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ICEICE--ITIT--11

A Preliminary Review of ResultsA Preliminary Review of ResultsTCT 2004TCT 2004

Cindy L. Grines, MD, FACCCindy L. Grines, MD, FACCICEICE--ITIT--1 National PI1 National PI

William Beaumont HospitalWilliam Beaumont HospitalRoyal Oak, MIRoyal Oak, MI

Intravascular Cooling Adjunctiveto Percutaneous Coronary Intervention

(Part 1)

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BackgroundBackground

•• PreclinicalPreclinicalHypothermia reduces MI size in multiple animal models80%* relative reduction in pigs (P < 0.001)

•• ClinicalClinicalCOOL-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.

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COOLCOOL--MIMI

Presented at TCT 2003 by WW O’Neill, MD

Anterior MIs Anterior MIs –– Day 30 SPECT Infarct SizeDay 30 SPECT Infarct Size

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ICEICE--ITIT--11Study ObjectiveStudy Objective

To evaluate the safety and efficacy of mild To evaluate the safety and efficacy of mild hypothermia, as induced with the Celsius hypothermia, as induced with the Celsius ControlControl™™ System,System, when used as an adjunct towhen used as an adjunct toPCI treatment of STEMIPCI treatment of STEMI

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Celsius ControlCelsius Control™™ SystemSystem

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Study DesignStudy DesignAcute STEMI

Anterior or Large Inferior

(< 6 hrs of Sx onset)

Standard Care (PCI)+

HypothermiaStandard Care (PCI)

1 : 1

• Primary Endpoint: Day 30 SPECT infarct size

• Secondary Endpoints:CK-MB, NYHA Functional Class at Day 30, MACE

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Acute MI LocationAcute MI LocationBy Baseline ECGBy Baseline ECG

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

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

PControlN = 114

HypothermiaN = 114

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

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DemographicsDemographics

Ethnicity0.6388%86%Caucasian

12%14%Non-Caucasian

Gender0.3480%75%Men

0.9957 ± 1257 ± 13Mean ± SD (years)

0.0946 (5%)14 (12%)Patients ≥ 75 yrs

20%25%Women

108 (95%)100 (88%)Patients < 75 yrs

Age

PControlN = 114

HypothermiaN = 114

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Baseline Clinical CharacteristicsBaseline Clinical Characteristics

0.250%3%CHF

0.502%0%Prior MI

1.0012%12%Prior thrombolytic

0.1946%54%Hypertension

0.2954%46%Smoker

1.001%1%TIA

0.371%4%Arrhythmia

0.1213%20%Diabetes

1.001%2%Stroke

PControlN = 114

HypothermiaN = 114

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Angiographic ParametersAngiographic Parameters

5%5%Grade 2

0.9169%74%Grade 023%20%Grade 1

3%2%Grade 3

0.56N = 83N = 79LV-gram Done0.1549 ± 1247 ± 11LVEF (Mean ± SD)

20%20%3-vessel34%28%2-vessel

N = 108N = 106Collateral Flow

0.8840%45%1-vessel

4%4%4-vessel2%3%Other

N = 114N = 114No. CAD Vessels

0.510.41 ± 0.710.35 ± 0.66Mean ± SD

PControlHypothermia

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PCI Results: TIMI FlowPCI Results: TIMI Flow

10%11%2

0%0%10.800%0%0

11%13%1

10%11%290%89%3

Final TIMI Flow

0.802.9 ± 0.32.9 ± 0.3Mean ± SD

11%12%3

0.9168%64%0Initial TIMI Flow

0.630.64 ± 1.10.69 ± 1.1Mean ± SD

PControlN = 105

HypothermiaN = 104

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PCI Results (Cont.)PCI Results (Cont.)

0.84132 ± 90137 ± 98Sx-to-Door (min)

1.00104 (99%)104 (100%)PCI Successful*

0.9014%13%Thrombectomy

1.0099%100%Stent

0.54101 / 105 (96%)98 / 104 (94%)Ancillary Device Used

0.621%2%Embolic Protection

0.2793 ± 42103 ± 66Door-to-Balloon (min)

PControlN = 105

HypothermiaN = 104

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

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Cooling ResultsCooling ResultsAll Patients (Mean Values)All Patients (Mean Values)

33

34

35

36

37

-2 0 2 4 6 8 10 12 14 16 18Time (hours)

Mean Manual Temp. (C)

Control Hypothermia

*

*P < 0.0001

* ** * * * *

* * *

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AgeAge--Stratified Mortality RatesStratified Mortality Rates

•• Hypothermia Arm: 9 deathsHypothermia Arm: 9 deathsAge ≥ 75 Mortality: 36% (5 / 14)Age < 75 Mortality: 4% (4 / 100)

•• Control Arm: 5 deathsControl Arm: 5 deathsAge ≥ 75 Mortality: 33% (2 / 6)Age < 75 Mortality: 3% (3 / 108)

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Major Adverse Cardiac EventsMajor Adverse Cardiac EventsAll PatientsAll Patients

0.2530severe CHF

0.59911MACE (any) @ 6 mo.

