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PCI in Patients Receiving Enoxaparin or UFH Following Fibrinolytic Therapy for STEMI: PCI ExTRACT-TIMI 25.

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  1. 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

  2. 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): 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 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

  3. 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 14.5 12.0 11.7 9.9 ENOX ENOX % % RR = 0.83 p = 0.000003 RR = 0.81 p = 0.000001 Days Days N Engl J Med 2006;354:1477-88.

  4. Objective To determine whether ENOX is superior to UFH as adjunctive therapy for patients undergoing PCI for STEMI who initially received fibrinolytic therapy.

  5. 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%

  6. Anticoagulation for PCI ONLY blinded study drug to be usedAll Pts receive BOTH blinded Enox/Plac AND UFH/Plac < 8h since SC dose > 8 h since SC dose Additional Enox/Plac NO 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 End of PCI No Closure Device Wait 6 hours after last sc/IV dose After PCI STUDY MEDICATION SHOULD NOT BE + Groin Hemostasis STARTED UNLESS CLINICALLY INDICATED

  7. Baseline Characteristics PCI Cohort N = 4,676 Age (yrs)-median 57 CrCl (ml/min)-median 87 Male (%) 82 UFH within 3 h (%) 20 Hypertension (%) 37 LMWH within 7 d (%) 0.7 Hyperlipidemia (%) 23 Killip Class I (%) 92 Current smoker (%) 51 TIMI Risk Score (STEMI) Diabetes (%) 16 > 3 (%) 27 Prior MI (%) 11 Anterior MI (%) 41 ALL P = NS for ENOX vs UFH

  8. Medications During Hospitalization PCI Cohort N = 4,676 Fibrinolytic 21 SK (%) Fibrin-specific (%) 79 ASA (%) 98 Beta Blocker (%) 86 ACEI / ARB (%) 80 Statin (%) 85 Clopidogrel (%) 68

  9. PCI Cohort: Primary EndpointDeath or Nonfatal MI by 30 days UFH 15 13.8% ENOX 10.7% 10 RR 0.77 p=0.001 Death or MI (%) 5 0 0 5 10 15 20 25 30 Days

  10. PCI Cohort: Safety Event ENOXUFH RR P-Value n=2,238 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 4.6%4.0% 1.15 (0.88-1.51) 0.31 Minor Bleed 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

  11. PCI Cohort: Death or Nonfatal reMI - Major Subgroups ENOX Better Odds Ratio UFH Better

  12. PCI Cohort:Nonfatal Recurrent MI by 30 days 15 UFH 10.9% 10 ENOX Non-Fatal MI (%) 7.8% RR 0.72 p<0.001 5 0 0 5 10 15 20 25 30 Days

  13. Incidence and Relative Timing of PCI Incidence of PCI: UFH 24.2% 25 p=0.027 ENOX 22.8% 20 Median time to PCI: UFH (n=2,404): 109 hours Enox (n=2,272): 122 hours 15 p=0.006 PCI (%) 10 5 0 0 5 10 15 20 25 30 Days

  14. Relative Timing of PCI: Urgent vs Non-Urgent PCI n=1885 UFH ENOX p=0.31 p=0.006 p=0.08 Hours n=278 n=442 n=1,829 n=2,404 n=1,885 n=2,272 Non- Urgent PCI All PCI Urgent PCI

  15. Outcomes by 30 Days in Patients Undergoing PCI on Blinded Study Drug UFH (n=1,075) RR 0.77P=0.002 ENOX (n=1,103) RR 0.75 P=0.33 % Events Major Bleed Death or Nonfatal reMI

  16. 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

  17. Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was NotDiscontinued (n=1501) UFH 20 18.9% 15 ENOX 14.2% RR0.75 p=0.018 Death or MI (%) 10 5 0 0 5 10 15 20 25 30 Days

  18. Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Discontinued and Resumed For PCI (n=677) 20 RR 0.41 p=0.004 UFH 15 14.4% Death or MI (%) 10 ENOX 5.9% 5 0 0 5 10 15 20 25 30 Days

  19. Conclusion • When compared to UFH as adjunctive therapy among patients undergoing PCI, ENOX: • Reduced death or MI • Reduced stroke • No difference in bleeding

  20. 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.

  21. 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.

  22. Back Up Slides

  23. Death at 30 days by PCI and randomization group 15 10 Death (%) p=0.07 for ENOX vs UFH in no PCI cohort 5 p=0.93 for ENOX vs UFH in PCI cohort 0 0 5 10 15 20 25 30 Days ENOX/PCI ENOX/no PCI UFH/PCI UFH/no PCI

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