Cardiogenic Shock Where Do We Go After The SHOCK Trial William W. O’Neill, MD Henry Ford Health System Medical Director Center for Structural Heart Disease Detroit, MI

Pathogenesis of Myocardial Dysfunction During Cardiogenic Shock Diffuse Multivessel Disease  Border Zone Dysfunction Diffuse Multivessel Disease  Lack of Compensatory Hyperkinesis Central Zone Dyskinesis PROFOUND FORWARD PUMP FAILURE Systemic Hypotension Acidosis Coronary Hypoperfusion

Probability of Survival Based On Arterial Blood Lactate 100 75 50 25 2 4 6 8 10 Probability of Survival (%) Lactate mM

Cardiogenic Shock Complicating Acute Myocardial Infarction U MICHIGAN EPERIENCE 1983-1985 Cardiogenic Shock Complicating Acute Myocardial Infarction Lee et al Circulation 1987

SHOCK Trial 1-Year Survival p=0.025 p=0.01

Mortality Based on Admission Blood Pressure in Thrombolytic Trials Hypotension SBP <= 90 * SBP <= 80 * systolic blood pressure in mmHg

Incidence of Cardiogenic Shock Growing Cardiogenic Shock in STEMI Increasing 1 STEMI Cardiogenic Shock in Medicare Age Increasing 2 56,508 36,969 53% A recent increase in the incidence of cardiogenic shock in both the overall STEMI population and the Medicare patient population emphasizes the importance of focusing on this critical patient population. While some believe this is partially driven by better documentation, the result is a rate approximately 50% higher than that documented in previous literature (10-12% vs 5-7%). 2010 2014 Age >65 only, excludes non-Medicare population 1. Dhaval Kolte et al. J Am Heart Assoc 2014 NATIONWIDE INPATIENT SAMPLE 2. Centers for Medicare and Medicaid database, MEDPAR FY14 HCS-PMA-PP01224-005 rA

Limitations of Conventional Therapy 2/21/2018 Limitations of Conventional Therapy Mortality Risk with Inotropes/Vasopressors1 N = 40 IABP-SHOCK II Randomized Controlled Trial2 N = 600 IABP (n=301) Medical Therapy (n=299) 41.3% 39.7% Conventional therapy is largely driven by the use of inotropes and vasopressors, which have long been known to be associated with high mortality rates as both dosage and number is increased. Recent randomized controlled trials have challenged the benefit of IABP in the setting in AMI cardiogenic shock . Even basic hemodynamic benefit was not observed because IABP is only augmenting the native heart function, which is low or nonexistent in this population. Large randomized controlled trials have also shown no mortality benefit. Meta-analysis of IABP and the PAMI-II trial showed an increased hazard risk for stroke leading to a class 3, harm/no benefit, level of evidence A, in 2014 ESC guideline updates 1- Samuels LE et al , J Card Surg. 1999 2- Thiele H et al. NEJM 2012 - Clinicaltrial.gov # NCT00491036 HCS-PMA-PP01224-033 rA

Inotrope Harm in Cardiogenic Shock Marked increase in MVO2 at a time of oxygen starvation. Tachycardia increases MVO2 and decreases diastolic interval. Marked increase in LVEDP causes further decrease in diastolic perfusion pressure and increased wall tension. Tachycardia mediated apoptosis may decrease myocardial recovery.

New FDA Indication For Cardiogenic Shock 2/21/2018 The Impella 2.5™, Impella CP®, Impella 5.0 ™ and Impella LD ™ catheters, in conjunction with the Automated Impella Controller console, are intended for short-term use (<4 days for the Impella 2.5 and Impella CP and <6 days for the Impella 5.0 and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs immediately (<48 hours) following acute myocardial infarction (AMI) or open heart surgery as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures with or without an intra-aortic balloon pump. The intent of the Impella system therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function. * Optimal medical management and conventional treatment measures include volume loading and use of pressors and inotropes, with or without IABP HCS-PMA-PP01224-002 rA

Hemodynamic Effects of Impella® Support Outflow (aortic root) Inflow (ventricle) aortic valve Cardiac Power Output Flow End Organ Perfusion MAP Coronary Perfusion Microvascular Resistance LVEDP and LVEDV O2 Demand Unloading to Myocardial Recovery O2 Supply Mechanical Work Wall Tension Est. In-Hospital Mortality Cardiac Power Output (Watts) Cardiac Power Output (MAP x Cardiac Output x 0.0022) Fincke, et. al. JACC, 2009 SHOCK TRIAL (n=189) The principles of the Impella heart pump design allow for direct unloading of the left ventricle from the inflow, and increased MAP and flow in the aorta from the outflow of the device. The ability to unload the left ventricle by reducing your Left ventricular end diastolic pressures and volumes reduce wall tension, microvascular resistance, and increasing coronary perfusion. This results in overall improvement in oxygen supply while simultaneously reducing oxygen demand. Fincke J, et al. Am Coll Cardiol 2004 den Uil CA, et al. Eur Heart J 2010 Mendoza DD, et al. AMJ 2007 Torgersen C, et al. Crit Care 2009 Torre-Amione G, et al. J Card Fail 2009 Suga H. et al. Am J Physiol 1979 Suga H, et al. Am J Physiol 1981 Burkhoff D. et al. Am J Physiol Heart Circ 2005 Burkhoff D. et al. Mechanical Properties Of The Heart And Its Interaction With The Vascular System. (White Paper) 2011 Sauren LDC, et al. Artif Organs 2007 Meyns B, et al. J Am Coll Cardiol 2003 Remmelink M, et al. atheter.Cardiovasc Interv 2007 Aqel RA, et al. J Nucl Cardiol 2009 Lam K,. et al. Clin Res Cardiol 2009 Reesink KD, et al. Chest 2004 Valgimigli M, et al.Catheter Cardiovasc Interv 2005 Remmelink M. et al. Catheter Cardiovasc Interv 2010 Naidu S. et al. Novel Circulation.2011 Weber DM, et al. Cardiac Interventions Today Supplement Aug/Sep 2009 HCS-PMA-PP01224-032 rA

