The INT egrelin and E noxaparin R andomized assessment of A cute C oronary syndrome Treatment T rial Sponsored by the Canadian Heart Research Centre, Key

TheThe INTINTegrelinegrelin and and EEnoxaparin noxaparin RRandomized assessment of andomized assessment of

AAcute cute CCoronary syndrome Treatment oronary syndrome Treatment TTrialrialTheThe INTINTegrelinegrelin and and EEnoxaparin noxaparin RRandomized assessment of andomized assessment of

AAcute cute CCoronary syndrome Treatment oronary syndrome Treatment TTrialrial

Sponsored by the Canadian Heart Research Centre,Sponsored by the Canadian Heart Research Centre,Key Pharmaceuticals, Division of Schering Canada Inc.Key Pharmaceuticals, Division of Schering Canada Inc.

and Millenium Pharmaceuticals Inc.and Millenium Pharmaceuticals Inc.Enoxaparin provided by Aventis CanadaEnoxaparin provided by Aventis Canada

As Presented by Shaun G Goodman on behalf As Presented by Shaun G Goodman on behalf of the INTERACT Trial Investigatorsof the INTERACT Trial Investigators

ACC 2002ACC 2002

The INTERACT StudyThe INTERACT Study

INTERACT Preliminary ResultsINTERACT Preliminary Results

The INTERACT StudyThe INTERACT Study

746 patients UA/NSTEMI Chest pain > 10 min within 24 hr 0.5 mm ST Segment depression/ transient elevation Positive cardiac markers (CK-MB or troponin)

180/2.0 dose eptifibatide for 48 hrsASA 160 mg initially 80-325 mg daily

746 patients UA/NSTEMI Chest pain > 10 min within 24 hr 0.5 mm ST Segment depression/ transient elevation Positive cardiac markers (CK-MB or troponin)

180/2.0 dose eptifibatide for 48 hrsASA 160 mg initially 80-325 mg daily

Treatment Group A UFH 70 IU/kg bolus/0.15 U/kg-

hr (aPTT 50-70 sec)(n = 366)

Treatment Group A UFH 70 IU/kg bolus/0.15 U/kg-

hr (aPTT 50-70 sec)(n = 366)

Treatment Group B1.0 mg/kg q12 enoxaparin

(n = 380)

Treatment Group B1.0 mg/kg q12 enoxaparin

(n = 380)

Endpoints: Primary - Major/Minor TIMI Bleeding Secondary - D/MI/recurrent ischemia

- ST segment monitoring

Endpoints: Primary - Major/Minor TIMI Bleeding Secondary - D/MI/recurrent ischemia

- ST segment monitoring

Goodman et al, ACC 2002Goodman et al, ACC 2002


INTERACT: Exclusion CriteriaINTERACT: Exclusion CriteriaINTERACT: Exclusion CriteriaINTERACT: Exclusion Criteria

• Uninterpretable 12 lead EKG at baseline

• Recent fibrinolysis or GP IIbIIIa inhibitor therapy

• Prior administration of unfractionated or low molecular weight heparin within the past 24 hours

• Administration of unfractionated or low molecular weight heparin for over 12 hours

• Uninterpretable 12 lead EKG at baseline

• Recent fibrinolysis or GP IIbIIIa inhibitor therapy

• Prior administration of unfractionated or low molecular weight heparin within the past 24 hours

• Administration of unfractionated or low molecular weight heparin for over 12 hours



INTERACT: Baseline CharacteristicsINTERACT: Baseline CharacteristicsINTERACT: Baseline CharacteristicsINTERACT: Baseline Characteristics

Weight (kg)Weight (kg)

Heart rate (beats/min)Heart rate (beats/min)

Systolic BP (mm Hg)Systolic BP (mm Hg)

Diastolic BP (mm Hg)Diastolic BP (mm Hg)

Killip ClassKillip Class

II

IIII

III-IVIII-IV

ST Deviation ST Deviation 0.1 mV, 0.1 mV, 2 leads2 leads

Index Infarction Index Infarction (Marker +)(Marker +)

UFHUFH(n=366)(n=366)

79 (68, 89)79 (68, 89)

72 (63, 82)72 (63, 82)

134 (120, 150)134 (120, 150)

77 (68, 87)77 (68, 87)

8888

10.710.7

1.41.4

21.521.5

85.385.3

EnoxaparinEnoxaparin(n=380)(n=380)

79 (70, 92)79 (70, 92)

70 (60, 81)70 (60, 81)

134 (120, 151)134 (120, 151)

77 (66, 87)77 (66, 87)

89.789.7

9.89.8

0.60.6

2323

81.881.8



MedicationsMedicationsMedicationsMedications

ASA (%)ASA (%)

Clopidogrel (%)Clopidogrel (%)

