Impella Technology Emergent Support Clinical Evidence and Investigations

1 The Current Use of Impella 2.5 in Acute Myocardial Infarction Complicated by Cardiogenic Shock: Results from the USpella Registry William W. O’Neill, MD * ; Theodore Schreiber, MD ‡ ; David H. W. Wohns, MD ± ; Charanjit Rihal, MD ¶ ; Srihari S. Naidu, MD # ; Andrew B. Civitello, MD † ; Simon R. Dixon, MBChB ** ; Joseph M. Massaro, PhD ║ ; Brijeshwar Maini, MD †† ; E. Magnus Ohman, MD ¶¶. From the * Henry Ford Hospital, Detroit, MI, USA; ‡ Detroit Medical Center, Detroit, MI, USA; ± Spectrum Health, Grand Rapids, MI, USA; ¶ Mayo Clinic, Rochester, MN, USA; # Winthrop University Hospital, Mineola, NY, USA; † Texas Heart Institute, Houston, TX, USA; ** Beaumont Hospital, Royal Oak, MI, USA; ║ Harvard Research Institute, Boston, MA, USA; †† Pinnacle Health Medical Center, Wormleysburg, PA, USA; ¶¶ Duke University Medical Center, Durham, NC, USA. O’Neill et al, J Interven Cardiol 2013;9999:1-11

Largest Cohort To Study The Current Use of Impella in Cardiogenic Shock

3Objective To evaluate the peri-procedural characteristics and outcomes of patients supported with Impella 2.5 prior to percutaneous coronary intervention (Pre-PCI) versus those who received it after PCI (Post-PCI) in the setting of cardiogenic shock (CS) complicating an acute myocardial infarction (AMI). O’Neill et al, J Interven Cardiol 2013;9999:1-11

Ongoing US Impella Registry Observational open registry for Impella in North America Sites invited to participate on June 10, 2009 ~1,200 patients enrolled to-date at 41 centers Includes all consecutive, unselected patients at each site Data obtained after IRB approval Data monitoring against source documentation Independent CEC for events adjudication (2 Ix + 1 CT Surgeon) CEC adjudicated events per FDA Impella 2.5 study definitions O’Neill et al, J Interven Cardiol 2013;9999:1-11

5 694 patients reported in USpella Registry Study Flow Chart (06/08-05/12) 445 patients provisional /elective support High risk PCI High risk PCI High risk CABG High risk CABG Balloon Aortic Valvuloplasty Balloon Aortic Valvuloplasty VT Catheter Ablation VT Catheter Ablation 95 patients With other forms of Shock Septic Shock Septic Shock Myocarditis Myocarditis Decompensated Cardiomyopathy Decompensated Cardiomyopathy Other procedures (CABG, valve repair) Other procedures (CABG, valve repair) 249 patients In profound Cardiogenic Shock 154 patients with AMI Cardiogenic Shock N= 63 Impella 2.5 initiated Pre PCI N= 91 Impella 2.5 initiated Post PCI O’Neill et al, J Interven Cardiol 2013;9999:1-11

6 Impella ® Insertion Timing (N= 154) O’Neill et al, J Interven Cardiol 2013;9999:1-11

7 Baseline Clinical Characteristics All N = 154 Impella Pre-PCI N = 63 Impella Post-PCI N = 91 p value Age, years 64.0±12.766±1263± Gender, Male 71.4%73.0%70.3%0.73 Hypertension 77.3%82.3%73.9%0.23 Diabetes 44.6%56.7%36.4%0.02 PVD 21.4%32.2%13.6%0.008 COPD 15.9%22.9%10.7%0.05 Stroke 9.4%15.3%5.1%0.04 Renal Insuff. 23.9%27.9%21.2%0.35 Prior AMI 38.6%43.3%35.3%0.33 STEMI presentation 74.7%55.6%87.9%<.0001 Prior CABG 14.2%19.4%10.5%0.13 Prior PCI 38.5%37.1%39.5%0.77 O’Neill et al, J Interven Cardiol 2013;9999:1-11

8 Baseline Clinical Characteristics All N = 154 Impella Pre-PCI N = 63 Impella Post-PCI N = 91 p value Preadmission CS63.4%63.5%63.3%0.98 Preadmission CA22.5%15.5%27.5%0.1 Transfer Admission48.9%57.1%42.9%0.09 Duration of Shock (hrs)0.2 <647.2%40.4%51.7% 6 – %19.3%11.5% %8.8%14.9% >2425.7%31.6%21.8% Number of Inotropes1.6±1.11.4±1.11.7± O’Neill et al, J Interven Cardiol 2013;9999:1-11

