Transcript ASSENT 3 Slides - Clinical Trial Results

ASSENT 3
Efficacy and Safety of Tenecteplase in
Combination with Enoxaparin, Abciximab or
Unfractionated Heparin: the ASSENT-3
Randomised Trial in Acute Myocardial
Infarction
The Assessment of the Safety and Efficacy of a New
Thrombolytic Regimen (ASSENT)-3 Investigators
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT-3 Trial Design
ST-Segment Elevation AMI (6095 patients)
150-325 mg Aspirin (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
Heparin
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Rationale for Inclusion of TNK-tPA
Monotherapy and Unfractionated Heparin
• TNK-tPA plus UFH (fully weight-adjusted)
– In spite of several 100,000s of patients studied in
thrombolysis trials, the optimal dose of concomitant
UFH remains unknown
– InTIME-II data with t-PA suggest lower ICH rates
with reduced, fully weight-adjusted UFH, and earlier
aPTT monitoring
– AHA/ACC-recommended fully weight-adjusted dose
of UFH never tested prospectively in a large-scale
trial
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
Pathophysiology of
Combination Therapy in AMI
Combination Therapy
 Thrombus
Reduces
Reinfarction*
 % Stenosis
 Myocardial Blush
 Minimum Diameter
 ST Resolution
 Epicardial Flow
Facilitates PCI
 Myocardial Flow
*Gibson et al. J Am Coll Cardiol. 1995;25:582-589.
Gibson et al. Circulation. 2001;103:2550-2554.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
Angiographic Predictors of Reocclusion
Incidence of reocclusion (%)
P=0.003
12
P=0.03
20
10.4
P=0.009
12
18.2
10
10
16
14
8
9
10.7
18
6
2
5.6
6
4
4
3.0
2
2
0
TIMI 2 TIMI 3
TIMI Flow
0
8
78
7
77
77.9
76
+
–
Collaterals
0
75
4
8
2.2
79
8.4
5
10
4
P=0.04
6
8
12
6
P=0.06
+
Ulcer
–
3.3
3
2
73
1
72
0
+
–
Thrombus
73.9
74
71
+
–
% Stenosis
Gibson et al. J Am Coll Cardiol. 1995;25:582-589.
Clinical Impact of Reocclusion: 810 patients, cath 90 min & 7 days later:
12.4% reocclude, 58% symptomatic, in-hospital mortality 11.0% vs 4.5% (P=0.01).
Ohman et al. Circulation. 1990;82:781-791.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
Thrombus Remains Following Thrombolysis: The Need
For Aggressive Antithrombotic / Antiplatelet Therapy
When a small camera is placed in the artery
(angioscopy), all 40 thrombolytic patients in a
study by Van Belle et al had some remaining
form of thrombus (shown in red here).
While thrombolysis reduces thrombus burden,
thrombus remains, & thrombolysis exposes
underlying ulcerated lesions.
The high frequency of persistent thrombotic
lesions underscores the need for effective
antithrombotic therapy following thrombolytic
administration.
Van Belle et al. Circulation. 1998;97:26-33.
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
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Rationale for Use of Enoxaparin
• Enoxaparin Advantages
– Reduced bleeding (because it binds less strongly to circulating
plasma, proteins, etc.)
