the subgroups of patients randomized to hypothermia and who reached

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 HospitalLund, Sweden

Disclosure statement: The study was partly sponsored by an unrestricted research grant from Innercool Therapies, a fully owned subsidiary of Philips Healthcare.

• In a pig model, we have shown that myocardial infarct size is significantly reduced only if the temperature < 35°C before reperfusion3.

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-IT4 and COOL MI5), 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 size1-2.

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.

RAPID MI-ICEThe 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 FeasibilitySecondary outcome: Reduction in infarct size

Timeline STEMI

Ambulance ReperfusionArrival Cathlab

30 min → several h 15 min 15 min

Angio-graphy

15 min

PCI

BuspironeMeperidine ivCold saline 1-2 l

Endovascular catheter placement

Temp

Feasibility

Arrival at cath lab

0 10 20 30 40 50 60 7033

34

35

36

37

HypothermiaControl

Time (min)

Tem

pera

ture

(C)

ECG Patient Info

Randomization

Time ofreperfusion

Initiation of cold saline

infusion

Initiation ofendovascular

cooling

Patient prep, catheterization Angiography, PCI

End of PCI

14 ± 5 min 14 ± 6 min 15 ± 3 min40 ± 6 min

HypothermiaControl

3 min prolonged procedure before reperfusion

Temp: 34.7 ± 0.3°C at reperfusion

All patients reached target temp

Clinical and Angiographic Data Variable Hypothermia (n=9) Control (n=9)Age 62 ± 10 58 ± 7 NS Women 2 2 NSHypertension 3 2 NSDiabetes 1 2 NSInfarct related artery  LAD 6 7 NS

RCA 3 2 NSInitial TIMI flow  0/1 7 8 NS

2/3 2 1 NSOnset of symptoms 174 ± 51 174 ± 62 NSto reperfusion (min)Door-to-balloon time (min) 43 ± 7 40 ± 6 NS

Successful revascularization 9 9 NSTIMI 3 flow post PCI 9 9 NSThrombectomy 8 7 NSAbciximab 6 6 NSBivalirudin 3 3 NS

2/20 patients, One from each group was excluded for technical reasons

Variable Hypothermia Control (n=9) (n=9)

30 day mortality 0 0Re-infarction 0 0 CABG 0 030 day MACE 0 0 Heart failure 0 3 VT/VF 0 2 Stroke 0 0 Infection 3 0 Major bleeding 0 0 Bradycardia 0 0

Safety

NT-proBNP day 1

Hypothermia Control0

500

1000

1500

2000

NT-

proB

NP

(ng/

l)

Reduction of infarct size Final Infarct Size/ Myocardium at Risk

Reduction in Troponin (Peak value)

Efficacy

p = 0·04

Hypothermia Control0

1020304050607080

Δ = 38%

Infa

rct s

ize

/ Myo

card

ium

at r

isk

Hypothermia Control012345678

Trop

onin

T (u

g/l)

p = 0·01Δ = 43%

Speckled infarction in pigWavefront 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

Speckled infarction in man

• 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