1. Selección lógica de antiplaquetarios en SCA-ICP
SOLACI Simposium, México, 9-VIII-2012
Dr. José Luis Ferreiro
Hospital Universitario de Bellvitge: Área de Enfermedades del Corazón
Unidad de Cardiología Intervencionista – Laboratorio de Investigación Cardiovascular 1

2. CONFLICTS OF INTEREST Honoraria for lectures: Research grants:
Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca
Research grants:
Spanish Society of Cardiology

3. AVAILABLE ANTIPLATELET DRUGS
COX-1 AA
TxA2
ADP
Thrombin
TxA2 INHIBITORS
P2Y12 INHIBITORS
COX-1 Inhibitors
Aspirin
Ticlopidine
Clopidogrel
Prasugrel
Ticagrelor
GP IIB/IIIA INHIBITORS
Abciximab
Tirofiban
Eptifibatide
5HT2A
fibrinogen
PGE
PI3K
Intracellular signaling
GP IIb/IIIa
GP VI
GP Ib/IX/V
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:

4. AGENTS ON DEVELOPMENT PAR-1 INHIBITORS P2Y12 INHIBITORS
COX-1 AA
TxA2
ADP
Thrombin
TxA2 INHIBITORS
P2Y12 INHIBITORS
PAR-1 INHIBITORS
TP inhibitors
Picotamide
Ridogrel
Ramatroban
Terutroban
EV-077
Cangrelor
Elinogrel
Vorapaxar
Atopaxar
5HT2A
fibrinogen
PGE
PI3K
Intracellular signaling
GP IIb/IIIa
GP VI
GP Ib/IX/V
GP VI antagonists
Kistomin
Revacept
GP Ib antagonists
6B4-Fab
5HT2A antagonists
APD791
EP antagonists
DG-041
P2Y1 inhibitors
MRS2179
MRS2500
PIP3K inhibitors
TGX-221
Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:

5. Does one size fit all??

6. INDEX Clopidogrel variability in response Novel P2Y12 inhibitors
Prasugrel
Ticagrelor
Subgroup analyses
Balancing efficacy and safety

7. Clopidogrel: Variability in Response

8. Primary Endpoint—MI / stroke/ CV Death
CLOPIDOGREL: EFFICACY
Primary Endpoint—MI / stroke/ CV Death
0.14 p=
N=12,562
20% RRR
0.12
Placebo + ASA*
0.10
0.08
Clopidogrel + ASA*
Cumulative Hazard Rate
0.06
Suboptimal response?
0.04
Slide 16 of Bates 10-1 Boston presentation
0.02
Primary outcome: 9.3% in clopidogrel + ASA group and 11.4% in placebo + ASA group.
0.00 3 6 9 12
Months of Follow-Up
*Other standard therapies were used as appropriate.
Yusuf S et al. N Engl J Med 2001;345:

9. CLOPIDOGREL: VARIABILITY IN RESPONSE20 15
↑ Bleeding risk
↑ Ischemic risk 10
Patients (n) 5
2.5
12.5
22.5
32.5
42.5
52.5
62.5
72.5
82.5
92.5
7.5
17.5
27.5
37.5
47.5
57.5
67.5
77.5
87.5
97.5
% Platelet aggregation (LTA-ADP 20mM)
Angiolillo DJ et al. Am J Cardiol 2006;97:38-43.

10. CURRENT/OASIS 7: STUDY DESIGN
Patients with UA/NSTEMI or STEMI planned for early invasive strategy i.e. intent for PCI as early as possible within 72 hours
n=25,087
Randomize
Double Blind
Clopidogrel Standard Dose Group 300 mg Day 1; 75 mg Days 2-30
Clopidogrel High Dose Group 600 mg Day 1; 150 mg Days 2-7; 75 mg Days 8-30
Randomize
Randomize
Open Label
ASA low dose At least 300 mg Day 1; mg Days 2-30
ASA high dose At least 300 mg Day 1; mg Days 2-30
ASA low dose At least 300 mg Day 1; mg Days 2-30
ASA high dose At least 300 mg Day 1; mg Days 2-30
Acute ASA dosing (325/325 vs. 325/81) in ACS
Objective
To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy.
Design
Multicenter, international, randomized, 2×2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA ( mg daily) versus low-dose ASA ( mg daily) in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients.
1. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S; CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J. 2008;156:
Primary Efficacy Outcome Composite of CV Death, MI, or stroke up to day 30 Primary Safety Outcome Major Bleeding up to day 30
Mehta SR et al. NEJM 2010;363:

