HIGH ON-TREATMENT PLATELET REACTIVITY: STATE-OF-ART DR. NIKITA LOMAKIN PHD, FACC HEAD OF THE INTENSIVE CARDIOLOGY DEPARTMENT HEAD OF THE OUT-PATIENT ANTITHROMBOTIC CLINIC CENTRAL CLINICAL HOSPITAL PRESIDENTIAL DEPARTMENT RUSSIAN FEDERATION MOSCOW

Overall number of patients in all clopidogrel studies > ACTIVE nSTEMI STEMI MI, STROKE AF ERA OF CLOPIDOGREL 2

CLOPIDOGREL PLUS ASPIRIN IS NO MORE GOLD STANDARD?

PLATO: REGIONAL DIFFERENCES Thromb Haemost 2011; 105: 752–759 4

TICAGRELOR SIGNIFICANTLY INCREASE MAJOR NON- CABG-RELATED BLEEDING Основная доля пациентов в PLATO (90%) не подвергалась АКШ P=0,025 P=0,026 Wallentin L et al, N Engl J Med. 2009;361:

nSTEMISTEMI Low risk Intermediate risk High riskPCIThrombolisys Optimal medical treatment Clopidogrel √√√√√√ Ticagrelor √√√ Prasugrel √√√√ TICAGRELOR VS CLOPIDOGREL VS PRASUGREL 6

Wallentin et al. NEJM 2009;361: Wiwiott et al. NEJM 2007;357: ,189 Eur 1,023 Eur 971 Eur 135 Eur 7

Число больных Агрегация тромбоцитов (%) DIFFERENCES IN ANTIPLATELET ACTIVITY ASA + CLOPIDOGREL Geisler T et al. Heart 2008; 94: 743–747

Is there an association between PFT results and adverse clinical events on P2Y 12 -inhibitors and/or aspirin therapy? CAN WE PREDICT ADVERSE OUTCOMES? What should we do based on results? CAN WE PREVENT ADVERSE OUTCOMES? PLATELET FUNCTION TESTING IN

After 600 mg clopidogrel loading dose, in patients with stable angina undergoing PCI Aradi D et al. Eur Heart J. 2014:35; Clopidogrel resistant Clopidogrel non-responder High on-clopidogrel platelet reactivity (HPR) 10

Meta-analysis on the clinical relevance of high on-clopidogrel platelet reactivity (HPR) patients, 21 studies Aradi et al. Am Heart J. 2010; 160: Aradi et al. Platelets 2012; 23:

Hamm CW et al. Eur Heart J. 2011;

Monitoring of antiplatelet response by platelet function assays is currently used for clinical research, but not in daily clinical practice. ESC guidelines on NSTE-ACS ESC/EACTS guidelines on myocardial revascularization Wijns W et al. Eur Heart J 2010;31: Hamm CW et al. Eur Heart J. 2011;

MAIN ARGUMENTS AGAINST PFT GRAVITAS (VerifyNow) —Low risk pts (stable angina) —Doubling dose of clopidogrel is not enough to prevent HPRT —Increased dose of clopidogrel was not associated with increased risk of bleeding —wrong PRU references GRAVITAS (VerifyNow) —Low risk pts (stable angina) —Doubling dose of clopidogrel is not enough to prevent HPRT —Increased dose of clopidogrel was not associated with increased risk of bleeding —wrong PRU references TRIGGER-PCI (VerifyNow) —Low risk pts (stable angina) —Six months follow-up —Random choice in swithing from clopidogrel to prasugrel TRIGGER-PCI (VerifyNow) —Low risk pts (stable angina) —Six months follow-up —Random choice in swithing from clopidogrel to prasugrel ARCTIC (VerifyNow) —Low risk pts (stable angina) —very complicated design (Iib/IIIa, prasugrel) —Primary end point was based on periprocedural MI (TRP in 6 hrs after PCI) ARCTIC (VerifyNow) —Low risk pts (stable angina) —very complicated design (Iib/IIIa, prasugrel) —Primary end point was based on periprocedural MI (TRP in 6 hrs after PCI) Trenk D et.al. Thromb Haemost 2013; 109: 834–845

