1. ACS/AMI: What is the Standard of Care for Antiplatelet Therapy in the USA?
George D. Dangas, MD, PhD
Professor of Medicine (Cardiovascular Disease)
The Icahn School of Medicine at Mount Sinai, New York, NY
Cardiovascular Research Technologies - CRT 2013
February 24, Washington, DC

2. George Dangas, MD Consulting: Astra Zeneca
Grant Support: SMS/Sanofi, The Medicines Co.
Advisory Board: Abbott Vascular, Ortho McNeil,
Regado Biosciences

3. Inhibitors of Platelet Activation
Clopidogrel/ticlopidine
ADP
Dipyridamole
P2Y12
PGI2
ADP
PDE Gi
P2X1
ADP Gs
ATP
Ca++ AC
cAMP
PIP2
Ca++
Collagen Thrombin TXA2 ??
GP IIb/IIIa
Receptor Gq
IP3
COX
Ca++
TP/
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TXA2
Aspirin
Schafer AI. Am J Med. 1996;101:199–209 & Schrör K. Vasc Med 1998;3:

4. Efficacy of New DAPT Rx: ACS+PCI
3 Active Controlled Trials (vs Standard Clop)
P<0.001
P=0.003
P=0.04
P=0.002
P<0.001
P=0.01
Def/Prob
NEJM 2007
Def/Prob
NEJM 2009
N=17,232
1-month FU
D/MI/CVA
ESC 2009
N=13,608
15-month FU
D/MI/CVA
NEJM 2007
N=11,289
1-year FU
D/MI/CVA
TCT 2009
Def/Prob
ESC 2009

5. Step-wise reloading increased % Inhibition and % responders
After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target.
Mean ±SD
Control
VASP-guided p
VASP after first LD, %
68 ±11
69 ±10
0.4
VASP after adjustment, % 
38 ±14*
*<0.001
Log rank p =0.007
MACE: CV death, MI, revascularization
Bonello et al. J Am Coll Cardiol 2008

6. Definite Stent Thrombosis in 4 Groups (Angiographically Proven)
C Standard, A Low
0.012
C Standard, A High
C Double, A Low
0.008
Cumulative Hazard
C Double, A High
0.004
Standard Clop
Double Clop HR P
Intn
High ASA
1.2
0.6
0.49
0.003
Low ASA
0.8
0.058
0.35
0.0 3 6 9 12 15 18 21 24 27 30
Days

7. PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel
IPA (%; 20 mM ADP)
IPA (%; 20 mM ADP)
P< for each
P<0.0001
N=201
Prasugrel 60 mg
Clopidogrel 600 mg
Clopidogrel 150 mg
Prasugrel 10 mg
Hours
14 Days
Wiviott et al Circ 2007 8 8

8. TIMI-38 STENT ANALYSIS Definite/Probable ST: BMS Only (N=6461)
EARLY ST
LATE ST
HR 0.45 [ ]
P=0.0009
HR 0.68 [ ]
P=0.24
CLOPIDOGREL
1.66%
PRASUGREL
% of Subjects
55%
0.78%
32%
0.75%
0.53%
DAYS
Wiviott et al, SCAI-ACCi2 2008 9

9. Inhibition of platelet aggregation after initial doses
AZD6140 Ticagrelor Inhibition of Platelet aggregation Compared With Clopidogrel in NSTEMI ACS Patients (DISPERSE-2)
Inhibition of platelet aggregation after initial doses
*P<0.05
Mean % inhibition of platelet aggregation derived from maximum aggregation response after addition of ADP 20 mol/l (optical aggregometry).
Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6

10. 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

11. Optimal Duration of Anti-platelet Therapy Post DES Still Unclear
ESC PCI
Updated Guidelines
2010
Cypher Stent®
Launch
2003
CURE (PCI-CURE)
20011
(6-12 months post PCI)
1 year
BMS Era
DES Era
FDA, ACC/AHA/SCAI Recommendations
2011
(1 year post PCI in pts at low risk of bleeding
AHA/ACC
Guidelines
2001
TAXUS®
Express2TM Stent
Launch
2004
AHA/ACC/SCAI
Updated Guidelines
2005
(9-12 months post PCI)
(TAXUS stent 6 months post PCI)
(Cypher stent 3 months post PCI)

12. Safety of New DAPT Regimens
3 Active Controlled Trials (vs Standard Clop)
P<0.001
P=0.32
Non-CABG related bleeding
P=0.001
P=0.002
P=0.03
N=25,087
1-month FU
CURRENT
major bleed
NEJM 2009
N=13,608
15-month FU
TIMI major+minor
bleed
NEJM 2007
N=18,864
12-month FU
PLATO
Major bleed
NEJM 2009
TIMI major+minor
bleed
NEJM 2007
PLATO
Major bleed
NEJM 2009

