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

Consultant: Verum Diagnostica.

Lecture fees: Abbott Vascular, AstraZeneca, Bayer, DSI/

Lilly, Krka, Pfizer, Roche, Verum Diagnostica.

• Monitoring platelet reactivity for ASA and

P2Y12-inhibitors

• Results and observations from the PECS-

HPR Registry

PA Gurbel, modified

Platelet

P2Y12

*Platelet*

Thrombin, Collagen, TxA2

Am

plific

atio

n

Procoagulant

Surface

P-selectin

CD-40LADP

Degranulation

AA Tx A2 TxA2

Am

plific

atio

n

Degranulation

ADP

Aggregation

GPIIb/IIIa

Activation

COX-1

clopidogrel, prasugrel, ticagrelor, cangrelor

Aspirin

<5%

Before

ASA

After

ASA

Kovács E et al. Thromb Res 2014.

LTA-AA

Non-acetylated

COX-1

Acetylated

COX-1

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

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

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

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

HPR: 25-30%

Good correlation between platelet function and active metabolite cc

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

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

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

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

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

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

Wiviott et al. NEJM 2007;357:2001-15.

Wallentin et al. NEJM 2009;361:1045-57.

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.

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.:

25-30% of patients (HPR):

Switch to prasugrel/ticagrelor

70-75% of patients:

Keep (generic) clopidogrel

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.

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%

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.

PÉCS-HPR REGISTRY

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)

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

PLATELET REACTIVITY AFTER PCI (n=741)

HPR

no HPR

Switch to prasugrel60 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.

PRASUGREL vs. HIGH-DOSE CLOPIDOGREL

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

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.

ISCHEMIC EVENTS

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

MAJOR BLEEDING (BARC 3, 5)

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

PFT-GUIDED ANTIPLATELET THERAPY: MORTALITY

PFT-GUIDED ANTIPLATELET THERAPY: MORTALITY

0

2

4

6

8

10

12

14

16

18

All-cause mortality

HPR: high-dose clopidogrel

HPR: prasugrel

Event ra

te (

%)

16.4%

6.6%

RRR: -60%

ARR: 9.8%

NNT: 11

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

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

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)

3372

98

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

Pla

tele

t fu

ncti

on

testi

ng

(M

ult

ipla

te®

, A

DP

tes

t)

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

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)

• 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.3III B

• 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.1IIb B

• 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.

THANK YOU FOR YOUR KIND ATTENTION!