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PCI in Patients Receiving Enoxaparin or UFH Following Fibrinolytic Therapy for STEMI: PCI ExTRACT-TIMI 25 C. Michael Gibson, Sabina A. Murphy, David A. Morrow, Carolyn H. McCabe, Dietrich C. Gulba, Gilles Montalescot, Servet Cetin, Oscar H. Kracoff, Basil S. Lewis, Nathan Roguin, Elliott M. Antman, Eugene Braunwald, for the ExTRACT-TIMI 25 Investigators 1 Disclosure The TIMI Study Group has received research / grant support in the past 2 yrs through the Brigham & Women’s Hospital with funding from (in alphabetical order): Accumetrics, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals LP Baxter Bayer Healthcare LLC Beckman Coulter, Inc. Biosite Incorporated Bristol-Myers Squibb CardioKinetix CV Therapeutics, Inc. Eli Lilly and Company FoldRx GlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corporation Integrated Therapeutics Corporation KAI Pharmaceuticals Merck & Co., Inc. Millennium Pharmaceuticals, Inc. Novartis Pharmaceuticals Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics Corporation Roche Diagnostics GmbH Sanofi-Aventis Sanofi-Synthelabo Recherche Schering-Plough Research Institute St Jude Medical The National Institutes of Health 2 Background: Main Results ExTRACT-TIMI 25 Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days Primary Endpoint: Death or non-fatal re-MI by 30 days UFH UFH 12.0 11.7 9.9 ENOX ENOX % RR = 0.83 p = 0.000003 Days 14.5 % RR = 0.81 p = 0.000001 Days N Engl J Med 2006;354:1477-88. 3 Objective To determine whether ENOX is superior to UFH as adjunctive therapy for patients undergoing PCI for STEMI who initially received fibrinolytic therapy. 4 Study Profile 20,479 Patients Randomized into ExTRACT-TIMI 25 10,256 Assigned ENOX 10,223 Assigned UFH 2,272 Underwent PCI by 30 days 22.8% 2,404 Underwent PCI by 30 days 24.2% 5 Anticoagulation for PCI ONLY blinded study drug to be used All Pts receive BOTH blinded Enox/Plac AND UFH/Plac < 8h since SC dose Additional Enox/Plac NO > 8 h since SC dose 0.3 mg/kg IV Additional UFH/Plac GP IIb/IIIa ACT 200 s* ACT 200 s* No GP IIb/IIIa ACT 250 s* ACT 250 s* *ACT TESTING ONLY BY UNBLINDED MEDICAL PROFESSIONAL Sheath Removal Closure Device No Closure Device After PCI + Groin Hemostasis End of PCI Wait 6 hours after last sc/IV dose STUDY MEDICATION SHOULD NOT BE STARTED UNLESS CLINICALLY INDICATED 6 Baseline Characteristics PCI Cohort N = 4,676 Age (yrs)-median 57 CrCl (ml/min)-median 87 Male (%) 82 UFH within 3 h (%) Hypertension (%) 37 LMWH within 7 d (%) 0.7 Hyperlipidemia (%) 23 Killip Class I (%) Current smoker (%) 51 TIMI Risk Score (STEMI) Diabetes (%) 16 Prior MI (%) 11 Anterior MI (%) 41 > 3 (%) ALL P = NS for ENOX vs UFH 20 92 27 7 Medications During Hospitalization PCI Cohort N = 4,676 Fibrinolytic 21 SK (%) Fibrin-specific (%) 79 ASA (%) Beta Blocker (%) ACEI / ARB (%) Statin (%) Clopidogrel (%) 98 86 80 85 68 8 UFH 13.8% 10 ENOX 10.7% 5 RR 0.77 p=0.001 0 Death or MI (%) 15 PCI Cohort: Primary Endpoint Death or Nonfatal MI by 30 days 0 5 10 15 20 25 30 Days 9 PCI Cohort: Safety Event ENOX n=2,238 UFH RR P-Value n=2,377 TIMI Major Bleed 1.4% 1.6% 0.87 (0.55-1.39) 0.56 TIMI Minor Bleed 3.3% 2.4% 1.34 (0.95-1.88) 0.09 TIMI Major or Minor Bleed 4.6% 4.0% 1.15 (0.88-1.51) 0.31 ICH 0.2% 0.4% 0.42 (0.13-1.35) 0.18 Stroke 0.3% 0.9% 0.30 (0.12-0.75) 0.006 10 PCI Cohort: Death or Nonfatal reMI Major Subgroups Subgroup No hx diabetes Hx diabetes Enox (%) 10.3 12.5 UFH (%) 13.2 17.3 Non-anterior MI Anterior MI 9.4 12.3 13.4 14.5 Sx onset to Lytic <=median Sx onset to Lytic >median 10.3 11.5 15.1 11.8 SK Fibrin specific 10.2 10.9 11.7 14.3 Time to PCI >=5 days Time to PCI 2-<5 days Time to PCI <48 hrs 7.8 8 20.8 9.2 13.9 23.2 No GP IIb/IIIa Inhibitor GP IIb/IIIa Inhibitor 9.5 17.1 12.3 20.2 No Clopidogrel Clopidogrel 12.4 9.8 13 14.2 0.25 0.5 ENOX Better 0.75 1 Odds Ratio 1.25 1.5 UFH Better 11 10 UFH 10.9% ENOX 7.8% 5 RR 0.72 p<0.001 0 Non-Fatal MI (%) 15 PCI Cohort: Nonfatal Recurrent MI by 30 days 0 5 10 15 20 25 30 Days 12 Incidence and Relative Timing of PCI Incidence of PCI: 15 Median time to PCI: p=0.006 5 10 UFH (n=2,404): 109 hours Enox (n=2,272): 122 hours 0 PCI (%) 20 25 UFH 24.2% p=0.027 ENOX 22.8% 0 5 10 15 Days 20 25 30 13 Relative Timing of PCI: Urgent vs Non-Urgent PCI UFH ENOX p=0.31 p=0.006 140 120 122.0 109.0 126.0 p=0.08 100 Hours 120.0 80 n=1885 67.0 79.0 n=278 n=442 60 40 20 0 n=2,404 n=2,272 All PCI Urgent PCI n=1,829 n=1,885 Non- Urgent PCI 14 Outcomes by 30 Days in Patients Undergoing PCI on Blinded Study Drug UFH (n=1,075) ENOX (n=1,103) RR 0.77 P=0.002 % Events 20 15 16.7 RR 0.75 P=0.33 13.0 10 5 0 2.4 Death or Nonfatal reMI 1.8 Major Bleed 15 PCI Performed on Blinded Study Drug Two scenarios in which a patient underwent PCI on study drug: 1) Blinded study drug never discontinued and PCI performed on blinded study drug 2) Blinded study drug discontinued prior to PCI and then resumed at time of PCI 16 15 UFH 18.9% ENOX 14.2% 5 10 RR 0.75 p=0.018 0 Death or MI (%) 20 Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Not Discontinued (n=1501) 0 5 10 15 Days 20 25 30 17 15 RR 0.41 p=0.004 10 UFH 14.4% 5 ENOX 5.9% 0 Death or MI (%) 20 Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Discontinued and Resumed For PCI (n=677) 0 5 10 15 Days 20 25 30 18 Conclusion • When compared to UFH as adjunctive therapy among patients undergoing PCI, ENOX: • Reduced death or MI • Reduced stroke • No difference in bleeding Conclusion (cont.) • ENOX was associated with ↓ risk of death or reMI both among patients in whom antithrombin was continued as well as discontinued prior to PCI. • ENOX associated with both delayed onset and ↓ occurrence of reMI, both of which may expand window of opportunity to perform PCI following fibrinolytic administration. 20 Clinical Implications • Among STEMI pts treated with lytic, ENOX can be administered as the sole antithrombin therapy before and during PCI without the need for additional antithrombin inhibition. • Periprocedural ENOX is preferable to UFH in the management of these patients. 21 Back Up Slides 22 10 5 p=0.07 for ENOX vs UFH in no PCI cohort p=0.93 for ENOX vs UFH in PCI cohort 0 Death (%) 15 Death at 30 days by PCI and randomization group 0 5 10 15 Days ENOX/PCI UFH/PCI 20 25 30 ENOX/no PCI UFH/no PCI 23