S TANFORD Tirofiban Given in the Emergency Room Before Primary Angioplasty (TIGER-PA) Pilot Study David P. Lee, MD, Alan C. Yeung, MD, Donald Schreiber,

STANFORD

Tirofiban Given in the Emergency Tirofiban Given in the Emergency Room Before Primary Angioplasty Room Before Primary Angioplasty

(TIGER-PA) (TIGER-PA) Pilot StudyPilot Study

David P. Lee, MD, Alan C. Yeung, MD,David P. Lee, MD, Alan C. Yeung, MD,

Donald Schreiber, MD, Michelle Huston, MDDonald Schreiber, MD, Michelle Huston, MD

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GP IIb/IIIa Inhibitors in Acute MIGP IIb/IIIa Inhibitors in Acute MI

• Key questions regarding new adjuvant Key questions regarding new adjuvant therapiestherapies

– Can we improve reperfusion times?Can we improve reperfusion times?

– Can we improve flow after reperfusion?Can we improve flow after reperfusion?

– Can we limit infarct size and thus Can we limit infarct size and thus complications?complications?

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GP IIb/IIIa Inhibitors in Acute MIGP IIb/IIIa Inhibitors in Acute MI

• Why a GP IIb/IIIa inhibitor could workWhy a GP IIb/IIIa inhibitor could work

– Early potent antiplatelet therapyEarly potent antiplatelet therapy

– Adjunctive use in PCI improves outcomesAdjunctive use in PCI improves outcomes

– May improve flowMay improve flow

– Relatively safe to useRelatively safe to use

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• N=483N=483• Abciximab in the ER or cath labAbciximab in the ER or cath lab

– 30-day MACE30-day MACE Any drug Any drug Int to treatInt to treat(n=409)(n=409) (n=483) (n=483)

ControlControl 12.012.0 11.211.2

AbciximabAbciximab 4.64.6 5.85.8PP value value 0.0050.005 0.0380.038

• 6-month MACE: no difference6-month MACE: no difference

RAPPORTRAPPORTReoPro in Acute myocardial infarction and ReoPro in Acute myocardial infarction and

Primary PTCA Organization Randomized TrialPrimary PTCA Organization Randomized Trial

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ADMIRALADMIRALAbciximab before Direct angioplasty and stenting Abciximab before Direct angioplasty and stenting

in Myocardial Infarction Regarding Acute and in Myocardial Infarction Regarding Acute and Long-term follow-upLong-term follow-upEventEvent *Abciximab*Abciximab PlaceboPlacebo

(n=150)(n=150) (n=150) (n=150) PP

Death, MI, urgent Death, MI, urgent TVR at 30 dTVR at 30 d 10.7%10.7% 20.0%20.0% 0.030.03

TIMI-3 initialTIMI-3 initial 21%21% 10%10%<0.01<0.01

24 h24 h 86%86% 78%78%<0.03<0.03

LVEFLVEF 24 h24 h 55%55% 51%51%

30 d30 d 63%63% 55%55%*26% received in ambulance or ER*26% received in ambulance or ER

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0%

10%

20%

30%

40%

50%

GRAPEGRAPEGlycoprotein Receptor Antagonist Glycoprotein Receptor Antagonist

Patency Evaluation Pilot (Patency Evaluation Pilot (N=60)N=60)

GRAPEGRAPE(n=60)(n=60)

45 min45 min

SPEEDSPEED(n=26)(n=26)

60 min60 min

TIMI-14ATIMI-14A(n=31)(n=31)

90 min90 min

All AbciximabAll Abciximab(n=117)(n=117)

GUSTO-IIbGUSTO-IIb(n=510)(n=510)

115 min115 minangio atangio at

PP < 0.0001 < 0.0001

18%23%

32%

23%

8%Pa

tie

nts

Wit

h T

IMI-

3 F

low

Pa

tie

nts

Wit

h T

IMI-

3 F

low

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TIGER-PATIGER-PAPilotPilot

• GoalsGoals

– To test the safety and efficacy of tirofiban in To test the safety and efficacy of tirofiban in the setting of an acute MIthe setting of an acute MI

– To compare early adjunctive use of tirofiban To compare early adjunctive use of tirofiban before primary PCI with peri-PCI usebefore primary PCI with peri-PCI use

