TIMI 11A A Multicenter Trial of the Safety and Tolerability of Two Doses of Enoxaparin in Patients With Unstable Angina and Non-Q-Wave Myocardial Infarction E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Design:Multicenter, Open-label, Dose-ranging Size:630 patients 15 centers Countries:USA and Canada Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Dose 2 N=309 Dose 1 N=320 IV Bolus IV Bolus Wgt Adj Fixed Dose 30 mg 30 mg 1.25 mg/kg 1.25 mg/kg Q 12 h (2-8d) 1.0 mg/kg 1.0 mg/kg Q 12 h (2-8d) < 65 kg > 65 kg 40 mg 60 mg Q12 h 40 mg 60 mg Q12 h Total Rx Period = 14 days < 65 kg > 65 kg Hospital PhaseHome Rx TIMI 11A Protocol Design E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Primary Evaluate safety and tolerability of two doses of enoxaparin in patients with UA/NQMIEvaluate safety and tolerability of two doses of enoxaparin in patients with UA/NQMISecondary Correlate anti-Xa levels with enoxaparin doseCorrelate anti-Xa levels with enoxaparin dose Provide preliminary data on clinical outcomes in the dose tiers evaluatedProvide preliminary data on clinical outcomes in the dose tiers evaluated Objectives E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Inclusion Criteria: Unstable angina or NQMIUnstable angina or NQMI – Rest angina > 5 minutes – New onset – Increasing angina Evidence of CADEvidence of CAD Exclusion Criteria: Recent thrombolytic therapyRecent thrombolytic therapy Creatinine > 2 mg/dLCreatinine > 2 mg/dL History of heparin-induced thrombocytopeniaHistory of heparin-induced thrombocytopenia E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Primary Endpoint: Major Hemorrhage overt hemorrhage associated with:Major Hemorrhage overt hemorrhage associated with: –>3 gm/dL fall in hemoglobin –Intracranial, retroperitoneal, or intraocular hemorrhage Secondary Endpoint: Anti-Xa levelsAnti-Xa levels Death, MI, recurrent ischemia leading to revascularizationDeath, MI, recurrent ischemia leading to revascularization E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Incidence of Major Hemorrhage Dose Tier mg/kg (n=321) InstrumentedSpontaneous6.5% 1.9% Dose Tier mg/kg (n=309) % of Patients Through Day 14 E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Incidence of Major Hemorrhage In-Hospital Period Only Dose Tier mg/kg (n=321) InstrumentedSpontaneous5.6% 1.3% Dose Tier mg/kg (n=309) % of Patients E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Summary of Major Event Incidence After Adjudication from Initial Hospitalization to Day 14 Primary Efficacy Outcome18 (5.6%)16 (5.2%) (death, MI, recurrent angina) Secondary Outcome14 (4.4%)11 (3.6%) (death, MI) Death7 (2.2%)2 (0.6%) Non-fatal MI7 (2.2%)9 (2.9%) Recurrent Angina Requiring Revascularization4 (1.2%)5 (1.6%) 1.25 mg/kg1.0 mg/kg (n = 321)(n = 309) All Treated Patients E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

N= mg/kg Instrumented Spontaneous 6.5% 1.9% T3B Hep + Plac N= % N= mg/kg Dose Tier 1Dose Tier 2 % TIMI 11 A Investigators. JACC 29: 1474,1997 TIMI 11A Primary Results Incidence of Major Hemorrhage thru 14 days

Days % Death / MI / Rec. Isch. Weight- adjusted dose Fixed dose 5.6% 5.2% 1.25 mg/kg (n=321) 1.0 mg/kg (n=309) Probability of Cardiovascular Events Death / MI / Rec Isch req. Revasc E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Steady-State Anti-Xa Levels in Patients with Unstable Angina Anti-Xa (IU/ml) 3rd dose Last dose 3rd dose Last dose 1.25 mg/kg 1.0 mg/kg Trough Peak E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

CRP Concentration N = 437N = 346 TIMI 11A Risk Stratification Baseline C-reactive Protein and Mortality Morrow et al. JACC 1998;31:1460-5

Conclusions Acute Phase Enoxaparin 1.0 mg/kg SQ q 12 H associated with a low rate of major hemorrhage comparable to historical rates of heparin in similar cohortsEnoxaparin 1.0 mg/kg SQ q 12 H associated with a low rate of major hemorrhage comparable to historical rates of heparin in similar cohorts Anti-Xa activity Dose-related increaseDose-related increase No accumulation after multiple dosesNo accumulation after multiple doses Cardiovascular event rates are comparable in both dose tiers E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

TIMI 11B The Effectiveness and Safety of Subcutaneous Enoxaparin Compared to Intravenous Unfractionated Heparin for Patients Presenting with Unstable Angina or Non-Q-wave MI: An International Double-blind, Randomized, Parallel Group, Multicenter Study Antman et al, Circulation 1999 Oct 12;100(15):