11. CURRENT OASIS-7 Trial Comparison of Clopidogrel Dosing: Primary Outcome and Components
Measure
Standard Dosing
Double Dosing
CV death, MI, and stroke, overall cohort (n=25,087)
4.4
4.2
PCI cohort (n=17,232)
4.5
3.9
No PCI cohort (n=7,855)
4.9
MI, overall cohort
2.2
1.9
PCI cohort
2.6
2.0
No PCI cohort
1.4
1.7
Double Better
Standard Better
P=0.016
There was no significant difference in the overall cohort of patients who received a higher loading and maintenance dose of clopidogrel, most likely because the patients who did not undergo PCI had no significant coronary disease by angiogram, or the drug was stopped when patients were scheduled for CABG surgery.
In focusing on the 17 232 patients who underwent PCI, there was a significant 15% reduction in cardiovascular, death, MI, and stroke, and this reduction was driven by a significant 22% reduction in the risk of MI. In addition, there was a significant 42% reduction in the risk of definite stent thrombosis.
clinical implications of this study are such that for every 1000 patients with ACS receiving PCI, doubling the loading and maintenance dose of clopidogrel will prevent an additional six MIs and seven stent thromboses with an excess three severe bleeds and no increase in fatal, CABG-related, or TIMI major bleeds. For those not undergoing PCI, they should continue using the standard dose of clopidogrel,
P=0.025
Mehta SR et al. NEJM 2010;363:
Odds Ratio

12. Novel P2Y12 Inhibitors

13. P2Y12 INHIBITORS Elinogrel Clopidogrel Prasugrel Ticagrelor Cangrelor
Group
Thienopyridine
CPTP
ATP analog
Quinazolinedione
Administration
oral IV
IV and oral
Receptor blockade
irreversible
reversible
Onset of action
2-8 h
30 min-4 h
30 min – 2 h
seconds
Offset of action
7-10 days
7-10 days
3-5 days
60-90 minutes
50 min (IV)
12 h (oral)
CYP drug interactions
yes no
Modified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-76 13

14. Novel ORAL P2Y12 Inhibitors
More potent and less variability!!
Angiolillo DJ et al. JACC Interv 2011

15. TRITON TIMI-38: STUDY DESIGN
Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI.
A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesis
All patients were to receive ASA.
Randomization was stratified by UA/NSTEMI vs STEMI
DB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg
- OR prasugrel with a LD of 60 mg and MD of 10 mg
DB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 months
The primary composite EP was CV death, MI, or Stroke through the end of the study
Key secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleeds
Two key substudies are evaluating pharmacokinetics and genomics
Wiviott SD et al. NEJM 2007;357: 15

16. PLATO: STUDY DESIGN
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
Wallentin L et al. NEJM 2009;361:

17. Differences between studies
TRITON VERSUS PLATO
Differences between studies
Population
TRITON: ACS undergoing PCI
PLATO: all ACS
Pretreatment (before PCI)
TRITON: Not allowed (except STEMI)
PLATO: Allowed
Loading dose of clopidogrel
TRITON: 300mg
PLATO: mg
Study length (median)
TRITON: 14.5 months
PLATO: 9 months

18. PRASUGREL VERSUS TICAGRELOR
TRITON TIMI 38
(prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)
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

19. GUIDELINES OK, but… what do we do? Clopidogrel Prasugrel Ticagrelor
Clopidogrel
Prasugrel
Ticagrelor
2011 ACCF/AHA UA/NSTEMI
Class I; LOE A
Class I; LOE B
Not FDA approved or marketed at the time of writing of Guidelines
2011 ACCF/AHA/SCAI PCI
Class I; LOE B*
2011 ESC NSTEACS
2010 ESC/EACTS/EAPCI
Myocardial Revascularization
Elective PCI: Class I; LOE A
NSTE-ACS: Class I; LOE B
STEMI: Class I; LOE C
NSTE-ACS: Class IIa; LOE B
STEMI: Class I; LOE B
OK, but… what do we do?

