1. We Should Tailor Antiplatelet Therapy Based on Platelet Function Testing and Genotyping
Paul A. Gurbel Sinai Center for Thrombosis Research Baltimore, Maryland, USA

2. Disclosures Honoraria/Consulting Research Grants/Support Pozen Pozen
Astra Zeneca
Nanosphere
Accumetrics
Helena
Multiplate
Portola
Daiichi
Honoraria/Consulting
Pozen
Novartis
Bayer
Astra Zeneca
Eli Lilly
Accumetrics
Nanosphere
Sanofi Aventis
Boehringer
Merck
Medtronic 2

3. BACKGROUND
We administer P2Y12 inhibitors to block platelet function to prevent thrombosis.
ALL of the clinical benefit of P2Y12 blockade is achieved by inhibition of platelet activation/function unless there is some unknown (undiscovered for 25 years!!!!!!!!!!!!!!!) major off-target effect VERY VERY HIGHLY UNLIKELY !!!!!!!!!!!!!!!!
Therefore, the patient without a measurable antiplatelet response is logically at increased risk for thrombotic event occurrence. 3

4. Major Reasons Why Genetic and Platelet Function Testing Should Be Considered to Personalize Antiplatelet Therapy 15 4 4 4 4

5. Sustained GPIIb/IIIa Activation
1) Post-PCI thrombotic/ischemic events are mediated by platelets.
2) P2Y12 receptor is a major player/modulates response to all agonists.
3) P2Y12 blockade with clopidogrel is the dominant therapy.
PCI Plaque rupture
Collagen/vWF
Clopidogrel
Prasugrel
Cangrelor
Ticagrelor
Elinogrel
TxA2 TF
P2Y12
Thrombin
Amplification
ADP
Granule Secretion
Platelet Aggregation
Sustained GPIIb/IIIa Activation
Hypercoagulability
Inflammation
(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)
Post-PCI Ischemic Events 5

6. 4) There is variability in platelet inhibition by clopidogrel.
Gurbel et al. Circulation. 2003;107:
% Inhibition
% of Patients 10 20
<= -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance = 31%
24 Hours
% Inhibition
% of Patients 11 22
<= -10
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance=31%
5 Days
30 Days
% Inhibition
% of Patients 14 28
<= -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Resistance=15%
5) There is variability in platelet aggregation during clopidogrel therapy.
5uM ADP-Induced Platelet Aggregation (%)
Cumulative Frequency (%)
75 mg Clopidogrel MD
(Adapted from Bliden et al. J Am Coll Cardiol. 2007;49:657-66) 20 40 60 80
100
5uM ADP-Induced Platelet Aggregation (%)
Relative Frequency (%)
24hr Post 300mg Clopidogrel LD
(Adapted from Gurbel et al.J Am Coll Cardiol. 2005;45:1392-6)
Cumulative Frequency (%)
21%
32%

7. There is now an overwhelming body of data (n > 10,000
There is now an overwhelming body of data (n > 10,000 !!!!!) - from multiple centers around the world - multiple P2Y12 receptor specific assays - confirming that variable antiplatelet response to clopidogrel and resistance (~15-30%) are not myths 6) 7 7 7 7

8. 7. We now better understand the many influences on clopidogrel metabolism that cause the unpredictable antiplatelet effect.
Intestinal Absorption
Esterases 90%
P-glycoprotein
(ABCB1 gene polymorphism) ?
Two Step Conversion
Hepatic P450
Cytochromes
10%
(45%) (36%) (19%)
2C19, 1A2, B6
PPI
R-warfarin
*2,*17
Smoking
Genetic Polymorphisms and Drug-Drug Interactions
Statin, CCB
S-warfarin
2C19, C9, A4, B6
(21%) (7%) (40%) (33%)
Variable Active Metabolite Generation
Adapted from Kauzi M et al. Drug Metab Dispos. 2010; Gurbel P et al. J Inv Cardiol. 2009
Wide Pharmacodynamic Response / High Platelet Reactivity
Worse Clinical Outcome 8

9. 8. We now identified a genetic locus unequivocally associated with clopidogrel response variability – we have come a long long way from believing that response variability is “normal”
Genome Wide Association Study ~ 500,000 SNP’s
13 SNP’s cluster (1.5 mb on 10q24)
Shuldiner AR et al, Gurbel PA. JAMA. 2009;302:849-57

