Presenter Disclosure Information Intracoronary Compared with Intravenous Bolus Abciximab Application in Patients with ST-Elevation Myocardial Infarction Undergoing Primary Coronary Intervention The following relationships exist related to this presentation: Off-label use of intracoronary abciximab

Intracoronary Compared with Intravenous Bolus Abciximab Application in Patients with ST-Elevation Myocardial Infarction Undergoing Primary Coronary Intervention The randomized Leipzig Immediate PercutaneouS Coronary Intervention Abciximab i.v. versus i.c. in ST-Elevation Myocardial Infarction Trial (LIPSIAbciximab-STEMI) Holger Thiele, Kathrin Schindler, Josef Friedenberger, Ingo Eitel, Georg Fürnau, Eigk Grebe, Dietmar Kivelitz, Gerhard Schuler

Abciximab i.v. + PCI - Mortality 6 Months Meta-analysis - No. Deaths/No. Patients (%) Control (n=1916) Abciximab better Control better Abciximab (n=1996) P-Value RAPPORT 11/242 (4.5) 10/241 (4.1) 0.83 ISAR-2 17/200 (8.5) 12/201(6.0) 0.33 ADMIRAL 11/151(7.3) 5/149 (3.4) 0.13 CADILLAC 45/1030 (4.4) 44/1052 (4.2) 0.83 Petronio et al 6/45 (13.3) 2/44 (4.5) 0.15 Zorman et al 7/51 (13.7) 5/112 (4.5) 0.04 ACE 21/197 (10.5) 10/197 (5.0) 0.04 Total 118/1916 (6.2) 88/1996 (4.4) 0.01 0,1 1,0 10,0 Odds Ratio (95% CI) De Luca et al. JAMA 2005;293:1759-1765

Abciximab-Bolus i.c. versus i.v. Potential Benefits: Higher concentration Faster reduction thrombus burden Improved TIMI-flow No-Reflow  Infarct size  Outcome 

Abciximab i.v. versus i.c. N=403; retrospective registry Events (%) 25 PCI Abciximab i.v 20.2 PCI Abciximab i.c. P=0.08 20 15.6 15 Events (%) P<0.002 10.2 P<0.04 9.5 10 4.6 2.8 5 0.3 0.3 Re-MI Death MACE Urgent TVR Wöhrle et al. Circulation 2003;107:1840-1843

Inclusion criteria Clinical Symptoms: AP < 12 hours persistent angina > 30 minutes ECG-Criteria: ST  > 1mm in  2 extremity leads ST  > 2mm in  2 anterior leads   Informed consent LIPSIAbciximab

Endpoints Primary study endpoint: - Infarct size delayed enhancement MRI (Days 1-4) - Extent microvascular obstruction Secondary study endpoints: - ST-segment resolution 90 min. - TIMI-flow pre + post PCI - TMPG pre + post PCI - Infarct size [CK as AUC (2 days)] - Combined clinical endpoint: Death, Re-MI, New CHF, TVR Projection: Final infarct size of 2010% (54% MO) i.v. abciximab. Power 80%, 2-sided -value of 0.05 to detect absolute difference of 5% infarct size (2% MO)  2x 68 patients. LIPSIAbciximab

Contrast-injection 2 mmol/kg/BW Bolus Gadobutrol i.v. MR – Image Acquisition Contrast-injection 2 mmol/kg/BW Bolus Gadobutrol i.v. 5 10 15 20 25 30 35 40 Time (min) 4CH+2 CH T2 3 x SA DE early SA Short axes DE late 4CH+2CH+SA Survey 3D IR – GRE sequence (TR/TE/flip 2.8/1.1/15°) SSFP sequence (TR/TE/flip = 3.2/1.2/60°) LIPSIAbciximab

MR Image Analysis Blinded observers: Manual drawing of endocardial, epicardial, papillary, infarcted + MO contours % Infarct size = (Infarct volume/volume LV mass) % MO = (MO-volume/volume LV mass) Thiele et al; JACC 2006;47:1641-1645

ECG Analysis +5.6 ECG +2.5 +1.3 +1.3 +5.6 +3.0 +4.7 +7.4 +2.4 1. Sum ST-elevation +2.5 +1.3 +1.3 +5.6 +3.0 +4.7 2. Measurement Same leads 90 min. +7.4 +2.4 % Resolution=(ST Base - ST 90min.) / (ST Base) Categorization: Complete > 70%, intermediate 30-70%, no < 30% LIPSIAbciximab

Study Profile Randomized (n=154) LIPSIAbciximab Abciximab i.v. (n=77) Abciximab i.c. (n=77) No MRI (n=6) Claustrophobia (n=2) Death (n=2) Refusal (n=1) PM (n=1) No MRI (n=10) Claustrophobia (n=1) Death (n=2) Refusal (n=2) PM (n=1) Obesity (n=2) Technical reasons (n=2) Lost to 30-day follow-up (n=0) Lost to 30-day follow-up (n=0) Primary endpoint analysis (n=71) Secondary endpoint analysis (n=77) Primary endpoint analysis (n=67) Secondary endpoint analysis (n=77) LIPSIAbciximab

Patient Characteristics i.v. i.c. p (n=77) (n=77) Age 66 (54; 72) 64 (54; 70) 0.29 Male 58 (75%) 63 (82%) 0.43 TIMI-risk 4 (1; 6) 4 (1;6) 0.98 Previous MI 7 (9%) 8 (10%) 0.93 Anterior MI 40 (52%) 44 (57%) 0.63 Smoking 39 (51%) 38 (49%) 0.92 Hypertension 57 (74%) 54 (70%) 0.72 Hyperlipidemia 31 (40%) 27 (35%) 0.66 Diabetes mellitus 22 (29%) 24 (31%) 0.86 LIPSIAbciximab

