Presentación "Manejo de la antiagregación ajustada a las pruebas de reactividad plaquetaria. Experiencia, Resultados y futuro de un programa nacional" del Dr. Daniel Aradi durante la Mesa Redonda de Antiagregación de la XXV Reunión Anual de la Sección de Hemodinámica y Cardiología Intervencionista (SHCI) de 2014 en Córdoba.

1. Platelet function testing to guide P2Y12-inhibitor treatment
in ACS patients after PCI:
Experience, results and future directions based on a
national program in Hungary
Dr. Aradi Dániel PhD
Assistant Professor
Head of Thrombosis Research Unit
Heart Center Balatonfüred and
University of Semmelweis,
Heart and Vascular Center
HUNGARY
June 12, 2014 I XXV. Annual Interventional Cardiology Meeting I Córdoba, Spain

2. Consultant: Verum Diagnostica.
Lecture fees: Abbott Vascular, AstraZeneca, Bayer, DSI/
Lilly, Krka, Pfizer, Roche, Verum Diagnostica.

3. • Monitoring platelet reactivity for ASA and
P2Y12-inhibitors
• Results and observations from the PECS-
HPR Registry

4. PA Gurbel, modified
Platelet
P2Y12
*Platelet*
Thrombin, Collagen, TxA2
Amplification
Procoagulant
Surface
P-selectin
CD-40L
ADP
Degranulation
AA Tx A2 TxA2
Amplification
Degranulation
ADP
Aggregation
GPIIb/IIIa
Activation
COX-1
clopidogrel, prasugrel, ticagrelor, cangrelor
Aspirin

5. <5%

6. Before
ASA
After
ASA
Kovács E et al. Thromb Res 2014.
LTA-AA
Non-acetylated
COX-1
Acetylated
COX-1

7. Stone G et al. Lancet. 2013;382:614-23.

8. Stone G et al. Lancet. 2013;382:614-23.

9. Aradi D et al. Eur Heart J. 2014:35;209-15.
Measuring the response to aspirin by platelet function testing is
not recommended in patients after PCI.
III B

10. Aradi D et al. Eur Heart J. 2014:35;209-15.
HPR: 25-30%

11. Good correlation between platelet function and active metabolite cc

12. Stone G et al. Lancet. 2013;382:614-23.

13. Stone et al. Lancet, 2013;382:614-23

14. Stone et al. Lancet, 2013;382:614-23

15. Aradi D et al. Eur Heart J. 2014:35;209-15.
In clopidogrel-treated patients, measuring ADP-dependent
platelet reactivity with platelet function assays may be
considered to assess the risk of ST …… after PCI.
IIb B

16. Aradi D et al. Eur Heart J. 2014:35;209-15.

17. Wiviott SD et al. Circulation 2007; 116: 2923-32. Gurbel PA et al. Circulation 2009;120:2577-85.

18. Wiviott et al. NEJM 2007;357:2001-15.
Wallentin et al. NEJM 2009;361:1045-57.

19. ESC guidelines on NSTE-ACS 2011
ESC guidelines on STEMI 2012
Steg PG et al. Eur Heart J 2012; 2569-619
Hamm CW et al. Eur Heart J. 2011; 2999-3054.
ESC 2014 revascularization guidelines
Baumbach. EuroPCR 2014.

20. SELECTIVE
„Acute coronary syndromes patients with either diabetes mellitus or
troponin positivity who undergo PCI with stenting and have no prior
TIA/stroke in history can receive 70% reimbursement for prasugrel
treatment for one year IF PLATELET FUNCTION TESTING SHOWS
HIGH ON-TREATMENT PLATELET REACTIVITY AFTER
CLOPIDOGREL.”
(At the time of this presentation, ticagrelor is not yet reimbursed in Hungary)
1st September 2011.:

21. 25-30% of patients (HPR):
Switch to prasugrel/ticagrelor
70-75% of patients:
Keep (generic) clopidogrel

22. 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.

