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On behalf of all PROTECT II Investigators

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1 On behalf of all PROTECT II Investigators
Prospective Multicenter Randomized Trial Comparing IMPELLA to IABP in High Risk PCI: 90 Day Results William O’Neill, Neal Kleiman, Jose Henriques, Simon Dixon, Joseph Massaro, Ioana Ghiu, Brijeshwar Maini, Suresh Mulukutla, Vladimir Dzavik, James Revenaugh, Hadley Wilson, Karim Benali, Magnus Ohman On behalf of all PROTECT II Investigators 2011

2 Background Patients with depressed LV function and complex anatomy have limited treatment options with the majority not eligible for CABG Prophylactic IABP hemodynamic support is used for ~28,000 high risk PCI patients annually in the US1 Impella provides superior hemodynamic support compared to IABP2,3 PROTECT II is the first FDA approved, prospective, multicenter study for patients requiring hemodynamic support during high risk PCI comparing outcomes between IABP and Impella 2.5 1 Health Research International 2009 report: - # US 2Maini et al, USpella registry TCT Seyfarth et al. JACC 2008;52(19):1584-8

3 Trial Hypothesis & Assumption
That the Impella system is superior to Intra-aortic balloon pump (IABP) in preventing intra- and post-procedural major adverse events. Assumption: 20% Major Adverse Events (MAE) rate for Impella vs. 30% for IABP, Power=80%, alpha=5%, N=654 patients. identifier: NCT

4 PROTECT II Trial Design
Patients Requiring Prophylactic Hemodynamic Support During Non-Emergent High Risk PCI on Unprotected LM/Last Patent Conduit and LVEF≤35% OR 3 Vessel Disease and LVEF≤30% R 1:1 IABP + PCI IMPELLA 2.5 + PCI Primary Endpoint = 30-day Composite MAE* rate Follow-up of the Composite MAE* rate at 90 days *Major Adverse Events (MAE) : Death, Stroke/TIA, MI (>3xULN CK-MB or Troponin) , Repeat Revasc, Cardiac or Vascular Operation of Vasc. Operation for limb ischemia, Acute Renal Dysfunction, Increase in Aortic insufficiency, Severe Hypotension, CPR/VT, Angio Failure

5 PROTECT II Committees & Partners
SPONSOR ABIOMED, Inc. DATA SAFETY MONITORING BOARD (DSMB) Regional Leaders: Brij Maini (North-East, USA) Hadley Wilson (South-East, USA) Suresh Mulukutla (East, USA) Simon Dixon (Central, USA) Neal Kleiman (Plains, USA) Jim Revenaugh (West, USA) Vlad Dzavik (Canada) Jose Henriques (Europe) EXECUTIVE COMMITTEE William O’Neill (Chair), Magnus Ohman, Neal Kleiman, Simon Dixon, Jose Henriques CLINICAL EVENTS COMMITTEE (CEC) DATA MANAGEMENT, DATA MONITORING, EVENTS ADJUDICATION, STATISTICAL ANALYSES Harvard Clinical Research Institute ANGIO CORELAB Harvard Beth Israel Deaconess 112 INVESTIGATOR SITES OPENED Principal Investigators and Clinical Research Coordinators USA, Canada, Europe ECHO CORELAB Duke Clinical Research Institute

6 PROTECT II Sites That Enrolled
Royal Alexandra St. Joseph’s Univ. of Alberta Univ. of Washington Ottawa Heart Boston, MA: Boston Medical Ctr Brigham & Women’s Mass General Hosp St. Elizabeth’s Toronto General Northern Michigan Strong Memorial Aurora St. Luke’s Henry Ford Providence Hospital Robert Packer Sutter Memorial William Beaumont Moffitt Heart Calif. Cardiovascular Intermountain Med Ctr UPMC AGH Hartford Hospital Loyola Oakwood Lankenau Bryan LGH Winthrop Univ. Univ of Chicago Riverside York Morristown New York City: Columbia University Mt. Sinai Weill Cornell St. Vincent’s Liberty Hospital Ruby Memorial Indiana Univ. Good Samaritan Geisinger Univ. of Kansas St. Louis Univ. Univ. of Cincinnati Owensboro King’s Daughters Univ of Maryland Duke USC Washington Adventist Banner Good Sam Integris Baptist Lourdes Hospital Forsyth Scripps Clinic Mercy Gilbert Univ. of OK Centennial Carolina Med Ctr Alvarado Hospital Emory University VA Dallas UAB Med College of GA Univ. of Texas Methodist DeBakey Texas Heart Institute AMC Amsterdam Munroe Regional Southwest Methodist Clear Lake Regional Texsan Univ. of Miami 72 Sites Enrolled 67 USA, 4 Canada, 1 Netherlands 6

