ICE-IT-1

Intravascular Cooling Adjunctive

to Percutaneous Coronary Intervention
(Part 1)

A Preliminary Review of Results

TCT 2004

Cindy L. Grines, MD, FACC

ICE-IT-1 National PI
William Beaumont Hospital
Royal Oak, MI
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 Background
• Preclinical
¾ Hypothermia reduces MI size in multiple animal models
¾ 80%* relative reduction in pigs (P < 0.001)
• Clinical
¾ COOL-MI Trial^
• 325 STEMI patients (157 control, 168 hypothermia)
– No difference in Day 30 SPECT infarct size (1o endpoint)
– Control Arm (13.8%) vs. Hypothermia Arm (14.1%), p = 0.83
• Cooling deemed safe and well-tolerated
• Possible “dose-response” relationship in anterior MI subgroup

*Dae MW, et al. Am J Physiol Heart Circ Physiol 2002;282:H1584-91.

^Presented at TCT 2003 by WW O’Neill. 2
 COOL-MI
Anterior MIs – Day 30 SPECT Infarct Size

Presented at TCT 2003 by WW O’Neill, MD

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 ICE-IT-1
Study Objective

To evaluate the safety and efficacy of mild

hypothermia, as induced with the Celsius
Control™ System, when used as an adjunct to
PCI treatment of STEMI

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Celsius Control™ System

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 Study Design
Acute STEMI
Anterior or Large Inferior
(< 6 hrs of Sx onset)

1 : 1
Standard Care (PCI)
Standard Care (PCI) +
Hypothermia

• Primary Endpoint: Day 30 SPECT infarct size

• Secondary Endpoints:
CK-MB, NYHA Functional Class at Day 30, MACE
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 Acute MI Location
By Baseline ECG

Hypothermia Control
P
N = 114 N = 114

Anterior 50 (44%) 49 (43%) NA*

Large Inferior 64 (56%) 65 (57%) NA*

*NA: randomization algorithm stratified on the basis of infarct location

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 Demographics
Hypothermia Control
P
N = 114 N = 114
Age
Mean ± SD (years) 57 ± 13 57 ± 12 0.99

Patients ≥ 75 yrs 14 (12%) 6 (5%) 0.094

Patients < 75 yrs 100 (88%) 108 (95%)
Gender
Men 75% 80% 0.34
Women 25% 20%
Ethnicity
Caucasian 86% 88% 0.63
Non-Caucasian 14% 12%

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Baseline Clinical Characteristics
Hypothermia Control
P
N = 114 N = 114
Stroke 2% 1% 1.00

TIA 1% 1% 1.00

Arrhythmia 4% 1% 0.37

Diabetes 20% 13% 0.12

Hypertension 54% 46% 0.19

Smoker 46% 54% 0.29

CHF 3% 0% 0.25

Prior MI 0% 2% 0.50

Prior thrombolytic 12% 12% 1.00

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 Angiographic Parameters
Hypothermia Control P
No. CAD Vessels N = 114 N = 114
1-vessel 45% 40% 0.88
2-vessel 28% 34%
3-vessel 20% 20%
4-vessel 4% 4%
Other 3% 2%
Collateral Flow N = 106 N = 108
Grade 0 74% 69% 0.91
Grade 1 20% 23%
Grade 2 5% 5%
Grade 3 2% 3%
Mean ± SD 0.35 ± 0.66 0.41 ± 0.71 0.51
LV-gram Done N = 79 N = 83 0.56
LVEF (Mean ± SD) 47 ± 11 49 ± 12 0.15
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 PCI Results: TIMI Flow
Hypothermia Control
P
N = 104 N = 105
Initial TIMI Flow
0 64% 68% 0.91
1 13% 11%
2 11% 10%
3 12% 11%
Mean ± SD 0.69 ± 1.1 0.64 ± 1.1 0.63
Final TIMI Flow
0 0% 0% 0.80
1 0% 0%
2 11% 10%
3 89% 90%
Mean ± SD 2.9 ± 0.3 2.9 ± 0.3 0.80

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 PCI Results (Cont.)
Hypothermia Control
P
N = 104 N = 105
PCI Successful* 104 (100%) 104 (99%) 1.00
Sx-to-Door (min) 137 ± 98 132 ± 90 0.84
Door-to-Balloon (min) 103 ± 66 93 ± 42 0.27
Ancillary Device
98 / 104 (94%) 101 / 105 (96%) 0.54
Used
Stent 100% 99% 1.00
Thrombectomy 13% 14% 0.90
Embolic Protection 2% 1% 0.62

*Success = final TIMI 2 or 3 flow, and <50% residual stenosis 12

 Cooling Results
All Patients (Mean Values)

Control Hypothermia
37
Mean Manual Temp. (C)

* * *
* * * * *
36 * *
*

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*P < 0.0001

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33
-2 0 2 4 6 8 10 12 14 16 18
Time (hours)
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Age-Stratified Mortality Rates

• Hypothermia Arm: 9 deaths

¾ Age ≥ 75 Mortality: 36% (5 / 14)
¾ Age < 75 Mortality: 4% (4 / 100)

