AGIR 2 Presenter Disclosure Information Eric Bonnefoy The following relationships exist related to this presentation: Research grantsMerck & Co, Iroko LabImportant (provided tirofiban free of charge for the AGIR2 study) Speakers honorariaEli LillyModest

AGIR 2 Comparison of Pre-hospital or Cath lab Administration of High Dose Tirofiban in Patients Undergoing Primary Angioplasty The AGIR 2 Study Eric Bonnefoy on behalf of AGIR 2 investigators and RESCUe and RESURCOR networks Hospices Civils de Lyon, France RESURCOR

AGIR 2 Background In patients undergoing primary PCI, GPIIbIIIa inhibitors improve angiographic and clinical outcome Early administration of GPIIbIIIa inhibitors improved pre-procedural epicardial flow On top of a high loading dose of clopidogrel, early high- dose tirofiban improved ST segment resolution and clinical outcome The extent of the benefit of pre-hospital tirofiban as compared with cath lab tirofiban on top of a high loading dose of clopidogrel is unknown

AGIR 2 Rationale If widely applied, pre-hospital initiation of GPIIbIIIa inhibitors would require a huge transfer of financial burden to emergency units increase the complexity of pre-hospital protocols in patients with acute ST segment elevation coronary syndrome (STEMI) Such a consequence would be particularly true in large emergency medicine-cardiology networks

AGIR 2 MICU Patient call STEMI undergoing primary PCI 600 mg clopidogrel 250 mg aspirin UFH 60 U/kg + inf Tirofiban 25/0.15 Angiography Pre-hospital MICU transportation Cath lab Randomize Open Label Medical Dispatcher

AGIR 2 RESURCOR 11 cath labs 17 MICU 20 miles 6 central triage centers (randomization) Lyon Annecy Grenoble Mont Blanc Valence

AGIR 2 The AGIR 2 investigators AmberieuMann Y AnnecySavary D BelleyCognet / Florent O Bourg-en-BresseSerre P BourgoinRodriguez JF CH Croix RousseGuillaumee F. CH Ed. HerriotCapel O. / Dubien PY CH Lyon sudFuster P. / David JS. Drôme NordGenevey P. / Cheval B GrenobleDebaty G MontelimarBusseuil C. / Pajot F PrivasWahiche M TarareBrilland R ValenceEchahed K VienneMatas O. / Bec JF VillefrancheGuillemard T. / Boyer M VoironEscallier C RESCUe Network - Coordinator : ElKhoury C RESURCOR Network - Coordinator : Belle L MICU SAMU 01Maupoint R. SAMU 07Wahiche M. SAMU 26Echahed K. SAMU 38Debaty G. SAMU 69Dubien PY. SAMU 74Savary D. Central Triage CathLab HCL L. PradelRioufol G. HCL Cx RousseBesnard C. St Joseph-St LucPerret T. Clin. TonkinChampagnac D. Inf. ProtestanteClaudel JP. Clin. SauvegardeHepp A. ValenceChapon P CH AnnecyBelle L. CHU GrenobleVanzetto G. Clin. BelledonneGuenot C. Clin. MutualisteBourlard P. AGIR2 Coordination Coordination : Bonnefoy E, Elkhoury C, Eydoux N, A Peiretti, Statistical analysis : Mercier C, Bisery A, Ecochard R HCL : Plattner V

AGIR 2 Study design ClinicalTrials.gov Identifier: NCT Sponsor: University Hospital of Lyon (HCL), France Multicenter, randomized, open label comparison Statistical analysis: Intention to treat – Biostatistic Unit - HCL Data management: clinical research center - Lyon Data analysis: ECGs, biological and procedural reports but not coronary angiograms, centrally collected and analyzed Merck & Co Inc and Iroko Laboratories supplied tirofiban free of charge to sponsor

AGIR 2 Enrollment Criteria Inclusion Criteria > 18 years Ischemic pain > 20 min and onset of symptoms < 12 hours ST elevation > 1 mm in 2 contiguous limb leads or >2 mm in 2 contiguous precordial leads Planned primary PCI Informed consent Major Exclusion Criteria High bleeding risk Fibrinolytics or GPIIbIIIa inhibitor < 7 days Transfer to cath lab > 90 min

