fata trial fata f acilitated a ngioplasty with t irofiban or a bciximab francesco saia on behalf of...
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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)
FATAFATATRIAL
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
FATAFATATRIAL
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
FATAFATATRIAL
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
FATAFATATRIAL
Study design Study design Spontaneous, randomized, multicenter, controlled, open-label trial
FATAFATATRIAL
• 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:
FATAFATATRIAL
• 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:
FATAFATATRIAL
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
FATAFATATRIAL
• 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
Endpoints and definitionsEndpoints and definitions
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
Endpoints and definitionsEndpoints and definitions
FATAFATATRIAL
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
Endpoints and definitionsEndpoints and definitions
FATAFATATRIAL
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
FATAFATATRIAL
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
FATAFATATRIAL
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)
FATAFATATRIAL
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
FATAFATATRIAL
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 %
FATAFATATRIAL
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)