1. OASIS-7
CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI
Shamir R. Mehta on behalf of the CURRENT Investigators
Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.

2. Background Clopidogrel
Clopidogrel 300 mg followed by 75 mg daily reduces major CV events across the spectrum of ACS and PCI
Recent data suggest that doubling the loading and maintenance doses of clopidogrel results in a higher and more rapid antiplatelet effect
Aspirin
Dose of ASA varies between Europe and North America
No large-scale RCT’s have compared high ( mg) versus low (75-100) dose aspirin in patients with ACS undergoing PCI

3. Relative Risk Reduction
Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI
Relative Risk Reduction
PCI
No PCI
CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI)
30%1
19%2
STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)
46%3
9%4
TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)
19%5
Not evaluated
1. Mehta SR, et al. Lancet 2001; 358(9281):
2. Fox KAA, et al. Circulation 2004;110:1202-8
3. Sabatine MS, et al. JAMA 2005; 294(10):
4. Chen ZM Lancet 2005;366:
4. Boersma E et al. Lancet 2002; 359:189
5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.

4. Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
Planned Early (<24 h) Invasive Management with intended PCI
Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose ( mg/d) vs Low dose ( mg/d)
Angio 24,769
(99%)
PCI 17,232
(70%)
No PCI 7,855 (30%)
No Sig. CAD 3,616
CABG 1,809
CAD 2,430
Compliance:
Clop in 1st 7d (median) 7d d d d
Efficacy Outcomes: CV Death, MI or stroke at day 30
Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)
Key Subgroup: PCI v No PCI
Complete Followup 99.8%

5. ASA Dose Comparison Primary Outcome and Bleedingmg mg HR
95% CI P
CV Death/MI/Stroke
PCI (2N=17,232)
4.2
4.1
0.98
0.76
No PCI (2N=7855)
4.7
4.4
0.92
0.44
Overall (2N=25,087)
0.96
0.47
Stent Thrombosis
2.1
1.9
0.91
0.37
TIMI Major Bleed
1.03
0.97
0.94
0.71
CURRENT Major Bleed
2.3
0.99
0.90
CURRENT Severe Bleed
1.7
1.00
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
No other significant differences between ASA dose groups

6. Clopidogrel Dose Comparison
2 Significant Interactions:
PCI v No PCI (P=0.016)
ASA dose (P=0.043)

7. Clopidogrel: Double vs Standard Dose Primary Outcome and ComponentsHR
95% CI P
Intn P
CV Death/MI/Stroke
PCI (2N=17,232)
4.5
3.9
0.85
0.036
0.016
No PCI (2N=7855)
4.2
4.9
1.17
0.14
Overall (2N=25,087)
4.4
0.95
0.370 MI
2.6
2.0
0.78
0.012
0.025
1.4
1.7
1.25
0.23
2.2
1.9
0.86
0.097
CV Death
0.96
0.68
1.0
2.8
2.7
0.77
2.1
0.628
Stroke
0.4
0.88
0.59
0.50
0.8
0.9
1.11
0.67
0.5
0.99
0.950

8. Clopidogrel Double vs Standard Dose Bleeding Overall Population
Hazard
Ratio
95% CI P
TIMI Major1
0.95
1.04
1.09
0.50
CURRENT Major2
2.0
2.5
1.25
0.01
CURRENT Severe3
1.5
1.9
1.23
0.03
Fatal
0.11
0.13
1.15
0.71
ICH
0.05
0.67
0.53
RBC transfusion ≥ 2U
1.76
2.21
1.26
CABG-related Major
0.9
1.0
1.10
0.48
1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

9. Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed)
Clopidogrel Standard Dose
0.012
42%
RRR
0.008
Cumulative Hazard
Clopidogrel Double Dose
0.004
HR 0.58
95% CI
P=0.001
0.0 3 6 9 12 15 18 21 24 27 30
Days

10. Clopidogrel: Double vs Standard Dose Major Efficacy Outcomes in PCI Patients
Day 30
Clopidogrel
StandardN=8684 %
Double N=8548
Hazard Ratio
95% CI
P value
Stent Thrombosis
2.3
1.6
0.71
0.002
Definite
1.2
0.7
0.58
0.001 MI
2.6
2.0
0.78
0.012
MI or stent thrombosis
3.7
3.0
0.80
0.008
CV Death
1.9
0.96
0.68
Stroke
0.4
0.88
0.59
CV Death/MI/Stroke
4.5
3.9
0.85
0.036

11. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
CV Death, MI or Stroke
Clopidogrel Standard
15% RRR
0.04
Clopidogrel Double
0.03
Cumulative Hazard
0.02
HR 0.85
95% CI
P=0.036
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

12. Clopidogrel Double vs Standard Dose Bleeding PCI Population
Hazard
Ratio
95% CI P
TIMI Major1
0.5
1.06
0.79
CURRENT Major2
1.1
1.6
1.44
0.006
CURRENT Severe3
0.8
1.39
0.034
Fatal
0.15
0.07
0.47
0.125
ICH
0.035
0.046
1.35
0.69
RBC transfusion ≥ 2U
0.91
1.49
0.007
CABG-related Major
0.1
1.69
0.31
1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

