Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!! Platelet Adhesion/Activation Aspirin x Thrombin ADP TxA2 Sustained GPIIb/IIIa Activation P2Y12 Blockers x Vorapaxar x Platelet Aggregation Hypercoagulability Inflammation Ischemic Events/Stent Thrombosis ADP = adenosine diphosphate. GP = glycoprotein. MI = myocardial infarction. PCI = percutaneous coronary intervention. TxA2 = thromboxane A2. Gurbel PA, Tantry US. Circulation. 2012;125:1276-1287. 2

Aggregation in 42% of pts on clopidogrel + aspirin: Aggregation on Aspirin, Aspirin + Clopidogrel, and Aspirin + Ticagrelor 8 hrs post-180 mg ticagrelor load 8 hrs post-600 mg clopidogrel Aggregation in 42% of pts on clopidogrel + aspirin: In same range as 50% of pts treated with aspirin alone! In Asians, it will be even higher than 42% 100 Aspirin 75-100 mg QD 42% 50% 80 60 Cumulative Frequency (%) 40 20 20 40 60 80 100 120 20uM ADP-induced Aggregation Gurbel PA, Tantry US. Circulation.2012;125:1276-1287. 3

VerifyNow P2Y12 Patient-based Meta-analysis: 2-year Outcomes 6 studies; n=3059 2-year MACE by PRU Quartile 2-year ST by PRU Quartile Very low ST rate ~ immunity ~3x risk between Q1 and Q4 ~8x risk between Q1 and Q4 MACE = major adverse cardiovascular event. PRU = platelet reactivity unit. ST = stent thrombosis. Brar SS, et al. J Am Coll Cardiol. 2011;58:1945-1954.

Group 2 : Conventional Arm Double Randomization of a Monitoring-adjusted Antiplatelet Treatment vs a Common Antiplatelet Treatment for DES Implantation Handout ARCTIC Study NCT00827411 Randomization before DES implantation N=2500 Group 2 : Conventional Arm No assessment of oral antiplatelet treatment effect Conventional therapy Group 2 : Monitoring Arm Assessment of aspirin and clopidogrel effect before DES and at day 7-14 Adjustment of antiplatelet treatment in suboptimal responders Primary Endpoints (6-18 m) All-cause Mortality, MI, Urgent Revascularization, ST, Ischemic Stroke DES = drug-eluting stent. Montalescot G, et al. To be presented at: The American Heart Association’s Scientific Sessions 2012; November 4-6, 2012; Los Angeles, CA. 5

Platelet Function in the Medically Managed ACS Patient: TRILOGY Platelet Function Substudy Handout UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization Prasugrel Clopidogrel 5 mg (≥ 75 years and/or < 60 kg), 10 mg (< 75 years and ≥ 60 kg) vs. 75 mg (for all) Aspirin < 100 mg (strongly recommended) for all TRILOGY Platelet Function Substudy: 2690 participants from 25 countries VerifyNow P2Y12 Assay: At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization 126 participants with no valid PRU measurement excluded from analysis** 2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278) included in final analysis Primary efficacy endpoint: - Composite of CV death, MI, and stroke through 30 months Key secondary endpoints: - All-cause death - MI ACS = acute coronary syndrome. Gurbel PA, et al. To be presented at: The American Heart Association’s Scientific Sessions 2012; November 4-6, 2012; Los Angeles, CA.

2012 Guideline Recommendations Regarding Platelet Function Testing Handout 2012 ACCF/AHA Guideline for Patients with UA/NSTEMI or After ACS and PCI1: Platelet function testing to determine platelet inhibitory response in patients with UA/NSTEMI (or after ACS and PCI) on P2Y12 receptor inhibitor therapy may be considered if results of testing may alter management – Class IIb - Level B evidence 2012 ESC Guideline for Patients Presenting without STEMI2: Increasing the maintenance dose of clopidogrel based on platelet function testing is not advised as routine but may be considered in selected cases – Class IIb - Level B evidence Genotyping and/or platelet function testing may be considered in selected cases when clopidogrel is used – Class IIb - Level B evidence NSTEMI = non-ST segment elevation myocardial infarction. STEMI = ST segment elevation myocardial infarction. UA = unstable angina. 1. Jneid H, et al. J Am Coll Cardiol. 2012;60:645-681. 2. Hamm CW, et al. Eur Heart J. 2011;32:2999-3054.

The Platelet Function Therapeutic Window and the Concept of Thrombosis Immunity Post-PCI Ischemic/Thrombotic Clinical Events Cumulative Frequency of Patients (%) ADP-induced Platelet Reactivity (%) 10 20 30 40 50 60 70 80 90 100 Too low platelet reactivity? Bleeding? Most ischemic events occur above a platelet reactivity cutoff Small increase above cutoff: increased ischemic risk Patients with ischemic events Immunity Thresholds ~170 PRU ~50% VASP-PRI ~35% 5 M ADP ~46% 20 M ADP ~416 AU MULTIPLATE ~65 mm MAKH-TEG Bleeding Threshold <85 PRU <188 AU <31mm MAKH The sigmoid cumulative frequency curve in patients with post-PCI ischemic/thrombotic clinical events relative to platelet reactivity to ADP; these data support the concept of a therapeutic window for P2Y12 blockade. Gurbel PA, et al. J Am Coll Cardiol. 2007;50:1822-1834. Gurbel PA, et al. Am Heart J. 2010;160:346-354. Campo G, et al. J Am Coll Cardiol. 2011;57:2474-2483. Jeong YH, et al. Presented at: European Society of Cardiology Congress 2011; August 27-31, 2011; Paris, France. Gurbel PA, et al. Thromb Haemost. 2011;106:263-264. Sibbing D, et al. Thromb Haemost 2010;103:151-159. Sibbing D, et al. J Thromb Haemost. 2010;8:250-256. 8

