Transcript Document

Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment
Elevation Acute Coronary Syndrome: A Randomized,
Double-blind, Placebo-Controlled Trial Evaluating the
Clinical Benefits of Early Front-loaded Eptifibatide in the
Treatment of Patients with Non-ST-segment Elevation
Acute Coronary Syndromes
Disclosures
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Funded by Millennium Pharmaceuticals and Schering
Plough
Individual disclosures
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Armstrong
Braunwald
Califf
Gibson
Giugliano
Harrington
Montalescot
Newby
Strony
Van de Werf
Study Structure—figure with the below
components
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Exec Comm
Steering Committee
Sponsor
Coordinating Centers—DCRI, TIMI, CVC
DSMB
Sites
CEC
Primary Objective
To demonstrate the superiority of a strategy of
early, routine eptifibatide begun shortly after
presentation compared with a strategy of
delayed, provisional use of eptifibatide pre-PCI in
reducing the composite of death, MI, recurrent
ischemia, and thrombotic bail-out within 96 hours
in patients with high-risk NSTE ACS managed
with an invasive strategy
Study Design
2 of 3 high-risk criteria:
1. Age > 60 years
2. + CKMB or TnT/I
3. ST  or transient ST 
(Or age 50-59, h/o CVD
and + CKMB or TnT/I)
High-risk NSTE ACS
n = 10,500 (9500)
Early, routine eptifibatide Placebo / provisional
(180/2/180)
eptifibatide pre-PCI
Randomize within 12 hours of presentation
Invasive strategy: 12 to 96 hours after randomization
1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout
2 Endpoint: 30-d Death/MI
Fade in safety endpoints at 120 hours (bleeding (GUSTO and TIMI scales),
transfusions, stroke, non-hemorrhagic SAEs
Key Exclusion Criteria
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Increased bleeding risk
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active bleeding or recent bleed
Recent surgery or trauma
Prior ICH or recent ischemic stroke
Serious concomitant illness or pregnancy
ESRD with dialysis < 30 days
Recent or planned use of direct thrombin
inhibitor, fXa inhibitor, abciximab/tirofiban
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amendment 1: bivalirudin at PCI
amendment 2: acute fondaparinux or bivalirudin
Blinded Study Drug Administration
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Double bolus and infusion regimen
 180 ug/Kg IV eptifibatide (or matching placebo)
bolus as soon as possible after randomization
 Immediate initiation of 2 ug/Kg/min eptifibatide (or
matching placebo) infusion (1 ug/Kg/min if CrCl
<50 cc/min)
 Second 180 ug/Kg IV eptifibatide (or matching
placebo) bolus 10 minutes after initial bolus
Provisional, blinded transition to open label
eptifibatide at time of PCI using blinded bolus kit
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PCI active if transition before wire crossed lesion
PCI bailout if after wire crossed the lesion
Statistical Methods
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Power = 85% to detect a 22.5% reduction in the primary
quadruple composite assuming an event rate of 5.8% with
placebo at alpha 0.048 after single interim efficacy analysis
Power = 85% for the key secondary efficacy endpoint of death
or MI at 30 days (15% RRR, placebo rate 12.7%); also at alpha
0.048, using step down testing procedure where formally tested
only if primary endpoint significant
Power after sample size reduction to 9500 patients
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98% for 96-hour primary composite endpoint
