Randomized Early versus Late AbciXimab in Acute Myocardial Infarction treated with primary coronary intervention (RELAx-AMI Trial) Mauro Maioli M.D., Francesco Bellandi M.D., Mario Leoncini M.D., Anna Toso M.D. and Roberto Piero Dabizzi M.D.. Division of Cardiology, Prato – Italy. Journal of American College Cardiology 2007; 48:

Investigations on glycoprotein IIb/IIIa inhibition in acute ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) have shown the efficacy of abciximab in improving clinical and angiographic outcome. Adjunctive abciximab therapy, administered in catheterization laboratory prior to primary PCI, is associated with a significant reduction in 30-day reinfarction and in short- and long-term mortality in patients with STEMI treated with primary angioplasty. The Admiral trial suggested that early abciximab administration was associated with marked amplification of treatment effect. However, the real benefit of early treatment has not yet been established. M. Maioli et al, JACC 2007;48: Background

Objectives of the trial In this prospective randomized trial on patients with AMI treated with primary stenting, we evaluated the impact on angiographic outcome, microvascular reperfusion, myocardial salvage and left ventricular function of abciximab administered in the emergency room compared to abciximab administered in the catheterization laboratory. M. Maioli et al, JACC 2007;48: End Points of the trial The primary endpoint of the trial was the pre-interventional angiographic finding evaluated in terms of TIMI grade flow. In addition, we analyzed cTFC and MBG. Secondary endpoints were infarct size (measured by cumulative release of serum cardiac markers) and left ventricular functional recovery at one month (echocardiographic ejection fraction and wall motion score index).

Flow patients through RELAx-AMI trial Patients referred for AMI n = 232 Randomized n = 210 Assigned to Early Abciximab n = 105 Assigned to Late Abciximab n = 105 One month echocardiographic analysis n = pts excluded 3 pts died 6 pts died One month echocardiographic analysis n = 99 M. Maioli et al, JACC 2007;48:

Methods Exclusion criteria: - previous AMI (7 pts) - previous PCI or CABG (6 pts) - LBBB (3 pts) - oral anticoagulation (2 pts) - contraindication to aspirin (2 pts) - recent stroke or surgery (2 pts) Study drugs: - Abciximab (0.25 mg/kg as a bolus followed by a 12-h infusion of mcg/kg/min) either in the emergency room (Early group) or in the catheterization laboratory (Late group) -, - Heparin as a bolus of 70 U/kg (maximum, 7000 U) together with 250 mg of aspirin intravenously, in the emergency room. - Clopidogrel 300 mg, immediately after the procedure M. Maioli et al, JACC 2007;48:

RELAx-AMI: Baseline clinical characteristics of the patients - 1 Early group (105 pts) Late group (105 pts) p Value Age (yrs)64±1066±12NS Age ≥ 75 yrs (%)17 (16)26 (25)NS Female gender (%)25 (24)27 (26)NS Hypertension (%)51 (49)48 (46)NS Diabetes mellitus (%)31 (29) NS History of smoking (%)45 (43)54 (51)NS Hyperlipidemia (%)43 (41)41 (39)NS Low-risk patients (%)36 (34)43 (41)NS Killip class ≥ 2 (%)20 (21)25 (26)NS Anterior AMI (%)52 (49) NS 2 vessel disease (%)32 (30)40 (38) NS 3 vessel disease (%)22 (21)25 (24) M. Maioli et al, JACC 2007;48:

Early group (105 pts) Late group (105 pts) p Value Symtom onset to admission (min) 85 (59-160)105 (63-170)NS Door to Abciximab (min)23 (15-37)60 (40-88)0.001 Door to Ballon (min)84 (67-107)73 (59-104)NS Start of Abciximab to ballon (min) 55 (46-72)14 (11-18)0.001 M. Maioli et al, JACC 2007;48: Procedural times are presented as median with interquartile ranges RELAx-AMI: Baseline clinical characteristics of the patients - 2

RELAx-AMI: Angiographic results - 1 Early Ab. 105 pts Late Ab. 105 pts p Value Initial TIMI flow grade (60%) 17 (16%) 25 (24%) 88 (84%) 6 (6%) 11 (10%) Initial cTFC (frames)78±3092± Initial Myocardial Blush Grade Grade 2 – 3 89 (85%) 16 (15%) 99 (94%) 6 (6%) M. Maioli et al, JACC 2007;48:

RELAx–AMI: TIMI flow and MBG at basal angiography M. Maioli et al, JACC 2007;48: Basal TIMI FlowBasal Myocardial Blush Grade p=.001p=.028

