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

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

OASIS-7

Shamir R. Mehta on behalf of the CURRENT InvestigatorsShamir 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.

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

Relative Risk Reduction

PCI No PCI

CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI)CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30%30%11 1919%%22

STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI)STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI) 46%46%33 9%9%44

TRITON: Prasugrel v clopidogrel 300/75mg TRITON: Prasugrel v clopidogrel 300/75mg (CVD/MI/Stroke)(CVD/MI/Stroke)

19%19%55 Not evaluatedNot evaluated

Benefits of Antiplatelet Therapy in ACS are Greater in Patients Undergoing PCI

1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.2. Fox KAA, et al. Circulation 2004;110:1202-83. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.4. Chen ZM Lancet 2005;366:1607-214. Boersma E et al. Lancet 2002; 359:1895. 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 PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232(70%)

Angio 24,769(99%)

Angio 24,769(99%)

No PCI 7,855 (30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

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)

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Clop in 1st 7d (median) 7d 7 d 2 d 7d

Complete Followup

99.8%

Complete Followup

99.8%

Compliance:Compliance:

ASA Dose ComparisonPrimary Outcome and Bleeding

ASA

75-100 mg

ASA

300-325 mg

HR 95% CI P

CV Death/MI/Stroke

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

No other significant differences between ASA dose groupsNo other significant differences between ASA dose groups

GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

Clopidogrel Dose Comparison

2 Significant Interactions:

1. PCI v No PCI (P=0.016)

2. ASA dose (P=0.043)

Clopidogrel: Double vs Standard DosePrimary Outcome and Components

Standard Double HR 95% CI P Intn P

CV Death/MI/Stroke

PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016

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

MI

PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025

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

CV Death

PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0

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

Stroke

PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50

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

Clopidogrel Double vs Standard DoseBleeding Overall Population

Clopidogrel

Standard

N=12579

Double

N=12508

Hazard

Ratio

95% CI P

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

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Dose

Clopidogrel Double Dose

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)

Clopidogrel: Double vs Standard DoseMajor Efficacy Outcomes in PCI Patients

Day 30 Clopidogrel

StandardN=8684

%

Double N=8548

%

Hazard Ratio

95% CI P value

Stent ThrombosisStent Thrombosis 2.32.3 1.61.6 0.710.71 0.57-0.890.57-0.89 0.0020.002

DefiniteDefinite 1.21.2 0.70.7 0.580.58 0.42-0.790.42-0.79 0.0010.001

MIMI 2.62.6 2.02.0 0.780.78 0.64-0.950.64-0.95 0.0120.012

MI or stent thrombosisMI or stent thrombosis 3.73.7 3.03.0 0.800.80 0.68-0.940.68-0.94 0.0080.008

CV DeathCV Death 1.91.9 1.91.9 0.960.96 0.77-1.190.77-1.19 0.680.68

StrokeStroke 0.40.4 0.40.4 0.880.88 0.55-1.410.55-1.41 0.590.59

CV Death/MI/StrokeCV Death/MI/Stroke 4.54.5 3.93.9 0.850.85 0.74-0.990.74-0.99 0.0360.036

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients

Clopidogrel Standard

Clopidogrel Double

HR 0.8595% CI 0.74-0.99

P=0.036

15% RRR15% RRR

CV Death, MI or StrokeCV Death, MI or Stroke

Clopidogrel Double vs Standard DoseBleeding PCI Population

Clopidogrel

Standard

N= 8684

Double

N=8548

Hazard

Ratio

95% CI P

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

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

0.50 1.50

Overall

NSTEMI/UA STEMI

MaleFemale

Age <= 65 yrsAge > 65 yrs

Non-DiabeticPrev Diabetic

No Inhosp GPIIb/IIIaGPIIb in hosp

No Prot Pump InhibProt Pump Inhib

Non-smokerCurrent Smoker

ASA LowASA High

17232

10886 6346

13009 4223

10975 6257

13400 3831

12288 4936

7675 5557

10845 6380

8620 8612

4.5

4.25.0

4.15.8

3.07.1

4.25.6

3.96.0

3.85.7

4.93.8

4.24.8

3.9

3.64.2

3.64.6

2.76.0

3.64.9

3.54.7

3.24.2

4.62.6

4.33.5

0.805

0.419

0.702

0.836

0.465

0.408

0.045

0.024

0.50 1.50

3.7

3.64.0

3.54.6

2.95.2

3.64.1

3.15.2

3.14.8

3.93.4

3.63.8

3.0

3.12.8

3.03.0

2.24.4

2.83.6

2.54.1

2.33.3

3.52.1

3.22.7

0.248

0.148

0.418

0.567

0.894

0.613

0.050

0.191

CV Death, MI or StrokeCV Death, MI or Stroke MI or Stent ThrombosisMI or Stent Thrombosis

Clopidogrel: Double v Standard DosePCI Cohort Subgroups

Std %Std % Double %Double % Std %Std % Double %Double %Intxn PIntxn P Intxn PIntxn P

Double Dose Better

Double Dose Better

Double Dose Better

Double Dose Better

Std Dose Better

Std Dose Better

Std Dose Better

Std Dose Better

2N2N

Clopidogrel HR 95% CI P P int’n

Standard Double

CV Death/MI/Stroke (Overall)

ASA High 4.6 3.8 0.83 0.70-0.99 0.0360.043ASA Low 4.2 4.5 1.07 0.91-1.27 0.42

MI/Stent Thrombosis (PCI pts)

ASA High 3.8 2.7 0.71 0.56-0.90 0.005 0.19

ASA Low 3.6 3.2 0.89 0.71-1.12 0.32

Major Bleed (Overall)

ASA High 2.2 2.4 1.08 0.86-1.37 0.510.099

ASA Low 1.9 2.7 1.43 1.13-1.81 0.003

Clopidogrel: Double vs Standard Dose by ASA Factorial

Definite Stent Thrombosis in 4 Groups (Angiographically Proven)

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

C Standard, A Low

C Standard, A High

C Double, A Low

C Double, A High

Standard Clop

Double Clop

HR PP

Intn

High ASA 1.2 0.6 0.49 0.003

Low ASA 1.2 0.8 0.6 0.058 0.35

ConclusionsClopidogrel Dose Comparison

1.1. Double-dose clopidogrel significantly reduced stent Double-dose clopidogrel significantly reduced stent thrombosis and major CV events (CV death, MI or stroke) thrombosis and major CV events (CV death, MI or stroke) in PCI.in PCI.

2.2. In patients not undergoing PCI, double dose clopidogrel In patients not undergoing PCI, double dose clopidogrel was not significantly different from standard dose (70% had was not significantly different from standard dose (70% had no significant CAD or stopped study drug early for CABG).no significant CAD or stopped study drug early for CABG).

3.3. There was a modest excess in CURRENT-defined major There was a modest excess in CURRENT-defined major bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds but no difference in TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds.bleeds or CABG-related bleeds.

ConclusionsASA Dose Comparison

No significant difference in efficacy or No significant difference in efficacy or bleeding between ASA 300-325 mg and bleeding between ASA 300-325 mg and ASA 75-100 mg.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

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. RankinJ.P. Bassand C. Joyner M. Ruda W.E. Boden N. Karatzas Z. Rumboldt A. Budaj A. Kastrati H.J. RupprechtE. Cardona J.H. Kim P.G. Steg S. Chrolavicius T.H. Koh J-F. Tanguay J. Col F. Lanas V. Valentin P. Commerford B. Lewis J. Varigos G. Di Pasquale C. Macaya H. WhiteR. Diaz T. Moccetti P. WidimskyJ. Eha G. Montalescot D. Xavier J.W. Eikelboom K. Niemela J. Zhu D.P. Faxon Z. Ongen J-R Zhu M. Flather A. Orlandini

P. Sleight (Chair)J.L. AndersonD.L. DeMetsJ. HirshD.R. Holmes JrD.E. Johnstone

S. ChrolaviciusS.R. MehtaA. RobinsonB. Jedrzejowski J. PogueR. AfzalL. BlakeW. Chen S. Di DiodatoM. LawrenceR. ManojlovicL. MastrangeloA. MeadE. PasadynT. SovereignL. Wasala

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

C. Joyner (Chair)M. Lawrence (Coordinator)

Steering Committee

DSMB

Adjudication Committee

Sponsors Project Office

Consultant: R. Peto

CURRENT Investigators from 597 sites in 39 countries

Supplementary Slides

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 No increase ↑ 4-fold

Fatal bleeding No increase ↑ 4-fold

Comparison of CURRENT and TRITON

22

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

Rand to Angio 3.4 h ACE/ARB 75.7

STEMI 29.2% PPI 40*

Rand to Angio 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

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0.05

0 3 6 9 12 15 18 21 24 27 30

C Std, A Lo

C Std, A Hi

C Double, A Lo

C Double, A Hi

Clop Standard

Clop Double

HR PP

Intn

ASA 300-325 mg 4.6 3.8 0.83 0.0360.043

ASA 75-100 mg 4.2 4.5 1.07 0.43

Clopidogrel: Double vs Standard Dose Primary Outcome

ASA Dose Comparison Death/MI/Stroke at 30 days

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 3 6 9 12 15 18 21 24 27 30

HR 0.96 (0.85-HR 0.96 (0.85-1.08)1.08)

P = 0.489P = 0.489

HR 0.96 (0.85-HR 0.96 (0.85-1.08)1.08)

P = 0.489P = 0.489

ASA 81-100 mgASA 300-325 mg

ASA Dose ComparisonPrimary Outcome

ASA Hazard P

81-100 mg 300-325 mg Ratio 95% CI value

% %

Primary Outcome

CV Death/MI/Stroke 4.4 4.2 0.96 0.85-1.08 0.489

Components

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

Cu

mu

lati

ve H

azar

d

0.0

0.00

50.

015

0.02

5

0 3 6 9 12 15 18 21 24 27 30

ASA Dose ComparisonDeath at 30 days

HR 0.86 (0.73-HR 0.86 (0.73-1.02)1.02)

P = 0.077P = 0.077

HR 0.86 (0.73-HR 0.86 (0.73-1.02)1.02)

P = 0.077P = 0.077

ASA 81-100 mgASA 300-325 mg

Secondary Outcomes (ASA)

ASA Hazard P

< 100 mg > 300 mg Ratio 95% CI value

% %

CV Death/MI/Stroke + RI 4.8 4.5 0.93 0.83-1.04 0.206

Total Death 2.5 2.2 0.86 0.73-1.02 0.077

Stent Thrombosis 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 P

< 100 mg > 300 mg Ratio 95% CI value% %

All Major Bleeding 2.3 2.3 0.99 0.84-1.17 0.904

Severe Bleeding 1.7 1.7 1.00 0.83-1.21 1.000

Other Major Bleeding 0.6 0.6 1.00 0.73-1.38 0.985

Minor Bleeding 4.4 4.9 1.12 1.00-1.25 0.059

ASA Dose ComparisonMajor Bleeding at 30 days

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

50.

010

0.01

50.

020

0 3 6 9 12 15 18 21 24 27 30

ASA < 100 mgASA > 300 mg

HR 0.99 (0.84-1.17)HR 0.99 (0.84-1.17)P = 0.904P = 0.904

HR 0.99 (0.84-1.17)HR 0.99 (0.84-1.17)P = 0.904P = 0.904

Details of Major Bleeding

ASA

81-100 mg

300-325 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

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