Gauging Responsiveness with A VerifyNow assay - Impact on Thrombosis And Safety The GRAVITAS trial Matthew J. Price MD, FACC, FSCAI Director, Cardiac Catheterization Laboratory, Scripps Clinic Director, Interventional Cardiology Research, Scripps Genomic Medicine La Jolla, California

Matthew J. Price, MD DISCLOSURES Consulting Fees Honoraria Accumetrics, Inc., Daiichi Sankyo, Inc., AstraZeneca, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership Honoraria Daiichi Sankyo, Inc. and Eli Lilly and Company Grants/Contracted Research Sanofi-Aventis U.S. LLC, Portola Inc. 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

Background There is significant variability in the inhibitory response to clopidogrel among individuals. Patients with high platelet reactivity on clopidogrel treatment appear to have a higher risk of ischemic events after PCI. Higher-dose clopidogrel regimens improve inhibition (decrease platelet reactivity) in patients who have high on-treatment reactivity with standard dosing. The safety and efficacy of tailored clopidogrel therapy based on platelet function testing has not been examined in a prospective, randomized fashion.

Background Clinically derived cut-offs for the VerifyNow P2Y12 device Study N Device Primary Endpoint Cutoff Method Price et al 380 VN P2Y12 6M CV death, MI, ST PRU > 235 ROC curve Patti et al 160 30-day CV death, MI, TVR PRU > 240 Marcucci et al 683 1 yr CV death, MI Breet et al 1052 1 yr death, MI, ST, CVA PRU > 236 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 Adapted from Price MJ, Circulation 2009 May 19;119(19):2625-32

G R A V T A S Primary Hypothesis: Adjusting the dose of clopidogrel in patients with high on-treatment reactivity after PCI with DES will reduce the hazard rate for ischemic events (CV death, non-fatal MI, and stent thrombosis) in the six months after randomization. Secondary Hypothesis: The hazard rate for ischemic events in patients with high on-treatment reactivity with the standard clopidogrel 75-mg/day will be significantly greater than similarly treated patients without high on-treatment reactivity.

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

Clopidogrel, Genotype, and Clinical Outcomes in ACS TRITON Results According to Carriage of Reduced Fxn CYP2C19 Allele in ACS Patients Receiving Clopidogrel 12.1% Carriers P= 0.01 8.0% Non-carriers However, the CYP2C19*2 genotype accounts for only 12% of the variation in clopidogrel response (Shuldiner et al, JAMA 2009) Mega JL et al, NEJM 2009;360:354-62

Exploring the Synergy Between Genetic and Platelet Function Testing In addition to CYP2C19 status, what are the independent predictors of clopidogrel non-responsiveness? Does genotype influence the incremental response to high dose maintenance clopidogrel? E.g., can high-dose maintenance therapy provide further platelet inhibition in patients with high on-treatment reactivity who are carriers of CYP2C19 loss-of-function alleles?

CYP2C19 CYP3A5 CYP2B6 CYP3A4 ABCB1 P2RY12 IRS-1 PAR-1 Exploring the Synergy Between PFT and Genetic Testing: The Effect of Genotype on Incremental Inhibition Provided by High-dose Clopidogrel PLATELET FUNCTION: VerifyNow P2Y12 at GRAVITAS index procedure (post standard dose clopidogrel) and after 30 days, 6 months of study drug AND GENOTYPE: Genetic panel from blood sample drawn at time of GRAVITAS platelet function testing or follow-up CYP2C19 CYP3A5 CYP2B6 CYP3A4 ABCB1 P2RY12 IRS-1 PAR-1 Baseline clinical characteristics (e.g., DM) Concomitant Meds (e.g., PPIs) Independent determinants of residual platelet reactivity (PRU) on standard clopidogrel therapy Effect of genetics, e.g., CYP2C19*2 carriage, on the incremental response to high-dose clopidogrel in non-responders to standard Rx ClinicalTrials.gov Identifier NCT00992420

G R A V T A S GRAVITAS is the first large scale, randomized, placebo controlled clinical trial to examine whether adjustment of clopidogrel therapy on the basis of platelet function testing safely improves outcomes after DES implantation. GRAVITAS is currently enrolling at 70 U.S. and 10 Canadian sites, and enrollment should be complete in the coming weeks. GIFT, a sub-study of GRAVITAS, will assess the independent predictors of platelet reactivity including genotype, and will assess the influence of genotype on the functional response to high-dose clopidogrel maintenance therapy.