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FATA

FATA. TRIAL. F acilitated A ngioplasty with T irofiban or A bciximab. Francesco Saia On behalf of the FATA Investigators. Washington DC, October 14 th 2008. FATA. TRIAL. Study organization. Principal Investigators. A. Marzocchi, A. Manari, G. Piovaccari. Clinical Management.

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FATA

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  1. FATA TRIAL FacilitatedAngioplastywithTirofibanorAbciximab Francesco Saia On behalf of the FATA Investigators Washington DC, October 14th 2008

  2. FATA TRIAL Study organization Principal Investigators A. Marzocchi, A. Manari, G. Piovaccari Clinical Management C. Marrozzini, F. Saia ECG Core Lab N. Taglieri, V. Ovi Angiographic Core Lab N. Taglieri, S. Silenzi, S. Virzì M.L. Bacchi-Reggiani, P. Guastaroba, E.Bonizzoni Statistical Analysis Data monitoring B. Petri, A. Schembari Sponsor 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)

  3. FATA TRIAL Participating centres and Investigators U. O. di Cardiologia, Ospedale Molinette, Torino S. Marra, F. Conrotto, P. Scacciatella 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, Bologna P. Sangiorgio, G. Casella, A. Rubboli, G. Nobile, G.Di Pasquale U. O.di Cardiologia, Ospedale degli Infermi, Rimini G. Piovaccari, A. Santarelli, N. Franco, D.Santoro, S. Carigi • 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, Modena • S. Tondi, P. Magnavacchi, G. Tosoni, G.R. Zennaro Servizio di Cardiologia Invasiva, Ospedale di Pesaro G. Binetti, L. Uguccioni, L. Marinucci

  4. FATA TRIAL Background • Abciximab, a monoclonal antibody fragment Gp IIb/IIIa inhibitor, has been shown to ameliorate myocardial perfusion and left ventricular recovery after pPCI, thus improving both early and late clinical outcome • Tirofiban, a small-molecule Gp IIb/IIIa inhibitor, when administered with a high-dose (25 µg/Kg) bolus, can achieve > 90% platelet aggregation inhibition 10 minutes after infusion, which is comparable or even better than what can be obtained with the standard dose of abciximab • At current market prices, treatment with HDB tirofiban would cost around one third of treatment with abciximab

  5. FATA TRIAL Scope of the study To demonstrate the equivalence between High Dose Bolus (HDB) Tirofiban and Abciximab as adjunctive therapy in patients with ST-Elevation acute Myocardial Infarction (STEMI) undergoing primary PCI (pPCI) in terms of effective myocardial reperfusion

  6. FATA TRIAL Study design Spontaneous, randomized, multicenter, controlled, open-label trial STEMI < 6 hours 660 patients > 18 years with STEMI <6h undergoing primary PCI (no LBBB) ASA 250 mg i.v. and UFH 70 IU/kg RANDOMIZATION 1:1 Tirofiban HDB Bolus 25 µg/kg, followed by 18h infusion of 0.15 µg/kg/min Abcixmab Bolus 0.25 mg/kg, followed by 12h infusion of 0.125 µg/kg/min PRIMARY PCI • Primary Endpoint:Rate of complete ST-segment resolution (STR) 90 minutes after first balloon inflation Abciximab vs Tirofiban

  7. FATA TRIAL Inclusion criteria All the following criteria had to be met: • Age>18 years • Chest pain persisting more than 20 minutes associated with ST-segment elevation of at least 0.1 mV in two or more contiguous ECG leads • Admission within 6 hours from symptoms onset • Release of written informed consent.

  8. FATA TRIAL Exclusion criteria Any of the following: • Complete left bundle branch block • Previous myocardial infarction in the same territory • Bleeding diathesis • Administration of fibrinolytic agents for the current episode • Post-anoxic coma • Known thrombocytopenia or leucopenia • Severe hepatic dysfunction • Severe renal failure (serum creatinine > 3 mg/dl) • Contraindication to aspirin, thienopyridines, or heparin • Limited life expectancy (< 1 year) • Childbearing potential • Recent major surgery (within 3 months) • Uncontrolled hypertension • History of stroke within the previous 30 days • History of intracranial disease (aneurysm, arterovenous malformation) • Major trauma within the previous six weeks • Oral anticoagulant therapy • Participation in another study in progress

  9. FATA TRIAL Endpoints and definitions PRIMARY ENDPOINT • Rate of complete ST-segment resolution (STR) 90 minutes after first balloon inflation of the infarct-related artery • STR was calculated as the percentage reduction in the summed ST elevation score between the pre- and the 90 min post- procedure ECGs • STR was defined complete when ≥70%

