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Tracy Wang, MD, MHS, MSc on behalf of

Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients with Acute Coronary Syndrome: an Analysis from the EARLY-ACS Trial. Tracy Wang, MD, MHS, MSc on behalf of

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Tracy Wang, MD, MHS, MSc on behalf of

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  1. Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients with Acute Coronary Syndrome: an Analysis from the EARLY-ACS Trial Tracy Wang, MD, MHS, MSc on behalf of Jennifer White, Pierluigi Tricoci, Robert Giugliano, Uwe Zeymer, Robert Harrington, Gilles Montalescot, Stefan James, Frans Van de Werf, Paul Armstrong, Eugene Braunwald, Robert Califf, Kristin Newby and the EARLY-ACS investigators

  2. The EARLY ACS trial was funded by Schering-Plough. These analyses were funded by research grant support from Merck & Co., Inc. • Wang: BMS/Sanofi, Schering Plough, The Medicines Co, Heartscape, Canyon Pharmaceuticals, Lilly/Daiichi Sankyo • White, Zeymer: nothing to disclose • Giugliano: Schering Plough, Merck, Daiichi Sankyo, BMS, Sanofi • Tricoci: Research grants from Merck • Harrington: Schering Plough, others at www.dcri.duke.edu/research/coi.jsp. • Montalescot: BMS, Boston Scientfic, Centocor, Cordis, Lilly, Fédération Française de Cardiologie, Fondation de France, Guerbet Medical, INSERM, ITC Edison, Medtronic, Pfizer, Sanofi-Aventis Group, Société Française de Cardiologie; Accumetrics, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Novartis, Portola, Schering-Plough, and The Medicines Company. • Van de Werf: Schering Plough, Roche. Advisory board and speakers fee from Schering Plough, Merck, Roche • Armstrong: Sanofi-Aventis, BMS, Merck, Abbott, GlaxoSmithKline, Pfizer, Regado, Hoffman-La-Roche, Boehringer Ingelheim, Eli Lilly, Schering Plough, Scios, Portola, Uppsala Clinical Research Center, AstraZeneca • Braunwald: Eli Lilly, Schering Plough, Daiichi Sankyo, Merck • Califf: Schering Plough, Merck. Others at www.dcri.duke.edu/research/coi.jsp. • Newby: Schering Plough, Merck. Others at www.dcri.duke.edu/research/coi.jsp.

  3. Background • ACC/AHA/ESC Guidelines recommend • For patients with NSTE ACS treated with early invasive strategy, either clopidogrel or GPI should be initiated upstream before angiography (Class I, level of evidence A) • For patients with high-risk features, upstream initiation of both clopidogrel and GPI can be considered (Class IIa, level of evidence B)

  4. Clopidogrel and GPI ISAR-REACT 2 RRR: 25% CREDO P=.03 P=NS GPI (N=826) No GPI (N=1289) % of Patients Placebo Better Clopidogrel Better * 1-yr Death/MI/Stroke *Death, MI, or uTVR Steinhubl S et al. JAMA 2002;288: 2411-20. Kastrati A et al. JAMA. 2006;295:1531-38.

  5. Study Design High-risk NSTE ACSn = 10,500 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) Routine, early eptifibatide Placebo / delayed provisional eptifibatide pre-PCI Randomized within 12 hours of presentation with planned angiography 12 to 96 hours after randomization Primary Endpoint: 96-hr Death, MI, recurrent ischemia requiring urgent revascularization, or thrombotic bailout Secondary Endpoints: 30-d Death or MI, 120-hr Bleeding

  6. EARLY-ACS Trial: Primary Endpoint 15 10.0% 10 Delayed provisional eptifibatide 9.3% Death, MI, RIUR or TBO (%) P = 0.23 5 Routine early eptifibatide 0 0 8 16 24 32 40 48 56 64 72 80 88 96 Time Since Randomization (Hours)

