Abiomed Presentation to FDA 515i Panel

Classification Determination for Non-roller

Type CPB Pumps

December 6, 2012

David Weber, PhD

Product and Regulatory Operations

Abiomed

Exhibit 99.2

Abiomed

•

U.S. Medical Device firm

•

Headquartered in Danvers, Massachusetts

•

450 employees

•

Expertise in pumping blood for over 30 years

•

Products & Clearance/Approvals:

–

Extracorporeal Ventricular Assist Devices (1

st

VADs in US); PMA for

Heart Recovery, 1992

–

Total Artificial Heart; HDE, 2007

–

IABP; 510(k) Clearance, 2007

–

Impella Microaxial Pumps; First 510(k) Clearance, 2008

2

•

Considerations for classification of

Impella for durations of support up to

6 hours

•

Discussion of Supporting Valid

Scientific Evidence

•

Controls & Concluding

Recommendations

•

Q&A

3

David Weber, PhD

Abiomed

Jeffrey Popma, MD

Beth Israel Deaconess

Medical Center, Boston

David Weber, PhD

William O’Neill, MD

Henry Ford Hospital, Detroit

Outline

Evolution of Nonroller-Type CPB Pumps

4

Expansion of “On Pump”

Concept to Cath Lab, EP lab

Surgical

Cardiopulmonary Bypass

(centrifugal)

Percutaneous

Cardiac Support

(centrifugal)

Percutaneous

Cardiac Support

(micro-axial)

Percutaneous

Cardiopulmonary Support (CPS)

(centrifugal)

1960s

1980s

Surgery suite

Cath Lab

•

Reduced size

•

Reduced invasiveness

•

Faster  set up

EP Lab

FDA

Clearance

for

Impella

®

2.5

(K063723)

5

Supporting Clinical Data

•

Total of 129 patients

•

100% from patients provided partial

circulatory support (

<

6 hrs) during

high risk PCI procedures

(n=20 from

FDA Safety Study

1

, n=109 from EU

registry)

•

510(k) Summary for K063723:

“Abiomed provided a detailed analysis

based on clinical data from a

combination of 109 OUS and 20 US

patients to address patient safety”

1.  Dixon, et al., JACC, 2009

6

Since its 510(k) clearance in 2008, > 15,000 implants have been performed,

~12,000 in the U.S.

Impella

®

Device

Impella

®

Use in United States Since Clearance

For use up to 6 hours, 90% of Impella use is for temporary

ventricular support in the setting of HRPCI

•

Median duration of support during HRPCI is 60-80mins

1,2

•

Majority of patients are surgical turn-downs

3

7

1.

60

mins

median

support

duration,

US

Registry

(Maini

et

al.,

CCI,

2012)

2.

78 mins median support duration, PROTECT II Study (O’Neill et al., Circulation, 2012)

3.

64%

deemed

inoperable

by

site

surgical

consultants

in

PROTECT

II

(O’Neill

et

al.,

Circulation,

2012)

8

Sufficient

Evidence

on

Impella

®

to

Identify

Risks and Benefits

193 peer-reviewed publications since 1994

124 publications Meet Definition of “Valid Scientific Evidence”

57 pertain to use     6 hours

21

CFR

Section

860.7(c)(2):

“Valid

Scientific

Evidence”

–

Well-controlled investigations

–

Partially controlled studies

–

Studies or objective trials without matched controls

–

Well-documented case histories

–

Reports of significant human experience

9

Largest Studies Supporting Reasonable 

N = 564 patients, 245 in FDA-approved protocol

EU Registry

US Registry

IDE Safety

Study

IDE Randomized

Study

Study name

Europella

USpella

PROTECT I

PROTECT II

Period

2004 -

2007

2009 -

2010

2006

-2007

2007-

2010

Tot. Patients

HR PCI , N=144

HR PCI , N=175

HR PCI, N=20

HR PCI, N=225 (Impella)

Tot. Centers

10

18

7

112

Publication

JACC, 2009

CCI, 2012

JACC, 2009

Circulation, 2012

Conclusion

“This large

multicenter registry

supports the safety,

feasibility, and

potential usefulness

of hemodynamic

support with Impella

2.5 in HR PCI.”

“The use of

Impella 2.5 in

HR PCI

appeared

feasible and safe

in the real-world

setting.”

“The Impella 2.5

system is safe,

easy to implant,

and provides

excellent

hemodynamic

support during

HR PCI.”