– Superior bioavailability at lower doses
– Longer half-life
– Does not require aPTT monitoring, due to more predictive
dose response
– Possible long-term cost advantage due to lower frequency of
aPTT monitoring
– Delivered subcutaneously with potential for even longer
durations of administration
– Enoxaparin has unique anti-Xa:anti-IIa ratio that distinguishes
it from others in its class
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Rationale for Half Dose TNK-tPA Plus FullDose Abciximab
Trial arm based on hypothesis that a thrombolytic agent
plus GP llb/llla inhibitor might result in improved
patency with enhanced safety
• Hypothesis based on
– Phase II angiographic trials that suggest there may
be improved patency with half-dose lytic plus GP
llb/llla inhibitor
– Enhanced safety profile of TNK-tPA, reduced risk of
major complications, especially in the elderly
(ASSENT 2)
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Inclusion Criteria
• Inclusion criteria were identical to those of the
Assessment of the Safety and Efficacy of a New
Thrombolytic Regimen (ASSENT)-2 trial:
 Age 18 years or older
 Onset of symptoms within 6 hours before randomization
 ST-segment elevation of 1 mm or more in two or more limb
leads, or 2 mm or more in two or more contiguous
precordial leads or left bundle-branch block.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Exclusion Criteria
Exclusion criteria on admission were:
• Systolic blood pressure of more than 180 mm Hg
• Diastolic blood pressure of more than 110 mm Hg, or both on
repeated measurements
• Use of abciximab or other glycoprotein IIb/IIIa inhibitors within
the preceding seven days
• Major surgery, biopsy of a parenchymal organ or substantial
trauma within two months
• Any head or other trauma occurring after onset of current
myocardial infarction; any known history of stroke, transient
ischemic attack or dementia; any known structural damage to the
central nervous system
• Current therapy with oral anticoagulants; treatment with
unfractionated heparin 5,000 U or a therapeutic subcutaneous
dose of low-molecular-weight heparin within 6 hours
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Exclusion Criteria (continued)
Exclusion criteria on admission were (continued):
• Known thrombocytopenia (100,000 cells/l)
• Known renal insufficiency (serum creatinine 2.5 mg% for men
and 2.0 mg% for women)
• Sustained cardiopulmonary resuscitation (more than 10 min) in
previous two weeks
• Pregnancy, lactation, or parturition in the previous 30 days
• Active participation in another investigative drug or device study
in the previous 30 days; previous enrolment in this study
• Inability to follow the protocol and to comply with the follow-up
requirements
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3:
TNK-tPA Weight-Adjusted Dosing
Weight (kg)
Full dose (mg)
Half dose (mg)
(in combination with abcix)
<60 (<132 lbs)
30.0
15.0
≥60 to <70 (133-154 lbs)
35.0
17.5
≥70 to <80 (155-176 lbs)
40.0
20.0
≥80 to <90 (177-198 lbs)
45.0
22.5
≥90 (>199 lbs)
50.0
25.0
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Trial Design
An international, multicenter, randomized (1:1:1), open-label, controlled, parallelgroup study in patients with ST-elevation AMI presenting within 6 hours of symptom
onset, treated with 1 of 3 different reperfusion regimens
randomization 1:1:1
enoxaparin IV bolus
UFH IV bolus
UFH IV bolus
Wt adj TNK-tPA
full-dose IV bolus
abciximab IV bolus
Wt adj TNK-tPA
full-dose IV bolus
enoxaparin SC injections
every 12 hours up to
discharge or
revascularization
(max of 7 days)
Wt adj TNK-tPA
half-dose IV bolus
UFH IV infusion for
up to 48 hours
abciximab IV infusion
for 12 hours
UFH IV infusion
for up to 48 hours
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Primary Endpoints
Primary Efficacy Endpoint: Composite of 30-day
mortality or in-hospital reinfarction or in-hospital
refractory ischemia.
Primary Efficacy Plus Safety Endpoint: Composite of
30-day mortality or in-hospital reinfarction or inhospital refractory ischemia plus in-hospital
intracranial haemorrhage or in-hospital major bleeding
other than intracranial.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Statistical Analysis Plan
• Statistical analysis was by intention-to-treat.
• A two-sided 95% confidence interval was calculated and an overall
chi-square test, comparing the three treatment groups, was
performed.
• Between groups pair wise comparisons are presented using the twosided 95% confidence interval of the relative risk.
• Non-parametric, covariate-adjusted rates were calculated for each
end point. Covariates used were gender, age, weight, infarct location,
previous infarct, Killip class, heart rate, time to tenecteplase
treatment and systolic blood pressure.
