1. Which Antiplatelet Therapy for PCI?
Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Investigator, TIMI Study Group

2. Disclosures CME Honoraria: Eli Lilly, Daiichi Sankyo; Accumetrics, Astra-Zeneca, Pfizer, Merck, Bayer. Consultancies: Sanofi-Aventis, BMS, Portola, Astra-Zeneca , Medco, ARENA Research Funding: Eli Lilly, Daiichi Sankyo, Merck-Schering Plough TIMI Study Group Receives Research Funding From: Eli Lilly, Daiichi Sankyo, Merck, Schering Plough, Sanofi-Aventis, AstraZeneca, Accumetrics

3. What antiplatelet therapy should we use for PCI?
It depends…
…but, mostly 3rd generation agents: prasugrel and ticagrelor

4. Goals of Antiplatelet Therapy for PCI?
Potent Antiplatelet Effect
Consistent Antiplatelet Effect
SAFETY !!! – choice of patients
Speed if rapid to cath lab
High risk NSTEACS
STEMI

5. Prasugrel: PRINCIPLE – TIMI 44 Results
Wiviott_ACC Platelet_Dr Wiviott's comments included_021910
Prasugrel: PRINCIPLE – TIMI 44 Results
Wiviott/p 2927/Figure 4
Loading Dose
Maintenance Dose
100
Wiviott/p 2926/col 2/para 3
100
Clopidogrel
Prasugrel
150 mg
10 mg 80
Prasugrel 60 mg * 80 * *
61.3* 60 60
IPA (20 mmol/L ADP, %)
IPA (20 mmol/L ADP, %)
PRINCIPLE-TIMI 44: Inhibition of platelet aggregation with loading and maintenance doses
46.1
At 6 hours, the extent of inhibition was 74.8% and 31.8% with prasugrel and clopidogrel loading doses, respectively (P < ).
Significantly greater inhibition was also observed at 30 minutes and up to 24 hours (P < for both comparisons). .
Wiviott SD, Trenk D, Frelinger AL, et al; PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):
Clopidogrel 600 mg 40 40 * 20 20 4 8 12 16 20 24
14 Days
Time (h)
*P< vs clopidogrel. IPA=inhibition of platelet aggregation; PRINCIPLE TIMI=Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction. Reprinted with permission from Wiviott S, et al. Circulation. 2007;116(25):

6. Prasugrel vs Clopiodogrel15
138 events
Clopidogrel
12.1
HR 0.81 ( ) P=0.0004
CV Death / MI / Stroke
9.9 10
NNT = 46
Prasugrel
Endpoint (%)
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. 5
35 events
TIMI Major NonCABG Bleeds
Prasugrel
2.4
HR 1.32 ( ) P=0.03
1.8
Clopidogrel
NNH = 167 30 60 90
180
270
360
450
Days
Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

7. TRITON-TIMI 38—Bleeding Events Safety Cohort (N=13,457)
Wiviott_ACC Platelet_Dr Wiviott's comments included_021910
TRITON-TIMI 38—Bleeding Events Safety Cohort (N=13,457)
Wiviott/p 2005/col 2/para 3; p 2007/col 1/para 1; p 2011/Table 3 4 2
Clopidogrel
ICH in patients with prior stroke/TIA (N=518)
Prasugrel
Clopidogrel: 0 (0%) Prasugrel: 6 (2.3%) P=0.02
Events (%)
More details of the bleeding events are shown on this slide.
The TIMI major non CABG bleed data are shown in the pair of bar graphs on the left, showing the increase in events with prasugrel
Life threatening bleeding--another key safety EP ( defined as requiring a 4 unit txn, fluid or inotropic support, surgical intervention, or an ICH) occurred in 0.9 % of clopidogrel and 1.4% of prasugrel subjects—a 0.5% ARI with prasugrel, associated with a P value of 0.01
Subcategories of life threatening bleeding are shown to the right.
Fatal bleeding occurred in 0.1% of pts with clopidogrel and was increased to 0.4% of patients with prasugrel—a 0.3% Absolute risk increase associated with a P value of
There was no difference in ICH overall in the trial—occurring in 0.3% of pts in both groups.
Of note, in the subgroup of 518 patients with a history of prior stroke or TIA, no ICH’s occurred with clopidogrel while 6 occurred with prasugrel—a significant difference at the 0.02 level.
ARD 0.6% HR 1.32 P=0.03 NNH=167
ARD 0.5% HR 1.52 P=0.01
ARD 0.2% HR=1.25 P=0.23
ARD 0.3% HR=4.19 P=0.002
ARD 0% HR=1.12 P=0.74
ARD=absolute risk difference; HR=hazard ratio; ICH=intracranial hemorrhage; TIA=transient ischemic attack; TIMI=Thrombolysis in Myocardial Infarction. Wiviott SD, et al. N Engl J Med. 2007;357(20): 7 7

