G Montalescot, L Bolognese, D Dudek, P Goldstein, C Hamm, JF Tanguay,

JM ten Berg, DL Miller, TM Costigan, J Goedicke, J Silvain, P Angioli,

J Legutko, M Niethammer, Z Motovska, JA Jakubowski, G Cayla,
LO Visconti, E Vicaut, P Widimsky for the ACCOAST investigators

COI DISCLOSURE FOR DR. MONTALESCOT are availalble @ http://www.action-coeur.org

Trial Conduct

Trial conduct
-

Coordinating Center: ACTION Study Group - Institute of Cardiology

Piti-Salptrire University Hospital, Paris, France

Sponsors: Daiichi-Sankyo Company, Ltd. and Eli Lilly and Company

Global Trial Operations: ICON Clinical Research and Quintiles

(site management), Inventiv (data management and statistical services),
Tata Consultancy Services (statistical programming)

External Academic Statistical Center : ACTION Study Group

Executive Committee: G Montalescot (Chairman), L Bolognese, D Dudek,

P Goldstein, C Hamm, JF Tanguay, J ten Berg, P Widimsky

Endpoint Adjudication Committee: M Flather (Chairman), A Bardaj,

A Baumbach, M Dalby, A Kapur, F Philippe, P Sabouret, AF van den Heuvel,
A Zaman

Data Safety Monitoring Board: M Bertrand (Chairman), C Di Mario, E Vicaut

Enrollment:
>4,000 patients in 19 Countries
Poland: 847
Sweden: 4

Canada: 146
Netherlands: 142
Belgium: 81
Portugal: 17
Germany: 529
France: 586
Czech Rep: 292
Austria: 172
Italy: 628

Finland: 42

Latvia: 5
Lithuania: 73
Slovakia: 47
Hungary: 134
Romania: 85
Turkey: 112
Israel: 131

Background

CURE Efficacy

CREDO Efficacy

CURE Safety*

CREDO Safety**

Yusuf S, et al. N Engl J Med 2001;345:494-502

Steinhubl SR, et al. JAMA 2002;288:2411-2420

P2Y12 Pre-treatment ESC Recommendations

Title

Citation

2011 ESC guidelines for the

management of acute coronary
syndromes in patients
presenting without persistent
ST-segment elevation

European Heart Journal

2011;32:29993054

2010 ESC/EACTS guidelines on

myocardial revascularization

European Heart Journal

2010;31:20:25012555

A P2Y12 inhibitor as
soon as possible
Clopidogrel 600mg
Ticagrelor
Clopidogrel 600mg
as soon as possible

Class

LOE

I
I

B
B

Death

Randomized CT

1/204
1/164
13/933
18/1053
32/1313
0/103
1/513
66/4283

0/205
4/171
24/930
24/1063
31/1345
2/96
0/515
85/4325

Rela=ve
Weight [%]
303 [012-7480] 10%
026 [003-232] 22%
053 [027-105] 232%
075 [041-140] 283%
106 [064-175] 431%
018 [001-385] 12%
302 [012-7425] 10%
080 [057-111] 100%

105/3511
114/5087
219/8598

49/1515
14/832
63/2347

092 [065-130]
134 [077-234]
104 [074-146]

682%
318%
100%

13/923
209/4879
12/217
18/467
6/1481
76/4477
334/12444

19/990
110/1076
6/166
18/574
18/2679
12/332
183/5817

073 [036-149]
039 [031-050]
156 [057-425]
124 [064-241]
060 [024-152]
046 [025-086]
068 [042-109]

162%
240%
119%
170%
129%
178%
100%

Events / Size, Clopidogrel

Pretreatment No Pretreat

ARMYDA5 Preload
CIPAMI
CLARITY PCI
CREDO
PCI CURE
Davlouros et al.
PRAGUE 8
All N=8,608

OR [CI 95%]

OR=080 CI 95% [057-111] P=017

Observa2onal from RCT

ACUITY PCI
REPLACE 2
All N=10,945
OR=104 CI 95% [074-146] P=083

Observa2onal

Amin et al.
Dorler et al.
Fefer et al.
Feldman et al.
Szuk et al.
Chan et al.
All
N=18,261
OR=068 CI 95% [042-109] P=011
Pre-treatment better
0

No Pre-treatment better
0,5

1,5

2,5

3,5

Bellemain-Appaix A et al. JAMA 2012;308:2507-2516

 Pre-treatment with aspirin and a P2Y12 antagonist

has been a class I recommendation and common
practice for the treatment of NSTE-ACS
However, no trial has ever randomized patients
presenting with NSTE-ACS, invasively managed,
to pre-treatment with clopidogrel, prasugrel or
ticagrelor vs. no pre-treatment.