81% for 30-day key secondary endpoint of death
or MI
Prespecified subgroups
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Proper: Age, baseline troponin, hospital type,
diabetes, early clopidogrel, UFH vs enoxaparin,
TIMI Risk Score
Post-randomization (improper): By management
strategy (PCI, CABG, medical)
Enrollment
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Use map of world with enrollment by country on the
map
Recognize top 20 (?30) enrollers worldwide—could
be a “build” on top of the map
Study Conduct
Patients randomized
Patients excluded for site conduct
Patients without informed consent
Intent-to-treat population
9492
64
22
9406
Patients who received no study drug
As-treated safety population
77
9329
Lost to follow-up
11
Baseline Characteristics
Age (years)
Female (%)
Region (%)
Most of World
North America
30.8
Diabetes mellitus (%)
Hypertension (%)
Dyslipidemia (%)
Prior MI (%)
Prior PCI (%)
Prior CABG (%)
Creatinine Clearance (cc/min)
Troponin or CKMB positive (%)
ST-segment shifts (%)
Presentation to rand (hours)
ERE (n=4722)
67 (60, 75)
32.0
DPE (n=4684)
68 (60, 75)
31.2
69.2
69.4
30.6
30.1
70.5
57.9
27.0
24.3
13.1
75 (56, 96)
85.9
61.6
5.4 (3.3, 8.8)
30.7
71.9
57.8
28.2
25.0
14.2
74 (56, 96)
87.0
62.0
5.7 (3.4,8.8)
In-hospital Management
ERE (n=4722) DPE (n=4684)
Cardiac Catheterization (%)
97.5
97.6
Randomization to cath (hours) 21.4 (16.9, 34.2) 21.4 (16.7, 31.0)
PCI (%)
58.5
59.7
Active provisional (%)
24.9
26.8
Bailout (%)
11.3
12.0
CABG (%)
13.2
12.9
Medically Treated only (%)
30.3
31.4
Use of Evidence-based Rx (%)
ASA
97.5
97.3
UFH or enoxaparin
94.3
94.2
Beta-blocker
87.7
87.7
Statin
86.4
86.9
ACEI / ARB
78.4
78.5
Clopidogrel (intended early)
74.8
75.2
Clopidogrel (any)
90.4
90.6
96-Hour Primary Efficacy Results
Death, MI, RIUR, TBO
ERE
(n=4722)
9.3
DPE
OR
P
(n=4684) (95% CI)
10.0
0.92
0.23
(0.80-1.06)
Death
0.8
0.9
0.96
0.87
(0.62-1.50)
Death / MI
7.5
8.3
0.89
0.13
(0.77-1.04)
Death / MI / RIUR
8.4
9.4
0.89
0.11
(0.77-1.03)
Kaplan-Meier Curves for Primary Endpoint
Death, MI, RIUR or TBO (%)
15
N
# Events
Hours to Event
Delayed provisional
eptifibatide
4684
469
25.9 (18.7, 48.4)
Early routine
eptifibatide
4722
439
31.1 (18.8, 62.2)
10.0%
10
9.3%
Delayed provisional eptifibatide
P = 0.23
(stratified for intended early
clopidogrel use)
5
Early routine eptifibatide
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Time Since Randomization (Hours)
30-Day Secondary Efficacy Results
Death or MI
ERE
(n=4722)
11.2
DPE
OR
P
(n=4684) (95% CI)
12.3
0.89
0.079
(0.79-1.01)
Death
2.8
2.6
1.10
(0.86-1.41)
0.46
Death, MI, RIUR
12.5
13.8
0.89
(0.79-1.01)
0.065
Kaplan-Meier Curves for 30-day Death or MI
15
12.4%
Death or MI (%)
Delayed provisional eptifibatide
11.2%
10
Early routine eptifibatide
P = 0.079
(stratified for intended early
clopidogrel use)
5
N
# Events
Days to Event
0
0
1
2
3
4
5 6
7 8
Delayed provisional
eptifibatide
4684
578
2.1 (1.0, 5.8)
Early routine
eptifibatide
4722
528
2.7 (1.0, 4.9)
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Time Since Randomization (Days)
96-hour Primary Efficacy Results
By Prespecified Subgroups
Early Routine
Eptifibatide, %
Delayed
Provisional
Eptifibatide, %
Overall
9.3
10.0
Men
Women
9.1
9.7
9.8
10.4
8.6
11.4
9.5
11.4
Troponin positive
Troponin negative
9.5
7.7
10.6
6.8
Diabetes
No Diabetes
8.9
9.5
10.6
9.8
8.8
10.8
9.5
11.5
8.9
9.5
10.5
9.8
High TIMI Risk Score (5 -7)
Intermediate TIMI Risk Score (3 -4)
Low TIMI Risk Score (0 -2)
10.4
9.4
6.8
10.8
10.1
8.0
