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



Funded by Millennium Pharmaceuticals and
Schering Plough
All authors disclose research grant funding and/or
consulting and speaking honoraria from Schering
Plough
Full Relationships with Industry disclosures for all
authors are listed in detail in the ACC.09 Presenter
Disclosure Digest
Study Structure
Study Chairman:
E. Braunwald
Study Co-Chairmen:
R. Califf, F. Van de Werf
35 Investigators
24 Countries represented
Cardiology and Emergency
Medicine
DCRI:
K. Newby,
L. Berdan,
R. Harrington
TIMI:
R. Giugliano
CVC:
P. Armstrong,
C. Sorochuk
Helpline:
P. Tricoci,
P. Sinnaeve
Chairman:
D. Weaver
Members:
J. Alpert,
E. Cohen,
D. Faxon,
L. Fisher,
F. Verheugt
Schering Plough
Physician Lead:
J. Strony
Ops leaders:
A. Kilian, L. Layton
440 sites
29 countries
Physician Lead:
M. Roe
Lead Coordinator:
D. Montgomery
Angio Core:
M. Gibson
Primary Goal

To compare the effect of 2 strategies for eptifibatide
administration in high-risk NSTE ACS patients
managed with an invasive diagnostic assessment:
 A strategy of routine, early administration of
eptifibatide to all patients shortly after presentation
 A strategy of delayed, provisional eptifibatide
administration at the physician’s discretion after
coronary angiography and prior to PCI
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
Routine, early eptifibatide
(180/2/180)
Placebo / delayed provisional
eptifibatide pre-PCI
Randomize within 12 hours of presentation
Invasive strategy: 12 to 96 hours after randomization
Primary Endpoint: 96-hr Death, MI, Recurrent ischemia
Safety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI
requiring urgent revascularization, or Thrombotic bailout
scales), Transfusions, Stroke, Non-hemorrhagic SAEs
Key Secondary Endpoint: 30-d Death or MI
Key Exclusion Criteria

Increased bleeding risk






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


amendment 1: allowed bivalirudin at PCI
amendment 2: allowed acute fondaparinux or
bivalirudin
Blinded Study Drug Administration

Investigational double bolus and infusion regimen

180 ug/Kg / 2 ug/kg/min / 180 ug/Kg IV eptifibatide (or
matching placebo)
• Infusion decreased to 1 ug/Kg/min if CrCl <50 mL/min)

Provisional, blinded cross over to open label
eptifibatide at time of PCI using blinded bolus kit
Bolus kit = Provisional use
Eptifibatide
Placebo
Coronary
Angio
PCI
Bolus Kit = Bailout use
Open label
Eptifibatide
Eptifibatide
Placebo
Open label
Eptifibatide
Statistical Methods

Power at original sample size (10,500 patients)



Primary quadruple composite at 96 hours
•85% Power for RRR 22.5% at alpha = 0.048
Death or MI at 30 days
•85% Power for RRR 15% at alpha = 0.048
Sample size reduced to 9500 patients when pooled
primary event rate greater than expected late in trial