13. Clopidogrel: Double v Standard Dose PCI Cohort Subgroups
CV Death, MI or Stroke
MI or Stent Thrombosis 2N
Std %
Double %
Intxn P
Std %
Double %
Intxn P
Overall
17232
4.5
3.9
3.7
3.0
NSTEMI/UA
10886
4.2
3.6
3.6
3.1
0.805
0.248
STEMI
6346
5.0
4.2
4.0
2.8
Male
13009
4.1
3.6
3.5
3.0
0.419
0.148
Female
4223
5.8
4.6
4.6
3.0
Age <= 65 yrs
10975
3.0
2.7
2.9
2.2
0.702
0.418
Age > 65 yrs
6257
7.1
6.0
5.2
4.4
Non-Diabetic
13400
4.2
3.6
3.6
2.8
0.836
0.567
Prev Diabetic
3831
5.6
4.9
4.1
3.6
No Inhosp GPIIb/IIIa
12288
3.9
3.5
3.1
2.5
0.465
0.894
GPIIb in hosp
4936
6.0
4.7
5.2
4.1
No Prot Pump Inhib
7675
3.8
3.2
3.1
2.3
0.408
0.613
Prot Pump Inhib
5557
5.7
4.2
4.8
3.3
Non-smoker
10845
4.9
4.6
3.9
3.5
0.045
0.050
Current Smoker
6380
3.8
2.6
3.4
2.1
ASA Low
8620
4.2
4.3
3.6
3.2
0.024
0.191
ASA High
8612
4.8
3.5
3.8
2.7
Double Dose Better
Std Dose Better
Double Dose Better
Std Dose Better
0.50
1.50
0.50
1.50

14. Clopidogrel: Double vs Standard Dose by ASA FactorialHR
95% CI P
P int’n
Standard
Double
CV Death/MI/Stroke (Overall)
ASA High
4.6
3.8
0.83
0.036
0.043
ASA Low
4.2
4.5
1.07
0.42
MI/Stent Thrombosis (PCI pts)
2.7
0.71
0.005
0.19
3.6
3.2
0.89
0.32
Major Bleed (Overall)
2.2
2.4
1.08
0.51
0.099
1.9
1.43
0.003

15. 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

16. Conclusions Clopidogrel Dose Comparison
Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) in PCI.
In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG).
There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.

17. Conclusions ASA Dose Comparison
No significant difference in efficacy or bleeding between ASA mg and ASA mg.

18. Clinical Implications
For every 1,000 patients with ACS receiving PCI, using double-dose clopidogrel for 7 days instead of standard dose will prevent an additional 6 MI’s and 7 stent thromboses with an excess of 3 severe bleeds and no increase in fatal, CABG-related or TIMI major bleeds.
Patients not undergoing PCI should continue to use the standard dose regimen of clopidogrel.

19. Acknowledgements CURRENT Investigators from 597 sites in 39 countries
Steering Committee
Sponsors
Project Office
M. Blumenthal (Bristol-Myers Squibb)
C. Gaudin (Sanofi-Aventis)
C. Marchese (Sanofi- Aventis)
P. Hornick (Bristol-Myers Squibb)
S. Chrolavicius
S.R. Mehta
A. Robinson
B. Jedrzejowski
J. Pogue
R. Afzal
L. Blake
W. Chen
S. Di Diodato
M. Lawrence
R. Manojlovic
L. Mastrangelo
A. Mead
E. Pasadyn
T. Sovereign
L. Wasala
S. Yusuf (Chair)
D. Foley
P. Pais
S.R. Mehta (P.I.)
M.G. Franzosi
R.J.G. Peters
S. Chrolavicius
C.B. Granger
L. Piegas
A. Ajani
M. Gupta
J. Probstfield
A. Avezum
S. Jolly
J. Rankin
J.P. Bassand
C. Joyner
M. Ruda
W.E. Boden
N. Karatzas
Z. Rumboldt
A. Budaj
A. Kastrati
H.J. Rupprecht
E. Cardona
J.H. Kim
P.G. Steg
T.H. Koh
J-F. Tanguay
J. Col
F. Lanas
V. Valentin
P. Commerford
B. Lewis
J. Varigos
G. Di Pasquale
C. Macaya
H. White
R. Diaz
T. Moccetti
P. Widimsky
J. Eha
G. Montalescot
D. Xavier
J.W. Eikelboom
K. Niemela
J. Zhu
D.P. Faxon
Z. Ongen
J-R Zhu
M. Flather
A. Orlandini
DSMB
P. Sleight (Chair)
J.L. Anderson
D.L. DeMets
J. Hirsh
D.R. Holmes Jr
D.E. Johnstone
Adjudication Committee
C. Joyner (Chair)
M. Lawrence (Coordinator)
Consultant: R. Peto

