(TITAN)-TIMI 34

TITAN

TTime to ime to IIntegrilin ntegrilin TTherapy in herapy in AAcute cute

myocardial infarctiomyocardial infarctioNN (TITAN)-TIMI 34(TITAN)-TIMI 34

TITAN-TIMI 34: Goal

To answer the following question:To answer the following question:Among patients intended to undergo Among patients intended to undergo primary PCI, does a strategy of early primary PCI, does a strategy of early initiation of eptifibatide in the ER prior initiation of eptifibatide in the ER prior to primary PCI yield superior pre-PCI to primary PCI yield superior pre-PCI angiographic outcomes compared to a angiographic outcomes compared to a strategy of initiating eptifibatide in the strategy of initiating eptifibatide in the cardiac catheterization laboratory after cardiac catheterization laboratory after diagnostic angiography?diagnostic angiography?

© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

TITAN-TIMI 34: Trial OrganizationTIMI Study GroupTIMI Study Group Eugene Braunwald, M.D. (Chairman)Eugene Braunwald, M.D. (Chairman)Brigham and Women’sBrigham and Women’s C. Michael Gibson, M.S., M.D. (Principal Investigator) C. Michael Gibson, M.S., M.D. (Principal Investigator) HospitalHospital Carolyn McCabe, B.S. (Director)Carolyn McCabe, B.S. (Director)

Ajay Kirtane, M.D. (Co-Investigator)Ajay Kirtane, M.D. (Co-Investigator)Christopher P. Cannon, M.D. (Co-Investigator)Christopher P. Cannon, M.D. (Co-Investigator)Polly Fish, B.S. (Project Manager)Polly Fish, B.S. (Project Manager)

Data Coordinating Center Data Coordinating Center TIMI Data Coordinating CenterTIMI Data Coordinating CenterSabina A. Murphy, M.P.H. (Director Biostatistics)Sabina A. Murphy, M.P.H. (Director Biostatistics)Jacqueline L. Buros, B.A. (Director Data Management)Jacqueline L. Buros, B.A. (Director Data Management)

Angiographic Core LabAngiographic Core Lab TIMI Angiographic Core LabTIMI Angiographic Core LabAjay Kirtane, M.D. (Principal Investigator)Ajay Kirtane, M.D. (Principal Investigator)Lauren N. Ciaglo, B.A.Lauren N. Ciaglo, B.A.

EKG Core LabEKG Core Lab TIMI EKG Core LabTIMI EKG Core LabBenjamin Scirica, M.D. (Director)Benjamin Scirica, M.D. (Director)


Primary PCIPrimary PCI

STEMI < 6 HRS Undergoing Primary PCI (n=343)STEMI < 6 HRS Undergoing Primary PCI (n=343)TITAN TIMI 34: Study DesignTITAN TIMI 34: Study Design

RANDOMIZERANDOMIZEOpen LabelOpen Label

ASA 160-325 mg po ASA 160-325 mg po HEPARIN 60 U/kg bolus (Max 4000U) and 7U/kg HEPARIN 60 U/kg bolus (Max 4000U) and 7U/kg

infusion (Max 800 U/hr)infusion (Max 800 U/hr)

““EARLY ER EPTIFIBATIDE”EARLY ER EPTIFIBATIDE” ““CATH LAB EPTIFIBATIDE”CATH LAB EPTIFIBATIDE”EPTIFIBATIDE 180/2.0/180EPTIFIBATIDE 180/2.0/180

TRANSFER TO CATH LABTRANSFER TO CATH LAB

DIAGNOSTIC ANGIODIAGNOSTIC ANGIO

PRIMARY ENDPOINT: Pre PCI TIMI Frame CountPRIMARY ENDPOINT: Pre PCI TIMI Frame Count

EPTIFIBATIDE 180/2.0/180EPTIFIBATIDE 180/2.0/180

TRANSFER TO CATH LABTRANSFER TO CATH LAB

DIAGNOSTIC ANGIODIAGNOSTIC ANGIO


TITAN-TIMI 34: Enrollment Criteria

Inclusion Criteria:• > 18 years of age• Clinical diagnosis of AMI ( ischemic pain > 20 min. )• Onset of symptoms < 6 hours• ST elevation > 1 mm in 2 contiguous limb leads or >2 mm in

