FATA

FATA

FATA

TRIAL

FFacilitated AAngioplasty with TTirofiban or AAbciximab

Francesco SaiaFrancesco SaiaOn behalf of the FATA InvestigatorsOn behalf of the FATA Investigators

Washington DC, October 14th 2008

Principal InvestigatorsPrincipal Investigators

FATAFATATRIAL

Study organizationStudy organization

A. Marzocchi, A. Manari, G. Piovaccari A. Marzocchi, A. Manari, G. Piovaccari

Clinical ManagementClinical Management C. Marrozzini, F. SaiaC. Marrozzini, F. Saia

ECG Core LabECG Core Lab N. Taglieri, V. OviN. Taglieri, V. Ovi

Angiographic Core LabAngiographic Core Lab N. Taglieri, S. Silenzi, S. VirzìN. Taglieri, S. Silenzi, S. Virzì

Statistical AnalysisStatistical Analysis M.L. Bacchi-Reggiani, P. Guastaroba, E.BonizzoniM.L. Bacchi-Reggiani, P. Guastaroba, E.Bonizzoni

Data monitoringData monitoring B. Petri, A. Schembari B. Petri, A. Schembari

SponsorSponsor Spontaneous study suppoted from the Fondazione Fanti-Melloni, a charitable institution linked to the University of Bologna, and with a research grant by Merck & Co. Inc. (the company had no role in the study design, analysis and interpretation of the data)

Spontaneous study suppoted from the Fondazione Fanti-Melloni, a charitable institution linked to the University of Bologna, and with a research grant by Merck & Co. Inc. (the company had no role in the study design, analysis and interpretation of the data)

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Participating centres and Investigators

U. O. di Cardiologia, Ospedale Molinette, Torino

S. Marra, F. Conrotto, P. Scacciatella

U. O. di Cardiologia, Ospedale Molinette, Torino

S. Marra, F. Conrotto, P. Scacciatella

U. O. di Cardiologia Interventistica, Ospedale S. Maria Nuova, Reggio Emilia

A. Manari, V. Guiducci, P. Giacometti, G.Pignatelli, U. Guiducci

U. O. di Cardiologia, Ospedale di Baggiovara, ModenaS. Tondi, P. Magnavacchi, G. Tosoni, G.R. Zennaro

U. O. di Cardiologia Interventistica, Ospedale S. Maria Nuova, Reggio Emilia

A. Manari, V. Guiducci, P. Giacometti, G.Pignatelli, U. Guiducci

U. O. di Cardiologia, Ospedale di Baggiovara, ModenaS. Tondi, P. Magnavacchi, G. Tosoni, G.R. Zennaro

Istituto di Cardiologia, Policlinico S. Orsola, Bologna A. Marzocchi, C. Marrozzini, P. Ortolani, T. Palmerini, F. Saia, N. Taglieri

Istituto di Cardiologia, Policlinico S. Orsola, Bologna A. Marzocchi, C. Marrozzini, P. Ortolani, T. Palmerini, F. Saia, N. Taglieri

U. O. di Cardiologia, Ospedale Maggiore, BolognaP. Sangiorgio, G. Casella, A. Rubboli, G. Nobile, G.Di Pasquale

U. O. di Cardiologia, Ospedale Maggiore, BolognaP. Sangiorgio, G. Casella, A. Rubboli, G. Nobile, G.Di Pasquale

Servizio di Cardiologia Invasiva, Ospedale di PesaroG. Binetti, L. Uguccioni, L. Marinucci

Servizio di Cardiologia Invasiva, Ospedale di PesaroG. Binetti, L. Uguccioni, L. Marinucci

U. O. di Cardiologia, Ospedale degli Infermi, RiminiG. Piovaccari, A. Santarelli, N. Franco, D.Santoro, S. Carigi

U. O. di Cardiologia, Ospedale degli Infermi, RiminiG. Piovaccari, A. Santarelli, N. Franco, D.Santoro, S. Carigi

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BackgroundBackground

• Abciximab,Abciximab, a monoclonal antibody fragment Gp a monoclonal antibody fragment Gp

