1. Should We Tailor Antiplatelet Therapy Based on Platelet Function Testing and Genotyping?
Matthew J. Price MD
Director, Cardiac Catheterization Laboratory,
Scripps Clinic, La Jolla, CA
Director, Interventional Cardiology Research,
Scripps Genomic Medicine, La Jolla, CA

2. Matthew J. Price, MD DISCLOSURES Consulting Fees Honoraria
Accumetrics, Inc., Daiichi Sankyo, Inc, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, AstraZeneca
Honoraria
Daiichi Sankyo, Inc. and Eli Lilly and Company
Grants/Contracted Research
Sanofi-Aventis U.S. LLC, Portola
Ownership Interest (Stocks, Stock Options or Other Ownership Interest)
I intend to reference unlabeled/unapproved uses of drugs or devices in my presentation.
I intend to reference clopidogrel and prasugrel

3. Berger-Price I: Prasugrel vs
Berger-Price I: Prasugrel vs. Clopidogrel, October 29th, 2009, La Jolla, CA
Mike Tyson
Evander Holyfield
Attendee review: “Dr. Price…seemed to be the winner”

4. Berger-Price II? PFT vs. No PFT, February 21, 2010, Washington DC

5. Platelet Function Testing in PCI:
Evidence for the Prosecution – EXHIBIT A
The level of platelet reactivity on clopidogrel is a risk factor for cardiovascular events after PCI
Biologically plausible
Strong and consistent association across studies
Evidence of dose-response relationship

6. Light Transmittance Aggregometry VASP-phosphorylation assay
Poor Outcome and Inadequate Clopidogrel Response: A strong and consistent association across studies N
Clinical Setting
Outcomes
Light Transmittance Aggregometry
Matetzky et al. 60
STEMI undergoing PCI
Post-primary PCI ischemic events (6 months)
Gurbel et al.
192
Nonemergent PCI
Post-PCI ischemic events (6 months)
120
Elective PCI
Post-PCI myonecrosis/inflammation
Cuisset et al.
106
ACS undergoing PCI
Post-PCI ischemic events (30 days)
Lev et al.
Post-PCI myonecrosis
150
Hochholzer et al.
802
Geisler et al.
379
Stable and unstable angina undergoing PCI
Post-PCI major cardiovascular events (3 months)
Bliden et al.
100
Chronic clopidogrel undergoing nonemergent PCI
Post-PCI ischemic events (12 months)
190
NSTEACS undergoing PCI
Periprocedural myocardial infarction
Angiolillo et al.
173
Type 2 DM on chronic dual antiplatelet therapy
Ischemic events (24 months)
Marcucci et al.
367
MI undergoing PCI
Müller et al.
105
Stent thrombosis
Buonamici et al.
804
PCI with drug eluting stent
VASP-phosphorylation assay
Bonello et al.
144
Stable angina and low-risk NSTEACS undergoing PCI
Post-PCI major adverse cardiac events (6 months)
Frere et al.
195
Barragan et al. 46
Subacute stent thrombosis
Blindt et al. 99
PCI with high risk for stent thrombosis
VerifyNow P2Y12 assay
Price et al.
380
PCI with drug eluting stents
MACE and stent thrombosis (6 months)
Patti et al.
160
PCI
Major adverse cardiac events (30 days)
683
Major adverse cardiac events (12 months)
De Miguel et al.
179
NSTEACS undergoing coronary angiography
Others
Sibbing et al.
1608
Elective PCI with drug eluting stent
Ajzenberg et al. 49
Angiollilo et al, Thromb Haemost, in press

7. These are NOT ‘Small’ Studies
These are NOT ‘Small’ Studies! Association between HRPR and 1-year outcome in 1,069 patients
POPular Study
N = 1069 patients
PFT provided further prognostic information in addition to classic risk factors
Breet, AHA 2009

8. Platelet Function Testing in PCI:
Evidence for the Prosecution – EXHIBIT B
Diagnostic cut-offs for PFT that are predictive of CV risk have been prospectively defined based on clinical outcomes and can currently be used by clinicians.