• Control Arm: 5 deaths

¾ Age ≥ 75 Mortality: 33% (2 / 6)
¾ Age < 75 Mortality: 3% (3 / 108)

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 Major Adverse Cardiac Events
All Patients

Hypothermia Control P
MACE thru Day 30 N = 114 N = 114
any MACE 10 6 0.29
death (any) 9 4 0.15
re-infarction 2 0 0.25
stroke 0 0 ***
severe CHF 0 3 0.25
MACE (any) @ 3 mo. 10 8 0.62
MACE (any) @ 6 mo. 11 9 0.59
MACE (any) @ 12 mo. 12 11 0.58
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 Major Adverse Cardiac Events
Patients < 75 years-old

Hypothermia Control P
MACE thru Day 30 N = 100 N = 108
any MACE 5 4 0.74
death (any) 4 2 0.43
re-infarction 1 0 0.48
stroke 0 0 ***
severe CHF 0 3 0.25
MACE (any) @ 3 mo. 5 5 1.00
MACE (any) @ 6 mo. 6 6 0.82
MACE (any) @ 12 mo. 7 8 0.77
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 Other Adverse Events
No Significant Differences

Hypothermia Control
P
N = 114 N = 114

Any General AE (thru 2d) 76% 69% 0.23

Any SAE (thru 2d) 17% 16% 0.86

Infection or FUO (thru 30d) 28% 25% 0.65

Any SAE (3d thru 30d) 12% 13% 0.70

Revascularization* (thru 30d) 13% 11% 0.66

*PTCA or CABG of any vessel

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 Primary Efficacy Endpoint
Day 30 SPECT Infarct Size

• Population Evaluable for Primary Endpoint

¾ 217 pts (108H / 109C)
¾ Includes 13 deaths (9H / 4C)
• Imputed “worst outcome” by AMI location
• 58% (of LV) imputed for anterior MI deaths
• 35% (of LV) imputed for inferior MI deaths
¾ Excludes 11 pts lost to follow-up (6H / 5C)

• Patients with Actual (Measured) SPECT

¾ 204 pts (99H / 105C)
¾ No imputed values
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 Primary Efficacy Endpoint
Mean SPECT Infarct Size (% of LV)

20 P = 0.77
23% Relative Reduction
P = 0.14

14.2
15 13.5 13.2

10.2
Hypothermia
% 10 Control

0 N = 108 N = 109 N = 99 N = 105

All Evaluable Measured*

Patients SPECT
*No imputed values
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 Primary Efficacy Endpoint
Mean SPECT Infarct Size^ (% of LV): By MI Location

25
20.9
20
15.3
15
Hypothermia
%
10 Control
7.4
6.5

0 N = 41 N = 45 N = 58 N = 60

Anterior Inferior
27% Relative Reduction 12% Relative Reduction
P = 0.15 P = 0.60

^No imputed values 20

 Site-Dependent Results
Relative Reductions in Mean SPECT Infarct Size

N Relative
Protocol Compliance P
(Hyp / Ctl) Reduction*

Excellent (6 sites) 58 / 58 44% 0.017

Good (15 sites) 20 / 31 11% 0.699

Fair (2 sites) 21 / 16 – 134% 0.104

TOTAL (23 sites) 99 / 105 23% 0.142

*Negative value represents an increase in infarct size (Hyp vs. Ctl)

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 Temp at PCI – All Sites
Anterior MIs – Mean SPECT Infarct Size^ (% of LV)
P = 0.13 (28% reduction)

25 P = 0.09 (43% reduction)

22.7

20
17.6
16.3

15 12.9 Control (N = 38)

% All Hypo (N = 36)
10 Tpci <35 (N = 10)
Tpci >35 (N = 26)
5

0
Hypothermia Control
^No imputed values 22
 Temp at PCI – All Sites
Inferior MIs – Mean SPECT Infarct Size^ (% of LV)
P = 0.60 (12% reduction)

P = 0.16 (39% reduction)

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7.7
8 7.4
6.5

6 Control (N = 59)
% 4.5
All Hypo (N = 50)
4 Tpci <35 (N = 19)
Tpci >35 (N = 31)
2

0
Hypothermia Control
^No imputed values 23
 Secondary Endpoint
Normalized Peak CK-MB (Value / ULN)
11% Relative Reduction
P = 0.096
60
54

50 48

40
CK-MB

Hypothermia
30
Control
20
P = 0.079

10 5.9 4.8

0 N = 70 N = 68 N = 88 N = 87

Admission Peak
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 Conclusions
• ICE-IT-1
¾ Baseline population imbalance
• Hypothermia arm had more elderly patients ≥ 75yrs.
• Age-adjusted mortality and MACE rates virtually identical

¾ Analysis of SPECT data (without imputed values)

• Suggests that a 20 – 40% relative reduction of infarct size is possible
• Cooling “dose response” observed (≤ 35°C at time of reperfusion)
– Observed in both anterior and inferior MIs.

• ICE-IT-2
¾ Initial planning underway

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