Transcript The GP IIb/IIIa antagonist may also be

EARLY ACS
Trial Rationale and Design
Robert A. Harrington, MD, FACC, FSCAI
Professor of Medicine
Duke Clinical Research Institute
Duke University Medical Center
NSTE Acute Coronary Syndromes:
Key Issues 2005

High-risk NSTE ACS patients



Platelet GP IIb/IIIa inhibitors




multiple medical therapies; invasive strategy of care
high event rates
Broad populations versus targeted high-risk
Timing of initiation: “upstream” versus PCI; CABG
Data in contemporary practice (concomitant therapies)
Clopidogrel


Timing of initiation
Bleeding risk in CABG
From the 1998 Archives…
And…

The Unabomber is sentenced.

Clinton testifies before a grand jury.

The Backstreet Boys make it big.
Death or MI at 30 Days
Freedom from Death / MI
1.0
Hazard Ratio (95% CI)
0.95
30-Day Death/MI


0.9
HR 0.96 (0.86-1.06)
0.85
Enoxaparin
0.8
UFH
0.8
1.1
0
5
10
15
20
25
Days from Randomization
30
Enoxaparin
Better
1
1.2
UFH
Better
Concomitant
Medications
Enoxaparin
UFH
(n = 4993)
(n = 4985)
Aspirin (%)
95
95
Beta blocker (%)
86
86
Ace inhibitor (%)
64
62
Statin (%)
69
70
Clopidogrel (%)
62
63
GP IIb-IIIa inhibitor (%)
56
58
“Protein-Targeted” Treatment Strategies in ACS:
Benefit of GPIIb/IIIa Inhibitor by Troponin Status
PARAGON B
PRISM
CAPTURE
COMBINED
0.125
2 0.125
1
TnT-negative
1
2 0.125
TnT-positive
-Newby LK, et al. Circ 103:2891;2001
1
Interaction
2
GP IIb/IIIa Blockade Before and After PCI:
CAPTURE, PURSUIT, PRISM-PLUS
Before PCI
Post-PCI
10%
Placebo
GP IIb/IIIa inhibitor
Death or MI
8%
6%
N=12,296
P=0.001
4%
8.0%
4.9%
4.3%
2.9%
N=2754
P=0.001
2%
0%
0
+24 h
+48 h
+72 h
+24 h
PCI
-Boersma E, et al. Circulation, 1999
+48 h
Abciximab vs. Placebo in PCI after pretreatment
with Clopidogrel (ISAR-REACT)
Kastrati et al. N Eng J Med 2004
Clopidogrel: Balancing Efficacy and Safety
Uncertainties Regarding Timing of Therapy
Early treatment
 Reduced early ischemic events
 Potential for bleeding if early CABG
needed
Wait until catheterization
 Avoid treatment of patients pre-CABG
 Lost opportunity for early benefit
ACC/AHA 2002 Guideline Update for the
Management of Patients with UA and NSTE MI
Class I
A platelet GP IIb/IIIa antagonist, should be administered, in addition
to aspirin and heparin, to patients in whom catheterization and PCI
are planned. The GP IIb/IIIa antagonist may also be administered
just prior to PCI. (Level of Evidence: A)
Class IIa
A platelet GP IIb/IIIa antagonist should be administered to patients
already receiving heparin, aspirin, and clopidogrel in whom
catheterization and PCI are planned. The GP IIb/IIIa antagonist
may also be administered just prior to PCI. (Level of Evidence: B)
Acute (< 24 hrs) Anti-Platelet Therapies
High-Risk NSTE ACS in CRUSADE
50%
40%
40%
40%
36%
30%
20%
20%
10%
0%
GP IIb/IIIa
Clopidogrel
GP IIb/IIIa +
Clopidogrel
Neither
CRUSADE Q2 2003 data
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
Trial Organization
Partnerships
International
Steering
Committee
Millennium
ScheringPlough
Sites
Patients
ICTI/ IVRS
DCRI/ CVC
TIMI
CTS Durham
Pharmacy
Millennium
 Sponsor
Schering-Plough (SPRI)
 Sponsor
 European Site Management
 Drug Distribution for sites
outside North America
International Steering Committee
 Scientific & Clinical Leadership
DCRI/ CVC
 Scientific & Clinical Leadership
 North American Site
Management
 Coordinating Center
 Data Management
TIMI
 Scientific & Clinical Leadership
Primary Objective
To demonstrate the superiority of early
eptifibatide compared to placebo (with
provisional use of eptifibatide in the cath lab) 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 early invasive strategy
Study Design
2 of 3 criteria:
High-risk NSTE
1. Age > 60 yo
2. + CKMB or TNT/I
n = 10,500
3. ST  or transient ST 
Eptifibatide (180/2/180)
ACS
Placebo
Randomize within 8 hours
Early invasive strategy: no sooner than next calendar day
1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout
2 Endpoint: 30 d Death/MI
Concomitant Therapies


Aspirin
Enoxaparin or Unfractionated Heparin




Dosing guides provided in protocol
Lessons from SYNERGY
Use of bivalirudin or other direct thrombin
inhibitor is prohibited
Clopidogrel
300 mg load / 75 mg daily dose

Randomization stratified by investigator’s
intention to start clopidogrel pre-cath
Blinded Study Drug Administration

Duration of infusion



Medically managed
• Minimum = 72 hours; maximum = 96 hours
Percutaneous coronary intervention
• Minimum = 72 hours; maximum of 96 hours
• Continue for 18 hours after procedure
Coronary Artery Bypass Surgery
• Maximum of 120 hours
• Continue infusion until 2 hours before surgery
Use of Eptifibatide in the Cath Lab
(1) After Angiography and Before PCI

Eptifibatide during PCI according to local
practice




PCI active treatment kits are available for use after
the diagnostic angiogram and before PCI begins
Kit contents are opposite of the initial study drug
assignment at randomization
PCI active kits are used for the bolus doses of
eptifibatide/placebo (no charge), open label hospital
supply of eptifibatide is used for the infusion
Use of PCI active kits before PCI begins is not
considered a study endpoint
Use of Eptifibatide in the Cath Lab
(2) After PCI Has Begun

Once the guidewire crosses the lesion, use of
bail-out study drug is permitted to manage
complications of PCI, but is considered an
endpoint event





Decrement in TIMI flow grade or abrupt closure
Dissection with decreased flow
Distal embolization
Side-branch closure
Clinical instability due to ischemia or prolonged
ischemia during the procedure
Study Endpoints

Primary Efficacy Composite (96 hours)





Key Secondary Efficacy Endpoint


All cause mortality
New MI*,
Recurrent ischemia requiring urgent
revascularization*,
Need for thrombotic bailout with GP IIb/IIIa*
Death or new MI* through 30 days
Safety Endpoints

Hemorrhage, transfusion, stroke*,
thrombocytopenia, SAEs, post-operative bleeding
*Adjudicated by independent, blinded CEC
Statistical Methods



Power = 85% to detect a 22.5% reduction in the
primary quadruple composite assuming an event
rate of 5.8% with placebo
Power = 85% for the key secondary efficacy
endpoint of death or MI at 30 days (15% RRR,
placebo rate 12.7%)
Prespecified subgroups


Proper: Age, baseline troponin, hospital type,
diabetes, early clopidogrel, UFH vs enoxaparin,
TIMI Risk Score
Improper: By management strategy (PCI, CABG,
medical)
Biomarker Substudy
Objectives
 Identify high-risk NTEACS patients
 Explore the ability of
eptifibatide to modulate
cardiac biomarkers
 Identify patients who
benefit most from early
eptifibatide



Local hospital lab: WBC,
creat, FBS, Hgb A1C
Core Lab (NA only):
inflammation, ischemia,
necrosis, hemodynamic
stress, thrombosis
 3 timepoints: baseline,
pre-cath, 1 day post-cath
DNA specimen: (NA only) at
baseline
Platelet Inhibition in NSTE ACS
Summary of Current Status

NSTE ACS remains major clinical challenge

Equipoise around best timing of initiation of GP
IIb/IIIa inhibitors in high-risk NSTE-ACS patients in
whom invasive strategy planned

Uncertainties about the use of clopidogrel in high-risk
NSTE-ACS in whom invasive strategy planned

Optimal combination of antithrombotic Rx is uncertain