Cooling in MI. Myocardial Protection and Preservation "Cell protection is the new challenge for...

Cooling in MI

Myocardial Protection and Preservation

"Cell protection is the new challenge for patient management in coronary

care units, the catheterization laboratory, and the operating room,

broadening our management strategies for acute coronary

syndromes"

"Cell protection may be the next breakthrough in clinical cardiology"

Pierre Theroux (Circulation 2000:101: 2874-2876)

The Continuum of Carefor the Ischemic Myocardium

• Reperfusion is not enough• Protecting and preserving the

myocardium is the next evolution of care for these patients

Reperfusion(PCI, Lytics, Anti-thrombotic)

Mechanical Prevention/ Support(Filters, Traps, LVAD)

MyocardialProtection &Preservation(EndovascularTemperatureTherapy)

Regeneration(EGF, Angiogenesis)

PRESENT FUTURE

Metabolic Support &Myocardial Preservation

• There is considerable research that demonstrates that cooling to mildly hypothermic levels (32-33°C)*:– Reduces infarct size– Decreases myocardial and whole body

metabolism and 02 demand on ischemic myocardium

– Enhances ATP retention and prolongs tissue viability

– Reduces inflammatory response– Decreases platelet aggregation– Increases myocardial efficiency

* Am J Physiol Heart Circ. Physiol 2002; 285: H1584-91, Basic Res Cardiol 1998; 93: 372-83, Am J Physiol Heart Circ. Physiol 1996; 270: H1189-99, Am J Physiol Heart Circ. Physiol 1998; 274: H786-793, Neurosurgery 1996; 39: 1200-5, Thromb Haemost 1994; 71: 633-40, Basic Res Cardiol 2001; 86: 195-205

Endovascular Temperature Therapy in

MIGoal: Cell protection and preservation in

ischemic tissues

• No current therapies preserve cells. Focus has been on reperfusion and mechanical barriers, i.e. filters

• Cell death continues during and after reperfusion is established

• Closed loop, 10 Fr central venous heat exchange catheter 0ptimized for rapid cooling and warming

• Easy-to-use heat exchange cassette facilitates rapid initiation of therapy and patient transfer

• Easy-to-use second generation controller efficiently delivers thermal energy

• U.S. FDA 510(k) clearance in June, 2002 for use in cardiac surgery to achieve and/or maintain normothermia

Endovascular TemperatureTherapy System

TM

Cooling in MIPre-Clinical Evidence

Pre-Clinical ResearchTemperature & Infarct Size*

100

80

60

40

20

0

34 35 36 37 38 39 40

Infa

rct

Siz

e(%

of

Are

a at

Ris

k)

Body Core Temperature (º C)

y = 20x - 720r = 0.84, p < 0.001

* Am J Physiol Heart Circ. Physiol 1996; 270: H1189-99

Pre-Clinical ResearchEndovascular Cooling in MI*

• Study Design– 22 human sized swine with LAD ligation to

simulate MI– Randomized to endovascular cooling (34°

C) or normothermia (38° C) utilizing the Reprieve™ System

– Measured hemodynamics, area at risk and infarct size

• Heart rate, Systolic BP, Stroke Volume and Cardiac Output

• Blue dye to identify area at risk• TTC and sestamibi TC99m to measure infarct

size



Ligation Reperfusion

Cooling

1 hour 3 hours

Occlusion Reperfusion

Re-Occlusion

Blue DyeTTC & Sestamibi

HR, SBP, SV, CO


Pre-Clinical Research -Endovascular Cooling in MI*

Normothermic (Red) vs. Cooled (Blue) Temperature Plots

Note: Temperature is not dependent on open artery.



