Hypothermia in Acute MI: Rationale and Results of the

RAPID MI-ICE StudyPresented by Goran Olivecrona, MD, PhD.

On behalf of 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, PhDHåkan Arheden, MD, PhD, David Erlinge, MD, PhD

Lund University

Skane University Hospital,

Lund, Sweden

Disclosure Statement of Financial Interest

• Grant/Research Support

• Consulting Fees/Honoraria

• Innercool, San Diego, CA

• Jolife AB, Sweden• Physio Control, Redmond WA• Cordis, Europe• Abbott Vascular, Europe• Edwards Lifesciences, Europe• Medtronic Vascular, Scandinavia• B Braun, Germany

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

The RAPID MI-ICE Study was partly sponsored by an unrestricted research grant from Innercool Therapies, a fully owned subsidiary of Philips Healthcare.

Practical experience from patients surviving drowning in cold water

Basic research in which hypothermia reduces ischemia induced necrosis of a large number of cell types. Prominent effect’s on neurological tissues.

Therapy to prevent brain damage after cardiac arrest (VF) with ROSC.

Hypothermia is used successfully during Cardiovascular Surgery.

Hypothermia Background

Final Infarct size (% of area at risk):

35 C 0% ! 36 C 20% 37 C 40% 38 C 60% 39 C 80%

Results:Greater myocardial salvage

with lower temperature

Hypothermia to Reduce Myocardial Infarct Size Animal studies (ligated LAD)

Hypothermia prior to ischemia1

Hypothermia after onset ischemia3

Results:80% relative reduction in

Infarct size1 Duncker et al. 1996 (Am J Physiol 270, H1189),2 Maeng et al. 2006 (Basic Res Cardio 101: 61-68)3Dae MW, et al. 2002 (Am J Physiol Heart Circ Physiol 282:H1584-91).

Reperfusion 3 h Start at Reperfusion

Ischemia 45 min

Hypothermia 3h

Reperfusion 4 h

Start before Ischemia

Ischemia 45

minHypothermia 5h

Reperfusion 3 h

Start after 20 min End 15 minof ischemia after reperfusion Slow warm up

Ischemia 60 minHypothermia 55 min

Hypothermia after reperfusion2

Results:No myocardial salvage

with hypothermia

• Two large randomized trials using hypothermia as adjunct

treatment to primary PCI in patients with acute MI (ICE-IT1 and COOL

MI2), 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 Grines CL et al. TCT 2004, 2O'Neill WW et al. TCT 2004

Hypothermia to Reduce Myocardial Infarct Size: Human Studies

Hypothermia to Reduce Myocardial Infarct Size: New Animal studies (LAD occluded with balloon)

Rapid induction of hypothermia with 1. Rapid infusion cold saline 2. Intravascular cooling catheter

Area at risk Final infarct size

39% 17%

39%P <0.05

35% 28%

42% 31%

Götberg M et al . BMC Cardiovasc Disord. 2008, 8:7,

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 prospectively randomized

• 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

The study is e-published ahead of print in Circulation: Cardiovasc Interv

Timeline STEMI

Ambulance ReperfusionCathlab

30 min → several h 15 min 15 min

Angio-graphy

15 min

PCI

BuspironeMeperidine ivCold saline 1-2 l

Endovascular catheter placement

Temp

Arrival at cath lab

0 10 20 30 40 50 60 7033

34

35

36

37

HypothermiaControl

Time (min)

Tem

per

atu

re (

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 min

40 ± 6 min

HypothermiaControl

3 min prolonged procedure before reperfusion

Temp: 34.7 ± 0.3°C at reperfusion

Feasibility- RAPID MI-ICE

All patients reached target temp

RAPID MI-ICE Clinical and Angiographic Data Variable Hypothermia (n=9) Control (n=9)

Age 62 ± 10 58 ± 7 NS

Women 2 2 NS

Hypertension 3 2 NS

Diabetes 1 2 NS

Infarct related artery  LAD 6 7 NS

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

2/3 2 1 NS

Onset of symptoms 174 ± 51 174 ± 62 NSto 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 NS2/20 patients, One from each group was excluded for technical reasons

Variable Hypothermia Control

(n=9) (n=9)

30 day mortality 0 0

Re-infarction 0 0

CABG 0 0

30 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

NT-proBNP day 1

Hypothermia Control0

500

1000

1500

2000

NT-

pro

BN

P (

ng

/l)

Safety- RAPID MI-ICE

Salvaged areas within the area at risk

T2 STIR MRI Evaluation- RAPID MI-ICE

Reduction of infarct size Final Infarct Size/ Myocardium at Risk

Reduction in Troponin (Peak value)

p = 0·04

Hypothermia Control0

10

20

30

40

50

60

70

80

Δ = 38%

Infa

rct

size

/ M

yoca

rdiu

m a

t ri

sk

Hypothermia Control0

1

2

3

4

5

6

7

8

Tro

po

nin

T (

ug

/l)

p = 0·01

Δ = 43%

Efficacy- RAPID MI-ICE

• Troponin T release was significantly reduced.

• Rapid induction of hypothermia with 1-2 l cold saline in combination with an endovascular cooling 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.

The study is e-published ahead of print in Circulation: Cardiovascular Interventions