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: )

The Continuum of Care for 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) Myocardial Protection & Preservation (Endovascular Temperature Therapy) Regeneration (EGF, Angiogenesis) PRESENTFUTURE

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 0 2 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: H , Basic Res Cardiol 1998; 93: , Am J Physiol Heart Circ. Physiol 1996; 270: H , Am J Physiol Heart Circ. Physiol 1998; 274: H , Neurosurgery 1996; 39: , Thromb Haemost 1994; 71: , Basic Res Cardiol 2001; 86:

Endovascular Temperature Therapy in MI Goal: 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 Temperature Therapy System TM

Cooling in MI Pre-Clinical Evidence

Pre-Clinical Research Temperature & Infarct Size* Infarct Size (% of Area at Risk) Body Core Temperature (º C) y = 20x r = 0.84, p < * Am J Physiol Heart Circ. Physiol 1996; 270: H

Pre-Clinical Research Endovascular 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 * Am J Physiol Heart Circ. Physiol 2002; 285: H

Pre-Clinical Research Endovascular Cooling in MI* LigationReperfusion Cooling 1 hour3 hours OcclusionReperfusion Re-Occlusion Blue Dye TTC & Sestamibi HR, SBP, SV, CO * Am J Physiol Heart Circ. Physiol 2002; 285: H

Pre-Clinical Research -Endovascular Cooling in MI* Normothermic (Red) vs. Cooled (Blue) Temperature Plots Note: Temperature is not dependent on open artery. * Am J Physiol Heart Circ. Physiol 2002; 285: H

Pre-Clinical Research Endovascular Cooling in MI* 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 * Am J Physiol Heart Circ. Physiol 2002; 285: H

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: H

P = 0.6 P < Pre-Clinical Research - Endovascular Cooling in MI* Area at Risk & Infarct Size * Am J Physiol Heart Circ. Physiol 2002; 285: H

Cooling in MI The 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:

Clinical Sites St Vincent’s HospitalMelbourne, Australia William Beaumont Hospital Royal Oak, MI Rush-Presbyterian-St.Luke’s Medical CenterChicago, IL Alton-Oschner Medical CenterNew Orleans, LA Beth Israel Medical CenterNew York, NY Brigham & Women's HospitalBoston, MA Stanford University Medical CenterPalo Alto, CA Heart Center SiegburgSiegburg, Germany * JACC 2002; 40:

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 99m Tc-sestamibi SPECT imaging * JACC 2002; 40:

Study Design 42 Patients Key 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 Patients Key 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 PCI + Endovascular Cooling PCI Alone PCI Alone Endpoints: In-hospital & 30-day MACE, SPECT Infarct size at 30 days * JACC 2002; 40:

COOL MI Feasibility Trial Endovascular Cooling Protocol Cooling initiated before PCI (in ER or cath lab) Target temperature 33 o 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:

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:

Patient Demographics* Cooling (n=21)Control (n=21) Age 52  9 ( ) 58 ± 14 ( ) Female2 (10%)5 (24%) Diabetes4 (19%)6 (29%)* Hypertension5 (24%)12 (57%) Hyperlipidemia9 (43%)5 (24%) Smoker14 (67%)11 (52%) Previous MI3 (14%)1 (5%) Previous PCI1 (5%)0 Previous CABG1 (5%)0 Anterior infarct9 (40%)10 (48%) Inferior infarct12 (60%)11 (52%) *p=0.02 * JACC 2002; 40:

Procedural Data* Cooling (n=21)Control (n=21) PCI performed20 (95%)21 (100%) Door-to-balloon (mins) 87 ± ± 44 Initial TIMI flow 0/116 (76%)14 (67%) 203 (14%) 35 (29%)4 (19%) Stent15 (71%)16 (76%) AngioJet use3 (14%)4 (19%) GP IIb/IIIa inhibitor15 (71%)18 (86%) Final TIMI-3 flow19 (90%) * JACC 2002; 40:

Core Temperature During Cooling* * JACC 2002; 40:

Hemodynamics During Cooling* TIME (Mins) AosAodHR * JACC 2002; 40:

In-hospital Adverse Events* Cooling (n=21)Control (n=21) Death Recurrent MI Repeat PCI CABG MACE Stroke/TIA Cardiogenic shock Pulmonary edema VT/VF Bradycardia Hematoma >6cm Transfusion 0 1 (5%) 0 1 (5%) 3 (14%) 1 (5%) 2 (10%) 0 2 (10%) 0 2 (10%) 0 2 (10%) 0 6 (29%) 4 (19%) 0 * JACC 2002; 40:

Final Infarct Size at 30-days ( Tc-99m SPECT)* ControlTest % Reduction Median82 75% Mean % * JACC 2002; 40: TIMI 0-1TIMI 2-3Median Group Infarct Size Assigned infarct size for patients who died

COOL MI Feasibility Trial Conclusion The feasibility study was successful –Safety –Feasibility of endovascular temperature therapy –Feasibility of shivering suppression –Feasibility of study design

COOL MI Pivotal Trial

COOL MI Pivotal Trial Summary  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 Key Exclusion : Prior MI < 1 month, Cardiogenic Shock, Hypersensitivity to cold or anti-shivering agents 400 Patients Key Inclusion: Acute MI >30 min and< 6 Hours, Anterior and Large Inferior MIs Key Exclusion : Prior MI < 1 month, Cardiogenic Shock, Hypersensitivity to cold or anti-shivering agents PCI + Endovascular Cooling PCI Alone PCI 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