7 PROTECT II Enrollment & Milestones
Goal: 654 pts 2/26 to 12/6/2010 Continued Enrollment 69% Achieved 4/3/2011 N=447, ACC Patients Enrolled Final analysis 2/26/2010 50% Enrollment Achieved Interim analysis 12/6/2010 DSMB recommends to halt the study for futility* based on assumption that trends in first half of trial (N=324) will be similar to trends in second half 6/2/2008 510(k) Clearance 11/27/2007 1st Patient 2008 2010 2009 2011 *PROTECT II DSMB Stopping rule for futility = Conditional power at interim analysis <40%. All major adverse events were adjudicated. Database not locked yet at the time of ACC’2011

8 Assessed for Eligibility
PROTECT II Study Flow Assessed for Eligibility N=1082 Randomized Intent-to-Treat N=447 Not Eligible: N=635 47.8% Met Exclusion criteria 30% Patient refusal, MD decision 13% Unknown 9.2% Referred for CABG Intent-To-Treat (ITT) population (N=447) IMPELLA N= 224 90day F/U, N=222 IABP N= 223 90day F/U, N=220 (N=12) (N=9) 1 withdrew consent post PCI (alive) 1 EF >=35% 1 Not 3VD or ULM 3 Active MI 1 Severe PVD 1 Platelets<70000 1 Creatinine>4 2 withdrew consent post PCI (alive) 3 EF >=35% 3 Not 3VD or ULM 1 Active MI 2 Severe PVD or AS IMPELLA 30day N= 215 90day F/U, N=213 IABP 30day N= 211 90day F/U, N=210 Per Protocol (PP) population (N=426) Per Protocol population= Patients that met all inclusion and exclusion criteria. Per Protocol population was pre-specified and patients were identified prospectively prior to the statistical analysis.

9 Baseline Characteristics
Patient Characteristics IABP (N=223) Impella (N=224) p-value Age 67±11 68±11 0.4 Gender-Male 81.2% 79.5% 0.651 History of CHF 83.4% 91.1% 0.015 Current NYHA (Class III / IV) 54.8% 58.1% 0.5 Diabetes Mellitus 50.7% 52.2% 0.7 Implantable Cardiac Defib. 31.1% 34.8% Prior CABG 28.7% 38.4% 0.03 LVEF 24.1±6.3 23.5±6.3 0.3 STS Mortality score 6±7 6±6 0.8 Not Surgical Candidate 64.1% 63.4% 0.9 Syntax score pre-PCI 29±13 30±14 9

10 Hemodynamic Support Effectiveness
Cardiac Power Output (Secondary Endpoint) Maximal Decrease in CPO on device Support from Baseline (in x0.01 Watts) IABP Impella N=138 N=141 - 4.2 ± 24 p=0.001 ± 27 CPO data available only for 279 patients (N=138 IABP and N=141 Impella) CPO= Cardiac Power Output = Cardiac Output x Mean Arterial Pressure x (Fincke R, Hochman J et al JACC 2004; 44: )

11 Procedural Differences
Procedural Characteristics IABP (N=223) Impella (N=224) p-value Use of Heparin 82.4% 93.5% <0.001 IIb/IIIa Inhibitors 26.1% 13.5% 0.001 Total Contrast Media (cc) 241±114 267±142 0.037 Rotational Atherectomy (RA) 9.5% 14.9% 0.088 Median # of RA Passes/lesion (IQ range) 1 (1-2) 3 (2-5) Median # of RA passes/pt (IQ range) 2.0 ( ) 5.0 ( ) 0.004 Median RA time/lesion (IQ range sec) 40 (20-47) 60 (40-97) 0.005 RA of Left Main Artery 3.1% 8.0% 0.024 % of SVG Treatment or RA use 17.5% 25.4% 0.041 Total Support Time (hour) 8.2±21.1 1.9±2.7 Discharge from CathLab on device 37.7% 5.7%

12 Per Protocol= Patients that met all incl./ excl. criteria.
PROTECT II MAE Outcome IABP IMPELLA MAE= Major Adverse Event Rate Intent to Treat (N=447) p=0.312 N=224 N=223 p=0.087 N=222 N=220 p=0.100 N=215 N=211 ↓ 21% MAE p=0.029 N=213 N=210 Per Protocol (N=426) Per Protocol= Patients that met all incl./ excl. criteria.

