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

DisclosuresDisclosures

Funded by Millennium Pharmaceuticals and Schering Plough

Individual disclosures Armstrong Braunwald Califf Gibson Giugliano Harrington Montalescot Newby Strony Van de Werf

Funded by Millennium Pharmaceuticals and Schering Plough

Individual disclosures Armstrong Braunwald Califf Gibson Giugliano Harrington Montalescot Newby Strony Van de Werf

Study Structure—figure with the below components

Study Structure—figure with the below components

Exec Comm Steering Committee Sponsor Coordinating Centers—DCRI, TIMI, CVC DSMB Sites CEC

Exec Comm Steering Committee Sponsor Coordinating Centers—DCRI, TIMI, CVC DSMB Sites CEC

Primary ObjectivePrimary 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

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 DesignStudy Design

High-risk NSTE ACS

n = 10,500 (9500)

High-risk NSTE ACS

n = 10,500 (9500)

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

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

Placebo / provisional eptifibatide pre-PCI

Placebo / provisional eptifibatide pre-PCI

Early, routine eptifibatide (180/2/180)

Early, routine eptifibatide (180/2/180)

Randomize within 12 hours of presentation

Invasive strategy: 12 to 96 hours after randomization

Randomize within 12 hours of presentation

Invasive strategy: 12 to 96 hours after randomization

2 of 3 high-risk criteria:1. Age > 60 years2. + CKMB or TnT/I3. ST or transient ST (Or age 50-59, h/o CVDand + CKMB or TnT/I)

2 of 3 high-risk criteria:1. Age > 60 years2. + CKMB or TnT/I3. ST or transient ST (Or age 50-59, h/o CVDand + CKMB or TnT/I)

Key Exclusion CriteriaKey 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: bivalirudin at PCI amendment 2: acute fondaparinux or bivalirudin

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: bivalirudin at PCI amendment 2: acute fondaparinux or bivalirudin

Blinded Study Drug AdministrationBlinded Study Drug Administration

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 PCI active if transition before wire crossed lesion PCI bailout if after wire crossed the lesion

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 PCI active if transition before wire crossed lesion PCI bailout if after wire crossed the lesion

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 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 98% for 96-hour primary composite endpoint 81% for 30-day key secondary endpoint of death or

MI Prespecified subgroups

Proper: Age, baseline troponin, hospital type, diabetes, early clopidogrel, UFH vs enoxaparin, TIMI Risk Score

Post-randomization (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 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 98% for 96-hour primary composite endpoint 81% for 30-day key secondary endpoint of death or

MI Prespecified subgroups

Proper: Age, baseline troponin, hospital type, diabetes, early clopidogrel, UFH vs enoxaparin, TIMI Risk Score

Post-randomization (improper): By management strategy (PCI, CABG, medical)

EnrollmentEnrollment

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

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 ConductStudy Conduct

Patients randomized 9492

Patients excluded for site conduct 64

Patients without informed consent 22

Intent-to-treat population 9406

Patients who received no study drug77

As-treated safety population 9329

Lost to follow-up 11

Patients randomized 9492

Patients excluded for site conduct 64

Patients without informed consent 22

Intent-to-treat population 9406

Patients who received no study drug77

As-treated safety population 9329

Lost to follow-up 11

Baseline CharacteristicsBaseline CharacteristicsERE (n=4722) DPE

(n=4684)Age (years) 67 (60, 75) 68 (60, 75)Female (%) 32.0 31.2Region (%) Most of World 69.2 69.4 North America 30.8 30.6Diabetes mellitus (%) 30.1 30.7Hypertension (%) 70.5 71.9Dyslipidemia (%) 57.9 57.8Prior MI (%) 27.0 28.2Prior PCI (%) 24.3 25.0Prior CABG (%) 13.1 14.2Creatinine Clearance (cc/min) 75 (56, 96) 74 (56, 96)Troponin or CKMB positive (%) 85.9 87.0ST-segment shifts (%) 61.6 62.0Presentation to rand (hours) 5.4 (3.3, 8.8) 5.7 (3.4,8.8)

