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Peter Clemmensen MD, PhD, FESC

Strategies to reduce AMI size during reperfusion therapy. Peter Clemmensen MD, PhD, FESC Department of Cardiology B, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Disclosure of Conflict of Interest.

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Peter Clemmensen MD, PhD, FESC

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  1. Strategies to reduce AMI size during reperfusion therapy Peter Clemmensen MD, PhD, FESC Department of Cardiology B, The Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

  2. Disclosure of Conflict of Interest The presenter has previously or currently been involved in research contracts, consulting or received research and educational grants from: AstraZeneca, Aventis, Bayer, Bristol Myers Squibb, Eli-Lilly, Merck, Myogen, Medtronic, Mitsubishi Pharma, Nycomed, Organon, Pfizer, Pharmacia, Sanofi-Synthelabo, Searle.

  3. Strategies to reduce AMI size during reperfusion therapy TARGETS Epicardial Flow Myocardial Perfusion Myocardial Oxygenation Myocyte surface Intracellular mechanisms “Inflammation” Organisational

  4. The GUARDIAN Trial(Guard During Ischemia Against Necrosis) • A multicenter, double-blind, randomized, placebo-controlled, phase IIb/III trial • The first large-scale trial to test the hypothesis that potent and selective Na+/H+ (NHE) inhibition with cariporide provides direct cardiocellular protection in high-risk coronary situations

  5. GUARDIAN Study Design Randomization Patients at riskMI / Death • Entry groups: • UA / non-Q-wave MI • High-risk PCI • High-risk CABG Drug administration IV cariporide for 2 to 7 days • Treatment arms: • Placebo • 20 mg tid • 80 mg tid • 120 mg tid Follow - up • 10 days • 36 days (primary endpoint) • 180 days • Primary Endpoint: • Death or MI • (ECG and CK-MB • evaluation by Core Lab)

  6. Primary Endpoint ResultsRelative Risk Entry/Trt Group Death/MI UAP/NQMI Placebo12.4% 20mg 13.6% 80mg 12.9% 120mg 12.6% PTCA Placebo 12.1% 20mg 9.4% 80 mg 12.5% 120 mg 11.1% CABG Placebo 16.7% 20mg 18.1% 80mg 18.2% 120mg 12.8% Relative Risk (95% C.I.) 0.8 1 1.2

  7. Epicardial vs. Myocardial Reperfusion

  8. No Reflow in Reperfused AMI CAG MCE Ito Circ. 1996;93:1993 CAG MCE

  9. Reperfusion Therapy Targets against No-Reflow GP IIb/IIIa receptor antagonists CD 9/11 receptor antagonists Complement System inhibition

  10. LIMIT AMI Trial (n=493) Methods rhuMAB (White Cell CD 18 blockade) +thrombolysis Endpoint: TIMI Frame Count Results: No difference ACC 2001

  11. APEX AMI Trial: Study Design 5745 patients > 18 yrs with acute MI within 6 hours of symptom onset; high-risk anterior lateral or inferior MI; planned primary PCI; or new left-bundle branch block excluding those with prior fibrinolytic therapy for treatment of the index MI; complement deficiency; pregnant; breast-feeding; isolated, low-risk, inferior wall MI Prospective. Double-Blind. Placebo-Controlled. Randomized. Mean follow-up 90 days. 23% female, mean age 61 years, mean follow-up 90 days. R Placebo 2 mg/kg bolus + 0.05 mg/kg/hr for 24 hours n=2885 Pexelizumab 2mg/kg bolus + 0.05 mg/kg/hr for 24 hours n=2860 90 days follow-up • Primary Endpoint: All-cause mortality through 30 days. • Secondary Endpoint: Death at day 90 and the composite of death, cardiogenic shock, or congestive heart failure through days 30 or 90. Armstrong et al., JAMA. 2007 Jan; 297(1):43 - 51.

