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OASIS-7 CURRENT OASIS 7: A 2 X 2 Factorial Randomized Trial of Optimal Clopidogrel OASIS-7 CURRENT OASIS 7: A 2 X 2 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, Mc. Master 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 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 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 300/75 mg (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. Study Design, Flow and Compliance 25, 087 ACS Patients (UA/NSTEMI 70. 8%, STEMI 29. 2%) ü Planned Early (<24 h) Invasive Management with intended PCI ü Ischemic ECG Δ (80. 8%) or ↑cardiac biomarker (42%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then 150 mg/d x 7 d 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 1 st 7 d (median) 7 d Efficacy Outcomes: Safety Outcomes: Key Subgroup: Angio 24, 769 (99%) No Sig. CAD 3, 616 7 d No PCI 7, 855 (30%) CABG 1, 809 2 d 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 7 d Complete Followup 99. 8%

ASA Dose Comparison Primary Outcome and Bleeding ASA HR 95% CI P 75 -100 ASA Dose Comparison Primary Outcome and Bleeding ASA HR 95% CI P 75 -100 mg 300 -325 mg PCI (2 N=17, 232) 4. 2 4. 1 0. 98 0. 84 -1. 13 0. 76 No PCI (2 N=7855) 4. 7 4. 4 0. 92 0. 75 -1. 14 0. 44 Overall (2 N=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 0. 99 0. 84 -1. 17 0. 90 CURRENT Severe Bleed 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. 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 Clopidogrel: Double vs Standard Dose Primary Outcome and Components Standard Double HR 95% CI P PCI (2 N=17, 232) 4. 5 3. 9 0. 85 0. 74 -0. 99 0. 036 No PCI (2 N=7855) 4. 2 4. 9 1. 17 0. 95 -1. 44 0. 14 Overall (2 N=25, 087) 4. 4 4. 2 0. 95 0. 84 -1. 07 0. 370 PCI (2 N=17, 232) 2. 6 2. 0 0. 78 0. 64 -0. 95 0. 012 No PCI (2 N=7855) 1. 4 1. 7 1. 25 0. 87 -1. 79 0. 23 Overall (2 N=25, 087) 2. 2 1. 9 0. 86 0. 73 -1. 03 0. 097 PCI (2 N=17, 232) 1. 9 0. 96 0. 77 -1. 19 0. 68 No PCI (2 N=7855) 2. 8 2. 7 0. 96 0. 74 -1. 26 0. 77 Overall (2 N=25, 087) 2. 2 2. 1 0. 96 0. 81 -1. 14 0. 628 PCI (2 N=17, 232) 0. 4 0. 88 0. 55 -1. 41 0. 59 No PCI (2 N=7855) 0. 8 0. 9 1. 11 0. 68 -1. 82 0. 67 Overall (2 N=25, 087) 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 Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel Standard Double Hazard 95% CI P N=12579 N=12508 Ratio TIMI Major 1 0. 95 1. 04 1. 09 0. 85 -1. 40 0. 50 CURRENT Major 2 2. 0 2. 5 1. 25 1. 05 -1. 47 0. 01 CURRENT Severe 3 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 ≥ 2 U 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 1 ICH, Hb drop ≥ 5 g/d. L (each unit of RBC transfusion counts as 1 g/d. L drop) or fatal bleed + disabling or intraocular or requiring transfusion of 2 -3 units 3 Fatal or ↓Hb ≥ 5 g/d. L, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units 2 Severe

Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed) 0. 008 42% RRR 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 18 Days 21 24 27 30

Clopidogrel: Double vs Standard Dose Major Efficacy Outcomes in PCI Patients Day 30 Clopidogrel 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 % % Stent Thrombosis Definite 2. 3 1. 2 1. 6 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 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: 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 Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standard Double Hazard 95% CI P N= 8684 N=8548 Ratio TIMI Major 1 0. 5 1. 06 0. 70 -1. 61 0. 79 CURRENT Major 2 1. 1 1. 6 1. 44 1. 11 -1. 86 0. 006 CURRENT Severe 3 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 ≥ 2 U 0. 91 1. 35 1. 49 1. 11 -1. 98 0. 007 CABG-related Major 0. 1 1. 69 0. 61 -4. 7 0. 31 1 ICH, Hb drop ≥ 5 g/d. L (each unit of RBC transfusion counts as 1 g/d. L drop) or fatal bleed + disabling or intraocular or requiring transfusion of 2 -3 units 3 Fatal or ↓Hb ≥ 5 g/d. L, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units 2 Severe

Clopidogrel: Double v Standard Dose PCI Cohort Subgroups CV Death, MI or Stroke 2 Clopidogrel: Double v Standard Dose PCI Cohort Subgroups CV Death, MI or Stroke 2 N Std % Double % Intxn P MI or Stent Thrombosis Std % Double % 3. 7 Intxn P 3. 0 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 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 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. 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 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 Definite Stent Thrombosis in 4 Groups (Angiographically Proven) 0. 008 C Standard, A High C Double, A Low 0. 004 C Double, A High Standard Clop 3 6 9 HR P 1. 2 0. 6 0. 49 1. 2 0. 8 0. 6 0. 058 P 0. 003 Low ASA 0 Double Clop High ASA 0. 0 Cumulative Hazard 0. 012 C Standard, A Low 12 15 Days 18 21 24 Intn 0. 35 27 30

Conclusions Clopidogrel Dose Comparison 1. Double-dose clopidogrel significantly reduced stent thrombosis and major CV 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 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 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 Sponsors S. Yusuf 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 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. De. Mets J. Hirsh D. R. Holmes Jr D. E. Johnstone Adjudication Committee C. Joyner (Chair) M. Lawrence (Coordinator) Consultant: R. Peto

Supplementary Slides Supplementary Slides

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

Baseline Characteristics and In Hospital Meds Baseline N=25, 088 Meds After Rand N=25, 088 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* H 2 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 C Std, A Hi 0. 04 C Double, A Lo C Std, A Lo 0. 02 0. 03 C Double, A Hi Clop Double HR 4. 6 3. 8 0. 83 0. 036 ASA 75 -100 mg 4. 2 4. 5 1. 07 0. 43 P P ASA 300 -325 mg 0. 01 Clop Standard 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. 85 -1. 08) P 0. 03 0. 01 0. 02 HR 0. 96 (0. 85 -1. 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 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 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 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 Major Bleeding at 30 Days (ASA) ASA Hazard < 100 mg > 300 mg % % All Major Bleeding 2. 3 Severe Bleeding Other Major Bleeding P Minor Bleeding Ratio 95% CI value 2. 3 0. 99 0. 84 -1. 17 0. 904 1. 7 1. 00 0. 83 -1. 21 1. 000 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. 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 No. of Major Bleeds Fatal Symptomatic Details of Major Bleeding ASA 81 -100 mg No. of Major Bleeds Fatal Symptomatic ICH Surgical Intervention Significant hypotension (inotropes) Hemoglobin drop > 5 g/d. L Transfusions 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 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