ASSENT-3 PLUS 1,639 patients with STEMI Treatment Group A Chest pain < 6 hrs Pt evaluated at home or in ambulance by emergency medical team 12-lead ECG transmitted to ED from the ambulance Pt randomized and treatment started during transport Treatment Group A Enoxaparin + TNK (n = 818) Treatment Group B UFH + TNK (n = 821) Endpoints: Primary Efficacy– 30 day Death or In-hospital MI or Refractory Ischemia Primary Efficacy plus Safety - 30 day Death or In-hospital MI, Refractory Ischemia, ICH or Major Bleed Wallentin et al, AHA 2002

ASSENT-3 PLUS: Primary Endpoints Death / MI / Refractory Ischemia/ ICH / Major Bleed Death / MI / Refractory Ischemia P=0.080 P=0.297 n=818 n=821 n=818 n=821 Enoxaparin + TNK UFH + TNK Enoxaparin + TNK UFH + TNK Wallentin et al, AHA 2002

ASSENT-3 PLUS: Individual Endpoints Death Recurrent MI Refractory Ischemia ICH P=0.028 P=0.067 P=0.047 P=0.234 Enoxaparin + TNK UFH + TNK Enoxaparin + TNK UFH + TNK Enoxaparin + TNK Enoxaparin + TNK UFH + TNK UFH + TNK Wallentin et al, AHA 2002

ASSENT-3 PLUS: Bleeding Results Stroke ICH Major Bleed P=0.026 P=0.047 P=0.168 Similar to prior studies Enoxaparin + TNK UFH + TNK Enoxaparin + TNK UFH + TNK Enoxaparin + TNK UFH + TNK Wallentin et al, AHA 2002

ASSENT 3 ICH Subgroups In subgroup analysis, ICH bleeding was greater in the enoxaparin group in patients >75 years old (6.71 vs. 0.76% p = 0.04) females (5.15% vs. 1.09%, p = 0.02), and low body weight (<60kg) patients (5.17% vs. 0%, p = 0.08) There was a non-statistically significant trend toward increased major bleeding in the enoxaparin group (4.04% vs. 2.80%, p = 0.168). Twenty-five percent of the patients in each arm continued on to PCI. None of those patients experienced ICH bleeding, suggesting full-dose TNKase is safe in the cath lab.

Why Was There More Bleeding in the Enoxaparin Group? Administration of additional enoxaparin was frequent The heparin bag is “visible”, the bolus of enoxaparin is “invisible” to people caring for the patient subsequently Occurred more in Europe This was a higher risk population

ASSENT-3 PLUS: Primary Endpoint by Age Group Death / MI / Refractory Ischemia Death / MI / Refractory Ischemia P=0.033 P=0.694 Enoxaparin + TNK UFH + TNK Enoxaparin + TNK UFH + TNK Wallentin et al, AHA 2002

ASSENT 3 Plus Supports the Concept that Time is Muscle Symptom onset to treatment times were reduced by 45 minutes. Fifty percent of patients were treated within 2 hours which represents a significant improvement over ASSENT-3 in which only 29% of the more than 4,000 patients receiving the same regimens in the hospital setting were treated within the same time period. Earlier treatment was associated with improved outcomes: 30 day mortality 4.4% (0-2hr), 6.2% (2-4hr), 10.4% (4-6hr). This data, combined with a meta-analysis of all pre-hospital thrombolysis studies showing a 16% improvement in mortality (Morrison et.al, JAMA May 2000), further supports the concept of “time is muscle” and early treatment. CM Gibson 2002

ASSENT-3 PLUS: Summary In the pre-hospital setting, treatment with enoxaparin plus TNK did not provide significant additional benefit over treatment with UFH plus TNK for STEMI. Pre-hospital TNK plus heparin does, however, appear to be safe and lower treatment times Reduced or weight-adjusted dosing of enoxaparin may be warranted in elderly and low weight patients Use of reduced dose enoxaparin in addition to TNK will be further investigated in the upcoming EXTRACT-TIMI trial CM Gibson 2002