Pathophysiology of Combination Therapy in AMI

Pathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMIPathophysiology of Combination Therapy in AMI

*Gibson et al. *Gibson et al. J Am Coll Cardiol.J Am Coll Cardiol. 1995;25:582-589. 1995;25:582-589.Gibson et al. Gibson et al. Circulation.Circulation. 2001;103:2550-2554. 2001;103:2550-2554.

Combination TherapyCombination Therapy

ThrombusThrombus

% Stenosis% Stenosis Minimum DiameterMinimum Diameter

Epicardial FlowEpicardial Flow

Myocardial BlushMyocardial Blush ST ResolutionST Resolution

Myocardial FlowMyocardial FlowFacilitates PCIFacilitates PCI

Reduces Reduces Reinfarction*Reinfarction*

Recent Clinical TrialsRecent Clinical TrialsRecent Clinical TrialsRecent Clinical Trials

Unfractionated heparinEnoxaparinUnfractionated heparinEnoxaparin

AbciximabAbciximab

NoneNone

ENTIRE

ACC/AHA heparin doseLow-dose heparinEnoxaparin

NoneAbciximab

None

ASSENT-3

Standard-dose heparinLow-dose heparin

NoneAbciximab

50% TNK-tPA50% TNK-tPA100% TNK-tPA100% TNK-tPA

100% TNK-tPA50% TNK-tPA100% TNK-tPA

100% r-PA50% r-PA

GUSTO-V

AnticoagulantGP IIb/IIIa

Receptor InhibitorLyticTrial

Clinical Trials: OngoingClinical Trials: OngoingClinical Trials: OngoingClinical Trials: Ongoing

Low-dose heparinLow-dose heparinLow-dose heparin

EptifibatideEptifibatideEptifibatide


INTEGRITI

Low-dose heparinLow-dose heparinLow-dose heparin

TirofibanTirofibanTirofiban


FASTER

AnticoagulantGP IIb/IIIa

Receptor InhibitorLyticTrial

54%54%

32%32%

GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality ReductionNeeded to Yield a 1% Mortality ReductionGUSTO-I: A 20% Increase in TIMI Grade 3 Flow is GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality ReductionNeeded to Yield a 1% Mortality Reduction

The GUSTO Angiographic Investigators. The GUSTO Angiographic Investigators. N Engl J Med.N Engl J Med. 1993;329:1615-1622. 1993;329:1615-1622.

0

30

50

60

40

20

% T

IMI

Gra

de

3 F

low

t-PA SK

10

t-PA

5

7.4%7.4%

6.3%6.3%

SK

876

TIMI Grade 3 Flow – Pooled Data From Dose TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent TrialsConfirmation Phases of Recent TrialsTIMI Grade 3 Flow – Pooled Data From Dose TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent TrialsConfirmation Phases of Recent Trials

0

40

80

100

60

20

% P

atie

nts

Wit

h T

IMI

Gra

de

3 F

low

GUSTO-I90 min

T14 t-PA90 min

T14 r-PA90 min

SPEED60-90 min

INTRO-AMI60 min

Pooled60-90 min

54

7370

47

40

56

7873

54 56

64

292292 6363 8787 9898 8181 3293295858 8888 100100 7575 321321

Lytic alone

Combination

SPEED: Results of Dose-Confirmation PhaseSPEED: Results of Dose-Confirmation PhaseSPEED: Results of Dose-Confirmation PhaseSPEED: Results of Dose-Confirmation Phase

• There was a 7.4% improvement in the rate of TIMI Grade 3 flow

• If a 20% improvement is required to improve mortality by 1%, then a 7.4% improvement would be predicted to improve mortality by 0.3%

The SPEED Study Group. The SPEED Study Group. Circulation.Circulation. 2000;101:2788-2794. 2000;101:2788-2794.

0

40

80

100

r-PA 10+10 U r-PA 5+5 U + Abx

60

20

Pat

ency

(%

)

TIMI-2

TIMI-3

n=109n=109 n=115n=115

21.621.6

54.954.947.547.5

28.728.7

GUSTO-V: Study DesignGUSTO-V: Study DesignGUSTO-V: Study DesignGUSTO-V: Study Design

The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.