98% power for primary endpoint, 81% power for
secondary endpoint
* Adjusted for single interim efficacy analysis
Enrollment (N = 9492)
N = 6595
N = 2897
160
136
625
2272
12
1342
11
374
103
472
128
155
175
50
447
260
96
510
23
178
837
192
51
452
118
57
23
177
47
Follow-up 99.9% complete worldwide
Enrollment
Top 20 Enrolling Sites
1/ Austria Franz Leisch (304)
11/ Germany Michael Gross (138)
2/ Netherlands A W J van ‘t Hof (301)
12/ Germany Uwe Zeymer (133)
3/ USA Kristin Newby (231)
13/ USA Yale Cohen (119)
4/ India Keyur Parikh (224)
14/ Portugal Luis Providencia (112)
5/ USA Amir Malik (209)
15/ Israel Uri Rosenshein (107)
6/ Israel Basil Lewis (198)
16/ Poland Piotr Ponikowski (95)
7/ Israel Arie Roth (174)
17/ France Khalife Khalife (94)
8/ Germany Peter Schuster (156)
18/ Israel Eugenia Nikolsky (92)
9/ Germany Martin Desaga (151)
19/ Switzerland Michael Pieper (90)
10/ Poland Maria Trusz-Gluza (138)
20/ Canada Manohara Senaratne (88)
Baseline Characteristics
Routine
Early
Eptifibatide
(n=4722)
Age (yrs)
67 (60, 75)
Female (%)
32
Diabetes mellitus (%)
30
Hypertension (%)
71
Dyslipidemia (%)
58
Prior MI (%)
27
Creatinine Clearance <50 mL/min (%)
18
Troponin positive (%)
84
ST-segment shifts (%)
62
Symptoms to presentation (hrs)
3.3 (1.4, 8.0)
Presentation to randomization (hrs) 5.4 (3.3, 8.8)
Delayed
Provisional
Eptifibatide
(n=4684)
68 (60, 75)
31
31
72
58
28
18
84
62
3.2 (1.5, 7.8)
5.7 (3.4, 8.8)
In-hospital Management
Cardiac Catheterization (%)
Randomization to cath (hrs)
In-hospital Management (%)
CABG
Medically Treated only
PCI
Provisional (before wire)
Bailout (after wire)
Use of Established Rx (%)
Beta-blocker
Statin
ACEI / ARB
Clopidogrel (intended early)
Routine
Early
Eptifibatide
Delayed
Provisional
Eptifibatide
(n=4722)
(n=4684)
98
98
21.4 (16.9, 34.2) 21.4 (16.7, 31.0)
13
30
13
31
59
25
11
60
27
12
88
86
78
75
88
87
79
75
96-Hour Primary Efficacy Results
Routine
Delayed
Early
Provisional
Eptifibatide Eptifibatide
OR
P
(95% CI)
(n=4722)
(n=4684)
Death, MI, RIUR, TBO
9.3%
10.0%
0.92
0.23
(0.80-1.06)
Death
0.8%
0.9%
0.96
0.87
(0.62-1.50)
Death or 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)
MI, myocardial infarction; RIUR, recurrent ischemia requiring
urgent revascularization; TBO, thrombotic bailout
Kaplan-Meier Curves for Primary Endpoint
Death, MI, RIUR or TBO (%)
15
10.0%
10
Delayed provisional
eptifibatide
9.3%
P = 0.23
(stratified for intended early
clopidogrel use)
5
Routine early
eptifibatide
0
0
8
16
24
32
40
48
56
64
72
80
Time Since Randomization (Hours)
88
96
30-Day Secondary Efficacy Results
Routine
Early
Eptifibatide
Delayed
Provisional
Eptifibatide
OR
(n=4722)
(n=4684)
(95% CI)
P
Death or MI
11.2%
12.3%
Death
2.8%
2.6%
1.10
(0.86-1.41)
0.46
13.8%
0.89
(0.79-1.01)
0.065
Death, MI, RIUR 12.5%
0.89
0.079
(0.79-1.01)
MI, myocardial infarction; RIUR, recurrent ischemia requiring
urgent revascularization
Kaplan-Meier Curves for 30-day Death or MI
Death or MI (%)
15
12.4%
Delayed provisional
eptifibatide
10
11.2%
Routine early
eptifibatide
5
P = 0.079
(stratified for intended early
clopidogrel use)
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30
Time Since Randomization (Days)
96-hour Primary Efficacy Results
Prespecified Subgroups
Odds Ratio for Upstream Routine Early
Eptifibatide (95% CI)
Eptifibatide, %
Baseline Characteristic
Delayed
Provisional
Eptifibatide, %
Overall
9.3
10.0
Men
Women
9.1
9.8
9.7
10.4
Age < 75 yr
Age > 75 yr
8.6
11.4
9.5
11.4
Troponin positive
Troponin negative
9.5
7.7
10.6
6.8
Diabetes
8.9
10.6
No Diabetes
9.5
9.8
Early clopidogrel intended
No early clopidogrel intended
8.8
10.8
9.5
11.5
0.5
0.6
0.7 0.8 0.9 1
Early Eptifibatide Better
2
Delayed Provisional Eptifibatide Better
30-day Death or MI
Prespecified Subgroups
Odds Ratio for Upstream
Eptifibatide (95% CI)
Baseline Characteristic
Routine Early
Eptifibatide, %
Delayed
Provisional
Eptifibatide, %
Overall
11.2
12.3
Men
11.4
12.0
Women
10.7
13.0
Age < 75 yr
Age > 75 yr
10.2
11.6
14.0
14.6
Troponin positive
11.6
13.0
Troponin negative
8.1
8.4
Diabetes
11.7
13.8
No Diabetes
10.9
11.7
Early clopidogrel intended
No early clopidogrel intended
10.3
13.7
12.0
13.4
0.5
0.6
0.7 0.8 0.9 1
Early Eptifibatide Better
2
Delayed Provisional Eptifibatide Better
Safety Results (through 120 hours)
Routine
Delayed
Early
Provisional
Eptifibatide Eptifibatide
(n=4686)
Bleeding (all patients, %)
TIMI major
2.6
TIMI major or minor
5.8
GUSTO severe
0.8
GUSTO moderate or severe
7.6
PRBC transfusion
8.6
Bleeding (CABG)
Re-operation for bleeding (%) 6.0
Chest tube output (mL/24 H) 720
Thrombocytopenia (<100K, %) 3.3
Stroke (total, %)
0.6
(n=4643)
OR
P
(95% CI)
1.8
3.4
0.9
5.1
6.7
1.42 (1.07-1.89) 0.015
1.75 (1.43-2.14) <0.001
0.99 (0.64-1.55) 0.97
1.52 (1.28-1.80) <0.001
1.31 (1.12-1.53) 0.001
8.4
770
2.8
0.8
0.70 (0.39-1.27)
-1.19 (0.93-1.51)
0.79 (0.48-1.30)
0.24
0.41
0.17
0.36
Small Molecule GP IIb/IIIa Inhibition in NSTE ACS
PURSUIT
PRISM
PRISM PLUS
Theroux
PARAGON B
PARAGON A
COMBINED 1998 (n = 23,967)
0.88 (0.79-0.97)
ACUITY Timing
EARLY ACS
0.25
0.92 (0.82-1.01)
EARLY ACS + ACUITY
0.89 (0.84-0.95)
COMBINED 2009 (n = 42,666)
0.50
1.0
2.0
Odds Ratio for 30-day Death or MI Relative to Control
4.0
Conclusions