• Since the results of the adjusted and non-adjusted analyses were
very similar only non-adjusted results are presented.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Statistical Power
• The study had 80% power to exclude with 95%
confidence (one-sided) a 1% higher incidence of these
end points in comparison with the control group
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Endpoint Adjudication
• Stroke: Reviewed blinded to treatment allocation by
the same stroke committee that reviewed the stroke
data in the ASSENT-2 trial.
• Reinfarction, refractory ischemia, bleeding
complications: No central adjudication. However,
definitions were provided to the investigators who, in
addition, had to reconfirm the occurrence of these end
points on a special form.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Endpoint Definitions
• Reinfarction in the first 18 hours: Recurrent symptoms of
ischemia at rest accompanied by new or recurrent ST-segment
elevations of 0.1 mV or more in at least two contiguous leads,
lasting at least 30 min.
• Reinfarction after 18 hours: New Q waves in two or more leads
and/or enzyme evidence of reinfarction (re-elevations of CK-MB
troponins or total CK above the upper limit of normal and
increased over the previous value).
• Refractory ischemia: Symptoms of ischemia with ST-segment
deviation or T wave inversion persisting for at least 10 min
despite medical management and not fulfilling the diagnosis of
reinfarction.
• Non-cerebral bleeding complications were defined as major
(requiring transfusion, intervention because of hemodynamic
compromise or both) or minor.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Randomization and Study Treatments
6095 patients with ST-segment elevation
acute myocardial infarction
2040 assigned full-dose
TNK-tPA plus enoxaparin
2017 assigned half-dose
TNK-tPA plus weight-adjusted,
reduced dose, unfractionated
heparin plus abciximab
At least 1 component
of study medication
not given: 21
Primary
composite
end points
unavailable: 3
2037 completed
follow-up
2038 assigned full-dose
TNK-tPA plus weight-adjusted
unfractionated heparin
At least 1 component
of study medication
not given: 61
Primary
composite
end points
unavailable: 1
2016 completed
follow-up
At least 1 component
of study medication
not given: 24
Primary
composite
end points
unavailable: 2
2036 completed
follow-up
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Concomitant Use of Medications In-Hospital
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
Calcium channel blockers
11
10
11
0.82
IV nitrates
73
71
73
0.25
Beta-blockers
84
84
83
0.73
ACE inhibitors
62
60
63
0.18
Angiogenesis II inhibitors
3.1
2.9
3.1
0.87
Statins
52
50
51
0.24
Aspirin
≤12h or upon randomization
in-hospital
97
96
97
95
97
95
0.53
0.40
Ticlopidine/Clopidogrel
30
28
32
0.014
Oral anticoagulants
4.3
4.8
5.2
0.41
Abciximab
6.5
4.2
8.9
<0.0001
Other GP IIb/IIIa inhibitors
6.8
3.7
7.1
<0.0001
Low-molecular-weight heparins
16.0
26.0
29.0
<0.0001
Thrombolytics
2.0
1.9
2.9
P Value
0.08
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Baseline Characteristics
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
Age (years)
61
61
61
0.41
Age >75 years
13
12
13
0.21
Women
23
24
23
0.40
Weight (kg)
79
79
79
0.73
Height (cm)
170
170
170
0.51
Time from onset of symptoms
to randomization (h)
2.7
2.7
2.8
0.33
Time from randomization
to TNK-tPA (h)
0.26
0.40
0.27
<0.0001
Killip class
I
II/III
IV
Systolic blood pressure (mm Hg)
89
10
0.3
88
11
0.4
88
12
0.4
134
133
133
3 way
P Value
0.61
0.66
Data are mean (SD) or percentages. CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Baseline Characteristics (Cont.)
