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PCI in Patients Receiving Enoxaparin PCI in Patients Receiving Enoxaparin or UFH Following Fibrinolytic Therapy or UFH Following Fibrinolytic Therapy

for STEMI:for STEMI:PCI ExTRACT-TIMI 25PCI ExTRACT-TIMI 25

C. Michael Gibson, Sabina A. Murphy, David A. Morrow, C. Michael Gibson, Sabina A. Murphy, David A. Morrow, Carolyn H. McCabe, Dietrich C. Gulba, Gilles Montalescot, Servet Cetin, Carolyn H. McCabe, Dietrich C. Gulba, Gilles Montalescot, Servet Cetin,

Oscar H. Kracoff, Basil S. Lewis, Nathan Roguin, Elliott M. Antman,Oscar H. Kracoff, Basil S. Lewis, Nathan Roguin, Elliott M. Antman,Eugene Braunwald, for the ExTRACT-TIMI 25 InvestigatorsEugene Braunwald, for the ExTRACT-TIMI 25 Investigators

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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

Integrated 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 MedicalThe National Institutes of HealthThe National Institutes of Health

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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Background: Main Results Background: Main Results ExTRACT-TIMI 25ExTRACT-TIMI 25

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

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

12.0

9.9

UFH UFH

ENOX ENOX

14.5

11.7

Days Days

%% RR = 0.83p = 0.000003

RR = 0.81p = 0.000001

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ObjectiveObjective

To determine whether ENOX is To determine whether ENOX is superior to UFH as adjunctive superior to UFH as adjunctive therapy for patients undergoing PCI therapy for patients undergoing PCI for STEMI who initially received for STEMI who initially received fibrinolytic therapy.fibrinolytic therapy.

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10,256 Assigned ENOX10,256 Assigned ENOX

20,479 Patients Randomized into 20,479 Patients Randomized into ExTRACT-TIMI 25ExTRACT-TIMI 25

2,272 Underwent2,272 Underwent

PCI by 30 daysPCI by 30 days

22.8%22.8%

10,223 Assigned UFH10,223 Assigned UFH

2,404 Underwent2,404 Underwent

PCI by 30 daysPCI by 30 days

24.2%24.2%

Study ProfileStudy Profile

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Anticoagulation for PCIAnticoagulation for PCI

< 8h since SC dose < 8h since SC dose >> 8 h since SC dose 8 h since SC dose

Additional Enox/PlacAdditional Enox/Plac NO NO 0.3 mg/kg IV 0.3 mg/kg IV

Additional UFH/PlacAdditional UFH/PlacGP IIb/IIIaGP IIb/IIIa ACT 200 s* ACT 200 s* ACT 200 s* ACT 200 s*No GP IIb/IIIaNo GP IIb/IIIa ACT 250 s* ACT 250 s* ACT 250 s* ACT 250 s* * *ACT TESTING ONLY BY UNBLINDED MEDICAL PROFESSIONALACT TESTING ONLY BY UNBLINDED MEDICAL PROFESSIONAL

Sheath RemovalSheath RemovalClosure DeviceClosure Device End of PCIEnd of PCI

No Closure Device No Closure Device Wait 6 hours after last sc/IV dose Wait 6 hours after last sc/IV dose

After PCIAfter PCI STUDY MEDICATION SHOULD NOT BE STUDY MEDICATION SHOULD NOT BE + Groin Hemostasis + Groin Hemostasis STARTED UNLESS CLINICALLY INDICATED STARTED UNLESS CLINICALLY INDICATED

ONLY blinded study drug to be usedONLY blinded study drug to be usedAll Pts receive BOTH blinded Enox/Plac AND UFH/PlacAll Pts receive BOTH blinded Enox/Plac AND UFH/Plac

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Baseline CharacteristicsBaseline Characteristics PCI Cohort PCI Cohort N = 4,676N = 4,676

4141

1111

1616

5151

2323

3737

8282

5757

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 = NS for ENOX vs UFHALL P = NS for ENOX vs UFH

2727

9292

0.70.7

2020

8787

> 3 (%)> 3 (%)

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

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

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

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

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

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Medications During HospitalizationMedications During Hospitalization

PCI Cohort PCI Cohort N = 4,676N = 4,676

808086869898

7979

2121

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

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

ASA (%)ASA (%)

Beta Blocker (%)Beta Blocker (%)

SK (%)SK (%)FibrinolyticFibrinolytic

8585Statin (%)Statin (%)6868Clopidogrel (%)Clopidogrel (%)

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PCI Cohort: Primary EndpointPCI Cohort: Primary EndpointDeath or Nonfatal MI by 30 daysDeath or Nonfatal MI by 30 days

ENOX

DaysDays

13.8%

0055

1010

1515

00 55 1010 1515 2020 2525 3030

De

ath

or

MI (

%)

De

ath

or

MI (

%)

UFH

10.7%

RR 0.77RR 0.77p=0.001p=0.001

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PCI Cohort: SafetyPCI Cohort: Safety

Event ENOX UFH RR P-Value n=2,238 n=2,377

TIMI Major Bleed 1.4% 1.6% 0.87 (0.55-1.39) 0.56

TIMI Minor Bleed 3.3% 2.4% 1.34 (0.95-1.88) 0.09

TIMI Major or 4.6% 4.0% 1.15 (0.88-1.51) 0.31 Minor Bleed

ICH 0.2% 0.4% 0.42 (0.13-1.35) 0.18

Stroke 0.3% 0.9% 0.30 (0.12-0.75) 0.006

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PCI Cohort: Death or Nonfatal reMI - Major Subgroups

