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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
50% TNK-tPA75% TNK-tPA100% TNK-tPA
INTEGRITI
Low-dose heparinLow-dose heparinLow-dose heparin
TirofibanTirofibanTirofiban
50% TNK-tPA75% TNK-tPA100% TNK-tPA
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
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
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.
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
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
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
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
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
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.
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
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.
The GUSTO-V Investigators. Lancet. 2001;357:1905-1914.
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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
TNK-tPA + Enox TNK-tPA + Abx TNK-tPA + UFH
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.”
The ASSENT-3 Investigators. Lancet. 2001;358:605-613.
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.”
The ASSENT-3 Investigators. Lancet. 2001;358:605-613.
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
12 U/kg/h infusion 36 h
ENOXvarying doses
+/- IV bolusIndex Hosp ( 8
d)
ENOXvarying doses
+/- IV bolusIndex Hosp ( 8
d)
ASAASA
ENOXvarying doses
+/- IV bolusIndex Hosp ( 8
d)
ENOXvarying doses
+/- IV bolusIndex Hosp ( 8
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
7 U/kg/h infusion 36 h
UFH 40 U/kg bolus
7 U/kg/h infusion 36 h
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