“The 30

-

day incidence of MAE

was not different for patients

with IABP or Impella

2.5

hemodynamic support.

However, trends for improved

outcomes were observed for

Impella

2.5 supported patients

at 90-days.”

Assurance of Safety & Effectiveness 

10

FDA 515i Panel Classification Determination

FDA 515i Panel Classification Determination

for Non-roller Type CPB Pumps

for Non-roller Type CPB Pumps

Clinical Evidence

Clinical Evidence

December 6, 2012

December 6, 2012

Jeffrey J. Popma, MD

Jeffrey J. Popma, MD

Director, Interventional Cardiology, BIDMC

Director, Interventional Cardiology, BIDMC

Professor of Medicine, Harvard Medical School

Professor of Medicine, Harvard Medical School

Disclosures:  Research Grant, Advisory Board (1), Travel

Disclosures:  Research Grant, Advisory Board (1), Travel

Clinical Summary: Objectives-I

•

FDA Executive Summary identified 5 studies using the

Impella 2.5 device, comprising 231 patients undergoing

HR-PCI.  We would request that the Panel also consider

additional analyses published after the 2011

ACC/AHA/SCAI guidelines not included in the FDA

Summary.

11

•

O’Neill et al  The PROTECT II study. Circ 2012;126(14):1717-27.

-

Dangas

et al (abstr). J Am Coll

Cardiol

2012:60:B21

-

Popma

et al. (abstr), J Am Coll

Cardiol

2012:59:A372

•

The USpella

Registry. CCI 2012;80(5):717-25.

12

Clinical Summary: Objectives-II

•

FDA Executive Summary provides a preliminary

overview of the primary endpoint of the PROTECT-II

study as described by the DSMB.  We would request that

the Advisory Panel also consider:

-

PROTECT-II Pre-defined analysis population (PP)

-

PROTECT-II:  Four pre-defined subgroup analyses

-

Other Registries and post-hoc analyses that describe

the totality of clinical evidence supporting the

reasonable safety and efficacy of the Impella 2.5

Impella 2.5 Clinical Evidence Base (N=799*)

Impella 2.5 Clinical Evidence Base (N=799*)

Three

Prospective

Clinical Trials

Design Type

Used in FDA

Submissions

Number of

Patients

Published  in

PROTECT

I

1

Safety

Feasibility

Yes

20

JACC Interv.

2009

PROTECT

II

2

Randomized

Yes

452 (225)

Circulation 2012

Cardio

ByPass

3

Randomized

No

199 (105)

EJCTS 2002

Two Post Market High Risk PCI Registries

Euro Registry

4

Multicenter

Open

Yes

144

JACC 2009

U.S. Registry

5

Multicenter

Open

No

175

CCI 2012

* Does not include control arm patients for randomized trials

13

•

In cardiogenic shock

-

Improvement in cardiac index (ISAR-SHOCK)

1

0.49±0.46 L/min/M

2

v. 0.11±0.31 L/min/M

2

with IABP (P < 0.02)

-

Increase in mean arterial pressure (USPella)

2

83±17 mmHg v. 59±15 with control-IABP (P < 0.0001)

•

In Elective High Risk PCI

Improved Hemodynamics with Impella 2.5

1

Seyfarth

et

al.

JACC.

2008;42:1594-8;

2

USpella

Registry.

Transcatheter

Therapeutics

2011

3

O’Neill, et al., Circulation. 2012;126:1717-1727

14

-

Preserved cardiac power output with Impella v. IABP

-4.2±24 v. -14.2±27 with IABP (P=0.001)

15

Pre-PCI

During PCI

Inoperable High-Risk PCI:

Hemodynamic Stability with Impella 2.5

Left Main –

Left Main –

Sole Remaining Vessel

Sole Remaining Vessel

LVEF < 35%

LVEF < 35%

16

Inoperable High-Risk PCI:

Hemodynamic Stability with Impella 2.5

60

80

17

Safety: Risks For Temp Ventricular Support

Safety: Risks For Temp Ventricular Support

Adapted from FDA Executive Summary: References in Appendix

Potential Risks (use <

6 hrs)

Reasonable Assurance to Support Safety

Alteration in

Blood Composition

Large prospective RCT  (N=199 patients) showed

favorable results of Impella compared to CPB in OPCABG

with respect to blood interaction

3

Inadequate

Tissue Perfusion

Prospective RCT showed superior hemodynamic support

and better tissue perfusion with Impella vs IABP

6

Embolism

Stroke = 0.5%

1,2,4,5

Non-CNS

thromboembolism

=

0.8%

3

Duration of Use

Median

ranges

from

60

[45;127]

to

78

[52,113]

min.