13 Study Device Learning Curve Effect
Per Protocol Population 90day Outcome (N=423) IABP IMPELLA N=82 N=63 N=68 N=65 MAE= Major Adverse Event Rate

14 Pre-Specified Sub-group Analysis (PP)
90 day MAE Relative Risk [95% CI] Group p-value Interaction 0.79 [0.64, 0.98] 0.029 0.70 [0.55, 0.89] 0.003 1.25 [0.79, 1.98] 0.316 0.84 [0.55, 1.28] 0.401 0.79 [0.62, 1.00] 0.048 1.11 [0.74, 1.66] 0.629 0.73 [0.57, 0.93] 0.009 0.89 [0.60, 1.32] 0.568 0.76 [0.59, 0.97] 0.027 Overall – Per Protocol (n=423) Impella better IABP better 0.0 0.5 1.0 1.5 2.0 PCI Procedure Without Atherectomy (n=371) 0.015 With Atherectomy (n=52) Anatomy ULM / Last conduit (n=100) 0.907 3VD (n=323) STS Mortality Score STS ≥ 10 (n=70) 0.043 STS < 10 (n=353) Roll in subject 1st Impella/IABP Pt per site (n=116) 0.923 After 1st Impella/IABP Pt (n=307) Per Protocol (PP)= Patients that met all incl./ excl. criteria.

15 PROTECT II 90-day Outcome (PP)
HRPCI w/o Atherectomy (N=371, 88%) HRPCI with Atherectomy (N=52, 12%) IMPELLA IABP IMPELLA IABP Composite 35.9% 51.1% (p=0.003) 68.8% 55.0% (p=0.316) Death MI (>3x ULN) Stroke/TIA Repeat Revascularization Vascular Complication Acute Renal Dysfunction Severe Hypotension CPR / VT Aortic Insufficiency Angio Failure 11.6% 8.9% (p=0.399) 12.5% 10.0% (p=0.784) 14.9% 17.4% (p=0.522) (p=0.03) 37.5% 10.0% 1.1% 2.6% (p=0.280) 3.1% 0.0% (p=0.425) 6.6% 10.5% (p=0.181) 3.1% 30.0% (p=0.006) 2.8% 3.7% (p=0.616) 0.0% 5.0% (p=0.202) 7.7% 11.6% (p=0.211) 21.9% 10.0% (p=0.271) 9.4% 12.1% (p=0.400) 18.8% 20.0% (p=0.911) 12.7% 10.0% (p=0.411) 9.4% 15.0% (p=0.537) 0.0% 0.0% 0.0% 0.0% 4.4% 2.1% (p=0.208) 0.0% 0.0% Per Protocol (PP)= Patients that met all incl./ excl. criteria.

16 Pre-specified High Risk PCI Without Atherectomy Group
PROTECT II MAE Outcome Pre-specified High Risk PCI Without Atherectomy Group Per Protocol= Patients that met all incl./ excl. criteria. ↓ 30% MAE p=0.003 N=181 N=190 Per Protocol (N=374) p=0.009 N=183 N=191 IMPELLA IABP Log rank test, p=0.005 Per Protocol (N=374)

17 Practical Implications of PROTECT II

18 PROTECT II Outcome** (PP)
IABP IMPELLA p=0.038 ↓ 29% MACCE p=0.037 ↓ 38% MACCE p=0.595 N=215 N=211 N=210 N=213 N=210 N=213 In-hospital MACCE Post-Discharge MACCE Total 90 days MACCE MACCE = Death/Stroke or TIA/MI/Repeat Revascularization **Using x8ULN for biomarkers or Q-wave for Peri-procedural MI (Stone et al Circulation 2001;104: ) and 2xULN for Spontaneous MI (Universal MI definition)