AGIR 2 End Points Primary endpoint TIMI grade 2-3 flow at initial angiography Key secondary endpoints Complete (>70%) ST segment resolution one hour after procedure Troponin I and CK peaks

AGIR 2 Sample size calculation Initial sample size: 300 patients with alpha risk 5% and 80% power to detect a 16% difference in primary endpoint Patients wrongly randomized or who withdrew their informed consent before angiography were excluded from all analyses With regard to drop-outs, recruitment was increased to 337 patients, to have at least 155 patients in each group

AGIR 2 Baseline characteristics Cath lab tirofiban N=156 Pre-hospital tirofiban N=164 p Age Male 79.5%75% 0.34 Diabetes 10.9%11.0% 0.98 Anterior AMI 43.6%51.2% 0.17 Killip class >2 8.3%11.6% 0.33 Onset < 6hrs 90.4%86.0% 0.61 Previous PCI 14.7%7.9% 0.05

AGIR 2 Angiographic procedures Cath lab tirofiban N=156 Pre-hospital tirofiban N=163 p Thrombus aspiration 32.7%40.8% 0.13 Bare metal stent 72.4%69.1% 0.52 Drug eluting stent 8.3%8.5% 0.92

AGIR 2 Time intervals and angiography Pre-hospital Tirofiban * * Times are expressed as median (min) Cath lab Tirofiban MICUCath lab * P<0.05 ANGIO

AGIR 2 TIMI grade 2-3 flow first angiography Pre-hospital tirofiban 39.7% 44.2% P=0.42 Cath lab tirofiban

AGIR 2 Initial TIMI grade flow Cath lab tirofiban N=156 Pre-hospital tirofiban N=163 p TIMI %32.5% 0.52 TIMI 2 9.0%11.7% TIMI %55.8% Final TIMI grade flow TIMI %93.3% 0.98 TIMI 2 6.4%3.7% TIMI %3.0%

AGIR 2 ST segment resolution >70% Cath lab tirofiban N=148 Pre-hospital tirofiban N= % 52.6% P=0.64 Cath lab tirofiban N=127 Pre-hospital tirofiban N= % 15.2% P=0.10 On admission to Cath lab One hour after PCI

AGIR 2 0% 50% 100% Cath lab tirofiban Pre-hospital tirofiban <30% 30-70% >70% P= P=0.07 >6 mm 4-6 mm 1-3 mm 0 mm Cath lab tirofiban Pre-hospital tirofiban ST segment resolution 60 minutes Residual ST segment 60 minutes

AGIR 2 Troponins and CK Cath lab tirofiban N=152 Pre-hospital tirofiban N=163 p CK max - UI CK 24 hrs - UI Troponin I max ng/ml Troponin I 24 hrs ng/ml

AGIR DeathSevere BleedingAcute stent thrombosis Stroke Cath lab tirofibanPre-Hospital tirofiban % p=0.15 p=0.29 p=0.26 In-hospital events

AGIR TIMI 2-3 ST 60 min >70% TIMI 2-3 Cath lab tirofibanPre-Hospital tirofiban Influence of time from onset of symptoms to first medical contact median P=0.24P=0.25P=0.83P=0.87 % P=0.26 P=0.39 ST 60 min >70%

AGIR 2 Influence of treatment period tirofiban to angiography p=0.35 p= TIMI 2-3 flowST 60 min >70% <10' 10'-45' >45' % (terciles)

AGIR 2 Conclusion Early initiation of tirofiban in pre-hospital settings, prior to primary PCI and on top of a loading dose of clopidogrel, does not yield superior TIMI grade 2-3 flow in the culprit artery compared to initiation of tirofiban in the cardiac catheterization laboratory No beneficial effects on post-PCI angiography, ST-segment resolution or peak troponin levels were found

AGIR 2 Clinical implication The AGIR 2 study did not question benefits of upfront administration of GPIIbIIIa inhibitors in primary PCI Its results do not support the necessity to initiate tirofiban administration in pre- hospital settings