Presented by Prof David Erlinge, MD, PhD, On behalf of the RAPID MI-ICE Investigators

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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 Hypothermia in Acute MI A large number of animal studies have shown that hypothermia reduces myocardial infarct size 1-2. In a pig model, we have shown that myocardial infarct size is significantly reduced only if the temperature < 35 C before reperfusion 3. 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) 1 Duncker et al (Am J Physiol 270, H1189), 2 Dae MW, et al (Am J Physiol Heart Circ Physiol 282:H )., 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

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: Secondary outcome: Safety and Feasibility Reduction in infarct size

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

6 Temperature (C) Feasibility ECG Patient Info Randomization Patient prep, catheterization Angiography, PCI 14 ± 5 min 14 ± 6 min 15 ± 3 min 40 ± 6 min Hypothermia Control 37 3 min prolonged procedure before reperfusion Hypothermia Control Temp: 34.7 ± 0.3 C at reperfusion Time (min) All patients reached target temp Arrival at cath lab Initiation of cold saline infusion Initiation of endovascular cooling Time of reperfusion End of PCI

7 Clinical and Angiographic Data Variable Hypothermia (n=9) Control (n=9) Age 62 ± ± 7 NS Women 2 2 NS Hypertension 3 2 NS Diabetes 1 2 NS Infarct related artery LAD 6 7 NS RCA 3 2 NS Initial TIMI flow 0/1 7 8 NS 2/3 2 1 NS Onset of symptoms 174 ± ± 62 NS to reperfusion (min) Door-to-balloon time (min) 43 ± 7 40 ± 6 NS Successful revascularization 9 9 NS TIMI 3 flow post PCI 9 9 NS Thrombectomy 8 7 NS Abciximab 6 6 NS Bivalirudin 3 3 NS 2/20 patients, One from each group was excluded for technical reasons

8 NT-proBNP (ng/l) Safety Variable Hypothermia Control (n=9) (n=9) NT-proBNP day 1 30 day mortality 0 0 Re-infarction 0 0 CABG day MACE 0 0 Heart failure VT/VF 0 2 Stroke Infection 3 0 Major bleeding Bradycardia Hypothermia Control

9 Infarct size / Myocardium at risk Troponin T (ug/l) Efficacy Reduction of infarct size Final Infarct Size/ Myocardium at Risk Reduction in Troponin (Peak value) Δ = 38% p = 0 04 Δ = 43% p = Hypothermia Control 0 Hypothermia Control

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

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