Outcomes and Optimal Antithrombotic Therapy in Women Undergoing Fibrinolysis for ST-Elevation Myocardial Infarction Jessica L. Mega, MD; David A. Morrow, MD, MPH; Erika Ostor, MD; Maria Dorobantu, MD, PhD; Jie Qin, MS; Elliott M. Antman, MD; Eugene Braunwald, MD

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 FoldRxGlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corporation The National Institutes of Health 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 TIMI Study Group has received research / grant support in the past 2 years through the Brigham & Women’s Hospital with funding from (in alphabetical order): Disclosures

Background Since the 1980s, the number of deaths attributed to CVD has been greater for women than men. Following STEMI, women experience higher rates of reinfarction and death. Women continue to be under-represented in RCTs, and questions have been raised about treatment-specific outcomes in women post ACS. ExTRACT – TIMI 25 allowed for the evaluation of the outcomes and optimal antithrombotic treatment strategy in 4,783 women undergoing fibrinolysis for STEMI.

STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) 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 ) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage 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 N Engl J Med 2006;354: Design

Baseline Characteristics CharacteristicWomen (N=4,783) Men (N=15,696) P Value Age, years68 (59, 75)57 (49, 66)<0.001 Cr Cl, ml/min66 (51, 84)87 (69, 109)<0.001 TRS > 359%29%<0.001 Sx to Lytic, hrs3.5 (2.4, 4.6)3.0 (2.1, 4.2)<0.001 Aspirin93%96%<0.001 Clopidogrel22%30%<0.001 Beta blocker84%86%0.009 ACE-I/ARB81%79%0.059 Statin64%71%<0.001 Angio 30 d22%32%<0.001 Revasc 30 d19%29%<0.001

Clinical Outcomes - Mortality 30d Mortality AdjustedOR adj 1.25, 95% CI d ICH AdjustedOR adj 0.81, 95% CI 0.52 – 1.26 OR % CI 2.40 – 2.99 Mortality at 30 Days (%)

Age (Yrs) Women (N) Men (N) 4,502 2,065 2,443 1,909 1,952 1, Mortality at 30 Days (%) Men Women Mortality by Age Group

Death or MI (%) Days After Randomization Unfractionated Heparin Enoxaparin WOMEN Relative Risk, 0.84 (95% CI 0.74 – 0.95) P=0.007 MEN Relative Risk, 0.82 (95% CI 0.74 – 0.90) P< % 15.4% 10.1% 8.2% Cumulative Incidence of Primary Endpoint

Women Day 30 Death, MI, or Urg Revasc Death, MI, or Major Bleed Men Men Women UFH (%) ENOX (%) Enoxaparin BetterUFH Better RRR (%) ARD (%) NNT Efficacy and Safety

Number of Events Death Nonfatal Urgent Revascularization Nonfatal MI Nonfatal TIMI Major Bleeding + + Women Men Events per 1,000 Subjects Treated with Enoxaparin

Conclusion Women presented with a profile of higher baseline risk and had increased short-term mortality. The RRR in Death and nonfatal MI for enoxaparin vs UFH was similar in women and men, with a larger ARD in women. Although the excess risk of bleeding with enoxaparin was seen for both women and men, net clinical benefit strongly favored enoxaparin in both sexes.