1. UFH b 60 U/kg inf 12 U/kg/h >36 h
ST MI < 6h
ASA
Standard Reperfusion: Full Dose TNK (0.53 mg/kg)
Combination Reperfusion: Abx + 1/2 dose TNK (0.27 mg/kg)
40(3000) 7 (800)
60(4000) 12 (1000)
60 (55-75) ST Res 60,180
UFH b 60 U/kg inf 12 U/kg/h >36 h
ENOX +/- IV bolus Index Hosp (< 8d)
UFH b 40 U/kg inf 7 U/kg/h >36 h
ENOX +/- IV bolus Index Hosp (< 8d)
In addition to its convenience advantage over unfractionated heparin, enoxaparin has several potential pharmacologic advantages that make it an attractive candidate as adjunctive therapy during pharmacologic reperfusion for STEMI. The ENTIRE-TIMI 23 trial was an open label Phase II angiographic study designed to evaluate various regimens of enoxaparin in patients receiving either standard reperfusion with full dose TNK or combination reperfusion with 1/2 dose TNK and abciximab.
Patients presenting within 6 hours of STEMI received aspirin and were randomized to the two forms of pharmacologic reperfusion (POINT) and to adjunctive antithrombin therapy with UFH or ENOX.
The UFH regimens were adminstered for a minimum of 36 hours and consisted of a bolus of 60 U/kg and initial infusion of 12 U/kg/h with full dose TNK and a bolus of 40 U/kg and initial infusion of 7 U/kg/h with combination reperfusion.
Treatment with enoxaparin utilized a strategy of continued therapy for the duration of the index hospitalization up to a maximum of 8 days unless the pt underwent successful PCI or was referred for CABGin which case enox dosing was stopped. Enox regimens tested included those with an intitial intravenous bolus followed by sc injections every 12 h as well as those beginning just with subcutaneous injections.
The primary efficacy endpoint was T3 flow at 60 min and the primary safety endpoint was TIMI major hemorrhage through 30 days. The major secondary endpoints included ST Res at min + ischemic events through 30 days.
10 Endpoint: TIMI 3 Flow (60 min), TIMI Major Hem (30D) 20 Endpoints: ST Res, Ischemic Events
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2. Enrollment Criteria Inclusion Age 21-75 Major Exclusion Criteria
Ischemic discomfort > 30 min within 6 h
ST elevation: limb > 1 mm , precordial > 2 mm
Major Exclusion Criteria
Cardiac: prior CABG, card. shock, MI/PCI < 7 d
Bleeding risk: BP > 180/110, Hx CVA or bleeding
Concomitant Rx: Abx < 7 d, Eptif / Tirof < 24 h Lytic Rx < 1 wk, LMWH/UFH < 24 h, oral A/C
The enrollment criteria shown on this slide are similar to other phase II angiographic trials and focus on identifying patients with a requisite level of ST elevation (POINT) and excluding those patients at risk of bleeding because of baseline conditions (POINT) or concomitant therapy (POINT).
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3. Study Organization
TIMI LCC Dr.E. Antman Dr. F. Van de Werf Dr.E. Braunwald Dr. P. Sinnaeve (CEC) Ms. S. Cutler
Sponsor: AVENTIS Dr. F. Bigonzi Ms. C. Hecquet Ms. G. Pisapia
Core Laboratories Angio: Dr. M. Gibson (TIMI) ECG: Dr. H. Heidbuchel (LCC)
The central units for the study are shown here.
This was a joint research effort of the members of the TIMI research group and LCC group listed.
The trial was sponsored by AVENTIS
The Angio Core lab was run by Dr. Gibson and the ECG Core lab by Dr. Heidbuchel.
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4. International Site Network Number of Centers = 43
Canada 12
Netherlands 261 Belgium 54 France Spain 71
USA 45
An international network of 43 centers in 6 countries randomized 488 patients of whom 483 were treated and form the basis of this report. 30 day followup is available on all 483 treated patients.
< Netherlands>
_________________________
February Sept 2001 : Randomized = 488, Rx= d Follow up =483 (100%)
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5. Baseline Characteristics All Treated Population (N= 483)
Age (y) 58 (51,66) Male % Anterior MI 35% Weight (kg) 81 (72,90) BP sys (120,150) Diabetes 14% HTN 26% Prior MI 11%
Time: Pain to Rx (h) 3.0 (2.1,3.9)
2.01a 2.02a
Selected baseline characteristics of the treated population are shown here.
The majority of patients were male, 35% had an anterior infarction and the median time from pain to treatment with TNK was 3.0 hours with an interquartile range of h
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6. TIMI 2+3 Flow 60 min Angio Evaluable Patients
FULL Dose TNK
HALF Dose TNK + Abx 80 80 78 81 77 76 70 T2
% Pts T3
3.03b
The 60 min angio data are shown here for the two UFH control groups plotted in green and the 5 experimental Enox regimens shown in yellow.
The structure of the ENOX regimens is shown at the bottom of the slide indicating whether an initial 30 mg IV bolus was used and the dose of the intial two sc injections separated by 12 hours. After administration of the first two sc injections at the doses shown all patients received 1.0 mg/kg every 12 hours for the remainder of the index hospitalization.
