1. The Big Antiplatelet Debate Why I Prefer Prasugrel Over Ticagrelor
Dominick J. Angiolillo, MD, PhD, FACC, FESC, FSCAI
Director of Cardiovascular Research
Associate Professor of Medicine
University of Florida College of Medicine - Jacksonville

2. Dominick J. Angiolillo, MD, PhD
Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc.,
Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Merck, Evolva
Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson&Johnson, Bristol Myers Squibb, Sanofi-Aventis

3. TRITON vs PLATO: Is there a winner?

4. TRITON vs PLATO Proof of concept: Higher IPA to Support ACS
Differences between trials
Patient Population
TRITON: ACS undergoing PCI
PLATO: Full spectrum ACS
2. Pretreatment
TRITON: No pretreatment (except STEMI)
PLATO: Pretreatment
3. Clopidogrel Loading Dose
TRITON: 300mg
PLATO: mg
4. Duration of trial (median)
TRITON: 14.5 months
PLATO: 9 months

5. (prasugrel vs clopidogrel) (ticagrelor vs clopidogrel)
TRITON TIMI 38
(prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)

6. Why I prefer prasugrel STEMI-PCI Diabetes Mellitus with ACS
Recurrent ACS while on Clopidogrel
Stent thrombosis

7. Why I prefer prasugrel
1. STEMI-PCI 2. Diabetes Mellitus with ACS 3. Recurrent ACS while on Clopidogrel 4. Stent thrombosis

8. Death, MI or Stroke in STEMI-PCI%
P=0.11
N=6364
N=7544
N=3534
Drug Double dose clopidogrel Ticagrelor Prasugrel
Follow-up 1 month 6-12 months 15 months

9. Primary Efficacy Endpoint Primary Efficacy Endpoint
STEMI
TRITON
PLATO
Primary Efficacy Endpoint
Time (Days) 5 10 15 50
100
150
200
250
300
350
400
450
Proportion of patients (%)
9.5
12.4
10.0
HR=0.79 (0.65–0.97) NNT=41
p=0.02
RRR=21%
p=0.002
RRR=32%
6.5
N=3534
P=0.02
N=7544
P=0.07
Primary Efficacy Endpoint 2 4 8 12 6 10
Clopidogrel
Ticagrelor
Cumulative incidence (%)
10.8
9.4
p=0.07
RRR=13%
Clopidogrel
Prasugrel
HR=0.87 (0.75 to 1.01) NNT=71
Time (Months)

10. Why I prefer prasugrel 1. STEMI-PCI 2. Diabetes Mellitus with ACS
3. Recurrent ACS while on Clopidogrel
4. Stent thrombosis

11. Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials
Study % of Events Hazard Ratio (95% confidence interval)
Standard New Drug/Approach
TRITON-TIMI (0.58 – 0.85)
PLATO (0.76 – 1.03)
CURRENT OASIS (0.66 – 1.15) (PCI Cohort)
0.5 1
1.5
New Drug/Approach Better
Standard Clopidogrel Better
CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction.
Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation 2011; 123:

12. TRITON TIMI-38: Diabetic Subgroup18
Clopidogrel
17.0 16
CV Death/MI/Stroke 14
12.2 12
HR 0.70 P<0.001
Prasugrel 10
Endpoint (%)
NNT = 21 8 6
TIMI Major Non-CABG Bleeds 4
Clopidogrel
2.6 2
2.5
Prasugrel 30 60 90
180
270
360
450
Days
Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:

13. TRITON TIMI-38: CV Death/MI/Stroke by Diabetic Status
Pras
Clop
Reduction in Risk
No DM
9.2%
10.6%
14%
DM No Insulin
11.5%
15.3%
26%
DM on Insulin
14.3%
22.2%
37%
0.3 1 2
Prasugrel better
Clopidogrel better
Wiviott SD, Braunwald E, Angiolillo DJ et al. Circulation. 2008;118:

14. Diabetes N=4662 Primary endpoint
16.2%
14.1%
CV death, MI or stroke (%)
10.2%
8.4%
No diabetes
Number at risk
Diabetes Ticagrelor Clopidogrel
No diabetes Ticagrelor Clopidogrel
Days after randomization
James S, Angiolillo DJ, Cornel JH et al. Eur Heart J 2010; 31:

15. Why I prefer prasugrel
1. STEMI-PCI 2. Diabetes Mellitus with ACS 3. Recurrent ACS while on Clopidogrel 4. Stent thrombosis

16. TRITON: 2nd Event following a Nonfatal Primary Endpoint
CVD/MI/Stroke
CV Death
Murphy SA, et al. Eur Heart J 2008;29:

17. Total Events: CVD / MI / Stroke
RECURRENT EVENTS
Total Events
P<0.001
Additional Events
P=0.40
First Events
P=0.002

18. Why I prefer prasugrel STEMI-PCI Diabetes Mellitus with ACS
Recurrent ACS while on Clopidogrel
Stent thrombosis

19. NEW APPROACHES: STENT THROMBOSIS
Hazard Ratio
[95% confidence interval]
Study
0.48 [ ]
0.73 [ ,94]
0.69 [ ,87]
TRITON-TIMI 38
PLATO
CURRENT-OASIS 7
% of events
Standard
New Drug / Approach
3,0
2.2
2.3
1.6
2.4
1.1
Better
Standard Clopidogrel
Ferreiro JL, Angiolillo DJ. Circ Cardiovasc Interv 2012

20. Why I prefer prasugrel STEMI-PCI Diabetes Mellitus with ACS
Recurrent ACS while on Clopidogrel
Stent thrombosis
Common factors:
- High thrombotic risk
- Benefits strongly outweigh the risk (increased ischemic benefit, minimal/no differences in bleeding)
- Cost-effective

21. Novel P2Y12 receptor antagonists: When “NOT to Use” or “Use with Caution”?
Prasugrel.
Contraindicated: high-risk bleeding; prior TIA/stroke; hypersensitivty
Precautions: elderly, low-weight; CABG/surgery (7days).
Ticagrelor.
Contraindicated: high-risk bleeding; prior hemorrhagic stroke; severe hepatic dysfunction
Precautions: COPD/asthma (dyspnea 14% of patients), bradyarrythmia without pacemaker; aspirin dose (<100mg);
compliance (b.i.d. administration); drug interactions (CYP 3A4 interfering agents); CABG/surgery (5-7days).

22. Unraveling some myths!
Bleeding
Mortality

23. (prasugrel vs clopidogrel) (ticagrelor vs clopidogrel)
TRITON TIMI 38
(prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)

24. Non-CABG and CABG-related major bleeding9 NS
Ticagrelor
Clopidogrel
7.9 8
Prasugrel vs Clopidogrel
2.4% vs 1.8%
ARD 0.6% HR 1.32 P=0.03 NNH=167
Ticagrelor vs Clopidogrel
2.8% vs 2.2%
ARD 0.6% HR 1.25 P=0.03 NNH=167
Non-CABG TIMI major bleeding
TRITON
PLATO
7.4 7 NS
5.8 6
5.3
p=0.026
K-M estimated rate (% per year) 5
4.5 4
3.8
p=0.03
2.8 3
2.2 2 1
Non-CABG PLATO major bleeding
Non-CABG TIMI major bleeding
CABG PLATO major bleeding
CABG TIMI major bleeding

25. Balance of Efficacy/Safety in patients <75 yrs, >60 kg, No prior TIA/stroke

26. CV Mortality in TRITON and PLATO
TRITON 2.4 vs. 2.1%; HR 0.89 (0.70 – 1.12); P = 0.31
PLATO 5.0 vs. 4.1%; HR 0.79 ( ); P < 0.001
If you apply the HR to the other population
HR necessary for P < 0.05 in TRITON = 0.78 (PLATO 0.79 → P = 0.06)
HR necessary for P < 0.05 in PLATO = 0.87 (TRITON 0.89 → P = 0.08)
Courtesy of Steve Wiviott

27. Adjusted HR* for Cardiovacular Death By MI Classification
Type 1 MI – 2.6—3.9—5.7
Type 2 MI ?
Type 4a MI – 1.6—2.4—3.6
Type 4b MI – 5.3—8.3—13.0
Type 4 MI – 2.7—3.7—5.2
Type 5 MI ?
All MI ?
*adjusted for age, gender, diabetes, hx of CHF, hx of MI, hypertension, dyslipidemia, renal dysfunction, prior MI, randomization group, severity of CAD and index event

28. Is there room for ticagrelor?
A. In patients with prior TIA/Ischemic stroke and:
Primary PCI- STEMI
Diabetes Mellitus with ACS
Recurrent ACS while on Clopidogrel
Stent thrombosis
B. High-risk medically managed ACS
C. Clopidogrel allergy

29. Elderly and Low-weight Patients
Facts:
Both populations are associated with increased bleeding regardless of management
Bleeding risk is further increased with both prasugrel and ticagrelor
Limited data on clinical effects associated with dose modification (e.g. 5mg prasugrel).
Overall, good experience with clopidogrel.
Practical perspective: I continue to use clopidogrel, particularly for long-term management, in my elderly and low-weight patients.

30. Conclusions: This is Why I Prefer Prasugrel
Prasugrel was specifically studied in ACS patients undergoing PCI, showing significant ischemic benefit with a favorable safety profile.
Fact #1: We cannot use new agents in all our ACS patients (cost-prohibitive!! ... and clopidogrel, now generic, is still a very good option)
Fact #2: The benefit of prasugrel is enhanced where we really need a new agent (STEMI, DM, recurrent events, stent thrombosis)!
Facts #3-5:
Prasugrel is a PCI drug.
I am an interventional cardiologist
This is an interventional meeting