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.
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 (300-325 mg)
versus low (75-100) dose aspirin in patients with ACS
undergoing PCI
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):527-33.
2. Fox KAA, et al. Circulation 2004;110:1202-8
3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.
4. Chen ZM Lancet 2005;366:1607-21
4. Boersma E et al. Lancet 2002; 359:189
5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.
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 (300-325 mg/d) vs Low dose (75-100 mg/d)
PCI 17,232
(70%)
Compliance:
Clop in 1st 7d (median) 7d
Efficacy Outcomes:
Safety Outcomes:
Key Subgroup:
Angio 24,769
(99%)
No Sig. CAD 3,616
7d
No PCI 7,855 (30%)
CABG 1,809
2d
CV Death, MI or stroke at day 30
Stent Thrombosis at day 30
Bleeding (CURRENT defined Major/Severe and TIMI Major)
PCI v No PCI
CAD 2,430
7d
Complete
Followup
99.8%
ASA Dose Comparison
Primary Outcome and Bleeding
ASA
ASA
HR
95% CI
P
75-100 mg
300-325 mg
PCI (2N=17,232)
4.2
4.1
0.98
0.84-1.13
0.76
No PCI (2N=7855)
4.7
4.4
0.92
0.75-1.14
0.44
Overall (2N=25,087)
4.4
4.2
0.96
0.85-1.08
0.47
Stent Thrombosis
2.1
1.9
0.91
0.73-1.12
0.37
TIMI Major Bleed
1.03
0.97
0.94
0.73-1.21
0.71
CURRENT Major Bleed
2.3
2.3
0.99
0.84-1.17
0.90
CURRENT Severe Bleed
1.7
1.7
1.00
0.83-1.21
1.00
CV Death/MI/Stroke
GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051
No other significant differences between ASA dose groups
Clopidogrel Dose Comparison
2 Significant Interactions:
1. PCI v No PCI (P=0.016)
2. ASA dose (P=0.043)
Clopidogrel: Double vs Standard Dose
Primary Outcome and Components
Standard
Double
HR
95% CI
P
PCI (2N=17,232)
4.5
3.9
0.85
0.74-0.99
0.036
No PCI (2N=7855)
4.2
4.9
1.17
0.95-1.44
0.14
Overall (2N=25,087)
4.4
4.2
0.95
0.84-1.07
0.370
PCI (2N=17,232)
2.6
2.0
0.78
0.64-0.95
0.012
No PCI (2N=7855)
1.4
1.7
1.25
0.87-1.79
0.23
Overall (2N=25,087)
2.2
1.9
0.86
0.73-1.03
0.097
PCI (2N=17,232)
1.9
1.9
0.96
0.77-1.19
0.68
No PCI (2N=7855)
2.8
2.7
0.96
0.74-1.26
0.77
Overall (2N=25,087)
2.2
2.1
0.96
0.81-1.14
0.628
PCI (2N=17,232)
0.4
0.4
0.88
0.55-1.41
0.59
No PCI (2N=7855)
0.8
0.9
1.11
0.68-1.82
0.67
Overall (2N=25,087)
0.5
0.5
0.99
0.70-1.39
0.950
Intn P
CV Death/MI/Stroke
0.016
MI
0.025
CV Death
1.0
Stroke
0.50
Clopidogrel Double vs Standard Dose
Bleeding Overall Population
Clopidogrel
Standard Double
Hazard
95% CI
P
N=12579
N=12508
Ratio
TIMI Major1
0.95
1.04
1.09
0.85-1.40
0.50
CURRENT Major2
2.0
2.5
1.25
1.05-1.47
0.01
CURRENT Severe3
1.5
1.9
1.23