24. 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%

25. In patients with acute coronary syndrome undergoing PCI,
prasugrel and ticagrelor should be the preferred choices over
clopidogrel unless contraindications exist and routine platelet
function testing is not recommended.
III B
In stable angina patients after uncomplicated PCI, standard-
dose clopidogrel should be preferred and routine platelet
function testing is not recommended.
III B
Genotyping and/or platelet function testing may be considered
in selected cases when clopidogrel is used.
IIb B
Hamm CW et al. Eur Heart J 2011.
ESC guidelines on Stable angina 2013.
ESC guidelines on NSTE-ACS 2011.
ESC guidelines on NSTE-ACS 2011.
Montalescot et al. Eur Heart J. 2013;34:2949-3003.

26. PÉCS-HPR REGISTRY

27. INCLUSION CRITERIA:
• Patients with ACS undergoing PCI with stent implantation
• Pretreatment with 600 mg clopidogrel or chronic treatment with clopidogrel (> 5 days)
EXCLUSION CRITERIA:
• Prior intracranial bleeding
• Indication for chronic oral anticoagulation
• Pretreated with prasugrel
• Concurrent study interfering with DAPT
PÉCS-HPR REGISTRY: CLINICAL IMPACT OF PRASUGREL VS
HIGH-DOSE CLOPIDOGREL BASED ON MULTIPLATE TESTING
AIMS:
• to evaluate the clinical and pharmacological impact of selecting P2Y12-inhibitors
based on Multiplate testing in consecutive ACS patients after PCI
• Prespecified cutoff for HPR: ADP-test ≥47 U
• Key efficacy outcomes: all-cause mortality, definite/probable ST, MI, stroke.
• Key safety outcomes: Non CABG-related major bleeding (BARC 3/5)

28. 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 PÉCS REGISTRY
n (study population) 2,214 2,440 423 741
Patient risk profile
AMI (%) 10% 27% 0% 84%
STEMI (%) 0.4% 0% 0% 48%
Shock (%) 0% 0% 0% 4.5%
All-cause mortality 0.8% 2% 0% 8.2%
Intervention
High-dose clopidogrel 100% 80% - 58%
High-dose ASA - 45% - -
Prasugrel - 12% 100% 42%
PFT Assay VerifyNow VerifyNow VerifyNow Multiplate
Aradi et al. J Am Coll Cardiol. 2014 Jan 20. E-pub ahead of print.
PÉCS-HPR REGISTRY vs. recent RCT-s on PFT

29. PLATELET REACTIVITY AFTER PCI (n=741)
HPR
no HPR
Switch to prasugrel
60 mg LD + 10 mg MD
Adjusted high-dose clopidogrel:
repeated 600 mg clopidogrel LD up to 4
times based on PFT + 75/150 mg MD
(proposed by Bonello et al.*)
75 mg generic clopidogrel
*: Bonello et al. JACC 2008;51:1404-11.Aradi et al. JACC 2014; 63: 1061-70.

30. PRASUGREL vs. HIGH-DOSE CLOPIDOGREL
Aradi et al. JACC 2014; 63: 1061-70.

31. MORTALITY AND STENT THROMBOSIS
HR: 2.94 (1.76 – 4.94) p < 0.001
HR: 1.12 (0.50 – 2.51) p = 0.79
-57%
RRR
Aradi et al. JACC 2014; 63: 1061-70.

32. ISCHEMIC EVENTS
Aradi et al. JACC 2014; 63: 1061-70.

33. MAJOR BLEEDING (BARC 3, 5)
Aradi et al. JACC 2014; 63: 1061-70.

34. PFT-GUIDED ANTIPLATELET THERAPY: MORTALITY

35. PFT-GUIDED ANTIPLATELET THERAPY: MORTALITY
0
2
4
6
8
10
12
14
16
18
All-cause mortality
HPR: high-dose clopidogrel
HPR: prasugrel
Eventrate(%)
16.4%
6.6%
RRR: -60%
ARR: 9.8%
NNT: 11
Aradi et al. JACC 2014; 63: 1061-70.