Study Design

ACCOAST design
NSTEMI + Troponin 1.5 times ULN local lab value
Clopidogrel naive or on long term clopidogrel 75 mg
n~4100 (event driven)

Randomize 1:1
Double-blind

CABG
or
Medical
Management
(no more prasugrel)

Prasugrel 30 mg

Placebo

Coronary
Angiography

Coronary
Angiography

Prasugrel 30 mg

Prasugrel 60 mg

PCI

PCI

CABG
or
Medical
Management
(no prasugrel)

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days
Montalescot G et al. Am Heart J 2011;161:650-656

Main Inclusion/Exclusion Criteria

Inclusion
NSTEMI symptoms within 48 hours prior to study entry
Elevated troponin (1.5 times ULN) per local lab(s)
Patient to be scheduled for coronary angiography and PCI within 2 hours to
24 hours of randomization and no later than 48 hours after randomization
Exclusion
STEMI patients
Medical history contraindicating therapy with prasugrel
History of stroke or transient ischemic attack (TIA)
LD of any P2Y12 antagonist 7 days of study entry
Montalescot G et al. Am Heart J 2011;161:650-656

Patient Disposition
Total Randomized
N=4038
5 Subjects Revoked Consent

ITT and All Treated

N= 4033

Pre-treatment
N=2037

No Pre-treatment
N=1996

Day 7
N=2009 (98.6%)

Day 7
N=1964 (98.4%)

Day 30 Visit
N=1958 (96.1%)

Day 30 Visit
N=1924 (96.4%)

Lost to Follow-up 1 (0.05)

Lost to Follow-up 2 (0.10)

Baseline Characteristics

Characteristics
Age (mean, yrs)
Female sex (%)
Weight (mean, kg)
BMI 30 (%)
CV risk factors (%)
Diabetes mellitus
Dyslipidemia
Hypertension
Current smoker
Region of enrolment (%)
Eastern Europe/Israel
Western Europe/Canada

Pre-treatment
(N =2037)
64
27
82
29

20
45
63
34

42
58

No Pre-treatment
(N =1996)
64
28.0
82
28

20
45
61
33

42
58

Baseline Characteristics

Characteristics
GRACE score (%)
<140
140
CRUSADE score (median)

Pre-treatment
(N =2037)

No Pre-treatment
(N =1996)

76
24
34

78
22
34

14.6
4.4

15.2
4.2

57
43

57
43

Timing (hr)
Symptom onset to 1st LD, median
1st LD to coronary angiogram, median
Access (%)
Femoral
Radial

Results

Pharmacodynamic Sub-Study

350

Placebo
LD1

Pre-treatment (30/30)
No Pre-treatment (0/60)

60 mg
LD2

*P<0.05

P2Y12 Reaction Units

300
250
Approximate
time of PCI

200
150
100

30 mg
LD1

*
*

50
0

30 mg
LD2

Pre LD1 Pre LD2

(baseline)

0.5

Hours (post LD2)

Data presented as median SEM. * p<0.05 relative to the No pre-treatment group. LD = loading dose.
Pretreatment=Prasugrel 30 mg/Prasugrel 30 mg; No Pre-treatment=Placebo/Prasugrel 60 mg

24

1 Efficacy End Point @ 7 + 30 days

(All Patients)
15

CV Death, MI, Stroke,

UR, GPIIb/IIIa Bailout
Pre-treatment
10.8

Endpoint (%)

Pre-treatment
10.0
10

No Pre-treatment
10.8
No Pre-treatment
9.8

Hazard Ratio, 1.02

(95% 0.84, 1.25)
P=0.81

Hazard Ratio, 0.997

(95% 0.83, 1.20)
P=0.98

0
0
No. at Risk, Primary
Efficacy End Point:
No pre-treatment
Pre-treatment

10

15

20

25

30

1752
1791

1621
1616

Days From First Dose

1996
2037

1788
1821

1775
1809

1769
1802

1762
1797

1 Efficacy Endpoint
(PCI Patients)
20

Endpoint (%)

15

Pre-treatment
13.1

CV Death, MI, Stroke,

UR, GPIIb/IIIa Bailout
PCI Cohort

No Pre-treatment
13.8

No Pre-treatment
13.1

10

Pre-treatment
14.1

HR, 1.03
(95% 0.84, 1.26)
P=0.77

HR, 1.01
(95% 0.82, 1.24)
P=0.93

0
0
No. at Risk, Efficacy
End Point:
No pre-treatment
Pre-treatment

10

15

20

25

30

1177
1186

1177
1172

Days From First Dose

1372
1389

1191
1206

1187
1202

1183
1194

1179
1189

1 Efficacy Endpoint Through 7 Days for

Prespecified Subgroups (All Patients)
Total
Patients

Pre-tx
n (%)