No clear differences were seen among the 7 regimens shown here with respect to T3 or T2+3 flow with, ENOX being at least as effective as UFH at this early timepoint.
We also did not observe any important differences among the ENOX regimens with respect to ST res, bleeding, or ischemic events and for that reason in subsequent slides they will be pooled for comparison with UFH. N= 73 70 71 67 36 68 30
UFH b 60 inf 12
ENOXAPARIN
b 30 sc 1.0
b --- sc 1.0
UFH b 40 inf 7
b --- sc 0.3
ENOXAPARIN
b 30 sc 0.3
b --- sc 0.75
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7. Angio Evaluable Patients
TIMI 2+3 Flow 60 min 75 78
FULL Dose TNK
HALF Dose TNK + Abx 80 77 78 70
140
275
T 2
% Pts
T 3
3.03b
This slide shows the pooled ENOX angio data stratified by Full dose TNK and 1/2 dose TNK + ABX in the large graph and collapsing across pharmacologic reperfusion regimens for an overall comparison with UFH in the inset graph at the top right.
The rate of T3 flow was about 50% for both UFH and ENOX at 60 min.
N =
Angio Evaluable Patients
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8. ECG Evaluable Patients
Complete ST Res 60 and 180 min
180 min
FULL Dose TNK
HALF Dose TNK + Abx
% Pts
109
228
3.04c and d
The rate of Complete ST resolution is shown on this slide.
In the pairs of bars shown in the large graph the data at 60 min appear on the left and those at 180 min at the right.
Although the data are similar among the groups at 60 min, differences emerged at 180 min.:
There was a progressive increase in the rate of comp ST res moving from std TNK dosing through comb ination reperfusion. (POINT)
A greater proportion of patients tended to achieve complete ST Res when ENOX was the antithrombin with Full dose TNK (POINT); the rates with the two antithrombins were similar with combination reperfusion (POINT).
The pooled data at 180 min show rates of comp ST Res of 45% for UFH and 51% for Enox N= 41 55 90
112 37 54 76
116
UFH
ENOX
UFH
ENOX
ECG Evaluable Patients
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9. TIMI Major Hemorrhage (30d)
FULL Dose TNK
HALF Dose TNK Abx
ICH (%)
0(0)
1(0.6)
1(1.3)
3(1.8)
159
324
% Pts
Bleeds `
5.01a and 5.04a
The rate of TIMI major hem through 30 days is plotted on this slide.
In the full dose TNK group it was 2.4% with UFH and 1.9% with ENOX.
As we have come to expect the rate of major hemorrhage was higher when combination reperfusion regimens were used. It was 5.2% with UFH and 8.5% with ENOX.
For the pooled data the rate was 3.8% with UFH and 5.2% with ENOX. None of the differences in hem rates shown on this slide achieved statistical singficance.
N =
All Treated Population
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10. TIMI Major Hemorrhage in Pts Undergoing PCI (N=224)
Instr 9/15 pts
TIMI Major Hemorrhage in Pts Undergoing PCI (N=224)
FULL Dose TNK
HALF Dose TNK + Abx 80
144
% Pts
Bleeds
Safety PCI table
46% of the patients underwent PCI and the rate of major hem is shown here for that cohort.
With full dose TNK it was 4.9% with UFH and 1.8% with ENOX
It was 7.7% versus 8.0% with respectively with combination reperfusion (POINT)
The pooled data were 6.3% verus 5.6 % (POINT)
Again none of these differences were significant
< instr vs spontaneous> 41 57 39 N= 87
All Treated Population
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11. All Treated Population
Death/MI (D30)
11.3
P=0.01
4.9
P=0.002
FULL Dose TNK
HALF Dose TNK + Abx
15.9
P=0.005
159
324
% Pts
6.5
5.5
4.05a
The incidence of death and nonfatal recurrent MI was significantly lower in the ENOX patients given Full dose TNK: 15.9% vs 4.4%. The majority of this was mediated by a significant reduction in the rate of recurrent MI.
For comb reperfusion Death and MI was 6.5 % with UFH and 5.5% with ENOX.
The pooled data show a significant reduction from 11.3% with UFH to 4.9% with ENOX.
4.4
P=0.003 MI
Death
N =
All Treated Population
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12. Death/MI/Major Hem (D30)
13.8
P=0.08
8.6
FULL Dose TNK
HALF Dose TNK + Abx
17.1
P=0.015
159
324
10.4
11.0
% Pts
6.3
Major Hem
4.05a
The composite endpoint of Death/MI/Major Hem through 30 days is shown here.
There was a significant reduction from 17.1% with UFH to 6.3% with Enox with full dose TNK . (POINT)
The rates were similar with comb reperf 10.4 % with UFH and 11.0% with Enox. (POINT)
The pooled data were 13.8% with UFH and 8.6% with Enox. (POINT) MI
Death
N =
All Treated Population
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13. Phase III Trials ASSENT 3
Enoxaparin for STEMI
Phase II Trials HART II AMI-SK ENTIRE-TIMI Circ 104:648,2001
Regimen tPA SK TNK 1/2 TNK +Abx
Comparator UFH Placebo UFH UFH
Angio Early = = =
Late
ST Res ? =
ReMI ?
