S TANFORD Tirofiban Given in the Emergency Room Before Primary Angioplasty (TIGER-PA) Pilot Study...

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

STANFORD

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?

STANFORD

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

STANFORD

• 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

STANFORD

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

STANFORD

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

STANFORD

Improved TIMI-grade Flow Improved TIMI-grade Flow with Early IIb/IIIa in Acute MIwith Early IIb/IIIa in Acute MI

0

5

10

15

20

25

30

35

GRAPE ADMIRAL TIMI-14

IIB/IIIAPlacebo

% w

ith

TIM

I-3

flow

N 60 300 888

STANFORD

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

STANFORD


• TargetsTargets

– 100 patients100 patients

– 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

STANFORD


• 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

STANFORD


• 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

STANFORD


• 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

STANFORD


• 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

STANFORD

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

STANFORD


• 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

STANFORD


• 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

STANFORD


• 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)

STANFORD


• 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

STANFORD


• 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

STANFORD


• Data analysisData analysis– Primary endpointPrimary endpoint

• Blinded observers for TIMI frame count, Blinded observers for TIMI frame count, myocardial perfusion and flow myocardial perfusion 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

STANFORD


• N=100 N=100 50 ER, 50 cath lab50 ER, 50 cath lab

• Patients screenedPatients screened 157157– Declined enrollmentDeclined enrollment 32 32

– Shock/IABPShock/IABP 9 9

– Signif comorbitiesSignif comorbities 14 14

– Recent IIb/IIIaRecent IIb/IIIa 2 2

Demographics

STANFORD


CharacteristicCharacteristic EarlyEarly LateLate pp

Age (y)Age (y) 63.5 63.5 12.612.6

66.4 66.4 14.3 14.3 NSNS

Gender (%male)Gender (%male) 6060 6464 NSNS

%Diabetes%Diabetes 2424 2424 NSNS

%HTN%HTN 3636 4040 NSNS

%Hyperlipidemia%Hyperlipidemia 3232 3232 NSNS

%Prev CAD%Prev CAD 1212 1010 NSNS

Demographics

STANFORD



CP duration (h)CP duration (h) 3.0 3.0 2.0 2.0 3.0 3.0 1.8 1.8 NSNS

Door-to-tirofiban (min)Door-to-tirofiban (min) 55.7 55.7 18.0 18.0 81.8 81.8 17.7 17.7 <0.001<0.001

Door-to-balloon (min)Door-to-balloon (min) 88.9 88.9 20.7 20.7 82.7 82.7 20.0 20.0 NSNS

Demographics

33 minute mean from drug-to-balloon

STANFORD



Culprit Vessel (%)Culprit Vessel (%)

LADLAD 4040 3636 NSNS

LCXLCX 2020 2020 NSNS

RCARCA 4040 4444 NSNS

Initial TGF (%)Initial TGF (%)

33 3232 1010 0.0070.007

22 1414 88

11 1010 22

00 4444 8080

Angiographic Outcomes

STANFORD



Initial CTFCInitial CTFC 44 44 20 20 66 + 2366 + 23 0.0050.005

% Initial TMPG-3% Initial TMPG-3 3232 66 0.0010.001

% Final TGF-3% Final TGF-3 9292 9292 NSNS

Final CTFCFinal CTFC 18 18 8 8 16 16 8 8 NSNS

% % Final TMPG-3Final TMPG-3 5050 4040 NSNS

Angiographic Outcomes

STANFORD

Initial TIMI-Grade FlowInitial TIMI-Grade Flow

00

1010

2020

3030

EarlyEarly LateLate

4040

TIMI-0 or 1TIMI-0 or 1TIMI-2TIMI-2TIMI-3TIMI-3

* * P P < 0.007< 0.007#

Pa

tie

nts

# P

ati

en

ts

32%

5050

14%

8%

10%


STANFORD

Initial CTFCInitial CTFC

00

2020

4040

6060

EarlyEarly LateLate

CT

FC

CT

FC

8080 * * P P = 0.005= 0.005

44

20 66

23


STANFORD

Initial TIMI-Myocardial Perfusion GradeInitial TIMI-Myocardial Perfusion Grade

00

1010

2020

3030

EarlyEarly LateLate

4040

TMPG-0 or 1TMPG-0 or 1

TMPG-2TMPG-2

TMPG-3TMPG-3

* * P P < 0.001< 0.001

# P

ati

en

ts#

Pa

tie

nts

32%5050

16%

12%

6%


STANFORD


Clinical Outcomes

EarlyEarly LateLate ppPeak CPKPeak CPK 1924 1924

169916992260 2260 1959 1959 NSNS

Time-to-peakTime-to-peak 10.0 10.0 7.1 7.1 11.1 11.1 6.5 6.5 NSNS

30-d Composite30-d Composite 6%6% 10%10% NSNS

DeathDeath 2%2% 2%2% NSNS

Re-MIRe-MI 00 2%2% NSNS

RehospRehosp 4%4% 6%6% NSNS

Urgent TVRUrgent TVR 0%0% 2%2% NSNS

STANFORD


ERER Cath LabCath Lab p p

*Minor bleeding*Minor bleeding 10%10% 6%6% NSNS

*Major bleeding*Major bleeding 2%2% 2%2% NSNS

TransfusionsTransfusions 10%10% 8%8% NSNS

PLT < 100KPLT < 100K 4%4% 0%0% NSNS

Clinical Outcomes

* TIMI-defined

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 Substudy

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

• 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, frame further improvement in TIMI flow, frame count, and blush when compared with count, and blush when compared with tirofiban given in the cath labtirofiban given in the cath lab

– Earlier reperfusion may translate into better Earlier reperfusion may translate into better clinical outcomesclinical outcomes


STANFORD

SummarySummary• GP IIb/IIIa receptor inhibitors may be GP IIb/IIIa receptor inhibitors may be

beneficial as an adjunct in acute MI with beneficial as an adjunct in acute MI with primary angioplastyprimary angioplasty

• 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


S TANFORD Tirofiban Given in the Emergency Room Before Primary Angioplasty (TIGER-PA) Pilot Study...

Documents

Transcript of S TANFORD Tirofiban Given in the Emergency Room Before Primary Angioplasty (TIGER-PA) Pilot Study...