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

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

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”

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

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

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

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

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.

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;53:849-856 Marcucci et al, Circulation 2009; 20;119(2):237-42 Patti, G. et al. J Am Coll Cardiol 2008;52:1128-1133 Price MJ et al. Eur Heart J 2008; 29(8):992-1000 Frere et al, Thromb Haemost. 2007;98(4):838-843. Cuisset et al, Am J Cardiol 2009; 104:1078-1082 nr = not reported Adapted from Price MJ, Circulation 2009 May 19;119(19):2625-32

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!

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

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. 2009 Nov 28.

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

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

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):1404-1411

G R A V T A S Successful PCI with DES without major complication or GPIIb/IIIa use VerifyNow P2Y12 Assay 12-24 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

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?

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!!