2 contiguous precordial leads

Major Exclusion Criteria:• Hemorrhagic risk factors• Current episode previously treated by fibrinolytics• Cardiogenic shock or hemodynamically significant

arrhythmias


LAD

Frame 1: Dye Touches Both

Borders & Moves

Forward

Frame 0: Dye Touches One or No Borders

Last Frame Definition

Frame 21: Dye first

enters

landmark

First Frame Definition

RCA

LCX

DistalLandmark

Normal Flow in the Absence of MI :

21.0 + 3.1 frames

1st branch off posterolateral

Last branch offmost distal OM

“Whale’s tail” or “pitchfork”or most distalbranch LAD atapex

Gibson, Circulation 1996; 93: 879-888

TITAN: Primary Endpoint Corrected TIMI Frame Count


0

1

2

3

4

5

6

7

8

6.2%

4.4%

2.0%n = 203 n = 46 n = 434

TMP Grade 3

p = 0.05

Mor

talit

y (%

)

n = 79

5.1%

Gibson et al, Circulation 2000

Normal ground glassappearance of blushDye mildly persistent

at end of washout

Dye strongly persistentat end of washout

Gone by next injection

Stain presentBlush persists

on next injection

No or minimal blush

TMP Grade 2 TMP Grade 1 TMP Grade 0

TITAN Other Angiographic Efficacy Endpoint: TITAN Other Angiographic Efficacy Endpoint: TIMI Myocardial Perfusion (TMP) GradesTIMI Myocardial Perfusion (TMP) Grades


TITAN-TIMI 34: Angiographic Perfusion ScoreTITAN-TIMI 34: Angiographic Perfusion Score

• Integrates epicardial and myocardial perfusionIntegrates epicardial and myocardial perfusion• Integrates flow before and after PCIIntegrates flow before and after PCI• Sum of the following:Sum of the following:

TIMI Flow Grade Before PCI (0-3)TIMI Flow Grade Before PCI (0-3)TIMI Myocardial Perfusion Grade Before PCI (0-3)TIMI Myocardial Perfusion Grade Before PCI (0-3)TIMI Flow Grade After PCI (0-3)TIMI Flow Grade After PCI (0-3)TIMI Myocardial Perfusion Grade After PCI (0-3)TIMI Myocardial Perfusion Grade After PCI (0-3)

Total Angiographic Perfusion Score: 0 - 12

Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.

Failed 0-3; Partial 4-9; Failed 0-3; Partial 4-9; Full 10-12Full 10-12


Relationship of Angiographic Perfusion Score Relationship of Angiographic Perfusion Score to SPECT Infarct Size & Mortalityto SPECT Infarct Size & Mortality


0

5

10

15

20

25

30

35

40

Failed Partial Full

% S

PEC

T In

farc

t Siz

e

Angiographic Perfusion Score

35.5%

16.2%12.5%

p=0.002

0

5

10

Failed Partial Full

11.1%

1.9%

0.0%

p=0.01

% D

eath

by

30 d

ays

Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.

Global Perfusion Score MethodologyGlobal Perfusion Score Methodology

Flow Grade: □ 0 □ 1 □ 2 □ 3Flow Grade: □ 0 □ 1 □ 2 □ 3

Blush Grade: □ 0 □ 1 □ 2 □ 3Blush Grade: □ 0 □ 1 □ 2 □ 3





Total Potential Score: 54 points© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

TITAN-TIMI 34: Top 10 Enrolling Sites

Site NameSite Name Principal Principal InvestigatorInvestigator

Research Research CoordinatorCoordinator EnrollmentEnrollment

11 Mount Clemens General HospitalMount Clemens General Hospital Samer KazzihaSamer Kazziha Rebecca Rebecca RichmondRichmond 3737

22 Carolina Cardiology Associates, PACarolina Cardiology Associates, PA Steve RohrbeckSteve Rohrbeck Tammy HedrickTammy Hedrick 3232

33 University of North CarolinaUniversity of North Carolina Mauricio CohenMauricio Cohen Kim WoodKim Wood 3131

44 Northridge HospitalNorthridge Hospital Ivan RokosIvan Rokos Kanchana Kanchana KarunaratneKarunaratne 3030

55 Tri-State Medical Group, CardiologyTri-State Medical Group, Cardiology Jeffrey LinsJeffrey Lins Gretchen Gretchen KalenakKalenak 2727