1,2,4,5

Fluid Leakage

Access

site

bleeding

req.

transfusion

=

3.6%

1,3,7

Device leakage malfunction = 0.2%

1,3

References in Appendix

Safety: Risks For Temp Ventricular Support

Potential Risk (use <

6 hrs)

Reasonable Assurance to Support Safety

Adverse Tissue Reaction

Two Large prospective RCT showed no evidence

of adverse tissue

3

or blood

5

reaction compared to

IABP

3

or CPB

5

respectively

Infection

3.2%

1,2,4,5

Structural / Tissue Damage

0% in 3 FDA trials and registries (N=564)

1,2,3,5,6,7

0.06% including all Impella literature in PubMed 

(1/1697 patients in 197 publications)

Local Heat Generation

Stroke= 0.5%

Non-CNS Thromboembolism (PE, DVT) = 0.8%

Flow Dynamics

Hemolysis rate = 0.8%

1,3,6,7

RCT showed no  complement activation and lower

inflammatory response compared to CPB

1,3

18

CABG is Preferred in Patients with Complex

Anatomy and Less Than High Surgical Risk

19

PROTECT II Trial Design

IMPELLA 2.5 +

PCI

IABP +

PCI

Primary Endpoint = 30-day Composite MAE* rate

1:1

R

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%

Follow-up of the Composite MAE* rate at 90 days

20

<

<

*Major Adverse Events (MAE) :

Death, MI (>3xULN CK-MB or Troponin) , Stroke/TIA, 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

21

Risk Assessment: SYNTAX vs PROTECT-II

1

2

SYNTAX

(n=903)

PROTECT

II

(n=448)

Age (Mean±SD)

65±10

67±11

Diabetes (%)

26

52

Prior MI  (%)

32

68

CHF (%)

4

87

Prior PCI (%)

0

39

Prior CABG (%)

0

33

LVEF

30%

(%)

1.3

92

Not Surgical Candidate (%)

0

64

Euroscore

(Mean±SD)

4±3

18±18

1

PCI

arm

in

SYNTAX

trial,

Serruys

et

al.

N

Engl

J

Med.

2009;

2

O’Neill

et

al.

Circulation

2012

PROTECT II Enrollment & Milestones

22

Initial

Initial

Goal: 654 pts

Goal: 654 pts

Time for data collection

Time for data collection

for interim analysis

for interim analysis

2008

2010

2009

2011

+ 125 Patients

+ 125 Patients

11/27/2007

11/27/2007

PROTECT II

PROTECT II

1st

1st

st

Patient

Patient

6/2/2008

510(k)

Clearance

2/26/2010

2/26/2010

50% Enrollment

50% Enrollment

Achieved

Achieved

(N=327)

(N=327)

12/6/2010

12/6/2010

69% Enrollment

69% Enrollment

(N=452)

(N=452)

12/6/2010

12/6/2010

Trial Halted for Futility

Trial Halted for Futility

Determination*

Determination*

*PROTECT

*PROTECT

II

II

protocol

protocol

Stopping

Stopping

rule

rule

for

for

futility

futility

=

=

power at interim analysis <40%.

Conditional

PROTECT II: ITT MAE (N=448)

PROTECT II: ITT MAE (N=448)

IABP

IABP

IMPELLA

IMPELLA

MAE= Major Adverse Event Rate.

MAE= Major Adverse Event Rate.

p=0.277

p=0.277

N=225

N=225

N=223

N=223

p=0.066

p=0.066

N=224

N=224

N=219

N=219

Log rank test, p=0.147

Log rank test, p=0.147

IABP

IABP

IMPELLA

IMPELLA

40.1%

49.3%

35.1%

40.6%

30 day MAE

90 day MAE

23

Adverse Events Directly Attributed to the

Device (90 days) 

Impella

(N=225)

IABP

(N=223)

Death

0

0

Stroke/TIA

0

0

Myocardial Infarction

0

0

Repeat Revascularization

0

0

Need for Cardiac ,Thorac. or Vasc. Operation

0

1

Acute Renal Dysfunction

0

0

CPR or VT req. Cardioversion

0

0

Increase in Aortic Insufficiency

0

0

Severe Hypotension

0

2

Total

0

3

CEC Adjudicated Adverse Events Directly

Related to the Device in PROTECT II

24

25

PROTECT-II: Additional Analyses in SAP

PROTECT-II: Additional Analyses in SAP

•

•

Pre-Specified Population Analyses:  Per Protocol

Pre-Specified Population Analyses:  Per Protocol

•

•

Predefined Secondary Analysis:

Predefined Secondary Analysis:

-

-

Learning Curve

Learning Curve

-

-

Operator-Technique (Rotational Atherectomy)

Operator-Technique (Rotational Atherectomy)

-

-

Anatomic Indications (Left Main v. 3 V CAD)

Anatomic Indications (Left Main v. 3 V CAD)

-

-

Extreme Surgical Co-Morbidity (STS PROM)

Extreme Surgical Co-Morbidity (STS PROM)

25

26

PROTECT II: Per Protocol MAE (N=427)

PROTECT II: Per Protocol MAE (N=427)

p=0.092

p=0.092

N=216

N=216

N=211

N=211

p=0.023

p=0.023

N=215

N=215

N=210

N=210

IABP

IABP

IMPELLA

IMPELLA

42.2%

51.0%

34.3%

40.0%

30 day MAE

90 day MAE

Log rank test, p=0.048

Log rank test, p=0.048

IABP

IABP

IMPELLA

IMPELLA

90 day MAE

Relative Risk

[95% CI]

Relative Risk

[95% CI]

Group

p-value

1.02 [0.70, 1.48]

0.936

0.76 [0.59, 0.97]

0.029

0.92 [0.62, 1.38]

0.697

0.74 [0.58, 0.95]

0.016

Learning Curve: 1st

Learning Curve: 1st

st

Patient Excluded

Patient Excluded

1   Impella/IABP Patient @ each site (n=119)

Intent-to-Treat

Impella better

IABP better

0.0

0.0

0.5

0.5

1.0

1.0

1.5

1.5

2.0

2.0

Per Protocol

After 1   Impella/IABP  Pt @ each site

(n=324)

1   Impella/IABP Pt @ each site (n=116)

After 1   Impella/IABP  Pt @ each site

(n=309)

27

st

st

st

st

90 day MAE

Relative Risk

[95% CI]

Relative Risk

[95% CI]

Group

p-value

0.75 [0.59, 0.95]

0.014

1.19 [0.75, 1.91]

0.444

0.70 [0.55, 0.89]

0.003

1.19 [0.75, 1.91]

0.444

Rotational Atherectomy: Sub-group

Rotational Atherectomy: Sub-group

Atherectomy (n=52)

No

Atherectomy (n=391)

Intent-to-Treat

Impella better

IABP better

0.0

0.0

0.5

0.5

1.0

1.0

1.5

1.5

2.0

2.0

Atherectomy (n=52)

No

Atherectomy (n=373)

Per Protocol

28

90 day MAE

Relative Risk

[95% CI]

Relative Risk

[95% CI]

Group

p-value

0.88 [0.59, 1.33]

0.552

0.81 [0.63, 1.03]

0.077

0.82 [0.53, 1.25]

0.351

0.78 [0.61, 0.99]

0.039

Anatomy Sub-group: Left Main vs 3VD

Anatomy Sub-group: Left Main vs 3VD

Left Main / Last Conduit (n=106)

Intent-to-Treat

Impella better

IABP better

0.0

0.0

0.5

0.5

1.0

1.0

1.5

1.5

2.0

2.0

Per Protocol

Left Main/ Last conduit (n=101)

3VD (n=324)

3VD (n=337)

29

90 day MAE

Relative Risk

[95% CI]

Relative Risk

[95% CI]

Group

p-value

1.08 [0.71, 1.63]

0.733

0.77 [0.61, 0.98]

0.030

1.14 [0.75, 1.71]

0.540

0.71 [0.56, 0.91]

0.006

Excessive Surgical Co-Morbidity

Excessive Surgical Co-Morbidity

STS 

10 (n=73)

Intent-to-Treat

Impella better

IABP better

0.0

0.0

0.5

0.5

1.0

1.0

1.5

1.5

2.0

2.0

Per Protocol

STS < 10 (n=370)

STS     10 (n=71)

STS < 10 (n=354)

30

Ongoing US Impella Registry

Ongoing US Impella Registry

•

Observational open registry for Impella in North America

•

Sites invited to participate on June 10, 2009

•

949 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 Cardiologists + 1

CT Surgeon)

•

CEC adjudicated events per FDA Impella 2.5 study definitions

31

32

Consistent Results in High-Risk PCI Impella Registries

US

Registry

(175)

