AGIR2

Comparison of Pre-hospital or Cath lab Administration of High Dose Tirofiban

in Patients Undergoing Primary AngioplastyThe AGIR2 Study

Eric Bonnefoyon behalf of AGIR2 investigators

and RESCUe and RESURCOR networksHospices Civils de Lyon, France

RESURCORRESURCOR

AGIR2Background

In patients undergoing primary PCI,

GPIIbIIIa inhibitors improve angiographic and clinical outcomeEarly 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 outcomeThe 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

MICUPatient

call

STEMI undergoing primary PCI

600 mg clopidogrel250 mg aspirinUFH 60 U/kg + inf

Tirofiban25/0.15

Tirofiban25/0.15

AngiographyAngiography

Pre-hospital

MICUtransportation

Cath lab

Randomize Open Label

Medical Dispatcher

AGIR2

RESURCORRESURCOR

11 cath labs

17 MICU

20 miles

6 central triage centers (randomization)

Lyon

Annecy

Grenoble

Mont Blanc

Valence

AGIR2

The AGIR2 investigators

Amberieu Mann YAnnecy Savary DBelley Cognet / Florent OBourg-en-Bresse Serre PBourgoin Rodriguez JFCH Croix Rousse Guillaumee F.CH Ed. Herriot Capel O. / Dubien PYCH Lyon sud Fuster P. / David JS.Drôme Nord Genevey P. / Cheval BGrenoble Debaty GMontelimar Busseuil C. / Pajot FPrivas Wahiche MTarare Brilland RValence Echahed KVienne Matas O. / Bec JFVillefranche Guillemard T. / Boyer MVoiron Escallier C

RESCUe Network -Coordinator : ElKhoury C RESURCOR Network -Coordinator : Belle L

MICU

SAMU 01 Maupoint R.SAMU 07 Wahiche M.SAMU 26 Echahed K.SAMU 38 Debaty G.SAMU 69 Dubien PY.SAMU 74 Savary D.

Central Triage

CathLab

HCL L. Pradel Rioufol G.HCL Cx Rousse Besnard C.St Joseph-St Luc Perret T.Clin. Tonkin Champagnac D.Inf. Protestante Claudel JP.Clin. Sauvegarde Hepp A.Valence Chapon PCH Annecy Belle L.CHU Grenoble Vanzetto G.Clin. Belledonne Guenot C.Clin. Mutualiste Bourlard P.

AGIR2 Coordination

Coordination : Bonnefoy E, Elkhoury C, Eydoux N, A Peiretti,Statistical analysis : Mercier C, Bisery A, Ecochard RHCL : Plattner V

AGIR2Study design

ClinicalTrials.gov Identifier: NCT00538317

Sponsor: University Hospital of Lyon (HCL), FranceMulticenter, randomized, open label comparisonStatistical analysis: Intention to treat – Biostatistic Unit -HCLData management: clinical research center - LyonData analysis: ECGs, biological and procedural reports but not coronary angiograms, centrally collected and analyzedMerck & Co Inc and Iroko Laboratories supplied tirofiban free of charge to sponsor

AGIR2

Enrollment CriteriaInclusion 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 endpointTIMI grade 2-3 flow at initial angiographyKey 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 characteristicsCath lab tirofiban

N=156

Pre-hospital tirofiban

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 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

AGIR2Time intervals and angiography

Pre-hospitalTirofiban

98

10461*

21

26 *

Times are expressed as median (min)

Cath lab Tirofiban 54

48

83

85

MICU Cath lab

* P<0.05

ANGIO

AGIR2TIMI grade 2-3 flow

first angiography

Pre-hospital tirofiban

39.7%44.2%P=0.42

Cath lab tirofiban

AGIR2

Initial TIMI grade flow

Cath lab tirofibanN=156

Pre-hospital tirofibanN=163 p

TIMI 3 30.8% 32.5%0.52TIMI 2 9.0% 11.7%

TIMI 0-1 60.3% 55.8%Final TIMI grade flow

TIMI 3 91.7% 93.3%0.98TIMI 2 6.4% 3.7%

TIMI 0-1 1.9% 3.0%

AGIR2ST segment resolution >70%

Cath lab tirofiban

N=148

Pre-hospital tirofiban

N=152

55.4% 52.6%P=0.64

Cath lab tirofiban

N=127

Pre-hospital tirofiban

N=112

8.7% 15.2%P=0.10

On admission to Cath lab

One hour after PCI

AGIR2

0%

50%

100%

Cath lab tirofiban

Pre-hospitaltirofiban

<30%30-70%>70%

55.4 52.6

35.1 32.2

9.5 15.1P=0.32

24.3 24.3

39.9 30.3

22.320.4

13.5 25

P=0.07

>6 mm4-6 mm1-3 mm0 mm

Cath lab tirofiban

Pre-hospitaltirofiban

ST segment resolution60 minutes

Residual ST segment 60 minutes

AGIR2

Troponins and CK

Cath lab tirofibanN=152

Pre-hospital tirofibanN=163

p

CK max - UI 1860+1568 2220+2202 0.10CK 24 hrs - UI 1047+907 1057+928 0.90

Troponin I max ng/ml 41.8+68.7 57.9+132.0 0.18Troponin I 24 hrs ng/ml 23.6+34.3 30.6+87.3 0.26

AGIR2

3.2

1.31.9

0.6

5.5

3.7

0.61.2

0

1

2

3

4

5

6

Death Severe Bleeding Acute stentthrombosis

Stroke

Cath lab tirofiban Pre-Hospital tirofiban% p=0.15

p=0.15

p=0.29p=0.26

In-hospital events

AGIR2

39.7

65.7

3948.651.2

56.6

37.3

50

010203040506070

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

Cath lab tirofiban Pre-Hospital tirofiban

Influence of time from onset of symptoms to first medical contact

< 100 min >median

P=0.24 P=0.25 P=0.83 P=0.87

%

P=0.26 P=0.39

ST 60 min >70%

AGIR2Influence of treatment period tirofiban to angiography

p=0.35

p=0.11

33.0

63.8

46.0 49.345.5

54.3

0

10

20

30

40

50

60

70

TIMI 2-3 flow ST 60 min >70%

<10'10'-45'>45'

%

(terciles)

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

AGIR2Clinical implication

• 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