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• TargetsTargets

– 100 patients planned100 patients planned

– 40% power to detect a 15% difference 40% power to detect a 15% difference in the TIMI frame count and flowin the TIMI frame count and flow

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• Inclusion criteriaInclusion criteria

– Chest pain within 12 hours of onsetChest pain within 12 hours of onset

– 1 mm ST-elevation in 2 or more 1 mm ST-elevation in 2 or more contiguous leads or new LBBBcontiguous leads or new LBBB

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• Exclusion criteriaExclusion criteria

– Age <18Age <18

– Major surgery, GI or GU bleed within 30 daysMajor surgery, GI or GU bleed within 30 days

– CVA within 1 year or with residual deficitCVA within 1 year or with residual deficit

– Known bleeding diathesisKnown bleeding diathesis

– Known intracranial diseaseKnown intracranial disease

– Cardiogenic shockCardiogenic shock

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• Exclusion criteria Exclusion criteria

– Uncontrolled HTN (SBP > 180, DBP > 100)Uncontrolled HTN (SBP > 180, DBP > 100)

– Prolonged CPRProlonged CPR

– Thrombolysis within 24 hoursThrombolysis within 24 hours

– Concomitant use of a GP IIb/IIIa inhibitorConcomitant use of a GP IIb/IIIa inhibitor

– Hemorrhagic retinopathyHemorrhagic retinopathy

– PLTs < 150KPLTs < 150K

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• Study designStudy design

– 1:1 open-label randomization to tirofiban in 1:1 open-label randomization to tirofiban in the ER (early) or in the cath lab (delayed)the ER (early) or in the cath lab (delayed)

– No PTCA in early arm if culprit lesion <50%No PTCA in early arm if culprit lesion <50%

– Delayed tirofiban if PTCA to be performedDelayed tirofiban if PTCA to be performed

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Final angiogramFinal angiogram

Acute myocardial infarctionAcute myocardial infarction

Meets inclusion criteriaMeets inclusion criteria

AngiogramAngiogram AngiogramAngiogram

Final angiogramFinal angiogram


Tirofiban in ERTirofiban in ER No tirofiban in ERNo tirofiban in ER

PTCA/stentPTCA/stent No PTCA if lesion No PTCA if lesion <50%<50%

No PTCANo PTCA Tirofiban if PTCA Tirofiban if PTCA to be performedto be performed

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• DosingDosing

– Tirofiban: 10 µg/kg over 3 minutes, Tirofiban: 10 µg/kg over 3 minutes, then 0.15 µg/kg/min x 24 hoursthen 0.15 µg/kg/min x 24 hours

– HeparinHeparin

• Early: 70 U/kg IV bolus, then 7.5 U/kg/hEarly: 70 U/kg IV bolus, then 7.5 U/kg/h

• Delayed: 100 U/kg IV bolus, then 10 U/kg/hDelayed: 100 U/kg IV bolus, then 10 U/kg/h

– All other medications including NTG, All other medications including NTG, -blockers at the investigator’s discretion-blockers at the investigator’s discretion

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• LaboratoriesLaboratories

BaselineBaseline 6 h6 h 12 h12 h 18 h18 h 24 h24 h

HbHb XX -- XX -- XX

HctHct XX -- XX -- XX

PLTPLT XX -- XX -- XX

CPKCPK XX XX XX XX XX

CPK-MBCPK-MB XX XX XX XX XX

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• EndpointsEndpoints– Primary endpoint Primary endpoint

• TIMI flowTIMI flow

• TIMI frame countsTIMI frame counts

– Secondary endpointSecondary endpoint• BleedingBleeding

– Minor: HctMinor: Hct10% or Hb10% or Hb3 g/dL3 g/dL

– Major: HctMajor: Hct15% or Hb15% or Hb5 g/dL5 g/dL

– Thrombocytopenia (PLTs< 90000)Thrombocytopenia (PLTs< 90000)

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• EndpointsEndpoints

– Tertiary endpoint (30 days)Tertiary endpoint (30 days)

• Repeat coronary revascularizationRepeat coronary revascularization

– Urgent vs nonurgentUrgent vs nonurgent

• Death (from any cause)Death (from any cause)

• New MI (CPK >2x normal)New MI (CPK >2x normal)

• Hospitalization for refractory ischemiaHospitalization for refractory ischemia

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• Adjuvant therapyAdjuvant therapy

