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

(PRINC) trial(PRINC) trial ACTRN12606000129583ACTRN12606000129583

11Gladding PA, Gladding PA, 11Webster MW, Webster MW, 11Zeng I, Zeng I, 11Farrell H, Farrell H, 11Stewart J, Stewart J, 11Ruygrok P, Ruygrok P, 11Ormiston J, Ormiston J, 22Gunes A, Gunes A, 33Perry J, Dahl M-L.Perry J, Dahl M-L.

11Green Lane Cardiovascular DepartmentGreen Lane Cardiovascular Department33Liggins Institute, Auckland, NZLiggins Institute, Auckland, NZ

22Uppsala University, SwedenUppsala University, Sweden

Funded by GLREF, NHFFunded by GLREF, NHFSupport from Sanofi NZSupport from Sanofi NZ

Optimal Clopidogrel DosingOptimal Clopidogrel Dosing

• Important for two reasons:Important for two reasons:1.1. Antiplatelet effect at PCI corresponds with Antiplatelet effect at PCI corresponds with

periprocedural infarction (ARMYDA-2)periprocedural infarction (ARMYDA-2)

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

MethodsMethods

Time table

Percutaneous coronaryintervention

n=60600 mg

Clopidogrel

-10 minutes Baseline 2 hours 4 hours 7 hours 7 days

n=31intraarterial

5mg Verapamil

n=29intraarterial

Placebo

n=37600 mg

Clopidogrel

n=23Placebo

Randomization

SamplingSampling Sampling Sampling Sampling

Discharge

n=2275 mg/dayClopidogrel

n=3875 mg/dayClopidogrel

Randomization

N=36150mg/dayClopidogrel

VerifyNow Platelet Function VerifyNow Platelet Function AnalyserAnalyser

VerifyNow P2Y12 assay correlates VerifyNow P2Y12 assay correlates well with Gold standard LTAwell with Gold standard LTA

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

Results of the PRINC (Results of the PRINC (PPlavix lavix RResponse esponse iin n CCoronary oronary

IntInteervention) trial.rvention) trial.

Placebo (n=29) Verapamil (n=31) P value Clopidogrel1200mg (n=37)

Clopidogrel 600mg (n=23)

P value Clopidogrel 75 (n=22)

Clopidogrel 150 (n=38)

P value

GenderMale 23(79%) 27(87%) 31(84%) 19(83%) 19(86%) 31(52%) 0.73

Age avg(SD) 64 (11) 71 (9.1) 0.02 70(10) 64(10) 0.06 68(9.4) 68(11) 0.99

EthnicityEuro 27(93%) 30(97%) 35(95%) 22(96%) 22(100%) 35(92%)

Maori 2(7%) 0(0%) 2(5%) 0(0%) 0(0%) 2(5%)

Other 0(0%) 1(3%) 0(0%) 1(4%) 0(0%) 1(3%) 0.7

ASA28(97%) 31(100%) 36(97%) 23(100%) 22(100%) 37(97%) >0.9

300mg 1(3%) 2(6%) 0(0%) 3(13%) 1(5%) 2(5%)

150mg 4(14%) 5(16%) 2(5%) 7(30%) 4(18%) 5(13%)

100mg 23(79%) 24(77%) 34(92%) 13(57%) 17(77%) 30(79%)

75mg 1(3%) 0(0%) 1(3%) 0(0%) 0(0%) 1(3%)

