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Göran Olivecrona, MD, Phd Department of Cardiology Lund University

Hypothermia in awake STEMI patients: Results from the RAPID MI-ICE trial and insights to the CHILL MI trial: Why Hypothermia is Cool again. Göran Olivecrona, MD, Phd Department of Cardiology Lund University Skåne University Hospital , Sweden. 2011. Potential conflicts of interest.

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Göran Olivecrona, MD, Phd Department of Cardiology Lund University

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  1. Hypothermia in awake STEMI patients: Results from the RAPID MI-ICE trial and insights to the CHILL MI trial: Why Hypothermia is Cool again Göran Olivecrona, MD, Phd Department of Cardiology Lund University Skåne University Hospital, Sweden 2011

  2. Potential conflicts of interest Speaker’s name: Göran Olivecrona I have the following potential conflicts of interest to report: Other(s)  Unrestricted Grant, Innercool, Inc, San Diego, CA  Minor Lectur honorariums Jolife AB, Medtronic, Abbott Vascular Cordis, Physio Control Terumo Edwards Lifesciences

  3. Treatment of Myocardial infarction:Revascularisation • Thrombolysis • Primary-PCI

  4. Background hypothermia for the heart • Hypothermia protects the heart during: •  Cardiac surgery •  Heart transplantations

  5. Hypothermia in the prevention of MI Animal studies Hypothermia Control Open surgery ligation of LAD in pigs. 34 C during 40 out of 60 min ischemia (Radiant). Ischemia 60 min Reperfusion 3 h. Hypothermia 55 min End 15 minafter reperfusionSlow warm up 2 h Start after 20 min ischemia 80% relative reduction in infarct size (P < 0.001) Based on this study on 22 animals two major clinical trials were conducted xxx Dae MW, et al. 2002, Am J Physiol Heart Circ Physiol

  6. Reperfusion injury Infarction size Reperfusion Ischemia Time

  7. Mechanism of Cardioprotection • Cyclosporin: Mitocondria • C5a inhib: Complement • Adenosine: Inflammation • Postcond: Myocyte(?) • PKCdelta-: Myocyte apoptosis • ?: Metabolism • ?: Reactive hyperemia • ?: Endothelium • ?: Systemic effects Hypothermia

  8. Hypothermia for MI • Twofailedlargerclinical studies COOL MI  ICE IT • Failed because only 1/3 randomized to Hypothermia reached <35°C at time of Reperfusion ?

  9. Hypothermia for MI • Is target temp <35°C the key? • How can that be achieved? • How can we cool the awake patient? More basic animal research needed

  10. Hypothermia protocol for rapid cooling Combination hypothermia: Cold saline (4ºC), 1000 ml iv infusion in 5 min as a ”kick start” for quick initiation of hypothermia together with an endovascular cooling catheter. Celsius Control System™ Endovascular cooling catheter (14 F) Initiation and maintaining hypothermia 1000 ml cold saline (4ºC) Quick initiation of hypothermia

  11. Infarct size/area at risk (Porcine model) 39% reduction ~ 5 min to reach < 35ºC with cold saline and endovascular cooling Pre-reperfusion cooling reduce infarct size. Post-reperfusion cooling has no effect Gotberg et al., BMC Cardiovascular Disorders, 2008

  12. Speckled infarction in pig Wavefront phenomenon (Jennings) Normothermia Hypothermia Hypothermia causes disruption of the wavefront phenomenon. Götberg M et al . BMC Cardiovasc Disord. 2008, 8:7 Also seen in hypothermia treatment by Dae et al., Am J Physiol, 2002, with SPECT

  13. RAPID MI-ICE • The Rapid Intravascular Cooling in Myocardial Infarction as Adjunctive to Percutaneous Coronary Intervention study • (Safety & Feasibility study in man) • 20 Patients • Anterior or large Inferior STEMI • <6 hrs from onset of symtoms • Rapid infusion 1-2 liters 4°C Saline solution. • Endovascular cooling with Philips InnerCool endovascular system with Accutrol catheter starting before angiogram and continuing 3 h after PCI • Cardiac MRI day 4±2, infarct size/ myocardium at risk (T2 stir) • Primary outcome: Safety and Feasibility • Secondary outcome: Reduction in infarct size Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