ST , lytic eligible, < 6 h (n=16,588)

ASA

No AbciximabNo Abciximab

2 x 10 U bolus (30’)

Full-dose r-PA

2 x 10 U bolus (30’)

Full-dose r-PA

Abciximab Abciximab

Low-dose Heparin:60 U/kg bolus followed by

7 U/kg/h infusion

Low-dose Heparin:60 U/kg bolus followed by

7 U/kg/h infusion

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

2 x 5 U bolus (30’)

Half-dose r-PA

2 x 5 U bolus (30’)

Half-dose r-PA

Standard Heparin: 5000 U bolus followed by

800 U/h (< 80 kg) or 1000 U/h ( 80 kg) infusion

Standard Heparin: 5000 U bolus followed by

800 U/h (< 80 kg) or 1000 U/h ( 80 kg) infusion

Primary End Point: 30-Day Mortality Primary End Point: 30-Day Mortality Primary End Point: 30-Day Mortality Primary End Point: 30-Day Mortality


0

% M

ort

alit

y

Days0 5 10 15 20 25 30

P=.43 for superiority

Non-Inferiority RR 0.95(95% CI, 0.84-1.08)

Std. Reteplase (n = 8260)Abx + Dose Reteplase (n = 8328)

4

6

2

5.9%

5.6%

GUSTO-V: Noninferiority AnalysisGUSTO-V: Noninferiority AnalysisGUSTO-V: Noninferiority AnalysisGUSTO-V: Noninferiority Analysis

Adapted with permission from the GUSTO-V Investigators. Lancet. 2001;357:1905-1914.

Non-Inferiority RR 0.95(95% CI, 0.84-1.08)

1.111.11

OR and 95% CI

0.00.0 2.02.01.01.0Abciximab + Abciximab + Half-dose r-PA superiorHalf-dose r-PA superior

Full-dose r-PAFull-dose r-PAsuperiorsuperior

Upper Boundary of 95% CI for NoninferiorityUpper Boundary of 95% CI for Noninferiority

A Comparison of the Outcomes With r-PA A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V TrialsMonotherapy in GUSTO-III vs GUSTO-V TrialsA Comparison of the Outcomes With r-PA A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V TrialsMonotherapy in GUSTO-III vs GUSTO-V Trials

The GUSTO-III Investigators. N Engl J Med. 1997;337:1118-1123.


0

3

7

8

5

1

2

6

4

GUSTO III GUSTO V

7.4%

5.9%

10,13810,138 8,2608,260

Death

P<.001

0

40

50

20

30

10

GUSTO III GUSTO V

48%

37%

10,13810,138 8,2608,260

Anterior MI

0

0.5

0.9

1.0

0.7

0.3

0.4

0.8

0.6

0.2

GUSTO III GUSTO V

0.91%

0.59%

10,13810,138 8,2608,260

ICH

P=.015

0.1

0.2

1.2

1.7

2.3

GUSTO-V: Causes of ReinfarctionGUSTO-V: Causes of ReinfarctionGUSTO-V: Causes of ReinfarctionGUSTO-V: Causes of Reinfarction

*Unblinded, unadjudicated


0

1

3

4

2

Myo

card

ial

Infa

rcti

on

(%

)

Any Q-wave Enzymatic Ischemic STChange*

3.5

0.5

1.6

2.7

r-PA

r-PA + Abx

P<.0001

Non-Intracranial Bleeding Through Discharge/Day 7Non-Intracranial Bleeding Through Discharge/Day 7Non-Intracranial Bleeding Through Discharge/Day 7Non-Intracranial Bleeding Through Discharge/Day 7


0

% o

f P

atie

nts

15

25

30

20

r-PA

r-PA + Abx

10

SevereBleeding

ModerateBleeding

MildBleeding

AnyBleeding

ReceivingTransfusions

5

0.5 1.1 1.83.5

11.4

20.0

13.7

24.6

4.05.7

ICH by Age GroupICH by Age GroupICH by Age GroupICH by Age Group

*Significant treatment interaction for the age 75 dichotomy; P=.033.


0

1

3

2

% o

f P

atie

nts

70 yrs > 70 yrs 75 yrs > 75 yrs

0.4

1.2

0.5

1.1

1.5

0.4

2.1

r-PA (n=8260)

r-PA + Abx (n=8328)

0.3

P=.66

P=.53

P=.27*

P=.069*

12/108812/1088 24/114924/114928/717928/717937/717237/717225/203025/2030 31/213531/213521/619321/619324/623024/6230

**

****

**

GUSTO-V: PCI Within 6 Hours (Urgent) GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7and Through Day 7GUSTO-V: PCI Within 6 Hours (Urgent) GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 7and Through Day 7

*P<.0001.