Design:Randomized, Double-blind, Placebo- controlled, Parallel Group, Multicenter Size:4020 patients 180 centers Countries:N. AmericaS. AmericaEurope CanadaArgentinaSpain USAUruguayFrance ChileGermany NetherlandsUK Antman et al, Circulation 1999 Oct 12;100(15):

Primary To demonstrate that uninterrupted enoxaparin SQ over 43 days is superior to UFH IV (72 H) followed by aspirin aloneTo demonstrate that uninterrupted enoxaparin SQ over 43 days is superior to UFH IV (72 H) followed by aspirin aloneSecondary Cost-effectiveness comparison of the different treatment armsCost-effectiveness comparison of the different treatment arms Objectives Antman et al, Circulation 1999 Oct 12;100(15):

Rest unstable angina or NQMIRest unstable angina or NQMI ST deviation > 0.5 mm or positive serum cardiac markersST deviation > 0.5 mm or positive serum cardiac markers Inclusion Criteria Antman et al, Circulation 1999 Oct 12;100(15):

Physician planning revascularization within 24 hoursPhysician planning revascularization within 24 hours Angina related to an evolving Q-wave MI angina precipitated by secondary causes (e.g., tachydysrhythmia, etc.)Angina related to an evolving Q-wave MI angina precipitated by secondary causes (e.g., tachydysrhythmia, etc.) CABG within 2 months, mechanical intervention within 6 monthsCABG within 2 months, mechanical intervention within 6 months History of heparin-induced thrombocytopeniaHistory of heparin-induced thrombocytopenia Exclusion Criteria Antman et al, Circulation 1999 Oct 12;100(15):

Primary Endpoint - Efficacy Death, MI, recurrent ischemia requiring urgent revascularization at study day 43Death, MI, recurrent ischemia requiring urgent revascularization at study day 43 Primary Endpoint - Safety Major hemorrhage at study day 43Major hemorrhage at study day 43 –Death –Transfusion of >2 units packed blood –> 3 gm/dL fall in hemoglobin –Intracranial, retroperitoneal, or intraocular hemorrhage Antman et al, Circulation 1999 Oct 12;100(15):

ENOX Bolus 30 mg IV Bolus 30 mg IV 1.0 mg / kg Q12h Pt. with UA/NQMI < 24 h Primary Endpoint: UFH > 3 days Bolus 70 U / kg INF 15 U / kg / h Major Bleeding Serious AEs ASA aPTT x control Hosp DC (or 8 days) TIMI 11B Protocol Design Death, MI, Urgent Revascularization Acute Phase Protocol Antman et al, Circulation 1999 Oct 12;100(15):

P=0.029 RRR 15 % UFH ENOX 16.7 % 14.2 % % Days 14.5 % 12.4 % P=0.048 RRR 15 % TIMI 11B Primary Results Death/MI/Urgent Revascularization at 14 Days E. Antman for The TIMI 11B Investigators Circulation 1999.

% Pts UFH ENOX 5.2 % 4.2 % RRR 18% P= % 5.5 % RRR 24% P=0.02 ESSENCE TIMI 11 B Hours from Randomization Efficacy Results Death/MI/Urgent Revasc. Early Rx Phase TIMI 11B E. Antman for The TIMI 11B Investigators Circulation 1999.

Efficacy Results TIMI 11B - ESSENCE Meta-Analysis OVERALL ESSENCE TIMI 11B OVERALL ESSENCE TIMI 11B OVERALL ESSENCE TIMI 11B Day Odds Ratio Enox Better UFH Better OR%p 0.77 ( ) ( ) ( ) N         UFH (%) Enox (%) Death/MI Antman E, Cohen M for The TIMI 11B & ESSENCE Investigators Circulation 1999.

Pt. with UA/NQMI < 24 h Death, MI, Severe Rec Isch Requiring Urgent Revasc Acute = Day 8 UFH iv > 72 h Major Bleeding Serious AEs ASA ENOX iv-b,sc Placebo sc ENOX sc Chronic = Day 43 TIMI 11B Protocol Design Antman et al, Circulation 1999 Oct 12;100(15):

Days P=0.048 RRR 12 % UFH ENOX 19.7 % 17.3 % % TIMI 11B Primary Results: Chronic Phase Death/MI/Urgent Revascularization at 43 Days E. Antman for The TIMI 11B Investigators Circulation 1999.

TIMI 11B Efficacy Results Efficacy of Enoxaparin Stratified by Baseline Risk High (N=593) Inter (N=1645) Low (N=1672) UFH (%) ENOX (%) OR (95 CI) Favors ENOX Favors UFH O.R (0.55,1.13) (0.66,1.08) 0.94 (0.72,1.23) B B % P=0.079 trend Day 43 Death/MI/UR at 43 Days Holper E. AHA 1998

TIMI 11B Efficacy Results Efficacy of Enoxaparin Stratified by Rx Strategy Med Rx Guzman ESC 1999 PCICABG OR (95 CI) 0.85 (0.62,1.16) 0.77 (0.45,1.31) 1.04 (0.55,1.95) D/MI/UR