1

EEnonoxxaparin and aparin and TThrombolysis hrombolysis RReperfusion for eperfusion for AAcute cute Myocardial InfarMyocardial Infarctctionion

ExTRACT-ExTRACT-TIMI 25TIMI 25

ACC 2006ACC 2006

Atlanta, GAAtlanta, GA

Disclosure StatementDisclosure Statement: : Dr. Antman received research grant support via the Dr. Antman received research grant support via the Brigham and Women’s Hospital from sanofi-aventisBrigham and Women’s Hospital from sanofi-aventis

2

BackgroundBackground

• Advantages of ENOX over UFHGreater anti Xa:anti IIa activityReliable A/C without monitoringConvenient sc administration

• Prior trials suggestENOX may be superior to UFH

• Pharmacologic reperfusion remains the most common treatment for STEMI

Definitive evaluation of ENOX vs UFH needed

3

Primary HypothesisPrimary Hypothesis

Compared to UFH, adjunctive antithrombin therapy with ENOX reduces the composite end point of all-cause mortality or non-fatal re-MI within 30 days in patients with STEMI who are eligible to receive fibrinolytic therapy.

4

Trial OrganizationTrial Organization

TIMI Study GroupTIMI Study GroupEugene BraunwaldEugene Braunwald Elliott M. AntmanElliott M. AntmanDavid A. Morrow David A. Morrow Carolyn H. McCabe Carolyn H. McCabeSabina Murphy Sabina Murphy Susan McHale Susan McHale

Sponsor: sanofi-aventis Sponsor: sanofi-aventis Frank JiangFrank Jiang Christophe GaudinChristophe GaudinPaul ChewPaul Chew Sylvie FontecaveSylvie FontecaveLu CuiLu Cui Kim GiordanoKim Giordano

Data Safety Monitoring BoardData Safety Monitoring BoardFrans Van de Werf (Chair) Frans Van de Werf (Chair) David DeMets David DeMets Desmond Julian Desmond Julian Jean Rouleau Jean Rouleau J. Ward Kennedy J. Ward Kennedy Jeffrey AndersonJeffrey Anderson

5

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

6

Enrollment: Enrollment: Oct 2002 - Oct 2005Oct 2002 - Oct 2005N = 20,479 (ITT)N = 20,479 (ITT)

48 Countries48 Countries 674 Sites674 Sites

ArgentinaArgentina FinlandFinland LatviaLatvia SingaporeSingapore

AustraliaAustralia FranceFrance LebanonLebanon SlovakiaSlovakia

AustriaAustria GermanyGermany LithuaniaLithuania South AfricaSouth Africa

BelarusBelarus GreeceGreece MalaysiaMalaysia SpainSpain

BelgiumBelgium Hong KongHong Kong MexicoMexico SwedenSweden

BrazilBrazil HungaryHungary NetherlandsNetherlands SwitzerlandSwitzerland

BulgariaBulgaria IndiaIndia New ZealandNew Zealand ThailandThailand

CanadaCanada IrelandIreland NorwayNorway TurkeyTurkey

ChileChile Israel Israel PolandPoland UkraineUkraine

ChinaChina ItalyItaly PortugalPortugal United KingdomUnited Kingdom

CroatiaCroatia JordanJordan RomaniaRomania United StatesUnited States

EstoniaEstonia Republic of Republic of KoreaKorea

Russian Russian FederationFederation

UruguayUruguay

7

Baseline CharacteristicsBaseline Characteristics ITT ITT N = 20,479N = 20,479

4444

1313

1515

4747

1818

4444

7777

5959

Prior MI (%)Prior MI (%)

Hypertension (%)Hypertension (%)

Hyperlipidemia (%)Hyperlipidemia (%)

Current smoker (%)Current smoker (%)

Diabetes (%)Diabetes (%)

Anterior MI (%)Anterior MI (%)

Male (%)Male (%)

Age (yrs)-medianAge (yrs)-median

ALL P = NSALL P = NS

3636

6464

8989

0.50.5

1616

8282

> 3 (%)> 3 (%)

LMWH within 7 d (%)LMWH within 7 d (%)

Killip Class I (%)Killip Class I (%)

TIMI Risk Score (STEMI)TIMI Risk Score (STEMI)

<< 3 (%) 3 (%)

UFH within 3 h (%)UFH within 3 h (%)

CrCl (ml/min)-medianCrCl (ml/min)-median

8

MedicationsMedications ITT ITT N = 20,479N = 20,479

808086869595

8080

2020

ACEI / ARB (%)ACEI / ARB (%)

Fibrin-specific (%)Fibrin-specific (%)

ASA (%)ASA (%)

Beta Blocker (%)Beta Blocker (%)

SK (%)SK (%)FibrinolyticFibrinolytic

7070Statin (%)Statin (%)

ALL P = NSALL P = NS

9

Primary End Point (ITT)Primary End Point (ITT)Death or Nonfatal MIDeath or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

ma

ry E

nd

Po

int

(%)

Pri

ma

ry E

nd

Po

int

(%)

ENOX

UFH

Relative RiskRelative Risk0.83 (0.77 to 0.90)0.83 (0.77 to 0.90)

P<0.0001P<0.0001

Days Days

9.9%

12.0%

Lost to follow up = 3 Lost to follow up = 3

17% RRR

10

Treatment Benefit over Time (ITT)Treatment Benefit over Time (ITT)Death or Nonfatal MIDeath or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

ma

ry E

nd

Po

int

(%)