RELAx-AMI: Angiographic results - 2 Early Ab. 105 pts Late Ab. 105 pts p Value Final TIMI flow grade (4%) 97 (92%) 5 (5%) 3 (3%) 97 (92%) NS Final cTFC (frames)27±1932± Final Myocardial Blush Grade Grade 2 – 3 22 (21%) 83 (79%) 44 (42%) 61 (58%) M. Maioli et al, JACC 2007;48:

RELAx–AMI: Myocardial Blush Grade at final angiography p=.001

RELAx-AMI: Procedural results Early Ab. 105 pts Late Ab. 105 pts p Value Reference vessel diameter (mm)3.2±0.43.2±0.5NS Initial minimal luminal diameter (mm)0.13± ± Initial extent of stenosis (%)95±1198±50.01 Final minimal luminal diameter (mm)3.1±0.73.0±0.7NS Final extent of stenosis (%)95±1198±50.01 Number of stents1.2±0.6 NS Direct stenting (%)31 (29)14 (13)0.004 Multiple stents (%)27 (26)26 (25)NS Lenght of stented segment (mm)23±822±10NS Procedural time (min)11±715± IABP (%)34 (32)42 (40)NS M. Maioli et al, JACC 2007;48:

RELAx-AMI: Electrocardiographic and Laboratory results Early Ab. 105 pts Late Ab. 105 pts p Value Precent preangiographic ST-segment elevation reduction 14±304± min post-PCI ST-segment elevation reduction ≥ 70% (%) 53 (50)37 (35)0.03 Basal CK-MB (ng/ml)9±1910±18NS Peak CK-MB (ng/ml)282±302362± Cumulative 48-h CK-MB release (ng/ml*h) 6483± ± Basal troponin I (ng/ml)1±31±2NS Peak troponin I (ng/ml)115±122172± Cumulative 48-h troponin I release (ng/ml*h) 3329± ± M. Maioli et al, JACC 2007;48:

RELAx-AMI: Electrocardiographic results M. Maioli et al, JACC 2007;48: minutes post PCI ST-T Resolution p=.004 p=.026

RELAx-AMI: One month left ventricle function recovery Early Ab. 105 pts Late Ab. 105 pts p Value Pre procedural EF (%) 42±841±8NS Pre procedural WMSI1.8±0.31.8±0.4NS One month post PCI EF (%) 51±947± One month post PCI WMSI1.4±.31.5± One month post PCI mean gain EF (%) 8±76±70.02 One month post PCI mean gain WMSI 0.4±.30.3± M. Maioli et al, JACC 2007;48:

GlobalRegional Early Abiciximab Late Abciximab RELAx-AMI: Left Ventricular Function by Timing of Abciximab administration NS p=.014 p=.023 p =.031 M. Maioli et al, JACC 2007;48:

RELAx-AMI: Scintigraphic evaluation Early Ab. 25 pts Late Ab. 26 pts p Value Initial perfusional defect (%)31±1437±15NS 7-day perfusion defect (%)14±1023± Myocardial salvage (%)18±915±80.2 Salvage Index0.6±0.20.4± F. Bellandi et al, Int J Cardiol 2006;108:36-42

Early Abiciximab Late Abciximab RELAx-AMI: Scintigraphic evaluation NS p=.028 p=.007 F. Bellandi et al, Int J Cardiol 2006;108:36-42

RELAx-AMI: one month clinical follow-up and bleeding complications Early Ab. 105 pts Late Ab. 105 pts p Value Death (%)3 (2.9)6 (5.7)NS Recurrent AMI (%)2 (1.9)4 (3.8)NS Repeated urgent PCI (%)2 (1.9)1 (0.9)NS Urgent CABG (%)1 (0.9) NS Stroke (%)-- MACE (%)6 (5.7%)9 (8.6)NS Major bleeding (%)1 (0.9) NS Minor bleeding (%)8 (7.6)5 (4.8)NS Blood transfusions (%)6 (5.7)4 (3.8)NS Thrombocytopenia (%)1 (0.9)4 (3.8)NS M. Maioli et al, JACC 2007;48:

Conclusion The results of the present trial suggest that, in patients with first AMI treated with PCI, early abciximab administration (i.e. in the emergency room) compared to treatment started in the catheterization laboratory significantly improves pre-procedural angiographic epicardial flow (evaluated by TIMI grade flow) and tissue perfusion (MBG 2 or 3). Moreover, post-interventional parameters of myocardial reperfusion (i.e., MBG  2 and ST-segment resolution) were also improved and this is associated with a smaller infarct size and with an improved left ventricular function at one month follow-up. M. Maioli et al, JACC 2007;48: