A pooled analysis of the effect of

endovascular cooling on infarct

size in patients with STEMI

David Erlinge1, Matthias Götberg1, Cindy Grines2,

Simon Dixon2, Kenneth Baran3, David Kandzari4 &

Göran K Olivecrona1

(1)Department of Cardiology, Skane University Hospital, Lund University,

221 85, Lund, Sweden.

(2) William Beaumont Hospital in Royal Oak, Michigan, USA

(3) Saint Paul Minnesota, MN, USA.

(4) Piedmont Heart Institute, Atlanta, GA, USA.

Cardioprotection with hypothermia

• Mild hypothermia (32-35° C) is one of the most

efficient methods to reduce infarct size in animal

models.

• Hypothermia protects during ischemia1

• Hypothermia protects against reperfusion injury2

• Hypothermia has no effect when initiated after

reperfusion3

1 Duncker et al. 1996 (Am J Physiol), Dae MW, et al. 2002 (Am J Physiol), Götberg M et al . BMC Cardiovasc Disord. 20082 Götberg M et al . Basic Research in Cardiology (in press)3 Tissier et al. 2010. Cardiovascular Research (Review)

Early clinical trials

22,7

16,3

12,9

17,6

0

5

10

15

20

25

Hypothermia Control

%Control (N = 38)

All Hypo (N = 36)

Tpci <35 (N = 10)

Tpci >35 (N = 26)

COOL-MI Trial (Radiant) ICE-IT (Innercool)

P = 0.09 (43% reduction)

• Both trials were negative in the overall cohort.

• Only 1/3 of the patients randomized to hypothermia reached a

temperature < 35°C at the time of reperfusion.

• In patients cooled to < 35º C before reperfusion, a trend for

reduction in infarct size was seen in both trials

RAPID MI-ICE: Design

Based on animal experiments we designed the

RAPID MI-ICE trial using a combination of cold

saline and an endovascular catheter to induce

rapid cooling

• 20 Patients

• Anterior or large Inferior STEMI

• <6 hrs from onset of symtoms

• Rapid infusion 1-2 liters 4°C Saline solution.

• Cooling with Philips InnerCool endovascular

system starting before angiogram and continuing

3h after PCI

RAPID MI-ICE: Results

We reached target temperature < 35°C at the time

of reperfusion in all cooled patients.

Hypothermia Control0

10

20

30

40

50

60

70

80

38%

Infa

rct

siz

e /

Myo

card

ium

at

risk

Reduction of infarct size

Final Infarct Size/ Myocardium at Risk

P=0.04

Hypothermia Control0

1

2

3

4

5

6

7

8 43%

Tro

po

nin

T (

ug

/l)

Reduction in Troponin

(AUC)

Götberg et al. Circulation Cardiovascular Interventions, 2010

Pooled analysis of

ICE-IT and RAPID MI-ICETo guide the design of our next trial CHILL-MI, we did a

pooled analysis of the two trials using the Philips Innercool

endovascular cooling system (ICE-IT and RAPID MI-ICE).

Infarct size was evaluated with SPECT at day 30 in ICE-IT

and with MRI after 4±2 days in RAPID MI-ICE.

Our questions were:

1.Is a core body temperature of <35°C before reperfusion

necessary?

2.Is there a difference in effect of hypothermia between

anterior and inferior infarcts?

3.Is there a difference in effect of hypothermia between

infarcts with long compared to short duration of

symptoms prior to reperfusion time?

Per Protocol Population

Patients were excluded from analysis if:

• Infarct size was not determined

• Prior MI or repeat MI prior to SPECT

• If cooling treatment was intended but never initiated

• If PCI was not performed

• If the onset-of symptoms to hospital presentation

exceeded 6 hours.

The ICE-IT study included 228 patients and RAPID

MI-ICE included 20 patients.

In the final per protocol population, 179 patients from

ICE-IT and 18 patients from RAPID MI-ICE were

examined for a total of 197 patients.

Results in pooled analysis

Infarct size was reduced

Contr

ol

Hyp

other

mia

0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

24%

Infarct size, all, p=0.049

Infa

rct

siz

e (

%L

VM

)

All patients (both anterior and inferior infarctions) regardless of temperature

at reperfusion (n= 103 control vs. 94 hypothermia).

Temperature at reperfusion

• Reaching temperature <35°C before

reperfusion results in a 37% reduction in infarct

size.

• Those not cooled before reperfusion did not

benefit

Control Hypothermia0.0

2.5

5.0

7.5

10.0

12.5

15.0

17.5

37%

All infarcts <35 C, p=0.01

Infa

rct

siz

e (

%L

VM

)

Treated with >35 C, p=n.s.

Contr

ol

Hyp

other

mia

0

5

10

15

20

Infa

rct

siz

e (

%L

VM

)

Anterior vs. Inferior

Anterior and inferior infarcts had a similar benefit

Contr

ol

Hyp

other

mia

0

5

10

15

20

2533%

Infarct size, anterior <35 C, p=0.03

Infa

rct

siz

e (

%L

VM

)

Control Hypothermia0.0

2.5

5.0

7.5

10.0

42 %

Infarct size, inferior <35 C, p=0.04

Infa

rct

siz

e (

%L

VM

)

Time to reperfusion

Early and late presenters had a similar trend

toward infarct reduction

Symptom to PCI < 4h, p=0.15

Contr

ol

Hyp

other

mia

0

5

10

15

Infa

rct

siz

e (

%L

VM

)

Symptom to PCI 4-6 h, p=0.07

Contr

ol

Hyp

other

mia

0

5

10

15

20

25

Infa

rct

siz

e (

%L

VM

)

Conclusion

• A pooled analysis of ICE-IT and RAPID MI-ICE

demonstrate that hypothermia induced by

endovascular cooling results in a significant

reduction in infarct size in the whole per protocol

population.

• Reaching temperature <35°C before reperfusion

results in a 37% reduction in infarct size.

• Those not cooled before reperfusion did not

benefit.

• Anterior and inferior infarcts had a similar benefit.

• Early and late presenters seem to have similar

benefit.

CHILL-MI

• Based on these results we have designed CHILL-MI as a

trial including both anterior and large inferior STEMI of up to 6

hours of symptoms prior to inclusion.

• Combination cooling with a rapid infusion of 1-2 liters 4°C

saline solution and endovascular cooling with Philips

InnerCool endovascular system starting before angiogram

and continuing 1 h after reperfusion.

• 10 participating centers in Sweden, Denmark, Germany and

Austria.

• 120 patients.

• Primary endpoint: Reduction in infarct size/myocardium at

risk both determined by cardiac MRI at day 4±2,

• Initiation meeting was held in Lund May 16.