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
P Value
Infarct location
Anterior
Inferior
Other
0.91
39
56
4.6
39
56
4.8
38
57
5.0
Heart rate (bpm)
75
75
74
0.23
Hypertension
41
41
41
0.99
Diabetes
19
18
18
0.66
Previous myocardial infarction
14
13
14
0.52
Prior CABG
3.6
3.3
2.6
0.19
Prior PCI
6.2
6.0
6.4
0.86
Current smoker
44
47
47
0.16
Data are mean (SD) or percentages. CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
Baseline Demographics of Large Scale Thrombolytic Trials
GUSTO I
90-93
Patients Randomized (ITT)
30647
GUSTO III
95-97
15059
InTIME II
97-99
ASSENT II
97-98
GUSTO V
99-01
ASSENT 3
00-01
ASSENT 3 ASSENT 3
00-01
00-01
15060
16949
16588
2040
2017
2038
Female, (%)
25
27
25
23
25
23
24
23
Age (median years)
62
63
62
61
61
61
61
61
Previous MI (%)
17
18
16
16
15
14
13
14
Diabetes (%)
15
16
14
16
16
19
18
18
Anterior MI (%)
39
48
42
40
37
39
39
38
Median Time (hrs) Between
Symptom and First Study Rx
2.8
2.7
2.9
2.8
2.7
2.7
2.7
2.8
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Primary Composite Endpoints at
Hospital Discharge and at 30 Days
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
3 way
P Value
30-day mortality or
in-hospital reinfarction
or in-hospital refractory
ischemia
11.4
11.1
15.4
<0.0001
30-day mortality or
in-hospital reinfarction
or in-hospital refractory
ischemia or in-hospital ICH
or in-hospital major bleeds
(other than ICH)
13.8
14.2
17.0
0.0081
Data are percentages and 95% confidence intervals. ICH, intracranial hemorrhage.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Days to Death or Reinfarction
or Refractory Ischemia
20
Unfractionated
Heparin
18
Probability (%)
16
14
15.4%
Enoxaparin
12
11.4%
11.1%
Abciximab
10
8
6
4
Log-rank test: P=0.0001
2
0
0
5
10
15
20
25
30
Days to Death or Reinfarction or Refractory Ischemia
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Days to Death or Reinfarction
or Refractory Ischemia or ICH or Major Bleeding
20
Unfractionated
Heparin
18
Probability (%)
16
17.0%
Abciximab
14
14.2%
13.8%
Enoxaparin
12
10
8
6
4
Log-rank test: P=0.0062
2
0
0
5
10
15
20
25
30
Days to Death or Reinfarction or Refractory Ischemia or ICH or Major Bleeding
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: 30 Day Mortality, Recurrent MI,
Refractory Ischemia
% Risk of 30 Day D / MI / Ref Isch
3 way P=0.0001
20.0%
p=0.0009*
p=0.0002*
15.4%
15.0%
11.4%
11.1%
TNK +
Enoxaparin
TNK +
Abciximab
10.0%
5.0%
0.0%
TNK
*P values are the Bonferroni p-values after correcting for multiple comparisons. The uncorrected p-values
were p=0.0002 for the enox vs UFH comparison, and <0.0001 for the abcix vs UFH comparison.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of 30 Day D / MI / Ref Isch / Maj Bleed / ICH
ASSENT 3: 30 Day Mortality, Recurrent MI,
Refractory Ischemia,
Bleeding, ICH
RefractoryMajor
Ischemia
3 way p=0.0062
p=0.0146*
p=0.057*
20.0%
17.0%
15.0%
13.8%
14.2%
TNK +
Enoxaparin
TNK +
Abciximab
10.0%
5.0%
0.0%
TNK