No Pre-tx
n (%)

Hazard Ratio
(95% CI)

4033

203 (9.97)

195 (9.77)

1.02 (0.84, 1.25)

PCI
CABG
Medical Management

2781
238
1014

185 (13.21)
9 (7.44)
9 (1.74)

181 (13.11)
8 (6.84)
6 (1.20)

1.01 (0.83, 1.25)

1.08 (0.42, 2.79)
1.45 (0.52, 4.09)

0.54

<75 years
>75 years

3318
715

160 (9.62)
43 (11.53)

162 (9.79)
33 (9.65)

0.99 (0.79, 1.23)

1.20 (0.76, 1.88)

0.45

2923
1110

152 (10.24)
51 (9.24)

149 (10.36)
46 (8.24)

0.99 (0.79, 1.24)

1.14 (0.76, 1.70)

0.54

205
3824

7 (6.80)
195 (10.09)

12 (11.76)
183 (9.68)

0.56 (0.22, 1.43)

1.05 (0.86, 1.28)

0.20

820
3213

46 (11.14)
157 (9.67)

37 (9.09)
158 (9.94)

1.25 (0.81, 1.93)

0.97 (0.78, 1.21)

0.30

232
3801

11 (9.82)
192 (9.97)

13 (10.83)
182 (9.70)

0.91 (0.41, 2.03)

1.03 (0.84, 1.26)

0.76

1990
2008

84 (8.24)
119 (11.91)

105 (10.82)
90 (8.92)

0.76 (0.57, 1.01)

1.36 (1.03, 1.78)

0.004

1998
2003

120 (12.07)
82 (8.02)

109 (10.86)
86 (8.77)

1.13 (0.87, 1.46)

0.91 (0.67, 1.23)

0.30

3079
852

154 (10.05)
44 (9.73)

143 (9.24)
47 (11.75)

1.09 (0.87, 1.37)

0.82 (0.55, 1.24)

0.24

2276
1711

125 (10.96)
76 (8.75)

111 (9.77)
83 (9.86)

1.14 (0.88, 1.47)

0.88 (0.64, 1.20)

0.21

1692
2341

66 (7.65)
137 (11.67)

63 (7.60)
132 (11.31)

Overall (pre-treatment vs. no pre-treatment)

Age
Sex

Male
Female
Weight
<60 kg
>60 kg
Diabetes
Yes
No
Prior clopidogrel treatment
Yes
No
Time from Sx to LD
<median
>median
Time from first LD to angio/PCI
<median
>median
GRACE score
<140
>140
Access
Femoral
Radial
Region
Eastern Europe/Israel
Western Europe/Canada
0.1

0.2

0.5

Pre-treatment better

No pre-treatment better

*Hazard ratio not evaluated for <10 events.

Interaction p-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup
interaction as fixed effects; PCI includes 11 patients with PCI + CABG.

Interaction
P-value

1.02 (0.72, 1.43) 0.93

1.03 (0.81, 1.31)

All TIMI (CABG or non-CABG) Major Bleeding

(All Treated patients)
5

Hazard Ratio, 1.90

(95% 1.19, 3.02)
P=0.006

Hazard Ratio, 1.97

(95% 1.26, 3.08)
P=0.002

Endpoint (%)

Pre-treatment
2.9

Pre-treatment
2.6

All TIMI Major Bleeding

1
No Pre-treatment

1.5

No Pre-treatment
1.4
0

No. at Risk, All TIMI

Major Bleeding:
No pre-treatment
Pre-treatment

10

15

20

25

30

1284
1297

1263
1280

Days From First Dose

1996
2037

1947
1972

1328
1339

1297
1310

1288
1299

TIMI, GUSTO, STEEPLE Bleeding Endpoints

Through 7 Days (All Treated Patients)

Event Rate (%)

Pre-treatment (N=2037)
No Pre-treatment (N=1996)

4
P<0.001

2,3

P=0.003

1,3

P=0.001

1,0
0,5

N=

27

Non-CABG TIMI Major Bleeding

0,9
0,2

20

GUSTO Severe or Life Threatening

Non-CABG Bleeding

46

18

STEEPLE Non-CABG Major

All TIMI Major Bleeding

(PCI Patients)
5

Endpoint (%)

