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									                                                                         AGIR2
                   Presenter Disclosure
                       Information
Eric Bonnefoy
       The following relationships exist related to this presentation:

Research grants           Merck & Co, Iroko Lab        Important
            (provided tirofiban free of charge for the AGIR2 study)
Speakers honoraria         Eli Lilly                    Modest
                                                  AGIR2
   Comparison of Pre-hospital or Cath lab
   Administration of High Dose Tirofiban
in Patients Undergoing Primary Angioplasty
             The AGIR2 Study

                  Eric Bonnefoy
          on behalf of AGIR2 investigators
       and RESCUe and RESURCOR networks
           Hospices Civils de Lyon, France

                                       RESURCOR
                  Background                            AGIR2

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
                                                   AGIR2
                  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
                                                                AGIR2
                               STEMI undergoing primary PCI
Patient                             600 mg clopidogrel
 call             MICU              250 mg aspirin
                                    UFH 60 U/kg + inf
                                        Randomize               Medical
                                        Open Label             Dispatcher
 Pre-hospital
                   Tirofiban
                     25/0.15


    MICU
transportation

   Cath lab                                    Tirofiban
                                                     25/0.15


                 Angiography                 Angiography
                                                                AGIR2
RESURCOR

                                                       Annecy


                                        Lyon       Mont Blanc
   11 cath labs
   17 MICU
   6 central triage centers
   (randomization)                             Grenoble
                              Valence




 20 miles
                                                                                      AGIR2
              The AGIR2 investigators
RESCUe Network -                       MICU
Coordinator : ElKhoury C
RESURCOR Network -                    Amberieu              Mann Y
Coordinator : Belle L                 Annecy                Savary D
                                      Belley                Cognet / Florent O
 Central Triage                       Bourg-en-Bresse       Serre P
SAMU 01            Maupoint R.        Bourgoin              Rodriguez JF
SAMU 07            Wahiche M.         CH Croix Rousse       Guillaumee F.
SAMU 26            Echahed K.         CH Ed. Herriot        Capel O. / Dubien PY
SAMU 38            Debaty G.          CH Lyon sud           Fuster P. / David JS.
SAMU 69            Dubien PY.         Drôme Nord            Genevey P. / Cheval B
SAMU 74            Savary D.          Grenoble              Debaty G
                                      Montelimar            Busseuil C. / Pajot F
 CathLab
                                      Privas                Wahiche M
HCL L. Pradel         Rioufol G.      Tarare                Brilland R
HCL Cx Rousse         Besnard C.      Valence               Echahed K
St Joseph-St Luc      Perret T.       Vienne                Matas O. / Bec JF
Clin. Tonkin          Champagnac D.   Villefranche          Guillemard T. / Boyer M
Inf. Protestante      Claudel JP.     Voiron                Escallier C
Clin. Sauvegarde      Hepp A.
Valence               Chapon P         AGIR2 Coordination
CH Annecy             Belle L.        Coordination : Bonnefoy E, Elkhoury C, Eydoux N, A Peiretti,
CHU Grenoble          Vanzetto G.
                                      Statistical analysis : Mercier C, Bisery A, Ecochard R
Clin. Belledonne      Guenot C.
Clin. Mutualiste      Bourlard P.     HCL : Plattner V
                                                             AGIR2
                   Study design
            ClinicalTrials.gov Identifier: NCT00538317


   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
                                                               AGIR2
                     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
                                             AGIR2
                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
                                               AGIR2
     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
                                             AGIR2
  Baseline characteristics
                  Cath lab    Pre-hospital
                  tirofiban     tirofiban
                    N=156        N=164        p
      Age         62.5+12.5    64.1+13.6     0.25
      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
                                              AGIR2
 Angiographic procedures


                      Cath lab Pre-hospital
                      tirofiban  tirofiban
                       N=156       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
      Time intervals and angiography                                AGIR2

                                            MICU        Cath lab



                                                             83

             Cath lab                 98
             Tirofiban                             54

                                                            26 *
                                                    48             ANGIO
                                                              21
           Pre-hospital
                                                   61*
            Tirofiban                 104
Times are expressed as median (min)
                                                             85
* P<0.05
                                AGIR2
TIMI grade 2-3 flow
 first angiography
            P=0.42
                     44.2%
    39.7%




    Cath lab     Pre-hospital
    tirofiban      tirofiban
                                                AGIR2

                         Cath lab Pre-hospital
                         tirofiban  tirofiban
Initial TIMI grade flow N=156         N=163     p
                  TIMI 3 30.8%        32.5%
                  TIMI 2    9.0%      11.7%    0.52
                TIMI 0-1 60.3%        55.8%
Final TIMI grade flow
                TIMI 3 91.7%         93.3%
                TIMI 2   6.4%         3.7%     0.98
              TIMI 0-1   1.9%         3.0%
ST segment resolution >70% AGIR2

                              One hour after PCI
                                        P=0.64
                              55.4%          52.6%
      On admission
      to Cath lab
             P=0.10
                 15.2%
    8.7%

   Cath lab Pre-hospital      Cath lab Pre-hospital
   tirofiban tirofiban        tirofiban tirofiban
     N=127            N=112     N=148            N=152
                                                                         AGIR2
       ST segment resolution               Residual ST segment
            60 minutes                          60 minutes
                  P=0.32                              P=0.07
100%
            9.5            15.1                13.5
                                                               25

           35.1                                22.3                   >6 mm
                           32.2                            20.4
                                  <30%                                4-6 mm
50%                                                                   1-3 mm
                                  30-70%       39.9        30.3
                                  >70%                                0 mm
           55.4            52.6
                                               24.3        24.3
 0%
          Cath lab Pre-hospital               Cath lab Pre-hospital
          tirofiban  tirofiban                tirofiban  tirofiban
                                            AGIR2
         Troponins and CK

                         Cath lab Pre-hospital
                         tirofiban  tirofiban  p
                           N=152      N=163
     CK max - UI        1860+1568 2220+2202 0.10
    CK 24 hrs - UI       1047+907 1057+928 0.90
 Troponin I max ng/ml 41.8+68.7 57.9+132.0 0.18
Troponin I 24 hrs ng/ml 23.6+34.3 30.6+87.3 0.26
                                                                       AGIR2
             In-hospital events

                Cath lab tirofiban   Pre-Hospital tirofiban
%   p=0.15
6         5.5
5
                    p=0.15
4                          3.7
    3.2                                   p=0.29
3
                                         1.9
                                                              p=0.26
2                    1.3                                             1.2
1                                              0.6             0.6

0
     Death       Severe Bleeding       Acute stent              Stroke
                                       thrombosis
                     Influence of time                                          AGIR2
                from onset of symptoms
                 to first medical contact
%                    Cath lab tirofiban        Pre-Hospital tirofiban
                                        < 100 min >
70                        65.7            median

60                               56.6
            51.2                                                         48.6 50
50
     39.7                                             39 37.3
40
30
20     P=0.24                P=0.25                    P=0.83               P=0.87

10
0
     TIMI 2-3        ST 60 min >70%                   TIMI 2-3          ST 60 min >70%

            P=0.26                                                 P=0.39
        Influence of treatment period AGIR2
            tirofiban to angiography


%                                      p=0.35
70                              63.8
                  p=0.11
60                                              54.3
                                        49.3
50                 46.0 45.5

40
                                                        <10'
           33.0
                                                        10'-45'
30                                                      >45'
                                                       (terciles)
20
10
    0
           TIMI 2-3 flow       ST 60 min >70%
                                                AGIR2
                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
        Clinical implication             AGIR2



• The AGIR2 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

								
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