19 Per Protocol Population, N=426
PROTECT II MACCE** Per Protocol Population, N=426 Death, Stroke, MI, Repeat revasc. IABP IMPELLA Log rank test, p=0.04 **Using x8ULN threshold for biomarkers or Q-wave for Peri-procedural MI (Stone et al Circulation 2001;104: ) and 2xULN threshold for biomarkers for Spontaneous MI (Universal MI definition)


21 Conclusion The use of Impella for hemodynamic support during high risk PCI is safe. The superior hemodynamic support of Impella appears to have led to significant procedural differences between the two arms. Impella arm had strong trends towards superior clinical outcomes for the entire intent-to-treat population with a significant reduction of the MAE rate in the per protocol population at 90 day follow-up. The clinical benefit was more pronounced for patients undergoing high risk PCI without atherectomy with the Impella support. There was a significant reduction of the MACCE rate in the per protocol population at 90 day follow-up when a more clinically relevant threshold of CK-MB release for peri-procedural MI** is considered. **Using x8ULN for biomarkers or Q-wave for Peri-procedural MI (Stone et al Circulation 2001;104: ) and 2xULN for Spontaneous MI (Universal MI definition)

22 Appendix

23 Combined Major Adverse Events
Primary Endpoint Combined Major Adverse Events Death (all cause mortality) Myocardial infarction (> x3 ULN in CK-MB or Troponin) Stroke/TIA Repeat revascularization (Any PCI/CABG post index procedure) Need for cardiac/vascular operation or vascular operation for limb ischemia Acute renal dysfunction Increase in Aortic insufficiency by more than one grade Hypotension ( SBP <90 mmHg for ≥ 5 min requiring pressor or IV fluid) CPR or Ventricular arrhythmia requiring cardioversion Angiographic failure

24 PROTECT II Top 20 Enrollers
Site # Pts Leaders Location University of Alabama, AL 40 Dr Zoghbi / Dr Misra/ DrAqel Mount-Sinai Medical Ctr, NY 26 Dr Sharma / Dr Kini University of Miami, FL 25 Dr Heldman / Dr O’Neill Columbia University, NY 21 Dr Collins / Dr Moses Pinnacle Health Med Ctr, PA Dr Maini Banner Good Sam. Med Ctr, AZ 17 Dr Pershad / Dr Byrne Methodist DeBakey, TX 15 Dr Kleiman VA Medical Ctr Dallas, TX 14 Dr Banerjee Univ. of Pittsburgh Med Ctr, PA Dr Mulukutla Academic Med. Ctr, Amsterdam, NL 11 Dr Henriques Site # Pts Leaders Location Toronto General Hospital, CAN 9 Dr Dzavik Massachusetts General Hosp, MA Dr Palacios UT Medical School at Houston, TX Dr Denktas Liberty Hosp, MO Dr Kramer University of Rochester, NY Dr Ling Intermountain Medical Ctr, UT 8 Dr Revenaugh Emory Univ. Hosp Midtown, GA Dr Liberman York Hospital, PA Dr Nicholson/ Dr Tolerico Northern Michigan Hosp, MI Dr Cannon Providence Hospital, MI Dr David

25 PROTECT II MAE Outcome Per Protocol Patient Population
All Patients (N=426) Without Atherectomy (N=374) ↓ 21% MAE p=0.029 N=213 N=210 IABP ↓ 30% MAE p=0.003 N=181 N=190 IMPELLA p=0.009 N=183 N=191 ↓ 30% MAE p=0.100 N=215 N=211 Per Protocol= Patients that met all incl./ excl. criteria.

26 Differential Impact of CK-MB Ratios
on Outcomes * Stone et al, Circulation 2001;104: ;

27 Differential Impact of CK-MB Level and MI Incidence in PROTECT II
With Peri-procedural MI Definition = Cardiac Biomarkers>3xULN With Peri-procedural MI Definition = Cardiac Biomarkers>8xULN** IMPELLA IABP IABP IMPELLA Log rank test, p=0.649 Log rank test, p=0.505 **8xULN (or Q-wave) is used as a relevant threshold for Peri-procedural MI (Stone et al, Circulation 2001;104: ). For Spontaneous MI (i.e, MI occurring after 72hours), 2xULN were used, unchanged from PROTECT II definition.

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