  12. APEX AMI Trial: Primary Endpoint Primary endpoint of 30 day mortality • There was no difference in the primary endpoint (mortality at 30 days) between placebo and pexelizumab (3.9% vs 4.1% respectively), ie, each experiencing a low mortality. p = 0.78 % patients Armstrong et al., JAMA. 2007 Jan; 297(1):43 - 51.

  13. F.I.R.E. – a Phase II trial of FX06 in STEMI FX06: A Novel Compound Small peptide derived from the human fibrin sequence Human fibrinopeptide Bß15-42, MW 3039 D Prepared by solid phase peptide synthesis Mode of action FX06: peptide that potently inhibits the binding of fibrin E1 fragment to vascular endothelial (VE) cadherin Preserves endothelial barrier function, prevents capillary leak Inhibits transmigration of inflammatory cells through endothelium Exhibits anti-inflammatory effect F.I.R.E. - Rationale To investigate the cardioprotective efficacy of FX06 as an adjunct to reperfusion therapy in patients with acute ST elevation myocardial infarction (STEMI) To assess safety and tolerability

  14. Study flowchart 4m MACE/CMR 0 min FX06 1.5h CKMB 10 min FX06 24h Troponin 48h Troponin 2m MACE 5-7d CMR 400 mg FX06 i.v. (n = 114) STEMI at - 6 to 0 hrs Primary PCI R Follow-up 4 months Placebo(n = 120) Visit 2 Visit 3 Visit 1 2 day in house follow up Treatment R = randomisation

  15. Acute Myocardial Infarction Imaged with LGE CMR LV lumen normal myocardium MVO zone necrotic core zone total LGE zone

  16. 5 days post PCI: No difference in total late enhancement zone Necrotic core significantly reduced (ITT Population) Median with 25- and 75-percentile 4.2 (0.30;9.93) 27.34(11.74;44.89) 21.68(8.33;47.09) 1.77 (0; 9.09) * statistically significant # Wilcoxon rank sum test • Incidence of microvascular obstruction (MVO): 27.6% versus 37.5% • (not statistically significant)

  17. 4 mths post PCI: No difference in • Total late enhancement zone • Scar mass (ITT population) Median with 25- and 75-percentile 2.84(0.35; 7.26) 19.32(7.51;31.37) 1.79(0;8.78) 15.37(5.70;36.43) # Wilcoxon rank sum test

  18. Clinical Results and Left Ventricular Function 8 Months after Primary PCI Performed with and without Distal ProtectionNew Observations from the DEDICATION Trial Henning Kelbæk, Klaus Kofoed, Leif Thuesen, Jens F. Lassen, Christian Juhl Terkelsen, Peter Clemmensen, Steffen Helqvist, Lene Kløvgaard, Anne Kaltoft, Lars Krusell, Kari Saunamäki, Erik Jørgensen, Hans E. Bøtker, Jan Ravkilde, Hans Henrik T. Hansen, Evald H. Christiansen, Thomas Engstrøm, Lars Køber Copenhagen University Hospital Rigshospitalet Aarhus University Hospital Skejby Denmark

  19. Number of Patients STEMI - PPCI n = 626 Randomization - Distal Protection n = 314 + Distal Protection n = 312

  20. Endpoints Primary: LVEF at 8 months Secondary: LVEF at discharge Δ LVEF from discharge to 8 months MACCE at 8 months

  21. TIMI flow pre and post procedure p < 0.001 post procedure* * By core lab analysis Distal Protection Conventional Treatment % of patients ns pre procedure

  22. 8 months Clinical Events p=0.52 p=1.00 p=1.00 p=0.17 p=0.11 p=0.73

  23. Change in LVEF after PPCI within groups Distal Protection 65 65 60 60  5.1%  5.6% 55 55 50 50 45 45 40 40 p < 0.01 35 35 30 30 Before Discharge 8-month Follow-Up n=247 n=257 Conventional Treatment L VEF, % p < 0.01 Before Discharge 8-month Follow-Up n=234 n=245  5.1% vs  5.6% = ns

