TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Phases of TrialPhases of Trial

ControlControl InvestigationalInvestigational

Accel tPAAccel tPA

Accel tPAAccel tPA

rPA (10 +10 U)rPA (10 +10 U)

No lyticNo lytic

Abx +Abx +

tPAtPA

SKSK

Abx + 50 mg tPA + LD/VLD HeparinAbx + 50 mg tPA + LD/VLD Heparin

AbxAbx + + rPA + LD/VLD Heparin rPA + LD/VLD Heparin

tPA Phase (N= 888)tPA Phase (N= 888) (Circ 99 : 2720,1999)(Circ 99 : 2720,1999)

rPA Phase (N=299)rPA Phase (N=299)

tPA + rPA Pooled Database (N=1187)tPA + rPA Pooled Database (N=1187)

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

ST ST , lytic eligible, < 12 h , lytic eligible, < 12 h

ControlControlFull Dose Lytic:Full Dose Lytic:

tPA 100 mgtPA 100 mgoror

rPA 10 + 10 UrPA 10 + 10 U

Reduced Dose LyticReduced Dose Lytic

tPA, SK,rPAtPA, SK,rPA

No AbciximabNo Abciximab AbxAbx: bolus 0.25 mg/kg: bolus 0.25 mg/kg inf 0.125 inf 0.125 g/kg/min x 12 hg/kg/min x 12 h

STD HeparinSTD Heparin (70 U/kg ; 15 U/kg/h) (70 U/kg ; 15 U/kg/h)

ASAASA

Low Dose HeparinLow Dose Heparin (60 U/kg ; 7 U/kg/h) (60 U/kg ; 7 U/kg/h)

Very Low Dose HeparinVery Low Dose Heparin (30 U/kg ; 4 U/kg/h) (30 U/kg ; 4 U/kg/h)

Angio (90 min) , In Hospital Events, 30 day F/UAngio (90 min) , In Hospital Events, 30 day F/U

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

TIMI 3 Flow (Core Lab) : 90 minTIMI 3 Flow (Core Lab) : 90 min

57

32 3042

3446

80

0

20

40

60

80

100

57

32 3042

3446

80

0

20

40

60

80

100

% Pts

% % PtsPts

TIMI 14TIMI 14TIMI 14 bolus 0.25 inf 0.125

bolus 0.25 bolus 0.25 inf 0.125inf 0.125

500K500K500K 750K750K750K 1.5M1.5M1.5MTIMI 1 + GUSTO 1

TIMI 1 + TIMI 1 + GUSTO 1GUSTO 1

tPA 100 mg

tPA tPA 100 mg100 mg

AbxAbxAbx SK 1.5 M U

SK 1.5 SK 1.5 M UM U

SK + Abx

SK + SK + AbxAbx

1.25M1.25M1.25M

UUU

152152 3131 44443131 4444429 55N =N =N =

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

TIMI 3 Flow (Core Lab) : 90 minTIMI 3 Flow (Core Lab) : 90 min

57 53

38

61 59 63

76 74 73

0

20

40

60

80

100

57 53

38

61 59 63

76 74 73

0

20

40

60

80

100

% Pts

% % PtsPts

20 mg20 20 mgmg 35 mg35 35 mgmg 50 mg50 50 mgmg

TIMI 14TIMI 14TIMI 14

tPAtPAtPA tPA + Abx tPA + Abx tPA + Abx

65 mg65 65 mgmg

bbb bbb bbbinf 30m

inf inf 30m30m

inf 30m

inf inf 30m30m

inf 60m

inf inf 60m60m

inf 60m

inf inf 60m60m

inf 60m

inf inf 60m60m

100 mg100 100 mgmg

Abx bolus Abx bolus 0.3 mg/kg0.3 mg/kg

152152 3636 4040 4949 2929 4646 2929 3939 3333N =N =N =

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Safety Observations:Safety Observations:Dose Finding Phase N= 677Dose Finding Phase N= 677

Major Hemorrhage*Major Hemorrhage* (6.6% --mostly instr.; ICH = 1.2%) (6.6% --mostly instr.; ICH = 1.2%)tPA control tPA control 5%5%Abx aloneAbx alone 3%3%tPA + AbxtPA + Abx 6%6%SK + AbxSK + Abx 10% (dose related increase)10% (dose related increase)

ThrombocytopeniaThrombocytopenia <100K <100K <50K<50K tPA ControltPA Control 3%3% 0.6%0.6%Reperf. reg. with AbxReperf. reg. with Abx 7%7% 1.4%1.4%

Mortality (30 days)Mortality (30 days)

4.0% --no important differences across groups4.0% --no important differences across groups

Major Hemorrhage*Major Hemorrhage* (6.6% --mostly instr.; ICH = 1.2%) (6.6% --mostly instr.; ICH = 1.2%)tPA control tPA control 5%5%Abx aloneAbx alone 3%3%tPA + AbxtPA + Abx 6%6%SK + AbxSK + Abx 10% (dose related increase)10% (dose related increase)

ThrombocytopeniaThrombocytopenia <100K <100K <50K<50K tPA ControltPA Control 3%3% 0.6%0.6%Reperf. reg. with AbxReperf. reg. with Abx 7%7% 1.4%1.4%

Mortality (30 days)Mortality (30 days)

4.0% --no important differences across groups4.0% --no important differences across groups

*Major Hemorrhage = ICH, Retroperitoneal, or *Major Hemorrhage = ICH, Retroperitoneal, or Hg > 5 gm/dL Hg > 5 gm/dL