Statin Y 28(97%) 28(93%) >0.9 35(95%) 21(95%) >0.9 21(95%) 35(95%) >0.90

BB 23(79%) 24(80%) >0.9 31(84%) 16(73%) 0.33 17(77%) 30(81%) 0.75

ACE 14(48%) 19(63%) 0.24 20(54%) 13(59%) 0.71 14(64%) 19(58%) 0.36

DM 4(14%) 7(23%) 0.67 7(19%) 4(17%) >0.9 1(5%) 10(26%) 0.04

HTN 18(62%) 16(52%) 0.41 19(51%) 15(65%) 0.29 10(45%) 24(63%) 0.18

CHF 0(0%) 2(6%) 0.49 1(3%) 1(4%) >0.9 1(5%) 1(3%) >0.90

Current Smoker 5(17%) 1(3%) 0.098 3(8%) 3(13%) 0.672(9%) 4(11%) >0.90

Prior CABG 2(7%) 4(13%) 0.67 5(14%) 1(4%) 0.39 3(14%) 3(8%) 0.66

Recent NSTEMI 0(0%) 4(13%) 0.11 2(5%) 2(9%) 0.630(0%) 4(11%) 0.29

Recent STEMI 2(7%) 1(3%) 0.61 1(3%) 2(9%) 0.552(9%) 1(3%) 0.55

Prior PCI 6(21%) 6(19%) >0.9 7(19%) 5(22%) >0.93(14%) 9(24%) 0.51

PVD 5(17%) 8(26%) 0.54 8(22%) 5(22%) >0.9 2(9%) 11(29%) 0.11

FHx CAD 12(41%) 12(39%) 0.83 12(32%) 12(52%) 0.13 10(45%) 14(37%) 0.51

EF avg (SD) 72 (10) 65 (20) 0.29 71(11) 63(24) 0.34 66(23) 69(11) 0.82

LMS disease 0 1 1 0 1 0

1VD 19 21 22 18 13 27

2VD 6 5 9 2 4 7

3VD 1 0 1 0 0 1

Multi stents 4(14%) 5(16%) >0.9 7(19%) 2(9%) 0.46 2(9%) 7(18%) 0.46

DES 9(31%) 12(39%) 0.53 14(38%) 7(30%) 0.56 7(32%) 14(37%) 0.69

BMI avg (sd) 28.4 (4.9) 29.3 (3.9) 0.36 29(5) 28(4) 0.41 28.7(3.8) 28.9(4.8) 0.98

Base PRU 356.3 (44.8) 336.8 (67.3) 0.28 353(64) 335(45) 0.14348(56) 345(60) 0.67

0.50 >0.9

0.38 >0.9

0.23 0.29

Randomisation EffectiveRandomisation Effective

Patients Well Matched in All Patients Well Matched in All Treatment Groups Treatment Groups c.f agec.f age

PRINCe studyPRINCe studyLoading with Clopidogrel

0

20

40

60

80

100

120

Baseline 2 4 7

Time (hrs)

% P

late

let

Inh

ibit

ion

Non-responders

Increase in Periprocedural MI Increase in Periprocedural MI (7hrs) in Clopidogrel (7hrs) in Clopidogrel

NonrespondersNonresponders

data presented are median (interquartile)

7 hours %inhibition > 10%

7 hours %inhibition ≤ 10%

p value*

N=52 N=8

Troponin at 7 hours

0.01(0.01,0.03) 0.05(0.01,0.29) 0.05

*Mann Whitney U test

Drug Response is Predictable Drug Response is Predictable Within the First Few HoursWithin the First Few Hours

r = 0.72r = 0.72p <0.0001p <0.0001

r = 0.65r = 0.65p <0.0001p <0.0001

r = 0.62r = 0.62p <0.0001p <0.0001

r = 0.75r = 0.75p <0.0001p <0.0001

r = 0.80r = 0.80p <0.0001p <0.0001

r = 0.72r = 0.72p <0.0001p <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%)

1,200mg Split Dose of Clopidogrel is 1,200mg Split Dose of Clopidogrel is More Effective than Single LDMore Effective than Single LD

P = 0.03

Standard600mg dose

Additional600mg dose

1,200mg split dosen = 37

600mg dosen = 23

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

clopidogrel 150mg clopidogrel 75mg

%in

hib

itio

n

Baseline

%inhibition at 7days

150mg Clopidogrel OD has a Greater 150mg Clopidogrel OD has a Greater Antiplatelet Effect than 75mg ODAntiplatelet Effect than 75mg OD

49.8%

5.5%3.7%

28.8%

P = 0.01

SafetySafety

Adverse Event:Adverse Event: 600mg600mg 1,200mg1,200mg

GIGIVomitingVomiting

DiarrhoeaDiarrhoea

00

00

11

11

RashRash 00 00

BleedingBleedingMinorMinor

MajorMajor

11

00

00

11

Biotransformation by CYP3A4, 3A5, C219, 2C9, 1A2Polymorphic variants

Clopidogrel Pharmacogenomics

MDR1 C3435T genotype

P2Y12 Receptor: H2 haplotype

CYP2C19 Genetic Variants CYP2C19 Genetic Variants Influence Clopidogrel ResponseInfluence Clopidogrel Response

2hr inh overall

*1*1 *2 or *4 carriers *1*17 *17*170

25

50

75

100 *p=0.0295

CYP2C19 genotype

2 h

r %

in

hib

itio

n

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