1. The Big Antiplatelet Debate: Why I Prefer Ticagrelor Over Prasugrel
Paul A. Gurbel, M.D.
Sinai Center for Thrombosis Research
Associate Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland, U.S.A. 1 1

2. Paul A. Gurbel, MD
Consulting: Eli Lilly and Company, Pozen, Inc., Accumetrics, Inc., Daiichi Sankyo, Novartis AG, Bayer Corporation, Sanofi-Aventis, Boehringer Ingelheim Vetmedica GmbH, Merck and Company, Inc. and Medtronic, Inc.
Grant Support: Daiichi Sankyo, Eli Lilly and Company, CSL, Haemoscope Corporation, Harvard Clinical Research Institute, Duke Clinical Research Institute, Pozen, Inc., Accumetrics, Inc., Helena Laboratories, Verum Diagnostica GmbH and Portola Pharmaceuticals, Inc.

3. Disclosures Honoraria/Consulting Research Grants/Support Nanosphere
Pozen
AstraZeneca
Daiichi Sankyo/Lilly
Accumetrics
Nanosphere
Boehringer
Merck
Medtronic
CSL
t2 Biosystems
Research Grants/Support
Nanosphere
Haemonetics
Daiichi Sankyo/Lilly
CSL Pharmaceuticals
HCRI
NIH
Dr. Gurbel has patents in the field of platelet function testing 3

4. 5 Reasons:
1) Mechanism (s) of Action

5. Do All P2Y12 Inhibitors Have the Same Basic Effect?
- Molecular structure of clop and pras are ~same - Equipotent AM
- No known significant off target effects
- At same level of platelet reactivity:
Thrombotic risk should be same
Prasugrel-AM
Clopidogrel-AM
ADP binding site
ADP
- Ticagrelor is in different class (CPTP) - ? Important off target effects:
- At same level of platelet reactivity: thrombotic risk ? less due to off target effect Off-target effect can’t be measured by PFT
Ticagrelor binds reversibly and independently from ADP
- inhibits conformational change
van Giezen JJ et al. Thromb Res. 2009;124:565-71 5

6. Off-Target Effect: Inhibition of Adenosine Reuptake Inhibition Ticagrelor and Coronary Blood Flow Velocity (CBFV)
pre-placebo
post-placebo
pre-ticagrelor
post-ticagrelor
p=0.008
Wittfeldt A et al. J Am Coll Cardiol 2013;61:723–7

7. Reason 2. Pharmacology ONSET/OFFSET Study Stable CAD pts Loading
Hours 20 40 60 80
100 4 8 12 16 24
Clopidogrel 600 mg
Ticagrelor 180mg
IPA (%; 20 mM ADP, Final) .5 *
Loading
*, P< ticagrelor vs clopidogrel;
†, P<0.005 ticagrelor vs clopidogrel;
‡, P<0.05, ticagrelor vs clopidogrel
Maintenance and Offset
Gurbel PA et al. Circulation. 2009;120: 7

8. Pharmacokinetics of Ticagrelor
Stable CAD pts
After 180mg LD
tmax ~2 hrs
At Steady State After Multiple Ticagrelor 90mg bid dosing
(4wks–ONSET; 2-4 wks RESPOND)
tmax ~2 hrs
Husted S and Gurbel PA et al. Clin Pharmacokinet. 2012;51: 8

9. Ticagrelor: Rapid Elimination of HPR
Predose hr hr hr hr hr ≥2 wks
% of Patients with VASP-PRI >50% 20 40 60 80
100
p< for all post-dose comparisons 76 74 82 65 94 96 5 97 8 4 2 47 11
Stable CAD pts
Ticagrelor (180mg/90mg bid)
Clopidogrel (600mg/75mg qd)
Bliden KP, Gurbel P et al. Am Heart J ;162:160-5.
Pooled Analysis of ONSET-OFFSET and RESPOND Studies
VASP-PRI (%)
Prasugrel
301 ACS pts undergoing PCI
VASP measured 6 hrs 60 mg prasugrel
Bonello L et al. J AM Coll Cardiol ;58:467–73
30-day MACE
25.2%

10. Ticagrelor: No Influence of CYP2C19 Genotype on PD
100
NSTEMI or STEMI + PCI (n =213)
LoF
Non-LoF
GoF
Prasugrel 75mg LD + 10mg qd 4 wks
Non-GoF
p=0.03
Cuisset T et al. J AM Coll Cardiol Intv 2012;5:1280-7
p-values between genotypes = NS
LoF
Non-LoF
GoF
Ticagrelor 180mgLD + 90mg BID 2-6 wks
Stable CAD (n =92) EM
Tantry US et al. Circ Cardiovasc Genet 2010;3; 80 60
VASP-PRI 40 20

11. Reason 3. Reduced Ischemic Events and Mortality (Despite Clopidogrel PreRx)

12. Influence on Ischemic Outcomes: Prasugrel vs. Ticagrelor
Wiviott SD et al. N Engl J Med. 2007;357: 5 10 15 30 60 90
180
270
360
450
Days after randomization
Cumulative Incidence (%)
12.1
9.9
Prasugrel
Clopidogrel
HR=0.81 (95%CI, ,p<0.001
n=13,608
Wallentin L et al. N Engl J Med. 2009;36:
n=18,624
~Parallel Curves Post-30D
Diverging Curves Post-30d
(despite clop pre-Rx)
Early Separation (? due to no clop pre-Rx)
No early Separation
- In Non-Clopidogrel Pretreated Patient:
? Use Prasugrel Early then Switch to Clopidogrel 12 12

13. Is the mortality reduction the trump card for ticagrelor in ACS?
Cardiovascular Death
Is the mortality reduction the trump card for ticagrelor in ACS? 60
120
180
240
300
360 6 4 3 2 1
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001 7 5
Days after randomisation
CV death (%)
Wallentin L et al. N Engl J Med. 2009;36: 60
120
180
240
300
360 8 4 2
Clopidogrel
Ticagrelor
3.4
4.3 6
Days after randomization
Cumulative incidence (%)
HR 0.82 (95% CI = 0.68–0.98), p=0.025
Invasive
Cannon CP et al. Lancet. 2010;375:283-93

14. Reason 4: No Difference in Overall TIMI Major or CABG-Related Bleeding in PLATO vs. Clopidogrel

15. Life-threatening/ Fatal bleeding Non-CABG major bleeding3 6 9
7.9
7.7
p=NS
2.8
2.2
p=0.03
5.3
5.8
Cumulative Incidence (%)
Ticagrelor
Clopidogrel
vs.
Wallentin L et al. N Engl J Med. 2009;361:

16. 5. No Influence of Genotype on Clinical Outcomes2 4 6 8 10 12 14
12.1
8.5
8.0
9.8
11.2
8.6
10.0
8.8
LoF Carriers
LoF Non-carriers
Primary Efficacy Outcome (%0
Clopidogrel
Prasugrel
Ticagrelor
Pint = ?
Pint = 0.46
Gurbel PA et al. Expert Rev Cardiovasc Ther. 2004;2:535-45 16

17. Why Do I Prefer Ticagrelor?
1) Potential Off Target Beneficial Effects
2) Pharmacologic Properties faster offset
- elimination of HPR
- no influence of genetics
3) Clinical Outcomes
- no influence of genetics
- benefit on top of clopidogrel preRx
- accruing benefit over time- KM curves continue to separate
- mortality benefit
- no difference in CABG –related bleeding vs clopidogrel