9 Baseline Clinical Characteristics All N = 154 Impella Pre-PCI N = 63 Impella Post- PCI N = 91 p value IABP prior to Impella48.7%34.9%58.2%0.004 Mechanical Ventilation65.5%54.8%73.3%0.02 LVEF (%)26.4± ± ± Troponin ng/mL5.7 [ ]5.7 [ ]5.7 [ ]0.82 eGFR mL/min/m249 [ ]49 [25 60]48 [ ]0.91 Serum Lactate mmol/L4.1 [ ]4.3 [ ]3.8 [ ]0.65 STS Mortality score21.7± ± ± STS Morbidity score64.2± ± ± O’Neill et al, J Interven Cardiol 2013;9999:1-11

10 All patients N = 154 Impella Pre-PCI N = 63 Impella Post-PCI N = 91 Pre Support On Support p value Pre Support On Support p value Pre Support On Support p value MAP, mmHg 62.7±19.2 (143) 94.4±23. 1 (143) < ±20.7 (59) 94.5±21.3 (59) < ±17.3 (84) 94.4±24.4 (84) < PCWP, mmHg 31.9±11.1 (25) 19.2±9.7 (25) < ±7.8 (11) 19.7±7.9 (11) ±13.4 (14) 18.9±11.1 (14) Cardiac Index, L/min/m 2 1.9±0.7 (23) 2.7±0.7 (23) < ±0.9 (7) 2.3±0.8 (7) ±0.6 (16) 2.9±0.6 (16) < Cardiac Power Output, Watt 0.48±0.17 (23) 1.06±0.4 8 (23) < ±0.2 (7) 0.83±0.4 (7) ±0.1 (16) 1.2±0.5 (16) <0.0001Hemodynamics O’Neill et al, J Interven Cardiol 2013;9999:1-11

11 All patients N = 154 Impella Pre-PCI N = 63 Impella Post-PCI N = 91 Pre Support On Support p value Pre Support On Support p value Pre Support On Support p value MAP, mmHg 62.7±19.2 (143) 94.4±23.1 (143) < ±20.7 (59) 94.5±21.3 (59) < ±17.3 (84) 94.4±24.4 (84) < PCWP, mmHg 31.9±11.1 (25) 19.2±9.7 (25) < ±7.8 (11) 19.7±7.9 (11) ±13.4 (14) 18.9±11.1 (14) Cardiac Index, L/min/m 2 1.9±0.7 (23) 2.7±0.7 (23) < ±0.9 (7) 2.3±0.8 (7) ±0.6 (16) 2.9±0.6 (16) < Cardiac Power Output, Watt 0.48±0.17 (23) 1.06±0.48 (23) < ±0.2 (7) 0.83±0.4 (7) ±0.1 (16) 1.2±0.5 (16) < P<0.0001P< Pre- Support OnSupport OnSupport OnSupport P=0.04 Cardiac power output (n=23) HemodynamicsP<0.0001P< Pre- Support On Support Pre- Support OnSupport OnSupport P< Mean arterial pressure (n=143) O’Neill et al, J Interven Cardiol 2013;9999:1-11

12 All patients N = 154 Impella Pre-PCI N = 63 Impella Post-PCI N = 91 Pre Support On Support p value Pre Support On Support p value Pre Support On Support p value MAP, mmHg 62.7±19.2 (143) 94.4±23.1 (143) < ±20.7 (59) 94.5±21.3 (59) < ±17.3 (84) 94.4±24.4 (84) < PCWP, mmHg 31.9±11.1 (25) 19.2±9.7 (25) < ±7.8 (11) 19.7±7.9 (11) ±13.4 (14) 18.9±11.1 (14) Cardiac Index, L/min/m 2 1.9±0.7 (23) 2.7±0.7 (23) < ±0.9 (7) 2.3±0.8 (7) ±0.6 (16) 2.9±0.6 (16) < Cardiac Power Output, Watt 0.48±0.17 (23) 1.06±0.48 (23) < ±0.2 (7) 0.83±0.4 (7) ±0.1 (16) 1.2±0.5 (16) < P<0.0001P< Pre- Support OnSupport OnSupport OnSupport P=0.04 Cardiac power output (n=23) Hemodynamics O’Neill et al, J Interven Cardiol 2013;9999:1-11

13 All N = 154 Impella Pre-PCI N = 63 Impella Post- PCI N = 91 p value Duration of support, (hrs)23.7 [ ]22.8 [ ]24.2 [ ]0.39 Median DTB Time*, min 63.5 [ ]112 [79 276]52 [34 81] <.0001 Suspected IRA Territory LM16.1%23.8%9.5%0.02 LAD52.6%53.9%51.4%0.76 Left Cx.10.9%4.8%16.2%0.03 RCA16.8%12.7%20.3%0.24 Graft3.7%4.8%2.7%0.52 Number of diseased vessels1.8± ± ± Number of significant Lesions2.57± ± ± Number of vessel treated1.42± ± ± TIMI Flow [0-1] Prior to PCI80.2%71.9%84.8%0.14 TIMI Flow [0-1] Post PCI8.7%4.6%11.9%0.19 Procedural Characteristics *: DTB time for patients admitted for STEMI O’Neill et al, J Interven Cardiol 2013;9999:1-11

