1. Cold saline and endovascular cooling induces rapid hypothermia before reperfusion in STEMI patients treated with primary PCI, is safe and reduces infarct size with a scattered myocardial salvage Presented by Prof David Erlinge, MD, PhD, On behalf of the RAPID MI-ICE Investigators Matthias Götberg, MD, Göran Olivecrona, MD,PhD, Sasha Koul, MD, Marcus Carlsson, MD, PhD, Henrik Engblom, MD, PhD, Martin Ugander, MD, PhD, Jesper van der Pals, MD, Lars Algotsson, MD, PhD Håkan Arheden, MD, PhD, David Erlinge, MD, PhD Lund University, Skane University Hospital Lund, Sweden Disclosure statement: The study was partly sponsored by an unrestricted research grant from Innercool Therapies, a fully owned subsidiary of Philips Healthcare.

2. In a pig model, we have shown that myocardial infarct size is significantly reduced only if the temperature < 35°C before reperfusion 3. 1 Duncker et al. 1996 (Am J Physiol 270, H1189), 2 Dae MW, et al. 2002 (Am J Physiol Heart Circ Physiol 282:H1584- 91)., 3 Götberg M et al. BMC Cardiovasc Disord. 2008, 8:7, 4 Grines CL et al. TCT 2004, 5 O'Neill WW et al. TCT 2004 Two large randomized trials using hypothermia as adjunct treatment to primary PCI in patients with acute MI (ICE-IT 4 and COOL MI 5 ), failed to reach primary endpoint. However, only 1/3 of the patients randomized to hypothermia reached a core body temperature < 35°C at the time of reperfusion. The subgroups of patients randomized to hypothermia and who reached < 35°C at the time of reperfusion seemed to benefit (RRR 49% and 43% respectively) Hypothermia in Acute MI A large number of animal studies have shown that hypothermia reduces myocardial infarct size 1-2.

3. Hypothermia in Acute MI We hypotesized that a combination of cold saline and endovascular cooling would cool all patients to target temp < 35°C before primary PCI reperfusion.

4. 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

5. Timeline STEMI Ambulance Reperfusion Arrival Cathlab 30 min → several h 15 min Angio- graphy 15 min PCI Buspirone Meperidine iv Cold saline 1-2 l Endovascular catheter placement Temp

6. Feasibility Arrival at cath lab ECG Patient Info Randomization Time of reperfusion Initiation of cold saline infusion Initiation of endovascular cooling Patient prep, catheterization Angiography, PCI End of PCI 14 ± 5 min14 ± 6 min15 ± 3 min 40 ± 6 min Hypothermia Control 3 min prolonged procedure before reperfusion Temp: 34.7 ± 0.3°C at reperfusion All patients reached target temp

7. Clinical and Angiographic Data VariableHypothermia (n=9)Control (n=9) Age62 ± 1058 ± 7NS Women2 2 NS Hypertension3 2 NS Diabetes1 2 NS Infarct related artery LAD6 7NS RCA3 2 NS Initial TIMI flow 0/17 8 NS 2/32 1 NS Onset of symptoms 174 ± 51174 ± 62NS to reperfusion (min) Door-to-balloon time (min)43 ± 740 ± 6NS Successful revascularization9 9NS TIMI 3 flow post PCI99NS Thrombectomy8 7 NS Abciximab6 6 NS Bivalirudin3 3 NS 2/20 patients, One from each group was excluded for technical reasons

8. VariableHypothermia Control (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 Safety NT-proBNP day 1 HypothermiaControl 0 500 1000 1500 2000 NT-proBNP (ng/l)

9. Reduction of infarct size Final Infarct Size/ Myocardium at Risk Reduction in Troponin (Peak value) Efficacy p = 0·04 HypothermiaControl 0 10 20 30 40 50 60 70 80 Δ = 38% Infarct size / Myocardium at risk HypothermiaControl 0 1 2 3 4 5 6 7 8 Troponin T (ug/l) p = 0·01 Δ = 43%

10. Speckled infarction in pig Wavefront phenomenon (Jennings) Hypothermia Normothermia 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

11. Speckled infarction in man

12. Troponin T release was significantly reduced. Rapid induction of hypothermia with 1-2 l cold saline and endovascular catheter is safe and feasible in awake patients with acute MI. Conclusions Myocardial infarct size was significantly reduced. A Randomized multicenter trial with hypothermia to reduce infarct size is planned (CHILL-MI). All patients reached target temperature, <35°C, at the time of reperfusion. Hypothermia disrupts the wavefront phenomenon into a speckled infarction. The study is accepted for publication in Circulation: Cardiovascular Interventions