EU

Registry

(N=144)

30 day Outcomes (%)

Death related to the device

All causes of Death

Myocardial Infarction

Stroke

Revascularization

Bleeding req. surgery

Site bleeding req. transfusion

Vascular complications

Valve damage

Hemolysis

0

4.0

1.1

0.6

0.6

1.7

3.4

4.0

0

0

0

5.5

0

0.7

0

0.7

5.5

4.0

0

0.7

2

1

1

Sjauw et al. J Am Coll Cardiol. 2009;54(25):2430-4. ²Maini  et al.  Catheter Cardiovasc Interv. 2012;80(5):717-25.;

33

Summary

Summary

•

Safety concerns mitigated with review of all

available clinical evidence associated with the use

of the Impella 2.5

•

Substantial improvements in hemodynamics have

been demonstrated with Impella 2.5 v. IABP

•

Examination of the totality of the clinical evidence

associated with the use of the Impella 2.5 v. IABP

support efficacy in defined patient populations

34

Conclusion

Conclusion

•

Comprehensive review of the totality of clinical

evidence associated with the use of the Impella

2.5 device for its labeled “< 6 hour”

indication

supports the safety and efficacy of this device,

particularly in patients undergoing high-risk PCI

•

Ongoing surveillance with a comprehensive

National Registry is recommended to understand

patient outcomes for these and other indications

when applied beyond a randomized study

35

References

References

1. Dixon SR, Henriques JP, Mauri L, Sjauw K, Civitello A, Kar B, Loyalka P, Resnic FS, Teirstein P, Makkar R, Palacios IF, Collins M, Moses J, Benali K, O'Neill WW. A

prospective feasibility trial investigating the use of the Impella 2.5 system in patients undergoing high-risk percutaneous coronary intervention (The PROTECT I Trial): initial

U.S. experience.. JACC Cardiovasc Interv. 2009 (2):91-6.

2. Griffith BP, Anderson MB, Samuels LE, Pae WE Jr, Naka Y, Frazier OH.The RECOVER I: A multicenter prospective study of Impella 5.0/LD for postcardiotomy circulatory

support. J Thorac Cardiovasc Surg. 2012 Mar 9. [Epub ahead of print]

3. O'Neill WW, Kleiman NS, Moses J, Henriques JP, Dixon S, Massaro J, Palacios I, Maini B, Mulukutla S, Dzavík V, Popma J, Douglas PS, Ohman M. A prospective,

randomized clinical trial of hemodynamic support with Impella 2.5 versus intra-aortic balloon pump in patients undergoing high-risk percutaneous coronary intervention: the

PROTECT II study. Circulation. 2012 ;126(14):1717-27. 

4. Seyfarth M, Sibbing D, Bauer I, Fröhlich G, Bott-Flügel L, Byrne R, Dirschinger J, Kastrati A, Schömig A.  A randomized clinical trial to evaluate the safety and efficacy of a

percutaneous left ventricular assist device versus intra-aortic balloon pumping for treatment of cardiogenic shock caused by myocardial infarction. J Am Coll Cardiol.

2008;52(19):1584-8.

5. Meyns B, Autschbach R, Böning A, Konertz W, Matschke K, Schöndube F, Wiebe K, Fischer. Coronary artery bypass grafting supported with intracardiac microaxial pumps

versus normothermic cardiopulmonary bypass: a prospective randomized trial. E. Eur J Cardiothorac Surg. 2002;22(1):112-7

6. Sjauw KD, Konorza T, Erbel R, Danna PL, Viecca M, Minden HH, Butter C, Engstrøm T, Hassager C, Machado FP, Pedrazzini G, Wagner DR, Schamberger R, Kerber S,

Mathey DG, Schofer J, Engström AE, Henriques JP. Supported high-risk percutaneous coronary intervention with the Impella 2.5 device the Europella registry. J Am Coll

Cardiol. 2009;54(25):2430-4. 

7. Real-world use of the Impella 2.5 circulatory support system in complex high-risk percutaneous coronary intervention: The USpella Registry. Maini B, Naidu SS, Mulukutla

S, Kleiman N, Schreiber T, Wohns D, Dixon S, Rihal C, Dave R, O'Neill W. Catheter Cardiovasc Interv. 2012;80(5):717-25.