IIb/IIIa inhibitor, has been shown to ameliorate IIb/IIIa inhibitor, has been shown to ameliorate

myocardial perfusion and left ventricular recovery myocardial perfusion and left ventricular recovery

after pPCI, thus improving both early and late clinical after pPCI, thus improving both early and late clinical

outcomeoutcome• TirofibanTirofiban, a small-molecule Gp IIb/IIIa inhibitor, when , a small-molecule Gp IIb/IIIa inhibitor, when

administered with a administered with a high-dose (25 µg/Kg) bolushigh-dose (25 µg/Kg) bolus, can , can

achieve > 90% platelet aggregation inhibition 10 achieve > 90% platelet aggregation inhibition 10

minutes after infusion, which is comparable or even minutes after infusion, which is comparable or even

better than what can be obtained with the standard better than what can be obtained with the standard

dose of abciximabdose of abciximab• At current market prices, treatment with HDB At current market prices, treatment with HDB

tirofiban would cost around one third of treatment tirofiban would cost around one third of treatment

with abciximabwith abciximab

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To demonstrate the To demonstrate the equivalenceequivalence between between

High Dose Bolus (HDB) TirofibanHigh Dose Bolus (HDB) Tirofiban and and

Abciximab Abciximab as adjunctive therapy in as adjunctive therapy in

patients with ST-Elevation acute patients with ST-Elevation acute

Myocardial Infarction (STEMI) undergoing Myocardial Infarction (STEMI) undergoing

primary PCI (pPCI) in terms of effective primary PCI (pPCI) in terms of effective

myocardial reperfusionmyocardial reperfusion

Scope of the studyScope of the study

Primary Endpoint:Primary Endpoint: Rate of complete ST-segment resolution (STR) Rate of complete ST-segment resolution (STR) 90 minutes after first balloon inflation 90 minutes after first balloon inflation Abciximab vs TirofibanAbciximab vs Tirofiban

AbcixmabBolus 0.25 mg/kg, followed by 12h

infusion of 0.125 µg/kg/min

Tirofiban HDBBolus 25 µg/kg, followed by 18h

infusion of 0.15 µg/kg/min

STEMI < 6 hours660 patients > 18 years with STEMI <6h undergoing primary PCI (no LBBB)

RANDOMIZATION 1:1

ASA 250 mg i.v. and UFH 70 IU/kg

PRIMARY PCI

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Study design Study design Spontaneous, randomized, multicenter, controlled, open-label trial

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• Age>18 yearsAge>18 years

• Chest pain persisting more than 20 minutes Chest pain persisting more than 20 minutes

associated with ST-segment elevation of at associated with ST-segment elevation of at

least 0.1 mV in two or more contiguous ECG least 0.1 mV in two or more contiguous ECG

leadsleads

• Admission Admission within 6 hourswithin 6 hours from symptoms from symptoms

onsetonset

• Release of written informed consent. Release of written informed consent.

Inclusion criteriaInclusion criteria

All the following criteria had to be met:

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• Complete left bundle branch blockComplete left bundle branch block

• Previous myocardial infarction in the Previous myocardial infarction in the

same territorysame territory

• Bleeding diathesisBleeding diathesis

• Administration of fibrinolytic agents for Administration of fibrinolytic agents for

the current episodethe current episode

• Post-anoxic comaPost-anoxic coma

• Known thrombocytopenia or leucopeniaKnown thrombocytopenia or leucopenia

• Severe hepatic dysfunctionSevere hepatic dysfunction

• Severe renal failure (serum creatinine > Severe renal failure (serum creatinine >

3 mg/dl)3 mg/dl)

• Contraindication to aspirin, Contraindication to aspirin,

thienopyridines, or heparinthienopyridines, or heparin

Exclusion criteriaExclusion criteria

• Limited life expectancy (< 1 year)Limited life expectancy (< 1 year)

• Childbearing potentialChildbearing potential

• Recent major surgery (within 3 Recent major surgery (within 3

months)months)

• Uncontrolled hypertensionUncontrolled hypertension

• History of stroke within the previous History of stroke within the previous

30 days30 days

• History of intracranial disease History of intracranial disease

(aneurysm, arterovenous (aneurysm, arterovenous

malformation)malformation)