10. On-treatment platelet reactivity to ADP is a powerful risk factor in the PCI patient.9) 10 10 10 10

11. Cumulative Frequency (%)
J Am Coll Cardiol. 2005;46:1820-6
Relation of On-Treatment Platelet Aggregation to 6 Month Post-PCI Ischemic Events
20 uM ADP Aggregation (%)
Cumulative Frequency (%) 10 20 30 40 50 60 70 80 90
100
? Threshold
Ischemic Event (n=38)
No Ischemic Event (n=154)
p<0.02 for mean values between groups 11

12. There is now an overwhelming body of data (n > 10,000
There is now an overwhelming body of data (n > 10,000 !!!!!) - from multiple centers around the world - multiple P2Y12 receptor specific assays - confirming that high on-treatment platelet reactivity
is a major, if not the most important risk factor in the PCI patient.
10) 12 12 12 12

13. Bonello L, Gurbel PA et al. J Am Coll Cardiol. 2010 ;56:919-33

14. Bonello L, Gurbel PA, et al. J Am Coll Cardiol. 2010 ;56:919-3314 14

15. There is now the important observation from multiple studies that ischemic risk accrues rapidly above a critical level of platelet reactivity:
the “threshold” concept
11) 15 15 15 15

16. Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-34.16

17. There is now an overwhelming body of data (n > 10,000
There is now an overwhelming body of data (n > 10,000 !!!!!) - from multiple centers around the world - that CYP 2C19 LOF carriage is a major risk factor in the PCI patient treated with clopidogrel.
12) 17 17 17 17

18. CYP 2C19 LOF carriage is a major risk factor in the PCI patient
Hulot J-S et al. J Am Coll Cardiol. 2010;56:134-43
MACE
23 studies, n = 11,959
Stent Thrombosis
Death

19. 13) There is evidence that alternative antiplatelet therapy (prasugrel or ticagrelor) may reduce the risk associated with LOF carriage.
TRITON TIMI-38
PLATO 14
12.1
11.2 12 10
8.5
8.6 8
Primary Efficacy Outcome (%0 6 4 2
Clopidogrel Prasugrel
Clopidogrel
Ticagrelor
Mega J et al. Circulation. 2009;119:
Mega J et al. N Engl J Med. 2009;360:354-62
Wallentin L et al. Lancet 20010;376: 19

20. There are now credible alternatives to overcome high platelet reactivity (HPR) during clopidogrel therapy.
14) 20 20 20 20

21. HPR is overcome by new agents
Ticagrelor (180mg/90mg bid)
Clopidogrel (600mg/75mg qd)
% of Patients with PRU >235
Predose hr hr hr hr hr ≥2 wks 20 40 60 80
100
p< for all post-dose comparisons 96 56 49 36 35 94 81 97 3 1 42 9
Gurbel P et al. Am Heart J (in press)

22. We now have recommendations to test patients on clopidogrel therapy:
FDA, AHA, ACCF, JACC White paper
15) 22 22 22 22

23. http://www. accessdata. fda 23

24. Functional Testing
Genetic Testing

25. 3 Major Reasons Why GRAVITAS was a “Negative Trial”25 25 25 25

26. PRU 1) High Dose Clopidogrel is a Poor Remedy for HPR High-Dose
Persistently 40% HPR at 30 days
500
p < 0.001
400
PRU
300
200
100
N=1109
N=1012
N=944
Post-PCI
30 d
6 mo
ITT population
Price MJ et al. Presented at AHA meetings 2010 26

27. 2) Low Event Rate-Only a powerful remedy for HPR in a high risk group would have provided a positive outcome
Observed event rates are listed; P value by log rank test.
Price MJ et al. Presented at AHA meetings 2010 27

28. 3) The cutoff was too high
ITT population-
Patients treated with standard dose clopidogrel for 6 mos (n=1691)
500
patients with CV death, MI, or ST
400
PRU
hrs post-PCI
300
230 PRU
200
170 PRU
? Immunity to thrombosis
This plot illustrates the PRUs 12 to 24 hours after PCI in the patients who had events, stratified by group.
The post-PCI PRUs in the patients without high reactivity were clustered within the upper range for that group, the majority near the threshold of 230 PRU.
This observation must be considered exploratory and hypothesis- generating.
100
N=1105
N= 586
High Residual
Reactivity
Not High
Residual Reactivity
Price MJ et al. Presented at AHA meetings 2010 28

29. 29 Summary ACT NOW TO AVOID A CATASTROPHE ???!!!!!!!!! 29
Platelet reactivity – the major driver for stent thrombosis, MI, restenosis - it is exactly why we give P2Y12 inhibitors in the first place.
HPR - greatest risk predictor in the PCI population
Should we wait for the “definitve” trial before we act
or ?
ACT NOW TO AVOID A CATASTROPHE ???!!!!!!!!! 29 29 29 29