1. Update on the New Antiplatelet Agents:
TRA-PCI
Update on the New Antiplatelet Agents:
PAR-1 Inhibitors
David J. Moliterno, MD, MPH Chief, Cardiovascular Medicine Professor & Vice-Chair of Medicine University of Kentucky Co-Director - Gill Heart Institute Lexington, KY

2. Update on the New Antiplatelet Agents: PAR-1 Inhibitors
David J. Moliterno, Richard C. Becker, Lisa Jennings, Gail Berman,
Bo Yang, John Strony, Enrico Veltri, and Robert A. Harrington
on behalf of the TRA–PCI Investigators
University of Kentucky
Gill Heart Institute

3. Platelet-Thrombin Interaction
Thrombus
Xa+Va+II
Fibrin
Fibrinogen
Thrombin

4. Platelet Receptors Platelet Platelet PAR-1 Thrombin PAR-4 GP IIb/IIIa
Fibrinogen GP
IIb/IIIa
P2Y1
ADP
P2Y12 GP
IIb/IIIa
TBX A2
TBXA2-R
Epinephrine
EPI-R
Serotonin
5HT2A
GP VI
Collagen
Anionic
phospholipid
surfaces
GP Ia

5. TRA Background
SCH is an oral, potent, selective thrombin receptor antagonist (TRA) being developed for the prevention and treatment of atherothrombosis.
Preclinical and early clinical studies have demonstrated SCH to have antithrombotic properties, with no increase in bleeding time or clotting times (aPTT, PT, ACT).
Galbulimima baccata
Himbicine derivative
Bark of the Australian Rhododendron
Found in the tropical zones of eastern Malaysia, New Guinea, northern Australia and the Solomon Islands.

6. Study Design Non-Urgent PCI or Cath possible PCI (All Receive Aspirin)
Randomization #1 — 3:1 SCH530348:Placebo (Single Loading Dose)
Sequential Groups: 1=10 mg; 2=20 mg; 3=40 mg, or Placebo
Cardiac Catheterization
Planned PCI (All Receive Clopidogrel and Antithrombin)
No PCI**
Randomization #2 1:1:1
Maintenance Therapy Once Daily for ~ 60 days
SCH Loading Dose  SCH
Or Placebo Loading Dose  Placebo
CABG
Medical Management
Quantify Postoperative Chest-Tube Drainage, Transfusions, and
Re-exploration
SCH
0.5 mg
n~100
1 mg
n~100
2.5 mg
n~100
Placebo
n~100
Safety: TIMI Major plus Minor Bleeding
Efficacy: Death/MACE
Safety: TIMI Major plus Minor Bleeding
* Primary Evaluable Cohort
**Secondary Evaluable Cohort

7. Demographics Placebo SCH 530348 All 10 mg 20 mg 40 mg 257 773 222 238
All Randomized
257
773
222
238
313
Primary Cohort (PCI)
151
422
129
120
173
Secondary Cohort
106
351 93
118
140
with CABG 24 52 10 18
Male
80%
70%
72%
66%
Age (mean, years) 62 63 65
Weight (mean, kg) 91 90 89 92
Diabetes Mellitus
30%
34%
37%
32%
33%
Prior MI
35%
38%
Prior Revascularization
47%
48%
50%
46%

8. PCI Cohort Medications
Placebo
(n = 151)
SCH
All
n = 422
10 mg
n = 129
20 mg
n = 120
40 mg
n = 173
Aspirin
148 (98%)
416 (99%)
127 (98%)
117 (98%)
172 (99%)
Clopidogrel
146 (97%)
408 (97%)
164 (95%)
75 mg
73 (48%)
191 (45%)
56 (43%)
52 (43%)
83 (48%)
300 mg
30 (20%)
85 (20%)
34 (26%)
21 (18%)
30 (17%)
600 mg
40 (26%)
125 (30%)
36 (28%)
39 (33%)
50 (29%)
Antithrombin Agent
Heparin
61 (40%)
181 (43%)
53 (41%)
76 (44%)
Bivalirudin
76 (50%)
196 (46%)
65 (50%)
51 (43%)
80 (46%)
GP IIb/IIIa
7 (5%)
37 (9%)
14 (12%)
16 (9%)

9. TIMI Major/Minor Bleeding
PCI Cohort
TIMI Major/Minor Bleeding 5%
p = 0.73
4.0% 4%
3.3%
p = 0.77
p = 0.70
2.8% 3%
2.5%
p = 0.35 2%
1.6% 1%
Placebo
n=151
All TRA
n=422
10 mg
n=129
20 mg
n=120
40 mg
n=173
SCH
p- value relative to placebo