20. CLOPIDOGREL: STEMI Patients with suboptimal response (%) ASA
89,2% patients with poor response to clopidogrel
24,3% patients with poor response to ASA
Patients with suboptimal response (%)
ASA
Clopidogrel
VerifyNow
24.3%
89.2%
LTA (AA/ADP)
38.9%
84.2%
MEA
95%
Ferreiro JL et al. Reunión de la Sección de Hemodinámica, Santander 2012.

21. Pretreatment allowed PRASUGREL: STEMI
Montalescot G et al. Lancet 2009;373:

22. Steg PG et al. Circulation 2010;122:2131-2141
TICAGRELOR: STEMI
K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)
HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07)
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Steg PG et al. Circulation 2010;122:

23. PRASUGREL: DM PATIENTS2 4 6 8 10 12 14 16 18 30 60 90
180
270
360
450
HR 0.70 P<0.001
Days
Endpoint (%)
CV Death/MI/Stroke
TIMI Major Non-CABG Bleeds
NNT=21
(n=3146)
17.0
12.2
Prasugrel
Clopidogrel
2.6
2.5
Wiviott SD et al. Circulation 2008;118:1626–36.

24. NEW STRATEGIES IN ACS: DM PATIENTS
TRITON-TIMI (0.58 – 0.85)
PLATO (0.76 – 1.03)
CURRENT OASIS (0.66 – 1.15) (PCI Cohort)
Study % of Events Hazard Ratio (95% confidence interval)
Standard New Drug/Approach
New Drug/Approach Better
Standard Clopidogrel Better
0.5 1
1.5
CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction.
Ferreiro JL et al. Circulation : 24

25. NEW STRATEGIES IN ACS/PCI: STENT THROMBOSIS
Hazard Ratio
[95% confidence interval]
Study
0.48 [ ]
0.73 [ ,94]
0.68 [ ,85]
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 et al. Circ Cardiovasc Interv 2012;5:

26. Useful in non-invasive strategy
TICAGRELOR
Useful in non-invasive strategy
James SK et al. BMJ 2011.

27. PRASUGREL: MEDICAL TREATMENT
Treatment Decision for Medical Management determined < 24 hrs
N = 7,800 < 75 yrs,
N ~ 2,500  75 yrs
Treatment Decision determined > 24 hrs OR chronic Clopidogrel Rx
Randomize < 24 h
Start/Continue Clopidogrel < 24 h
Randomize between 1-7 days
Clopidogrel
300 mg LD
75 mg MD
Prasugrel
30 mg LD
10/5 mg MD*
Clopidogrel
75 mg MD
Prasugrel
10/5 mg MD*
* 5 mg MD of prasugrel for age  75 yrs or weight < 60 kg
Median duration of treatment ~ 18 months

28. TICAGRELOR: CKD
CKD
Renal function analytic control 1 month after initiating therapy
CV death, MI or stroke (%)
p for interaction = 0,13
Normal renal function
Days after randomization
James S et al. Circulation. 2010;122:1056–1067.