1.02-1.49
0.03
Fatal
0.11
0.13
1.15
0.56-2.35
0.71
ICH
0.05
0.03
0.67
0.19-2.37
0.53
RBC transfusion ≥ 2U
1.76
2.21
1.26
1.06-1.51
0.01
CABG-related Major
0.9
1.0
1.10
0.85-1.42
0.48
Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
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
1ICH,
2Severe
Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed)
0.008
42%
RRR
0.004
Clopidogrel Double Dose
HR 0.58
95% CI 0.42-0.79
P=0.001
0.0
Cumulative Hazard
0.012
Clopidogrel Standard Dose
0
3
6
9
12
15
Days
18
21
24
27
30
Clopidogrel: Double vs Standard Dose
Major Efficacy Outcomes in PCI Patients
Day 30
Clopidogrel
Standard
N=8684
Double Hazard
N=8548 Ratio
95% CI
P
value
%
%
2.3
1.6
0.71
0.57-0.89
0.002
1.2
0.7
0.58
0.42-0.79
0.001
MI
2.6
2.0
0.78
0.64-0.95
0.012
MI or stent thrombosis
3.7
3.0
0.80
0.68-0.94
0.008
CV Death
1.9
1.9
0.96
0.77-1.19
0.68
Stroke
0.4
0.4
0.88
0.55-1.41
0.59
CV Death/MI/Stroke
4.5
3.9
0.85
0.74-0.99
0.036
Stent Thrombosis
Definite
Clopidogrel: Double vs Standard Dose
Primary Outcome: PCI Patients
CV Death, MI or Stroke
Clopidogrel Standard
0.02
0.03
Clopidogrel Double
0.01
HR 0.85
95% CI 0.74-0.99
P=0.036
0.0
Cumulative Hazard
0.04
15% RRR
0
3
6
9
12
15
Days
18
21
24
27
30
Clopidogrel Double vs Standard Dose
Bleeding PCI Population
Clopidogrel
Standard Double
Hazard
95% CI
P
N= 8684
N=8548
Ratio
TIMI Major1
0.5
0.5
1.06
0.70-1.61
0.79
CURRENT Major2
1.1
1.6
1.44
1.11-1.86
0.006
CURRENT Severe3
0.8
1.1
1.39
1.02-1.90
0.034
Fatal
0.15
0.07
0.47
0.18-1.23
0.125
ICH
0.035
0.046
1.35
0.30-6.04
0.69
RBC transfusion ≥ 2U
0.91
1.35
1.49
1.11-1.98
0.007
CABG-related Major
0.1
0.1
1.69
0.61-4.7
0.31
Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
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
1ICH,
2Severe
Clopidogrel: Double v Standard Dose
PCI Cohort Subgroups
CV Death, MI or Stroke
2N
Std %
Double %
Intxn P
MI or Stent Thrombosis
Std %
Double %
3.7
3.0
Intxn P
Overall
17232
4.5
3.9
NSTEMI/UA
STEMI
10886
6346
4.2
5.0
3.6
4.2
0.805
3.6
4.0
3.1
2.8
0.248
Male
Female
13009
4223
4.1
5.8
3.6
4.6
0.419
3.5
4.6
3.0
3.0
0.148
Age <= 65 yrs
Age > 65 yrs
10975
6257
3.0
7.1
2.7
6.0
0.702
2.9
5.2
2.2
4.4
0.418
Non-Diabetic
Prev Diabetic
13400
3831
4.2
5.6
3.6
4.9
0.836
3.6
4.1
2.8
3.6
0.567
No Inhosp GPIIb/IIIa
GPIIb in hosp
12288
4936
3.9
6.0
3.5
4.7
0.465
3.1
5.2
2.5
4.1
0.894
No Prot Pump Inhib
Prot Pump Inhib
7675
5557
3.8
5.7
3.2
4.2
0.408
3.1
4.8
2.3
3.3
0.613
10845
6380
4.9
3.8
4.6
2.6
0.045
3.9
3.4
3.5
2.1
0.050
8620
8612
4.2
4.8
4.3
3.5
0.024
3.6
3.8
3.2
2.7
0.191