  7. Secondary Endpoint: 30-day Death or MI 15 12.4% Delayed provisional eptifibatide 10 11.2% Death or MI (%) Routine early eptifibatide P = 0.079 5 0 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 Time Since Randomization (Days)

  8. Secondary Endpoint: Bleeding Routine EarlyEptifibatide(n=4686) DelayedProvisional Eptifibatide(n=4643) Bleeding (all patients, %) TIMI major 2.6 1.8 1.42 (1.07-1.89) 0.015 GUSTO moderate or severe 7.6 5.1 1.52 (1.28-1.80) <0.001 PRBC transfusion 8.6 6.7 1.31 (1.12-1.53) 0.001 OR(95% CI) P

  9. Clopidogrel Use in EARLY-ACS • Clopidogrel use and timing were determined by treating physician • Randomization in the EARLY-ACS Trial was stratified by declared intent for upstream clopidogrel use • In this analysis, we examined whether upstream clopidogrel pre-treatment influenced the benefit or safety of routine, upstream eptifibatide use prior to angiography.

  10. Study Population EARLY-ACS Patients N = 9,406 No cardiac catheterization (n=240) Final Study Population N =9,166 (97%) Median time to angiography 21 hrs (IQR 17 - 33) No upstream Clopidogrel N = 2271 (25%) Upstream Clopidogrel N = 6895 (75%)

  11. Baseline Characteristics Upstream Clopidogrel N = 6895 (75%) No upstream Clopidogrel N = 2271 (25%)

  12. Presentation Upstream Clopidogrel N = 6895 (75%) No upstream Clopidogrel N = 2271 (25%)

  13. Efficacy 96h Death/MI/ RIUR/TBO 30-day Death/MI

  14. Efficacy (adjusted) Adjusted OR (95% CI) Death/MI/RIUR/TBO at 96 hours Upstream Clopidogrel 0.93 (0.79 – 1.10) No Clopidogrel 0.94 (0.72 – 1.22) p for interaction = 0.99 Death/MI at 30 days Upstream Clopidogrel 0.85 (0.73 – 0.99) No Clopidogrel 1.02 (0.80 – 1.30) p for interaction = 0.23 0 1 2 3 Early eptifibatide better Provisional eptifibatide better

  15. Death or MI at 30 days Delayed Provisional Delayed Provisional Early Routine Early Routine No Upstream Clopidogrel Upstream Clopidogrel days days

  16. Bleeding (adjusted) Adjusted OR (95% CI) TIMI Major Bleeding Upstream Clopidogrel 1.54 (1.07 – 2.24) No Clopidogrel 1.13 (0.69 – 1.84) p for interaction = 0.31 GUSTO Mod/Severe Bleeding Upstream Clopidogrel 1.72 (1.37 – 2.16) No Clopidogrel 1.29 (0.96 – 1.74) p for interaction = 0.13 Transfusion 1.38 (1.04 – 1.83) Upstream Clopidogrel 1.23 (1.01 – 1.51) No Clopidogrel p for interaction = 0.52 0 1 2 3 Early eptifibatide better Provisional eptifibatide better

  17. Limitations • Confounding inherent to subgroup comparison • Attenuated by stratified randomization strategy • Large regional differences in clopidogrel treatment patterns • Results are hypothesis generating • 30-day death/MI risk reduction with early eptifibatide use was statistically significant, but interaction term not significant

  18. Conclusions Among NSTE ACS patients undergoing angiography, routine pre-procedure eptifibatide use did not improve short-term ischemic outcomes but may be associated with a reduction in 30-day death/MI among patients pre-treated with clopidogrel Eptifibatide use increased bleeding risk; this risk was slightly accentuated by the addition of clopidogrel

  19. Implications • Future investigation is needed to identify subgroups of patients with high likelihood of benefit from more intensive platelet inhibition without a significant excess in bleeding risk • It might be reasonable to consider early eptifibatide and clopidogrel pre-treatment in these high-risk NSTE ACS patients intended for angiography

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