8. ABIOMED IDE  G050017- Autopsy reports 2006 and 2007.

9. Dangas et al. Impact of Hemodynamic Support with Impella vs. Intraaortic Balloon Counterpulsation on Prognostically Important Ischemic Endpoints: Results

from the PROTECT-II Trial. ., J Am Coll Cardiol 2012:60:B21

10. Popma et al., Impella Improves Clinical Outcomes When Extensive Revascularization is Performed: The PROTECT II Study. ., J Am Coll Cardiol 2012:59:13-

ppA372

11. Alasnag MA, Gardi DO, Elder M, Kannam H, Ali F, Petrina M, Kheterpal V, Hout MS, Schreiber TL.Use of the Impella 2.5 for prophylactic circulatory support during

elective high-ris11.k percutaneous coronary intervention. Cardiovasc Revasc Med. 2011;12(5):299-303

Special Controls Have Been Identified

and

Implemented

to Mitigate Known Risks

36

1.

Extensive testing submitted for 510(k):

Non-clinical Performance/Bench testing (41 tests on average per

application)

Clinical data (Impella 2.5: 129 patients)

Testing includes evaluations of structural/tissue damage to heart,

local heat generation and flow dynamics

2.

Impella Post Market Registry:

Local IRB approval, Independent CEC, Corelab

3.

Physician and Staff Certification Programs

4.

Appropriate caution and warnings added to package insert based on

post market data (studies, registries)

General and Special Controls are In Place

to Mitigate Potential Risks to Public Health

37

Potential Risk (use <

6 hrs)

Implemented Controls

Alteration in blood composition

Performance/Bench Testing, Labeling, Registry

Inadequate tissue perfusion

Performance/Bench Testing, Labeling, Registry

Embolism

Performance/Bench Testing, Labeling, Registry

Duration of use

Labeling, Registry

Fluid leakage

Performance/Bench Testing, Labeling, Registry

Adverse tissue reaction

Biocompatibility Testing

Infection

Sterility and Shelf-life testing, Registry

General and Special Controls are In Place

to Mitigate Potential Risks to Public Health

38

Potential Risk (use <

6 hrs)

Implemented Controls

Structural/tissue damage to heart

Performance/Bench Testing, Labeling, Training, Registry

Local heat generation

Performance/Bench Testing, Registry

Flow dynamics

Performance/Bench Testing, Registry

•

Abiomed Recommendation:

Establish

an

inclusive

Prospective

National

Registry

of

Percutaneous

Circulatory

Support

•

Leveraging current infrastructure of the Impella Registry

•

On-going registry, in cooperation with FDA and the appropriate

professional society, would enhance the current risk mitigation

controls for class II regulation of these devices

•

Combined with existing data, can potentially support future PMA

indications

39

Recommendation to Expand US Impella

®

Registry

Impella

®

Safety

Record

Supports

Effectiveness of Current Controls

•

Since 2008, Impella has been used over 15,000 times worldwide and

has

had

no

recalls

in

the

United

States

and

1

recall

outside

the

US

which effected a total of 4 units

•

There have been a total of 49 MDR’s since its introduction for an

overall MDR rate of 0.32%

•

Only 16 of these MDR’s were associated with Adverse Events, for an

MDR with AE rate of 0.11%

40

Conclusion

41

For temporary ventricular support up to 6 hours, including support

provided during HRPCI, Impella meets the requirements for a class II

designation

42

Conclusion

Further, we recommend the establishment of a prospective national

registry of percutaneous circulatory support as an added special

control for class II regulation of current and future devices

Sufficient information (valid scientific evidence) exists to identify risks

and benefits

The risks to health have been identified and quantified

Special

controls

have

been

currently

implemented

to

mitigate

these

risks

Impella safety record supports effectiveness of current controls

Thank you

43

44

APPENDIX

45

(thru 11/15/12)

Impella

®

MDR

Rate

Compared

to

IAB

*

* Assumes 75,000 IABs used each year

0.01%

0.07%

0.16%

0.03%

0.07%

0.73%

Death

Injury

Malfunction

Impella

IAB

1.13%

0.32%

0.44%

0.26%

0.23%

0.44%

0.88%

1.36%

0.78%

0.42%

2008

2009

2010

2011

2012

Impella

IAB

Procedural Characteristics

Procedural Characteristics

Procedural Characteristics

Procedural Characteristics

IABP

IABP

(N=211)

(N=211)

Impella

Impella

(N=216)

(N=216)

p-value

p-value

Use of Heparin

82.4%

93.5%

<0.001

IIb/IIIa Inhibitors

26.5%

13.4%

<0.001

Total Contrast Media (cc)