3
HR, 2.69
(95% 1.13, 6.40)
P=0.02

All TIMI Major Bleeding

PCI Cohort

HR, 2.65
(95% 1.23, 5.70)
P=0.010

Pre-treatment
1.4

Pre-treatment
1.7

No Pre-treatment
0.5

No Pre-treatment
0.7

0
0
No. at Risk, All TIMI
Major Bleeding:
No pre-treatment
Pre-treatment

10

15

20

25

30

1268
1280

1249
1269

Days From First Dose

1372
1389

1356
1364

1302
1314

1280
1293

1272
1282

All TIMI Major Bleeding for Prespecified

Subgroups Through 7 days (All Treated Patients)

Total
Patients

Pre-tx
(%)

No Pre-tx
(%)

Overall (pre-treatment vs. no pre-treatment)

Age
Sex

Hazard Ratio Interaction

(95% CI)
P-value

4033

52 (2.55)

27 (1.35)

1.90 (1.19, 3.02)

PCI
CABG
Medical Management*

2781
238
1014

22 (1.57) 11 (0.80)
25 (20.66) 16 (13.68)
5 (0.97)
0 (0.00)

1.98 (0.96, 4.09)

1.59 (0.85, 2.98)
NE

0.74

<75 years
>75 years

3318
715

36 (2.16)
16 (4.29)

22 (1.33)
5 (1.46)

1.64 (0.96, 2.78)

2.95 (1.08, 8.05)

0.31

2923
1110

31 (2.09)
21 (3.80)

21 (1.46)
6 (1.08)

1.43 (0.82, 2.49)

3.61 (1.46, 8.95)

0.09

205
3824

5 (4.85)
47 (2.43)

1 (0.98)
26 (1.37)

NE
1.78 (1.10, 2.87)

0.35

820
3213

6 (1.45)
46 (2.83)

6 (1.47)
21 (1.32)

0.98 (0.32, 3.05)

2.16 (1.29, 3.62)

0.22

1990
2008

28 (2.75)
24 (2.40)

18 (1.86)
9 (0.89)

1.50 (0.83, 2.71)

2.70 (1.25, 5.80)

0.23

1998
2003

27 (2.72)
24 (2.35)

12 (1.20)
15 (1.53)

2.28 (1.16, 4.51)

1.54 (0.81, 2.93)

0.41

2051
1789

23 (2.23)
27 (2.97)

10 (0.98) 2.29 (1.09, 4.81)

15 (1.71) 1.75 (0.93, 3.28)

0.59

3079
852

34 (2.22)
16 (3.54)

18 (1.16)
8 (2.00)

1.92 (1.09, 3.41)

1.76 (0.75, 4.12)

0.87

2276
1711

29 (2.54)
22 (2.53)

18 (1.58)
8 (0.95)

1.62 (0.90, 2.91)

2.67 (1.19, 6.00)

0.66

1692
2341

14 (1.62)
38 (3.24)

5 (0.60)
22 (1.89)

2.69 (0.97, 7.47)

1.74 (1.03, 2.94)

0.46

Male
Female
Weight
<60 kg*
>60 kg
Diabetes
Yes
No
Time from Sx to LD
<median
>median
Time from first LD to angio/PCI
<median
>median
CRUSADE score
<median
>median
GRACE score
<140
>140
Access
Femoral
Radial
Region
Eastern Europe/Israel
Western Europe/Canada
0.2

0.5

Pre-treatment better

10

15

No pre-treatment better

*Hazard ratio not evaluated for <10 events.

Interaction p-value is from a Cox proportional hazards model with treatment, subgroup, and the treatment-by-subgroup interaction as fixed
effects; CRUSADE score is a post-hoc analysis; PCI includes 11 patients with PCI + CABG.

Non-CABG TIMI Major Bleeding Endpoints

Through 7 Days (All Treated Patients)

3,0

Event Rate (%)

2,5

Pre-treatment (N=2037)

Most Frequent Locations of Major Bleed

No Pre-treatment (N=1996)

2,0
P=0.003

1,5

1,33
P=0.002

1,0

0,83
P not evaluable

0,45

0,5

0,05

0
0,15

0,0

N=

27

Non-CABG TIMI Major Bleeding

Fatal Bleeding

17

Life Threatening Bleeding

Conclusions

Conclusions
In NSTE-ACS patients managed invasively within 48
hours of admission, pre-treatment with prasugrel does
not reduce major ischemic events through 30 days but
increases major bleeding complications.
The results are consistent among patients undergoing
PCI supporting treatment with prasugrel once the
coronary anatomy has been defined.
No subgroup appears to have a favorable risk/benefit
ratio of pre-treatment.
Reappraisal of routine pre-treatment strategies in NSTEACS is needed.

Thank you to all inves=gators in 19

countries, at 171 Centers

Slides available at www.action-coeur.org