This document reports on Dr. Montalescot's research grants and consulting/lecture fees from various pharmaceutical companies. It discloses potential conflicts of interest from his relationships with ADIR, Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, and several other companies.

1. Dr. Montalescot reports research Grants to the Institution or Consulting/Lecture Fees from ADIR, Amgen,
AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess
Medical, Brigham Women’s Hospital, Cardiovascular Research Foundation, Celladon, CME Resources, Daiichi-
Sankyo, Eli-Lilly, Europa, Elsevier, Fédération Française de Cardiologie, Fondazione Anna Maria Sechi per il
Cuore, Gilead, ICAN, Janssen, Lead-Up, Menarini, Medtronic, MSD, Pfizer, Sanofi-Aventis, The Medicines
Company, TIMI Study Group, WebMD.

2. The definition
The term “pretreatment” refers to the initiation
of a treatment (P2Y12 inhibitor) either in the
ambulance, an emergency department, in the
coronary care unit, or in the catheterization
laboratory prior to the definition of coronary

3. A “concept” born with CURE…

4. CURE Efficacy
Yusuf S, et al. N Engl J Med 2001;345:494-502
When cath, 10 days waiting …
20% PCI
57% no cath…
N=12,562
N=2,658
0.020.040.060.08
5 10 15 20 25 30
Clopidogrel
Placebo
0.0
RR 0.70
95% CI 0.50-0.97
P=0.03
Days following PCI
CumulativeHazardRate
Mehta SR et al. Lancet 2001:358:527-33
1°EP: CV Death, MI, Urgent Revascularization

5. A “concept” invalidated with
clopidogrel !

7. A “concept” invalidated with
prasugrel !!

8. ACCOAST
Prasugrel 30 mg
Prasugrel 60 mgPrasugrel 30 mg
Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days
PCI
1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa inh. Bailout, at 7 days
Placebo
Coronary
Angiography
n~4100 (event driven)
Coronary
Angiography
PCI
CABG
or
Medical
Management
(no prasugrel)
CABG
or
Medical
Management
(no more prasugrel)
Montalescot G et al. Am Heart J 2011;161:650-656
Randomize 1:1
Double-blind
NSTEMI + Troponin ≥ 1.5 times ULN local lab value
Clopidogrel naive or on long term clopidogrel 75 mg
Randomization before angiography (mandatory)
The licensed loading dose of prasugrel is 60mg

9. Primary Efficacy and Safety Endpoints
(All Patients)
Days From First Dose
0 5 10 15 20 25 30
Endpoint(%)
0
5
10
15
No Pre-treatment
10.8
HR, 1.02
(95% 0.84, 1.25)
P=0.81
1996
2037
1788
1821
1775
1809
1769
1802
1762
1797
1752
1791
CV Death, MI, Stroke,
UR, GPIIb/IIIa Bailout Pre-treatment
10.8
1621
1616
No. at Risk, Primary
Efficacy End Point:
No pre-treatment
Pre-treatment
HR, 0.997
(95% 0.83, 1.20)
P=0.98
Pre-treatment
10.0
No Pre-treatment
9.8
Days From First Dose
0 5 10 15 20 25 30
Endpoint(%)
0
1
2
3
4
5
Pre-treatment
2.9
No Pre-treatment
1.5
HR, 1.97
(95% 1.26, 3.08)
P=0.002
All TIMI Major Bleeding
HR, 1.90
(95% 1.19, 3.02)
P=0.006
Pre-treatment
2.6
No Pre-treatment
1.4
1996
2037
1947
1972
1328
1339
1297
1310
1288
1299
1284
1297
1263
1280
No. at Risk, All TIMI
Major Bleeding:
No pre-treatment
Pre-treatment
Montalescot G et al. N Engl J Med.2013;369(11):999-1010

10. Timing? risk of waiting
Montalescot et al. N Engl J Med 2013;369:999–1010 Silvain et al. ACCOAST-timing, JACC 2018
1° endpoint

11. Studies of pretreatment with oral P2Y12
receptor inhibitors
Capodanno D & Angiolillo DJ. Circ Cardiovasc Interv 2015

12. Randomized studies only (All patients)
Bellemain-Appaix A et al. BMJ 2014

13. Real life of pre-treatment
ARIAM-Andalucia (M. Amendro-Delia et al)
N=9621

14. PRAGUE 18 study
n=1230, prasugrel vs ticagrelor
1° Endpoint
Death, MI, Stroke, urg revasc, MB @D7
Key 2° Endpoint
Death, MI, Stroke @D30
Motovska Z et al. Circ 2016

15. • Prasugrel and ticagrelor excluded (= Class I recommendations)
• PCI patients only (= post-hoc studies only)
• Mixing of STEMI and NSTE-ACS (= mixing of opposite situations)
• >90% of patients come from registries (= multiple biases)
• No loading in no pretreatment arm of some studies (= no treatment at all)

17. ISAR-REACT 5

18. A “concept” never tested with
ticagrelor (and cangrelor)….

19. Ticagrelor in NSTE-ACS: PLATO
All patients were
pretreated before
the angiogram…
Cath 74%
PCI 46%

20. A debate also in the guidelines!

21. SCAD Guidelines
NSTE-ACS Guidelines
DAPT Guidelines
A P2Y12 inhibitor is recommended, in addition to aspirin, for 12 months unless there are
contra-indications such as excessive risk of bleeds..
I A
It is not recommended to administer prasugrel in patients in whom coronary anatomy is not
known.
III B
Pretreatment with clopidogrel (when coronary anatomy is not known) is not recommended. III A
Revasc Guidelines
NSTE-ACS: It is recommended to give P2Y12 inhibitors at the time of first medical contact I B
Pretreatment with prasugrel in patients in whom coronary anatomy is not known, is not
recommended
III B
In patients with SCAD pre-treatment with clopidogrel may be considered if the probability of
PCI is high.
IIb C
Pre-treatment with a P2Y12 inhibitor is generally recommended in patients in whom coronary
anatomy is known and the decision to proceed to PCI is made as well as in patients with
STEMI
I A
In NSTE-ACS patients undergoing invasive management, ticagrelor or clopidogrel if ticagrelor
is not an option, should be considered as soon as the diagnosis is established.
IIa C
In NSTE-ACS patients it is not recommended to administer prasugrel in patients in whom
coronary anatomy is not known.
III B

23. Just apply the evidence and use the
right options

24. Lower platelet reactivity
(Verify Now)
300
250
200
150
100
50
0
Integral Crushed Chewed
1
Hours
Venetsanos D et al.
Thromb Res 2017;149:88–94
Asher E et al.
Thromb Haemost 2017
P2Y12 Reaction Units (PRU)
Rollini F et al.
JACC 2016
Ticagrelor Prasugrel
Crushed, chewed or orodispersible

25. CHAMPION-PHOENIX: IV P2Y12 inhibitor cangrelor
Death/ MI/ IDR/ Stent Thrombosis within 48 Hours
Bhatt DL et al. N Engl J Med 2013; 368: 1303-1313
cangrelor
clopidogrel
5.9%
4.7%
Log Rank P Value = 0.006
EventRate(%)
TIMI Major 48h 0.1% 0.1% >0.999
TIMI Minor 48h 0.2% 0.1% 0.08
Death 48h 0.3% 0.3% 0.99

26. Conclusions
 Bleeding risk increases with pretreatment
 Ischemic risk is not reduced with pretreatment
 No mortality effect with pretreatment
 Look first (at coronaries) and Treat (selectively)
 Do not Treat (routinely) to Watch complications
 Early start only justified if long wait (>48hrs) for cath or no cath
strategy
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