1. The advent of fibrinolytic therapy had a dramatic effect on the treatment of acute myocardial infarction (AMI), in part because of its ease of use, rapid administration, and ready availability. Traditionally, fibrinolytics have been used in conjunction with unfractionated heparin (UFH). This strategy resulted in restoration of complete blood flow in 54% to 65% of patients. Our understanding of the pathogenic mechanisms underlying AMI has advanced. Whereas we used to think that AMI occurred at the site of a high-grade stenosis, we now know that most AMIs occur in vessels that are <50% occluded and that rupture of the fibrous cap overlying a vulnerable plaque triggers the coronary thrombus. We also know that the coronary thrombus is composed of fibrin, platelets, and thrombin. These insights led to the theory that a multiple or combination pharmacologic approach might improve outcomes. One of the most promising was the combination of a fibrinolytic with an antiplatelet (glycoprotein [GP] IIb/IIIa receptor inhibitors) and antithrombin/anticoagulation agent.
Our understanding of the pathogenic mechanisms underlying AMI has continued to advance. We have come to understand that the coronary thrombus in acute MI is composed of fibrin, platelets, and thrombin. While fibrinolytics act upon the fibrin component of the clot, antiplatelet agents might further improve clot lysis by acting upon the platelet component of the clot. Furthermore, it is possible that fibrinolytic agents may activate platelets. To this end, antiplatelet agents such as the glycoprotein (GP) IIb/IIIa receptor antagonists may be effective when used in combination with fibrinolytic agents.
Finally, while fibrinolytic agents may rapidly lyse the occlusive thrombus, a tight, thrombotic residual stenosis may remain which may in turn lead to reocclusion and reinfarction. Reinfarction is associated with a 10% to 15% mortality rate. The addition of antithrombotic agents to a fibrinolytic regimen may be beneficial in reducing the risk of reocclusion following successful thrombolysis.
Early trials that combined full-dose fibrinolytics and UFH with GP IIb/IIIa receptor inhibitors demonstrated improved patency in the infarct-related artery and improved time to ST-segment resolution after therapy, but this improvement was offset by increased bleeding. As a result, subsequent trials utilized lower doses of fibrinolytics. These small trials served as the basis for the design of the large-scale trials that are the focus of this presentation.

2. Pathophysiology of Combination Therapy in AMI
Reduces Reinfarction*
 Thrombus
 % Stenosis
 Minimum Diameter
 Myocardial Blush
 ST Resolution
There are compelling pathophysiologic reasons why combination therapy may benefit the management of acute MI. In Phase II angiographic trials, combination therapy has been shown to improve thrombus burden. This in turn has been related to improvements in both epicardial and microvascular coronary blood flow before and after percutaneous coronary intervention (PCI). Arteries were opened earlier and with better blood flow than with thrombolytic monotherapy. Another potential benefit of combination therapy may also lie in the ability of combination therapies to reduce thrombus burden and thereby reduce reinfarction rates.
References
Gibson CM, de Lemos JA, Murphy SA, et al. Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy. Circulation. 2001;103:
Gibson CM, Cannon CP, Piana RN, et al. Angiographic predictors of reocclusion after thrombolysis: results from the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. J Am Coll Cardiol. 1995;25:
 Epicardial Flow
Facilitates PCI
 Myocardial Flow
*Gibson et al. J Am Coll Cardiol. 1995;25:
Gibson et al. Circulation. 2001;103:

3. Recent Clinical Trials
GP IIb/IIIa
Receptor Inhibitor
Trial
Lytic
Anticoagulant
GUSTO-V
100% r-PA
50% r-PA
None
Abciximab
Standard-dose heparin
Low-dose heparin
ASSENT-3
100% TNK-tPA
50% TNK-tPA
None
Abciximab
ACC/AHA heparin dose
Low-dose heparin
Enoxaparin
Several large clinical trials evaluating various agents have been published recently (GUSTO-V, ASSENT-3) and several other Phase II angiographic studies are due to be completed in the next few months (ENTIRE, INTEGRITI, FASTER). This presentation will critically examine the results and clinical implications of the GUSTO-V and ASSENT-3 trials and will review the trial designs of the ongoing trials.
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
ENTIRE
50% TNK-tPA
100% TNK-tPA
Abciximab
None
Unfractionated heparin
Enoxaparin

4. Clinical Trials: Ongoing
GP IIb/IIIa
Receptor Inhibitor
Trial
Lytic
Anticoagulant
FASTER
50% TNK-tPA
75% TNK-tPA
100% TNK-tPA
Tirofiban
Low-dose heparin
INTEGRITI
50% TNK-tPA
75% TNK-tPA
100% TNK-tPA
Eptifibatide
Low-dose heparin
Shown here are the treatment strategies in two of the recently completed Phase II trials involving combination therapy. The Fibrinolytic and Aggrastat ST Elevation Resolution (FASTER) trial is examining tenecteplase (TNK-tPA) in various doses (½, ¾, and full-dose) with tirofiban and low-dose heparin. The Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial is examining TNK-tPA in various doses (½, ¾, and full-dose) with eptifibatide and low-dose heparin.