13. Challenging the guidelines
One-year dual antiplatelet therapy is:
Too long!
Not long enough!

14. What is the ‘Optimal’ Trial for the ‘Optimal’ DAPT Duration
What is the ‘Optimal’ Trial for the ‘Optimal’ DAPT Duration? DAPT durations, inclusion of BMS, landmarking and ‘event-free’ patients
Inclusion Group, N
DAPT Duration
DES Type
1° Endpoint
2° Endpoint(s)
DAPT
20, month event free
12 vs 30 months
All DES, BMS
D/MI/Stroke at 33 mos
Def/prob ST at 33 mos
GUSTO Bleeding
ISAR-SAFE
6, month event free
6 vs 12 months
All DES
D/MI/Stroke/TIMI major bleed at 15 mos
Individual component endpoints
REAL-LATE
2, month event free
12 vs 24 months
2-yr Cardiac D/MI
ARC ST, Bleeding
ZEST-LATE
SES, PES, ZES
2-yr D/MI
OPTIMIZE
3, non-STEMI
3 vs. 12 months
Endeavor ZES
1-yr D/MI/Stroke/TIMI major bleed
ARC ST
SEASIDE
900 non-ACS
6 months
1-yr D/MI/Stroke
CYP2C19

15. Dual Antiplatelet Therapy (DAPT) Study
12 mo
18 mo
DES n=15,245
BMS n=5400
All patients on
aspirin + open-label
thienopyridine
therapy for
12 months
50% of patients continue on
dual antiplatelet therapy
(clopidogrel or prasugrel)
50% of patients receive
aspirin + placebo
1:1 Randomization
at month 12
Total 33-month patient evaluation including additional 3-month follow-up
PI: Laura Mauri, Co-PI: Dean Kereiakes 16

16. Should we consider shorter Duration of DAPT with new generation DES?

17. Impact of the Everolimus-Eluting Drug Eluting Stent on Stent Thrombosis: A Meta-Analysis of 13 Randomized Trials involving 17,097 Patients
Usman Baber MD MS, et al
aMount Sinai Medical Center, New York, NY bKaiser Permanente, Pasadena, CA cCardiovascular Research Foundation, New York, NY dSeoul National University Hospital, Seoul, Korea eAsan Medical Center, Seoul, Korea fDeutsches Herzzentrum, Technische Universität, Munich, Germany 18

18. Stent Thrombosis

19. PRODIGY Study Flow Chart
Intent-to-stent
1:1:1:1
Balancing
Randomization
Xience V®
Taxus®
Endeavor®
BMS
High Late Loss
Inhibition
Moderate Late Loss
Inhibition
Mild Late Loss
Inhibition
No late Loss
Inhibition
30-Days
2° Gen
1° Gen
2° Gen
1:1
1° Endpoint Randomization
Short
DAPT
Prologned
DAPT
Aspirin
Clopidogrel
Aspirin
Clopidogrel
6 mos
6 mos
6 mos
6 Mos*
12 mos
12 mos
12 mos
18 mos
18 mos
18 mos
24 mos
24 mos
Valgimigli et al, 2011
24 Mos
*: <6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI

20. Overall Death, MI or CVA Primary Endpoint CEC adjudicated 24 mo DAPT
10.1
10.0
P=0.91 %
Hazard Ratio: 0.98 ( )
No. at Risk
24-Month Clopidogrel
6-Month Clopidogrel

21. Type II, III or V BARC bleeding
Key Safety Endpoint
Type II, III or V BARC bleeding
CEC adjudicated
24 mo DAPT
6 mo DAPT P=
7.4 %
3.5
Hazard Ratio: 0.46 ( )
No. at Risk
24-Month Clopidogrel
6-Month Clopidogrel

22. Most recent data: RESET Trial
2,148 patients enrolled and randomized
E-ZES + 3-month DAPT
Standard Therapy:
Other DES with 12-month DAPT
E-ZES + 3-month DAPT (n=1059)
Standard therapy (n=1058)
Diabetes mellitus
subset (N=292)
Acute coronary syndrome
subset (N=601)
Short-length DES
Subset (N=681)
Long-length DES
Subset (N=543)
E-ZES
(n=301)
R-ZES
(n=300)
E-ZES
(n=341)
SES
(n=340)
E-ZES
(n=271)
E-ZES
(n=146)
R-ZES
(n=146)

23. (Cardiovascular Death, MI, ST, TVR, or bleeding at 1 year)
Primary Endpoint
(Cardiovascular Death, MI, ST, TVR, or bleeding at 1 year) 8
Standard therapy
E-ZES + 3-month DAPT 6
Difference = 0.0%
95% CI, -2.5 to 2.5; p = 0.84
4.7%
Cumulative event rate (%) 4
4.7%
p-value for non-inferiority < 0.01 2 6 12
Months

24. In ACS/AMI, the DAPT Stardard of Care in the US
2nd Generation DES
(ZES, EES)
With or without potent antiplatelet agents (prasugrel, ticagrelor)
Short term DAPT
Favors the stronger antiplatelet agents/regimens
Is Closely related to type of stent & adherence