Maj Hem = = = =
Let us place the findings of ENTIRE -TIMI 23 in perspective with the other phase II trials of ENOX for STEMI: HART II and AMI SK
The pharmacologic reperfusion regimen and the comparator (either UFH or placebo) are shown in the first two rows. (POINT)
Angiographic observations obtained at an early time point such as 60 or 90 minutes shows ENOX to be equally effective to UFH. (POINT)
Late angiographic patency however is higher with ENOX (POINT)
When full dose lytic monotherapy is used Complete ST Res at 180 min is higher and recurrent MI is lower with ENOX. A similar favorable pattern with respect to recurrent MI is seen when ENOX is given with combination reperfusion with 1/2 dose TNK + Abx.
Major hemorrhage is similar with ENOX and UFH regardless of the form of pharmacologic reperfusion(POINT)
This constellation of a reduction in the rate of recurrent ischemic events without an increased risk of major hemorrhage when Enox is the adjunctive antithrombin therapy with full dose lytic therapy was also observed in the recently reported ASSENT 3 trial.
Although much of the research over the last 2 decades has focused on advances in fibrinolytics and antiplatelet therapy we have been stalled in our use of the familiar but problematic antithrombin UFH---the available data on enoxaparin suggest we now have a way to move forward in the antithrombin arena as well.
Phase III Trials ASSENT 3
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14. Back Up Slides
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15. Coverage During Rescue PCI
Anti Xa Levels: Dose Response Pharmacokinetic Model 1 . 6
30 mg IV mg/kg sc FULL DOSE TNK
Coverage During Rescue PCI 1 . 4
30 mg IV mg/kg sc 1/2 DOSE TNK + Abx 1 . 2 1 .
aXa (IU/ml) . 8 . 6
1.0 mg/kg sc . 4
0.75 mg/kg sc . 2
0.3 mg/kg sc . 2 4 6 8 1 1 2
TIME (h)
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16. Treatment Duration HALF Dose TNK + Abx FULL Dose TNK 82 160 77 164 159
324
2.02a 82
160 77
164
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17. Hemorrhage Requiring Transfusion > 2 Units
FULL Dose TNK
HALF Dose TNK + Abx
159
324
% Pts
5.04a
Among pts who had major hem
N =
All Treated Population
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18. UFH >36 h ENOX Index Hosp (< 8d)
ST MI < 6h
ASA
Standard Reperfusion: Full Dose TNK
Combination Reperfusion: Abx + 1/2 dose TNK
UFH >36 h
ENOX Index Hosp (< 8d)
UFH >36 h
ENOX Index Hosp (< 8d)
Target ACT 250 s Each bolus < 5000 U
Target ACT 200 s Each bolus < 5000 U
None
None/0.3
if PCI after 60 min angiogram
Sheath Removal :
4 h p PCI or ACT < 180s
8 h p last SC
4 h p PCI or ACT < 180s
8 h p last SC 4 h p last IV
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19. Endpoints Efficacy Safety Primary TFG at 60 min
Secondary TFG 2/3 cTFC,TMPG Thrombus Burden MLD, %Stenosis STRES 60,180 min Death, ReMI Rec Angina
Primary TIMI Maj Hem ICH
Secondary TIMI Minor Hem Plt Ct
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20. International Site Network
Dr. Wells 6 Dr. Dangoisse 6
TopEnrollers Worldwide Dr. Louwerenburg 48 Dr. Van Kesteren 34 Dr. Wesdorp 32
International Site Network
Dr. Van den Branden 17
Dr. Van der Heyden 16
Dr. G. McKendall 17
Canada 12
Dr. J -P Bassand 25
Netherlands Belgium 54 France 45 Spain 71
Dr. Fiol-Sala 20 Dr. Bayon 18
USA 45
February September 2001 : Total = 488
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21. Death/MI (D30) Time to Events20
TNK + UFH % 15
P=0.003
Log Rank
% Pts 10
1/2 TNK +Abx + UFH % 1/2 TNK +Abx + ENOX 5.5% 5
TNK + ENOX 4.4% 5 10 15 20 25 30
Days since Randomization
FINAL

22. Death/MI/Rec Isch (D30) Time to Events
TNK + UFH % 25 20
P=0.006
Log Rank
1/2 TNK +Abx + UFH % 1/2 TNK +Abx + ENOX %
% Pts 15 10
TNK + ENOX % 5 5 10 15 20 25 30
Days since Randomization
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23. Recurrent MI Pts NOT Undergoing PCI (N=259)
FULL Dose TNK
HALF Dose TNK + Abx 79
180
% Pts
Bleeds N= 41
103 38 77
All Treated Population
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24. Recurrent MI Pts Undergoing PCI (N=224)
8.8
FULL Dose TNK
HALF Dose TNK + Abx
2.8
14.6 80
144
% Pts
3.4
2.6
1.8
AFTER PCI
BEFORE PCI
N =
All Treated Population
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