Unfractionated heparin only
Low molecular weight heparin only
9.1
11.0
9.9
9.9
Primary Care Hospital
Tertiary Care Hospital
9.0
9.4
9.7
10.1
10.3
7.3
11.2
10.9
10.6
8.6
11.2
11.5
Odds Ratio for Upstream
Eptifibatide (95% CI)
Baseline Characteristic
Age < 75 yr
Age > 75 yr
Upfront clopidogrel intended
No upfront clopidogrel intended
Randomized < 4 hours
Randomized > 4 hours
North America
Western Europe
Eastern Europe
Middle East, Africa and Asia
0.50
0.60
0.70
0.80
0.90 1.00
Early Eptifibatide Better
2.00
Delayed Provisional Eptifibatide Better
30-day Death or MI
By Prespecified Subgroups
Early Routine
Eptifibatide, %
Delayed
Provisional
Eptifibatide, %
Overall
11.2
12.3
Men
Women
11.4
10.7
12.0
13.0
Age < 75 yr
Age > 75 yr
10.2
14.0
11.6
14.6
Troponin positive
11.6
13.0
Troponin negative
8.1
8.4
Diabetes
No Diabetes
11.7
10.9
13.8
11.7
Upfront clopidogrel intended
10.3
12.0
No upfront clopidogrel intended
13.7
13.4
Randomized < 4 hours
11.1
12.8
Randomized > 4 hours
11.2
12.1
High TIMI Risk Score (5 -7)
13.2
13.3
Intermediate TIMI Risk Score (3 -4)
10.9
12.8
8.1
9.1
Unfractionated heparin only
Low molecular weight heparin only
11.3
11.3
13.0
12.8
Primary Care Hospital
Tertiary Care Hospital
10.7
11.3
12.3
12.4
North America
Western Europe
Eastern Europe
Middle East, Africa and Asia
13.2
10.2
14.5
11.0
14.5
8.8
15.2
11.6
Odds Ratio for Upstream
Eptifibatide (95% CI)
Baseline Characteristic
Low TIMI Risk Score (0 -2)
0.50
0.60
0.70
0.80
0.90 1.00
Early Eptifibatide Better
2.00
Delayed Provisional Eptifibatide Better
Safety Results (through 120 hours)
ERE
DPE
OR(95%CI)
(n=4686) (n=4643)
Bleeding (overall)
TIMI Major
TIMI major or minor
GUSTO Severe
GUSTO Moderate or Severe
PRBC transfusion
Bleeding (CABG)
Re-operation for bleeding
Chest tube output (mL/24 H)
Thrombocytopenia (nadir <100K)
Stroke
P
2.6
5.8
0.8
7.6
8.6
1.8
3.4
0.9
5.1
6.7
1.42 (1.07-1.89)
1.75 (1.43-2.14)
0.99 (0.64-1.55)
1.52 (1.28-1.80)
1.31 (1.12-1.53)
0.015
<0.001
0.97
<0.001
0.001
6.0
720
3.3
0.6
8.4
770
2.8
0.8
0.70 (0.39-1.27) 0.24
-0.41
0.79 (0.48-1.30) 0.36
Conclusions
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Among high-risk NSTE ACS patients, a strategy of
early, routine eptifibatide compared with delayed
provisional eptifibatide at PCI
 did not significantly reduce the primary composite
of D/MI/RIUR/TBO at 96h (9.3% vs. 10.0%, OR
0.92; 0.80-1.06; p = 0.234)
 resulted in a trend toward reduction in death or MI
at 30 days (11.2% vs. 12.3%; OR 0.89; 0.79-1.03;
p = 0.079), but no difference in 30-day mortality
(x.x% vs. y.y%; OR 0.xx; 0.yy-0.zz; p = 0.aa)
 resulted in significantly higher rates of non-lifethreatening bleeding and transfusions
Implications
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The results of EARLY ACS do not support a
strategy of early, routine eptifibatide use among
NSTE ACS patients managed with an invasive
strategy
It may be reasonable to consider early
eptifibatide use in selected high-risk subsets of
ACS patients with low risk of bleeding who are
scheduled to undergo PCI
In selected high-risk NSTE ACS patients who
are also at increased bleeding risk, a delayed
provisional eptifibatide strategy pre-PCI would
be reasonable
Primary and Key Secondary Efficacy Results
By Clopidogrel Strata at Randomization
ERE
DPE
OR (95% CI)
96-hr Death, MI, RIUR, TBO
Clopidogrel intended
8.8
No Clopidogrel intended 10.8
9.5
11.5
0.92 (0.78-1.08)
0.93 (0.72-1.20)
30-day Death / MI
Clopidogrel intended
No Clopidogrel intended
12.0
13.4
0.85 (0.73-0.91)
1.03 (0.81-1.31)
10.3
13.7