Among high-risk NSTE ACS patients, a strategy of
routine, early eptifibatide compared with delayed,
provisional eptifibatide at PCI

did not significantly reduce the primary composite
of death, MI, RIUR, or TBO at 96h

resulted in a trend toward reduction in death or MI
at 30 days, but no difference in 30-day mortality

resulted in higher rates of non-life-threatening
bleeding and transfusions
Implications

The results of EARLY ACS do not support a strategy
of routine early eptifibatide use in high-risk NSTE
ACS patients managed with an invasive strategy

If subgroups of patients with high likelihood of benefit
and low bleeding risk could be identified, it might be
reasonable to consider early eptifibatide use in
selected high-risk NSTE ACS patients who are
intended to undergo angiography
Available Today at www.nejm.org
EARLY ACS Steering Committee
Australia P. Aylward
New Zealand H. White
Austria K. Huber
Norway D. Atar
Canada M. Labinaz, A. Langer, J-F. Tanguay
Poland W. Ruzyllo
Czech Rep P. Widimsky
Portugal M. Carrageta
Denmark P. Grande
Russia V. Sulimov
France G. Steg
Spain A. Betriu
Germany C. Bode, U. Zeymer
South Africa A. Dalby
Hungary M. Keltai
Switzerland F. Mach
India D. Prabhakaran
United Kingdom K. Fox, K Karsch
Israel B. Lewis
United States B. Gibler, N. Kleiman, H.
Herrmann, J. Hochman, J. Hoekstra, M.
Ohman, W. O’Neill, C. Pollack, M.
Schweiger
Italy D. Ardissino
Netherlands A. van ‘t Hof
Back-up slides
Strategy During
First 96 Hours
CABG (N=268)
Pre-CABG Events = 33
Post-CABG Events = 52
PCI (N=2723)
Pre-PCI Events = 87
Post-PCI Events = 243
Total Events on Medical Treatment = 71 + 82 +33
Events Risk
Medical
186
4718
Post PCI
201
52
Post CABG
CABG (N=251)
Pre-CABG Events = 22
Post CABG Events = 46
Medical Only (N=1706)
Total Events = 71
PCI (N=2666)
Pre-PCI Events = 82
Post-PCI Events = 201
Group
N=3490
N=5389
N=519
Delayed Provisional Eptifibatide (N=4680)
Total Events = 469
Early Eptifibatide (N=4718)
Total Events = 439
Medical Only (N=1784)
Total Events = 71
Medical Only
PCI
CABG
Randomization
N=9406
Rate
Total Events on Medical Treatment = 71 + 87 + 22
Group
Events Risk
4.1%
Medical
180
4680
4.0%
2584
8.0%
Post PCI
243
2636
10.5%
235
23.4%
46
229
20.6%
Post CABG
Rate
Primary and Key Secondary Efficacy Results
By Clopidogrel Strata at Randomization
Routine
Early
Eptifibatide
Delayed
Provisional
Eptifibatide
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