• Results– Cooling reduced infarct size by 80%

• Major protection occurred at target temp of 34°C

• No increase in arrhythmia

– Cardiac output maintained during ischemia and reperfusion• Decrease in heart rate• Increase in stroke volume


Pre-Clinical Research - Endovascular Cooling in MI*

Area at Risk & Infarct Size

Sestamibi

AAR/TTC

HypothermiaNormothermia

White area = infarcted tissue* Am J Physiol Heart Circ. Physiol 2002; 285: H1584-91

0

10

20

30

40

50

AAR (% LV) IF (% AAR)

%

Normothermia

Cooled

P = 0.6

P < .000001

Pre-Clinical Research - Endovascular Cooling in MI*

Area at Risk & Infarct Size


Cooling in MIThe COOL MI™ Feasibility

Trial

Systemic Hypothermia as an Adjunct

to Primary Angioplasty for Acute Myocardial Infarction*

Results of a Safety and Feasibility Study

SR Dixon, MBChB; RJ Whitbourn, MBBS, FRACP; Michael W. Dae, MD, FACC; Eberhard Grube, MD; Warren Sherman, MD,

FACC; Gary L. Schaer, MD, FACC; Stephen Jenkins, MD, FACC; Donald S. Baim, MD, FACC; Raymond J. Gibbons, MD, FACC;

Richard E. Kuntz, MD, FACC; Jeffrey J. Popma, MD, FACC; Thanh T. Nguyen, DO; William W. O'Neill, MD, FACC

* JACC 2002; 40: 1928-34

Clinical Sites

• St Vincent’s Hospital Melbourne, Australia

• William Beaumont Hospital Royal Oak, MI

• Rush-Presbyterian-St.Luke’s Medical Center Chicago, IL

• Alton-Oschner Medical Center New Orleans, LA

• Beth Israel Medical Center New York, NY

• Brigham & Women's Hospital Boston, MA

• Stanford University Medical Center Palo Alto, CA

• Heart Center Siegburg Siegburg, Germany

* JACC 2002; 40: 1928-34

Study Objective

• To determine:– Feasibility and safety of endovascular

cooling in patients with acute MI undergoing

primary PCI– Feasibility of shivering management– Preliminary efficacy assessment

• Infarct size at 30-days with 99mTc-sestamibi SPECT imaging

* JACC 2002; 40: 1928-34

Study Design

42 PatientsKey Inclusion: Acute MI < 6 Hours, Anterior and Large Inferior MI’s

Key Exclusion: Prior MI < 1 month, Cardiogenic Shock, Hypersensitivity to cold or anti-shivering agents

42 PatientsKey Inclusion: Acute MI < 6 Hours, Anterior and Large Inferior MI’s


PCI + Endovascular

Cooling

PCI + Endovascular

Cooling

PCI

Alone

PCI

Alone

Endpoints: In-hospital & 30-day MACE, SPECT Infarct size at 30 daysEndpoints: In-hospital & 30-day MACE, SPECT Infarct size at 30 days

* JACC 2002; 40: 1928-34

COOL MI Feasibility Trial Endovascular Cooling

Protocol• Cooling initiated before PCI (in ER or cath

lab)

• Target temperature 33o C

• Cooling maintained for 3-hours after PCI

• Re-warming over 1-2 hours

• Core temperature monitored with naso-esophageal probe

• Skin warming (forced air blanket), oral buspirone and, intravenous meperidine used to prevent shivering

* JACC 2002; 40: 1928-34

Shivering Management

Skin Sensor

Management

Drug-Brain

Threshold

Endovascular

Temperature

Optimal Endovascular Therapy is dependent on successfully managing three interdependent

factors•Adequate dosing with Buspirone and Meperidine to reduce shivering threshold

•Use of warm air blanket to “fool” skin receptors

•Rate of cooling the core and temperature maintentance

* JACC 2002; 40: 1928-34

Patient Demographics*

Cooling (n=21)

Control (n=21)

Age 52 9 (39 - 73)

58 ± 14 (32 - 83)

Female 2 (10%) 5 (24%)Diabetes 4 (19%) 6 (29%)*Hypertension 5 (24%) 12 (57%)Hyperlipidemia 9 (43%) 5 (24%)Smoker 14 (67%) 11 (52%)Previous MI 3 (14%) 1 (5%)Previous PCI 1 (5%) 0Previous CABG 1 (5%) 0Anterior infarct 9 (40%) 10 (48%)Inferior infarct 12 (60%) 11 (52%)

*p=0.02*p=0.02* JACC 2002; 40: 1928-34

Procedural Data*

Cooling (n=21)

