The 90 Minute Wall: 60% Rates of TIMI Grade 3 Flow % TIMI 3 Flow

60 60 5763

0

20

40

60

80

100

tPA rPA NPA TNK40

60 60 5763

0

20

40

60

80

100

tPA rPA NPA TNK40

The 90 Minute Wall:The 90 Minute Wall: 60% Rates of TIMI Grade 3 Flow

60% Rates of TIMI Grade 3 Flow

% T

IMI 3

Flo

w%

TIM

I 3 F

low

What Do We Need to Do to Achieve Another 1% Mortality Reduction in AMI?

What Do We Need to Do to Achieve Another 1% Mortality Reduction in AMI?

0

10

20

30

40

50

60

tPA SK

0

10

20

30

40

50

60

tPA SK

% T

IMI

Gra

de

3 F

low

% T

IMI

Gra

de

3 F

low

5 6 7 8

SK

tPA

5 6 7 8

SK

tPA

Mortality (%)Mortality (%)

A 20% improvement in TIMI Grade 3 flow led to a 1% improvement in

mortality in GUSTO 1

A 20% improvement in TIMI Grade 3 flow led to a 1% improvement in

mortality in GUSTO 1

54%54%

32%32%

6.3%6.3%

7.4%7.4%

Microvascular Dysfunction Following AMIMicrovascular Dysfunction Following AMI

Microvascular Obstruction

Platelet microembolization

Thrombosis

Reperfusion Injury

Neutrophil aggregation

Complement activation

Free radical generation

Endothelial dysfunction, spasm, microvascular constriction

Microvascular Obstruction

Platelet microembolization

Thrombosis

Reperfusion Injury

Neutrophil aggregation

Complement activation

Free radical generation

Endothelial dysfunction, spasm, microvascular constriction

Paradoxical Activation of Coagulation Following Thrombolytic Administration

Paradoxical Activation of Coagulation Following Thrombolytic Administration

• Thrombin generation• Clot bound thrombin exposed as lysis proceeds• Plasmin activation• Rapid flow through a narrow lumen increases

shear force & activates platelets• Activated platelets in turn activate plasminogen

inactivator (PAI 1)

• Thrombin generation• Clot bound thrombin exposed as lysis proceeds• Plasmin activation• Rapid flow through a narrow lumen increases

shear force & activates platelets• Activated platelets in turn activate plasminogen

inactivator (PAI 1)

CM Gibson Annals Int Med 1999CM Gibson Annals Int Med 1999

Motivation for the Development of Combination Therapy

Motivation for the Development of Combination Therapy

• Improved lysis of thrombus (more rapid & more complete), better flow

• Reduced reocclusion

• Improved microvascular function

• Improved safety (reduced bleeding due to reduction in dose of thrombolytic agent)

• Improved lysis of thrombus (more rapid & more complete), better flow

• Reduced reocclusion

• Improved microvascular function

• Improved safety (reduced bleeding due to reduction in dose of thrombolytic agent)


ST Segment Acute MI Trials Involving GP 2b3a InhibitorsST Segment Acute MI Trials Involving GP 2b3a Inhibitors

Combination TherapyWith Thrombolytic Agents

Combination TherapyWith Thrombolytic Agents

PCI TrialsPCI Trials

Full Dose Lytic + GP 2b3a

Full Dose Lytic + GP 2b3a

Reduced Dose Lytic + GP 2b3aReduced Dose Lytic + GP 2b3a

TAMI 8Impact AMIParadigm

SK- Eptifibatide

TAMI 8Impact AMIParadigm

SK- Eptifibatide

TIMI 14SPEED

INTRO AMI

TIMI 14SPEED

INTRO AMI

FASTERENTIRE

INTEGRITI

FASTERENTIRE

INTEGRITI

GRAPERAPPORTADMIRALCADILLAC

GRAPERAPPORTADMIRALCADILLAC


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

Group IGroup I

tPA tPA << 100 mg 100 mg

Group IGroup I

tPA tPA << 100 mg 100 mgGroup IIGroup II

dose tPAdose tPA

Group IIGroup II

dose tPAdose tPA

Group IIIGroup III

dose SKdose SK

Group IIIGroup III

dose SKdose SKGroup IVGroup IV

No lyticNo lytic

Group IVGroup IV

No lyticNo lytic

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

No ReoProNo ReoProNo ReoProNo ReoPro ReoProReoPro: 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

ReoProReoPro: 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)

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

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

ASAASAASAASA

TIMI 14TIMI 14TIMI 14TIMI 14

TIMI 14 Study Group, Circulation 1999; 99: 2720. TIMI 14 Study Group, Circulation 1999; 99: 2720.