66 Genesis Medical CenterGenesis Medical Center Nicolas ShammasNicolas Shammas Caroline SloaneCaroline Sloane 2020

77 St. Joseph's Regional Medical St. Joseph's Regional Medical CenterCenter Mahesh BikkinaMahesh Bikkina Karen TurnbullKaren Turnbull 1616

88 University Of CincinnatiUniversity Of Cincinnati Saeb KhourySaeb Khoury Cindy WernerCindy Werner 1515

99 Brigham and Women's HospitalBrigham and Women's Hospital Daniel SimonDaniel Simon Rachel Rachel MonbouquetteMonbouquette 1414

1010 Genesis Healthcare SystemGenesis Healthcare System Abdulhay AlbiriniAbdulhay Albirini Terri CampbellTerri Campbell 1414


TITAN-TIMI 34: Top 11-20 Enrolling Sites

Site NameSite Name Principal Principal InvestigatorInvestigator

Research Research CoordinatorCoordinator EnrollmentEnrollment

1111 Trinity Medical CenterTrinity Medical Center Aswartha PothulaAswartha Pothula Cynthia AntonioCynthia Antonio 1111

1212 Vanderbilt University Medical Vanderbilt University Medical CenterCenter David ZhaoDavid Zhao Dawn MyersDawn Myers 1010

1313 Cardiology Associates of Cardiology Associates of MississippiMississippi Barry BertoletBarry Bertolet Kelly GlennKelly Glenn 1010

1414 MedCentral MansfieldMedCentral Mansfield Greg EatonGreg Eaton Kathy JurdenKathy Jurden 99

1515 University Hospitals of ClevelandUniversity Hospitals of Cleveland Tom LassarTom Lassar Stacey MazzurcoStacey Mazzurco 99

1616 Decatur Memorial HospitalDecatur Memorial Hospital Peter KatsiyiannisPeter Katsiyiannis Rebecka SongerRebecka Songer 77

1717 West Chester CardiologyWest Chester Cardiology Mian JanMian Jan Cindy BrockwayCindy Brockway 77

1818 Seattle Cardiovascular ResearchSeattle Cardiovascular Research Thomas AmidonThomas Amidon Lynn RoyalLynn Royal 66

1919 Veterans Affairs Medical Center Veterans Affairs Medical Center (111C2)(111C2) Saeb KhourySaeb Khoury Jackie EdwardsJackie Edwards 55

2020 Northeast Cardiology AssociatesNortheast Cardiology Associates Peter Ver LeePeter Ver Lee Cindy WhitedCindy Whited 55


TITAN-TIMI 34: Baseline Characteristics


CharacteristicCharacteristic ER EptifibatideER Eptifibatiden=174n=174

Cath Lab Cath Lab EptifibatideEptifibatide

n=142n=142P valueP value

Age (yrsAge (yrs++SD)SD) 59.1 +/- 13.1 yrs59.1 +/- 13.1 yrs 60.1 +/- 12.6 yrs60.1 +/- 12.6 yrs NSNSMaleMale 74.7%74.7% 73.2%73.2% NSNSHypertensionHypertension 42.2%42.2% 40.9%40.9% NSNSHyperlipidemiaHyperlipidemia 32.2%32.2% 31.2%31.2% NSNSCurrent smokerCurrent smoker 49.4%49.4% 40.1%40.1% NSNSDiabetesDiabetes 15.5%15.5% 18.3%18.3% NSNS

Prior MIPrior MI 14.9%14.9% 10.6%10.6% NSNS

Anterior MIAnterior MI 35.2%35.2% 39.6%39.6% NSNS

0%

20%

40%

0 50 100

% P

atie

nts

with

CTF

C <

X ax

isTITAN-TIMI 34 Primary Endpoint:

Pre-PCI TIMI Frame Count


p < 0.05p < 0.05

p=0.046 adjusting for infarct locationp=0.046 adjusting for infarct location

Primary Analysis: Modified Intent-to-TreatPrimary Analysis: Modified Intent-to-Treat

Frame CountFrame Count

EREREptifibatideEptifibatide


0

10

20

30

40

50

60

70

80

90

100

CTF

CTF

CC

p < 0.05p < 0.05 84.3 84.3 ++ 30.7 30.7 (n=137)(n=137)