ERE (n=4722) DPE (n=4684)

Age (years) 67 (60, 75) 68 (60, 75)Female (%) 32.0 31.2Region (%) Most of World 69.2 69.4 North America 30.8 30.6Diabetes mellitus (%) 30.1 30.7Hypertension (%) 70.5 71.9Dyslipidemia (%) 57.9 57.8Prior MI (%) 27.0 28.2Prior PCI (%) 24.3 25.0Prior CABG (%) 13.1 14.2Creatinine Clearance (cc/min) 75 (56, 96) 74 (56, 96)Troponin or CKMB positive (%) 85.9 87.0ST-segment shifts (%) 61.6 62.0Presentation to rand (hours) 5.4 (3.3, 8.8) 5.7 (3.4,8.8)

In-hospital ManagementIn-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 12.0CABG (%) 13.2 12.9Medically Treated only (%) 30.3 31.4Use 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

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 12.0CABG (%) 13.2 12.9Medically Treated only (%) 30.3 31.4Use 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 Results96-Hour Primary Efficacy Results

ERE DPE OR P

(n=4722) (n=4684) (95% CI)

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 / 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)

ERE DPE OR P

(n=4722) (n=4684) (95% CI)

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 / 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 EndpointKaplan-Meier Curves for Primary EndpointD

eath

, M

I, R

IUR

or

TB

O (

%)

Dea

th,

MI,

RIU

R o

r T

BO

(%

)

00

55

1010

1515

Time Since Randomization (Hours)Time Since Randomization (Hours)

00 44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848 5252 5656 6060 6464 6868 7272 7676 8080 8484 8888 9292 9696

10.0%10.0%

9.3%9.3%

Delayed provisional eptifibatide

4684469

25.9 (18.7, 48.4)

Delayed provisional eptifibatide

4684469

25.9 (18.7, 48.4)

Early routineeptifibatide

4722439

31.1 (18.8, 62.2)

Early routineeptifibatide

4722439

31.1 (18.8, 62.2)

P = 0.23P = 0.23(stratified for intended early

clopidogrel use)(stratified for intended early

clopidogrel use)

N# Events

Hours to Event

N# Events

Hours to Event

Delayed provisional eptifibatideDelayed provisional eptifibatide

Early routine eptifibatideEarly routine eptifibatide

30-Day Secondary Efficacy Results30-Day Secondary Efficacy Results

ERE DPE OR P (n=4722) (n=4684) (95% CI)

Death or MI 11.2 12.3 0.89 0.079

(0.79-1.01)

Death 2.8 2.6 1.10 0.46

(0.86-1.41)

Death, MI, RIUR 12.5 13.8 0.89 0.065

(0.79-1.01)

ERE DPE OR P (n=4722) (n=4684) (95% CI)

Death or MI 11.2 12.3 0.89 0.079

(0.79-1.01)

Death 2.8 2.6 1.10 0.46

(0.86-1.41)

Death, MI, RIUR 12.5 13.8 0.89 0.065

(0.79-1.01)

Kaplan-Meier Curves for 30-day Death or MIKaplan-Meier Curves for 30-day Death or MID

eath

or

MI

(%)

Dea

th o

r M

I (%

)

00

55

1010

1515

Time Since Randomization (Days)Time Since Randomization (Days)

00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919 2020 2121 2222 2323 2424 2525 2626 2727 2828 2929 3030

12.4%12.4%

11.2%11.2%

P = 0.079P = 0.079

(stratified for intended early clopidogrel use)

(stratified for intended early clopidogrel use)

Delayed provisional eptifibatide

4684578

2.1 (1.0, 5.8)

Delayed provisional eptifibatide

4684578

2.1 (1.0, 5.8)

Early routineeptifibatide

4722528

2.7 (1.0, 4.9)

Early routineeptifibatide

4722528

2.7 (1.0, 4.9)