– If a stent is placed, ticlopidine 250 mg po bid If a stent is placed, ticlopidine 250 mg po bid or clopidogrel 75 mg po qd x or clopidogrel 75 mg po qd x 14 d 14 d

– Heparin may be stopped temporarily for early Heparin may be stopped temporarily for early sheath removalsheath removal

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• Data analysisData analysis– Primary endpointPrimary endpoint

• Blinded observer for TIMI frame count and flow Blinded observer for TIMI frame count and flow at baseline and after PTCAat baseline and after PTCA

– Secondary endpointSecondary endpoint• Data monitoring for CBC and CPKsData monitoring for CBC and CPKs

• Safety monitor for bleeding eventsSafety monitor for bleeding events

– Tertiary endpointTertiary endpoint• Clinical follow-up by chart review and telephoneClinical follow-up by chart review and telephone

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• N=54 N=54 30 ER, 24 cath lab30 ER, 24 cath lab

• Patients to date Patients to date 54 (registry=83)54 (registry=83)

• Average age Average age 65 ± 13 years65 ± 13 years

• Male:female Male:female 7:27:2

• Anterior 22, lateral 7, inferior 25Anterior 22, lateral 7, inferior 25

• Mean time from ER to cath lab: 83 minutesMean time from ER to cath lab: 83 minutes

• Mean time for tirofiban to cath lab: 34 minutesMean time for tirofiban to cath lab: 34 minutes

INTERIMINTERIM

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Initial CTFCInitial CTFC

00

2020

4040

6060

00

11

22

33

ERER Cath LabCath Lab ERER Cath LabCath Lab

CT

FC

CT

FC T

GF

TG

F

* * PP=0.002=0.002

* * PP=0.01=0.01 Mean = 34 minMean = 34 min


TGFTGF

INTERIMINTERIM

STANFORD

Initial TGFInitial TGF

00

1010

2020

3030

ERER Cath LabCath Lab

TGFTGF4040

TIMI-0 or 1TIMI-0 or 1

TIMI-2TIMI-2

TIMI-3TIMI-3**

* * PP=0.002=0.002

# P

ati

en

ts#

Pa

tie

nts


INTERIMINTERIM

STANFORD

30-day MACE include 1 patient in each group admitted for 30-day MACE include 1 patient in each group admitted for chest pain and 1 patient who had SAT and repeat PCI at chest pain and 1 patient who had SAT and repeat PCI at

6 days in the cath lab group with no deaths.6 days in the cath lab group with no deaths.


• ComplicationsComplications

ERER Cath LabCath Lab

Minor bleedingMinor bleeding 44 22

Major bleedingMajor bleeding 11 11

30 d MACE30 d MACE 11 22

INTERIMINTERIM

STANFORD

• 10 patients in the Cath Lab group underwent measurements of platelet inhibition with the Accumetrics Ultegra RPFA while in the Cath Lab

•Time points: baseline, 20m, 40m, EOC

TIGER-PATIGER-PAPilot Pilot

Platelet SubstudyPlatelet SubstudyINTERIMINTERIM

STANFORD

% p

late

let i

nh

ibiti

on

0

20

40

60

80

100

Baseline Post Bolus 20 min 40 min EOC

TIGER-PATIGER-PAPilot Pilot

Platelet SubstudyPlatelet Substudy

STANFORD

TIGER-PATIGER-PA

• SummarySummary

– Pilot study to determine safety and efficacy of Pilot study to determine safety and efficacy of tirofiban given in the ER before primary PTCAtirofiban given in the ER before primary PTCA

– Tirofiban given early in the ER may lead to Tirofiban given early in the ER may lead to further improvement in TIMI flow and frame further improvement in TIMI flow and frame count compared with tirofiban given in the count compared with tirofiban given in the cath labcath lab

STANFORD

SummarySummary

• GP IIb/IIIa receptor inhibitors may be GP IIb/IIIa receptor inhibitors may be beneficial as an adjunct in acute MIbeneficial as an adjunct in acute MI

• Safe and well toleratedSafe and well tolerated

• Further large-scale trials are needed to Further large-scale trials are needed to better delineate a long-term benefitbetter delineate a long-term benefit

Documents

S TANFORD Tirofiban Given in the Emergency Room Before Primary Angioplasty (TIGER-PA) Pilot Study David P. Lee, MD, Alan C. Yeung, MD, Donald Schreiber,