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

2. Paul A. Gurbel, MD
Consulting: Eli Lilly and Company, Pozen, Inc., Accumetrics, Inc., Daiichi Sankyo, Novartis AG, Bayer Corporation, Sanofi-Aventis, Boehringer Ingelheim Vetmedica GmbH, Merck and Company, Inc. and Medtronic, Inc.
Grant Support: Daiichi Sankyo, Eli Lilly and Company, CSL, Haemoscope Corporation, Harvard Clinical Research Institute, Duke Clinical Research Institute, Pozen, Inc., Accumetrics, Inc., Helena Laboratories, Verum Diagnostica GmbH and Portola Pharmaceuticals, Inc.

3. Post-PCI/MI Thrombotic Events- A “Plateletcentric” Problem!!!!
PCI/ACS
Platelet Adhesion /Activation
Thrombin
ADP
TxA2
Sustained GPIIb/IIIa Activation
P2Y12 Blockers x
Platelet Aggregation
Hypercoagulability
Inflammation
Ischemic Events/Stent Thrombosis
Gurbel PA et al. Circulation. 2012;125: 4

4. Platelet Function Testing

5. How can we rationalize giving this drug blindly
Aggregation On Aspirin and Aspirin + Clopidogrel
Clopidogrel is a highly unpredictable and overall weak antiplatelet agent.
Aggregation in 42% of pts on C+A is in the same range as 50% of pts treated with A alone!
How can we rationalize giving this drug blindly
to patients with high risk CVD?
100
42%
50%
8hr post- 600mg Clopidogrel
Aspirin mg qd 80 60
Cumulative Frequency (%) 40 20 20 40 60 80
100
120
20uM ADP-Induced Aggregation
Gurbel PA and Tantry US. Circulation ;125: 6

6. Relation of On-Treatment Platelet Reactivity to ADP to Post-PCI Ischemic Events:
Early Evidence
Gurbel PA et al. J Am Coll Cardiol. 2005; 46:1820-6
~Immunity from Ischemic Event Occurrence
46% 7

7. VerifyNow P2Y12 Patient Based Meta-Analysis : 2 Year Outcomes
6 studies, n=3,059
2 Yr MACE by PRU Quartile
2 Yr Stent Thrombosis by PRU Quartile
Very low ST rate ~ immunity
~3x risk between Q1 and Q4
~8x risk between Q1 and Q4
Brar SS, et al. J Am Coll Cardiol. 2011;58:1945–54

8. Personalization of Antiplatelet Therapy: Relation of HPR to Outcomes
We now have data in tens of thousands of patients: High Platelet Reactivity to ADP (HPR) is a major risk factor for post-PCI thrombotic event occurrence.
Gurbel PA and Tantry US. Circulation ;125: 9

9. ADAPT-DES Registry: 30 Day ST by HPR
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
Days 5 10 15 20 25 30
0.81%
0.21%
P2Y12 PRU > 208 (n=3607)
P2Y12 PRU ≤ 208 (n=4834)
P <0.001
HR [95% CI]=
3.89 [1.90, 7.98]
Definite/Probable ST (%)
~ 4X Increase
absolute difference = 0.6%
N=8349
Multivariable (Cox PHR) model: 50% of 30 d definite or probable stent thrombosis solely attributable to HPR!
Multivariable Propensity Score Adjusted Risk of VerifyNow PRU > year Adverse Events
Event Adj HR [95%CI] P value ST, def/prob [1.43, 4.31] Definite 3.05 [1.62, 5.75] MI 1.42 [1.09, 1.86] Major bleeding 0.73 [0.61, 0.89] Death, all-cause 1.20 [0.85, 1.70] 0.30
Stone G, et al. Presented at TCT 2011 and 2012

10. Have Failed to Show Benefit of Tailoring
- Low risk patients (all trials)
- Remedy for HPR (high dose clopidogrel) suboptimal (GRAVITAS, ARCTIC)
- Low post-D/C event rates (all trials):
- Incomplete protocol following (ARCTIC) - difficult to perform positive randomized trial with adequate n
Why Aren't We Tailoring?
GRAVITAS, TRIGGER-PCI and ARCTIC 3 Major Prospective Trials of Personalized Antiplatelet Therapy- in the PCI Patient
Have Failed to Show Benefit of Tailoring

