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Intracoronary Compared with Intravenous Bolus Abciximab Application During Primary

Intracoronary Compared with Intravenous Bolus Abciximab Application During Primary Percutaneous Coronary Intervention Cardiac Magnetic Resonance Substudy of the AIDA STEMI trial. Holger Thiele, MD; Jochen Wöhrle, MD; Henning Suenkel, BSc; Josephine Meissner, MD; Sebastian Kerber, MD;

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Intracoronary Compared with Intravenous Bolus Abciximab Application During Primary

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  1. Intracoronary Compared with Intravenous Bolus Abciximab Application • During Primary • Percutaneous Coronary Intervention • Cardiac Magnetic Resonance Substudy of the • AIDA STEMI trial Holger Thiele, MD; Jochen Wöhrle, MD; Henning Suenkel, BSc; Josephine Meissner, MD; Sebastian Kerber, MD; Bernward Lauer, MD; Matthias Pauschinger, MD; Ralf Birkemeyer, MD; Christoph Axthelm, MD; Rainer Zimmermann, MD; Petra Neuhaus, PhD; Oana Brosteanu, PhD; Steffen Desch, MD; Matthias Gutberlet, MD; Gerhard Schuler, MD; Ingo Eitel, MD on behalf of the AIDA STEMI Investigators

  2. Disclosures Off-label use of IC abciximab Funding: Unrestricted grant by Lilly, Germany University of Leipzig – Heart Center University of Leipzig, Clinical Trial Centre Leipzig: supported by the Federal Ministry of Education and Research (BMBF) FKZ 01KN1102 • Potential Conflict of Interest: • Research Funding: • Terumo, Lilly. Maquet Cardiovascular, Teleflex Medical • Consulting:Maquet Cardiovascular, Avidal • Speaker Honoraria: • Lilly, Astra Zeneca, Daiichi Sankyo, Boehringer Ingelheim, Maquet Cardiovascular, Medicines Company

  3. GP IIb/IIIa IC versus IV IPA Periphery (20 μmol/L ADP) GpIIb/IIIa Receptor-Blockade 110 110 P=0.67 100 100 P=0.013 P=0.995 P<0.001 P=0.001 90 90 80 80 70 70 60 60 %IPA % Receptor-Blockade 50 50 40 40 30 30 20 20 10 10 0 0 15 min post Bolus 60 min post Bolus Bolus 1 Bolus 2 30 min post Bolus Baseline Bolus 1 Bolus 2 Peripheral blood Blood coronary sinus IC Eptifibatide n=21 IV Eptifibatide n=19 Background 2 x Bolus within 10 min. 180 μg/kg eptifibatide IC versus IV, subsequently 2 μg/kg-1 .min-1 continuous infusion i.v. for 18 h Deibele et al. Circulation 2010;121:784-791

  4. 30-day Mortality Intracoronary abciximab Intravenous abciximab Odds ratio Odds ratio Events Total Events Total Weight Study or Subgroup M-H, Fixed 95% M-H, Fixed 95% CICERO 2010 CRYSTAL AMI 2010 Dominguez-Rodriguez 2009 EASY-MI 2010 Iversen 2011 Thiele 2008 5 0 0 0 2 2 263 23 25 52 170 77 33.7% 7.4% 44.8% 14.1% 0.69 0.29 (0.01;7.59) Not estimable Not estimable 0.20 (0.04;0.92) 0.66 (0.11;4.05) 271 25 25 53 185 77 7 1 0 0 9 3 Total (95%) 636 610 0.43 (0.20;0.94) 100.0% 9 20 Total events Heterogeneity: Chi2 =1.88, df=3 (P=0.60);I2=0% 0.01 0.1 1 10 100 Test for overall effect: Z=2.11 (P=0.03) Favors IV Favors IC 30-day Myocardial Infarction Intracoronary abciximab Intravenous abciximab Odds ratio Odds ratio Study or Subgroup M-H, Fixed 95% M-H, Fixed 95% Events Total Events Total Weight 3 0 5 0 271 53 185 77 4 0 8 2 263 52 170 77 27.5% 55.5% 17.0% 0.72 (0.16;3.27) Not estimable 0.56 (0.18;1.75) 0.19 (0.01;4.13) CICERO 2010 EASY-MI 2010 Iversen 2011 Thiele 2008 Total (95%) 586 0.54 (0.23;1.28) 562 100.0% 636 14 Total events 8 Heterogeneity: Chi2 =0.58, df=2 (P=0.75);I2=0% 0.01 0.1 1 10 100 Test for overall effect: Z=1.39 (P=0.17) Favors IC Favors IV 30-day Target Vessel Revascularization Intracoronary abciximab Intravenous abciximab Odds ratio Odds ratio Study or Subgroup M-H, Fixed 95% M-H, Fixed 95% Events Total Events Total Weight 9 0 7 0 CICERO 2010 EASY-MI 2010 Iversen 2011 Thiele 2008 10 0 16 2 263 52 170 77 0.87 (0.35;2.17) Not estimable 0.38 (0.15;0.94) 0.19 (0.01;4.13) 271 53 185 77 27.5% 55.5% 17.0% 562 100.0% 0.53 (0.29;0.99) Total (95%) 586 636 Total events 16 28 Heterogeneity: Chi2 =2.58, df=2 (P=0.36);I2=2% Test for overall effect: Z=2.00 (P=0.05) 0.01 0.1 1 10 100 Favors IC Favors IV Background Abciximab IC versus IV Navarese et al. Platelets 2011;1-8