Non-smoker
Current Smoker
ASA Low
ASA High
Double Dose
Better
0.50
1.50
Std Dose
Better
Double Dose
0.50
Better
Std Dose
1.50 Better
Clopidogrel: Double vs Standard Dose
by ASA Factorial
Clopidogrel
Standard
HR
95% CI
P
P int’n
Double
CV Death/MI/Stroke (Overall)
ASA High
4.6
3.8
0.83
0.70-0.99
0.036
ASA Low
4.2
4.5
1.07
0.91-1.27
0.42
0.043
0.19
MI/Stent Thrombosis (PCI pts)
ASA High
3.8
2.7
0.71
0.56-0.90
0.005
ASA Low
3.6
3.2
0.89
0.71-1.12
0.32
ASA High
2.2
2.4
1.08
0.86-1.37
0.51
ASA Low
1.9
2.7
1.43
1.13-1.81
0.003
Major Bleed (Overall)
0.099
Definite Stent Thrombosis in 4 Groups
(Angiographically Proven)
0.008
C Standard, A High
C Double, A Low
0.004
C Double, A High
0.0
Cumulative Hazard
0.012
C Standard, A Low
0
3
6
9
Standard
Clop
Double
Clop
HR
P
High ASA
1.2
0.6
0.49
0.003
Low ASA
1.2
0.8
0.6
0.058
12
15
Days
18
21
24
P
Intn
0.35
27
30
Conclusions
Clopidogrel Dose Comparison
1. Double-dose clopidogrel significantly reduced stent
thrombosis and major CV events (CV death, MI or stroke)
in PCI.
2. 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).
3. There was a modest excess in CURRENT-defined major
bleeds but no difference in TIMI major bleeds, ICH, fatal
bleeds or CABG-related bleeds.
Conclusions
ASA Dose Comparison
No significant difference in efficacy or
bleeding between ASA 300-325 mg and
ASA 75-100 mg.
Clinical Implications
1. 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.
2. Patients not undergoing PCI should continue to
use the standard dose regimen of clopidogrel.
Acknowledgements
CURRENT Investigators from 597 sites in 39 countries
Steering Committee
S. Yusuf (Chair)
D. Foley
P. Pais
S.R. Mehta (P.I.)
S. Chrolavicius
A. Ajani
A. Avezum
J.P. Bassand
W.E. Boden
A. Budaj
E. Cardona
S. Chrolavicius
J. Col
P. Commerford
G. Di Pasquale
R. Diaz
J. Eha
J.W. Eikelboom
D.P. Faxon
M. Flather
M.G. Franzosi
C.B. Granger
M. Gupta
S. Jolly
C. Joyner
N. Karatzas
A. Kastrati
J.H. Kim
T.H. Koh
F. Lanas
B. Lewis
C. Macaya
T. Moccetti
G. Montalescot
K. Niemela
Z. Ongen
A. Orlandini
R.J.G. Peters
L. Piegas
J. Probstfield
J. Rankin
M. Ruda
Z. Rumboldt
H.J. Rupprecht
P.G. Steg
J-F. Tanguay
V. Valentin
J. Varigos
H. White
P. Widimsky
D. Xavier
J. Zhu
J-R Zhu
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
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
Supplementary Slides
Comparison of CURRENT and TRITON
CV Death, MI or Stroke
Definite Stent Thrombosis
TIMI Major Bleed
CABG-related Bleeding
Fatal bleeding
CURRENT PCI
TRITON
N=17,232
N=13,608
↓ 15%
↓ 19%
↓ 21% (w high dose ASA)
