A Randomized Comparison Of A Clopidogrel High Loading And Maintenance Dose Regimen Versus Standard Dose And High Versus Low Dose Aspirin In 25,000 Patients With Acute Coronary Syndromes (current Oasis 7) – Shamir R. Mehta

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: 3. PCI v No PCI (P=0.016) 5. 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

ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units 1 2

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 StandardN Double Hazard =8684 N=8548 Ratio

95% CI

P value

%

%

Stent Thrombosis Definite

2.3 1.2

1.6 0.7

0.71 0.58

0.57-0.89 0.42-0.79

0.002 0.001

MI MI or stent thrombosis

2.6 3.7

2.0 3.0

0.78 0.80

0.64-0.95 0.68-0.94

0.012 0.008

CV Death Stroke

1.9 0.4

1.9 0.4

0.96 0.88

0.77-1.19 0.55-1.41

0.68 0.59

CV Death/MI/Stroke

4.5

3.9

0.85

0.74-0.99

0.036

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

ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units 1 2

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 • 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.

Acknowledgements CURRENT Investigators from 597 sites in 39 countries Steering Committee

Sponsors

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

M. Blumenthal (Bristol-Myers Squibb) C. Gaudin (Sanofi-Aventis) C. Marchese (Sanofi- Aventis) P. Hornick (Bristol-Myers Squibb)

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

Project Office 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

Supplementary Slides

Comparison of CURRENT and TRITON CURRENT PCI

TRITON

N=17,232

N=13,608

↓ 15%

↓ 19%

Definite Stent Thrombosis

↓ 21% (w high dose ASA) ↓ 42%

↓ 58%

TIMI Major Bleed CABG-related Bleeding Fatal bleeding

↓ 51% (w high dose ASA) No increase No increase No increase

↑ 32% ↑ 4-fold ↑ 4-fold

CV Death, MI or Stroke

Baseline Characteristics and In Hospital Meds Baseline

N=25,088

Age (y)

61.4

Female UA/NSTEMI Rand to Angio STEMI Rand to Angio

N=25,088

GP IIb/IIIa inhibitor

31.8

27.4%

Statin

87.2

70.8%

Beta Blocker

82.5

ACE/ARB

75.7

PPI

40*

H2 Blocker

11.3

3.4 h 29.2% 0.5 h

Diabetes

23.4

Prior Stroke

4.1

Ischemic ECG Δ

80.8

↑ Biomarker

Meds After Rand

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

0.05

Clopidogrel: Double vs Standard Dose Primary Outcome C Std, A Hi

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

0.04

C Double, A Lo C Std, A Lo

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

%

%

2.3

Severe Bleeding Other Major Bleeding

All 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

No. of Major Bleeds Fatal Symptomatic ICH Surgical Intervention Significant hypotension (inotropes) Hemoglobin drop > 5 g/dL Transfusions

81-100 mg

300-325 mg

287 16 5 49 56

283 15 6 45 58

232 258

240 255

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

ASA Dose Comparison: Subgroups 2N Primary Composite NSTEMI STEMI Non-Diabetic Prev Diabetic GRACE <140 GRACE >=140 Age <= 65 yrs Age > 65 yrs

81- 100 mg 300-325 mg

P interaction

25087 17757 7321 19196 5870 13394 3516 15762 9316

4.4 4.2 4.8 4.0 5.6 3.0 8.3 3.1 6.6

4.2 3.9 5.0 3.8 5.6 2.8 7.1 2.7 6.8

No Prot Pump Inhib 15193 Prot Pump Inhib 3204

4.3 4.2

4.2 4.6

0.483

Weight >= 60kg Weight < 60kg

22504 2358

4.1 5.7

4.1 4.7

0.339

Non-smoker Current Smoker

16688 8369

4.9 3.3

4.7 3.1

0.977

No PCI With PCI

7855 17232

4.7 4.2

4.4 4.1

0.724

0.446 0.585 0.575 0.145

0.4

0.7

1.0 HR (95% CI)

1.3

1.6

1.9