10. CABG Cohort Bleeding Placebo (n=24) SCH 530348 All (n=52) 10 mg
Any Bleed 24 52 10 18
TIMI Major/Minor
19 (79%)
48 (92%)
9 (90%)
17 (94%)
22 (92%)
Non-TIMI
8 (33%)
18 (35%)
3 (30%)
6 (33%)
9 (39%)
Transfusion
PRBC
11 (46%)
32 (62%)
8 (80%)
9 (50%)
15 (63%)
>2 Units 5 9 2
Chest Tube Drainage (ml)
996
988
1393
1015
870
Re-exploration 3 1

11. PCI Cohort MACE Results
Placebo
n= 151
SCH
All
n=422
10 mg
n= 129
20 mg
n=120
40 mg
n=173
Death/MACE/Stroke
13 (8.6%)
26 (6.2%)
12 (9.3%)
6 (5.0%)
8 (4.6%)
Death/MACE*
25 (5.9%)
11 (8.5%)
Death/MI
11 (7.3%)
19 (4.5%)
7 (5.4%)
5 (4.2%)
7 (4.0%)
Death
2 (0.5%)
1 (0.8%)
1 (0.6%)
MACE
24 (5.7%) MI
18 (4.3%)
6 (3.5%)
Recurrent ischemia
1 (0.7%)
1 (0.2%)
Revascularization
6 (1.4%)
3 (2.3%)
2 (1.2%)
Stroke
MACE = Major Adverse Cardiac Event (myocardial infarction, ischemia requiring hospitalization, coronary revascularization) MI = Myocardial Infarction * = primary efficacy endpoint

12. PCI Cohort 60-Day Death or MACE SCH 530348 8.6% 8.5% 5.9% 5.0% 4.6%
10%
p = 0.98
8.6%
8.5% 8%
p = 0.26
5.9%
p = 0.25 6%
5.0%
p = 0.15
4.6% 4% 2%
Placebo
n=151
All TRA
n=422
10 mg
n=129
20 mg
n=120
40 mg
n=173
SCH
p- value relative to placebo

13. PCI Cohort 60-Day Death or MI SCH 530348 7.3% 5.4% 4.5% 4.2% 4.0%
10% 8%
7.3%
p = 0.53
p = 0.19 6%
5.4%
p = 0.28
4.5%
p = 0.20
4.2%
4.0% 4% 2%
Placebo
n=151
All TRA
n=422
10 mg
n=129
20 mg
n=120
40 mg
n=173
SCH
p- value relative to placebo

14. Myocardial Infarction
PCI Cohort
Myocardial Infarction 8% 4% 2% 6%
10%
Placebo
10mg
20mg
40mg
p = 0.52
p = 0.28
p = 0.12 1 2 3 4 5 6 7
Days

15. Platelet Aggregation Substudy
Subjects with >80% IPA to 15 M TRAP
100% 96
30 minutes
60 minutes
90 minutes
120 minutes 82
80% 68
60% 54 53 46 43
40% 29 21
20% 6
Placebo
n=23
10 mg
n=15
20 mg
n=18
40 mg
n=33
SCH

16. PCI Cohort Results after Day 60
Placebo
SCH
All
0.5 mg
1.0 mg
2.5 mg
Number
149
413
136
139
138
TIMI Major/Minor
4 (1.0%)
2 (1.5%)
2 (1.4%)
TIMI Major
2 (0.5%)
1 (0.7%)
TIMI Minor
Non-TIMI bleeding
8 (5.4%)
25 (6.1%)
8 (5.9%)
6 (4.3%)
11 (8.0%)

17. Subjects with >80% IPA to 15 M TRAP
Platelet Aggregation
Subjects with >80% IPA to 15 M TRAP
100
100
100%
30 days 91 91
60 days
80%
60%
40%
20% 9 11
Placebo
0.5 mg
1.0 mg
2.5 mg
SCH

18. Conclusions
TRA was not associated with an increase in TIMI major, minor, or non-TIMI bleeding
Using 15 M TRAP-induced platelet aggregation:
40 mg loading dose of SCH achieved ≥ 80% IPA in 1-2 hours in 68-96% subjects
1 mg and 2.5 mg maintenance doses sustained ≥ 80% IPA at 30 and 60 days in all subjects
While not statistically significant, SCH was associated with:
Death/MACE: 32% overall; 46% with 40 mg
MI: 41% overall; 52% with 40 mg

19. TRA•CER
Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome
NSTEACS
N = 10,000
SCH
40 mg bolus, 2.5 mg daily
n=5000
Placebo
(and usual therapy)
n=5000
• 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •

20. Thrombin Receptor Antagonist
TRA•2P—TIMI 50
Thrombin Receptor Antagonist
for 2º Prevention
Hx MI, CVA, PVD
N ~ 18,000
SCH
2.5 mg daily
N~9,000
Placebo
(and usual therapy)
N~9000
• 1-Year Cardiovascular Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revas •