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Abciximab Improves the Speed and Abciximab Improves the Speed and Extent of Thrombolysis: 60 + 90 min Extent of Thrombolysis: 60 + 90 min

TIMI 3 FlowTIMI 3 Flow

4557

4049

58 62 6374

0

20

40

60

80

100

4557

4049

58 62 6374

0

20

40

60

80

100 tPAtPAtPA tPA + Abx tPA + Abx tPA + Abx

bolusbolusbolus bolus + 30 min inf

bolus + bolus + 30 min inf30 min inf

bolus + 60 min inf

bolus + bolus + 60 min inf60 min inf

100 mg100 mg100 mg

trend trend trend

60m60m60m 90m90m90m 60m60m60m 90m90m90m60m60m60m 90m90m90m 60m60m60m 90m90m90m

p< 0.0002 p< 0.0002 p< 0.0002 p< 0.02 p< 0.02 p< 0.02

% Pts

% % PtsPts

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Abciximab Facilitates ThrombolysisAbciximab Facilitates Thrombolysis tPA PhasetPA Phase

TIMI Frame Count- 60 min

P=0.001

0

20

40

60

80

100

00 2020 4040 6060 8080 100100

43

72

0

20

40

60

80

100P=0.0009

tPA 100 mg

TIMI 3 Flow- 60 min

tPA 50 mg + Abx

% P

ts

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

70 73 77

0

20

40

60

80

100

TIMI 3 Flow : 90 minTIMI 3 Flow : 90 minrPA PhaserPA Phase

10 + 10 U

87 88 75

5 + 5 U 10 + 5 U

% P

ts

N =

rPA rPA + Abx

rPA dose

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

TIMI 3 Flow : 90 minTIMI 3 Flow : 90 min tPA + tPA + rPA PhasesrPA Phases

627470 73

0

20

40

60

80

100

215 148 88

tPA50 mg

rPA5 + 5 U

% Pts

N =

Full Dose Lytic 50% Lytic+ Abx

87

tPA100 mg

rPA10 + 10 U

P=0.014

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Determinants of TIMI 3 flow at 90 MinDeterminants of TIMI 3 flow at 90 MintPA + rPA pooledtPA + rPA pooled

0.2 1 5

TIMI 3 Flow (N=610)

LAD

Time (per hour)

Abciximab

More LikelyLess LikelyO.R.

O.R. (95 CI)

0.93 (0.88,0.99)

1.57 (1.09,2.26)P=0.01

0.73 (0.51,1.04)

Lytic

Non Significant

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Evaluation of Myocardial PerfusionEvaluation of Myocardial Perfusion1. 1. ST Resolution:ST Resolution: Schr Schrööder JACC 26: 1657,1995der JACC 26: 1657,1995

CompleteComplete ( (>>70%) 70%) PartialPartial (30-70%) (30-70%) NoneNone ( (<< 30%) 30%)

2. 2. TIMI Myocardial Perfusion GradeTIMI Myocardial Perfusion Grade (MPG) (MPG)

CM Gibson Circulation 1999

TMP Grade 0 TMP Grade 1 TMP Grade 2 TMP Grade 3No or

minimal blushStain present.

Blush persists on next injection

Dye strongly persistent at end of washout. Gone by next injection

Normal ground glass appearance

of blush. Dye mildly persistent

at end of washout

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

Abciximab Improves Abciximab Improves Myocardial PerfusionMyocardial Perfusion

37

59

0

20

40

60

80

100

tPA tPA + Abx

% P

ts

Complete (> 70%) ST RES--90 min

P<0.001

N=125 N=221

42

60

0

20

40

60

80

100

rPA rPA + Abx

TMPG 2/390 min

P=0.08

N=33 N=66

de Lemos et al AHA 1999 C.M. Gibson 1999

tPA Phase rPA Phase

TIMI 14TIMI 14

Antman et al. Circ 99: 2720,1999

ConclusionsConclusionsReperfusion regimens to achieve TIMI 3 flow:Reperfusion regimens to achieve TIMI 3 flow:

1. Abciximab alone =1. Abciximab alone =full dose SK alonefull dose SK alone2. Abciximab augments 2. Abciximab augments rate and extent rate and extent ofof thrombolysis with thrombolysis with dose lytics dose lytics

60 min60 min 90 min90 min

tPA tPA tPA (50 mg)tPA (50 mg) tPA tPA tPA (50 mg)tPA (50 mg) 100mg 100mg + Abx + Abx 100mg 100mg + Abx+ Abx

TIMI 3 Flow 43% TIMI 3 Flow 43% 72%*72%* 62% 62% 77%*77%*

3. Safety profile encouraging3. Safety profile encouraging

Reperfusion regimens to achieve TIMI 3 flow:Reperfusion regimens to achieve TIMI 3 flow:1. Abciximab alone =1. Abciximab alone =full dose SK alonefull dose SK alone2. Abciximab augments 2. Abciximab augments rate and extent rate and extent ofof thrombolysis with thrombolysis with dose lytics dose lytics

60 min60 min 90 min90 min

tPA tPA tPA (50 mg)tPA (50 mg) tPA tPA tPA (50 mg)tPA (50 mg) 100mg 100mg + Abx + Abx 100mg 100mg + Abx+ Abx

TIMI 3 Flow 43% TIMI 3 Flow 43% 72%*72%* 62% 62% 77%*77%*

3. Safety profile encouraging3. Safety profile encouraging

* p=0.0009 unadjusted* p=0.0009 unadjusted* p=0.0009 unadjusted* p=0.0009 unadjusted * p=0.01 unadjusted* p=0.01 unadjusted* p=0.01 unadjusted* p=0.01 unadjusted