• Major trauma within the previous six Major trauma within the previous six

weeksweeks

• Oral anticoagulant therapyOral anticoagulant therapy

• Participation in another study in Participation in another study in

progress progress

Any of the following:

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PRIMARY ENDPOINT

• Rate of Rate of complete complete ST-segment resolution ST-segment resolution

(STR) 90 minutes after first balloon inflation (STR) 90 minutes after first balloon inflation

of the infarct-related artery of the infarct-related artery

• STR was calculated as the percentage STR was calculated as the percentage

reduction in the summed ST elevation score reduction in the summed ST elevation score

between the pre- and the 90 min post- between the pre- and the 90 min post-

procedure ECGsprocedure ECGs• STR was defined complete when STR was defined complete when ≥70%≥70%

Endpoints and definitionsEndpoints and definitions

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• In-hospital incidence of In-hospital incidence of majormajor and and minorminor

bleedingsbleedings

SAFETY ENDPOINT

• Major bleedingsMajor bleedings (combination of the TIMI and GUSTO criteria) (combination of the TIMI and GUSTO criteria)

– requiring transfusion or surgeryrequiring transfusion or surgery

– reduction in haemoglobin of more than 5 g/dlreduction in haemoglobin of more than 5 g/dl

– intracranial haemorrhageintracranial haemorrhage

• Minor bleedingsMinor bleedings

– local haematomalocal haematoma

– any other clinically relevant bleeding that did not meet criteria for any other clinically relevant bleeding that did not meet criteria for

severityseverity


FATAFATATRIAL

• Clinical:Clinical: incidence of death, re-infarction and incidence of death, re-infarction and

target vessel revascularization (TVR) in-H and target vessel revascularization (TVR) in-H and

at 30 daysat 30 days

SECONDARY ENDPOINTS

– ReinfarctionReinfarction

• recurrence of typical clinical symptoms and new ECG changes with a recurrence of typical clinical symptoms and new ECG changes with a

new elevation of the CK MB levels >2 times the upper limit of normalnew elevation of the CK MB levels >2 times the upper limit of normal

– Target Vessel RevascularizationTarget Vessel Revascularization

• TVR was defined any revascularization, either surgical or TVR was defined any revascularization, either surgical or

percutaneous, to treat the IRA. TVR was defined “urgent” when percutaneous, to treat the IRA. TVR was defined “urgent” when

performed within 24 hours from the index procedureperformed within 24 hours from the index procedure


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SECONDARY ENDPOINTS

– TIMI flow gradeTIMI flow grade

• 0, 1, 2 or 3 according to standard criteria0, 1, 2 or 3 according to standard criteria

– Myocardial Blush GradeMyocardial Blush Grade

• 0 - no myocardial blush or contrast density, or MB “staining” 0 - no myocardial blush or contrast density, or MB “staining”

• 1 - minimal myocardial blush or contrast density1 - minimal myocardial blush or contrast density

• 2 - moderate myocardial blush or contrast density but less than that obtained 2 - moderate myocardial blush or contrast density but less than that obtained

during angiography of a contralateral or ipsilateral non–IRAduring angiography of a contralateral or ipsilateral non–IRA

• 3 - normal myocardial blush or contrast density3 - normal myocardial blush or contrast density

• Angiographic:Angiographic: pre- and post- procedural TIMI pre- and post- procedural TIMI

flow 3 rates, and post-procedure myocardial flow 3 rates, and post-procedure myocardial

blush grade blush grade


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Statistical analysisStatistical analysis

• The The primary hypothesisprimary hypothesis was that was that HDB tirofiban would be HDB tirofiban would be

equivalent to abciximabequivalent to abciximab in achieving complete ST-resolution in achieving complete ST-resolution

• 71%71% complete STR expected for complete STR expected for ABCIXIMABABCIXIMAB based on a pilot based on a pilot

studystudy• 50%50% expected rate of complete STR in patients treated with expected rate of complete STR in patients treated with

primary PCI primary PCI withoutwithout IIb/IIIa inhibitors (51% in the Zwolle IIb/IIIa inhibitors (51% in the Zwolle

experience)experience)• Margin of equivalence fixed at Margin of equivalence fixed at Δ Δ 10%10%, consistent with the , consistent with the

preservation of a difference of at least 50 percent of the preservation of a difference of at least 50 percent of the

effect of abciximab as compared with that of placebo effect of abciximab as compared with that of placebo

• 660 patients660 patients (i.e. 330 pts per arm) were (i.e. 330 pts per arm) were

required to have required to have 80% power80% power and and alpha = 0.05alpha = 0.05

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Study flowStudy flow

46 Did not meet inclusion criteria 2 NSTEMI 3 pericarditis 3 Aortic dissections 3 Unstable angina 9 Recurrent STEMI in same site 2 STEMI with new LBBB 24 STEMI with pain-to-ECG > 6 h

341 Abciximab3 received Tirofiban

6 STR not assessable3 dead during procedure

2 missing ECG1 AIVR

5 STR not assessable1 dead during procedure

3 missing ECG1 AIVR

335 Included in primary analysis

351 HDB Tirofiban 5 received Abciximab

346 Included in primary analysis

738 Patients Assessed for Eligibility

692 Randomized

2.924 patients with STEMI<6h undergoing primary PCI at participating centers

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Baseline clinical characteristicsBaseline clinical characteristics

0.9946.4 46.3 Anterior AMI

0.405.1 3.8 Prior PCI

0.191.1 0.3 Prior CABG

0.036.0 2.6 Prior MI0.4528.2 30.8 Family history of CAD

36.243.1 0.09Current smoker0.2849.345.2 Hypercholesterolemia

0.6118.8 17.3 Diabetes

0.1658.1 52.8 HypertensionRisk factors

0.0371.8 78.9 Male gender

0.4965.0 12.763.4 12.5Age, y

P

Tirofiban(n=351)

Abciximab(n =341)

4.04.1IV1.12.3III

11.18.8II

83.884.7I0.49Killip class

0.944.0 4.1 Cardiogenic shock

FATAFATATRIAL

Baseline angiographic Baseline angiographic characteristicscharacteristics

0.971.11.2Left main disease

19.917.33

37.036.420.72Multivessel disease

8.3 11.1 1

60.4 60.4 0

0.47Pre-procedure TIMI flow grade0.192.33.5No PCI

0.2387.5 90.3 Infarct-related artery stenting

P

Tirofiban(n=351)

Abciximab(n =341)

0.9 0.3 Left main

45.0 46.0 LAD12.0 12.6 Left circumflex

40.7 38.5Right1.42.1 No obstructive lesions

0.80Infarct related artery

16.5 13.5

14.815.0 23

FATAFATATRIAL

TIMI flow - PRETIMI flow - PRE

0

10

20

30

40

50

60

70

TIMI 0 TIMI 1 TIMI 2 TIMI 3

ABC TIR

P = 0.47

%

60.4 60.4

13.516.5

11.18.3

15.0 14.8

FATAFATATRIAL

Time intervalsTime intervals

0.7125 (12-45)25 (12.5-45)Study drug to balloon

0.6812 (4-32)13 (4-35)Study drug to angiography

0.9770 (53-93)71 (53-97)ECG to balloon

0.9040 (23-61)40 (24.5-63)ECG to study drug

0.98153 (118-226)160 (115-220)Pain to balloon

0.99121 (86-190)125 (90-190)Pain to study drug

0.874 (46-130)80 (45-125)Pain to ECG

P Abciximab

minTirofiban

min

All values are expresses as Median (IQR)

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Primary EndpointPrimary Endpoint

PER PROTOCOL

PER TREATMENT

Equivalence boundary

Abciximab better Tirofiban better

-10,35-3,40 3,56

-3,18 3,78

-15,00 -10,00 -5,00 0,00 5,00 10,00 15,00

-10,13

= EQUIVALENCE NOT DEMONSTRATED

70.45

67.05

18.50

14.45

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ST-resolutionST-resolution

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ABC TIR

Absent STR (<30%)

Partial STR (30-69%)

Complete STR (≥70%)

9.85

19.70

Δ -3.4 %

Δ -4.6 %

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50% ST-resolution50% ST-resolution

-15.00 -10.00 -5.00 0.00 5.00 10.00

Equivalence boundary

PER PROTOCOL

PER TREATMENT

-8,19-14,08 -2.30

Abciximab better Tirofiban better

Post-hoc analysisPost-hoc analysis

-7,83 -1,93-13,73

FATAFATATRIAL

Safety endpointsSafety endpoints

0

0,5

1

1,5

2

2,5

3

3,5

4

MajorBleedings

ICH Local Other MinorBleedings

P = NS for all

ABC TIR

%1.8

1.4

0 0

0.6

0.3

1.11.2 1.2

0.3

FATAFATATRIAL

Clinical endpointsClinical endpoints

0

1

2

3

4

5

Allevents

Death Re-IMA UrgentTVR

Allevents

Death Re-IMA TVR

1.8

2.3

1.5

1.1

0.3

0.6

0

0.3

1.8

2.8

1.5

2.0

0.3

0.60.8

0

P = NS for all

In-hospital 30-day

ABC TIR

%

FATAFATATRIAL

TIMI flow - POSTTIMI flow - POST

0

10

20

30

40

50

60

70

80

90

100

TIMI 0 TIMI 1 TIMI 2 TIMI 3

ABC TIR

P = 0. 70%

1.2 2.3

89.1 90.6

2.1 1.17.6 6.0

FATAFATATRIAL

Myocardial BlushMyocardial Blush

0

10

20

30

40

50

60

MBG 0 MBG 1 MBG 2 MBG 3

ABC TIR

P = 0. 39%

19.921.9

45.449.4

10.3 10.9

24.3

17.7

FATAFATATRIAL

Multivariable predictors of complete Multivariable predictors of complete STRSTR

0.9710.782 - 1.2680.996Number of vessel diseased

0.5830.346 - 1.8180.793Prior myocardial infarction

0.1160.923 – 2.0751.384Current smoker

0.4490.807– 1.6241.145Abciximab

0.4160.764- 1.9171.210Diabetes

0.6520.583- 1.4030.904Male gender

0.8700.982- 1.0150.999Age (each increment year)

0.0110.426- 0.8970.618Hypertension

0.0081.139– 2.3691.643Pre-procedural TIMI grade flow >0

0.0400.996 - 1.0000.998Pain-to-balloon (each min increment)

<.00010.260 - 0.5290.371Anterior myocardial infarction

P 95.0% C.I.OR

FATAFATATRIAL

ConclusionsConclusions

• This study This study failed to show the equivalence of HDB failed to show the equivalence of HDB

tirofiban as compared to standard abciximabtirofiban as compared to standard abciximab to achieve to achieve

complete ST-resolution in the setting of pPCIcomplete ST-resolution in the setting of pPCI

• The The absolute differenceabsolute difference in rates of complete ST- in rates of complete ST-

resolution observed between abciximab and tirofiban resolution observed between abciximab and tirofiban

was smallwas small (3.4%), and the question whether this could (3.4%), and the question whether this could

translate into a different clinical benefit is legitimatetranslate into a different clinical benefit is legitimate

• Further studies are necessary to clarify:Further studies are necessary to clarify:

– If there is a clinical difference between abciximab and small If there is a clinical difference between abciximab and small

molecule IIb/IIIa inhibitorsmolecule IIb/IIIa inhibitors

– If these drugs have different profiles of efficacy in different If these drugs have different profiles of efficacy in different

patientspatients

FATAFATATRIAL

LimitationsLimitations

• Study treatment open-label (but core-lab assessment of Study treatment open-label (but core-lab assessment of

primary endpoint and secondary angiographic EPs)primary endpoint and secondary angiographic EPs)

• Despite randomization, there are some difference in the Despite randomization, there are some difference in the

distribution of the characteristics such as proportion of distribution of the characteristics such as proportion of

patients with prior MI, smoking status and female patients with prior MI, smoking status and female

gender.gender.

• Rates of short-term mortality and bleeding Rates of short-term mortality and bleeding

complications were quite low as compared to most of complications were quite low as compared to most of

those reported in the medical literature. Possible those reported in the medical literature. Possible

explanations:explanations:

– Radial approach in around 25% of the patientsRadial approach in around 25% of the patients

– Evident, though not planned, patient selection (25% of Evident, though not planned, patient selection (25% of

candidates for pPCI were screened) candidates for pPCI were screened)

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