Control (n=21)

PCI performed 20 (95%) 21 (100%)Door-to-balloon (mins)

87 ± 30 104 ± 44

Initial TIMI flow 0/1

16 (76%) 14 (67%)

2

0 3 (14%)

3

5 (29%) 4 (19%)

Stent 15 (71%) 16 (76%)AngioJet use 3 (14%) 4 (19%)GP IIb/IIIa inhibitor

15 (71%) 18 (86%)

Final TIMI-3 flow 19 (90%) 19 (90%)* JACC 2002; 40: 1928-34

Core Temperature During Cooling*

* JACC 2002; 40: 1928-34

Hemodynamics During Cooling*

020406080

100120140160180

0 30 60 90 120 150 180 210 240TIME (Mins)

Aos Aod HR

* JACC 2002; 40: 1928-34

In-hospital Adverse Events*

Cooling (n=21)

Control (n=21)

DeathRecurrent MIRepeat PCICABGMACEStroke/TIACardiogenic shockPulmonary edemaVT/VFBradycardiaHematoma >6cmTransfusion

000

1 (5%)000

1 (5%)3 (14%)3 (14%)1 (5%)1 (5%)

2 (10%)0

2 (10%)0

2 (10%)0

2 (10%)0

6 (29%)4 (19%)

00

* JACC 2002; 40: 1928-34

Final Infarct Size at 30-days(Tc-99m SPECT)*

Control Test % Reduction

Median 8 2 75%

Mean 10.8 6.6 39%* JACC 2002; 40: 1928-34

0

5

10

15

20

25

30

35

40

45

50

Infa

rct

Siz

e a

t 3

0 d

ay

s (

%L

V) TIMI 0-1

TIMI 2-3

Testn=18

Controln=18

TIMI 0-1 TIMI 2-3 Median Group Infarct Size

Assigned infarct size for patients who died

COOL MI Pivotal Trial

COOL MI Pivotal TrialSummary

Multi-center, prospective randomized study consisting of 400 patients at up to 25 sites

Designed to evaluate the safety and effectiveness of endovascular cooling as an adjunctive therapy to PCI in patients with AMI when compared to PCI alone

Adult patients with chest pain >30 min but <6 hrs, diagnosed with anterior or large inferior infarcts and eligible for primary PCI

Study Design

400 Patients

Key Inclusion: Acute MI >30 min and< 6 Hours, Anterior and Large Inferior MIs


400 Patients

Key Inclusion: Acute MI >30 min and< 6 Hours, Anterior and Large Inferior MIs


PCI + Endovascular Cooling

PCI + Endovascular Cooling

PCI AlonePCI

Alone

Primary Effectiveness Endpoint: SPECT Infarct size at 30 days

Primary Safety Endpoint: MACE, all-cause mortality and adverse events

Secondary Endpoints: LVEF (using SPECT at 30 days), Cardiac Enzymes, Myocardial Blush, ST-segment resolution and hematological responses

Primary Effectiveness Endpoint: SPECT Infarct size at 30 days

Primary Safety Endpoint: MACE, all-cause mortality and adverse events

Secondary Endpoints: LVEF (using SPECT at 30 days), Cardiac Enzymes, Myocardial Blush, ST-segment resolution and hematological responses

COOL MI Pivotal Trial Study Management

• Principal Investigator: William O’Neill, MD, Director Division of Cardiology, William Beaumont Hospital

• Data Management & Analysis: Harvard Clinical Research Institute (HCRI) – Richard Kuntz, MD

• Nuclear Imaging Core Laboratory: Mayo Clinic – Raymond Gibbons, MD

• Angiographic Core/Blush Laboratory: HCRI – Jeffrey Popma, MD

• ECG Core Laboratory: HCRI – Peter Zimetbaum, MD

COOL MI Pivotal Trial Summary

• Initial clinical results with endovascular temperature therapy in AMI support the pre-clinical findings of decreased infarct size.

• Pivotal trial initiated in late 2001, enrollment nearly complete as of 1/1/2003

• Results to be presented in 2003

Cooling in MI. Myocardial Protection and Preservation "Cell protection is the new challenge for...

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