Reperfusion Times i.v. i.c. p (n=77) (n=77) Door-to-Balloon (min) 29 (21;49) 31 (22;40) 0.77 Symptom-Balloon (min) 218 (159;323) 244 (163;433) 0.47 LIPSIAbciximab

Medication i.v. i.c. p (n=77) (n=77) ASA 77 (100%) 77 (100%) 1.0 Clopidogrel 77 (100%) 77 (100%) 1.0 ACE/AT-1 77 (100%) 76 (99%) 1.0 Beta-blocker 76 (99%) 76 (99%) 1.0 Statines 77 (100%) 76 (99%) 1.0 Aldosterone ant. 10 (13%) 10 (13%) 1.0 Abciximab pre PCI 53 (70%) 64 (83%) 0.14 Abciximab complete 72 (94%) 73 (95%) 0.94 LIPSIAbciximab

TIMI-flow Pre-PCI Abciximab i.v. Abciximab i.c. p=0.51 LIPSIAbciximab N=51 N=44 N=18 N=15 N=9 N=5 N=6 N=4 LIPSIAbciximab

TIMI-Flow Post-PCI Abciximab i.v. Abciximab i.c. p=0.91 LIPSIAbciximab N=64 N=65 N=8 N=10 N=1 N=2 N=1 N=1 LIPSIAbciximab

TMPG Pre-PCI Abciximab i.v. Abciximab i.c. p=0.67 LIPSIAbciximab N=57

TMPG Post-PCI Abciximab i.v. Abciximab i.c. p=0.15 LIPSIAbciximab N=50

ST-Segment-Resolution (90 min) %Resolution=(ST Base - ST 90min.) / (ST Base) p=0.007 77% (66.7; 100) 70% (45.2; 83.5) % i.v. i.c. LIPSIAbciximab

ST-Segment-Resolution (90 min) i.v. i.c. 90 p=0.03 80 n=50 70 60 n=38 % 50 n=32 40 n=22 30 20 n=7 10 n=3 >70% 30-70% <30% >70% 30-70% <30% LIPSIAbciximab

Primary Study Endpoint DE-MRI i.v. i.c. % LV IS 23.4 (13.6; 33.2) 15.1 (6.1; 25.2) p=0.01 30 p=0.01 MO early 1.1 (0.0; 3.7) 3.4 (0.1; 7.3) 25 p=0.02 MO late 0.1 (0.0; 1.6) 1.1 (0.0; 2.8) 20 15 10 5 LIPSIAbciximab

Infarct Size - CK (Area Under the Curve) p=0.007 736 (416; 1304) mol/l/h mol/l 575 (359; 863) mol/l/h Time (h) LIPSIAbciximab

Combined Clinical Endpoint (Death, Re-MI, new CHF, TVR) 20 p=0.06 15 i.v. % 10 5 i.c. 5 10 15 20 25 30 Days after randomization LIPSIAbciximab

Predefined Subgroup Analysis – Primary Endpoint Variable % of patients Early MO (% LV) Late MO (% LV) Infarct size (% LV) Total 100 p=0.01 p=0.02 p=0.01 Non-anterior infarction 52 p=0.13 p=0.34 p=0.04 Anterior Infarction 48 p=0.06 p=0.04 p=0.04 Symptom – Reperfusion < 4 h 54 p=0.22 p=0.22 p=0.26 Symptom – Reperfusion 4–8 h 29 p=0.03 p<0.001 p=0.003 Symptom – Reperfusion > 8 h 17 p=0.04 p=0.02 p=0.004 TIMI = 3 post PCI 86 p=0.14 p=0.25 p=0.01 TIMI < 3 post PCI 14 p=0.06 p=0.01 p=0.009 TMPG = 3 post PCI 70 p=0.31 p=0.55 p=0.10 TMPG < 3 post PCI 30 p=0.001 p=0.005 p=0.01 15 10 5 5 10 15 6 5 4 3 2 1 1 2 3 4 5 6 60 50 40 30 20 10 10 20 30 40 50 60 Abciximab i.v. Abciximab i.c. Abciximab i.v. Abciximab i.c. Abciximab i.v. Abciximab i.c. LIPSIAbciximab

Summary + Conclusions Abciximab-bolus i.c. injection during primary PCI leads to - improved perfusion (ECG) - trend towards improved angiographic perfusion - reduction microvascular obstruction - reduction infarct size - trend towards improved clinical outcome Adequately powered trial necessary

Study Design Abciximab i.v. vs. i.c.-STEMI Controlled, randomized, multicenter, open-label 1) Angina > 30 min, < 12 h; 2) 12-lead-ECG: STEMI; 3) Informed consent Randomization (n=1868) Abciximab i.v. (n=934) Abciximab i.c. (n=934) Primary PCI After wire passage abciximab-bolus i.v. Primary PCI After wire passage abciximab-bolus i.c. Abciximab i.v. continuously Abciximab i.v. continuously TIMI-flow pre + post PCI TIMI-flow pre + post PCI Core-Lab ECG 90 min + 24 h post PCI ECG 90 min + 24 h post PCI CK + CK-MB every 8 h for 48 h CK +CK-MB every 8 h for 48 h Díscharge or rehabilitation Discharge or rehabilitation 90 day follow-up: primary enpoint 90 day follow-up: primary endpoint 12 month follow-up (by telephone) 12 month follow-up (by telephone)

Thank you for your attention thielh@medizin.uni-leipzig.de