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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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
• 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
TIGER-PATIGER-PAPilotPilot
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
TIGER-PATIGER-PAPilotPilot
CharacteristicCharacteristic EarlyEarly LateLate pp
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
TIGER-PATIGER-PAPilotPilot
CharacteristicCharacteristic EarlyEarly LateLate pp
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
TIGER-PATIGER-PAPilotPilot
CharacteristicCharacteristic EarlyEarly LateLate pp
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%
TIGER-PATIGER-PAPilotPilot
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
TIGER-PATIGER-PAPilotPilot
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%
TIGER-PATIGER-PAPilotPilot
STANFORD
TIGER-PATIGER-PAPilotPilot
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
TIGER-PATIGER-PAPilotPilot
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
TIGER-PATIGER-PAPilotPilot
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
TIGER-PATIGER-PAPilotPilot