*P values are the Bonferroni p-values after correcting for multiple comparisons. The uncorrected p-values
were p=0.0037 for the enox vs UFH comparison, and 0.0142 for the abcix vs UFH comparison.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Odds Ratios for Death at 30 Days or InHospital Reinfarction or Refractory Ischemia
Death at 30 Days or
In-Hospital Reinfarction or
Refractory Ischemia (%)
UFH
Overall event rate
Gender
Male
Female
Infarct location
Anterior
Other
Time to TNK-tPA (h)
0-2
ENOX or
ABCIX
Relative Risk
(95% CI)
15.4
11.4
11.1
0.74 (0.63, 0.87)
0.72 (0.61, 0.84)
14.8
10.4
9.8
15.1
14.8
0.70
0.66
0.87
0.85
(0.58,
(0.55,
(0.65,
(0.64,
0.84)
0.80)
1.17)
1.14)
14.6
13.6
9.5
9.5
0.75
0.70
0.72
0.73
(0.60,
(0.56,
(0.58,
(0.58,
0.94)
0.88)
0.91)
0.91)
13.0
8.9
9.8
10.9
12.6
13.3
0.77
0.53
0.69
0.76
0.77
0.82
(0.59,
(0.38,
(0.53,
(0.60,
(0.56,
(0.60,
1.01)
0.74)
0.84)
0.96)
1.06)
1.10)
17.4
19.4
13.0
16.8
>2-4
14.2
>4
16.3
ENOX vs UFH
ABCIX vs UFH
UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab.
ENOX or
ABCIX
Better
0.5
UFH
Better
1
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
2
ASSENT 3: Odds Ratio for Death at 30 Days or InHospital Reinfarction or Refractory Ischemia (Cont.)
Death at 30 Days or
In-Hospital Reinfarction or
Refractory Ischemia (%)
UFH
Age (years)
≤75
13.8
>75
26.2
Diabetes
Yes
13.8
No
15.8
ENOX or
ABCIX
Relative Risk
(95% CI)
10.0
9.0
20.9
26.6
0.73
0.65
0.80
1.02
(0.61,
(0.54,
(0.59,
(0.76,
0.87)
0.78)
1.09)
1.36)
12.4
18.0
11.2
9.5
0.90
1.31
0.71
0.60
(0.62,
(0.93,
(0.60,
(0.50,
1.30)
1.84)
0.85)
0.72)
ENOX vs UFH
ABCIX vs UFH
UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab.
ENOX or
ABCIX
Better
UFH
Better
*
0.5
1
* There was a statistically significant interaction between treatment with abciximab and
diabetes, such that diabetics had poorer outcomes with abciximab therapy (p=0.0004).
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
2
ASSENT 3: Odds Ratios for Days to Death or Reinfarction or
Refractory Ischemia or ICH or Major Bleeding
Death at 30 Days or In-Hospital
Reinfarction or Refractory Ischemia
or ICH or Major Bleeding (%)
UFH
Overall event rate
Gender
Male
Female
Infarct location
Anterior
Other
Time to TNK-tPA (h)
0-2
ENOX or
ABCIX
Relative Risk
(95% CI)
17.0
13.7
14.2
0.81 (0.70, 0.93)
0.84 (0.73, 0.97)
16.2
11.9
12.55
20.1
20.0
0.73
0.77
1.01
1.01
(0.61,
(0.65,
(0.78,
(0.78,
0.88)
0.92)
1.31)
1.30)
16.0
16.6
12.3
12.8
0.78
0.83
0.82
0.85
(0.63,
(0.67,
(0.67,
(0.70,
0.96)
1.02)
1.00)
1.03)
16.2
13.0
11.9
13.5
13.9
16.9
0.88
0.71
0.75
0.87
0.77
0.94
(0.69,
(0.53,
(0.60,
(0.70,
(0.57,
(0.71,
1.14)
0.95)
0.94)
1.07)
1.05)
1.23)
19.9
20.5
15.0
18.3
>2-4
15.8
>4
18.0
ENOX vs UFH
ABCIX vs UFH
UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab.
ENOX or
ABCIX
Better
0.5
UFH
Better
1
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
2
ASSENT 3: Odds Ratio for Death, Reinfarction or
Refractory Ischemia, ICH or Major Bleeding (Cont.)