9. 30-day Recurrent ischemic events
Increasing Clarity for the Practicing Clinician:
Clinically-Derived Cut-Offs from Prospective Studies
Study N
Device
Primary Endpt
Cutoff
Method
Sens
Spec
NPV
Price et al
380
VerifyNow P2Y12
6M CV death, MI, ST
PRU > 235
ROC curve
78%
70%
99%
Patti et al
160
30-day CV death, MI, TVR
PRU > 240
81%
53% nr
Marcucci et al
683
1 yr CV death, MI
61%
96%
Breet et al
1052
1 yr death, MI, ST, CVA
PRU > 236
Sibbing et al
1608
Multiplate Analyzer
30-day Stent thrombosis
468 AU·min
84%
Frere et al
195
VASP
30-day Recurrent ischemic events
PRI > 53%
93%
50%
Cuisset et al
598
LTA (10 umol)
Definite/Probable ST
ADP-ag > 67%
68%
Sibbing et al, J Am Coll Cardiol 2009;53:
Marcucci et al, Circulation 2009; 20;119(2):237-42
Patti, G. et al. J Am Coll Cardiol 2008;52:
Price MJ et al. Eur Heart J 2008; 29(8):
Frere et al, Thromb Haemost. 2007;98(4):
Cuisset et al, Am J Cardiol 2009; 104:
nr = not reported
Adapted from Price MJ, Circulation 2009 May 19;119(19):

10. Platelet Function Testing in PCI:
Evidence for the Prosecution – EXHIBIT C
Most patients on clopidogrel (those without high on-treatment reactivity) have terrific outcomes, while intensive antiplatelet therapy for everyone increases bleeding!

11. Clopidogrel and Outcomes: Prasugrel-like for Most Pts!
TRITON Results According to Carriage of Reduced Fxn CYP2C19 Allele in Pts Receiving Clopidogrel
12.1%
Carriers
P= 0.01
8.0%
Non-carriers
Reduced function allele present in 30% of population
Mega JL et al, NEJM 2009;360:354-62

12. Intense P2Y12 inhibition is Associated with Bleeding
Distribution of Major Bleeding events after PCI according to Multiplate PFT
n=34 major bleeding
events
n=2,533 patients (after 600 mg clopidogrel)
*ROC cut-off = 188 AU*min: Area under ROC curve = 0.61 (95% CI 0.51 to 0.70; P=0.017)
Sibbing D et al, J Thromb Haemost Nov 28.

13. On-Treatment Reactivity With Clopidogrel versus Prasugrel
New P2Y12 inhibitors provide reactivity below the range of clopidogrel
Little overlap between strongest clopidogrel response and weakest prasugrel response
Varenhorst C et al, Am Heart J, 2009

14. Platelet Function Testing in PCI:
Evidence for the Prosecution – EXHIBIT D
Initial data from randomized trials support the principle of individualized P2Y12 inhibitor therapy in patients undergoing PCI

15. Adjusted Clopidogrel Loading Doses According to VASP Decreases MACE in Patients With High On-Treatment Reactivity undergoing PCI
 MACE; n (%)
Control
(n=84)
VASP-guided
(n=78)
Cardiovascular death
2 (2)
Acute and Sub-acute stent thrombosis
4 (5)†
Revascularization
Overall MACE
8 (10)*
Log rank p =0.007
MACE: CV death, MI, revascularization
† p =0.059
* p =0.007
Bonello et al, J Am Coll Cardiol. 2008;51(14):

16. G R A V T A S
Successful PCI with DES without major complication or GPIIb/IIIa use
VerifyNow P2Y12 Assay hours post-PCI
PRU ≥ 230?
Yes No
Normal On-treatment Reactivity
High On-treatment Reactivity
Random Selection R
ACS A B C
N = 1100
N = 1100
N = 583
“Tailored Therapy”
clopidogrel 600-mg*, then
clopidogrel 150-mg/day
“Standard Therapy”
placebo loading dose, then clopidogrel 75mg +placebo/day
“Standard Therapy”
placebo loading dose clopidogrel 75mg +placebo/day
Clinical Follow-up And Platelet Function Assessment at 30 days, 6M
Primary Endpoint: 6 month CV Death, Non-Fatal MI, ARC definite/prob ST
Safety Endpoint: GUSTO Moderate or Severe Bleeding
*total first day dose
Price MJ et al, Am Heart J 2009

17. CYP2C19 Genotyping: The next frontier
The effect of clopidogrel is entirely due to the formation of the active metabolite.
Loss-of-function polymorphisms of the CYP2C19 enzyme lead to decreased levels of the active metabolite, and in turn, lower levels of platelet inhibition, strikingly so in homozygotes.
Why give a drug in patients when you know it can’t do its job?

18. CASE CLOSED!! Closing Arguments
Thrombosis after PCI is mediated by platelets.
Inhibition of platelets reduces thrombotic events.
Clopidogrel doesn’t inhibit platelets in some patients, whom can be identified easily.
These high-risk patients can be given stronger platelet inhibitor therapy, which should lead to greater net clinical benefit for the entire population.
No single randomized trial will be able to definitively “prove” the value of changing Rx based on PFT, given the many potential therapeutic options (e.g., prasugrel, cilostazol, high-dose clopidogrel).
CASE CLOSED!!