5. GUSTO-I: A 20% Increase in TIMI Grade 3 Flow is Needed to Yield a 1% Mortality Reduction60
54% 50
t-PA
6.3% 40
32%
% TIMI Grade 3 Flow 30 20 SK
7.4%
Recently completed Phase II angiographic studies have utilized the incidence of TIMI Grade 3 flow as a surrogate end point. The value of TIMI Grade 3 flow as a surrogate end point for mortality was demonstrated in the GUSTO-I trial. The GUSTO-I angiographic investigators demonstrated that the 22% improvement in TIMI Grade 3 Flow at 90 minutes of recombinant tissue plasminogen activator over Streptokinase (SK) resulted in a 1.1% improvement in mortality. It has therefore been predicted that it would require a 20% improvement in the rate of TIMI Grade 3 flow to yield a 1% improvement in mortality. Thus, this trial satisfies the criteria for a surrogate mortality end point: TIMI Grade 3 flow is associated with improved mortality and changes in a reperfusion regimen that yield higher rates of TIMI Grade 3 flow are associated with a lower mortality. If current monotherapy regimens yield 54% to 60% rates of TIMI Grade 3 flow, then combination therapy would need to increase these rates to 74% to 80% to achieve a 1% reduction in mortality.
References
The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329: 10
t-PA SK 5 6 7 8
The GUSTO Angiographic Investigators. N Engl J Med. 1993;329:

6. % Patients With TIMI Grade 3 Flow
TIMI Grade 3 Flow – Pooled Data From Dose Confirmation Phases of Recent Trials
100
Lytic alone
Combination 80 78 73 73 70 64 60 56 56 54 54
% Patients With TIMI Grade 3 Flow 47 40 40
While data from the dose finding phases of these trials were quite encouraging, shown here is data from dose confirmation phases of various Phase II angiographic studies of combination therapy. Overall, there was an 8% difference improvement in TIMI Grade 3 Flow among patients treated with combination therapy. If a 20% improvement is required to improve mortality by 1%, then an 8% improvement might be anticipated to improve mortality by 8/20 of 1% or by about 0.4%.
References
The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329:
Antman EM, Giuglano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 Trial. Circulation. 1999;99:
The SPEED Study Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000;101: 20
292 63 58 87 88 98
100 81 75
329
321
GUSTO-I
90 min
T14 t-PA
90 min
T14 r-PA
90 min
SPEED
60-90 min
INTRO-AMI
60 min
Pooled
60-90 min

7. SPEED: Results of Dose-Confirmation Phase
100
TIMI-2
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%
TIMI-3 80
28.7
21.6 60
Patency (%)
54.9
47.5 40
The pilot study preceding the GUSTO-V trial was the SPEED trial. Shown here are the findings from the dose confirmation phase of the SPEED trial. There was a 7.4% improvement in the rate of TIMI Grade 3 Flow. Based upon the previous data from GUSTO-I, if a 20% improvement in TIMI Grade 3 flow yields a 1% improvement in mortality, a 7.4% improvement would be predicted to give a 7.4 / 20 or approximately a 0.3% improvement in mortality. Indeed, this was observed in the subsequent Phase III mortality trial, GUSTO-V, as demonstrated in the slides that follow.
References
The SPEED Study Group. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation. 2000;101:
The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1993;329: 20
n=109
n=115
r-PA U
r-PA 5+5 U + Abx
The SPEED Study Group. Circulation. 2000;101:

8. GUSTO-V: Study Design ST , lytic eligible, < 6 h (n=16,588)
ASA
No Abciximab
Abciximab
2 x 10 U bolus (30’)
Full-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 U/h ( 80 kg) infusion
Low-dose Heparin:
60 U/kg bolus followed by 7 U/kg/h infusion
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-V trial was designed as a non-inferiority trial to demonstrate that combination therapy was superior to standard AMI therapy. Full-dose r-PA plus standard unfractionated heparin (UFH) was compared with the combination of half-dose r-PA plus abciximab plus low-dose UFH in patients with ST-segment elevation AMI.
GUSTO-V was an open-label study that randomized patients to r-PA at the standard dose of two 10 U boluses given over 2 to 5 minutes at 30-minute intervals or combination therapy with half-dose r-PA (two 5 U boluses over 2 to 5 minutes at 30-minute intervals) plus abciximab (0.25 mg/kg bolus and µg/kg per min infusion [maximum of 10 µg/min]) for 12 hours plus half-dose r-PA (two boluses of 5 U given 30 minutes apart).
All patients were administered aspirin (150 to 325 mg orally or 250 to 500 mg intravenously) at the time of randomization.
Heparin administration was adjusted by a nomogram to achieve an activated partial thromboplastin time (aPTT) of between 50 and 70 seconds, but because abciximab has an anticoagulant effect, the dosing for heparin varied according to the treatment assignment. For patients treated with full-dose r-PA, the heparin dose was a 5000 U bolus followed by a 1000 U/h infusion for those patients weighing at least 80 kg (or an 800 U/h infusion for those weighing less than 80 kg). In the combination therapy arm, patients received a 60 U/kg heparin bolus (maximum 5000 U) followed by an infusion of 7 U/kg per hour. This heparin dose of 60 U/kg is low, but not as low as the 40U/kg that was assessed in some of the earlier dose finding pilot studies that preceded GUSTO-V.
The primary end point of this study was mortality at 30 days, and the secondary end point was clinical and safety events at 30 days. Reinfarction and complications of AMI were recorded until only day 7 or hospital discharge.
Inclusion criteria included the following:
Continuous symptoms of chest discomfort for at least 30 minutes and no more than 6 hours from time onset to randomization
ECG evidence of AMI with ST-segment elevation or new left-bundle branch block
Exclusion criteria included the following:
One blood pressure measurement higher than 180 mmHg systolic and 110 mmHg diastolic
Weight >120 kg
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
1º end point: mortality at 30 days
2º end point: clinical and safety events at 30 days
The GUSTO-V Investigators. Lancet. 2001;357:

9. Primary End Point: 30-Day Mortality6
5.9%
5.6% 4
P=.43 for superiority
% Mortality
Non-Inferiority RR 0.95
(95% CI, ) 2
The primary end point of the GUSTO-V trial was all cause 30-day mortality by an intent to treat analysis. A statistical penalty was paid for the multiple interim looks at the data for the test of superiority (ie, the P-value required to achieve statistical significance was made more stringent, down to a P-value of .025).
The mortality among r-PA monotherapy patients was 5.9% (n=8260) while it was 5.6% (n=8328) among patients treated with low-dose r-PA and full-dose abciximab (P=.43). Thus, combination therapy with low-dose r-PA along with full-dose abciximab was not superior to r-PA monotherapy (P=.43).
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
Std. Reteplase (n = 8260)
Abx +  Dose Reteplase (n = 8328) 5 10 15 20 25 30
Days
The GUSTO-V Investigators. Lancet. 2001;357:

10. GUSTO-V: Noninferiority Analysis
Upper Boundary of 95% CI for Noninferiority
1.11
OR and 95% CI
Non-Inferiority RR 0.95 (95% CI, )
With the advent of improved adjunctive therapies in acute MI, mortality rates continue to slowly decline. Thus, achieving absolute reductions in mortality becomes increasingly difficult. In order to account for these recent reductions in absolute mortality rates in AMI trials, statistical analyses of data from AMI trials often now employ odds ratios (OR) rather than absolute differences.
In the GUSTO-V trial, the OR for the difference between the 2 drugs was up to 1.08, which was within the upper boundary of the 95% confidence interval (CI)—or 1.11—that was prespecified for equivalence. Thus, the combination of half-dose r-PA plus abciximab was “noninferior” to full-dose r-PA. A noninferiority analysis also preserves the ability to demonstrate superiority, if that is in fact observed.
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
0.0
Abciximab + Half-dose r-PA superior
1.0
Full-dose r-PA superior
2.0
Adapted with permission from the GUSTO-V Investigators. Lancet. 2001;357:

11. A Comparison of the Outcomes With r-PA Monotherapy in GUSTO-III vs GUSTO-V Trials8 50
48%
1.0
7.4%
0.91%
0.9 7 40
0.8 6
5.9%
37%
0.7 5
0.59% 30
0.6 4
0.5 20
0.4 3
0.3 2 10
0.2
Prior to the results of ASSENT-3 where the mortality was 5.4% for TNK-tPA plus enoxaparin, the 5.9% mortality for r-PA monotherapy was the lowest recorded to date in a major trial. However, as this slide demonstrates, the same drug may be associated with a different mortality in different trials depending upon the risk of the population studied. As has been well demonstrated in the past, anterior myocardial infarction is a major predictor of mortality in acute myocardial infarction (AMI). This slide demonstrates that the magnitude of the mortality difference for the same agent, r-PA monotherapy in GUSTO-V versus GUSTO-III trial, is directly proportional to the lower number of anterior MIs enrolled in GUSTO-V. These data again emphasize that the proportion of anterior MI patients enrolled is a major determinant of the overall mortality in a Phase III trial. Likewise, the rate of intracranial hemorrhage (ICH) was lower in GUSTO-V than in GUSTO-III, despite the fact that the same drug, r-PA monotherapy, was studied in both trials. This may reflect either the risk of the population or changes in concomitant drug administration such as heparin.
References
The GUSTO-III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med. 1997;337:
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 1
0.1
10,138
8,260
10,138
8,260
10,138
8,260
GUSTO III
GUSTO V
GUSTO III
GUSTO V
GUSTO III
GUSTO V
Death
Anterior MI
ICH
The GUSTO-III Investigators. N Engl J Med. 1997;337:
The GUSTO-V Investigators. Lancet. 2001;357:

12. GUSTO-V: Causes of Reinfarction4
P<.0001
3.5
r-PA 3
r-PA + Abx
2.7
2.3
Myocardial Infarction (%) 2
1.7
1.6
1.2 1
The risk of reinfarction was reduced in the GUSTO-V trial. The specific type of reinfarction that was diagnosed is shown. As can be seen, the majority of the reinfarctions were classified as such on the basis of ischemic ST changes in the setting of acute MI. New Q-wave development was quite infrequent, as were creatine kinase (CK) release infarctions.
The precise timing of reinfarction was also not clear. In particular, it is unclear if the reinfarctions occurred before PCI or as a complication of adjunctive PCI. Though there were more early PCIs in the monotherapy arm, if there are late PCIs in the combination therapy arm, these may be accompanied by CK release MIs. Indeed if PCIs were only performed later in the combination therapy arm (ie, if combination therapy only delayed PCI), these were not accounted for in the reinfarction data as the data were only collected to 7 days.
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
0.5
0.2
Any
Q-wave
Enzymatic
Ischemic ST
Change*
*Unblinded, unadjudicated
The GUSTO-V Investigators. Lancet. 2001;357:

13. Non-Intracranial Bleeding Through Discharge/Day 730 25
r-PA
24.6
r-PA + Abx
20.0 20
% of Patients 15
13.7
11.4 10
Combination therapy of r-PA plus abciximab resulted in higher rates of bleeding and transfusion in the GUSTO-V trial. In patients of all ages, the overall risk of bleeding (24.6% vs 13.7%, P<.0001) and the need for transfusion (of both blood and platelets) was significantly increased with combination therapy (5.7% vs 4.0%, P<.0001).
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
5.7 5
3.5
4.0
1.8
1.1
0.5
Severe
Bleeding
Moderate
Bleeding
Mild
Bleeding
Any
Bleeding
Receiving
Transfusions
The GUSTO-V Investigators. Lancet. 2001;357:

14. ICH by Age Group % of Patients 3 2 1 r-PA (n=8260) r-PA + Abx (n=8328)
2.1 2
P=.53
1.5
% of Patients
1.2
1.1 1
P=.27*
P=.66
In the GUSTO-V trial, the risk of ICH tended to be increased among patients over the age of 75 (2.1% vs 1.1%, P=.069). When a test of interaction was used to determine if there was a relationship between age and the effect of combination therapy on the rate of bleeding, the interaction term was significant (P=.033). This has raised concerns regarding the safety of combination therapy in the elderly. It also raises a question as to whether pharmacologic dosing should be both weight and age adjusted. A 40 U dose of heparin was also studied in the preceding SPEED pilot study, and the bleeding may have been lower with this dose than the 60 U dose that was studied in GUSTO-V. Lower adjunctive heparin dosing is being used in other ongoing combination therapy trials. The analysis of the data at over age 70 was prespecified while the analysis at over 75 years of age was not prespecified.
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
0.5
0.4
0.4
0.3
24/6230
21/6193
25/2030
31/2135
37/7172
28/7179
12/1088
24/1149
 70 yrs
> 70 yrs
 75 yrs
> 75 yrs
*Significant treatment interaction for the age 75 dichotomy; P=.033.
The GUSTO-V Investigators. Lancet. 2001;357:

15. GUSTO-V: PCI Within 6 Hours (Urgent) and Through Day 730 *
27.9 *
25.4 25 20
Urgent
PCI (%) 15
Through Day 7 * 10
8.6 *
Urgent PCI within the first 6 hours was performed in significantly fewer patients who received the combination of half-dose r-PA plus abciximab compared with those who received full-dose r-PA monotherapy. The rate of PCI within 6 hours was 8.6% in the full-dose r-PA group and 5.6% in the combination therapy group (half-dose r-PA plus abciximab group; P<.0001). At 7 days, the use of PCI was 27.9% and 25.4%, respectively (P<.0001).
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
5.6 5
r-PA
r-PA + Abx
*P<.0001.
The GUSTO-V Investigators. Lancet. 2001;357:

16. GUSTO-V: Event Rates in Those Requiring Urgent PCI12
r-PA
n=1173
r-PA + Abx 10
9.6
9.0 8
6.7
Myocardial Infarction (%) 6
5.4
4.8 4
2.8
Although this reduced rate of PCI was viewed as encouraging, there was concern because, among the 1173 patients who underwent urgent PCI, mortality was slightly higher among those who received the combination half-dose r-PA plus abciximab, although this was not significant. The reason(s) for this higher rate in mortality is not clear and may have been due in part to a slightly higher risk profile among patients who were treated with combination therapy.
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357: 2
Death
Repeat MI
Death Plus Repeat MI
Heartwire News. September 2, GUSTO-V: Combination half-dose fibrinolytic plus IIb/IIIa blocker. An Alternative approach to MI?

17. GUSTO-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
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
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:

18. 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-2 ASSENT-Plus AMI-SK
Less reocclusion: HART-2
Fewer reinfarctions: ASSENT-Plus AMI-SK Wilson, et al.
ASSENT-3 is the first large-scale trial to test LMWH
Angioscopy studies have shown that a large proportion of patients have persistent thrombus at the culprit stenosis up to one month following thrombolytic administration. The presence of thrombus is in turn associated with the risk of reinfarction. To this end, the antithrombotic agent enoxaparin may be effective in reducing reinfarction. Indeed, enoxaparin has been demonstrated to improve late patency and to lower reinfarction rates in several smaller preceding Phase I and II trials. In ASSENT-3, enoxaparin was given for up to a total of 7 days.

19. ASSENT-3: Study Design ST-Segment Elevation AMI (n=6095 patients)
150 to 325 mg ASA (daily)
Randomized
Full-dose TNK-tPA Plus Enoxaparin
Half-dose TNK-tPA Plus Abciximab Plus Low-dose Heparin
Full-dose TNK-tPA Plus Weight- adjusted UFH
The Assessment of the Safety and Efficacy of a New Thrombolytic Therapy (ASSENT)-3 trial was designed to test TNK-tPA with three other agents (enoxaparin, abciximab, and UFH) to find the optimal pharmacologic reperfusion strategy for AMI. ASSENT-3 included over 6000 patients with ST-elevation MI who were randomized to 1 of 3 treatment groups:
Full-dose TNK-tPA plus the low-molecular-weight heparin, enoxaparin, given up to discharge or revascularization with a maximum of 7 days
Half-dose TNK-tPA plus the platelet GP IIb/IIIa receptor inhibitor, abciximab, for 12 h and low-dose UFH
Full-dose TNK-tPA plus weight-adjusted UFH for 48 h according to the revised 1999 ACC/AHA guidelines. This was the first large trial to assess the ACC/AHA heparin dosing regimen.
Inclusion criteria included the following:
Symptom onset within 6 hours of randomization
ECG evidence of AMI with ST-segment elevation
Exclusion criteria included the following:
Systolic BP >180 mmHg and/or diastolic BP >110 mmHg on repeated measurements.
The dosing of the antithrombotic and antiplatelet therapy was as follows: Patients assigned weight-adjusted intravenous UFH received a bolus of 60 U/kg (maximum of 4000 U) and initial infusion of 12 U/kg per h (maximum 1000 U/h) adjusted to maintain an aPTT of s for 48 hours with subsequent heparin administration left to the discretion of the treating physician. The first blood sample for activated partial thromboplastin time measurement was drawn after 3 hours.
Patients assigned enoxaparin combination therapy received an intravenous bolus of 30 mg immediately followed by the first subcutaneous dose of 1 mg/kg. This subcutaneous dose was repeated every 12 hours up to hospital discharge or revascularization with a maximum duration of therapy of 7 days. The first two subcutaneous doses could not exceed 100 mg.
Patients assigned to abciximab combination therapy received 0.25 mg/kg bolus and g/kg/min (maximum of 10 g/min) for 12 h. Because abciximab has an anticoagulant effect, a lower dose of UFH was given: 40 U/kg bolus (maximum of 3000 U) followed by 7 U/h (maximum of 800U/h) to achieve a partial thromboplastin time between 50 and 70 s. Also in this group, the first aPTT was measured after 3 hours.
Aspirin ( mg) was given to all patients. Intravenous boluses of UFH, enoxaparin and abciximab were to be given before the bolus of TNK-tPA.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
The ASSENT-3 Investigators. Lancet. 2001;358:

20. ASSENT-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.
The co-primary end points of ASSENT-3 are shown here:
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 ICH or in-hospital major bleeding (other than intracranial bleeding).
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:

21. ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia
3-way P=.0001 20
P=.0009*
P=.0002*
15.4 15
11.4
11.1
% Risk of 30-Day D/MI/Ref Isch 10 5
Shown here are the results of the primary efficacy end point in a bar graph format. After correcting for multiple testing (Bonferroni), conventional significance was reached for the primary efficacy end point when the enoxaparin group was compared to the UFH group (P=.0009) and when the abciximab group was compared to the UFH group (P=.0002).
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
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.

22. % Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH
ASSENT-3: 30-Day Mortality, Recurrent MI, Refractory Ischemia, Major Bleeding and ICH
3-way P=.0062 20
P=.0146*
P=.057*
17.0 15
14.2
13.8
% Risk of 30-Day D/MI/ Ref Isch/Maj Bleed/ICH 10 5
Shown here are the results of the primary efficacy and safety composite end point presented in a graphic format. When compared with full-dose TNK-tPA and UFH, full-dose TNK-tPA with enoxaparin and half-dose TNK-tPA with abciximab were associated with significant reductions in the efficacy plus safety composite end point (3-way P=.0062).
For the comparison of full-dose TNK-tPA plus enoxaparin vs full-dose tenecteplase plus UFH, the P-value was P=.0037 for the primary efficacy and safety end point. For the comparison of half-dose TNK-tPA plus abciximab vs full-dose TNK-tPA plus UFH, the P-value was for the primary efficacy and safety end point. After correcting for multiple testing (Bonferroni), conventional significance was reached for the primary efficacy and safety end point at 30 days in the enoxaparin group (P=.0146) but not in the abciximab group (P=.057).
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
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=.0037 for the enox vs UFH comparison, and P=.0142 for the abx vs UFH comparison.

23. Kaplan-Meier Curves Primary Efficacy Plus Safety End Point
Primary Efficacy End Point 20 20 18 18
UFH
UFH 16 16
Abx 14 14
Enox* 12 12
Enox*
Abx*
Probability (%) 10
Probability (%) 10 8 8 6 6 4 4
Shown here are the data displayed as Kaplan-Meier Curves. The event rates separated early on after treatment within the first few days. After correcting for multiple comparisons, statistical significance was reached for the TNK-tPA plus enoxaparin group in both the primary efficacy and primary efficacy plus safety end points, compared with the TNK-tPA plus UFH group. In patients treated with TNK-tPA combination therapy, statistical significance was reached for the primary efficacy end point but not the primary efficacy plus safety end point.
Thus, the ASSENT-3 trial showed a significant benefit in efficacy and safety for the TNK-tPA plus enoxaparin regimen.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
log-rank P=.0001
*vs UFH
log-rank P=.0062
*vs UFH + Abx 2 2 5 10 15 20 25 30 5 10 15 20 25 30
Days to death, reinfarction, or refractory ischemia
Days to death, reinfarction, refractory ischemia, ICH, or major bleeding
Reprinted with permission from the ASSENT-3 Investigators. Lancet. 2001;358:

24. % Risk of 30-Day Efficacy and Safety End Point
ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients >75 Years of Age 45
P=.001* 40
36.9 35 30
28.0
25.5 25
% Risk of 30-Day Efficacy and Safety End Point 20 15 10
This slide shows the results of the primary efficacy and safety end point among elderly patients over the age of 75 in a bar graph format. In patients over the age of 75, the risk of death/MI/ refractory ischemia, ICH, or major bleeding was 25.5% for TNK-tPA plus enoxaparin, 36.9% for TNK-tPA plus abciximab, and 28% for TNK-tPA plus UFH. 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).
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 5
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
*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).

