1. EARLY ACS Trial Rationale and Design
Robert A. Harrington, MD, FACC, FSCAI
Professor of Medicine
Duke Clinical Research Institute
Duke University Medical Center

2. NSTE Acute Coronary Syndromes: Key Issues 2005
High-risk NSTE ACS patients
multiple medical therapies; invasive strategy of care
high event rates
Platelet GP IIb/IIIa inhibitors
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

4. From the 1998 Archives…

5. And… The Unabomber is sentenced.
Clinton testifies before a grand jury.
The Backstreet Boys make it big.

6. Death or MI at 30 Days 5 10 15 20 25 30
0.8
0.85
0.9
0.95
1.0
Freedom from Death / MI
Days from Randomization
UFH
Enoxaparin
1.1
HR 0.96 ( )

7. 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
Concomitant Medications

8. “Protein-Targeted” Treatment Strategies in ACS: Benefit of GPIIb/IIIa Inhibitor by Troponin Status
TnT-positive
TnT-negative
Interaction
PARAGON B
PRISM
CAPTURE
COMBINED
0.125 1 2
-Newby LK, et al. Circ 103:2891;2001

9. GP IIb/IIIa Blockade Before and After PCI: CAPTURE, PURSUIT, PRISM-PLUS
Before PCI
Post-PCI
10%
Placebo
GP IIb/IIIa inhibitor
8.0% 8% 6%
N=12,296
P=0.001
Death or MI
4.9%
4.3% 4%
2.9%
N=2754
P=0.001 2% 0%
+24 h
+48 h
+72 h
+24 h
+48 h
PCI
-Boersma E, et al. Circulation, 1999

10. Abciximab vs. Placebo in PCI after pretreatment with Clopidogrel (ISAR-REACT)
Kastrati et al. N Eng J Med 2004

11. 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

12. 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)

13. GP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither
Acute (< 24 hrs) Anti-Platelet Therapies High-Risk NSTE ACS in CRUSADE
36% 0%
10%
20%
30%
40%
50%
GP IIb/IIIa Clopidogrel GP IIb/IIIa Neither
Clopidogrel
CRUSADE Q data

14. 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

15. Trial Organization Partnerships Sites TIMI Millennium Sponsor
Schering-Plough (SPRI)
European Site Management
Drug Distribution for sites outside North America
International Steering Committee
Scientific & Clinical Leadership
DCRI/ CVC
North American Site Management
Coordinating Center
Data Management
TIMI
International
Steering
Committee
Schering-
Plough
Millennium
Sites
Patients
ICTI/ IVRS
DCRI/ CVC
CTS Durham
Pharmacy
TIMI

16. 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

17. 1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout
Study Design
2 of 3 criteria:
Age > 60 yo
+ CKMB or TNT/I
ST  or transient ST 
High-risk NSTE ACS
n = 10,500
Eptifibatide (180/2/180)
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

18. 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

19. 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

20. Eptifibatide during PCI according to local practice
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

21. 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

22. Study Endpoints Primary Efficacy Composite (96 hours)
All cause mortality
New MI*,
Recurrent ischemia requiring urgent revascularization*,
Need for thrombotic bailout with GP IIb/IIIa*
Key Secondary Efficacy Endpoint
Death or new MI* through 30 days
Safety Endpoints
Hemorrhage, transfusion, stroke*, thrombocytopenia, SAEs, post-operative bleeding
*Adjudicated by independent, blinded CEC

23. 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)

24. Biomarker Substudy Objectives Identify high-risk NTE-ACS 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

25. 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