Pri

ma

ry E

nd

Po

int

(%)

ENOX

UFH

Days Days

9.9%(1017)

12.0%(1223)

4.7%

5.2%

RRRR0.90 0.90

(0.80 to 1.01)(0.80 to 1.01)

P=0.08P=0.08

48 h48 h

UFH ENOX

206 events

11

Major Secondary End PointMajor Secondary End PointDeath or Nonfatal MI Death or Nonfatal MI

or Urgent Revascularization (ITT) or Urgent Revascularization (ITT)

Se

con

dar

y E

nd

Po

int

(%)

Se

con

dar

y E

nd

Po

int

(%)

Days Days

0

3

6

9

12

15

0 5 10 15 20 25 30

ENOX

UFH

11.7% (1199)

14.5% (1479)

5.3%

6.1%

RR 0.88 RR 0.88 (0.79 to 0.98)(0.79 to 0.98)

P=0.02P=0.02

48 h48 h

UFH ENOX

280 events

19% RRR

RR 0.81 RR 0.81 (0.75 to 0.87)(0.75 to 0.87)

P<0.0001P<0.0001

12% RRR

12

Outcomes at 30 Days (ITT)Outcomes at 30 Days (ITT)

7.5

4.5

2.8

6.9

3

2.1

0

1

2

3

4

5

6

7

8

Death Nonfatal MI Urg Revasc

RRRR

P valueP value

0.920.92

0.110.11

0.670.67

<0.0001<0.0001

0.740.74

0.00080.0008

%%

8%

33%

26%

UFHUFH

ENOXENOX

Death or Nonfatal MI - Day 30 Death or Nonfatal MI - Day 30 Major SubgroupsMajor Subgroups

> Median

< Median

Fibrin-specific

Streptokinase

Prior MI

No Prior MI

DM

No DM

Other

Anterior

0.5 1 2

PRIOR MI

OVERALLOVERALL

DIABETES

FIBRINOLYTIC

INFARCT

LOCATION

ENOX Better UFH BetterRelative Risk

TIME TO Rx

20,479

1123

1721

1720

1318

2312

17

Reduction In Risk (%)

>= 75

< 75AGE (y)

206

Female

MaleSEX 1816

All Interaction TestsAll Interaction TestsP = NSP = NS

P < 0.0001

14

Death or Nonfatal MI - Day 30Death or Nonfatal MI - Day 30Medical Rx vs Any PCIMedical Rx vs Any PCI

0.00040.00040.0010.001

%

% E

ven

tsE

ven

ts

0

5

10

15

PCI Medical Rx

ENOX

UFH

Medical Rx

N = 15,223 (75%) Any PCI

N = 4,676 (23%)

ENOX

UFH

P ValueP Value

9.7

RRR 16%

11.413.8

10.7

RRR 23%

15

Death or Nonfatal MI - Day 30Death or Nonfatal MI - Day 30Clopidogrel UseClopidogrel Use

0.00050.0005 0.00060.0006

%

% E

ven

tsE

ven

ts

0

5

10

15

No Clop Clop

ENOX

UFH

No Clopidogrel

N = 14,752 (78%) Clopidogrel Used*

N = 5,727 (28%)

ENOX

UFH

P ValueP Value

10.4

RRR15%

12.211.4

8.7

RRR24%

* 2546 clopidogrel treated * 2546 clopidogrel treated patients did not undergo PCIpatients did not undergo PCI

16

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

1.4 0.9 0.7

2.11.3 0.8

0

2

4

6

8

10 UFHUFHENOXENOX

%

% E

ven

tsE

ven

ts

Major BleedMajor Bleed(fatal + nonfatal)(fatal + nonfatal)

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

17

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

18

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)

++

19

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.

Publication of Primary ResultsPublication of Primary Results

Slides and Full Listing of Trial Participants at www.TIMI.orgSlides and Full Listing of Trial Participants at www.TIMI.org

www.NEJM.orgwww.NEJM.org

21

22

Trial Results In Perspective:Trial Results In Perspective: Major Bleeding Rates Major Bleeding Rates

5

2.5

1.40.9

3.3

2.11.3

0

2

4

6

8

10

% P

ts w

ith

Maj

or

Ble

ed%

Pts

wit

h M

ajo

r B

leed

KeeleyKeeleyLancet 2003Lancet 2003

EikelboomEikelboomCirc. 2005Circ. 2005

Major BleedMajor Bleed(Total)(Total)

Lytic ArmsLytic Arms

UFH UFH

LMWHLMWH UFH UFH

UFH UFH ENOX ENOX

UFH UFH ENOX ENOX

NonfatalNonfatal Major BleedMajor Bleed

Major Bleeds in Prior TrialsMajor Bleeds in Prior TrialsPooled DataPooled Data

23

Trial Results In Perspective:Trial Results In Perspective:PCI vs Lysis for STEMIPCI vs Lysis for STEMI

7

2.2

3.4

0

2

4

6

8

10

% E

ven

ts%

Eve

nts

(3

0-42

Da

ys)

(30-

42 D

ays

)

ReinfarctionReinfarction

Lytic Arms (UFH) PCI

ArmsENOX

Overview of 23 RCTs Overview of 23 RCTs Keeley Lancet 2003Keeley Lancet 2003

The significant advance in adjunctive therapy with enoxaparin has The significant advance in adjunctive therapy with enoxaparin has

narrowed the gap between PCI and Lysis as reperfusion for STEMI.narrowed the gap between PCI and Lysis as reperfusion for STEMI.