2. Post-PCI/MI Thrombotic Events – A Plateletcentric Problem!!!!
Platelet Adhesion/Activation
Aspirin x
Thrombin
ADP
TxA2
Sustained GPIIb/IIIa Activation
P2Y12 Blockers x
Vorapaxar x
Platelet Aggregation
Hypercoagulability
Inflammation
Ischemic Events/Stent Thrombosis
ADP = adenosine diphosphate. GP = glycoprotein. MI = myocardial infarction. PCI = percutaneous coronary intervention. TxA2 = thromboxane A2.
Gurbel PA, Tantry US. Circulation. 2012;125: 2

3. Aggregation in 42% of pts on clopidogrel + aspirin:
Aggregation on Aspirin, Aspirin + Clopidogrel, and Aspirin + Ticagrelor
8 hrs post-180 mg ticagrelor load
8 hrs post-600 mg clopidogrel
Aggregation in 42% of pts on clopidogrel + aspirin:
In same range as 50% of pts treated with aspirin alone!
In Asians, it will be even higher than 42%
100
Aspirin mg QD
42%
50% 80 60
Cumulative Frequency (%) 40 20 20 40 60 80
100
120
20uM ADP-induced Aggregation
Gurbel PA, Tantry US. Circulation.2012;125: 3

4. VerifyNow P2Y12 Patient-based Meta-analysis: 2-year Outcomes
6 studies; n=3059
2-year MACE by PRU Quartile
2-year ST by PRU Quartile
Very low ST rate ~ immunity
~3x risk between Q1 and Q4
~8x risk between Q1 and Q4
MACE = major adverse cardiovascular event. PRU = platelet reactivity unit. ST = stent thrombosis.
Brar SS, et al. J Am Coll Cardiol. 2011;58:

5. Group 2 : Conventional Arm
Double Randomization of a Monitoring-adjusted Antiplatelet Treatment vs a Common Antiplatelet Treatment for DES Implantation
Handout
ARCTIC Study
NCT
Randomization before DES implantation
N=2500
Group 2 : Conventional Arm
No assessment of oral antiplatelet treatment effect
Conventional therapy
Group 2 : Monitoring Arm
Assessment of aspirin and clopidogrel effect before DES and at day 7-14
Adjustment of antiplatelet treatment in suboptimal responders
Primary Endpoints (6-18 m) All-cause Mortality, MI, Urgent Revascularization, ST, Ischemic Stroke
DES = drug-eluting stent.
Montalescot G, et al. To be presented at: The American Heart Association’s Scientific Sessions 2012; November 4-6, 2012; Los Angeles, CA. 5

6. Platelet Function in the Medically Managed ACS Patient:
TRILOGY Platelet Function Substudy
Handout
UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization
Prasugrel Clopidogrel mg (≥ 75 years and/or < 60 kg), 10 mg (< 75 years and ≥ 60 kg) vs mg (for all) Aspirin < 100 mg (strongly recommended) for all
TRILOGY Platelet Function Substudy: 2690 participants from 25 countries
VerifyNow P2Y12 Assay: At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization
126 participants with no valid PRU measurement excluded from analysis**
2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278) included in final analysis
Primary efficacy endpoint: - Composite of CV death, MI, and stroke through 30 months
Key secondary endpoints: - All-cause death - MI
ACS = acute coronary syndrome.
Gurbel PA, et al. To be presented at: The American Heart Association’s Scientific Sessions 2012; November 4-6, 2012; Los Angeles, CA.

7. 2012 Guideline Recommendations Regarding Platelet Function Testing
Handout
2012 ACCF/AHA Guideline for Patients with UA/NSTEMI or After ACS and PCI1:
Platelet function testing to determine platelet inhibitory response in patients with UA/NSTEMI (or after ACS and PCI) on P2Y12 receptor inhibitor therapy may be considered if results of testing may alter management – Class IIb - Level B evidence
2012 ESC Guideline for Patients Presenting without STEMI2:
Increasing the maintenance dose of clopidogrel based on platelet function testing is not advised as routine but may be considered in selected cases – Class IIb - Level B evidence
Genotyping and/or platelet function testing may be considered in selected cases when clopidogrel is used – Class IIb - Level B evidence
NSTEMI = non-ST segment elevation myocardial infarction. STEMI = ST segment elevation myocardial infarction. UA = unstable angina.
1. Jneid H, et al. J Am Coll Cardiol. 2012;60: Hamm CW, et al. Eur Heart J. 2011;32:

8. The Platelet Function Therapeutic Window and the Concept of Thrombosis Immunity
Post-PCI Ischemic/Thrombotic Clinical Events
Cumulative Frequency of Patients (%)
ADP-induced Platelet Reactivity (%) 10 20 30 40 50 60 70 80 90
100
Too low platelet reactivity?
Bleeding?
Most ischemic events occur above a platelet reactivity cutoff
Small increase above cutoff: increased ischemic risk
Patients with ischemic events
Immunity Thresholds ~170 PRU
~50% VASP-PRI
~35% 5 M ADP ~46% 20 M ADP
~416 AU MULTIPLATE
~65 mm MAKH-TEG
Bleeding Threshold
<85 PRU <188 AU <31mm MAKH
The sigmoid cumulative frequency curve in patients with post-PCI ischemic/thrombotic clinical events relative to platelet reactivity to ADP; these data support the concept of a therapeutic window for P2Y12 blockade.
Gurbel PA, et al. J Am Coll Cardiol. 2007;50: Gurbel PA, et al. Am Heart J. 2010;160: Campo G, et al. J Am Coll Cardiol. 2011;57: Jeong YH, et al. Presented at: European Society of Cardiology Congress 2011; August 27-31, 2011; Paris, France. Gurbel PA, et al. Thromb Haemost. 2011;106: Sibbing D, et al. Thromb Haemost 2010;103: Sibbing D, et al. J Thromb Haemost. 2010;8: 8