↓ 42%
↓ 58%
↓ 51% (w high dose ASA)
No increase
No increase
No increase
↑ 32%
↑ 4-fold
↑ 4-fold
Baseline Characteristics and In Hospital
Meds
Baseline
N=25,088
Meds After Rand
N=25,088
Age (y)
61.4
GP IIb/IIIa inhibitor
31.8
Female
27.4%
Statin
87.2
UA/NSTEMI
70.8%
Beta Blocker
82.5
ACE/ARB
75.7
PPI
40*
H2 Blocker
11.3
Rand to Angio
STEMI
Rand to Angio
3.4 h
29.2%
0.5 h
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
22
C Std, A Hi
0.04
C Double, A Lo
C Std, A Lo
0.01
0.02
0.03
C Double, A Hi
Clop
Standard
Clop
Double
HR
P
ASA 300-325 mg
4.6
3.8
0.83
0.036
ASA 75-100 mg
4.2
4.5
1.07
0.43
P
Intn
0.043
0.0
Cumulative Hazard
0.05
Clopidogrel: Double vs Standard Dose
Primary Outcome
0
3
6
9
12
15
Days
18
21
24
27
30
0.03
0.01
0.02
HR 0.96 (0.851.08)
P = 0.489
ASA 81-100 mg
ASA 300-325 mg
0.0
Cumulative Hazard
0.04
ASA Dose Comparison
Death/MI/Stroke at 30 days
0
3
6
9
12
15
Days
18
21
24
27
30
ASA Dose Comparison
Primary Outcome
ASA
Hazard
P
81-100 mg
300-325 mg
%
%
4.4
4.2
0.96
0.85-1.08 0.489
CV Death
2.3
2.0
0.88
0.74-1.04 0.134
MI
2.1
2.0
0.97
0.82-1.15 0.726
Stroke
0.5
0.6
1.18
0.84-1.67 0.330
Ratio
95% CI
value
Primary Outcome
CV Death/MI/Stroke
Components
0.015
0.005
HR 0.86 (0.731.02)
P = 0.077
ASA 81-100 mg
ASA 300-325 mg
0.0
Cumulative Hazard
0.025
ASA Dose Comparison
Death at 30 days
0
3
6
9
12
15
18
21
24
27
30
Secondary Outcomes (ASA)
ASA
Hazard
< 100 mg
> 300 mg
%
%
CV Death/MI/Stroke + RI
4.8
Total Death
Stent Thrombosis
P
Ratio
95% CI
value
4.5
0.93
0.83-1.04
0.206
2.5
2.2
0.86
0.73-1.02
0.077
1.4
1.3
0.90
0.73-1.12
0.347
Definite
0.7
0.6
0.89
0.66-1.21
0.458
Probable
0.8
0.7
0.90
0.67-1.20
0.471
Major Bleeding at 30 Days (ASA)
ASA
Hazard
< 100 mg
> 300 mg
%
%
All Major Bleeding
2.3
Severe Bleeding
Other Major Bleeding
Minor Bleeding
P
Ratio
95% CI
value
2.3
0.99
0.84-1.17
0.904
1.7
1.7
1.00
0.83-1.21
1.000
0.6
0.6
1.00
0.73-1.38
0.985
4.4
4.9
1.12
1.00-1.25
0.059
0.015
0.005
0.010
HR 0.99 (0.84-1.17)
P = 0.904
ASA < 100 mg
ASA > 300 mg
0.0
Cumulative Hazard
0.020
ASA Dose Comparison
Major Bleeding at 30 days
0
3
6
9
12
15
Days
18
21
24
27
30
Details of Major Bleeding
ASA
81-100
mg
300-325
mg
No. of Major Bleeds
Fatal
Symptomatic ICH
287
16
5
283
15
6
Surgical Intervention
Significant hypotension
(inotropes)
Hemoglobin drop > 5 g/dL
49
56
45
58
232
258
240
255
Transfusions
Sites of Major Bleeding
ASA
81-100 mg
300-325 mg
No. of Major Bleeds
287
283
Cardiac Tamponade
27
20
Surgical
115
107
Intracranial
6
6
Retroperitoneal
11
14
Gastrointestinal
30
47*
Puncture Site
40
46
*P=0.051