Acute Myocardial Infarction are Thrombolitics Enough ?

Augustin J. DeLago M.D.,F.A.C.C.Director,Catheterization LaboratoryDirector,Invasive CardiologyThe Heart Institute Albany Medical Center

Early evidence of reduced mortality

after IC SK

Evidence of mortality benefit

after IV SK(GISSI)

GUSTO-I, TIMI:•Lytics, 90-min CBF

reduce mortality•New lytics created

Management Strategies in AMI

8.9

4.4

TIMI 2TIMI 0-1

30-d

ay m

ort

alit

y (%

)

1010

88

66

44

00

22

7.4

TIMI 390-minute angiography

P=0.08

P=0.009

Patency ~ Mortality

Ross AM et al. N Engl J Med. 1993;329:1615–1622.

The Open Artery

Hypothesis

• Reperfusion of the IRA results in LV preservation

• Open the artery early to improve outcomes

GUSTO-I: The Benefit of Reperfusion

INFARCT

ASSENT-2• Designed to test the superior fibrin specificity of tenecteplase vs alteplase

(equivalence study)• Outcome: No difference in mortality

The Mortality Ceiling With ModernFibrinolytics

Percentage of survival

AlteplaseTenecteplase

Su

rviv

al p

rob

abili

ty

Innovations in the Managementof AMI

INFARCT

• Designed to test the theory that reteplase would be superior to alteplasebecause of its superior angiographic data

• Outcome: No difference in mortality

The Mortality Ceiling With ModernFibrinolytics

Ohman EM. Oral presentation, ACC 1999.

GUSTO-III Survival Curve

AlteplaseReteplase

Alteplase mortality rate (11.0%)Reteplase mortality rate (11.21%)P=0.6630

days

mo

rtality

(%

)16

12

8

4

0

Innovations in the Managementof AMI

• Mortality ceiling (6% to 7%)

• Successful reperfusion (45% to 60%)

• ICH risk (0.5% to 1.5%)

• Approximately 40% of patients do not achieve TIMI-3 flow at 90 minutes

• Critical time dependence for reperfusion to achieve optimal outcomes

Limitations of Fibrinolysis

Innovations in the Managementof AMI

GP IIb/IIIa Inhibitors

Steric hindranceNonspecificBinds with 3 chain on GP IIb/IIIa,

v33

Competitive blockadeHighly specific for GP IIb/IIIaMimic amino acid sequences

AbciximabSmall molecule

Artist’s conception

Binding Competitive Competitive

Half-lifePlasma ~2 h ~2 h

<10 minBiologic ~2 h ~2 h

Days

Clearance Renal Renal Renal/Spleen

GP IIb/IIIa Inhibitors

EptifibatideAbciximab Tirofiban

Benefits of GP IIb/IIIa Inhibition in AMI:

Review of Clinical Trials

GP IIb/IIIa Inhibitors

EPIC: AMI Subset – Post Hoc Analysis

Lefkovits J et al. Am J Cardiol. 1996;77:1045–1051.

Dea

th/r

e-M

I/u

rgen

t T

VR

(%

)

30 days 6 months0

102030405060708090

100

26.121.1

4.5

47.8

32.3

4.5

Placebo (n=23) Abciximab bolus(n=19)

Abciximab bolus + infusion (n=22)

P=0.06

P=0.002

83%

91%

TIMI 3 Flow : 90 TIMI 3 Flow : 90 minmin

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=0.014p=0.014

TIMI 14TIMI 14

tPA +tPA + rPA PhasesrPA Phases

Abciximab Improves ST Res-Abciximab Improves ST Res-90 min90 min

40

58

0

20

40

60

80

100

Lytic Lytic +Abx

de Lemos et al AHA 1999

Complete (> 70%)ST Res

P<0.0005

N=179 N=329

tPA + rPA pooledtPA + rPA pooled

TIMI 14TIMI 14

GP IIb/IIIa Inhibitors in Primary PTCA

RAPPORT

ObjectiveEvaluate safety and efficacyof abciximab as adjunctive therapy to primary PTCA

End Points• Primary: Composite of

any-cause death, recurrentMI, repeat TVR within

6 months•Secondary: Composites ofdeath, MI, urgent TVR at

7 days and 30 days

Brener SJ et al. Circulation. 1998;98:734–741.

RAPPORT30-Day End Points (Intent-to-Treat)

P=0.03%

of

Pat

ien

ts

Death, re-MI, orurgent

intervention

Urgentintervention

Death or re-MI

P=0.52P=0.006

0

5

10

15

11.2

5.8 5.84.6

6.6

1.7

Placebo (n=242)

Abciximab (n=241)

48%

74%

Brener SJ et al. Circulation. 1998;98:734–741.

N: 64 392/83 200 403 300

Random: No No Yes YesYes

PCI: PTCA PTCA Stent PTCAStent

P: 0.06 0.04 0.03 <0.05<0.05

26.1

4.5

9.7

3.6

9.2

2

11.2

5.8

15.3

7.3

0

10

20

30

Control

Abciximab

30-d Mortality, MI, Urgent ReV

PCI with Adjunctive GP IIb/IIIa

Per

cen

t

Trial EPIC GUSTO-III Neumann RAPPORT ADMIRAL

.

6.5

2.6

7

1.0*

3.64.3

75.7 5.6 5.5

11.9

8.7*

6.5

4.4*

0

5

10

15

PAMI ZWOLLE MAYO GUSTO-IIb MITI CCP Weaver

Lytic PTCA

*P<0.05

30-d Mortality or Discharge

N 395 395 103 1138 3145 20,683 2606

Herrmann HC. Am J Cardiol. 2000;85:10C-16C.

Lysis vs Primary PTCA

Per

cen

t

Reperfusion in AMI

FIBRINOLYSIS

PRIMARY PTCA

• Reduces mortalityReduces mortality

• Well studiedWell studied

• Widely availableWidely available

• Lower mortalityLower mortality

• Anatomic definitionAnatomic definition

• Avoids hemorrhageAvoids hemorrhage

Facilitated Percutaneous Coronary Intervention:

Evidence for the Efficacy of a New Approach

Potential Benefits of Facilitated PCI

• May be cost-effective if combination pharmacologic therapy lessens the need for PCI

• Improves patient stability during intervention

– Patients with open arteries have less shock, IABP, pacemaker, arrest

– Higher technical success due to less hectic procedure, better distal vessel visualization

• Fuses best aspects of fibrinolysis and primary PCI

– Earlier and greater TIMI-3 flow rates

– May improve myocardial tissue perfusion

Nonqualifying PCI (n=43)

SPEED study (n=528)

Primary end point= TIMI-3 flow

Dose-finding (n=305)

Confirmation (n=223)

60-90 min angiogram

(n=466) No early PCI (n=162)

Facilitated PCI

(n=323)

Abciximab + reteplase

Abciximab + reteplase (5+5 U) vs full-dose reteplase (10+10 U)

Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–1496.

SPEED: Study Population

TIMI Grade 3 Flow at 60-90 Min

29%

51%

62%

48%

0

50

100

Angiographic Core Lab ReadingAngiographic Core Lab Reading

r-PAAlone

60 U HepAbciximab+ r-PA 5 + 5

40 U HepAbciximab+ r-PA 5 + 5

p = 0.2

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

AbciximabAlone

p = 0.06

SPEEDSPEED

ACC 1999: Oral Presentation

Freedom From Mortality, MI, Urgent ReV at 30 days

Early PCI No Early PCI

80

85

90

95

100

0 10 20 30

94.4%

83.8%

P<0.05

SPEED: Clinical Success

Pe

rce

nt

Herrmann HC et al. J Am Coll Cardiol. 2000;36:1489–1496.