25. % Risk of 30-Day Efficacy and Safety End Point
ASSENT-3: Primary Efficacy and Safety End Point of Death, Reinfarction or Refractory Ischemia, ICH or Major Bleeding in Patients with Diabetes 30
P=.0007* 25
22.3 20
16.5
% Risk of 30-Day Efficacy and Safety End Point 15
13.9 10
This slide shows the results of the primary efficacy and safety end point among patients with diabetes in a bar graph format. Among diabetic patients, the risk of death/MI/refractory ischemia, ICH, or major bleeding was 13.9% for TNK-tPA plus enoxaparin, 22.3% for TNK-tPA plus abciximab, and 16.5% for TNK-tPA plus UFH. There was a statistically significant interaction between treatment with abciximab and patients with diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007).
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 5
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
*There was a statistically significant interaction between treatment with abciximab and diabetes, such that diabetics had poorer outcomes with abciximab therapy (P=.0007).

26. ASSENT-3: 30-Day Mortality10
3-way P=.25 8
6.6
6.0 6
5.4
% Risk of 30-Day Mortality 4
The 30-day mortality rate among patients treated with TNK-tPA and enoxaparin was the lowest reported in a large scale trial to date. A 3-way P-value showed no statistically significant difference across the 3 arms in 30-day mortality.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH

27. ASSENT-3: 30-Day Death or MI10
3-way P=.0198
9.1 8
7.3
6.8 6
% Risk of 30-Day Death or MI 4
The enoxaparin arm was associated with the lowest rate of death or MI at 30 days (3-way P=.0198).
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH

28. ASSENT-3: In-Hospital Recurrent MI5
3-way P=.0009
4.2 4 3
2.7
% Risk of In-Hospital Recurrent MI
2.2 2
The enoxaparin and abciximab arms were associated with a lower rate of recurrent MI compared with the UFH arm.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 1
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH

29. ASSENT-3: In-Hospital Refractory Ischemia10
3-way P<.0001 8
6.5 6
% Risk of 30-Day Refractory Ischemia
4.6 4
3.2
The enoxaparin and abciximab arms were associated with a lower rate of refractory ischemia compared with the UFH arm.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH

30. ASSENT-3: Incidence of In-Hospital Thrombocytopenia and Noncerebral Bleeding Complications
Enox Abx UFH P-Value (n=2040) (n=2017) (n=2038) 3-way
Any thrombocytopenia <.0001
Thrombocytopenia <.0001
<20,000 cells/µL
20,000 to 50,000 cells/µL
50,000 to 100,000 cells/µL
Bleeding episodes
Total 25.6* <.0001
Major 3.0*
Minor 22.6* <.0001
Blood transfusion 3.4*
Significantly more major bleeding complications (P=.0002), more transfusions (P=.001), and a higher rate of thrombocytopenia (P=.0001) were observed in the abciximab group compared with the UFH group.
In patients above 75 years and in patients with diabetes, the rate of major bleeding complications was three times as high in the abciximab group than in the UFH group: 13.3% vs 4.1% and 7.0% vs 2.2%, respectively. More major bleedings and blood transfusions were also observed in the enoxaparin group as compared with UFH but these differences were not statistically significant.
References
The Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-3 Investigators. Lancet. 2001;359 (In press).
*While 3-way P-value is significant, Enox vs UFH comparison P=NS

31. ASSENT-3: In-Hospital Stroke Rates
Unclassified
Hemorrhagic conversion
Ischemic stroke*
Intracranial hemorrhage
Total strokes
0.15
0.07
0.40
0.64
0.94
0.88
1.49
1.62
Abx (n=2017)
Enox (n=2040)
0.59
0.05
0.77
0.00
0.57
0.54
0.98
0.93
1.52
P-Value
UFH (n=2038)
Total stroke and intracranial hemorrhage rates were similar in the three groups.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
*Including hemorrhagic conversion

32. Patients Undergoing PCI: Mortality8
ASSENT-3: In-Hospital PCI
GUSTO-V: Urgent PCI 7
6.7 6
5.4 5
Mortality (%) 4
3.7 3
2.7
2.5
One of the goals of combination therapy was to improve outcomes following rescue/adjunctive PCI. Shown here are the mortality rates of patients undergoing either elective in-hospital PCI or urgent PCI with or without combination therapy. These nonrandomized data do not show a mortality benefit to the addition of abciximab to thrombolytic monotherapy, and in fact the mortality rates are slightly higher among patients treated with combination therapy. Patients treated with combination therapy may have had a greater number of comorbidities, and this may account in part for the observed results. The benefit of facilitated PCI with combination therapy requires further prospective evaluation.
References
The GUSTO-V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet. 2001;357:
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358: 2 1
TNK-tPA + Enox
TNK-tPA + Abx
TNK-tPA + UFH
r-PA + UFH
r-PA + Abx