77.5 77.5 ++ 32.2 32.2 (n=168)(n=168)




0

5

10

15

20

25

30

Pre

- PC

I TM

PG 3

(%)

Pre

- PC

I TM

PG 3

(%)



24.3%24.3%

14.2%14.2%

p = 0.026p = 0.026

(41/169)(41/169) (20/141)(20/141)



TITAN-TIMI 34: Secondary Angiographic Endpoint TIMI Flow Grades

0

5

10

15

20

25

30

35

40

45

50

Pre

- PC

I TIM

I 2 o

r 3 F

low

(%)

Pre

- PC

I TIM

I 2 o

r 3 F

low

(%)



46.2%46.2%

36.6%36.6%

(79/171)(79/171) (52/142)(52/142)

TIMI 2 or 3TIMI 2 or 3p = 0.087p = 0.087

24%19%p=NSp=NS

TIMI 3TIMI 3

TITAN-TIMI 34: Pre-PCI Flow Throughout Heart



4238

0

10

20

30

40

50



Global Perfusion Global Perfusion ScoreScore

n=125n=125 n=99n=99

p = 0.008p = 0.00855.8

52.1

0

10

20

30

40

50

60

70p = 0.03



Global Frame Count Global Frame Count (Ave. 3 Arteries)(Ave. 3 Arteries)


0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

Pre

- PC

I MLD

(mm

)Pr

e - P

CI M

LD (m

m)



0.330.33

0.210.21

p = 0.026p = 0.026

(n=169)(n=169) (n=138)(n=138)80

82

84

86

88

90

92

Pre

- PC

I % S

teno

sis

Pre

- PC

I % S

teno

sis



87.5%87.5%

91.0%91.0%p = 0.048p = 0.048

(n=169)(n=169) (n=139)(n=139)


TITAN-TIMI 34 Pre-PCI Quantitative Angiography


0

5

10

15

20

25

Post

- PC

I CTF

CPo

st -

PCI C

TFC



20202222

p = 0.14p = 0.14

0

20

40

60

80

100

Post

- PC

I TIM

I 3 F

low

(%)

Post

- PC

I TIM

I 3 F

low

(%)



86.7%86.7% 89.1%89.1%

p = NSp = NS

0

5

10

15

20

25

30

35

40

Post

- PC

I TM

PG 3

(%)

Post

- PC

I TM

PG 3

(%)



37.0%37.0% 36.7%36.7%

p = NSp = NS

(47/128)(47/128)(57/154)(57/154)(n=138)(n=138) (n=116)(n=116) (137/158)(137/158) (122/137)(122/137)


TITAN-TIMI 34 Post-PCI Flow

TITAN-TIMI 34: Full Angiographic Perfusion


0

5

10

15

20

25

Full

Ang

iogr

aphi

c Fu

ll A

ngio

grap

hic

Perf

usio

n (A

PS 1

0-12

) %

Perf

usio

n (A

PS 1

0-12

) %



21.1%21.1%

12.5%12.5%

p = 0.059p = 0.059

(32/152)(32/152) (16/128)(16/128)


Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.

TITAN-TIMI 34: Treated as Intended in Protocol Analysis


ER Group: ER Group: Drug at least 15 minutes before 1Drug at least 15 minutes before 1stst

injection on angioinjection on angio (n=127)(n=127)

Cath Lab Cath Lab Group:Group:

Drug after 1Drug after 1stst injection on injection on angio (n=114)angio (n=114)

First Injection on Angio = Time 0First Injection on Angio = Time 0

0%

25%

50%

75%

100%

-60 -50 -40 -30 -20 -10 0 10 20

% P

atie

nts

with

Tim

e fr

om

Bol

us to

Cat

h <X

axi

s

0%

20%

40%

0 50 100

% P

atie

nts

with

CTF

C <

X ax

is


p = 0.021p = 0.021


Secondary Analysis: Treated per ProtocolSecondary Analysis: Treated per Protocol

TITAN-TIMI 34 Primary Endpoint:Pre-PCI TIMI Frame Count



Frame CountFrame Count

0

10

20

30

40

50

60

70

80

90

100

75.3 75.3 ++ 32.1 32.1(n=124)(n=124)

84.4 84.4 ++ 30.7 30.7(n=109)(n=109)