N# Events

Days to Event

N# Events

Days to Event

Delayed provisional eptifibatideDelayed provisional eptifibatide

Early routine eptifibatideEarly routine eptifibatide

96-hour Primary Efficacy ResultsBy Prespecified Subgroups

96-hour Primary Efficacy ResultsBy Prespecified Subgroups

0.700.70 0.800.800.500.50 0.600.60 0.900.90 1.001.00 2.002.00

Baseline CharacteristicBaseline Characteristic

Odds Ratio for UpstreamOdds Ratio for Upstream

Eptifibatide (95% CI)Eptifibatide (95% CI)Early Routine Early Routine

Eptifibatide, %Eptifibatide, %

Delayed Delayed Provisional Provisional

Eptifibatide, %Eptifibatide, %

OverallOverall

MenMenWomenWomen

Age < 75 yrAge < 75 yr

Age Age >> 75 yr75 yr

Troponin positiveTroponin positiveTroponin negativeTroponin negative

DiabetesDiabetesNo DiabetesNo Diabetes

Randomized Randomized << 4 hours4 hoursRandomized > 4 hoursRandomized > 4 hours

High TIMI Risk Score (5High TIMI Risk Score (5 -- 7)7)Intermediate TIMI Risk Score (3Intermediate TIMI Risk Score (3 -- 4)4)Low TIMI Risk Score (0Low TIMI Risk Score (0 -- 2)2)

Unfractionated heparin onlyUnfractionated heparin only

Low molecular weight heparin onlyLow molecular weight heparin only

Primary Care HospitalPrimary Care HospitalTertiary Care HospitalTertiary Care Hospital

9.39.3 10.010.0

9.19.1 9.89.89.79.7 10.410.4

8.68.6 9.59.511.411.4 11.411.4

9.59.5 10.610.67.77.7 6.86.8

8.98.9 10.610.69.59.5 9.89.8

8.98.9 10.510.59.59.5 9.89.8

10.410.4 10.810.89.49.4 10.110.16.86.8 8.08.0

9.19.1 11.011.0

9.99.9 9.99.9

9.09.0 9.79.7

9.49.4 10.110.1

Early Eptifibatide BetterEarly Eptifibatide Better Delayed Provisional Eptifibatide BetterDelayed Provisional Eptifibatide Better

Upfront clopidogrel intendedUpfront clopidogrel intendedNo upfront clopidogrel intendedNo upfront clopidogrel intended

8.88.8 9.59.510.810.8 11.511.5

North AmericaNorth America

Western EuropeWestern Europe

Eastern EuropeEastern Europe

10.310.3 10.610.6

7.37.3 8.68.6

11.211.2 11.211.2

Middle East, Africa and AsiaMiddle East, Africa and Asia 10.910.9 11.511.5

30-day Death or MI By Prespecified Subgroups

30-day Death or MI By Prespecified Subgroups

0.700.70 0.800.800.500.50 0.600.60 0.900.90 1.001.00 2.002.00

OverallOverall 11.211.2 12.312.3

MenMen 11.411.4 12.012.0WomenWomen 10.710.7 13.013.0

Age < 75 yrAge < 75 yr 10.210.2 11.611.6Age Age >> 75 yr75 yr 14.014.0 14.614.6

Troponin positiveTroponin positive 11.611.6 13.013.0

Troponin negativeTroponin negative 8.18.1 8.48.4

DiabetesDiabetes 11.711.7 13.813.8

No DiabetesNo Diabetes 10.910.9 11.711.7

Randomized Randomized << 4 hours4 hours 11.111.1 12.812.8

Randomized > 4 hoursRandomized > 4 hours 11.211.2 12.112.1

High TIMI Risk Score (5High TIMI Risk Score (5 -- 7)7) 13.213.2 13.313.3

Intermediate TIMI Risk Score (3Intermediate TIMI Risk Score (3 -- 4)4) 10.910.9 12.812.8

Low TIMI Risk Score (0Low TIMI Risk Score (0 -- 2)2) 8.18.1 9.19.1

Unfractionated heparin onlyUnfractionated heparin only 11.311.3 13.013.0

Low molecular weight heparin onlyLow molecular weight heparin only 11.311.3 12.812.8