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Stone et al. Lancet, 2013;382: ADAPT-DES: DEFINITE / PROBABLE ST in 1 year PRU 235 PRU

Price MJ et al. JAMA 2011; 305: Collet et al. N Engl J Med. 2012;367: Trenk D et al. J Am Coll Cardiol 2012;59: GRAVITASARCTICTRIGGER PCI n (study population)2,2142, Patient risk profile AMI (%)10%27%0% STEMI (%)0.4%0% Shock (%)0% All-cause mortality0.8%2%0% Intervention High-dose clopidogrel100%80%- High-dose ASA-45%- Prasugrel-12%100% PFT AssayVerifyNow Results 1° Endpoint 2.3% vs. 2.3%31.1% vs. 34.6% 0.0% vs. 0.5%

Copyright © The American College of Cardiology. All rights reserved. Optimizing P2Y 12 Receptor Inhibition in Patients With Acute Coronary Syndrome on the Basis of Platelet Function Testing: Impact of Prasugrel and High-Dose Clopidogrel J Am Coll Cardiol. 2014;63(11): doi: /j.jacc

HR: 2.94 (1.76 – 4.94) p < HR: 1.12 (0.50 – 2.51) p = 0.79 Aradi et al. J Am Coll Cardiol Jan 20. E-pub ahead of print. 19

HPRT ON PRASUGREL?

ARADI et al. TCT2012 HPRT ON TICAGRELOR?

PIANO-3 ESRD TRIAL JS Woo, et al % OF CKD COULD BE TICAGRELOR RESISTANT 22

J Am Coll Cardiol. 2011;57(4): doi: /j.jacc ВЫСОКАЯ ОСТАТОЧНАЯ АКТИВНОСТЬ ТРОМБОЦИТОВ У ПАЦИЕНТОВ С ХБП 23

Aradi et al. Eur Heart J Sep 25. E-pub ahead of print. Aradi et al. Am Heart J. 2010; 160: HPR LPR 24

Sibbing et al. JTH P=0.001 Cuisset et al. Eurointervention TIMI major and minor bleeds at 30 days In-hospital TIMI major bleeding 25

ESC EXPERT PAPER

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In clopidogrel-treated patients, measuring ADP-dependent platelet reactivity with platelet function assays may be considered to predict the risk of ST and bleeding after PCI. IIbB Where the availability of prasugrel and ticagrelor is restricted or limited to certain indications, platelet function testing may be considered to identify patients with HPR, who are at heightened risk for thrombotic complications on clopidogrel and require a potent P2Y12- inhibitor (prasugrel or ticagrelor). IIbC Administration of high-dose clopidogrel in ACS patients with HPR is not recommended. IIIB Platelet reactivity is one of the most important prognostic biomarkers after PCI to PREDICT outcomes -- Low platelet reactivity (LPR) predicts the risk for bleeding -- These results suggest the relevance of a therapeutic window for P2Y12- inhibitors -- 29

PFT IN CCH PCIVERIFYNOW LTA-1 DAY1 LTA-2 DAY2 1 month 12 MONTHS STOP THERAPY HPR IN HOSPITALOUT-PATIENT

Пациент Д.,74 года ИБС- длительно АКШ- ДА,ВТК, ПКА +МКШ ПМЖВ 2006 Стентирование ПКА ХБП- программный гемодиализ ОКС ЖКК Hb массивные Язв. дефекты LTA-Agr 61% ЧКВ НЕОБХОДИМ: -Препарат неудаляющейся гемодиал -Быстрый эффект -Обратимого действия -Минимально эффективная доза ½ НАГРУЗ ДОЗЫ + PRU=193- OK LTA контроль 35% Амбулаторный этап

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