241±115

267±141

0.035

Rotational Atherectomy (RA)

9.0%

14.2%

0.083

Median # of RA Passes/lesion (IQ range)

1 (1-2)

3 (2-5)

0.001

Median # of RA passes/pt (IQ range)

2.0 (2.0-4.0)

5.0 (3.5-8.5)

0.003

Median RA time/lesion (IQ range sec)

40 (20-47)

60 (40-97)

0.004

RA of Left Main Artery

3.1%

8.0%

0.024

Total Support Time (hours)

8.23±21.0

1.86±2.7

<0.001

Discharge from Cath Lab on device

37.7%

5.6%

<0.001

Hemodynamic Support Effectiveness

Hemodynamic Support Effectiveness

CPO=

Cardiac

Power

Output

=

Cardiac

Output

x

Mean

Arterial

Pressure

x

0.0022

(Fincke

R,

Hochman

J

et

al

JACC

2004;

44:340-348)

Cardiac Power Output

Cardiac Power Output

Maximal Decrease in CPO on device Support

Maximal Decrease in CPO on device Support

from Baseline (in x0.01 Watts)

from Baseline (in x0.01 Watts)

IABP

IABP

Impella

Impella

N=138

N=138

N=141

N=141

-

4.2 ±

24

-

14.2 ±

27

p=0.001

p=0.001

CPO

data

available

only

for

279

patients

(N=138

IABP

and

N=141

Impella)

47

CoreLab Analysis Shows No Evidence of

Damage to Cardiac or Valve Structures

Aortic/Mitral valve injury

Valve prolapse

Chordal rupture

Papillary muscle rupture

Aortic aneurysm

Structural damage to heart chambers

or septum

0%

0%

0%

0%

0%

0%

0%

0%

0%

0%

0%

0%

Structure

PROTECT I

(N=20)

1

PROTECT II

(N=225)

2

1

Dixon et al. JACC Interv. 2009;

2

O’Neill et al Circulation 2012

49

O’Neill et al 2012

Maini et al 2012

Chandola et al 2012

Dixon et al. 2009

Henriques and al. 2006

Valgimigli and al. 2005

Vlasselaers and al. 2005

Meyns and al. 2003

Siengenthaler and al. 2005

Cantena and al. 2005

Catena and al. 2004

Colombo and al. 2003

Strecker and al. 2004

Jurmann and al. 2004

1.2 hrs

1 hr

2 weeks

1.3 hrs

Up to 2 hrs

~ 2.5 hrs

6 days

2-8 days

1-10 days

N.A

2-19 days

18 days

6 days

1-7 days

2.5

2.5

5.0

2.5

2.5

2.5

2.5

5.0

5.0

5.0

5.0

5.0

5.0

5.0

225

175

1

20

19

1

1

16

24

1

8

1

1

6

TTE

TTE

TTE

TTE

TTE / Angio

Angio

Serial TEE

Serial TEE

Serial TEE

3D TTE / 2D TEE

Serial TEE

Serial TEE

Serial TEE

Serial TEE

No

No

1 patient

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

No

Study

Device

n

LOS

Imaging

Modality

Aortic

Regurgitation

Echo findings

Trauma / valve

LOS=length

of

support;

TEE

=

Trans-oesophageal

echocardiogram

Over 330 Cases with Imaging Showed No

Device Related Valve Regurgitation or Trauma

50

Results of a Randomized Study Supports

Results of a Randomized Study Supports

Blood Compatibility of IMPELLA

Blood Compatibility of IMPELLA

®

®

Leucocytes (10x9/l)

Granulocytes (%)

Eosinophilic leucocytes (%)

Basophilic leucytes (%)

Monocytes (%)

Lymphocytes (%)

Platelets (10x9/l)

Antithrombin III (%)

D-Dimers (ug/dl)

Granulocyte elastase (ug/l)

Complement C3 (g/l)

IMPELLA

(n=105)

12.3 ±

4.4

78 ±

8.1

1.48 ±

0.98

0.65 ±

0.41

5.31 ±

2.56

14 ±

7.5

144 ±

54

60 ±

15

0.75 ±

0.65

150 ±

126

0.65 ±

0.2

Cardio-Pulmonary

Bypass     

p-value

11.3 ±

4.4

78 ±

6.1

1.26 ±

0.97

0.65 ±

0.41

5.1 ±

2.72

13 ±

6.8

163 ±

50

68 ±

15

1.06 ±

2.2

259 ±

195

0.73 ±

0.2

N.S

N.S

N.S

N.S

N.S

N.S

N.S

0.0007

N.S

0.00001

0.008

Meyns and al.  Eur. J. Cardio-thoracic Surgery 22 (2002): 112-117

(n=94)