Primary Care HospitalPrimary Care Hospital 10.710.7 12.312.3

Tertiary Care HospitalTertiary Care Hospital 11.311.3 12.412.4

Upfront clopidogrel intendedUpfront clopidogrel intended 10.310.3 12.012.0

No upfront clopidogrel intendedNo upfront clopidogrel intended 13.713.7 13.413.4

Baseline CharacteristicBaseline CharacteristicOdds Ratio for UpstreamOdds Ratio for Upstream

Eptifibatide (95% CI)Eptifibatide (95% CI)Early Routine Early Routine

Eptifibatide, %Eptifibatide, %

Delayed Delayed Provisional Provisional

Eptifibatide, %Eptifibatide, %

Early Eptifibatide BetterEarly Eptifibatide Better Delayed Provisional Eptifibatide BetterDelayed Provisional Eptifibatide Better

North AmericaNorth America

Western EuropeWestern Europe

Eastern EuropeEastern Europe

13.213.2 14.514.5

10.210.2 8.88.8

14.514.5 15.215.2

Middle East, Africa and AsiaMiddle East, Africa and Asia 11.011.0 11.611.6

Safety Results (through 120 hours)Safety Results (through 120 hours)

ERE DPE OR(95%CI) P

(n=4686) (n=4643)

Bleeding (overall)

TIMI Major 2.6 1.8 1.42 (1.07-1.89) 0.015

TIMI major or minor 5.8 3.4 1.75 (1.43-2.14)<0.001

GUSTO Severe 0.8 0.9 0.99 (0.64-1.55) 0.97

GUSTO Moderate or Severe 7.6 5.1 1.52 (1.28-1.80)<0.001

PRBC transfusion 8.6 6.7 1.31 (1.12-1.53) 0.001

Bleeding (CABG)

Re-operation for bleeding 6.0 8.4 0.70 (0.39-1.27) 0.24

Chest tube output (mL/24 H) 720 770 -- 0.41

Thrombocytopenia (nadir <100K) 3.3 2.8

Stroke 0.6 0.8 0.79 (0.48-1.30) 0.36

ERE DPE OR(95%CI) P

(n=4686) (n=4643)

Bleeding (overall)

TIMI Major 2.6 1.8 1.42 (1.07-1.89) 0.015

TIMI major or minor 5.8 3.4 1.75 (1.43-2.14)<0.001

GUSTO Severe 0.8 0.9 0.99 (0.64-1.55) 0.97

GUSTO Moderate or Severe 7.6 5.1 1.52 (1.28-1.80)<0.001

PRBC transfusion 8.6 6.7 1.31 (1.12-1.53) 0.001

Bleeding (CABG)

Re-operation for bleeding 6.0 8.4 0.70 (0.39-1.27) 0.24

Chest tube output (mL/24 H) 720 770 -- 0.41

Thrombocytopenia (nadir <100K) 3.3 2.8

Stroke 0.6 0.8 0.79 (0.48-1.30) 0.36

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-life-threatening bleeding and transfusions

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-life-threatening bleeding and transfusions

ConclusionsConclusions

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

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

ImplicationsImplications

Primary and Key Secondary Efficacy ResultsBy Clopidogrel Strata at Randomization

Primary and Key Secondary Efficacy ResultsBy Clopidogrel Strata at Randomization

ERE DPE OR (95% CI)

96-hr Death, MI, RIUR, TBO

Clopidogrel intended 8.8 9.5 0.92 (0.78-1.08)

No Clopidogrel intended 10.8 11.5 0.93 (0.72-1.20)

30-day Death / MI

Clopidogrel intended 10.3 12.0 0.85 (0.73-0.91)

No Clopidogrel intended 13.7 13.4 1.03 (0.81-1.31)

ERE DPE OR (95% CI)

96-hr Death, MI, RIUR, TBO

Clopidogrel intended 8.8 9.5 0.92 (0.78-1.08)

No Clopidogrel intended 10.8 11.5 0.93 (0.72-1.20)

30-day Death / MI

Clopidogrel intended 10.3 12.0 0.85 (0.73-0.91)

No Clopidogrel intended 13.7 13.4 1.03 (0.81-1.31)