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.
ClinicalTrials.gov 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.