RP Giugliano MD, SM; MT Roe, MD, MHS; RA Harrington MD; CM Gibson, MS, MD; U Zeymer, MD; F Van de...

RP Giugliano MD, SM; MT Roe, MD, MHS; RA Harrington MD; CM Gibson, MS, MD; U Zeymer, MD; F Van de Werf, MD, PhD; KW Baran, MD; HP

Hobbach, MD; LH Woodlief, MS; KL Hannan, BA; S Greenberg, PhD; J Miller, BS; MM Kitt, MD; J Strony, MD; CH McCabe, BS; E Braunwald, MD; RM

Califf, MD on behalf of the INTEGRITI InvestigatorsBoston, MA; Durham, NC; Kassel and Siegen, Germany; Leuven, Belgium; St.

Paul, MN; South San Francisco, CA; and Kenilworth, NJ

Combination Reperfusion Therapy With Eptifibatide and Reduced-Dose Tenecteplase

for ST-Elevation Myocardial Infarction: Results from the Integrilin and Tenecteplase in

Acute Myocardial Infarction (INTEGRITI) Phase II Angiographic Trial

Prior Studies Combining Lytic + GP IIb/IIIa Inhibitors

Prior Studies Combining Lytic + GP IIb/IIIa Inhibitors

• Angiographic Trials– Higher rates of early TIMI 3 flow– Reduced time to restoration of flow– Improved myocardial reperfusion– Less reocclusion / re-elevation of ST

• Large Clinical Trials– No difference in mortality– Less reinfarction, recurrent ischemia– More bleeding

• Angiographic Trials– Higher rates of early TIMI 3 flow– Reduced time to restoration of flow– Improved myocardial reperfusion– Less reocclusion / re-elevation of ST

• Large Clinical Trials– No difference in mortality– Less reinfarction, recurrent ischemia– More bleeding

PRIMARY OBJECTIVE and KEY ENTRY CRITERIA

PRIMARY OBJECTIVETo Identify optimal dose of eptifibatide + TNK:

TIMI 3 flow at 60 minutes Favorable safety profile

Typical Entry Criteria for Angio MI TrialTypical Entry Criteria for Angio MI Trial• ST ST MI MI• Sx onset < 6 hSx onset < 6 h• Age < 76 yrsAge < 76 yrs

• Lytic eligibleLytic eligible• No prior CABGNo prior CABG• No cardiogenic shockNo cardiogenic shock

Dose Finding

Aspirin

ST ST , lytic eligible, < 6 h, lytic eligible, < 6 h

Reduced dose heparinReduced dose heparin

50% TNK-tPA(0.25 mg/kg)

+ eptifibatide (180 / 2 / 90)



Part 1Part 1

2 TNK doses2 TNK doses





Part 2Part 2

2 EPT doses2 EPT doses

ST ST , lytic eligible, < 6 h, lytic eligible, < 6 h

ControlControl

DoseConfirmation

DoseConfirmation

60 minutes: TIMI flow60 minutes: TIMI flow / ST-Segment Resolution / ST-Segment Resolution

Full-dose TNK-tPA(0.5 mg/kg)

ACC/AHA Guideline Heparin (60 U/kg; 12 U/kg/h)

No Eptifibatide

ExperimentalExperimental

Low-dose Heparin(60 U/kg ; 7 U/kg/h)

Eptifibatide: Bolus: #1 = 180 g/kg; Infusion: 2.0 g/kg/m Bolus #2 = 180 g/kg

50% TNK-tPA

AspirinAspirin

Baseline Characteristics

NN 418 418

Median AgeMedian Age 58 years 58 years

MaleMale 77% 77%

Anterior MIAnterior MI 33% 33%

Median Time Sx onset ->Tx Median Time Sx onset ->Tx 2.9 hours 2.9 hours

Prior MIPrior MI 13% 13%

DiabetesDiabetes 14% 14%

Killip Killip >> IIII 13% 13%

60 Minute Flow (Core lab)Dose Finding

% pts

7777 79798484

9696PART 1: 2 doses TNKPART 1: 2 doses TNK PART 2: 2 doses EPTPART 2: 2 doses EPT

50% TNK +50% TNK +ept 180/90ept 180/90

50% TNK +50% TNK +ept 180/90ept 180/90

75% TNK +75% TNK +ept 180/90ept 180/90

50% TNK +50% TNK +ept 180/180ept 180/180

676568

64

0

20

40

60

80

100

TIMI 2

TIMI 3

P=0.02

N= 22 28 54 55

60 Minute Flow (Core lab)Dose Confirmation

60 Minute Flow (Core lab)Dose Confirmation

4959 62

0

20

40

60

80

100

TIMI 2

TIMI 3

% pts% pts

77777777 85858585 89898989

Dose ConfirmationDose ConfirmationDose ConfirmationDose Confirmation Dose Finding + ConfirmationDose Finding + ConfirmationDose Finding + ConfirmationDose Finding + Confirmation