8. Summary: Prasugrel Beyond Standard Clopidogrel
Speed of Onset ++
Extent of Inhibition ++
Poor Responders
- -
Genetic Effects
- -
Ischemic Events/Stent Thrombus
- -
Bleeding Risk
+ +
Indications
ACS with PCI, w/o known Stroke or TIA
Guidelines
PCI/STEMI 2009; UA/NSTEMI 2011

9. 20 µM ADP- Final Extent     * * IPA % † ‡ 100 Last
Maintenance Dose
Loading Dose
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12) * * ‡ † 90 80  70 60
IPA %  50  40 30 20 10 
weeks
Onset Maintenance Offset
Time (hours) 9

10. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)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
Adapted from Wallentin L, et al. N Engl J Med. 2009;361:

11. Secondary efficacy endpoints over time
Myocardial infarction
Cardiovascular death 7
6.9 7
Clopidogrel 6 6
5.8
Clopidogrel
5.1 5
Ticagrelor 5 4 4
4.0
Ticagrelor
Cumulative incidence (%)
Cumulative incidence (%) 3 3 2 2 1 1
HR 0.84 (95% CI 0.75–0.95), p=0.005
HR 0.79 (95% CI 0.69–0.91), p=0.001 60
120
180
240
300
360 60
120
180
240
300
360
Days after randomisation
Days after randomisation
No. at risk
Ticagrelor
9,333
8,678
8,520
8,279
6,796
5,210
4,191
9,333
8,294
8,822
8,626
7119
5,482
4,419
Clopidogrel
9,291
8,560
8,405
8,177
6,703
5,136
4,109
9,291
8,865
8,780
8,589
7079
5,441
4,364
Adapted from Wallentin L, et al. N Engl J Med. 2009;361:

12. Time to non-procedure-related PLATO major bleeding
Completeness of follow-up 99.97% = five patients lost to follow-up 4
Ticagrelor 3
3.06
2.31 2
K-M estimated rate (% per year)
Clopidogrel 1
HR 1.31 (95% CI 1.08–1.60), p=0.006 60
120
180
240
300
360
Days from first IP dose
No. at risk
Ticagrelor
9,235
7,641
7,247
6,979
5,496
4,067
3,698
Clopidogrel
9,186
7,718
7,371
7,134
5,597
4,147
3,764

13. Summary: Ticagrelor Beyond Standard Clopidogrel
Speed of Onset ++
Extent of Inhibition ++
Poor Responders
- -
Genetic Effects
- -
Ischemic Events/Stent Thrombus
- -
Bleeding Risk +
Indications
ACS with or without PCI
Guidelines
Pending

14. Clinical Considerations: Summary
Clopidogrel
Prasugrel
Ticagrelor
Anti-thrombotic ++
+++
+++
Bleeding Risk ++
++++
+++
Indications
ACS, PCI
ACS with PCI
ACS
Black Boxed Warnings
Genetic
Bleeding, Stroke/TIA
Bleeding, ASA >100
Cautions
2C19/DDI
Age >75, Wt < 60
Dyspnea
Cost
$$ (▼)
$$$
$$$
Convenience/Compliance QD QD
BID
CABG
5 days
7 days
5 days

15. Clinical Considerations: Summary
Clopidogrel
Prasugrel
Ticagrelor
Anti-thrombotic ++
+++
+++
Bleeding Risk ++
++++
+++
Indications
ACS, PCI
ACS with PCI
ACS
Black Boxed Warnings
Genetic
Bleeding, Stroke/TIA
Bleeding, ASA >100
Cautions
2C19/DDI
Age >75, Wt < 60
Dyspnea
Cost
$$ (▼)
$$$
$$$
Convenience/Compliance QD QD
BID
CABG
5 days
7 days
5 days

16. Clinical Considerations: Summary
Clopidogrel
Prasugrel
Ticagrelor
Anti-thrombotic ++
+++
+++
Bleeding Risk ++
++++
+++
Indications
ACS, PCI
ACS with PCI
ACS
Black Boxed Warnings
Genetic
Bleeding, Stroke/TIA
Bleeding, ASA >100
Cautions
2C19/DDI
Age >75, Wt < 60
Dyspnea
Cost
$$ (▼)
$$$
$$$
Convenience/Compliance QD QD
BID
CABG
5 days
7 days
5 days

