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

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