20. Supplementary Slides

21. Comparison of CURRENT and TRITON
CURRENT PCI
N=17,232
TRITON
N=13,608
CV Death, MI or Stroke
↓ 15%
↓ 21% (w high dose ASA)
↓ 19%
Definite Stent Thrombosis
↓ 42%
↓ 51% (w high dose ASA)
↓ 58%
TIMI Major Bleed
No increase
↑ 32%
CABG-related Bleeding
↑ 4-fold
Fatal bleeding

22. Baseline Characteristics and In Hospital Meds
Meds After Rand
Age (y)
61.4
GP IIb/IIIa inhibitor
31.8
Female
27.4%
Statin
87.2
UA/NSTEMI
70.8%
Beta Blocker
82.5
Rand to Angio
3.4 h
ACE/ARB
75.7
STEMI
29.2%
PPI
40*
0.5 h
H2 Blocker
11.3
Diabetes
23.4
Prior Stroke
4.1
Ischemic ECG Δ
80.8
↑ Biomarker 42
Variables equally balanced among the randomized groups
*38.6% low dose ASA v 41.4% high dose ASA and 40% standard dose Clop v 40% high dose Clop

23. Clopidogrel: Double vs Standard Dose Primary Outcome
0.05
C Std, A Hi
C Double, A Lo
C Std, A Lo
0.04
C Double, A Hi
0.03
Cumulative Hazard
0.02
Clop Standard
Clop Double HR P
Intn
ASA mg
4.6
3.8
0.83
0.036
0.043
ASA mg
4.2
4.5
1.07
0.43
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days

24. Death/MI/Stroke at 30 days
ASA Dose Comparison
Death/MI/Stroke at 30 days
Days
Cumulative Hazard
0.0
0.01
0.02
0.03
0.04 3 6 9 12 15 18 21 24 27 30
HR 0.96 ( ) P = 0.489
ASA mg
ASA mg

25. ASA Dose Comparison Primary Outcome
Hazard P mg mg
Ratio
95% CI
value %
Primary Outcome
CV Death/MI/Stroke
4.4
4.2
0.96
0.489
Components
CV Death
2.3
2.0
0.88
0.134 MI
2.1
0.97
0.726
Stroke
0.5
0.6
1.18
0.330

26. ASA Dose Comparison Death at 30 days HR 0.86 (0.73-1.02) P = 0.077
0.025
0.015
Cumulative Hazard
HR 0.86 ( ) P = 0.077
0.005
ASA mg
ASA mg
0.0 3 6 9 12 15 18 21 24 27 30

27. Secondary Outcomes (ASA)
Hazard P
< 100 mg
> 300 mg
Ratio
95% CI
value %
CV Death/MI/Stroke + RI
4.8
4.5
0.93
0.206
Total Death
2.5
2.2
0.86
0.077
Stent Thrombosis
1.4
1.3
0.90
0.347
Definite
0.7
0.6
0.89
0.458
Probable
0.8
0.471

28. Major Bleeding at 30 Days (ASA)
Hazard P
< 100 mg
> 300 mg
Ratio
95% CI
value %
All Major Bleeding
2.3
0.99
0.904
Severe Bleeding
1.7
1.00
1.000
Other Major Bleeding
0.6
0.985
Minor Bleeding
4.4
4.9
1.12
0.059

29. ASA Dose Comparison Major Bleeding at 30 days
Cumulative Hazard
0.0
0.005
0.010
0.015
0.020 3 6 9 12 15 18 21 24 27 30
ASA < 100 mg
ASA > 300 mg
HR 0.99 ( ) P = 0.904

30. Details of Major Bleeding
ASA mg mg
No. of Major Bleeds
287
283
Fatal 16 15
Symptomatic ICH 5 6
Surgical Intervention 49 45
Significant hypotension (inotropes) 56 58
Hemoglobin drop > 5 g/dL
232
240
Transfusions
258
255

31. Sites of Major Bleeding
ASA mg mg
No. of Major Bleeds
287
283
Cardiac Tamponade 27 20
Surgical
115
107
Intracranial 6
Retroperitoneal 11 14
Gastrointestinal 30
47*
Puncture Site 40 46
*P=0.051

32. ASA Dose Comparison: Subgroupsmg mg
P interaction
Primary Composite
25087
4.4
4.2
NSTEMI
17757
4.2
3.9
STEMI
7321
4.8
5.0
0.446
Non-Diabetic
19196
4.0
3.8
Prev Diabetic
5870
5.6
5.6
0.585
GRACE <140
13394
3.0
2.8
GRACE >=140
3516
8.3
7.1
0.575
Age <= 65 yrs
15762
3.1
2.7
Age > 65 yrs
9316
6.6
6.8
0.145
No Prot Pump Inhib
15193
4.3
4.2
Prot Pump Inhib
3204
4.2
4.6
0.483
Weight >= 60kg
22504
4.1
4.1
Weight < 60kg
2358
5.7
4.7
0.339
Non-smoker
16688
4.9
4.7
Current Smoker
8369
3.3
3.1
0.977
No PCI
7855
4.7
4.4
With PCI
17232
4.2
4.1
0.724
0.4
0.7
1.0
1.3
1.6
1.9
HR (95% CI)