0.1549death (any)

0.2502re-infarction

***00stroke

0.62810MACE (any) @ 3 mo.

0.29610any MACE

0.581112MACE (any) @ 12 mo.

P

N = 114N = 114MACE thru Day 30

ControlHypothermia

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Major Adverse Cardiac EventsMajor Adverse Cardiac EventsPatients < 75 yearsPatients < 75 years--oldold

0.2530severe CHF

0.8266MACE (any) @ 6 mo.

0.4324death (any)

0.4801re-infarction

***00stroke

1.0055MACE (any) @ 3 mo.

0.7445any MACE

0.7787MACE (any) @ 12 mo.

P

N = 108N = 100MACE thru Day 30

ControlHypothermia

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Other Adverse EventsOther Adverse EventsNo Significant DifferencesNo Significant Differences

0.6611%13%Revascularization* (thru 30d)

0.6525%28%Infection or FUO (thru 30d)

0.8616%17%Any SAE (thru 2d)

0.7013%12%Any SAE (3d thru 30d)

0.2369%76%Any General AE (thru 2d)

PControlN = 114

HypothermiaN = 114

*PTCA or CABG of any vessel

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Primary Efficacy EndpointPrimary Efficacy Endpoint

•• Population Evaluable for Primary EndpointPopulation Evaluable for Primary Endpoint217 pts (108H / 109C)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

Excludes 11 pts lost to follow-up (6H / 5C)

•• Patients with Actual (Measured) SPECTPatients with Actual (Measured) SPECT204 pts (99H / 105C)No imputed values

Day 30 SPECT Infarct SizeDay 30 SPECT Infarct Size

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Primary Efficacy EndpointPrimary Efficacy EndpointMean SPECT Infarct Size (% of LV)Mean SPECT Infarct Size (% of LV)

13.5

10.2

14.213.2

0

5

10

15

20

All EvaluablePatients

Measured*SPECT

% HypothermiaControl

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

*No imputed values

23% Relative Reduction

P = 0.14P = 0.77

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Primary Efficacy EndpointPrimary Efficacy EndpointMean SPECT Infarct Size^ (% of LV): Mean SPECT Infarct Size^ (% of LV): By MI LocationBy MI Location

^No imputed values

15.3

6.5

20.9

7.4

0

5

10

15

20

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Anterior Inferior

% HypothermiaControl

N = 41 N = 45

27% Relative Reduction

P = 0.15

N = 58 N = 60

12% Relative Reduction

P = 0.60

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SiteSite--Dependent ResultsDependent Results

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

0.69911%20 / 31Good (15 sites)

0.14223%99 / 105TOTAL (23 sites)

0.104– 134%21 / 16Fair (2 sites)

0.01744%58 / 58Excellent (6 sites)

PRelative Reduction*

N(Hyp / Ctl)

Protocol Compliance

Relative Reductions in Mean SPECT Infarct SizeRelative Reductions in Mean SPECT Infarct Size

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22.7

16.3

12.9

17.6

0

5

10

15

20

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Hypothermia Control

%Control (N = 38)All Hypo (N = 36)Tpci <35 (N = 10)Tpci >35 (N = 26)

Temp at PCI Temp at PCI –– All SitesAll SitesAnterior MIsAnterior MIs –– Mean SPECT Infarct Size^ (% of LV)Mean SPECT Infarct Size^ (% of LV)

P = 0.13 (28% reduction)

^No imputed values

P = 0.09 (43% reduction)

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7.4

6.5

4.5

7.7

0

2

4

6

8

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Hypothermia Control

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

Temp at PCI Temp at PCI –– All SitesAll SitesInferior MIsInferior MIs –– Mean SPECT Infarct Size^ (% of LV)Mean SPECT Infarct Size^ (% of LV)

P = 0.60 (12% reduction)

^No imputed values

P = 0.16 (39% reduction)

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5.9

48

4.8

54

0

10

20

30

40

50

60

Admission Peak

CK

-MB

HypothermiaControl

Secondary EndpointSecondary EndpointNormalized Peak CKNormalized Peak CK--MB (Value / ULN)MB (Value / ULN)

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

P = 0.079

11% Relative Reduction

P = 0.096

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ConclusionsConclusions•• ICEICE--ITIT--11

Baseline population imbalance• Hypothermia arm had more elderly patients ≥ 75yrs. • Age-adjusted mortality and MACE rates virtually identical

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.

•• ICEICE--ITIT--22Initial planning underway