TIMI 14: TIMI 2/3 Flow (Core Lab): 90 min TIMI 14: TIMI 2/3 Flow (Core Lab): 90 min

58

32 3042 39

47 54 6179

69

21

24

3927

32 2120

1520

16

0

20

40

60

80

100

58

32 3042 39

47 54 6179

69

21

24

3927

32 2120

1520

16

0

20

40

60

80

100

tPAtPAtPAtPA 50 mg tPA + ReoPro50 mg tPA + ReoPro50 mg tPA + ReoPro50 mg tPA + ReoPro

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

ReoProReoProReoProReoProSK SK 1.5M U1.5M U

SK SK 1.5M U1.5M U

SK + SK + ReoProReoPro


% % PtsPts

% % PtsPts

94949494

79797979

48484848

TIMI 14TIMI 14TIMI 14TIMI 14

79797979

54545454

81818181

6666666675757575 81818181

bbbb inf inf 30’30’

inf inf 30’30’

inf inf 60’60’

inf inf 60’60’

inf inf 60’60’

inf inf 60’60’

146146 3131 429429 3636 4949 4747 2828 4646 3636N =N =N =N =

100 mg100 mg100 mg100 mg

bolus 0.25 bolus 0.25 inf 0.125inf 0.125

bolus 0.25 bolus 0.25 inf 0.125inf 0.125

500 500 KK

500 500 KK

750 750 KK

750 750 KK

1.25 1.25 MM

1.25 1.25 MM

UUUU

3434

89898989

TIMI 1 + TIMI 1 + GUSTO 1GUSTO 1

TIMI 1 + TIMI 1 + GUSTO 1GUSTO 1


TIMI Frame Count: 90 minTIMI Frame Count: 90 minTIMI 14TIMI 14TIMI 14TIMI 14

00101020203030404050506060707080809090

100100

00 1010 2020 3030 4040 5050 6060 7070 8080 9090 100100

% P

atie

nts

% P

atie

nts

% P

atie

nts

% P

atie

nts

Corrected TIMI Frame CountCorrected TIMI Frame CountCorrected TIMI Frame CountCorrected TIMI Frame Count

Normal Normal Flow Flow

cTFC < 28cTFC < 28

Normal Normal Flow Flow

cTFC < 28cTFC < 28tPA 100 mg tPA 100 mg 3737tPA 100 mg tPA 100 mg 3737

tPA (bolus/60 m inf)+ ReoPro tPA (bolus/60 m inf)+ ReoPro 3131tPA (bolus/60 m inf)+ ReoPro tPA (bolus/60 m inf)+ ReoPro 3131

ReoPro ReoPro 100100 ReoPro ReoPro 100100

SK + ReoPro SK + ReoPro 4545SK + ReoPro SK + ReoPro 4545

TFCTFC Median Median

TFCTFC Median Median


TIMI 14TIMI 14

Circ 99: 2720,1999

Abciximab Facilitates ThrombolysisAbciximab Facilitates Thrombolysis

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

62%

76% 77% 77%69%

0%

25%

50%

75%

100%

62%

76% 77% 77%69%

0%

25%

50%

75%

100%

TIMI-14: TIMI 3 Flow (Core Lab) at 90 MinTIMI-14: TIMI 3 Flow (Core Lab) at 90 Min

t-PA100 mg

t-PA100 mg

AllAllDose Conf.Dose Conf.

Dose FindDose Find

t-PA (50 mg*) + Abciximab t-PA (50 mg*) + Abciximab

Low-dose HeparinLow-dose Heparin Very Low-doseHeparin

Very Low-doseHeparin

214214 8787 616158582929

p < 0.02p < 0.02

*(bolus 15 mg; infusion 35 mg x 60 m)*(bolus 15 mg; infusion 35 mg x 60 m)*(bolus 15 mg; infusion 35 mg x 60 m)*(bolus 15 mg; infusion 35 mg x 60 m)TIMI 14 Study Group, Circulation 1999; 99: 2720. TIMI 14 Study Group, Circulation 1999; 99: 2720.

Abciximab Improves Myocardial PerfusionAbciximab Improves Myocardial Perfusion

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

Complete (>70%) ST Resolution at 90 Min.Complete (>70%) ST Resolution at 90 Min.

Myocardial Perfusion Grade 2/3 at 90 Min.

Myocardial Perfusion Grade 2/3 at 90 Min.

% P

atie

nts

% P

atie

nts

% P

atie

nts

% P

atie

nts

N=125N=125 N=221N=221 N=33N=33 N=66N=66

tPAtPA rPArPAtPA + AbxtPA + Abx rPA + AbxrPA + Abx

p<0.001p<0.001 p<0.08p<0.08

de Lemos AHA 1999de Lemos AHA 1999 Gibson AHA 1999Gibson AHA 1999

29%

51%48%

62%

0

50

100

29%

51%48%

62%

0

50

100

TIMI Grade 3 Flow at 60–90 MinAngiographic Core Lab Reading

TIMI Grade 3 Flow at 60–90 MinAngiographic Core Lab Reading

n = 107 n = 103 n = 75 n = 66

r-PAr-PA 60 U Hep60 U Hep 40 U Hep40 U Hep AbciximabAbciximabAloneAlone AbciximabAbciximab AbciximabAbciximab AloneAlone

+ r-PA 5 + 5+ r-PA 5 + 5 + r-PA 5 + 5+ r-PA 5 + 5

n = 107 n = 103 n = 75 n = 66

r-PAr-PA 60 U Hep60 U Hep 40 U Hep40 U Hep AbciximabAbciximabAloneAlone AbciximabAbciximab AbciximabAbciximab AloneAlone

