Is There a Role for Antiplatelet or Genetic Testing to Tailor Antiplatelet Therapy in 2017? Paul A. Gurbel, M.D. Inova Center for Thrombosis Research and Drug Development Inova Heart and Vascular Institute Falls Church, Virginia 1 1

Disclosures Honoraria/Consulting Astra Zeneca Boehringer Merck Janssen Bayer Research Grants/Support Haemonetics DCRI NIH Merck MedImmune Coramed Dr. Gurbel has patents in the field of platelet function testing 2

Indisputable Evidence: Coronary Thrombotic Events are “Platelet-Centric” Mechanism of ACS- A “Platelet-Centric” View “Vulnerable Plaque” “Plaque Rupture” Endothelium” “Plaque Erosion” Platelet Activation- Upstream Mediator Basic evidence: Platelets mediate - Adhesion molecule expression1 - Adhesion/internalization of monocytes  initiation of atherogenesis2-4 - oxLDL formation - Development of vulnerable plaque5 Gawaz M et al. Circulation. 1998;98:1164-71 Schulz C et al. Circulation. 2007;116:764-73 Gawaz M et al. J Thromb Haemost. 2008;6: 235-42 Afek A et al. Microvasc Res. 2009;77:364-9 Navarese EP et al. Ann Intern Med. 2016 ;164:600-7. Angiographic evidence (IVUS): HPR associated with - Coronary atherosclerosis burden, periprocedural MI6 and calcification7 - Culprit lesion atherosclerotic burden and adverse plaque morphology8 6. Mangiacapra F et a. J Am Coll Cardiol Intv 2013;3:35-40 7. Chirumamilla AP et al. J Am Coll Cardiol Img 2012;5:540-9 Yun KH et al. J Am Call Cardiol Img 2016;9849-54

THE PARADOX in CV Medicine Platelet - mediated thrombosis: - leading cause of death in patients CVD In current practice, nothing is done to: - assess intrinsic thrombogenicity - confirm adequate antiplatelet effects - non selective - “one-size-fits-all” - depersonalized therapy In many pts clopidogrel has no PD effect- should you give your high risk pt a placebo? 4

No Other Better Mechanism to Explain Clinical Outcomes Of TRITON and PLATO P2Y12 Inhibition = Clinical Efficacy TRITON TIMI 38 PLATO Wiviott SD et al. N Engl J Med 2007;357:2001-15 Wallentin L. et al. N Engl J Med. 2009;361:1045-57 Wiviott SD. et al. Circulation. 2007;116:2923-32 Gurbel PA, et al. Circulation. 2009;120:2577-85 =

Link of HPR to Thrombosis is Solid and Indisputable With Event s n=38 p<0.02 ? Threshold 20 uM ADP Aggregation (%) Cumulative Frequency (%) 10 20 30 40 50 60 70 80 90 100 Without Events n=154 Evidence for the Link Between Poor Platelet Inhibition and Post-PCI Thrombotic Events The PREPARE POST-STENTING Study Gurbel PA et al. J Am Coll Cardiol. 2005; 46:1820-6

HPR (Unblocked P2Y12 Signaling/Poor Response to Clopidogrel) is an Independent Risk Factor for Post-PCI Events ADAPT-DES Registry: - 8,349 patients undergoing PCI - Multicenter study Kirtane AJ et al. J Am Coll Cardiol Intv 2015;8:1978–87 2-Year Rates of Definite/Probable ST Clinically Relevant Bleeding Quantifying P2Y12 Blockade As a Clinical Tool Tantry US, Gurbel PA et al. J Am Coll Cardiol. 2013;62:2261-73 Therapeutic Window Concept for P2Y12 Receptor Reactivity

Efficacy of PFT-Guided Antiplatelet Therapy in PCI Patients: Systematic review and meta-analysis (10 studies) Aradi D et al. Int J Cardiol. 2013;167:2140-8. Discordance Between These Studies and Personalized Antiplatelet Therapy Studies Study (n) PFT Patients Therapy for HPR Outcome (%) GRAVITAS (2,214) VerifyNow P2Y12 Assay Stable CAD (60%) NSTE-ACS (10%) 75mg CLP vs ReLD 600mg LD/150mg MD MACE: 2.3 vs. 2.3 Major bleeding:1.4 vs. 2.3 ARCTIC (2,440) Stable CAD (63%) NSTE-ACS (27%) Baseline: 600mg LD/75mg MD CLP ( 97%) or 60mg LD/10mg MD PRS (3%) At 14 – 30d: Add 75mg CLP (90%) or PRS (<10%) MACE : 34.6 vs. 31.1 ST : 1 vs. 0.7 Major bleeding: 2.3 vs. 2.3 ANTARCTIC (1,312) >75 yrs ACS/PCI “Adjusting” - de-intensification to clopidogrel in an attempt to reduce bleeding MACE : 28% vs. 28% BARC (types 1, 2, 3, 4, or 5): 39% vs. 38% Price MJ et al. JAMA. 2011;305:1097-105. Collet J-P et al. N Engl J Med 2012;367:2100-2109. Cayla G et al. Lancet. 2016;388:2015-2022

Reasons for Discordant Observations - Patients: Stable CAD patients vs. High risk ACS patients - PFT to measure HPR: VerifyNow vs. Multiplate/VASP/TEG - Drug to Over come HPR: High dose CLP vs. PRS or TIG - All underpowered studies: Need ~17,000 patients needed to prove or disprove personalized antiplatelet therapy strategy De Caterina R et al. N Engl J Med. 2013;368:871 Incomplete monitoring Treatment with low-dose prs resulted in need to Rx HPR in only 4% Randomization was initiated 14 days after PCI: missing potential beneficial effect of PFM on early outcomes Nat Rev Cardiol. 2016;13:639-640

The Ongoing PFT Based Personalized Trial: TROPICAL -ACS 15 Europecenters, open label, prospective, randomized trial Multiplate Analyzer ACS patients undergoing successful PCI, N=2,600 Monitoring Arm Control Arm 7d prasugrel 5/10mg qd 7d clopidogrel 75mg qd 14d prasugrel 5/10mg qd PFT: ADPtest 11.5m prasugrel 5/10mg qd 11.5m prasugrel 5/10mg qd 11.5m clopidogrel 75mg qd Uniform Antiplatelet therapy with prasugrel Personalized Antiplatelet therapy with prasugrel Primary Endpoint: 1 y MI, stroke, CV death and bleeding Secondary Endpoints: Individual incidences of bleeding, stent thrombosis, all-cause mortality Cost-effective analysis NCT01742117

PFT to Guide Timing of Surgery: TARGET-CABG Study 500 1000 1500 2000 2500 3000 3500 mL Clopidogrel naïve On Clopidogrel 4 hrs 12 hrs 24 hrs p = NS Post-Surgery Primary Endpoint: 24 Hr Chest Output Clopidogrel naïve (n=95) TEG MAADP On clopidogrel (n=96) Wait 5 d Wait 3-5 d < 1 d 35-50mm >50mm Primary Endpoint: 24 hrs chest output Secondary Endpoint: Hospital duration <35mm CATHETERIZATION Thrombelastography (TEG) Better preoperative balance than intra- and postoperative correction which is not measurable 50% - > Ischemic events – surrogate marker for clotting > 50%: normal values in ASPECT (CAD + aspirin) and association with ischemic events – assumption that surrogate marker for clotting < 30%: responder – wait 5 days (biological half life) N = 139 Cutoff: 60: 6 pts 50: 31/139 = 23% < 30: 46/139 = 33% 30-50%: 63/139 = 46% Secondary Endpoint: ~ 50% shorter waiting time than recommended in the current guidelines. Mahla E, Gurbel PA et al. Circ Cardiovasc Interv. 2012;5:261-269

Genetic Testing

Sinai Hospital of Baltimore Study Platelet Aggregation, % 13 SNP’s Sinai Hospital of Baltimore Study Platelet Aggregation, % 100 80 60 40 20 1 2 No. of CYP2C19*2 Alleles P=.92 Pre-clopidogrel P=.02 Post-clopidogrel HR=2.42; 95% CI, 1.18–4.99; P=0.02 50 90 Days 40 30 20 10 180 270 360 No. of CYP2C19*2 Alleles 1 % Experiencing Event

Presented at AHA 2016 at New Orleans

Study Design MACE: Death, MI, or stroke within 12 months following index PCI In patients with CYP2C19 LOF, CV outcomes can be improved when clinical genotype made available and alternative therapy prescribed early after PCI

The Ongoing Genotyping Based Personalized Trial (TAILOR PCI) Multicenter, open label, prospective, randomized trial (n=5,270) CYP2C19 genotyping by Spartan-TM Bioscience assay Clopidogrel 75 mg /d Genotyping at the end of 1 year for LoF or wild type allele Conventional Arm Wild type Clopidogrel 75mg/d Active Arm Prospective Genotyping LoF carriers Ticagrelor 90 mg/bid ACS/Stable patients undergoing PCI Primary Endpoint: 1 y non-fatal MI, non-fatal stroke, CV death, severe recurrent ischemia, and stent thrombosis Secondary Endpoints: Number of LoF carriers with major or minor bleeding NCT01742117

PFT and Genetic Testing in 2017? #1 We don’t have a definitive prospective study to dispute its utility #2 But, we do have - totality of evidence: - huge biologic plausibility - huge observational database: ex vivo high reactivity = risk - huge prospective randomized trial data: less thrombosis with more P2Y12 inhibition - intriguing new IVUS studies- link of HPR to: atherosclerotic burden/adverse plaque morphology #3 Platelet function testing to guide timing of surgery

At IHVI, phenotyping and genotyping will be done in all cath pts