Death at 30 Days or In-Hospital
Reinfarction or Refractory Ischemia
or ICH or Major Bleeding (%)
UFH
Age (years)
≤75
15.4
>75
28.0
Diabetes
Yes
16.5
No
17.2
ENOX or
ABCIX
Relative Risk
(95% CI)
12.0
11.2
25.5
36.9
0.78
0.74
0.91
1.30
(0.66,
(0.63,
(0.69,
(1.01,
0.92)
0.88)
1.20)
1.68)
13.9
22.3
13.7
12.5
0.84
1.35
0.80
0.74
(0.60,
(1.00,
(0.68,
(0.62,
1.19)
1.82)
0.94)
0.87)
ENOX vs UFH
ABCIX vs UFH
UFH, unfractionated heparin; ENOX, enoxaparin; ABCIX, abciximab.
ENOX or
ABCIX
Better
0.5
UFH
Better
1
*There was a statistically significant interaction between treatment with abciximab and
diabetes, such that diabetics had poorer outcomes with abciximab therapy (p=0.0007), and
likewise, patients over the age of 75 had poorer outcomes with abciximab (p=0.0010).
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
2
% Risk of 30 Day Efficacy & Safety Endpoint
ASSENT 3:ASSENT
Primary Efficacy
and
Safety
Endpoint of Death,
3:
30
Day
Mortality
Reinfarction or Refractory Ischemia, ICH or Major Bleeding in
Patients > 75 Years of Age
*p=0.001
40.0%
36.9%
35.0%
30.0%
28.0%
25.5%
25.0%
20.0%
15.0%
10.0%
5.0%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
*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=0.0010).
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of 30 Day Efficacy & Safety Endpoint
ASSENT 3: Primary Efficacy and Safety Endpoint of Death, Reinfarction or
Refractory Ischemia, ICH or Major Bleeding in Patients with Diabetes
*p=0.0007
25.0%
22.3%
20.0%
16.5%
15.0%
13.9%
10.0%
5.0%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
*There was a statistically significant interaction between treatment with abciximab and
diabetes, such that diabetics had poorer outcomes with abciximab therapy (p=0.0007).
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Frequency of Individual Endpoints at
Hospital Discharge and at 30 Days
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
3 way
P Value
Death at 30 days
5.4
6.6
6.0
0.25
In-hospital reinfarction
2.7
2.2
4.2
0.0009
In-hospital refractory
ischemia
4.6
3.2
6.5
<0.0001
In-hospital ICH
0.9
0.9
0.9
0.98
Major bleeding
(other than ICH)
3.0
4.3
2.2
0.0005
Data are percentages. ICH, intracranial hemorrhage.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of 30 Day Mortality
ASSENT3:
3: 30
30 Day
ASSENT
DayMortality
Mortality
3 way p=0.25
10.0%
6.6%
5.4%
6.0%
5.0%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT
DayDeath
Mortality
ASSENT
3: 3:
3030Day
or MI
% Risk of 30 Day Death or MI
3 way p=0.0198
10.0%
9.1%
6.8%
7.3%
5.0%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of In-Hospital Recurrent MI
ASSENT
3: 30 Day Mortality
ASSENT
3: In-Hospital
Recurrent MI
3 way p=0.0009
5.0%
4.2%
2.7%
2.2%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of 30 Day Refractory Ischemia
3: 30 Day
Mortality Ischemia
ASSENTASSENT
3: In-Hospital
Refractory
10.0%
3 way p< 0.0001
6.5%
5.0%
4.6%
3.2%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of Intracranial Hemorrhage
ASSENT 3: 30
Day Mortality
ASSENT
In-Hospital
ICH
p=NS
5.0%
0.9%
0.9%
0.9%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT
3: 30ofDay
Mortality
ASSENT
3: Risk
Major
Bleeding
3 Way p = 0.005
% Risk of Major Hemorrhage
p=NS
p=0.0002
5.0%
4.3%
3.0%
2.2%