+ r-PA 5 + 5+ r-PA 5 + 5 + r-PA 5 + 5+ r-PA 5 + 5

Dose escalation and confirmation combinedDose escalation and confirmation combined

p = 0.2p = 0.2p 0.06p 0.06

AbciximabAbciximab0.25 mg/kg bolus0.25 mg/kg bolus0.125 0.125 g/kg/ming/kg/min

r-PA r-PA 5 + 5 U5 + 5 U

HeparinHeparin

AbciximabAbciximab0.25 mg/kg bolus0.25 mg/kg bolus0.125 0.125 g/kg/ming/kg/min

r-PA r-PA 5 + 5 U5 + 5 U

HeparinHeparin

Primary Endpoint: 30-Day MortalityPrimary Endpoint: 30-Day MortalityPrimary Endpoint: 30-Day MortalityPrimary Endpoint: 30-Day Mortality

16,600 patients16,600 patients

Acute MI ST elevation Symptoms 6 hrs Acute MI ST elevation Symptoms 6 hrs

r-PA r-PA 10 + 10 U10 + 10 U

HeparinHeparin

r-PA r-PA 10 + 10 U10 + 10 U

HeparinHeparin

GUSTO-IV AMI: ProtocolGUSTO-IV AMI: Protocol

INTRO AMI: TIMI Grade 3 Flow at 90 MinutesINTRO AMI: TIMI Grade 3 Flow at 90 Minutes

6167

6167

77

0

10

20

30

40

50

60

70

80

90

6167

6167

77

0

10

20

30

40

50

60

70

80

90

3333 3030 3131 3030 4848

Integrilin bolus 180 180 180 180/90 180/90Integrilin infusion 1.33 1.33 2.0 1.33 1.33tPA bolus 25 15 15 25 15tPA infusion 35 35 35

Integrilin bolus 180 180 180 180/90 180/90Integrilin infusion 1.33 1.33 2.0 1.33 1.33tPA bolus 25 15 15 25 15tPA infusion 35 35 35

0

5

10

15

20

25

0

5

10

15

20

25

Major Hemorrhage (Investigator)Major Hemorrhage (Investigator)

%%PtsPts

%%PtsPts

tPAtPAtPAtPA ReoPReoProro

ReoPReoProro


SK + SK + ReoProReoPro tPA + ReoProtPA + ReoPro tPA + ReoProtPA + ReoPro

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

ICHICHICHICH InstrInstrInstrInstrSpontSpontSpontSpont

N = 164N = 164N = 164N = 164 32323232 37373737 49494949 51515151 6666 38383838 42424242 50505050 36363636 53535353 37373737 48484848 35353535

0000 0000

6666 6666 55558888

14141414

67676767

5555 4444

8888 8888

5555

15151515

500 500 KK

500 500 KK

750 K750 K750 K750 K 1.25 1.25 MM

1.25 1.25 MM

1.5 M1.5 M1.5 M1.5 M 20202020 35353535 50505050 65656565

RP RP 0.3mg0.3mg

100 100 mgmg

100 100 mgmg

b 0.25 inf b 0.25 inf 0.1250.125

b 0.25 inf b 0.25 inf 0.1250.125

12121212

ALL ALL SKSK

ALL ALL SKSK

6666

143143143143 339339339339

ALL ALL tPAtPA

ALL ALL tPAtPA


Advantages of Combination Pharmacotherapy

Advantages of Combination Pharmacotherapy

• Quick and easy to administer, no learning curve

• Widely available at all times of the night and day at all hospitals

• Achieves patency early• Prejunctive therapy does not preclude

mechanical intervention

• Quick and easy to administer, no learning curve

• Widely available at all times of the night and day at all hospitals

• Achieves patency early• Prejunctive therapy does not preclude

mechanical intervention


The New Time Dependent Open Artery and Open Microvascular Hypothesis

The New Time Dependent Open Artery and Open Microvascular Hypothesis

• The Five Laws:– Not all TIMI Grade 3 Flow is Created Equally– TIMI Grade 3 Flow is Necessary but not Sufficient– It is the Achievement of TIMI Grade 3 Flow in both

the Epicardial Artery and the Microvasculature that Optimizes Clinical Outcomes

– Faster is Better: The Faster Achievement of Faster Flow Optimizes Clinical Outcomes

– Location, location, location: Drug efficacy and clinical outocmes must be interpreted in the context of infarct artery location

• The Five Laws:– Not all TIMI Grade 3 Flow is Created Equally– TIMI Grade 3 Flow is Necessary but not Sufficient– It is the Achievement of TIMI Grade 3 Flow in both

the Epicardial Artery and the Microvasculature that Optimizes Clinical Outcomes

– Faster is Better: The Faster Achievement of Faster Flow Optimizes Clinical Outcomes

– Location, location, location: Drug efficacy and clinical outocmes must be interpreted in the context of infarct artery location

CM Gibson 2000CM Gibson 2000

Documents

The 90 Minute Wall: 60% Rates of TIMI Grade 3 Flow % TIMI 3 Flow