14 All N = 154 Impella Pre-PCI N = 63 Impella Post- PCI N = 91 p value Duration of support, (hrs)23.7 [ ]22.8 [ ]24.2 [ ]0.39 Median DTB Time*, min 63.5 [ ]112 [79 112]52 [34 81] <.0001 Suspected IRA Territory LM16.1%23.8%9.5%0.02 LAD52.6%53.9%51.4%0.76 Left Cx.10.9%4.8%16.2%0.03 RCA16.8%12.7%20.3%0.24 Graft3.7%4.8%2.7%0.52 Number of diseased vessels1.8± ± ± Number of significant Lesions2.57± ± ± Number of vessel treated1.42± ± ± TIMI Flow [0-1] Prior to PCI80.2%71.9%84.8%0.14 TIMI Flow [0-1] Post PCI8.7%4.6%11.9%0.19 Procedural Characteristics *: DTB time for patients admitted for STEMI p=0.01p=0.006p=0.007 Pre-PCI Post-PCIPre-PCIPost-PCIPre-PCIPost-PCI Extent of Revascularization O’Neill et al, J Interven Cardiol 2013;9999:1-11

15 All N = 154 Impella Pre-PCI N = 63 Impella Post- PCI N = 91 p value Duration of support, (hrs)23.7 [ ]22.8 [ ]24.2 [ ]0.39 Median DTB Time*, min 63.5 [ ]112 [79 112]52 [34 81] <.0001 Suspected IRA Territory LM16.1%23.8%9.5%0.02 LAD52.6%53.9%51.4%0.76 Left Cx.10.9%4.8%16.2%0.03 RCA16.8%12.7%20.3%0.24 Graft3.7%4.8%2.7%0.52 Number of diseased vessels1.8± ± ± Number of significant Lesions2.57± ± ± Number of vessel treated1.42± ± ± TIMI Flow [0-1] Prior to PCI80.2%71.9%84.8%0.14 TIMI Flow [0-1] Post PCI8.7%4.6%11.9%0.19 Procedural Characteristics *: DTB time for patients admitted for STEMI O’Neill et al, J Interven Cardiol 2013;9999:1-11 p=0.01p=0.006p=0.007 Pre-PCI Post-PCIPre-PCIPost-PCIPre-PCIPost-PCI Extent of Revascularization EuroShock

16Outcome Cum survival Post-PCI Pre - PCI Days from initiation of Impella 2.5 support Number of patients at risk O’Neill et al, J Interven Cardiol 2013;9999:1-11 Log-Rank, p=0.004

17 Survival to Discharge by Timing of PCI Timing of Support Initiation (154) Post-PCI 60.0% Pre-PCI 40.0% Impella Support Initiation STEMI N=35 N=80 Post-PCI 71.4% Pre-PCI 45.5% Impella Support Initiation NSTEMI N=28 N=11 Pre-PCI 65.1% Post-PCI 40.7% Impella Support Initiation Survival to Discharge By timing of PCI P=0.003 N=63 N=91 All Pts. 50.7% O’Neill et al, J Interven Cardiol 2013;9999:1-11 N154

18 Independent Predictors of In-Hospital Mortality Using a Multivariate Analysis* Parameter Tested* Odds-ratio Odds-ratio [CI 95%] p-value Initiation of Impella support prior to PCI Age Number of inotropes Cardiogenic shock onset prior to admission Mechanical ventilation * The multivariate analysis logistic model included the following as candidates for entry age, gender, history of chronic obstructive pulmonary disease, diabetes, peripheral vascular disease or prior stroke, STEMI vs. NSTEMI, cardiac arrest prior to admission, onset and duration of CS, patient transfer from outlying facility, evidence of anoxic brain injury pre-Impella support, need for mechanical ventilation, systolic and diastolic blood pressure, level of inotropic support pre-Impella support and potential use of IABP prior to Impella support, and baseline serum creatinine levels. O’Neill et al, J Interven Cardiol 2013;9999:1-11

19 Outcome to Discharge by Sub-groups O’Neill et al, J Interven Cardiol 2013;9999:1-11

20 Support Strategy (N=154) IABP Pre-PCI (N=53) IABP Pre-PCI (N=53) No support Pre-PCI (N=38) No support Pre-PCI (N=38) Impella Pre-PCI (N=63) Impella Pre-PCI (N=63) PCI Survival to discharge N=63 N=38 N=53 Impella Post PCI Impella Post PCI PCI Impella Post PCI Impella Post PCI Continue Impella Continue Impella Outcome By Support Strategy O’Neill et al, J Interven Cardiol 2013;9999:1-11 P=0.0116