29. PRASUGREL: VULNERABLE SUBGROUPS
Risk (%)
Yes
+ 54
Prior Stroke / TIA
-16 No
Pint = 0.006 -1
>=75
Age
Pint = 0.18
-16
< 75
< 60 kg +3
Wgt
>=60 kg
Pint = 0.36
-14
As a result of the discordance between efficacy and safety with prasugrel –signficant reductions in events at the cost of a significant increase in bleeding we performed a series of post-hoc exploratory analyses to identify subgroups of patients that did not have a favorable net clinical benefit or who had net harm.
The group with a prior cerebrovascular event (shown in red) had more primary endpoint events and increased bleeding with prasugrel, resulting in a significant net clinical benefit favoring clopidogrel. Patients without a prior cerebrovascular event, shown in green, had a net clinical benefit favoring prasugrel. The P value for interaction was significant at
Elderly patients and those with a low body weight (shown in yellow) tended to have better efficacy but more bleeding with prasugrel, resulting in a net clinical benefit near unity. The younger patients and those with higher body weights (shown in green) had siginificant net clinical benefit favoring prasugrel. The interaction P values for the elderly and low weight patients did not reach statistical significance.
-13
OVERALL
0.5 1 2
Prasugrel Better
Clopidogrel Better HR
Wiviott SD et al. NEJM 2007;357: 29

30. CV Death, Nonfatal MI, or Nonfatal Stroke (%)
AGE & DM 30
Clopidogrel
Prasugrel
HR=0.72 (95% CI, 0.6–0.9)
HR=0.64 (95% CI, 0.4–1.0)
HR=0.82 (95% CI, 0.7–0.9)
HR=1.1 (95% CI, 0.8–1.4) 25
P=0.034
21.8 20
P=NS
P=0.002
CV Death, Nonfatal MI, or Nonfatal Stroke (%) 15
16.4
15.3
14.8
14.9
P=0.004 10
10.8
9.5
7.8 5
PRESENTATION TIPS
This slide shows the data by patient’s age (≥75 years of age or <75 years of age) with and without diabetes.
Indicate that this subgroup analysis was post hoc.
KEY POINTS
This slide shows the efficacy results of prasugrel in patients <75 or ≥75 years of age ± diabetes, representing various subpopulations of the TRITON-TIMI 38 trial.
Prasugrel reduced the primary endpoint in a specific high-risk patient subgroup: ≥75 years with diabetes.
There is an increase in the hazard ratio (favoring clopidogrel) in patients ≥75 years without diabetes.
The TRITON-TIMI 38 trial was not designed or powered to demonstrate independent efficacy or safety in patients with diabetes who were <75 years or ≥75 years.
BACKGROUND
Patients ≥75 years of age who received prasugrel had an increased risk of fatal bleeding events (1.0%) compared with patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received prasugrel and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age, use of prasugrel is generally not recommended in these patients, except in high-risk situations (diabetes and past history of MI) where its effect appears to be greater and its use may be considered.
REFERENCE
Effient® (prasugrel) prescribing information. Daiichi Sankyo, Inc. and Eli Lilly and Company.
n=1327
n=1336
n=249
n=234
n=4585
n=4551
n=652
n=674
<75 years
≥75 years
<75 years
≥75 years
With Diabetes
Without Diabetes
*Composite of CV death, nonfatal MI, or nonfatal stroke. 30 30

31. Balancing Ischemic and Bleeding Risk

32. BALANCING ISCHEMIA / BLEEDING
Inhibition of platelet aggregation
High risk of
ischemic events
bleeding events
Risk of any event
“Sweet spot”
Ischemic risk
Ischemic risk
Bleeding risk
Bleeding risk
Ferreiro JL et al. Thromb Haemost 2010;103:

33. Therapeutic Window Elective PCI OR 0.40, 95% CI 0.22-0.75
Sibbing et al. JACC 2010;56:317-8

34. Therapeutic Window Elective PCI
Campo G et al. J Am Coll Cardiol. 2011;57:

35. CONCLUSIONS Clopidogrel: Great variability in response
Novel P2Y12 inhibitors: Prasugrel and Ticagrelor
Proof of concept: More potent platelet inhibition is needed in ACS
Risk of bleeding, but favorable efficacy and safety profile
Subgroup analyses has limitations, but may help to define strategy
Prasugrel: only ACS undergoing PCI
Particular benefit in DM, STEMI, stent thrombosis
Contraindications: high risk of bleeding, prior stroke
Considerations: elderly, low-weight patients; CABG: 7 days
Ticagrelor: full spectrum of ACS
Particular benefit: CKD; reduction in CV mortality
Contraindications: high risk of bleeding, intracranial hemorrhage
Considerations: ASA dose, comorbidities (COPD), compliance; CABG: 5 days
Several agents: Which one is the best? Individualized therapy
Balance between ischemia and bleeding
Platelet function testing may play a role

