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HIGH ON-TREATMENT PLATELET REACTIVITY:STATE-OF-ART
DR. NIKITA LOMAKIN
PHD, FACCHEAD OF THE INTENSIVE CARDIOLOGY DEPARTMENTHEAD OF THE OUT-PATIENT ANTITHROMBOTIC CLINIC
CENTRAL CLINICAL HOSPITALPRESIDENTIAL DEPARTMENT
RUSSIAN FEDERATION
MOSCOW
Overall number of patients in all clopidogrel studies > 160 000
ACTIVE
nSTEMI
STEMI
MI, STROKE
AF
ERA OF CLOPIDOGREL2
CLOPIDOGREL PLUS ASPIRIN IS NO MORE GOLD STANDARD?
PLATO: REGIONAL DIFFERENCES
Thromb Haemost 2011; 105: 752–759
4
0.00%
1.00%
2.00%
3.00%
4.00%
5.00%
6.00%
7.00%
2.80%2.20%
TIMI major bleeding definition
Ticagrelor Plavix
0.00%
1.00%
2.00%
3.00%
4.00%
5.00%
6.00%
7.00%
8.00%
9.00%
4.50%3.80%
PLATO bleeding definition
Ticagrelor Plavix
TICAGRELOR SIGNIFICANTLY INCREASE MAJOR NON-CABG-RELATED BLEEDING
10%
90%
CABG NON-CABG
Основная доля пациентов в PLATO (90%) не подвергалась АКШ
P=0,025P=0,026
Wallentin L et al, N Engl J Med. 2009;361:1045-1057
5
nSTEMI STEMI
Low risk
Intermediate
riskHigh risk PCI Thrombolisys
Optimal medical
treatment
Clopidogrel√ √ √ √ √ √
Ticagrelor√ √ √
Prasugrel√ √ √ √
TICAGRELOR VS CLOPIDOGREL VS PRASUGREL6
HUGE COST DIFFERENCE
Wallentin et al. NEJM 2009;361:1045-57. Wiwiott et al. NEJM 2007;357:2001-15.
1,189 Eur
1,023 Eur 971 Eur
135 Eur
7
Чи
сло
бо
ль
ны
х
Агрегация тромбоцитов (%)
DIFFERENCES IN ANTIPLATELET ACTIVITYASA + CLOPIDOGREL
Geisler T et al. Heart 2008; 94: 743–747
• Is there an association between PFT results and adverse clinical events on P2Y12-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 20149
After 600 mg clopidogrel loading dose, in patients with stable angina undergoing PCI
What parameter should we measure: P2Y12 inhibitors
Aradi D et al. Eur Heart J. 2014:35;209-15.
Clopidogrel resistantClopidogrel non-responder
High on-clopidogrel platelet reactivity (HPR)
10
Meta-analysis on the clinical relevance of high on-clopidogrel platelet reactivity (HPR)
13 507 patients, 21 studies
Aradi et al. Am Heart J. 2010; 160: 543-51.
Aradi et al. Platelets 2012; 23: 167-76.
HIGH-ON-CLOPIDOGREL-PLATELET –REACTIVITY AND THROMBOTIC EVENTS
Hamm CW et al. Eur Heart J. 2011; 2999-3054.
ESC 2011 GUIDELINES ON NSTE-ACS12
PLT FUNCTION TESTING IN CLINICAL GUIDELINES
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 2011.
ESC/EACTS guidelines on myocardial revascularization 2010.
Wijns W et al. Eur Heart J 2010;31:2501-55. Hamm CW et al. Eur Heart J. 2011; 2999-3054.
13
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
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)
Trenk D et.al. Thromb Haemost 2013; 109: 834–845
2/3
14
Stone et al. Lancet, 2013;382:614-23
ADAPT-DES: DEFINITE / PROBABLE ST in 1 year
PRU 235 PRU 20815
Price MJ et al. JAMA 2011; 305: 1097-105.Collet et al. N Engl J Med. 2012;367:2100-9.Trenk D et al. J Am Coll Cardiol 2012;59:2159-64.
GRAVITAS ARCTIC TRIGGER PCI
n (study population) 2,214 2,440 423
Patient risk profile
AMI (%) 10% 27% 0%
STEMI (%) 0.4% 0% 0%
Shock (%) 0% 0% 0%
All-cause mortality 0.8% 2% 0%
Intervention
High-dose clopidogrel 100% 80% -
High-dose ASA - 45% -
Prasugrel - 12% 100%
PFT Assay VerifyNow VerifyNow VerifyNow
Results
1° Endpoint 2.3% vs. 2.3% 31.1% vs. 34.6% 0.0% vs. 0.5%
WHAT PATIENTS SHOULD WE MEASURE?WHAT SHOULD WE DO BASED ON RESULTS?
Copyright © The American College of Cardiology. All rights reserved.
Optimizing P2Y12 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):1061-1070. doi:10.1016/j.jacc.2013.12.023
CLINICAL RESULTS:MORTALITY OR STENT THROMBOSIS
HR: 2.94 (1.76 – 4.94) p < 0.001
HR: 1.12 (0.50 – 2.51) p = 0.79
Aradi et al. J Am Coll Cardiol. 2014 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 2014
47% OF CKD COULD BE TICAGRELOR RESISTANT22
J Am Coll Cardiol. 2011;57(4):399-408. doi:10.1016/j.jacc.2010.09.032
ВЫСОКАЯ ОСТАТОЧНАЯ АКТИВНОСТЬ ТРОМБОЦИТОВ У ПАЦИЕНТОВ С ХБП23
Aradi et al. Eur Heart J. 2013 Sep 25. E-pub ahead of print.Aradi et al. Am Heart J. 2010; 160: 543-51.
ASSOCIATIONS BETWEEN LPR AND BLEEDING
HPR
LPR
24
LPR(n=975)
No LPR(n=1558)
Sibbing et al. JTH 2010.
P=0.001
LPR(n=119)
No LPR(n=478)
Cuisset et al. Eurointervention 2009.
TIMI major and minor bleeds at 30 daysIn-hospital TIMI major bleeding
ASSOCIATIONS BETWEEN LOW PLATELET REACTIVITY AND BLEEDING
25
ESC EXPERT PAPER
THERAPEUTIC WINDOW HYPOTHESIS28
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.
IIb B
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).
IIb C
Administration of high-dose clopidogrel in ACS patients with HPR is not recommended. III B
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
PCIVERIFYNOWLTA-1DAY1
LTA-2DAY2 1 month
12 MONTHSSTOP THERAPY
HPR
IN HOSPITAL OUT-PATIENT
Пациент Д. ,74 годаИБС- длительноАКШ- ДА,ВТК, ПКА +МКШ ПМЖВ 2006Стентирование ПКА 04-13ХБП- программный гемодиализ 07-13
29-07ОКС
30-07ЖКК
Hb 130-80массивныеЯзв. дефекты
29-07LTA-Agr61%
02-08ЧКВ
НЕОБХОДИМ:- Препарат неудаляющейся гемодиал- Быстрый эффект- Обратимого действия- Минимально эффективная доза
½ НАГРУЗ ДОЗЫ
+
PRU=193- OK
LTA контроль35%
Амбулаторный этап
10 ОКТЯБРЯ 2014 ГОДА
www. cardiology2014.ru
8 (495) 530-01-26