ASSENT-3 PLUSASSENT-3 PLUS

1,639 patients with STEMI 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

1,639 patients with STEMI 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 AEnoxaparin + TNK

(n = 818)

Treatment Group AEnoxaparin + TNK

(n = 818)

Treatment Group BUFH + TNK

(n = 821)

Treatment Group BUFH + 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

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 2002Wallentin et al, AHA 2002

14.2%

17.4%

0%

5%

10%

15%

20%

14.2%

17.4%

0%

5%

10%

15%

20%

Enoxaparin+ TNK

Enoxaparin+ TNK

UFH+ TNKUFH

+ TNK

P=0.080P=0.080

Death / MI / Refractory IschemiaDeath / MI / Refractory Ischemia Death / MI / Refractory Ischemia/ ICH / Major Bleed

Death / MI / Refractory Ischemia/ ICH / Major Bleed

ASSENT-3 PLUS: Primary EndpointsASSENT-3 PLUS: Primary EndpointsASSENT-3 PLUS: Primary EndpointsASSENT-3 PLUS: Primary Endpoints

Wallentin et al, AHA 2002Wallentin et al, AHA 2002

n=818 n=821

18.3%

20.3%

0%

5%

10%

15%

20% 18.3%

20.3%

0%

5%

10%

15%

20%

P=0.297P=0.297

Enoxaparin+ TNK

Enoxaparin+ TNK

UFH+ TNKUFH

+ TNK

n=818 n=821

3.6%

5.9%

0%

2%

4%

6%

8%

3.6%

5.9%

0%

2%

4%

6%

8%

4.4%

6.5%

0%

2%

4%

6%

8%

4.4%

6.5%

0%

2%

4%

6%

8%7.5%

6.0%

0%

2%

4%

6%

8% 7.5%

6.0%

0%

2%

4%

6%

8%P=0.234P=0.234

DeathDeath

ASSENT-3 PLUS: Individual EndpointsASSENT-3 PLUS: Individual EndpointsASSENT-3 PLUS: Individual EndpointsASSENT-3 PLUS: Individual Endpoints

ICHICHP=0.028P=0.028

Recurrent MIRecurrent MI

Enoxaparin+ TNK

Enoxaparin+ TNK

UFH+ TNKUFH

+ TNK

2.2%

1.0%

0%

1%

2%

3%

2.2%

1.0%

0%

1%

2%

3%

P=0.047P=0.047P=0.067P=0.067

Refractory IschemiaRefractory Ischemia

Wallentin et al, AHA 2002Wallentin et al, AHA 2002

Enoxaparin+ TNK

Enoxaparin+ TNK

UFH+ TNKUFH

+ TNKEnoxaparin

+ TNKEnoxaparin

+ TNKUFH

+ TNKUFH

+ TNKEnoxaparin

+ TNKEnoxaparin

+ TNKUFH

+ TNKUFH

+ TNK

4.0%

2.8%

0%

2%

4%

6%

4.0%

2.8%

0%

2%

4%

6%

2.2%

1.0%

0%

1%

2%

3%

4%

2.2%

1.0%

0%

1%

2%

3%

4%

2.9%

1.3%

0%

1%

2%

3%

4%

2.9%

1.3%

0%

1%

2%

3%

4%P=0.026P=0.026 P=0.047P=0.047

StrokeStroke ICHICH

P=0.168P=0.168

Major BleedMajor Bleed

ASSENT-3 PLUS: Bleeding ResultsASSENT-3 PLUS: Bleeding ResultsASSENT-3 PLUS: Bleeding ResultsASSENT-3 PLUS: Bleeding Results

Enoxaparin

+ TNK

Enoxaparin

+ TNKUFH

+ TNK

UFH

+ TNK

Wallentin et al, AHA 2002Wallentin et al, AHA 2002

Enoxaparin

+ TNK

Enoxaparin

+ TNKUFH

+ TNK

UFH

+ TNK

Enoxaparin

+ TNK

Enoxaparin

+ TNKUFH

+ TNK

UFH

+ TNK

Similar to prior studies

Similar to prior studies

ASSENT 3 ICH SubgroupsASSENT 3 ICH SubgroupsASSENT 3 ICH SubgroupsASSENT 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.

• 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?Why Was There More Bleeding in the Enoxaparin Group?Why Was There More Bleeding in the Enoxaparin Group?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

• 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

11.2%

15.2%

0%

5%

10%

15%

20%

11.2%

15.2%

0%

5%

10%

15%

20%

Enoxaparin+ TNK

Enoxaparin+ TNK

UFH+ TNKUFH

+ TNK

P=0.033P=0.033

Death / MI / Refractory IschemiaDeath / MI / Refractory Ischemia

ASSENT-3 PLUS: Primary Endpoint by Age GroupASSENT-3 PLUS: Primary Endpoint by Age GroupASSENT-3 PLUS: Primary Endpoint by Age GroupASSENT-3 PLUS: Primary Endpoint by Age Group

Wallentin et al, AHA 2002Wallentin et al, AHA 2002

Age <75Age <75

35.6%33.3%

0%

10%

20%

30%

40%35.6%

33.3%

0%

10%

20%

30%

40%

Enoxaparin+ TNK

Enoxaparin+ TNK

UFH+ TNKUFH

+ TNK

P=0.694P=0.694

Death / MI / Refractory IschemiaDeath / MI / Refractory Ischemia

Age >75Age >75

ASSENT 3 Plus Supports the Concept that Time is MuscleASSENT 3 Plus Supports the Concept that Time is MuscleASSENT 3 Plus Supports the Concept that Time is MuscleASSENT 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.

• 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 2002CM Gibson 2002

ASSENT-3 PLUS: SummaryASSENT-3 PLUS: SummaryASSENT-3 PLUS: SummaryASSENT-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

• 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 2002CM Gibson 2002