IV Beta BlockerIV Beta Blocker

Oral Beta BlockerOral Beta Blocker

Calcium BlockerCalcium Blocker

IV NitrateIV Nitrate

Oral NitrateOral Nitrate

ACE InhibitorACE Inhibitor

Lipid LoweringLipid Lowering


95.695.6

15.315.3

14.214.2

79.279.2

22.122.1

35.335.3

58.758.7

56.356.3

51.451.4


95.895.8

16.316.3

16.616.6

84.784.7

18.718.7

38.438.4

47.647.6

56.156.1

50.350.3



Study Drug AdministrationStudy Drug AdministrationStudy Drug AdministrationStudy Drug Administration

Pre-study Heparin (%)Pre-study Heparin (%)

Time from symptom onsetTime from symptom onset

Eptifibatide duration (hrs)Eptifibatide duration (hrs)

Study drug duration Study drug duration 48 hrs48 hrs


19.419.4

5.7 5.7 4.6 4.6

45.4 45.4 12.9 12.9

45.7 45.7 13.4 13.4


2020

6.0 6.0 4.84.8

45.8 45.8 13.2 13.2

41.5 41.5 20.1 20.1

Preliminary ResultsPreliminary Results



Activated Partial Thromboplastin Time (aPTT)Activated Partial Thromboplastin Time (aPTT)Activated Partial Thromboplastin Time (aPTT)Activated Partial Thromboplastin Time (aPTT)

aPTT aPTT 12 hrs12 hrs

Sub-therapeutic (<1.5x)Sub-therapeutic (<1.5x)

Therapeutic (1.5-2x)Therapeutic (1.5-2x)

Supra-therapeutic (>2x)Supra-therapeutic (>2x)

aPTT >12-24 hrsaPTT >12-24 hrs

Sub-therapeutic (<1.5x)Sub-therapeutic (<1.5x)

Therapeutic (1.5-2x)Therapeutic (1.5-2x)

Supra-therapeutic (>2x)Supra-therapeutic (>2x)

aPTT value aPTT value 12 hrs12 hrs

aPTT value >12-24hrsaPTT value >12-24hrs


(n=342)(n=342)

14.314.3

16.716.7

6969

(n=330)(n=330)

13.913.9

46.746.7

39.439.4

97 (61, 148)97 (61, 148)

67 (54, 90)67 (54, 90)

Preliminary ResultsPreliminary Results



30-Day Coronary Angiography30-Day Coronary Angiographyand Revascularizationand Revascularization

30-Day Coronary Angiography30-Day Coronary Angiographyand Revascularizationand Revascularization

Angiography (%)Angiography (%)

Time to angio (hrs)Time to angio (hrs)

PCI (%)PCI (%)

Time to PCI (hrs)Time to PCI (hrs)

CABG (%)CABG (%)

Time to CABG (hrs)Time to CABG (hrs)


64.764.7

101 (60, 168)101 (60, 168)

30.230.2

109 (60, 232)109 (60, 232)

12.112.1

335 (207, 470)335 (207, 470)


62.162.1

100 (65, 164)100 (65, 164)

26.926.9

135 (76, 335)135 (76, 335)

12.712.7

306 (160, 460)306 (160, 460)



Non-CABG BleedingNon-CABG BleedingNon-CABG BleedingNon-CABG Bleeding

0.3%

0.8%

4.1%

1.8%

0%

1%

2%

3%

4%

5%

0.3%

0.8%

4.1%

1.8%

0%

1%

2%

3%

4%

5%

MajorMajor MinorMinor

P=0.084P=0.084

TIMI Scale1TIMI Scale1

2.2%

0.8%

3.3%

2.1%2.2%

0.8%

3.3%

2.1%

P=0.37P=0.37

GUSTO ScaleGUSTO Scale

P=0.62P=0.62

1 1 Hct Hct 15% or Hgb 15% or Hgb 50 g/L50 g/L

00

P=0.14P=0.14

00

SevereSevere ModerateModerate MildMild

(Lytic and GP IIb/IIIa Inhibitor trials)(Lytic and GP IIb/IIIa Inhibitor trials)



8.5%

5.3%

0%

2%

4%

6%

8%

10%8.5%

5.3%

0%

2%

4%

6%

8%

10%

UFHUFH EnoxaparinEnoxaparin

P=0.083P=0.083

AllAll

30-Day Major Bleeding30-Day Major Bleeding30-Day Major Bleeding30-Day Major Bleeding

5.5%

2.9%

0%

2%

4%

6%

8%

10%

5.5%

2.9%

0%

2%

4%

6%

8%

10%


P=0.079P=0.079

Non-CABG RelatedNon-CABG Related

TIMI Scale (LMWH trials)TIMI Scale (LMWH trials)



25%

33%

0%

10%

20%

30%

40%

25%

33%

0%

10%

20%

30%

40%

3.8%

1.1%

0%

2%

4%

6%

3.8%

1.1%

0%

2%

4%

6%

4.6%

1.8%

0%

2%

4%

6%

4.6%

1.8%

0%

2%

4%

6%


P=0.03P=0.03 P=0.014P=0.014

Major Bleeds – 96 HoursMajor Bleeds – 96 Hours Major Bleeds – 48 HoursMajor Bleeds – 48 Hours

P=0.024P=0.024MInor Bleeds – 96 HoursMInor Bleeds – 96 Hours

INTERACT: Non-CABG Bleeding ResultsINTERACT: Non-CABG Bleeding ResultsUsing TIMI CriteriaUsing TIMI Criteria

INTERACT: Non-CABG Bleeding ResultsINTERACT: Non-CABG Bleeding ResultsUsing TIMI CriteriaUsing TIMI Criteria

UFHUFH EnoxaparinEnoxaparin UFHUFH EnoxaparinEnoxaparin



25.1%

14.1%

0%

5%

10%

15%

20%

25%

30%25.1%

14.1%

0%

5%

10%

15%

20%

25%

30%


P=0.0002P=0.0002

0-48 Hours0-48 Hours

INTERACT: Ischemic Events by ST Segment INTERACT: Ischemic Events by ST Segment Monitoring During the First 96 hoursMonitoring During the First 96 hours

INTERACT: Ischemic Events by ST Segment INTERACT: Ischemic Events by ST Segment Monitoring During the First 96 hoursMonitoring During the First 96 hours

25.9%

12.7%

0%

5%

10%

15%

20%

25%

30%25.9%

12.7%

0%

5%

10%

15%

20%

25%

30%


P=0.0001P=0.000148-96 Hours48-96 Hours


n=346n=346 n=357n=357 n=320n=320 n=322n=322


12.6%

8.4%

0%

5%

10%

15%

12.6%

8.4%

0%

5%

10%

15%

13.5%

16.2%

0%

5%

10%

15%

20%

13.5%

16.2%

0%

5%

10%

15%

20%9.0%

5.0%

0%

2%

4%

6%

8%

10% 9.0%

5.0%

0%

2%

4%

6%

8%

10%


P=0.031P=0.031 P=0.30P=0.30

Death / MIDeath / MI Death / MI /Recurrent Ischemia

Death / MI /Recurrent Ischemia

P=0.064P=0.064

INTERACT: 30 Day EventsINTERACT: 30 Day EventsINTERACT: 30 Day EventsINTERACT: 30 Day Events

UFHUFH EnoxaparinEnoxaparin UFHUFH EnoxaparinEnoxaparin

Death / MI /Re-Ischemia with ECG Change

Death / MI /Re-Ischemia with ECG Change


n=366 n=366 n=366n=380 n=380 n=380


INTERACT: SummaryINTERACT: SummaryINTERACT: SummaryINTERACT: Summary

Compared to a regimen of Eptifibatide and Unfractionated Heparin, Eptifibatide and Enoxaparin is associated with

– Lower rates of major hemorrhage– Higher rates of minor hemorrhage– Lower rates of death or recurrent MI– Lower rates of ischemia during and immediately

following treatment

Compared to a regimen of Eptifibatide and Unfractionated Heparin, Eptifibatide and Enoxaparin is associated with

– Lower rates of major hemorrhage– Higher rates of minor hemorrhage– Lower rates of death or recurrent MI– Lower rates of ischemia during and immediately

following treatment



LimitationsLimitationsLimitationsLimitations

• This was open-label study, but endpoints were adjudicated in a blinded fashion as was the continuous ECG monitoring

• The time to coronary angiography/ revascularization (median 110 hours) was longer than that in TACTICS TIMI 18 where the median time to catheterization was 21 hours

• This was open-label study, but endpoints were adjudicated in a blinded fashion as was the continuous ECG monitoring

• The time to coronary angiography/ revascularization (median 110 hours) was longer than that in TACTICS TIMI 18 where the median time to catheterization was 21 hours



ConclusionsConclusionsConclusionsConclusions

• Among patients treated with eptifibatide in the setting of high risk non-ST elevation ACS, administration of enoxaparin is associated with improves outcomes compared to currently recommended therapy (UF Heparin) based on better safety and efficacy

• Among patients treated with eptifibatide in the setting of high risk non-ST elevation ACS, administration of enoxaparin is associated with improves outcomes compared to currently recommended therapy (UF Heparin) based on better safety and efficacy


Documents

The INT egrelin and E noxaparin R andomized assessment of A cute C oronary syndrome Treatment T rial Sponsored by the Canadian Heart Research Centre, Key