EARLY ACSTrial Rationale and Design

EARLY ACSTrial Rationale and Design

Robert A. Harrington, MD, FACC, FSCAI

Professor of Medicine

Duke Clinical Research Institute

Duke University Medical Center

Robert A. Harrington, MD, FACC, FSCAI

Professor of Medicine

Duke Clinical Research Institute

Duke University Medical Center

NSTE Acute Coronary Syndromes:Key Issues 2005

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

From the 1998 Archives…From the 1998 Archives…

And…And…

The Unabomber is sentenced.The Unabomber is sentenced.

Clinton testifies before a grand jury.Clinton testifies before a grand jury.

The Backstreet Boys make it big.The Backstreet Boys make it big.

Death or MI at 30 Days

30-Day Death/MI30-Day Death/MI

0.80.8 11 1.21.2

Hazard Ratio (95% CI)

Enoxaparin

Better

UFH

Better0 5 10 15 20 25 30

0.8

0.85

0.9

0.95

1.0

Free

dom

from

Dea

th /

MI

Days from Randomization

UFHUFHEnoxaparinEnoxaparin

HR 0.96 (0.86-1.06)HR 0.96 (0.86-1.06)

1.11.1

Concomitant Medications

EnoxaparinEnoxaparin UFHUFH(n = 4993)(n = 4993) (n = 4985)(n = 4985)

Aspirin (%)Aspirin (%) 9595 9595

Beta blocker (%)Beta blocker (%) 8686 8686

Ace inhibitor (%)Ace inhibitor (%) 6464 6262

Statin (%)Statin (%) 6969 7070

Clopidogrel (%)Clopidogrel (%) 6262 6363

GP IIb-IIIa inhibitor (%)GP IIb-IIIa inhibitor (%) 5656 5858

“Protein-Targeted” Treatment Strategies in ACS:Benefit of GPIIb/IIIa Inhibitor by Troponin Status“Protein-Targeted” Treatment Strategies in ACS:Benefit of GPIIb/IIIa Inhibitor by Troponin Status

TnT-positiveTnT-positiveTnT-negativeTnT-negative InteractionInteraction

PARAGON BPARAGON B

PRISMPRISM

CAPTURECAPTURE

COMBINEDCOMBINED

0.1250.1250.1250.1250.1250.125 111111 2222 22

-Newby LK, et al. Circ 103:2891;2001-Newby LK, et al. Circ 103:2891;2001

GP IIb/IIIa Blockade Before and After PCI: CAPTURE, PURSUIT, PRISM-PLUS

GP IIb/IIIa Blockade Before and After PCI: CAPTURE, PURSUIT, PRISM-PLUS

0%

2%

4%

6%

8%

10%

PCIPCI

N=2754N=2754P=0.001P=0.001

N=12,296N=12,296P=0.001P=0.001

+24 h +48 h +72 h +24 h +48 h

-Boersma E, et al. Circulation, 1999-Boersma E, et al. Circulation, 1999

4.3%4.3%

2.9%2.9%

8.0%8.0%

4.9%4.9%

Dea

th o

r M

ID

eath

or

MI

Before PCIBefore PCI Post-PCIPost-PCI

PlaceboPlacebo

GP IIb/IIIa inhibitorGP IIb/IIIa inhibitor

0

Abciximab vs. Placebo in PCI after pretreatment with Clopidogrel (ISAR-REACT)

Abciximab vs. Placebo in PCI after pretreatment with Clopidogrel (ISAR-REACT)

Kastrati et al. N Eng J Med 2004

Clopidogrel: Balancing Efficacy and SafetyUncertainties Regarding Timing of Therapy

Clopidogrel: Balancing Efficacy and SafetyUncertainties 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

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

Class IClass I

A platelet GP IIb/IIIa antagonist, should be administered, in addition A platelet GP IIb/IIIa antagonist, should be administered, in addition to aspirin and heparin, to patients in whom catheterization and PCI to aspirin and heparin, to patients in whom catheterization and PCI are planned. are planned. The GP IIb/IIIa antagonist may also be administered The GP IIb/IIIa antagonist may also be administered just prior to PCI.just prior to PCI. (Level of Evidence: A) (Level of Evidence: A)

ACC/AHA 2002 Guideline Update for the ACC/AHA 2002 Guideline Update for the Management of Patients with UA and NSTE MIManagement of Patients with UA and NSTE MI

Class IIaClass IIa

A platelet GP IIb/IIIa antagonist should be administered to patients A platelet GP IIb/IIIa antagonist should be administered to patients already receiving heparin, aspirin, and clopidogrel in whom already receiving heparin, aspirin, and clopidogrel in whom catheterization and PCI are planned. catheterization and PCI are planned. The GP IIb/IIIa antagonist The GP IIb/IIIa antagonist may also be administered just prior to PCI.may also be administered just prior to PCI. (Level of Evidence: B) (Level of Evidence: B)

Acute (< 24 hrs) Anti-Platelet Therapies High-Risk NSTE ACS in CRUSADE

Acute (< 24 hrs) Anti-Platelet Therapies High-Risk NSTE ACS in CRUSADE

CRUSADE Q2 2003 dataCRUSADE Q2 2003 data

36%36%

0%0%

10%10%

20%20%

30%30%

40%40%

50% 50% 40%40% 40%40%

GP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither Clopidogrel

GP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither Clopidogrel

20%20%

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

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 OrganizationTrial OrganizationPartnerships

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

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

International International SteeringSteering

CommitteeCommittee

International International SteeringSteering

CommitteeCommitteeSchering-Schering-

PloughPloughSchering-Schering-

PloughPlough

ICTI/ IVRSICTI/ IVRSICTI/ IVRSICTI/ IVRS

CTS DurhamCTS DurhamPharmacyPharmacy

CTS DurhamCTS DurhamPharmacyPharmacyTIMITIMITIMITIMI

DCRI/ CVCDCRI/ CVCDCRI/ CVCDCRI/ CVC

MillenniumMillenniumMillenniumMillennium

SitesSitesPatientsPatients SitesSites

PatientsPatients

Primary ObjectivePrimary 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

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 DesignStudy Design

High-risk NSTE ACS

n = 10,500

High-risk NSTE ACS

n = 10,500

1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout

2 Endpoint: 30 d Death/MI

1 Endpoint: 96-hr Death/MI/Urgent Revasc/Thrombotic bailout

2 Endpoint: 30 d Death/MI

PlaceboPlaceboEptifibatide (180/2/180)Eptifibatide (180/2/180)

Randomize within 8 hours

Early invasive strategy: no sooner than next calendar day

Randomize within 8 hours

Early invasive strategy: no sooner than next calendar day

2 of 3 criteria:1. Age > 60 yo2. + CKMB or TNT/I3. ST or transient ST

Concomitant TherapiesConcomitant 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

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 AdministrationBlinded 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

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

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

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

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

Use of Eptifibatide in the Cath Lab(2) After PCI Has Begun

Use of Eptifibatide in the Cath Lab(2) After PCI Has Begun

Study EndpointsStudy 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

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

Statistical MethodsStatistical 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)

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 SubstudyBiomarker Substudy

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

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

Objectives Identify high-risk NTE-

ACS patients Explore the ability of

eptifibatide to modulate cardiac biomarkers

Identify patients who benefit most from early eptifibatide

Objectives Identify high-risk NTE-

ACS patients Explore the ability of

eptifibatide to modulate cardiac biomarkers

Identify patients who benefit most from early eptifibatide

Platelet Inhibition in NSTE ACSSummary of Current Status

Platelet Inhibition in NSTE ACSSummary 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