  14. ECG Patient Info Randomization Patient prep, catheterization Angiography, PCI Hypothermia 14 ± 5 min 14 ± 6 min 15 ± 3 min Control 40 ± 6 min Arrival at cath lab Initiation of cold saline infusion Time of reperfusion Initiation of endovascular cooling End of PCI Feasibility 3 min prolonged procedure before reperfusion Temp: 34.7 ± 0.3°C at reperfusion All patients reached target temp Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

  15. Clinical and Angiographic Data VariableHypothermia (n=9)Control (n=9) Age62 ± 1058 ± 7 NS Women2 2 NS Hypertension 3 2 NS Diabetes 1 2 NS Infarct related artery   LAD 6 7 NS RCA 3 2 NS Initial TIMI flow 0/17 8 NS 2/32 1 NS Onset of symptoms 174 ± 51 174 ± 62 NS to reperfusion (min) Door-to-balloon time (min) 43 ± 7 40 ± 6 NS Successful revascularization9 9 NS TIMI 3 flow post PCI99 NS Thrombectomy8 7 NS Abciximab6 6 NS Bivalirudin3 3 NS 2/20 patients, One from each group was excluded for technical reasons Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

  16. Safety VariableHypothermia Control (n=9) (n=9) 30 day mortality0 0 Re-infarction0 0 CABG0 0 30 day MACE0 0 Heart failure0 3 VT/VF0 2 Stroke0 0 Infection3 0 Major bleeding0 0 Bradycardia0 0 NT-proBNP day 1 2000 1500 1000 NT-proBNP (ng/l) 500 0 Hypothermia Control Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

  17. Efficacy Reduction of infarct size Final Infarct Size/ Myocardium at Risk Reduction in Troponin (Peak value) Δ = 38% Δ = 43% p = 0·04 p = 0·01 80 8 70 7 60 6 50 5 Troponin T (ug/l) 40 Infarct size / Myocardium at risk 4 30 3 20 2 1 10 0 0 Hypothermia Control Hypothermia Control Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

  18. Speckledinfarction in man Gotberg et al. Circ Cardiovasc Interv. 2010 Oct;3(5):400-7.

  19. CHILL-MI Rapid Endovascular Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the Treatment of Acute Myocardial Infarction A Randomized, Controlled Study of the Use of Central Venous Catheter Core Cooling combined with cold saline as an Adjunct to Percutaneous Coronary Intervention For the Treatment of Acute Myocardial Infarction Principal Investigators David Erlinge and Göran Olivcecrona http://clinicaltrials.gov/ct2/show/NCT01379261?term=olivecrona&rank=1

  20. Protocol Patients will receive 1-2 liters of cold (4° C) saline solution upon arrival to cath lab, together with buspirone and meperidine. Endovascular cooling will begin prior to diagnostic angiography and PCI. After first reperfusion, cooling will be maintained for 1 hour. Then the cooling catheter will be removed and the patient will spontaneously rewarm at CCU. 120 patients at 10 sites in Europe

  21. Endpoint Primary Efficacy Endpoint: Cardiac MRI infarct size as a percentage of area at risk at 4±2 days. (MRI)

  22. Conclusions • Rapid induction of hypothermia with iv cold saline and • endovascular catheter reduces Infarct size by 38% in animals • and 39% in humans (infarct size/ area at risk). • Hypothermia treated animals and humans exhibit a • morphologically “different” infarkt (Speckled infarct) as • opposed to the wave front Phenomenon. • All patients in RAPID MI-ICE reached target temperature, • <35°C, before reperfusion. • Troponin T release was significantly reduced. • A larger trial to verify findings from animal research and • RAPID MI-ICE is needed: CHILL-MI (Start June 2011)

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