TNK TNK TNK TNK 50% TNK +50% TNK +ept 180/180ept 180/18050% TNK +50% TNK +ept 180/180ept 180/180

N: 106 105 159

50% TNK +50% TNK +ept 180/180ept 180/18050% TNK +50% TNK +ept 180/180ept 180/180

P=0.15

P=0.17

cTFC in INTEGRITI at 60 mDose Finding + Dose ConfcTFC in INTEGRITI at 60 mDose Finding + Dose Conf

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80 90 100Corrected TIMI Frame Count

100% --- 103 40

50% 180/180 154 34

TNK Eptifibatide N cTFCTNK Eptifibatide N cTFCTNK Eptifibatide N cTFCTNK Eptifibatide N cTFC

% pts

MedianMedian

Median ST-Segment Median ST-Segment Resolution at 60 minResolution at 60 min

71%61%

75%

0%

20%

40%

60%

80%

100%

ST res

N = 53 61 89

50% TNK +50% TNK +ept 180/180ept 180/180

Dose ConfirmationDose Confirmation Dose Find + Conf Dose Find + Conf

TNKTNK 50% TNK +50% TNK +ept 180/180ept 180/180

P=0.08

Myocardial Perfusion Myocardial Perfusion Grade 2/3 at 60 minGrade 2/3 at 60 min

49%45%52%

0%

20%

40%

60%

80%

100%

% pts

50% TNK +50% TNK +ept 180/180ept 180/180

50% TNK +50% TNK +ept 180/180ept 180/180

TNKTNK

Dose Confirmation Dose Find + ConfDose Confirmation Dose Find + Conf

N: 107 105 159

P=0.68

48% 50%54%

MPG 3

MPG 2

40

62

13

4549

23

5251

0

20

40

60

80

100 Tenecteplase monotherapy

Eptifibatide (180/2/180) + 50% TNK (Dose Finding and Dose Confirmation)

% pts

N: 106 159

TFG 3 All 3 Complete ST Res

TMPG 3

46 8153 88107 159

Angiographic and ECG Outcomes at 60 min

Angiographic and ECG Outcomes at 60 min

Hemorrhagic Events Dose Conf Dose Conf DC+DF DC+DF

TNKTNK 100% 100% 50% 50% 50% 50%

Eptifibatide Eptifibatide -- -- 180/180 180/180 180/180 180/180

# patients# patients 119 119 118 118 177 177

TIMI Major, nTIMI Major, n 3 3 (3%) (3%) 9 9 (8%) (8%) 13 13 (7%) (7%)

• ICHICH (2) (2) (0) (0) (1) (1)

• SpontaneousSpontaneous (0) (0) (3) (3) (4) (4)

• InstrumentedInstrumented (1) (1) (6) (6) (8) (8)

TIMI 3 FLOW - Dose Confirmation

7073

4740

5249

7378

54564859

0

20

40

60

80

100Lytic alone

Combination

SPEEDrPA

TIMI 14 tPA

% p

ts w

ith

TIM

I 3 F

low

ENTIRE-T23TNK (UFH)

INTEGRITITNK

105106 586398 1006773 87 88

TIMI 14 rPALytic:

60 min 90 min

Weighted Ave = + 6.6% difference

7581

INTRO-AMItPA

Summary of INTEGRITI Final Results

Summary of INTEGRITI Final Results

EPTIFIBATIDE + 50% TNK vs TNK mono1. Trends towards improved rates of

– TIMI 3 epicardial flow and IRA patency

– corrected TIMI Frame count

– ST resolution

– Patent microcirculation

2. Trend towards more major hemorrhage

EPTIFIBATIDE + 50% TNK vs TNK mono1. Trends towards improved rates of

– TIMI 3 epicardial flow and IRA patency

– corrected TIMI Frame count

– ST resolution

– Patent microcirculation

2. Trend towards more major hemorrhage

Academic GroupsTIMI Study OfficeDuke Clinical Res Inst

Core LaboratoriesAngio - CM GibsonECG - DA MorrowCont ECG - M Krucoff

SponsorsCOR Therapeutics, IncSchering-Plough Research Institute

Study Organization

US39

Canada1

Belgium3

7 Countries, 67 Hospitals

Germany13

France7

Nether.3

S Afr1

RP Giugliano MD, SM; MT Roe, MD, MHS; RA Harrington MD; CM Gibson, MS, MD; U Zeymer, MD; F Van de...

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