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ExTRACT-TIMI 25ExTRACT-TIMI 25 : :

New DataNew Data

Elliott M. Antman, MDElliott M. Antman, MD

This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology

Content Distributed by Cardiosource

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DisclosureDisclosure

Accumetrics, Inc. Accumetrics, Inc. Amgen, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals LPAstraZeneca Pharmaceuticals LPBaxterBaxterBayer Healthcare LLCBayer Healthcare LLCBeckman Coulter, Inc. Beckman Coulter, Inc. Biosite IncorporatedBiosite IncorporatedBristol-Myers SquibbBristol-Myers SquibbCardioKinetixCardioKinetixCV Therapeutics, Inc. CV Therapeutics, Inc. Eli Lilly and CompanyEli Lilly and CompanyFoldRxFoldRxGlaxoSmithKlineGlaxoSmithKlineINO Therapeutics LLCINO Therapeutics LLCInotek Pharmaceuticals CorporationInotek Pharmaceuticals Corporation

The National Institutes of HealthThe National Institutes of HealthIntegrated Therapeutics CorporationIntegrated Therapeutics CorporationKAI PharmaceuticalsKAI PharmaceuticalsMerck & Co., Inc.Merck & Co., Inc.Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Novartis PharmaceuticalsNovartis PharmaceuticalsNuvelo, Inc. Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Pfizer, Inc. Roche Diagnostics CorporationRoche Diagnostics CorporationRoche Diagnostics GmbHRoche Diagnostics GmbHSanofi-AventisSanofi-AventisSanofi-Synthelabo RechercheSanofi-Synthelabo RechercheSchering-Plough Research InstituteSchering-Plough Research InstituteSt Jude MedicalSt Jude Medical

The TIMI Study Group has received research / grant support in the past 2 yrs The TIMI Study Group has received research / grant support in the past 2 yrs through the Brigham & Women’s Hospital with funding from (in alphabetical order):through the Brigham & Women’s Hospital with funding from (in alphabetical order):

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STEMI < 6 hSTEMI < 6 hLytic eligibleLytic eligible

Lytic choice by MDLytic choice by MD(TNK, tPA, rPA, SK)(TNK, tPA, rPA, SK)

ENOXENOX

< 75 y: 30 mg IV bolus < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC)SC 1.0 mg / kg q 12 h (Hosp DC)

≥≥ 75 y: No bolus75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DCSC 0.75 mg / kg q 12 h (Hosp DC))

CrCl CrCl << 30: 1.0 mg / kg q 24 30: 1.0 mg / kg q 24 hh

Double-blind, double-dummyDouble-blind, double-dummy

ASAASA

Day 30Day 3011°° Efficacy Endpoint: Death or Nonfatal MI Efficacy Endpoint: Death or Nonfatal MI1° Safety Endpoint: TIMI Major Hemorrhage1° Safety Endpoint: TIMI Major Hemorrhage

Protocol DesignProtocol Design

UFHUFH60 U / kg bolus (4000 U) 60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hDuration: at least 48 hCont’d at MD discretionCont’d at MD discretion

N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.

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Main ResultsMain Results

Primary Endpoint:Primary Endpoint:Death or non-fatal re-MI by 30 daysDeath or non-fatal re-MI by 30 days

Primary Endpoint:Primary Endpoint:Death or non-fatal re-MI by 30 daysDeath or non-fatal re-MI by 30 days

Main Secondary Endpoint:Main Secondary Endpoint:Death, non-fatal re-MI, urgent Death, non-fatal re-MI, urgent

revascularization by 30 daysrevascularization by 30 days

Main Secondary Endpoint:Main Secondary Endpoint:Death, non-fatal re-MI, urgent Death, non-fatal re-MI, urgent

revascularization by 30 daysrevascularization by 30 days

12.0

9.9

UFH UFH

ENOX ENOX

14.5

11.7

Days Days

%% RR = 0.83p = 0.000003

RR = 0.81p = 0.000001

N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.

33% RRR in reMI by 48 h (P=0.002)33% RRR in reMI by 48 h (P=0.002)19% RRR in Death/MI by 72 h (P<0.001)19% RRR in Death/MI by 72 h (P<0.001)33% RRR in reMI by 48 h (P=0.002)33% RRR in reMI by 48 h (P=0.002)19% RRR in Death/MI by 72 h (P<0.001)19% RRR in Death/MI by 72 h (P<0.001)

12% RRR in by 48 h (P=0.02)12% RRR in by 48 h (P=0.02)12% RRR in by 48 h (P=0.02)12% RRR in by 48 h (P=0.02)

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Death or Nonfatal MIDeath or Nonfatal MITreatment Effect Over TimeTreatment Effect Over Time

8

7

6

5

4

3

2

1

0.5 1 2

UFHUFH (%)(%)

ENOXENOX (%) (%)

RRRRRR (%) (%)

4.14.1 3.63.6 1111

ARDARD(%)(%)

0.50.5

NNTNNT

200200

5.25.2 4.74.7 1010 0.50.5 200200

6.76.7 5.45.4 1919 1.31.3 7777

7.57.5 5.95.9 2222 1.61.6 6363

8.28.2 6.46.4 2222 1.81.8 5656

8.78.7 6.86.8 2222 1.91.9 5353

9.29.2 7.17.1 2222 2.12.1 4848

9.39.3 7.27.2 2323 2.12.1 4848

Days From Rand.