PCI Cohort: Death or Nonfatal reMI - Major Subgroups

ENOX Better Odds Ratio

UFH Better

0.25 0.5 0.75 1 1.25 1.5

SubgroupNo hx diabetesHx diabetes

Non-anterior MIAnterior MI

Sx onset to Lytic <=medianSx onset to Lytic >median

SKFibrin specific

Time to PCI >=5 daysTime to PCI 2-<5 daysTime to PCI <48 hrs

No GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor

No ClopidogrelClopidogrel

Enox (%) UFH (%)10.3 13.212.5 17.3

9.4 13.412.3 14.5

10.3 15.111.5 11.8

10.2 11.710.9 14.3

7.8 9.28 13.9

20.8 23.2

9.5 12.317.1 20.2

12.4 139.8 14.2

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PCI Cohort:Nonfatal Recurrent MI by 30 days

PCI Cohort:Nonfatal Recurrent MI by 30 days

UFH

ENOX

05

1015

0 5 10 15 20 25 30

No

n-F

ata

l MI (

%)

7.8%

10.9%

Days

RR 0.72RR 0.72

p<0.001p<0.001

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Incidence and Relative Timing of PCI

Incidence and Relative Timing of PCI

ENOX

UFH

Days

22.8%

24.2%

05

1015

2025

0 5 10 15 20 25 30

PC

I (%

)

p=0.027

Median time to PCI:UFH (n=2,404): 109 hoursEnox (n=2,272): 122 hours

Incidence of PCI:

p=0.006

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n=1885

Relative Timing of PCI: Relative Timing of PCI: Urgent vs Non-Urgent PCIUrgent vs Non-Urgent PCI

109.0

67.0

120.0122.0

79.0

126.0

0

20

40

60

80

100

120

140

UFHUFHENOXENOX

Ho

urs

Ho

urs

All PCIAll PCI

p=0.006p=0.006 p=0.31p=0.31

Urgent PCIUrgent PCI Non- Urgent PCINon- Urgent PCI

n=1,885 n=1,829n=278 n=442

p=0.08p=0.08

n=2,404 n=2,272

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Outcomes by 30 Days in Patients Outcomes by 30 Days in Patients Undergoing PCI on Blinded Study DrugUndergoing PCI on Blinded Study Drug

16.7

2.4

13.0

1.8

0

5

10

15

20

UFH UFH (n=1,075)(n=1,075)

ENOX ENOX (n=1,103)(n=1,103)

%

% E

ven

tsE

ven

ts

Death or Nonfatal reMIDeath or Nonfatal reMI Major Bleed Major Bleed

RR 0.77RR 0.77P=0.002P=0.002

RR 0.75RR 0.75P=0.33P=0.33

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PCI Performed on Blinded PCI Performed on Blinded Study DrugStudy Drug

Two scenarios in which a patient underwent PCI on study drug:

1) Blinded study drug never discontinued and PCI performed on blinded study drug

2) Blinded study drug discontinued prior to PCI and then resumed at time of PCI

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05

10

15

20

0 5 10 15 20 25 30Days

UFH

ENOX14.2%

18.9%

De

ath

or

MI (

%)

De

ath

or

MI (

%)

Death or Nonfatal MI by 30 days Among PCI Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Patients in Whom Study Drug Was

NotNot Discontinued Discontinued (n=1501)(n=1501)

RRRR 0.750.75

p=0.018p=0.018

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Death or Nonfatal MI by 30 days Among PCI Death or Nonfatal MI by 30 days Among PCI Patients in Whom Study Drug Was Patients in Whom Study Drug Was

Discontinued and Resumed For PCI Discontinued and Resumed For PCI (n=677)(n=677)0

51

01

52

0

0 5 10 15 20 25 30Days

UFH

ENOX5.9%

14.4%

De

ath

or

MI (

%)

De

ath

or

MI (

%)

RR 0.41RR 0.41p=0.004p=0.004

ConclusionConclusion

• When compared to When compared to UFHUFH as adjunctive as adjunctive therapy among patients undergoing PCI, therapy among patients undergoing PCI, ENOX:ENOX:

• Reduced death or MIReduced death or MI

• Reduced strokeReduced stroke

• No difference in bleedingNo difference in bleeding

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• ENOX was associated with ↓ risk of death or reMI both among patients in whom antithrombin was continued as well as discontinued prior to PCI.

• ENOX associated with both delayed ENOX associated with both delayed onset and ↓ occurrence of reMI, both of onset and ↓ occurrence of reMI, both of which may expand window of which may expand window of opportunity to perform PCI following opportunity to perform PCI following fibrinolytic administration.fibrinolytic administration.

Conclusion (cont.)Conclusion (cont.)

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Clinical ImplicationsClinical Implications

• Among STEMI pts treated with lytic, Among STEMI pts treated with lytic, ENOX can be administered as the sole ENOX can be administered as the sole antithrombin therapy before and antithrombin therapy before and during PCI without the need for during PCI without the need for additional antithrombin inhibition.additional antithrombin inhibition.

• Periprocedural ENOX is preferable to Periprocedural ENOX is preferable to UFH in the management of these UFH in the management of these patients.patients.

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Back Up SlidesBack Up Slides

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Death at 30 days by PCI and randomization group

05

1015

0 5 10 15 20 25 30Days

ENOX/PCI ENOX/no PCIUFH/PCI UFH/no PCI

p=0.07 for ENOX vs UFH in no PCI cohort

p=0.93 for ENOX vs UFH in PCI cohort

De

ath

(%

)D

ea

th (

%)