36. Individualized therapy
Does one size fit all??
Individualized therapy

37. NO riesgo alto de sangrado Riesgo alto de sangrado
Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA
IAMCEST
IAM extenso*
ECG: Anterior (≥4 derivaciones) e Inferoposterior
KT: Segmento proximal (arteria extensa)
IAM no extenso
CLOPIDOGREL
TICAGRELOR
PRASUGREL
NO riesgo alto de sangrado
Riesgo alto de sangrado
Valorar: edad >80 años; ictus previo; HTA severa; antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa; IRC severa; IQ reciente o ineludible
No ictus previo y >60Kg y ≤75 años
(Individualizar en DM >75 años)
Ictus previo o ≤60Kg o >75 años
*A valorar Inhibidores de la GP IIb/IIIa en pacientes con alto contenido trombótico

38. SCASEST Riesgo alto* Riesgo bajo / intermedio CLOPIDOGREL** TICAGRELOR
alteraciones segmento ST; elevación troponina >10 veces el límite inferior;
angor refractario; insuficiencia cardiaca
Riesgo bajo / intermedio
CLOPIDOGREL**
TICAGRELOR
PRASUGREL
NO riesgo alto de sangrado
Riesgo alto de sangrado
Valorar: edad >80 años; ictus previo; HTA severa; antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa; IRC severa; IQ reciente o ineludible
No ictus previo y >60Kg
(Individualizar en >75 años)
Ictus previo o ≤60Kg
*A valorar uso upstream de Inhibidores de la GP IIb/IIIa en pacientes con:
a) angor refractario pese a tratamiento completo o b) cambios ECG extensos con insuficiencia cardiaca DM
No DM
**Valorar ticagrelor en pacientes con IRC
(Pacientes en que se indica estrategia invasiva)
Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA

39. Unidad de Cardiología Intervencionista
Jefe de Sección: Dr. J.A. Gómez-Hospital
Dr. José Luis Ferreiro
Dr. Gerard Roura
Dr. Francesc Jara
Dr. Luis Teruel
Dr. Josep Gómez-Lara
Dra. Silvia Homs
Dr. Guillermo Sánchez-Elvira
Dr. Daniel Rivero
Laboratorio de Investigación Cardiovascular
Director: Dr. José Luis Ferreiro
Sra. Gabriela Sosa
Sra. Paula Campreciós
Sra. Laia Rosenfeld
Sra. Olga Cañavate
Sra. Sonia Gómez
Dr. Kristian Rivera
Dra. Ana Marcano
Heart Diseases Institute. Director: Dr. Ángel Cequier
Interesados en fellowship:

40. Gracias por su Atención Interesados en fellowship:

42. Backup slides

43. CLOPIDOGREL IN ACS/PCI
UA/NSTEMI
PCI
Acute STEMI
COMMIT
(CCS-2)
1 Year
1 Year
30 Days
+ Benefit
+ Benefit
+ Benefit
Looking across the full spectrum, there is now data on the use of clopidogrel in STEMI in addition to the data on the use of clopidogrel in NSTEMI, unstable angina, PCI and secondary prevention. The results of CHARISMA will be discussed later in the lecture.
NEJM 2005
NEJM 2001
JAMA 2002
Lancet 2005

44. TRITON TIMI-38: EFFICACY AND SAFETY TIMI Major NonCABG Bleeds15
138 events
Clopidogrel
12.1
HR 0.81 ( ) P=0.0004
CV Death / MI / Stroke
9.9 10
NNT = 46
Prasugrel
Endpoint (%) 5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
This slide depicts the balance of efficacy and safety observed in the trial.
At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46
At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrel—a 0.6% Absolute risk increase.
The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value of
The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167.
2.4
HR 1.32 ( ) P=0.03
1.8
Clopidogrel
NNH = 167 30 60 90
180
270
360
450
DAYS
Wiviott SD et al. NEJM 2007;357: 44

