Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction
Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Ex. TRACT-TIMI 25 ACC 2006 Atlanta, GA Disclosure Statement: Dr. Antman received research grant support via the Brigham and Women’s Hospital from sanofi-aventis 1
Background • Advantages of ENOX over UFH Greater anti Xa: anti IIa activity Reliable A/C without monitoring Convenient sc administration • Prior trials suggest ENOX may be superior to UFH • Pharmacologic reperfusion remains the most common treatment for STEMI Definitive evaluation of ENOX vs UFH needed 2
Primary Hypothesis Compared to UFH, adjunctive antithrombin therapy with ENOX reduces the composite end point of all-cause mortality or non-fatal re-MI within 30 days in patients with STEMI who are eligible to receive fibrinolytic therapy. 3
Trial Organization TIMI Study Group Eugene Braunwald David A. Morrow Sabina Murphy Elliott M. Antman Carolyn H. Mc. Cabe Susan Mc. Hale Sponsor: sanofi-aventis Frank Jiang Paul Chew Lu Cui Christophe Gaudin Sylvie Fontecave Kim Giordano Data Safety Monitoring Board Frans Van de Werf (Chair) Desmond Julian J. Ward Kennedy David De. Mets Jean Rouleau Jeffrey Anderson 4
Protocol Design STEMI < 6 h Lytic eligible ASA Lytic choice by MD (TNK, t. PA, r. PA, SK) Double-blind, double-dummy ENOX < 75 y: 30 mg IV bolus SC 1. 0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0. 75 mg / kg q 12 h (Hosp DC) UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion Cr. Cl < 30: 1. 0 mg / kg q 24 h Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage 5
Enrollment: Oct 2002 - Oct 2005 N = 20, 479 (ITT) Argentina Finland Latvia Singapore Australia France Lebanon Slovakia Austria Germany Lithuania South Africa Belarus Greece Malaysia Spain Belgium Hong Kong Mexico Sweden Brazil Hungary Netherlands Switzerland Bulgaria India New Zealand Thailand Canada Ireland Norway Turkey Chile Israel Poland Ukraine China Italy Portugal United Kingdom Croatia Jordan Romania United States Estonia Republic of Korea Russian Federation Uruguay 48 Countries 674 Sites 6
Baseline Characteristics ITT N = 20, 479 Age (yrs)-median 59 Cr. Cl (ml/min)-median 82 Male (%) 77 UFH within 3 h (%) Hypertension (%) 44 LMWH within 7 d (%) 0. 5 Hyperlipidemia (%) 18 Killip Class I (%) Current smoker (%) 47 TIMI Risk Score (STEMI) Diabetes (%) 15 < 3 (%) 64 Prior MI (%) 13 > 3 (%) 36 Anterior MI (%) 44 ALL P = NS 16 89 7
Medications ITT N = 20, 479 Fibrinolytic 20 SK (%) Fibrin-specific (%) 80 ASA (%) Beta Blocker (%) ACEI / ARB (%) Statin (%) ALL P = NS 95 86 80 70 8
Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%) UFH 12. 0% 17% RRR 9. 9% ENOX Relative Risk 0. 83 (0. 77 to 0. 90) P<0. 0001 Lost to follow up = 3 Days 9
Treatment Benefit over Time (ITT) Death or Nonfatal MI 48 h Primary End Point (%) UFH 206 events ENOX 12. 0% (1223) 9. 9% (1017) 5. 2% 4. 7% RR 0. 90 (0. 80 to 1. 01) P=0. 08 UFH ENOX Days 10
Major Secondary End Point Death or Nonfatal MI or Urgent Revascularization (ITT) Secondary End Point (%) 48 h UFH 280 events 19% RRR ENOX 14. 5% (1479) 11. 7% (1199) RR 0. 81 (0. 75 to 0. 87) P<0. 0001 6. 1% 5. 3% 12% RRR RR 0. 88 (0. 79 to 0. 98) P=0. 02 UFH ENOX Days 11
Outcomes at 30 Days (ITT) 8% UFH ENOX 33% % 26% RR 0. 92 0. 67 0. 74 P value 0. 11 <0. 0001 0. 0008 12
Death or Nonfatal MI - Day 30 Major Subgroups Reduction In Risk (%) Male SEX All Interaction Tests P = NS Female 20 6 < 75 AGE (y) >= 75 INFARCT LOCATION Anterior DIABETES No DM 11 23 Other B 17 21 B 17 20 DM No Prior MI PRIOR MI Prior MI FIBRINOLYTIC 13 18 Streptokinase Fibrin-specific 23 12 < Median TIME TO Rx > Median B 20, 479 OVERALL 18 16 0. 5 ENOX Better P < 0. 0001 1 Relative Risk 17 2 UFH Better 13
Death or Nonfatal MI - Day 30 Medical Rx vs Any PCI 13. 8 % Events 11. 4 10. 7 9. 7 RRR 23% RRR 16% UFH ENOX Any PCI N = 4, 676 (23%) P Value 0. 001 Medical Rx N = 15, 223 (75%) 0. 0004 14
Death or Nonfatal MI - Day 30 Clopidogrel Use % Events 12. 2 11. 4 10. 4 RRR 15% 8. 7 RRR 24% UFH ENOX No Clopidogrel Used* N = 14, 752 (78%) N = 5, 727 (28%) P Value 0. 0005 0. 0006 * 2546 clopidogrel treated patients did not undergo PCI 15
Bleeding Endpoints (TIMI) 30 Days % Events UFH ENOX ARD 0. 7% RR 1. 53 ARD 0. 4% RR 1. 39 ARD 0. 1% RR 1. 27 P<0. 0001 P = 0. 014 P = 0. 14 Major Bleed Nonfatal Major Bleed ICH (fatal + nonfatal) 16
Net Clinical Benefit at 30 Days Prespecified Definitions Death or Nonfatal MI or Nonfatal Disabl. Stroke Death or Nonfatal MI or Nonfatal Major Bleed Death or Nonfatal MI or Nonfatal ICH UFH (%) ENOX (%) RRR (%) 12. 3 10. 1 18 12. 8 11. 0 14 12. 2 10. 1 17 P <0. 0001 0. 8 0. 9 ENOX Better 1 RR 1. 25 UFH Better 17
For Every 1000 Pts Treated with Enoxaparin Events / 1000 Pts + (No increase in nonfatal ICH) Nonfatal re. MI Urgent Revasc. Death Nonfatal TIMI Major Bleed 18
Clinical Implication A strategy of ENOX is clearly preferable to the current standard of UFH as the antithrombin to support fibrinolysis, the most common form of reperfusion for STEMI used worldwide. 19
Publication of Primary Results www. NEJM. org Slides and Full Listing of Trial Participants at www. TIMI. org 20
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Trial Results In Perspective: Major Bleeding Rates % Pts with Major Bleeds in Prior Trials Pooled Data UFH LMWH ENOX UFH Keeley Lancet 2003 Lytic Arms Eikelboom Circ. 2005 Major Bleed (Total) UFH ENOX Nonfatal Major Bleed 22
Trial Results In Perspective: PCI vs Lysis for STEMI (30 -42 Days) % Events Overview of 23 RCTs Keeley Lancet 2003 Lytic Arms (UFH) PCI Arms ENOX Reinfarction The significant advance in adjunctive therapy with enoxaparin has narrowed the gap between PCI and Lysis as reperfusion for STEMI. 23
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