  5. Follow-up Background Study Design, Flow, and Compliance 2065 patients with suspected STEMI willing to participate Randomised (n=2065) Allocation • Intravenous abciximab (n=1033) • Received intervention (n=993) • Did not receive intervention (n=40) • STEMI not confirmed, no abciximab bolus (n=23) • emergency CABG, no abciximab bolus (n=8) • exclusion criteria detected before or during PCI, no abciximab bolus (n=5) • technical problems with PCI, no abciximab bolus (n=4) • Intracoronary abciximab (n=1032) • Received intervention (n=995) • Did not receive intervention (n=37) • STEMI not confirmed, no abciximab bolus (n=23) • emergency CABG, no abciximab bolus (n=5) • exclusion criteria detected before or during PCI, no abciximab bolus (n=5) • technical problems with PCI, no abciximab bolus (n=4) • Lost to follow-up (n=101) • Withdrew informed consent (n=31) • Lost to follow-up (n=15) • Incomplete documentation (n=15) • Premature study termination before receiving abciximab bolus (n=40 – see description above) • Lost to follow-up (n=97) • Withdrew informed consent (n=33) • Lost to follow-up (n=17) • Incomplete documentation (n=10) • Premature study termination before receiving abciximab bolus (n=37 – see description above) Primary endpoint analysis Analyzed at 90-day follow-up (n=935) Analyzed at 90-day follow-up (n=932) Thiele et al. Lancet 2012;379:923-31

  6. Background Combined Clinical Endpoint p=0.54 Cumulative event free survival from death, reinfarction and congestive heart failure [%] Intracoronary Abciximab Intravenous Abciximab Time from randomization [days] Thiele et al. Lancet 2012;379:923-31

  7. Background Congestive Heart Failure p=0.03 Intracoronary Abciximab Intravenous Abciximab Cumulative event free survival of congestive heart failure [%] Time from randomization [days] Thiele et al. Lancet 2012;379:923-31

  8. AIDA STEMI CMR Substudy • CMR enables investigation of mechanistic and pathophysiological effects of intracoronary + intravenous abciximab application on myocardial damage and reperfusion injury. • To determine potential benefits of intracoronary abciximab application on infarct size, myocardial salvage, microvascular obstruction and ventricular function to further evaluate the benefit with respect to congestive heart failure. Thiele et al. Am Heart J 2010;159:547-554

  9. CMR Prognostic Implications Prognostic relevance validated Prognostic relevance validated Prognostic relevance partly validated Prognostic relevance validated Prognostic relevance partly validated Prognostic relevance Hemorrhage Myocardial salvage Microvascular obstruction Infarct size LV Volumes + Ejection fraction Desch et al. Trials 2011:12:e204-215

  10. Methods Study Organization and Study Sites Investigator Initiated Trial 22 study sites in Germany 8 CMR study sites CMR core laboratory:Ingo Eitel (Coordinator) Josephine Meissner Henning Sünkel Holger Thiele DSMB:Uwe Zeymer Hans-Richard Arntz Christoph BodeKarl Wegscheider Steering Committee: Holger Thiele Jochen Wöhrle Oana Brosteanu Gerhard Schuler CRO: Clinical Trial Center Leipzig

  11. CMR Protocol Contrast-Injection 1,5 mmol/kg/BW Bolus Gd i.v. Area at risk + Hemorrhage late MO + Infarct size EF, EDV, ESV Methods 35 40 0 5 10 15 20 25 30 Time (min) Delayed enhancement 4CH + 2CH + SA T2 SA Function 4CH+2 CH FunctionShort axes Survey Thiele et al. Am Heart J 2010;159:547-554

  12. Methods CMR Image Analysis • Core laboratory assessed by blinded observers: • Edema • Hemorrhage • Endocardial contours • Epicardial contours • Infarct • Microvascular obstruction Area at risk = Volume Edema/Volume LV mass %Infarct Size = Volume Infarct/Volume LV mass %MO = MO-Volume/Volume LV mass %Hemorrhage = T2 hypointense core/Volume LV mass Myocardial salvage = Edema-Infarct Size Myocardial salvage index = Edema-Infarct Size/Edema Thiele et al. JACC 2010; 2010;55:2201-2209 Eitel et al. JACC 2010; 55:2470–2479