17. Clinical Considerations: Summary
Clopidogrel
Prasugrel
Ticagrelor
Anti-thrombotic ++
+++
+++
Bleeding Risk ++
++++
+++
Indications
ACS, PCI
ACS with PCI
ACS
Black Boxed Warnings
Genetic
Bleeding, Stroke/TIA
Bleeding, ASA >100
Cautions
2C19/DDI
Age >75, Wt < 60
Dyspnea
Cost
$$ (▼)
$$$
$$$
Convenience/Compliance QD QD
BID
CABG
5 days
7 days
5 days

18. Choice of APT ACS? STEMI vs. NSTEMI? Bleeding Risk Prior APT
Rapid PCI?
Patient choice/cost/compliance

19. Rapid /No DAPT Delayed/Prior DAPT CABG PCI CABG PCI Med Rx Med Rx
ACS
High Bleeding Risk
Standard Clopidogrel Pathway
Yes
Yes
N o
N o
Standard Clopidogrel Pathway
Timing of Dx Catheterization
And Prior APT
Rapid /No DAPT
Delayed/Prior DAPT
Load Clopidogrel or Ticagrelor
if Appropriate
Dx Catheterization
Dx Catheterization
CABG
PCI
Med Rx
CABG
PCI
Med Rx
No DAPT
Prasugrel*
Ticagrelor
Clopidogrel
Ticagrelor
Stop DAPT
Ticagrelor
Prasugrel* if no load
Clopidogrel
Ticagrelor
* Without Contraindication (STROKE/TIA)

20. Standard Clopidogrel Pathway Standard Clopidogrel Pathway
ACS
High Bleeding Risk
Standard Clopidogrel Pathway
Yes
Yes
N o
Bleeding Risks:
Active Bleeding
Major Surgery
Thrombolytic Therapy
Oral anticoagulants
Prior ICH or Previous Severe Bleeding
Severe Liver Disease
Any history of STROKE/TIA for Prasugrel
Other (mostly long term):
Cost
Coverage
Compliance Concerns
Standard Clopidogrel Pathway

21. Timing of Dx Catheterization * Without Contraindication (STROKE/TIA)
ACS
High Bleeding Risk
Yes
N o
Timing of Dx Catheterization
Rapid /No DAPT
Delayed/Prior DAPT
Dx Catheterization
CABG
PCI
Med Rx
No DAPT
Prasugrel*
Ticagrelor
Clopidogrel
Ticagrelor
* Without Contraindication (STROKE/TIA)

22. Rapid /No DAPT Delayed/Prior DAPT CABG PCI Med Rx ACS
High Bleeding Risk
Yes
N o
Timing of Dx Catheterization
Rapid /No DAPT
Delayed/Prior DAPT
Load Clopidogrel or Ticagrelor
if Appropriate
Dx Catheterization
CABG
PCI
Med Rx
Stop DAPT
Ticagrelor
Prasugrel* if no load
Clopidogrel
Ticagrelor
* Without Contraindication (STROKE/TIA)

23. Rapid /No DAPT Delayed/Prior DAPT CABG PCI CABG PCI Med Rx Med Rx ACS
High Bleeding Risk
Standard Clopidogrel Pathway
Yes
Yes
N o
N o
Standard Clopidogrel Pathway
Timing of Dx Catheterization
Rapid /No DAPT
Delayed/Prior DAPT
Load Clopidogrel or Ticagrelor
if Appropriate
Dx Catheterization
Dx Catheterization
CABG
PCI
Med Rx
CABG
PCI
Med Rx
No DAPT
Prasugrel*
Ticagrelor
Clopidogrel
Ticagrelor
Stop DAPT
Ticagrelor
Prasugrel* if no load
Clopidogrel
Ticagrelor
* Without Contraindication (STROKE/TIA)

24. Stent Thrombosis in STEMI Pts by PCI Timing at 15 mo
P-interaction=0.78
**We could present this slide as a Forest/Tornado plot instead**
Stent thrombosis and TIMI major bleeding events were infrequent, however bleeding associated with prasugrel as compared to clopidogrel was consistent in the STEMI cohort, and either PCI subgroup, with the overall trial result (PPCI 15m HR 1.52 [ ]; SecPCI 15m HR 0.39 [ ]).
HR 0.55 ( ) p=0.048
HR 0.63 ( ) p=0.25
Stent Thrombosis (ARC Definite/Probable)

25. PLATO STE-ACS: Stent thrombosis
Stent thrombosis,* %[Steg 2010:K]
Ticagrelor (n=3752)
Clopidogrel (n=3792)
p value
Definite†
1.6
2.4
0.03
Probable or definite†
2.6
3.4
0.05
Possible, probable, or definite†
3.3
4.3
0.04
HR (95% CI)
A lower percentage of patients treated with ticagrelor experienced stent thrombosis compared with those treated with clopidogrel, regardless of how stent thrombosis was defined[Steg 2010:K,M]
There was also a 1.0% absolute reduction (25% relative) in the risk of all stent thromboses and a 0.8% absolute (34% relative) reduction in definite stent thrombosis[Steg 2010:K]
These results are broadly consistent with those observed in the overall PLATO population[Wallentin 2009:J]
Definite: 1.3 vs. 1.9% (HR [95% CI] = 0.67[0.50–0.91]; p=0.009)
Probable or definite: 2.2 vs. 2.9% (HR [95% CI] = 0.75[0.59–0.95]; p=0.02)
Possible, probable or definite: 2.9 vs. 3.8% (HR [95% CI] = 0.77[0.62–0.95]; p=0.01]
Academic Research Consortium definitions of stent thrombosis (also see back-up slide 23)[Cutlip 2007:A]
Definite stent thrombosis*
Angiographic confirmation of stent thrombosis†
The presence of a thrombus‡ that originates in the stent or in the segment 5 mm proximal or distal to the stent and presence of at least 1 of the following criteria within a 48-hour time window:
Acute onset of ischaemic symptoms at rest
New ischaemic ECG changes that suggest acute ischaemia
Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI)
Nonocclusive thrombus
Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) non-calcified filling defect or lucency surrounded by contrast material (on three sides or within a coronary stenosis) seen in multiple projections, or persistence of contrast material within the lumen, or a visible embolisation of intraluminal material downstream
Occlusive thrombus
TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most adjacent proximal side branch or main branch (if originates from the side branch)
Pathological confirmation of stent thrombosis
Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved following thrombectomy
Probable stent thrombosis
Clinical definition of probable stent thrombosis is considered to have occurred after intracoronary stenting in the following cases:
Any unexplained death within the first 30 days§
Irrespective of the time after the index procedure, any MI that is related to documented acute ischaemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
Possible stent thrombosis
Clinical definition of possible stent thrombosis is considered to have occurred with any unexplained death from 30 days after intracoronary stenting until end of trial follow-up
*Definite stent thrombosis is considered to have occurred by either angiographic or pathological confirmation
†The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is not considered a confirmed stent thrombosis (silent occlusion)
‡Intracoronary thrombus
§For studies with ST-elevation MI population, one may consider the exclusion of unexplained death within 30 days as evidence of probable stent thrombosis
Cutlip DE, et al. Circulation 2007;155:2344–2351.
Steg PG, et al. Circulation 2010;122:2131–2141.
Wallentin L, et al. N Engl J Med 2009;361:1045–1057.
1.0
*As per Academic Research Consortium definitions.[Cutlip 2007:A]
†Denominator is number of patients receiving at least one stent. ACS, acute coronary syndromes; CI, confidence interval; HR, hazard ratio; STE, ST-segment elevation.
Cutlip DE, et al. Circulation 2007;155:2344–2351; Steg PG, et al. Circulation 2010;122:2131–2141.
Ticagrelor better
Clopidogrel better

26. STEMI PCI PCI Planned No DAPT PPCI Prior DAPT CABG CABG Med Rx Med Rx
High Bleeding Risk
Or Other Concerns
Standard Clopidogrel Pathway
Yes
N o
Planned
PPCI
No DAPT
Prior DAPT
Load Prasugrel or Ticagrelor
if Rapidly Available
Load Ticagrelor
If Rapidly Available
Dx Catheterization
Dx Catheterization
CABG
PCI
Med Rx
CABG
PCI
Med Rx
No DAPT
Prasugrel*
Ticagrelor
Clopidogrel
Ticagrelor
Stop DAPT
Ticagrelor
Prasugrel* if no load
Clopidogrel
Ticagrelor
* Without Contraindication (STROKE/TIA)

27. Summary
Platelet P2Y12 inhibitors act by inhibiting platelet activation and aggregation
This results in reduction of myocardial infarction, stent thrombosis and increased bleeding
More intensive inhibition of P2Y12 intensifies these outcomes regardless of mechanism
Appropriate choice of patients allows for optimized clinical outcomes

28. Summary
Patients undergoing PRIMARY PCI for STEMI are a special population:
Rapid Care requiring rapid onset therapy
High Thrombotic Risk
Generally Lower Risk for Bleeding (Demographics)
These patients are well-suited for newer, more intensive, consistent therapies.

29. GO PATS!