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Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!

Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!. Platelet Adhesion/Activation. PCI/MI. Aspirin. x. P2Y 12 Blockers. ADP. TxA 2. Thrombin. Vorapaxar. x. x. Sustained GPIIb / IIIa Activation. Ischemic Events/Stent Thrombosis. Hypercoagulability. Inflammation.

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Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!

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  1. Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!! Platelet Adhesion/Activation PCI/MI Aspirin x P2Y12Blockers ADP TxA2 Thrombin Vorapaxar x x Sustained GPIIb/IIIa Activation Ischemic Events/Stent Thrombosis Hypercoagulability Inflammation ADP = adenosine diphosphate. GP = glycoprotein. MI = myocardial infarction. PCI = percutaneous coronary intervention. TxA2 = thromboxane A2. Gurbel PA, Tantry US. Circulation. 2012;125:1276-1287. Platelet Aggregation

  2. Aggregation on Aspirin, Aspirin + Clopidogrel, and Aspirin + Ticagrelor 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 42% 50% 80 8 hrs post-600 mg clopidogrel 8 hrs post-180 mg ticagrelor load 60 Aspirin 75-100 mg QD Cumulative Frequency (%) 40 20 0 0 20 40 60 80 100 120 20uM ADP-induced Aggregation GurbelPA, TantryUS. Circulation.2012;125:1276-1287.

  3. VerifyNow P2Y12Patient-based Meta-analysis: 2-year Outcomes Very low ST rate ~ immunity 6 studies; n=3059 2-year MACE by PRU Quartile 2-year ST by PRU Quartile ~8x risk between Q1 and Q4 ~3x risk between Q1 and Q4 MACE = major adverse cardiovascular event. PRU = platelet reactivity unit. ST = stent thrombosis. Brar SS, et al. J Am CollCardiol. 2011;58:1945-1954.

  4. The Platelet Function Therapeutic Window and the Concept of Thrombosis Immunity Post-PCI Ischemic/Thrombotic Clinical Events 100 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 90 80 BleedingThreshold <85 PRU<188 AU<31mm MAKH 70 60 Cumulative Frequency of Patients (%) 50 Most ischemic events occur above a platelet reactivity cutoff Small increase above cutoff: increased ischemic risk 40 30 Too lowplatelet reactivity? 20 Bleeding? 10 0 ADP-induced Platelet Reactivity (%) 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 CollCardiol. 2007;50:1822-1834. Gurbel PA, et al. Am Heart J. 2010;160:346-354. Campo G, et al. J Am CollCardiol. 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. ThrombHaemost. 2011;106:263-264. Sibbing D, et al. ThrombHaemost 2010;103:151-159. Sibbing D, et al. J ThrombHaemost. 2010;8:250-256.

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

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

  7. Other Ischemic Endpoints

  8. Key Safety Outcomes STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17

  9. Platelet Function Substudy Design UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization Prasugrelvs.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 P2Y12Assay At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization Primary efficacy endpoint: -Composite of CV death, MI, and stroke through 30 months Key secondary endpoints: - All-cause death - MI 126 without valid PRU measurement excluded from analysis 2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278) included in final analysis

  10. 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

  11. Relationship of PRU Values with Ischemic Event Occurrence Through 30 Months

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