Drug and dose adjustments if high platelet reactivity at Day 14 ARCTIC Trial Design Standard of care VerifyNow P2Y12 + ASA Drug (ASA, clopidogrel, prasugrel, GPIIbIIIa i) and dose adjustments if high platelet reactivity Coronary angiogram Stent-PCI Randomized Drug and dose adjustments if high platelet reactivity at Day 14 12-month FU Primary endpoint at 12 months: Death, MI, stroke, ST, urgent revascularization Statistical considerations: Assuming an annual risk of 9% and a 33% relative risk reduction (α risk at 5% and error β of 20%, bilateral test), 2466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12

Adjustment Rules ARU>550 (Aspirin) VerifyNow before DES-PCI Reload with 500 mg IV aspirin GPIIb/IIIai+ clopidogrel (re)LD (>600 mg) or prasugrel LD 60 mg then, MD clopidogrel 150 mg or prasugrel 10mg VerifyNow before DES-PCI %inh<15% and/or PRU>235 (P2Y12)

Adjustment Rules ARU>550 (Aspirin) GPIIb/IIIai+ clopidogrel (re)LD (>600 mg) or prasugrel LD 60 mg then, MD clopidogrel 150 mg or prasugrel 10mg ARU>550 (Aspirin) Reload with 500 mg IV aspirin VerifyNow before start of DES-PCI %inh<15% and/or PRU>235(P2Y12) %inh<15% and/or PRU>235 Doubling the aspirin dose ↗ Clopidogrel dose by at least 75 mg or switch to prasugrel 10mg if clopidogrel 150mg  ↘ 75mg if prasugrel  clopidogrel 75mg ARU>550 %inh>90% VerifyNow @ day 14-30

Death, MI, stroke, stent thrombosis, urgent revascularization Primary Endpoint to 1 year Death, MI, stroke, stent thrombosis, urgent revascularization

Stent thrombosis or urgent revascularization Main Secondary Endpoint to 1 year Stent thrombosis or urgent revascularization

Other Ischemic Endpoints   Conventional Monitoring HR [95%CI] P Death or myocardial Infarction - % 28.8 31.7 1.11 [0.96; 1.29] 0.15 Any death - % 1.6 2.3 1.41 [0.79; 2.50] 0.24 Myocardial infarction - % 28.4 30.3 1.08 [0.93; 1.25] 0.32 Stent thrombosis - % 0.7 1 1.34 [0.56; 3.18] 0.51 Stroke or TIA- % 0.6 1.15 [0.42; 3.18] 0.78 Urgent revascularization - % 4.2 4.5 1.06 [0.73; 1.55] 0.76

Key Safety Outcomes   Conventional Monitoring HR [95%CI] P Major bleeding - % 3.3 2.3 0.70 [0.43; 1.14] 0.15 Minor bleeding - % 1.7 1.0 0.57 [0.28; 1.16] 0.12 Major or minor bleeding - % 4.5 3.1 0.69 [0.46; 1.05] 0.08 STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17

Platelet Function Substudy Design UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization Prasugrel vs. Clopidogrel 10 mg (< 75 years and ≥ 60 kg) 75 mg (for all) 5 mg (≥ 75 years; < 75 years and < 60 kg) Aspirin ≤ 100 mg (strongly recommended) for all PFS: 2690 (28% of total) participants from 25 countries VerifyNow P2Y12 Assay At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization 2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278) included in final analysis 126 without valid PRU measurement excluded from analysis Primary efficacy endpoint: - Composite of CV death, MI, and stroke through 30 months Key secondary endpoints: - All-cause death - MI Source: Q113, Q111, Q331 [Source: Figure 1 on page 19] Reference: Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1. Pras00045111

Kaplan-Meier Event Curves: Landmark at 30 Days HPR Cut-Point > 208 PRU Primary Efficacy Endpoint With HPR Without HPR The P values for each panel compare the hazard between the two groups throughout the time period represented. All MI Events All-Cause Death

Relationship of PRU Values with Ischemic Event Occurrence Through 30 Months Unadjusted Results HR (95% CI) p-value PRU as time-dependent covariate (per 60-unit increase) CVD/MI/stroke 1.09 (1.02-1.16) 0.008 All-cause death 1.09 (1.01-1.18) 0.03 All MI 1.02 (0.94-1.11) 0.60 30-day HPR PRU cut-point > 208 1.43 (1.10-1.86) 0.01 1.38 (0.99-1.91) 0.06 1.37 (0.96-1.95) 0.08 30-day HPR PRU cut-point > 178 1.35 (1.05-1.73) 0.02 1.27 (0.92-1.75) 0.15 1.34 (0.96-1.86) 0.09 Adjusted Results HR (95% CI) p-value 1.03 (0.96-1.11) 0.44 0.99 (0.90-1.08) 0.79 0.97 (0.88-1.07) 0.53 1.16 (0.89-1.52) 0.28 1.03 (0.74-1.44) 0.84 1.13 (0.79-1.62) 0.50 1.13 (0.87-1.45) 0.35 0.99 (0.71-1.38) 0.95 1.13 (0.80-1.58) 0.49