  10. FATA TRIAL Endpoints and definitions SAFETY ENDPOINT • In-hospital incidence of major and minor bleedings • Major bleedings (combination of the TIMI and GUSTO criteria) • requiring transfusion or surgery • reduction in haemoglobin of more than 5 g/dl • intracranial haemorrhage • Minor bleedings • local haematoma • any other clinically relevant bleeding that did not meet criteria for severity

  11. FATA TRIAL Endpoints and definitions SECONDARY ENDPOINTS • Clinical: incidence of death, re-infarction and target vessel revascularization (TVR) in-H and at 30 days • Reinfarction • recurrence of typical clinical symptoms and new ECG changes with a new elevation of the CK MB levels >2 times the upper limit of normal • Target Vessel Revascularization • TVR was defined any revascularization, either surgical or percutaneous, to treat the IRA. TVR was defined “urgent” when performed within 24 hours from the index procedure

  12. FATA TRIAL Endpoints and definitions SECONDARY ENDPOINTS • Angiographic: pre- and post- procedural TIMI flow 3 rates, and post-procedure myocardial blush grade • TIMI flow grade • 0, 1, 2 or 3 according to standard criteria • Myocardial Blush Grade • 0 - no myocardial blush or contrast density, or MB “staining” • 1 - minimal myocardial blush or contrast density • 2 - moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non–IRA • 3 - normal myocardial blush or contrast density

  13. FATA TRIAL Statistical analysis • The primary hypothesis was that HDB tirofiban would be equivalent to abciximab in achieving complete ST-resolution • 71% complete STR expected for ABCIXIMAB based on a pilot study • 50% expected rate of complete STR in patients treated with primary PCI without IIb/IIIa inhibitors (51% in the Zwolle experience) • Margin of equivalence fixed at Δ 10%, consistent with the preservation of a difference of at least 50 percent of the effect of abciximab as compared with that of placebo • 660 patients (i.e. 330 pts per arm) were required to have 80% power and alpha = 0.05

  14. FATA TRIAL Study flow 2.924 patients with STEMI<6h undergoing primary PCI at participating centers 738 Patients Assessed for Eligibility 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 692 Randomized 341 Abciximab 3 received Tirofiban 351 HDB Tirofiban 5 received Abciximab 6 STR not assessable 3 dead during procedure 2 missing ECG 1 AIVR 5 STR not assessable 1 dead during procedure 3 missing ECG 1 AIVR 346 Included in primary analysis 335 Included in primary analysis

  15. FATA TRIAL Baseline clinical characteristics Abciximab (n =341) Tirofiban (n=351) P Age, y 63.4  12.5 65.0  12.7 0.49 Male gender 78.9 71.8 0.03 Risk factors Hypertension 52.8 58.1 0.16 Diabetes 17.3 18.8 0.61 Hypercholesterolemia 45.2 49.3 0.28 43.1 Current smoker 0.09 36.2 30.8 28.2 0.45 Family history of CAD Prior MI 2.6 6.0 0.03 Prior CABG 0.3 1.1 0.19 Prior PCI 3.8 5.1 0.40 Anterior AMI 46.3 46.4 0.99 Cardiogenic shock 4.1 4.0 0.94 0.49 Killip class 84.7 83.8 I 8.8 11.1 II 2.3 1.1 III 4.1 4.0 IV

  16. FATA TRIAL Baseline angiographic characteristics Abciximab (n =341) Tirofiban (n=351) P Infarct related artery 0.80 No obstructive lesions 2.1 1.4 Right 38.5 40.7 Left circumflex 12.6 12.0 LAD 46.0 45.0 Left main 0.3 0.9 0.23 Infarct-related artery stenting 90.3 87.5 No PCI 3.5 2.3 0.19 Pre-procedure TIMI flow grade 0.47 0 60.4 60.4 1 11.1 8.3 2 15.0 14.8 3 13.5 16.5 Multivessel disease 0.72 2 36.4 37.0 3 17.3 19.9 Left main disease 1.2 1.1 0.97

  17. FATA TRIAL TIR ABC TIMI flow - PRE 70 60.4 60.4 60 50 P = 0.47 40 % 30 16.5 20 15.0 14.8 13.5 11.1 8.3 10 0 TIMI 0 TIMI 1 TIMI 2 TIMI 3