21 30 Day Survival Pre-PCI 57.4% Post-PCI 38.2% USpella Registry* p=0.004 N=63 N= % N=120 EUROSHOCK Registry *: Kaplan Meier analysis estimated 30 day survival O’Neill et al, J Interven Cardiol 2013;9999:1-11

22 Conclusion and Limitations Retrospective data, therefore hypothesis generating and no definite conclusion on causalityRetrospective data, therefore hypothesis generating and no definite conclusion on causality Decision for the timing to implant Impella and extent of revascularization was operatorDecision for the timing to implant Impella and extent of revascularization was operator Although multivariate analysis reduces the bias of potential confounding factors there might be still some biasesAlthough multivariate analysis reduces the bias of potential confounding factors there might be still some biases These results are in favour of early initiation of hemodynamic support with active unloading of the LV prior to PCI in terms of completeness of revascularization and survival in the setting of CS complicating an AMI. O’Neill et al, J Interven Cardiol 2013;9999:1-11

23 Prospective pilot study for Impella 5.0/LDProspective pilot study for Impella 5.0/LD Demonstrate safety and potential efficacyDemonstrate safety and potential efficacy Postcardiotomy patients who present with marginal or low cardiac output or cardiogenic shock post weaning from CPBPostcardiotomy patients who present with marginal or low cardiac output or cardiogenic shock post weaning from CPB RECOVER I B Griffith et al, J of Thoracic and Cardiovascular Surgery, 2012

24 Overall Patient Population is Sick (N=17) Patient CharacteristicValue Age58+9[43-72] Gender (Male in %)76 Ejection Fraction (%)22+7[10-35] Valvular Disease (%)43 CHF%82 NYHA (Class III, IV)71 Cardiac Surgery Procedure - Elective30% (n=5) - Urgent35% (n=6) - Emergent35% (n=6)

25 Hemodynamic Improvement After Pump Support †Average Duration of Pump Support = 3.5 days [1.7;13 days] Cardiac Index (p < 0.001) PA Diastolic (p < 0.001) Pump insertion Baseline Pump insertion Baseline

26 Benchmark of Outcomes Predicted vs Observed In-Hospital Mortality 2 of Roques F et al. Eur Heart J., 2003 May; 24(9): out of 17 withdrew consent after explant 1

27 Robert Wood Johnson University Lemaire A, Anderson M, Lee L, et al. The Impella Device for Acute Mechanical Circulatory Support in Patients in Cardiogenic Shock,Annals of Thoracic Surgery, patients underwent Impella placement from Jan 1, 2006 to Dec 31, 2011 Recovery (88%) Bridge to Bridge (11%) 31/35 4/35

28 47 patients underwent Impella placement from Jan 1, 2006 to Dec 31, patients underwent Impella placement from Jan 1, 2006 to Dec 31, 2011 Age = 60.23± 13 yearsAge = 60.23± 13 years AMI Cardiogenic Shock 23%AMI Cardiogenic Shock 23% Post Cardiotomy Shock 68%Post Cardiotomy Shock 68% Acute Decompensated Cardiomyopathy 6%Acute Decompensated Cardiomyopathy 6% Myocarditis with Cardiogenic Shock 2%Myocarditis with Cardiogenic Shock 2% Impella 5.0/LD 80%Impella 5.0/LD 80% Impella %Impella % Ventricular function recovery 88% of survivorsVentricular function recovery 88% of survivors Transitioned to Longer term device 8%Transitioned to Longer term device 8% 30 day mortality 25%30 day mortality 25% Lemaire A, Anderson M, Lee L, et al. The Impella Device for Acute Mechanical Circulatory Support in Patients in Cardiogenic Shock In Press, Annals of Thoracic Surgery, 2013 Robert Wood Johnson University

29 Survival to One year Lemaire A, Anderson M, Lee L, et al. The Impella Device for Acute Mechanical Circulatory Support in Patients in Cardiogenic Shock In Press, Annals of Thoracic Surgery, 2013 Robert Wood Johnson University

% survival to 1 year in PCCS 42.9% survival to 1 year in AMI and acute decompensated heart failure 88% of survivors recovered native heart function making heart recovery the most likely outcome following use of Impella Lemaire A, Anderson M, Lee L, et al. The Impella Device for Acute Mechanical Circulatory Support in Patients in Cardiogenic Shock In Press, Annals of Thoracic Surgery, 2013 Robert Wood Johnson University

31Conclusion On of the largest single center series of patients undergoing placement of Impella device for acute cardiogenic shock Outcomes showed improved results compared with historical data Myocardial recover was accomplished in most patients. The 30 day mortality and complication rate was acceptable in these critical patients Lemaire A et al. Ann Thorac Surg Jan;97(1):133-8.