The document discusses the use of platelet function testing to guide P2Y12-inhibitor treatment in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI) in Hungary. It emphasizes that prasugrel and ticagrelor are preferred over clopidogrel unless contraindications exist, with routine platelet function testing not recommended, though it may be considered in select clopidogrel-treated cases. The findings from the Pécs-HPR registry suggest that a multiplate-guided approach may improve clinical outcomes in high-risk patients by switching from clopidogrel to more effective P2Y12 inhibitors.

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!