9. Drug and dose adjustments if high platelet reactivity at Day 14
ARCTIC Trial Design
Standard of care
VerifyNow
P2Y12 + ASA
Drug (ASA, clopidogrel, prasugrel, GPIIbIIIa i) and dose adjustments if high platelet reactivity
Coronary angiogram
Stent-PCI
Randomized
Drug and dose adjustments if high platelet reactivity at Day 14
12-month FU
Primary endpoint at 12 months:
Death, MI, stroke, ST, urgent revascularization
Statistical considerations:
Assuming an annual risk of 9% and a 33% relative risk reduction (α risk at 5% and error β of 20%, bilateral test), 2466 patients were necessary to demonstrate the superiority of the strategy of monitoring and adjustment
ARCTIC study protocol - Collet JP, et al. Am Heart J 2011;161:5-12

10. Adjustment Rules ARU>550 (Aspirin) VerifyNow before DES-PCI
Reload with 500 mg IV aspirin
GPIIb/IIIai+ clopidogrel (re)LD (>600 mg) or prasugrel LD 60 mg then,
MD clopidogrel 150 mg or prasugrel 10mg
VerifyNow before DES-PCI
%inh<15% and/or PRU>235 (P2Y12)

11. Adjustment Rules ARU>550 (Aspirin)
GPIIb/IIIai+ clopidogrel (re)LD (>600 mg) or prasugrel LD 60 mg then,
MD clopidogrel 150 mg or prasugrel 10mg
ARU>550 (Aspirin)
Reload with 500 mg IV aspirin
VerifyNow before start of DES-PCI
%inh<15% and/or PRU>235(P2Y12)
%inh<15% and/or PRU>235
Doubling the aspirin dose
↗ Clopidogrel dose by at least 75 mg or switch to prasugrel 10mg
if clopidogrel 150mg  ↘ 75mg
if prasugrel  clopidogrel 75mg
ARU>550
%inh>90%
day 14-30

12. Death, MI, stroke, stent thrombosis, urgent revascularization
Primary Endpoint to 1 year
Death, MI, stroke, stent thrombosis, urgent revascularization

13. Stent thrombosis or urgent revascularization
Main Secondary Endpoint to 1 year
Stent thrombosis or urgent revascularization

14. Other Ischemic Endpoints
Conventional
Monitoring
HR [95%CI] P
Death or myocardial Infarction - %
28.8
31.7
1.11 [0.96; 1.29]
0.15
Any death - %
1.6
2.3
1.41 [0.79; 2.50]
0.24
Myocardial infarction - %
28.4
30.3
1.08 [0.93; 1.25]
0.32
Stent thrombosis - %
0.7 1
1.34 [0.56; 3.18]
0.51
Stroke or TIA- %
0.6
1.15 [0.42; 3.18]
0.78
Urgent revascularization - %
4.2
4.5
1.06 [0.73; 1.55]
0.76

15. Key Safety Outcomes
Conventional
Monitoring
HR [95%CI] P
Major bleeding - %
3.3
2.3
0.70 [0.43; 1.14]
0.15
Minor bleeding - %
1.7
1.0
0.57 [0.28; 1.16]
0.12
Major or minor bleeding - %
4.5
3.1
0.69 [0.46; 1.05]
0.08
STEEPLE definitions - Montalescot G, et al. N Engl J Med 2006; 355:1006–17

16. Platelet Function Substudy Design
UA/NSTEMI (N = 9326, 52 countries) planned medical management without revascularization
Prasugrel vs. Clopidogrel 10 mg (< 75 years and ≥ 60 kg) 75 mg (for all) 5 mg (≥ 75 years; < 75 years and < 60 kg)
Aspirin ≤ 100 mg (strongly recommended) for all
PFS: 2690 (28% of total) participants from 25 countries
VerifyNow P2Y12 Assay At baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 mos after randomization
2564 participants (prasugrel, n = 1286 and clopidogrel, n = 1278) included in final analysis
126 without valid PRU measurement excluded from analysis
Primary efficacy endpoint: - Composite of CV death, MI, and stroke through 30 months
Key secondary endpoints: - All-cause death - MI
Source: Q113, Q111, Q331
[Source: Figure 1 on page 19]
Reference:
Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1.
Pras

17. Kaplan-Meier Event Curves: Landmark at 30 Days HPR Cut-Point > 208 PRU
Primary Efficacy Endpoint
With HPR
Without HPR
The P values for each panel compare the hazard between the two groups throughout the time period represented.
All MI Events
All-Cause Death

18. Relationship of PRU Values with Ischemic Event Occurrence Through 30 Months
Unadjusted Results
HR (95% CI)
p-value
PRU as time-dependent covariate (per 60-unit increase)
CVD/MI/stroke
1.09 ( )
0.008
All-cause death
1.09 ( )
0.03
All MI
1.02 ( )
0.60
30-day HPR PRU cut-point > 208
1.43 ( )
0.01
1.38 ( )
0.06
1.37 ( )
0.08
30-day HPR PRU cut-point > 178
1.35 ( )
0.02
1.27 ( )
0.15
1.34 ( )
0.09
Adjusted Results
HR (95% CI)
p-value
1.03 ( )
0.44
0.99 ( )
0.79
0.97 ( )
0.53
1.16 ( )
0.28
1.03 ( )
0.84
1.13 ( )
0.50
1.13 ( )
0.35
0.99 ( )
0.95
1.13 ( )
0.49