36. PREDICTORS OF MORTALITY AT 1 YEAR
Univariate Cox regression model
HR (95%CI) P
Definite or probable ST 15.67 (8.57-28.66) <0.0001
Myocardial infarction 3.53 (1.79-6.97) <0.0001
Stroke 3.29 (0.46-23.77) 0.24
TVR 0.48 (0.21-1.11) 0.09
Major bleeding (BARC 3 or 5) 7.11 (3.96-12.77) <0.0001
Aradi et al. JACC 2014; 63: 1061-70.
Univariate Cox regression model
HR (95%CI) P
Multivariate model
HR (95%CI) P
Definite or probable ST 15.67 (8.57-28.66) <0.0001 9.30 (4.66-18.54) <0.0001
Myocardial infarction 3.53 (1.79-6.97) <0.0001 -
Stroke 3.29 (0.46-23.77) 0.24 -
TVR 0.48 (0.21-1.11) 0.09 -
Major bleeding (BARC 3 or 5) 7.11 (3.96-12.77) <0.0001 3.75 (1.92-7.34) <0.0001

37. PFT-GUIDED ANTIPLATELET THERAPY: MORTALITY
0
20
40
60
80
100
120
140
160
180
ST Major bleeding Mortality
HPR: high-dose
clopidogrel
HPR: prasugrel
Intensifying treatment in 1,000 ACS patients who have
HPR on MULTIPLATE by two strategies
Events(count)
33
72
98

38. ACS patients
(n=2600)
undergoing
successful PCI
7 days
clopidogrel
75 mg qd
7 days
prasugrel
5/10 mg qd
14 days prasugrel
5/10 mg qd
11 ½ months
prasugrel
5/10 mg qd
11 ½ months
prasugrel
5/10 mg qd
11 ½ months
clopidogrel
75 mg qd
Plateletfunctiontesting
(Multiplate®,ADPtest)
Control group:
Uniform
antiplatelet
therapy with
prasugrel
Monitoring
group:
Personalized
antiplatelet
therapy with
clopidogrel or
prasugrel
HPR
ADPtest
≥ 46 Units
no HPR
R*
ADPtest
< 46 Units
Control group
(n=1300)
Monitoring group
(n=1300)
*1:1 randomization prior to
hospital discharge
TESTING RESPONSIVENESS TO PLATELET INHIBITION ON CHRONIC ANTIPLATELET
TREATMENT FOR ACUTE CORONARY SYNDROMES (TROPICAL-ACS) TRIAL

39. Steering Committee:
PI: Dirk Sibbing / Co-PI: Julinda Mehilli (LMU, Munich)
Study Chair: Steffen Massberg (LMU, Munich)
Daniel Aradi (Balatonfüred, Local-PI - Hungary)
Kurt Huber (Vienna, Local-PI - Austria)
Franz-Josef Neumann (Bad Krotzingen)
Jörg Hausleiter (Munich)

41. • When measured with a specific method, chemical
ASA resistance (=lack of acetylation of COX-1) is
rare (<5%)1
• Clinical relevance of ASA response testing is
questionable (no relation with ST in ADAPT-
DES)2
CONCLUSIONS_1
1: Kovács E et al. Thromb Res 2014.
2: Stone GW et al. Lancet, 2013;382:614-23
3: Aradi D et al. Eur Heart J. 2014:35;209-15.
Measuring the response to aspirin by platelet function testing is
not recommended in patients after PCI.3 III B

42. • Large variability regarding PR on clopidogrel is
real (≈30% HPR)1,2
• HPR is an independent (p<0.0001) and valuable
(HR>2.00) predictor of early ST2
• No RCT evidence so far that tailored treatment
improves outcomes3,4 – standard of care in ACS
is prasugrel / ticagrelor
CONCLUSIONS_2
2: Stone GW et al. Lancet, 2013;382:614-23
1: Aradi D et al. Eur Heart J. 2014:35;209-15. 3: Price MJ et al. JAMA 2011; 305: 1097-105.
4: Collet et al. N Engl J Med. 2012;367:2100-9.
In clopidogrel-treated patients, measuring ADP-dependent
platelet reactivity with platelet function assays may be
considered to assess the risk of ST …… after PCI.1
IIb B

43. • Prasugrel/ticagrelor is restricted or limitedly
available due to huge cost difference in many Eu
countries
• Data from PÉCS-HPR registry suggests that a
Multiplate-guided approach may provide clinical
benefits in high-risk patients and by switching pts
with HPR to prasugrel/ticagrelor instead of using
high-dose clopidogrel1
• TROPICAL-ACS study may confirm such strategy
CONCLUSIONS_3
1: Aradi D et al. Eur Heart J. 2014:35;209-15.

44. THANK YOU FOR YOUR KIND ATTENTION!