  13. Methods 401 assigned to intravenous abciximab Incomplete CMR scan - Scan terminated n=3 - T2 poor image quality n=40 - DE poor image quality n=10 Analyzed CMR data - LV function n=401 - T2-weighted imaging n=361 - DE imaging n=391 - MO n=390 - Hypointense core/Hemorrhage n=353 Study Design, Flow, and Compliance 2065 patients enrolled and randomly assigned No CMR (n=1270) 795 patients underwent CMR 394 assignedtointracoronary abciximab Incomplete CMR scan - Scan terminated n=4 - T2 poor image quality n=39 - DE poor image quality n=7 Analyzed CMR data - LV function n=394 - T2-weighted imaging n=355 - DE imaging n=387 - MO n=384 - Hypointense core/Hemorrhage n=346

  14. Results Patient Characteristics

  15. Results Study Procedures and Medications

  16. Infarct size 50 Median [IQR] 16% [9, 25] Median [IQR] 17% [8, 25] 40 p=0.52 30 Infarct size, %LV 20 10 0 IC abciximab N=385 IV abciximab N=389 Results Area at Risk + Infarct Size Area at risk Median [IQR] 35% [25, 48] Median [IQR] 35% [26, 48] p=0.97 Area at risk, %LV IC abciximab N=344 IV abciximab N=354

  17. Results Myocardial Salvage Index Median [IQR] 52 [35, 69] Median [IQR] 50 [29, 69] p=0.25 Myocardial salvage index IC abciximab N=342 IV abciximab N=352

  18. Hemorrhage p=0.19 37% 32% Presence Hemorrhage, % IC abciximab N=346 IV abciximab N=353 Results Reperfusion Injury Microvascular obstruction p=0.19 52% 47% Presence MO, % IC abciximab N=384 IV abciximab N=390

  19. Results CMR – LV Ejection Fraction Median [IQR] 51% [43, 58] Median [IQR] 50% [42, 58] p=0.95 LV ejection fraction, % IC abciximab N=342 IV abciximab N=352

  20. Results Infarct Size - Subgroups Mean Difference (95% CI) Infarct size (%LV) Baseline variable N Mean Difference (95% CI) p-value for interaction IC abciximab IV abciximab All Patients Male sex Female sex Age < 75 years Age ≥ 75 years Anterior MI Non-anterior MI Killip-class II to IV Killip-class I TIMI flow post PCI 0 to II TIMI-flow post PCI III Symptom onset-randomization < 3 h Symptom onset-randomization 3-6 h Symptom onset-randomization > 6h Thrombectomy No thrombectomy Prasugrel No prasugrel 774 586 188 656 118 353 388 91 683 89 685 334 296 136 187 587 173 419 18 (13) 18 (13) 18 (12) 18 (13) 18 (12) 21 (14) 15 (10) 28 (16) 16 (11) 24 (14) 17 (12) 17 (13) 19 (13) 18 (12) 20 (12) 17 (13) 18 (13) 19 (13) 18 (13) 18 (12) 19 (12) 18 (12) 21 (12) 21 (14) 15 (10) 25 (13) 17 (12) 19 (9) 18 (13) 15 (12) 20 (13) 20 (12) 19 (13) 18 (12) 17 (11) 19 (13) -0.2 (-2.9;1.5) 0.1 (-2.0;2.1) -1.4 (-4.9;2.1) 0.2 (-1.7;2.1) -3.1 (-7.6;1.3) 0.1 (-2.8;3.0) -0.7 (-2.7;1.3) 3.0 (-3.1;9.0) -0.9 (-2.8; 0.8) 4.4 (-0.5;9.3) -0.9 (-2,8;1.0) 2.0 (-0.7;4.6) -1.6 (-4.5;1.3) -1.2 (-5.3;2.8) 1.4 (-2.2;5.0) -0.8 (-2.9;1.2) 0.6 (-3.0;4.3) 0.2 (-2.2;2.7) 0.52 0.49 0.46 0.11 0.79 0.42 0.50 0.71 0.96 0.50 0.85 0.37 0.60 0.47 0.78 0.84 0.89 -6 -4 -2 0 2 4 6 IV better IC better

  21. Clinical Outcome 12 Months – CMR Substudy Results

  22. CMR and Outcome Results

  23. Summary + Conclusions • This largest multicenter CMR study in STEMI patients to date demonstrates that IC as compared to IV abciximab did not result in a difference in myocardial damage and/or reperfusion injury. • The results of the AIDA STEMI CMR substudy therefore confirm the lack of difference in the combined endpoint of death, reinfarction or congestive heart failure of the AIDA STEMI trial.

  24. Acknowledgement AIDA STEMI Investigators from 22 sites in Germany Steering Committee Clinical Trial Center at University Leipzig ECG Core Lab MRI Core Lab Sponsors Study Sites DSMB CEC

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