5.65.6

25.425.427.927.9

8.68.6

0

15

25

30

20

10

PC

I (%

)

Urgent

Through Day 7

5

r-PA r-PA + Abx

2.8

9.0

5.4

GUSTO-V: Event Rates in Those Requiring Urgent PCIGUSTO-V: Event Rates in Those Requiring Urgent PCIGUSTO-V: Event Rates in Those Requiring Urgent PCIGUSTO-V: Event Rates in Those Requiring Urgent PCI

Heartwire News. September 2, 2001. GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI?

6.7

4.8

9.6

0

4

10

12

8

Myo

card

ial

Infa

rcti

on

(%

)

r-PA

r-PA + Abx

n=1173

Death Repeat MI Death Plus Repeat MI

2

6

GUSTO-V: ConclusionsGUSTO-V: ConclusionsGUSTO-V: ConclusionsGUSTO-V: Conclusions

• Compared with r-PA monotherapy, combination therapy with r-PA and abciximab resulted in

– A mortality rate that was not inferior to r-PA monotherapy

– Fewer nonfatal reinfarctions (primarily a reduced incidence of recurrent ST elevation)

– A lower rate of urgent revascularization

– More noncerebral bleeding complications, transfusions, and thrombocytopenia

– A higher rate of ICH in elderly patients over the age of 75 years

ASSENT-3: Rationale for Use of Enoxaparin ASSENT-3: Rationale for Use of Enoxaparin ASSENT-3: Rationale for Use of Enoxaparin ASSENT-3: Rationale for Use of Enoxaparin

• TNK-tPA plus enoxaparin

– Favorable effects of LMWHs in recent small-scale thrombolysis trials

– Higher late patency: HART-2ASSENT-PlusAMI-SK

– Less reocclusion: HART-2

– Fewer reinfarctions: ASSENT-PlusAMI-SKWilson, et al.

• ASSENT-3 is the first large-scale trial to test LMWH

ASSENT-3: Study DesignASSENT-3: Study DesignASSENT-3: Study DesignASSENT-3: Study Design

ST-Segment Elevation AMI (n=6095 patients)ST-Segment Elevation AMI (n=6095 patients)

150 to 325 mg ASA (daily)150 to 325 mg ASA (daily)

RandomizedRandomized

Full-dose TNK-tPAPlus Enoxaparin

Full-dose TNK-tPAPlus Enoxaparin

Half-dose TNK-tPAPlus Abciximab

Plus Low-dose Heparin

Half-dose TNK-tPAPlus Abciximab

Plus Low-dose Heparin

Full-dose TNK-tPAPlus Weight-adjusted UFH

Full-dose TNK-tPAPlus Weight-adjusted UFH

The ASSENT-3 Investigators. Lancet. 2001;358:605-613.

ASSENT-3: Primary End PointsASSENT-3: Primary End PointsASSENT-3: Primary End PointsASSENT-3: Primary End Points

• Primary Efficacy End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia.

• Primary Efficacy Plus Safety End Point: Composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia plus in-hospital intracranial haemorrhage or in-hospital major bleeding other than intracranial.

ASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory IschemiaRefractory IschemiaASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory IschemiaRefractory Ischemia

0

5

10

15

20

% R

isk

of

30-D

ay D

/MI/

Ref

Isc

h

TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH

*P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0002 for the enox vs UFH comparison, and P<.0001 for the abx vs UFH comparison.

11.4 11.1

15.4

3-way P=.0001

P=.0002*P=.0009*

ASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICHRefractory Ischemia, Major Bleeding and ICHASSENT-3: 30-Day Mortality, Recurrent MI, ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICHRefractory Ischemia, Major Bleeding and ICH

% R

isk

of

30-D

ay D

/MI/

Ref

Isc

h/M

aj B

leed

/IC

H

*P-values are the Bonferroni P-values after correcting for multiple comparisons. The uncorrected P-values were P=.0037 for the enox vs UFH comparison, and P=.0142 for the abx vs UFH comparison.

0

5

10

15

20


13.8 14.2

17.0

3-way P=.0062

P=.057*P=.0146*

Kaplan-Meier Curves Kaplan-Meier Curves Kaplan-Meier Curves Kaplan-Meier Curves

UFH

Abx*

5 10 15 20 25 30

0

2

4

6

8

10

12

14

16

20

18

0

Enox*

log-rank P=.0001*vs UFH

Days to death, reinfarction, orrefractory ischemia

Primary Efficacy End Point

Pro

bab

ility

(%

)

Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:605-613.

5 10 15 20 25 30

0

2

4

6

8

10

12

14

16

20

18

0

log-rank P=.0062*vs UFH + Abx

Days to death, reinfarction, refractoryischemia, ICH, or major bleeding

Primary Efficacy PlusSafety End Point

Pro

bab

ility

(%

)

UFH

Abx

Enox*

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of AgeBleeding in Patients >75 Years of Age

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of AgeBleeding in Patients >75 Years of Age

*There was a statistically significant interaction between treatment with abciximab and age such that patients over the age of 75 had poorer outcomes with abciximab (P=.001).

% R

isk

of

30-D

ay E

ffic

acy

and

Saf

ety

En

d P

oin

t

0

15

25

35

45


25.5

36.9

28.0

P=.001*

5

20

30

40

10

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with DiabetesBleeding in Patients with Diabetes

ASSENT-3: Primary Efficacy and Safety End Point of ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with DiabetesBleeding in Patients with Diabetes

*There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007).

% R

isk

of

30-D

ay E

ffic

acy

and

Saf

ety

En

d P

oin

t

0

15

25

30


13.9

22.3

16.5

P=.0007*

5

20

10

ASSENT-3: 30-Day MortalityASSENT-3: 30-Day MortalityASSENT-3: 30-Day MortalityASSENT-3: 30-Day Mortality

0

4

8

10


5.4

6.66.0

3-way P=.25

6

2

% R

isk

of

30-D

ay M

ort

alit

y

ASSENT-3: 30-Day Death or MIASSENT-3: 30-Day Death or MIASSENT-3: 30-Day Death or MIASSENT-3: 30-Day Death or MI

% R

isk

of

30-D

ay D

eath

or

MI

0

4

8

10


6.87.3

9.13-way P=.0198

6

2

ASSENT-3: In-Hospital Recurrent MIASSENT-3: In-Hospital Recurrent MIASSENT-3: In-Hospital Recurrent MIASSENT-3: In-Hospital Recurrent MI%

Ris

k o

f In

-Ho

spit

alR

ecu

rren

t M

I

0

2

4

5


2.7

2.2

4.2

3-way P=.0009

3

1

ASSENT-3: In-Hospital Refractory IschemiaASSENT-3: In-Hospital Refractory IschemiaASSENT-3: In-Hospital Refractory IschemiaASSENT-3: In-Hospital Refractory Ischemia%

Ris

k o

f 30

-Day

Ref

ract

ory

Isc

hem

ia

0

4

8

10


4.6

3.2

6.5

3-way P<.0001

6

2

ASSENT-3: Incidence of In-Hospital Thrombocytopenia ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complicationsand Noncerebral Bleeding ComplicationsASSENT-3: Incidence of In-Hospital Thrombocytopenia ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complicationsand Noncerebral Bleeding Complications

*While 3-way P-value is significant, Enox vs UFH comparison P=NS

Enox Abx UFH P-Value(n=2040) (n=2017) (n=2038) 3-way

Any thrombocytopenia 1.2 3.2 1.3 <.0001

Thrombocytopenia <.0001<20,000 cells/µL 0.1 0.5 0.220,000 to 50,000 cells/µL 0.2 0.6 0.250,000 to 100,000 cells/µL 0.9 2.0 1.0

Bleeding episodesTotal 25.6* 39.7 21.1 <.0001Major 3.0* 4.3 2.2 .0005Minor 22.6* 35.4 18.8 <.0001

Blood transfusion 3.4* 4.2 2.3 .0032

ASSENT-3: In-Hospital Stroke RatesASSENT-3: In-Hospital Stroke RatesASSENT-3: In-Hospital Stroke RatesASSENT-3: In-Hospital Stroke Rates

*Including hemorrhagic conversion

Unclassified

Hemorrhagic conversion

Ischemic stroke*

Intracranial hemorrhage

Total strokes

0.150.15

0.070.07

0.400.64

0.940.88

1.491.62

Abx(n=2017)

Enox(n=2040)

0.590.05

0.770.00

0.570.54

0.980.93

0.941.52

P-ValueUFH

(n=2038)

Patients Undergoing PCI: MortalityPatients Undergoing PCI: Mortality

ASSENT-3: In-Hospital PCI GUSTO-V: Urgent PCI

0

5

7

8

6

3

Mo

rtal

ity

(%)

4

2

1

2.5

3.7

2.7

5.4

6.7

TNK-tPA +Enox

TNK-tPA +Abx

TNK-tPA +UFH

r-PA +UFH

r-PA +Abx

How Does Actual Weight Compare to How Does Actual Weight Compare to Estimated Weight?Estimated Weight?How Does Actual Weight Compare to How Does Actual Weight Compare to Estimated Weight?Estimated Weight?

Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

Correlation Between Estimated and Actual Patient Weight in TIMI 10BCorrelation Between Estimated and Actual Patient Weight in TIMI 10B

40.5

36.4

188.5

Act

ual

Pat

ien

t W

eig

ht

(kg

)

Estimated Patient Weight (kg)

R2=0.93, P<.0001

181

Weight-Based Dosing of Thrombolysis: How Well Do We Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Translate Into Estimate Weight? How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and Errors With Administration of Thrombolytic Drugs and Adverse Outcomes? Adverse Outcomes?

Weight-Based Dosing of Thrombolysis: How Well Do We Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Translate Into Estimate Weight? How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and Errors With Administration of Thrombolytic Drugs and Adverse Outcomes? Adverse Outcomes?

1. Errors in estimating weight are uncommon, especially those that would lead to a dose change (1.3% or 49/3730 for TNK-tPA and 4.5% or 13/290 for t-PA).

2. No adverse outcomes were seen among patients who received an incorrect dose, suggesting a broad safety profile for the new single-bolus agent TNK-tPA.

Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

ASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding TNK-tPA + Abciximab TherapyTNK-tPA + Abciximab TherapyASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding TNK-tPA + Abciximab TherapyTNK-tPA + Abciximab Therapy

• “The results obtained with half-dose tenecteplase plus abciximab are very similar to those with half-dose reteplase and abciximab seen in GUSTO-V.”

• “In both trials, these benefits are obtained at the cost of a higher rate of major bleeding complications and blood transfusions.”

• “No benefit and perhaps even harm was observed in patients above 75 years and in diabetics.”

• “Taken together they suggest that caution should be exercised regarding the use of conjunctive therapy with abciximab in elderly patients with an acute myocardial infarction treated with a fibrinolytic agent.”


ASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding EnoxaparinEnoxaparinASSENT-3: Study Group Conclusions Regarding ASSENT-3: Study Group Conclusions Regarding EnoxaparinEnoxaparin

“In view of the present data and the ease of administration, enoxaparin might be considered an attractive alternative anticoagulant treatment when given in combination with tenecteplase.”


ENTIRE TIMI-23: Study DesignENTIRE TIMI-23: Study DesignENTIRE TIMI-23: Study DesignENTIRE TIMI-23: Study Design

ST MI <6h (n=461)ST MI <6h (n=461)

UFH60 U/kg bolus

12 U/kg/h infusion 36 h

UFH60 U/kg bolus


ENOXvarying doses

+/- IV bolusIndex Hosp ( 8

d)

ENOXvarying doses


d)

ASAASA

ENOXvarying doses


d)

ENOXvarying doses


d)

Combination Reperfusion:

Half-dose TNK-tPA + Abx(0.27 mg/kg)

Combination Reperfusion:

Half-dose TNK-tPA + Abx(0.27 mg/kg)

Standard Reperfusion:

Full-dose TNK-tPA(0.53 mg/kg)

Standard Reperfusion:

Full-dose TNK-tPA(0.53 mg/kg)

Antman E, et al. Eur Heart J. 2001;22:15. Abstract 145.

UFH 40 U/kg bolus


UFH 40 U/kg bolus


Outstanding IssuesOutstanding IssuesOutstanding IssuesOutstanding Issues

• Should enoxaparin replace UFH as the optimal antithrombin agent for AMI?

• Will similar improvements in efficacy and safety occur if enoxaparin is combined with a less fibrin-specific agent such as r-PA?

• Will physicians accept the use of enoxaparin in selected patients with ST-elevation MI who may require rescue PCI?

• Will trials of TNK-tPA plus the small molecule GP IIb/IIIa receptor inhibitors produce results similar to ASSENT-3?

• What is the optimal strategy for facilitated PCI?

Future Trials: Potential Downstream TargetsFuture Trials: Potential Downstream TargetsFuture Trials: Potential Downstream TargetsFuture Trials: Potential Downstream Targets

• Large embolii: Filters

• Small embolii (thrombii): Filters & GP IIb/IIIa inhibitors, p-selectin inhibitors

• Vasoconstrictor release: GP IIb/IIIa inhibitors

• Spasm: Adenosine, Ca channel blockers, alpha blockers, avoid over sizing with PCI, high pressure inflations, serotonin inhibitors, endothelin inhibitors

• Endothelial & Myocardial swelling: Myocardial cooling, Ca channel blockers, DHEA, Na / H pump inhibitors, anti-inflammatory approaches

Documents

Pathophysiology of Combination Therapy in AMI