0.0%
TNK +
Enoxaparin
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Incidence of In-Hospital Thrombocytopenia
and Noncerebral Bleeding Complications
Any thrombocytopenia
Thrombocytopenia
<20,000 cells/µL
20,000 to 50,000 cells/µL
50,000 to <100,000 cells/µL
Bleeding episodes
Total
Major
Minor
Blood transfusion
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
1.2
3.2
1.3
P Value
3 way
<0.0001
<0.0001
0.1
0.2
0.9
*
*
*
3.4 *
25.6
3.0
22.6
0.5
0.6
2.0
0.2
0.2
1.0
39.7
4.3
35.4
21.1
2.2
18.8
<0.0001
0.0005
<0.0001
4.2
2.3
0.0032
* While 3 way p value is significant, Enoxaparin vs UFH comparison p=NS
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of Major Hemorrhage
ASSENT 3:ASSENT
Risk of3:Major
Bleeding
in
Patients
30 Day Mortality
Over 75 Years
15.0%
13.3%
10.0%
4.1%
5.0%
0.0%
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
% Risk of Major Hemorrhage
ASSENT 3:ASSENT
Risk of3:Major
Bleeding
in
Patients
30 Day Mortality
With Diabetes
10.0%
7.0%
5.0%
2.2%
0.0%
TNK +
Abciximab
TNK
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Frequency of In-Hospital Cardiac Events
and Procedures
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
P Value
Sustained hypotension
2.1
2.8
2.8
0.27
Pulmonary edema and/or
cardiogenic shock
5.2
5.2
5.6
0.78
Major arrhythmias
8.5
9.3
10.5
0.11
32.5
2.6
1.7
2.4
11.9
17.4
32.1
1.5
1.5
2.9
9.1
19.4
35.3
2.8
1.7
3.5
14.4
16.5
0.06
0.01
0.94
0.10
<0.0001
0.04
Invasive cardiac procedures
Any
IABP
Urgent CABG
Non-urgent CABG
Urgent PCI
Non-urgent PCI
IABP, intra-aortic balloon pump; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Frequency of In-Hospital Cardiac Events
and Procedures (Cont.)
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
Pericarditis
0.7
1.0
0.6
0.23
Acute mitral regurgitation
0.1
0.3
0.3
0.35
Pulmonary embolism
0.1
0.3
0.1
0.19
Tamponade
0.4
0.3
0.3
0.89
Acute ventricular septum defect
0.5
0.4
0.5
0.85
Electromechanical dissociation
1.3
1.5
1.4
0.84
Killip class >1
4.5
4.9
4.8
0.82
0
0
0.1
0.67
Anaphylaxis
P Value
IABP, intra-aortic balloon pump; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: In-Hospital Stroke Rates
Enoxaparin
(n=2040)
Abciximab
(n=2017)
Unfractionated
Heparin
(n=2038)
Total strokes
1.62
1.49
1.52
0.94
Intracranial hemorrhage
0.88
0.94
0.93
0.98
Ischemic stroke*
0.64
0.40
0.54
0.57
Hemorrhagic conversion
0.07
0.07
0.00
0.77
Unclassified
0.15
0.15
0.05
0.59
P Value
*Including hemorrhagic conversion
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Study Group Conclusions Regarding TNK +
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. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: 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”.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.
ASSENT 3: Unanswered Questions
• “Whether enoxaparin is a desirable anticoagulant in
conjunction with less fibrin-specific agents or whether
enoxaparin can replace unfractionated heparin in
combination with a platelet glycoprotein IIb/IIIa
inhibitor and what role various pharmacologic
combinations will ultimately have in conjunction with
early coronary intervention needs to be determined”.
The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT 3 randomised trial. Lancet 2001;358:605-13.