11. Genetic Testing

12. A genetic locus unequivocally associated with clopidogrel response variability
Shuldiner AR and Gurbel PA, et al. JAMA. 2009;302:849-57
Genome Wide Association Study ~ 500,000 SNP’s
13 SNP’s cluster (1.5 mb on 10q24)

13. CYP2C19 LoF = ~ 30% Americans & ~ 2% are homozygotes
2C19 LoF Carriage Associated With Post-PCI Thrombotic Outcomes
Carriers
Non-carriers
JAMA 2010;304:
Hulot:Meta-analysis
TRITON TIMI-38
Primary Outcomes (%)
J Am Coll Cardiol ;56:134-43
9.3
7.8 10
12.6
8.4
12.1 8
8.5
9.8 2 4 6 12 14
Mega:Meta-Analysis
1 LoF LoF None LoF LoF None LoF LoF None Clopidogrel Prasugrel
n=11,959
2.9
0.9
4.9
n=5,694
Stent Thrombosis
n=9,685
2.2
0.94
5.7
n=5,787
n=1,477
n=1,466
Mega Circ 2009;119: ;NEJM 2009;360:354-62
1.3
1.5
0.9
1.6
1.8
3.3
4.7
2.8
4.0
CYP2C19 LoF = ~ 30% Americans & ~ 2% are homozygotes
Platelet reactivity in the clopidogrel-treated homozygotes is very high
- a subject of FDA “boxed warning” 14

14. The RAPID Program: Spartan RX CYP2C19 System
Buccal Swab/Real Time PCR
60 minutes to identify:
CYP2C19*2 carrier status
Heterozygous vs. Homozygous
Patients undergoing PCI for
non ST-ACS or stable CAD
N=200
Rapid Genotyping
N=102
Platelet Function Testing at 1 week
CYP2C19*2 Carriers
N=23
Non-Carriers
N=74
Prasugrel 10 mg OD
Clopidogrel 75 mg OD
Standard Therapy
N=98
Point-of-Care Genotyping
Roberts JD et al. Lancet. 2012;379:

15. RAPID GENE Trial: Results
Rapid Genotyping
(N=91)
Standard Therapy
(N=96)
Carriers of CYP2C19*2 allele no.(%)
23 (25.3)
23 (24.0)
Heterozygous CYP2C19*2 no.(%)
19 (20.9)
20 (20.8)
Homozygous CYP2C19*2 no.(%)
4 (4.4)
3 (3.1)
Performance Characteristics of Rapid Testing vs. Direct DNA Sequencing
Sensitivity – 100%
Specificity – 99.4%
Prevalence of HPR (%)
p = 0.01 31 10 20 30
Rapid Genotyping
Standard Therapy 40 15
(PRU>208)
Roberts JD et al. Lancet. 2012;379:

16. Cost Analysis Clopidogrel is pharmacodynamically effective in ~ 65%
Unselected use of new agents : more bleeding more cost
Selective use of generic clopidogrel : more economical
No convincing evidence that prasugrel or ticagrelor confer more benefit in clopidogrel responders. 2 4 6 8 10 12 14
TRITON TIMI-38
PLATO
12.1
8.5
8.0
9.8
11.2
8.6
10.0
8.8
LoF Carriers 30%
LoF Non-carriers
LoF Carriers
30%
Primary Efficacy Outcome (%0
Clopidogrel
Prasugrel
Ticagrelor
Gurbel PA et al. Expert Rev Cardiovasc Ther. 2004;2:535-45 17

17. Consensus/Guidelines/Alerts/FDA Statements Addressing Platelet Function Testing
IIb
III-No Benefit: Routine Analysis

18. Why We Should Tailor Antiplatelet Therapy Based on Platelet Function Testing and Genotyping
Because specific genotypes and HPR are associated with stent thrombosis and death during clopidogrel therapy.
2) There are no proven reasons why antiplatelet agents reduce thrombosis other than inhibiting P2Y12 receptor.
3) Because ARCTIC and GRAVITAS have limitations and shouldn’t be used to disprove the utility of personalization
4) How can we rationalize giving a placebo in one third of patient population to prevent the most catastrophic event?
5) How can we rationalize giving an expensive drug associated with more bleeding to all patients when a 33 cents /day drug works in two third of patients population?