RRRRENOX BetterENOX Better UFH BetterUFH Better

P<0.001P<0.001

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Bleeding Endpoints (TIMI) Bleeding Endpoints (TIMI) 30 Days30 Days

1.4

0.40.9 0.7

2.1

0.81.3

0.8

0

1

2

3

4

5 UFHUFHENOXENOX

%

% E

ven

tsE

ven

ts

Major BleedMajor Bleed(Total)(Total)

ICH ICH

ARD 0.7%ARD 0.7%RR 1.53RR 1.53

P<0.0001P<0.0001

ARD 0.1%ARD 0.1%RR 1.27RR 1.27

P = 0.14P = 0.14

NonfatalNonfatalMajor BleedMajor Bleed

ARD 0.4%ARD 0.4%RR 1.39RR 1.39

P = 0.014P = 0.014

ARD 0.4%ARD 0.4%RR 1.84RR 1.84

P = 0.001P = 0.001

FatalFatalMajor BleedMajor Bleed

N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.

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Net Clinical BenefitNet Clinical Benefit at 30 Days at 30 Days

11 1.251.250.90.90.80.8

Death or Nonfatal MI or Death or Nonfatal MI or Nonfatal ICHNonfatal ICH

Death or Nonfatal MI or Death or Nonfatal MI or Nonfatal Major BleedNonfatal Major Bleed

Death or Nonfatal MI orDeath or Nonfatal MI or Nonfatal Disabl. Stroke Nonfatal Disabl. Stroke

ENOX BetterENOX Better UFH BetterUFH BetterRRRR

UFH (%) ENOX (%) RRR (%)

12.3 10.1 18

12.8 11.0 14

12.2 10.1 17

Prespecified DefinitionsPrespecified Definitions

P <0.0001

P <0.0001

P <0.0001

N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.

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For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin

-15

-7 -6

4

-20

-15

-10

-5

0

5

Eve

nts

/ 1

000

Pts

Eve

nts

/ 1

000

Pts

Nonfatal Nonfatal reMIreMI

UrgentUrgent Revasc. Revasc.

DeathDeath Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed

(No increase in (No increase in nonfatal ICH)nonfatal ICH)

++

N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.

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For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin

Age < 75 vs Age < 75 vs >> 75 75

-15

-7-5

4

-12

-7

-3

2

-20

-15

-10

-5

0

5 < 75>=75

Nonfatal Nonfatal reMIreMI

Nonfatal UrgentNonfatal Urgent Revasc. Revasc.

DeathDeath Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed

Eve

nts

/ 1

000

Pts

Eve

nts

/ 1

000

Pts

AHA 2006AHA 2006

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For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin

GenderGender

-16

-13

-8

5

-3

-15

-8

3

-20

-15

-10

-5

0

5

10 Women (N=4783) 23%

Men ( N= 15,696) 77%

Eve

nts

/ 1

000

Pts

Eve

nts

/ 1

000

Pts

DeathDeath NFMINFMI URUR Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed

(No increase in (No increase in nonfatal ICH)nonfatal ICH)

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For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin

DiabetesDiabetes

-23

-12

-2

5

-3

-15

-8

3

-25

-20

-15

-10

-5

0

5

10 DMNoDM

Eve

nts

/ 1

000

Pts

Eve

nts

/ 1

000

Pts

DeathDeathp = 0.039p = 0.039p = 0.39p = 0.39

NFMINFMIp = 0.011p = 0.011

p < 0.0001p < 0.0001

URURp = 0.76p = 0.76

p = 0.0006p = 0.0006

Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed

p = 0.21p = 0.21p = 0.04p = 0.04

(No increase in (No increase in nonfatal ICH)nonfatal ICH)

DMDMNo DMNo DM

AHA 2006AHA 2006

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For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin

Clopidogrel Use (No PCI)Clopidogrel Use (No PCI)

-21

-31

4

10

-35

-30

-25

-20

-15

-10

-5

0

5

10

15

No ClopidogrelNo Clopidogrel Clopidogrel UsedClopidogrel Used

Eve

nts

/ 1

000

Pts

Eve

nts

/ 1

000

Pts

Death, MI, Rec Isch, StrokeDeath, MI, Rec Isch, Stroke

Nonfatal Major BleedNonfatal Major Bleed

AHA 2006AHA 2006

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Death or Nonfatal MI - Day 30 Death or Nonfatal MI - Day 30 Lytic AdministeredLytic Administered

0.5 1 2ENOX BetterENOX Better UFH BetterUFH Better

RRRR

UFH (%) ENOX (%) RRR (%)

SK (N=4139)SK (N=4139)

TNK (N=3986)TNK (N=3986)

rPA (N=1122)rPA (N=1122)

tPA (N=11,175)tPA (N=11,175)

11.8 10.2 13

11.5 9.4 18

11.4 8.4 27

12.2 10.1 17

Interaction TestsInteraction TestsP = NSP = NS

AHA 2006AHA 2006

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Clinical ImplicationClinical Implication

A strategy ofA strategy of ENOXENOX is is clearly preferable to the clearly preferable to the current standard of current standard of UFHUFH as as the antithrombin to support the antithrombin to support fibrinolysis, the most fibrinolysis, the most common form of reperfusion common form of reperfusion for STEMI used worldwide.for STEMI used worldwide.