Improvement in Cardiac Index ISAR SHOCK Randomized Controlled Trial Hemodynamic Stability & LV Unloading with Impella ® (L/min/m2) Seyfarth et al., JACC, 2008 Augmented CI Ventricular Unloading Impella 2.5 Native Heart Pre-Support On Impella 1.71±0.45 2.20±0.64 1.73±0.59 1.84±0.71 On IABP N.S. P= 0.02 Native CI N=26 The same hemodynamic improvements can be seen in a randomized controlled trial called ISAR SHOCK with the Impella 2.5. Improvement in cardiac index while simultaneously unloading the left ventricle with statistical improvement over results observed with the IABP. HCS-PMA-PP01224-014 rA

Impella® Reduces Need for Inotropes/Pressors 2/21/2018 Impella® Reduces Need for Inotropes/Pressors Impella 2.5 Reduction in Inotropes/Pressors in 24 Hours Impella 5.0 Reduction in Inotropes/Pressors Over days ISAR-SHOCK RCT1 N=25 RECOVER I FDA IDE Study2 (N=16) 1- Seyfarth et al. JACC 2008 2- Griffith et a. J Thorac Cardiovasc Surg 2012 HCS-PMA-PP01224-030 rA

Decrease in Inotropes/Pressors in Right Heart Failure 2/21/2018 Pump Implant TO UPDATE Cohort A Cohort B Average time of Impella RP support Anderson MB. et al., J Ht Lg Transplant. 2015 HCS-PMA-PP01224-031 rA

The cVAD Registry: A Global Initiative The catheter based VAD Registry is a worldwide observational clinical registry designed to monitor patient safety and real-world outcomes of patients supported with Impella 2.5/CP/5.0/LD/RP Impella Approved: USA, Canada, Panama, Colombia, Venezuela, Brazil, Portugal, Spain, France, Italy, Greece, Switzerland, Austria, Germany, Belgium, Luxemburg, Netherland, Ireland, UK, Denmark, Norway, Sweden, Finland, Russia, China, Saudi Arabia, Kuwait Impella Approved and cVAD Registry Active: USA, Canada, Spain, France, Italy, Switzerland, Germany, Netherland, UK, Denmark

Global cVAD Registry Overview (as of March 2016) ~3,000 existing patients (legacy) 74 Sites (932 Impella users) and growing 10 Countries 5 sub-specialties (Interventional cardiology, Cardiac Surgery, Heart Failure, Electrophysiology, Structural Heart) Representative of real world setting Well established operating mechanisms and operations Baseline, procedural, hemodynamic, imaging, outcome and adverse events data with up to 1 year follow-up

Mortality Based on the Number of Inotropes Used Before Impella Support Early Initiation of Impella Support Is Associated with Improved Outcomes in AMICS Mortality Based on the Number of Inotropes Used Before Impella Support p<0.001, (N=287) Number of Inotropes

Early Initiation of Impella Support Is Associated with Improved Outcomes in AMICS Mortality Based on Duration of Cardiogenic Shock Before Impella Support p=0.01, (N=140) [0.1 - 1.3 hrs[ [1.3 - 4.8 hrs[ [4.8 - 243 hrs] Duration of Cardiogenic Shock Distribution

Early Initiation of Impella Support Is Associated with Improved Outcomes in AMICS Log-rank test, p=0.004

SG Use Associated with Improved Outcomes Distribution of Survival to Explant at Impella Sites (379 sites supported >4 AMICS patients) Survival Total # of Patients N=68 N=147 N=277 N=488 N=777 N=465 N=425 N=331 N=99 N=62 Abiomed Internal Clinical Quality Data AMI/CGS April 2015 – March 2016

Significant Increase in Survival with Use of Swan p<.00001 N=1894 N=1612 Abiomed Internal Clinical Quality Data AMI/CGS April 2015 – March 2016

Detroit Cardiogenic Shock Initiative

CARDIOGENIC SHOCK A CHANGE IN PARADIGM DOOR TO BALLOON DOOR TO SUPPORT