CTF

C

p = 0.021p = 0.021



60

80

100

FFAASSTTEERR

FFLLOOWW

TITAN-TIMI 34: Duration of Therapy and Pre-PCI TIMI Frame Count

n=165n=165 n=111n=111 n=17n=17

Mea

n TI

MI F

ram

e C

ount

Mea

n TI

MI F

ram

e C

ount

Duration of Therapy Before First InjectionDuration of Therapy Before First Injection

p = 0.003 for linear trendp = 0.003 for linear trend

In cath lab to In cath lab to 15 min prior15 min prior

15 min to 6015 min to 60min. priormin. prior

> 60 min. > 60 min. priorprior

85.685.6

76.676.6

68.668.6

Earlier TreatmentEarlier Treatment© © TIMI 2005. Duplication prohibited by lawTIMI 2005. Duplication prohibited by law

TITAN-TIMI 34: Pre-PCI TIMI Grade 2 or 3 Flow and Full Perfusion


0%

10%

20%

30%

40%

50%

Pre

- PC

I TIM

I 2 o

r 3 F

low

(%)

Pre

- PC

I TIM

I 2 o

r 3 F

low

(%)



46.8%46.8%

34.2%34.2%

(59/126)(59/126) (39/114)(39/114)

p = 0.047p = 0.047

Secondary Analysis: Treated per ProtocolSecondary Analysis: Treated per Protocol

0%

10%

20%

30%

Full

Ang

iogr

aphi

c Pe

rfus

ion

(%)

Full

Ang

iogr

aphi

c Pe

rfus

ion

(%)



23.9%23.9%

13.2%13.2%

p = 0.041p = 0.041

Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.

(28/117)(28/117) (14/106)(14/106)


2.32.1

0

1

2

3

Dea

th (%

)D

eath

(%)



DeathDeathp = NSp = NS

2.9

7.1

0

2

4

6

8

CH

F (%

)C

HF

(%)



n=173n=173 n=142n=142


TITAN-TIMI 34 Clinical Endpoints at Discharge/Day 5

CHFCHFp = 0.082p = 0.082

n=173n=173 n=142n=142


OutcomeOutcomeER ER

Eptifibatide Eptifibatide (n=174)(n=174)

Cath Lab Cath Lab Eptifibatide Eptifibatide

(n=142)(n=142)P-valueP-value

TIMI Major TIMI Major (Hgb (Hgb >5 g/dL or ICH) >5 g/dL or ICH) 1.7%1.7% 3.5%3.5% NSNS

TIMI Minor TIMI Minor (Hgb (Hgb 3-5 g/dL) 3-5 g/dL) 5.2%5.2% 4.2%4.2% NSNS

TIMI Major or MinorTIMI Major or Minor 6.9%6.9% 7.8%7.8% NSNS

Transfusion PRBCTransfusion PRBC 9.8%9.8% 7.0%7.0% NSNS

Stroke or ICHStroke or ICH 0.0%0.0% 0.0%0.0% NSNS

Thrombocytopenia (Plt. < 100K)Thrombocytopenia (Plt. < 100K) 2.3%2.3% 1.4%1.4% NSNS

TITAN-TIMI 34: Bleeding EventsTITAN-TIMI 34: Bleeding EventsNon CABG Through Discharge; Site AssessmentNon CABG Through Discharge; Site Assessment


TITAN-TIMI 34: Conclusions


A strategy of early initiation of A strategy of early initiation of eptifibatide in the emergency room eptifibatide in the emergency room prior to primary PCI for ST segment prior to primary PCI for ST segment elevation MI yields superior pre-PCI elevation MI yields superior pre-PCI TIMI frame counts (epicardial flow) and TIMI frame counts (epicardial flow) and superior TIMI myocardial perfusion superior TIMI myocardial perfusion compared to a strategy of initiating compared to a strategy of initiating eptifibatide in the cardiac eptifibatide in the cardiac catheterization laboratorycatheterization laboratory

TITAN-TIMI 34: Clinical Implications


Among patients who are to undergo Among patients who are to undergo primary PCI for STEMI, GP IIbIIIa primary PCI for STEMI, GP IIbIIIa inhibition should be initiated as soon inhibition should be initiated as soon as possible prior to cardiac as possible prior to cardiac catheterization.catheterization.

(TITAN)-TIMI 34

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