Days

Results in a Perspective

31%

54%

0%

25%

50%

75%

100%

SK t-PA

22%

45%

0%

25%

50%

75%

100%

SK t-PA

48%

62%

0%

25%

50%

75%

100%

r-PA Abciximabr-PA 5 + 5

GUSTO-190-min

Meta-analysis60-min

SPEED60-min

23% 23%14%

p < 0.001 p = 0.06

ACC 1999: Oral Presentation

Trial Protocol (n = 16,600)

ST , lytic eligible, < 6 hASA

No Abciximab

2 x 10 U bolus (30’)Reteplase

Abciximab*

Low Dose Heparin:

60 U/kg bolus followed by a 7 U/kg/h infusion

1º endpoint: mortality at 30 days2º endpoint: clinical and safety events at 30 days

2 x 5 U bolus (30’)Reteplase

Standard Heparin: 5,000 U bolus followed by either

800 U/hr (pts < 80 kg) or 1,000 U/hr (pts > 80 kg) infusion

* 0.25mg/kg bolus followed by 0.125 g/kg/min infusion for 12 hours

GUSTO-IV AMIGUSTO-IV AMI

Suggested Treatment Strategy

Abciximab

Low Dose Heparin:

60 U/kg bolus followed by a 7 U/kg/h infusion

Half Dose Lytic

URGENT PCI IF PERSISTENT CHEST PAIN OR ST ELEVATION

Future Studies

• FASTER

• ASSENT III

• GUSTO V - MI

• INTEGRITI

• FINESSE

TNK + TirofibanTNK + Tirofiban

Phase IIbPhase IIb

[ Spring 2001 ][ Spring 2001 ]

TNK + TirofibanTNK + Tirofiban

Phase IIbPhase IIb

[ Spring 2001 ][ Spring 2001 ]TNK + AbciximabTNK + Abciximab

TNK + heparinTNK + heparin

TNK + LMW heparinTNK + LMW heparin

approx 6000 ptsapprox 6000 pts

Phase IIbPhase IIb

[ Spring 2001 ][ Spring 2001 ]

TNK + AbciximabTNK + Abciximab

TNK + heparinTNK + heparin

TNK + LMW heparinTNK + LMW heparin

approx 6000 ptsapprox 6000 pts

Phase IIbPhase IIb

[ Spring 2001 ][ Spring 2001 ]

r-PA + Abciximabr-PA + Abciximab

r-PA + heparinr-PA + heparin

16,600 pts16,600 pts

Phase IIIPhase III

[ Spring 2001 ][ Spring 2001 ]

r-PA + Abciximabr-PA + Abciximab

r-PA + heparinr-PA + heparin

16,600 pts16,600 pts

Phase IIIPhase III

[ Spring 2001 ][ Spring 2001 ]

TNK + EptifibatideTNK + Eptifibatide

Phase IIbPhase IIb

[ Starting now ][ Starting now ]

TNK + EptifibatideTNK + Eptifibatide

Phase IIbPhase IIb

[ Starting now ][ Starting now ]

Abciximab + PCIAbciximab + PCI

Abciximab + r-PA + PCIAbciximab + r-PA + PCI

2700 pts; starting now2700 pts; starting now

Abciximab + PCIAbciximab + PCI

Abciximab + r-PA + PCIAbciximab + r-PA + PCI

2700 pts; starting now2700 pts; starting now

Summary

• Several aspects of combined fibrinolytic and GP IIb/IIIa inhibition reperfusion strategy remain to be clarified

• Further reductions in mortality should be expected with more inclusion of platelet inhibition in reperfusion strategies for ST-elevation MI

• Combined pharmacologic and catheter-based reperfusion approaches will offer optimal treatment to more patients

• Optimal dosing of unfractionated heparin added to combined fibrinolysis and GP IIb/IIIa inhibition

• Clinical importance of differences among GP IIb/IIIa antagonists in potency, effects on other adhesion molecules, and efficacy in protecting microvasculature

• Validation of the safety and efficacy of early invasive management combined with potent platelet inhibition

Evolving Questions