51

MAE= Major Adverse Event Rate

MAE= Major Adverse Event Rate

N=91

N=91

N=85

N=85

N=64

N=64

N=68

N=68

N=69

N=69

N=66

N=66

Study Device Learning Curve Effect

Study Device Learning Curve Effect

90day MAE Outcome

90day MAE Outcome

Intent-to-Treat

Intent-to-Treat

IABP

IABP

IMPELLA

IMPELLA

2008

2009

2010

52

PROTECT II MAE Outcome

PROTECT II MAE Outcome

Pre-specified High Risk PCI Without Atherectomy Group

Pre-specified High Risk PCI Without Atherectomy Group

MAE= Major Adverse Event Rate

MAE= Major Adverse Event Rate

39.6%

48.7%

30.6%

38.5%

30 day MAE

90 day MAE

21% MAE

p=0.014

p=0.014

N=192

N=192

N=202

N=202

p=0.06

p=0.06

N=193

N=193

N=203

N=203

23% MAE

IMPELLA

IMPELLA

IABP

IABP

Log rank test, p=0.03

Log rank test, p=0.03

Intent-to-Treat (N=396)

Intent-to-Treat (N=396)

IABP

IABP

IMPELLA

IMPELLA

90 day MAE

Relative Risk

[95% CI]

Relative Risk

[95% CI]

Group

p-value

Interaction

p-value

0.79 [0.64, 0.97]

0.023

0.70 [0.55, 0.89]

0.003

1.25 [0.75, 1.91]

0.444

Confounder: Use of Atherectomy

Confounder: Use of Atherectomy

Pre-Specified Sub-group Analysis

Pre-Specified Sub-group Analysis

With Atherectomy (n=52, 12%)

Without Atherectomy (n=373, 88%)

PCI Procedure

Overall

–

Per

Protocol

(n=425)

Impella better

IABP better

0.08

MAE = Major Adverse Event ; Per Protocol (PP)= Patients that met

MAE = Major Adverse Event ; Per Protocol (PP)= Patients that met

all incl./ excl. criteria.

all incl./ excl. criteria.

Without Atherectomy

Without Atherectomy

MI (>3x ULN)

MI (>3x ULN)

Repeat Revascularization

Repeat Revascularization

14.8%

14.8%

6.6%

6.6%

17.4%

17.4%

10.5%

10.5%

IMPELLA

IMPELLA

IABP

IABP

37.5%

37.5%

3.1%

3.1%

10.0%

10.0%

With Atherectomy

With Atherectomy

IMPELLA

IMPELLA

IABP

IABP

(p=0.006)

(p=0.006)

(p=0.03)

(p=0.03)

(p=0.492)

(p=0.492)

(p=0.171)

(p=0.171)

30.0%

30.0%

0.0

0.0

0.5

0.5

1.0

1.0

1.5

1.5

2.0

2.0

54

1.

Earnshaw, et al.  Arch. of Intern Med., 2011.

2.

Feldman, et al.  JACC, 2005. COMPANION

3.

Choudhry, et al. JACC, 2011. JUNIPER

4.

Chen, et al.  ISPOR, 2009.CHARISMA

<$100,000 Threshold

9.

Winkelmayer, et al.  Medical Decision Making, 2002.

10.

Moore, et al.

BMC Health Services Research 2009

11.

Slaughter, et al.  AHA, 2011.

12.

Russo, et al.  ACC 2010.

5.

Maini, et al.  TCT, 2011 PROTECT II

6.

Feldman, et al.  JACC, 2005. COMPANION

7.

Reynolds, et al.  ACC, 2011.

8.

Reynolds, et al. Circ Arrhythm Electrophysiol, 2009

$274k

$199k

$39,367

$39,367

Comparative Cost-Effectiveness Studies

Comparative Cost-Effectiveness Studies

$0

$25

$50

$75

$100

$125

$150

$175

Aspirin

MI

CRT-P

C-reactive

Protein

Clopidogrel

Impella

PROTECT II

CRT-D

TAVI

(LYG)

AF

ablation

Dialysis

(LYG)

MRI v.

Mammo

LVAD 1

DT(LYG)

LVAD 2

DT(LYG)