel increases the antiplatelet effectclopidogrel increases the antiplatelet effect
• 150mg OD > 75mg OD antiplatelet effect150mg OD > 75mg OD antiplatelet effect
• Response can be measured robustly with Response can be measured robustly with a POC analyser & predicted early (2hrs)a POC analyser & predicted early (2hrs)
• Pharmacogenetics might predict response Pharmacogenetics might predict response before Rx but phenotyping is still very before Rx but phenotyping is still very effectiveeffective
Jo PerryJo Perry
Mark WebsterMark Webster
Ralph StewartRalph Stewart
Irene ZengIrene Zeng
Helen FarrellHelen Farrell
Arzu GunesArzu GunesM-L DahlM-L Dahl
Auckland City Hospital Pharmacy Auckland City Hospital Pharmacy Clinical Trials UnitClinical Trials Unit