33. How Does Actual Weight Compare to Estimated Weight?
Correlation Between Estimated and Actual Patient Weight in TIMI 10B
188.5
R2=0.93, P<.0001
Actual Patient Weight (kg)
TNK-tPA is dosed based upon estimated patient weight. Each dose category is 22 pounds wide. The patient does not need to be weighed; the weight can simply be estimated. Cannon et al have studied how the patient’s estimated weight compares to the actual weight. They found that the two were closely correlated as shown here.
References
Cannon CP, Gibson CM, Murphy SA, McCabe CH, Van de Werf F, Braunwald E. Weight-based dosing of thrombolysis: How well do we estimate weight? How often would this translate into errors with administration of thrombolytic drugs? A comparison of single-bolus TNK with t-PA in TIMI 10B. J Am Coll Cardiol. 2001;37:323A.
40.5
36.4
181
Estimated Patient Weight (kg)
Reprinted with permission from Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

34. Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight
Weight-Based Dosing of Thrombolysis: How Well Do We Estimate Weight? How Often Would This Translate Into Errors With Administration of Thrombolytic Drugs and Adverse Outcomes?
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).
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.
Errors in estimating weight are uncommon, especially those that would lead to a dose change (a 22 pound error occurred in 1.3% or 49/3730 cases for TNK-tPA and 4.5% or 13/290 for t-PA). 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.
References
Cannon CP, Gibson CM, Murphy SA, McCabe CH, Van de Werf F, Braunwald E. Weight-based dosing of thrombolysis: How well do we estimate weight? How often would this translate into errors with administration of thrombolytic drugs? A comparison of single-bolus TNK with t-PA in TIMI 10B. J Am Coll Cardiol. 2001;37:323A.
Cannon CP, et al. J Am Coll Cardiol. 2001;37:323A.

35. ASSENT-3: Study Group Conclusions Regarding TNK-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 conclusions of the ASSENT-3 study group regarding the combination of half-dose TNK-tPA plus full-dose abciximab are shown here.
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
The ASSENT-3 Investigators. Lancet. 2001;358:

36. ASSENT-3: Study Group Conclusions Regarding Enoxaparin
“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.”
Lecture Notes
The ASSENT 3 Study Group concluded the following:
“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.”
References
The ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial in acute myocardial infarction. Lancet. 2001;358:
The ASSENT-3 Investigators. Lancet. 2001;358:

37. ENTIRE TIMI-23: Study Design
ST  MI <6h (n=461)
ASA
Standard Reperfusion:
Full-dose TNK-tPA (0.53 mg/kg)
Combination Reperfusion:
Half-dose TNK-tPA + Abx (0.27 mg/kg)
The ENTIRE TIMI-23 trial was designed to assess the efficacy and safety of enoxaparin versus UFH as adjunctive antithrombin therapy either with full-dose TNK-tPA or with half-dose TNK-tPA in combination with intravenous abciximab. This was a Phase II open-label, angiographic trial conducted at 43 sites in 6 countries. 488 patients were randomized into one of the treatment regimens shown on this slide and were stratified by anterior versus nonanterior location of MI. The primary efficacy end point was TIMI Grade 3 flow at 60 minutes, and the primary safety end point was TIMI major hemorrhage at 30 days.
The major secondary end points included ST segment resolution at 60 and 180 minutes and ischemic events through 30 days.
Results of this study were presented at the European Society of Cardiology meeting held in Stockholm in September However, the results have not yet been published in the public domain.
Source:
Antman E, Gibson M, Heidbuchel H, et al. Enoxaparin with or without GP IIb/IIIa inhibition as reperfusion strategy in ST-segment elevation MI – results of the ENTIRE-TIMI 23 trial. Eur Heart J. 2001;22:15. Abstract 145.
UFH 60 U/kg bolus 12 U/kg/h infusion  36 h
ENOX varying doses +/- IV bolus Index Hosp ( 8 d)
 UFH 40 U/kg bolus 7 U/kg/h infusion  36 h
 ENOX varying doses +/- IV bolus Index Hosp ( 8 d)
Antman E, et al. Eur Heart J. 2001;22:15. Abstract 145.

38. Outstanding 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?
Important questions remain: Should enoxaparin replace UFH as the ideal antithrombin agent for AMI? Fibrinolytic agents do not appear to be interchangeable, so will similar outcomes be observed if enoxaparin is combined with a less fibrin-specific agent such as r-PA? Will cardiologists accept the use of enoxaparin in 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 similar or better results than ASSENT-3 and ENTIRE? What is the optimal strategy for facilitated PCI?
All these questions require further evaluation in randomized prospective trials.

39. Future 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
The focus of acute MI therapy is beginning to shift from simple restoration of epicardial coronary artery blood flow to the restoration of tissue level perfusion. Potential downstream targets are shown on this slide.