45. Cumulative incidence (%) Days after randomisation
PLATO: EFFICACY 13 12
Clopidogrel
11.7 11 10
9.8 9
Ticagrelor 8 7
Cumulative incidence (%) 6 5 4 3 2 1
HR 0.84 (95% CI 0.77–0.92), p=0.0003 60
120
180
240
300
360
Days after randomisation
No. at risk
Ticagrelor
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel
9,291
8,521
8,362
8,124
6,743
5,096
4,047
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Wallentin L et al. NEJM 2009;361:

46. PLATO: SAFETY K-M estimated rate (% per year)
Non-CABG PLATO major bleeding
Non-CABG TIMI major bleeding
CABG PLATO major bleeding
CABG TIMI major bleeding
p=0.026
p=0.03 NS 9 8 7 6 5 4 3 2 1
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
Ticagrelor
Clopidogrel
Wallentin L et al. NEJM 2009;361:

47. PRASUGREL VERSUS TICAGRELOR
Efficacy
A reduction in: Prasugrel Ticagrelor CV Death/MI/Stroke 19% %
Stent thrombosis 52%    25%
MI 24% 16%
CV death 11% 21%
Early benefit 18% 12%
(3 days) (30 days)
Late benefit 20% 20%
(~14.5 mo) (~9 mo) 47

48. FROM CLOPIDOGREL TO PRASUGREL
“SWITCHING”:
FROM CLOPIDOGREL TO PRASUGREL
Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU
Angiolillo DJ et al. J Am Coll Cardiol 2010; 56:

49. TICAGRELOR: CABG
Major Fatal/Life-Threatening Bleeding by Days from Last Dose of Treatment to CABG
100%
Ticagrelor
80%
Clopidogrel
60%
% Patients with Bleeding
post-CABG
40%
20% 0% 1 2 3 4 5 6 7
>8
Days
Bleeding differences favor ticagrelor >5 days post discontinuation

50. ISSUE OF PRETREATMENT NSTEMI / Troponin +, n~4100+ (Event Driven)
Clopidogrel Naive or Longterm 75mg
Plan Angio/PCI >2h and <24h
Diagnosis +
Transfer
to Cathlab
>2h to <24h
Randomize
Pras 30
Inactive
Angio
Angio
Cathlab
Pras 30
Pras 60
PCI
PCI
PE: CV-D, MI, stroke, Urgent Revasc., GPI 7d
SEs: All TIMI Major 7d; 7d
Pras 10(5)
for 30d
30d FU 50

51. PRASUGREL AFTER CLOPIDOGREL LOADING
TRansferring from clopIdogrel loading Dose to Prasugrel Loading dose in ACS patiEnTs (TRIPLET)
Phase 2 randomized, double blind, double dummy, 3-arm, parallel, active comparator, controlled study
Arm A
Placebo < 24hr pre-PCI
Prasugrel 60mg during PCI
Prasugrel 10mg MD
ARM B
Clopidogrel 600mg < 24hr pre-PCI
Arm C
Prasugrel 30mg during PCI

52. PRASUGREL RELOAD
Patients on aspirin (81 mg/day) and prasugrel (10 mg/day) ≥ 14 days post-PCI
10 mg prasugrel
(N=22)
30 mg prasugrel
(N=21)
60 mg prasugrel
Pharmacodynamic testing: 1 hour
Pharmacodynamic testing: Baseline
Pharmacodynamic testing: 4 hour
Figure 1
Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press] 52

53. P2Y12 Reactivity Index (%)
PRASUGREL RELOAD * † ** ††
P2Y12 Reactivity Index (%)
Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]

54. PRASUGREL: CABG
Wiviott SD et al. NEJM 2007;357: