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

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):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) 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 7 d 2 d 7d 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%

ASA Dose Comparison Primary Outcome and Bleeding 75-100 mg 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) 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 0.99 0.84-1.17 0.90 CURRENT Severe Bleed 1.7 1.00 0.83-1.21 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: PCI v No PCI (P=0.016) ASA dose (P=0.043)

Clopidogrel: Double vs Standard Dose Primary Outcome and Components HR 95% CI P Intn P CV Death/MI/Stroke PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036 0.016 No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14 Overall (2N=25,087) 4.4 0.95 0.84-1.07 0.370 MI 2.6 2.0 0.78 0.64-0.95 0.012 0.025 1.4 1.7 1.25 0.87-1.79 0.23 2.2 1.9 0.86 0.73-1.03 0.097 CV Death 0.96 0.77-1.19 0.68 1.0 2.8 2.7 0.74-1.26 0.77 2.1 0.81-1.14 0.628 Stroke 0.4 0.88 0.55-1.41 0.59 0.50 0.8 0.9 1.11 0.68-1.82 0.67 0.5 0.99 0.70-1.39 0.950

Clopidogrel Double vs Standard Dose Bleeding Overall Population 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 0.67 0.19-2.37 0.53 RBC transfusion ≥ 2U 1.76 2.21 1.26 1.06-1.51 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 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

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 0.42-0.79 P=0.001 0.0 3 6 9 12 15 18 21 24 27 30 Days

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 0.57-0.89 0.002 Definite 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 0.96 0.77-1.19 0.68 Stroke 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

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 0.74-0.99 P=0.036 0.01 0.0 3 6 9 12 15 18 21 24 27 30 Days

Clopidogrel Double vs Standard Dose Bleeding PCI Population Hazard Ratio 95% CI P TIMI Major1 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 1.39 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 1.49 1.11-1.98 0.007 CABG-related Major 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 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

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

Clopidogrel: Double vs Standard Dose by ASA Factorial 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 0.036 0.043 ASA Low 4.2 4.5 1.07 0.91-1.27 0.42 MI/Stent Thrombosis (PCI pts) 2.7 0.71 0.56-0.90 0.005 0.19 3.6 3.2 0.89 0.71-1.12 0.32 Major Bleed (Overall) 2.2 2.4 1.08 0.86-1.37 0.51 0.099 1.9 1.43 1.13-1.81 0.003

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

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.

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 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

Supplementary Slides

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

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

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 300-325 mg 4.6 3.8 0.83 0.036 0.043 ASA 75-100 mg 4.2 4.5 1.07 0.43 0.01 0.0 3 6 9 12 15 18 21 24 27 30 Days

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 (0.85-1.08) P = 0.489 ASA 81-100 mg ASA 300-325 mg

ASA Dose Comparison Primary Outcome 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 0.97 0.82-1.15 0.726 Stroke 0.5 0.6 1.18 0.84-1.67 0.330

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 (0.73-1.02) P = 0.077 0.005 ASA 81-100 mg ASA 300-325 mg 0.0 3 6 9 12 15 18 21 24 27 30

Secondary Outcomes (ASA) Hazard P < 100 mg > 300 mg Ratio 95% CI value % CV Death/MI/Stroke + RI 4.8 4.5 0.93 0.83-1.04 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 0.67-1.20 0.471

Major Bleeding at 30 Days (ASA) Hazard P < 100 mg > 300 mg Ratio 95% CI value % All Major Bleeding 2.3 0.99 0.84-1.17 0.904 Severe Bleeding 1.7 1.00 0.83-1.21 1.000 Other Major Bleeding 0.6 0.73-1.38 0.985 Minor Bleeding 4.4 4.9 1.12 1.00-1.25 0.059

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 (0.84-1.17) P = 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 Retroperitoneal 11 14 Gastrointestinal 30 47* Puncture Site 40 46 *P=0.051

ASA Dose Comparison: Subgroups 81- 100 mg 300-325 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)