  24. Cardioprotective Effects of Mechanical Postconditioning in Patients Treated with Primary PCI Evaluated with Magnetic Resonance Thomas Engstrøm, Jacob T Lønborg, Niels Vejlstrup, Erik Jørgensen, Steffen Helqvist, Kari Saunamäki, Peter Clemmensen, Lene Holmvang, Marek Treiman, Jan S Jensen, Henning Kelbæk Copenhagen University Hospital Rigshospitalet Denmark

  25. Occluded Reperfusion coronary artery Conventional treatment Post- conditioning 30 30 30 30 30 30 30 30 sec Balloon inflations - deflations Postconditioning Reperfusion injury Reperfusion injury

  26. Endpoints • Primary: • Infarct size measured with CMR 3 months after the initial • procedure (analysis blinded)

  27. Outcomes CMR p=0.007 Δ 32% p=0.987 p=0.007 p=0.037

  28. Strategies to reduce AMI size during reperfusion therapy TARGETS Epicardial Flow Myocardial Perfusion Myocardial Oxygenation Myocyte surface Intracellular mechanisms “Inflammation” Organisational

  29. Early treatment in AMI: reappraisal of the golden hour Boersma et al. Lancet 1996;348: 771-75

  30. Odds for Mortality Associated with Longer Door-to-drug Time P=0.0001 P=0.01 P=NS n=28,624 n=33,867 n=11,616 n=10,316 Cannon et al. JACC 2000 (Abstract, Suppl A)

  31. Use of Thrombolytic Therapies in Eligible Patients RT=reperfusion therapy Barron HV, et al. Circulation 1998

  32. Mortality in Men and Women, by Age  Adapted from Chandra NC et al. Arch Intern Med 1998

  33. STEMI In-hospital mortality 40% 20% <10%

  34. Conclusions Lack of myocardial reperfusion is not uncommen despite angiographic patency of the infarct related coronary (epicardial) artery Hybrid reperfusion strategies have not overcome this limitation after either fibrinolysis or primary PCI

  35. Conclusions With the current <10% case fatality rate in STEMI, it becomes increasingly difficult for new treatment principles to demonstrate superiority on hard endpoints. Conditioning currently holds the greater potential. In the quest to salvage more mycardium and save more lives, there remains a large potential in optimizing the STEMI networks and improving pre-hospital and hospital organisations.

  36. Circulation 2002;105:1285-1290

  37. SAFER Distal protection Guardwire (median graft age 10.4 y) n=406 Enrolled n=801 Stent implantation Standard guide wire (median graft age 10.9 y) n=395 Circulation 2002;105:1285-1290

  38. SAFER Event rate at 30 days (%) p=0.004 p=0.08 Circulation 2002;105:1285-1290

  39. SAFER Angiographic events (%) p=0.001 p=0.001 Circulation 2002;105:1285-1290

  40. FIRE Filter Wire n=332 Enrolled n=651 Stent implantation Guard Wire n=319 Circulation 2003;108:548-553

  41. FIRE Event rate at 30 days (%) Circulation 2003;108:548-553

  42. X-tract + X-Sizer (75% SVG) n=400 Enrolled n=797 Stent implantation - X-Sizer (72% SVG) n=397 JACC 2003;42:2007-2013

  43. X-tract Event rate at 30 days (%) p=0.04 JACC 2003;42:2007-2013

  44. X-tract Angiographic events (%) p=0.04 JACC 2003;42:2007-2013

  45. FINDINGS / COMPOSITION Fibrin Thrombi Fatty streaks Calcificed plaque Blood clots Endothelium Leucocytes Macrophage foam cells DIPLOMAT Filter debris analysis

  46. DIPLOMAT Filter debris analysis * Discover: Native (n=35) Mean 247 + 21 SVG (n=49) Mean 313 + 19

  47. ST Resolution and Mortality ST-RES > 70% ST-RES 30-70% ST-RES < 30% AJC

  48. HYBRID REPERFUSION TIMI 3, 90 min tPA 15/35 Abx tPA 5/5 Abx tPA 15/35 Eptifibatide

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