  18. Time intervals FATA TRIAL Tirofiban min Abciximabmin P Pain to ECG 80 (45-125) 74 (46-130) 0.8 Pain to study drug 125 (90-190) 121 (86-190) 0.99 Pain to balloon 160 (115-220) 153 (118-226) 0.98 ECG to study drug 40 (24.5-63) 40 (23-61) 0.90 ECG to balloon 71 (53-97) 70 (53-93) 0.97 Study drug to angiography 13 (4-35) 12 (4-32) 0.68 Study drug to balloon 25 (12.5-45) 25 (12-45) 0.71 All values are expresses as Median (IQR)

  19. FATA TRIAL Primary Endpoint Equivalence boundary 3,56 -3,40 -10,35 PER PROTOCOL -3,18 3,78 -10,13 PER TREATMENT Abciximab better Tirofiban better -15,00 -10,00 -5,00 0,00 5,00 10,00 15,00 = EQUIVALENCE NOT DEMONSTRATED

  20. FATA TRIAL 9.85 14.45 19.70 18.50 Absent STR (<30%) Partial STR (30-69%) 70.45 67.05 Complete STR (≥70%) ST-resolution Δ -4.6 % 100% 90% 80% 70% 60% Δ -3.4 % 50% 40% 30% 20% 10% 0% ABC TIR

  21. FATA TRIAL 50% ST-resolution Equivalence boundary -8,19 -2.30 -14,08 PER PROTOCOL Post-hoc analysis -7,83 -1,93 -13,73 PER TREATMENT Abciximab better Tirofiban better -15.00 -10.00 -5.00 0.00 5.00 10.00

  22. FATA TRIAL TIR ABC Safety endpoints 4 3,5 P = NS for all 3 2,5 % 1.8 2 1.4 1,5 1.2 1.2 1.1 1 0.6 0.3 0,5 0.3 0 0 0 Major ICH Local Other Minor Bleedings Bleedings

  23. FATA TRIAL TIR ABC Clinical endpoints 5 4 P = NS for all 3 2.8 % 2.3 2.0 1.8 2 1.8 1.5 1.5 1.1 1 0.8 0.6 0.6 0.3 0.3 0.3 0 0 0 All Death Re-IMA Urgent All Death Re-IMA TVR events TVR events In-hospital 30-day

  24. FATA TRIAL TIR ABC TIMI flow - POST 100 90.6 89.1 90 80 70 P = 0. 70 60 % 50 40 30 20 7.6 10 6.0 2.3 2.1 1.2 1.1 0 TIMI 0 TIMI 1 TIMI 2 TIMI 3

  25. FATA TRIAL TIR ABC Myocardial Blush 60 49.4 50 45.4 40 P = 0. 39 % 30 24.3 21.9 19.9 17.7 20 10.9 10.3 10 0 MBG 0 MBG 1 MBG 2 MBG 3

  26. FATA TRIAL Multivariable predictors of complete STR OR 95.0% C.I. P Anterior myocardial infarction 0.371 0.260 - 0.529 <.0001 0.998 0.996 - 1.000 0.040 Pain-to-balloon (each min increment) Pre-procedural TIMI grade flow >0 1.643 1.139– 2.369 0.008 Hypertension 0.618 0.426- 0.897 0.011 Age (each increment year) 0.999 0.982- 1.015 0.870 Male gender 0.904 0.583- 1.403 0.652 Diabetes 1.210 0.764- 1.917 0.416 Abciximab 1.145 0.807– 1.624 0.449 Current smoker 1.384 0.923 – 2.075 0.116 Prior myocardial infarction 0.793 0.346 - 1.818 0.583 Number of vessel diseased 0.996 0.782 - 1.268 0.971

  27. FATA TRIAL Conclusions • This study failed to show the equivalence of HDB tirofiban as compared to standard abciximab to achieve complete ST-resolution in the setting of pPCI • The absolute difference in rates of complete ST-resolution observed between abciximab and tirofiban was small (3.4%), and the question whether this could translate into a different clinical benefit is legitimate • Further studies are necessary to clarify: • If there is a clinical difference between abciximab and small molecule IIb/IIIa inhibitors • If these drugs have different profiles of efficacy in different patients

  28. FATA TRIAL Limitations • Study treatment open-label (but core-lab assessment of primary endpoint and secondary angiographic EPs) • Despite randomization, there are some difference in the distribution of the characteristics such as proportion of patients with prior MI, smoking status and female gender. • Rates of short-term mortality and bleeding complications were quite low as compared to most of those reported in the medical literature. Possible explanations: • Radial approach in around 25% of the patients • Evident, though not planned, patient selection (25% of candidates for pPCI were screened)

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