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PROTECT II. Prospective Multicenter Randomized Trial Comparing IMPELLA to IABP in High Risk PCI: 90 Day Results.

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protect ii

PROTECT II

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

slide2

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

2Maini et al, USpella registry TCT 2010. 3Seyfarth et al. JACC 2008;52(19):1584-8

1 Health Research International 2009 report: - #0514-1-US-1209-204.

slide3

Trial Hypothesis & Assumption

Hypothesis:

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: NCT00562016

slide4

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

slide5

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

slide6

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

Strong Memorial

Northern Michigan

Henry Ford

Aurora St. Luke’s

Robert

Packer

Providence Hospital

Sutter Memorial

William Beaumont

Moffitt Heart

Hartford Hospital

Intermountain Med Ctr

Calif. Cardiovascular

UPMC

AGH

Oakwood

Lankenau

Winthrop Univ.

Loyola

Bryan LGH

York

Univ of Chicago

New York City:

Columbia University

Mt. Sinai

Weill Cornell

Riverside

Morristown

St. Vincent’s

Ruby Memorial

Liberty Hospital

Indiana Univ.

Geisinger

Good Samaritan

St. Louis Univ.

Univ. of Cincinnati

Univ. of Kansas

Univ of Maryland

King’s Daughters

Duke

Owensboro

Washington Adventist

USC

Banner Good Sam

Lourdes Hospital

Integris Baptist

Forsyth

Carolina Med Ctr

Scripps Clinic

Centennial

Mercy Gilbert

Univ. of OK

Alvarado Hospital

Emory University

UAB

VA Dallas

Med College of GA

Univ. of Texas

Texas Heart Institute

Methodist DeBakey

Munroe Regional

Clear Lake Regional

Southwest Methodist

AMC

Amsterdam

Univ. of Miami

Texsan

72 Sites Enrolled

67 USA, 4 Canada, 1 Netherlands

slide7

PROTECT II Enrollment & Milestones

Goal: 654 pts

2/26 to 12/6/2010

Continued Enrollment

69% Achieved

4/3/2011

N=447, ACC

Final analysis

2/26/2010

50% Enrollment

Achieved

Interim analysis

Patients Enrolled

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

2008

2009

2010

2011

11/27/2007

1st Patient

*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

slide8

PROTECT II Study Flow

Assessed for Eligibility

N=1082

  • Not Eligible: N=635
    • 47.8% Met Exclusion criteria
    • 30% Patient refusal, MD decision
    • 13% Unknown
    • 9.2% Referred for CABG

Randomized

Intent-to-Treat

N=447

IABP

N= 223

90day F/U, N=220

IMPELLA

N= 224

90day F/U, N=222

Intent-To-Treat (ITT) population

(N=447)

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

1 Platelets<70000

(N=9)

(N=12)

Per Protocol (PP) population

(N=426)

IABP

30day N= 211

90day F/U, N=210

IMPELLA

30day N= 215

90day F/U, N=213

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.

slide10

Hemodynamic Support Effectiveness

Cardiac Power Output

(Secondary Endpoint)

Maximal Decrease in CPO on device Support from Baseline (in x0.01 Watts)

Impella

IABP

N=138

N=141

- 4.2 ± 24

p=0.001

- 14.2 ± 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 0.0022 (Fincke R, Hochman J et al JACC 2004; 44:340-348)

slide12

PROTECT II MAE Outcome

Intent to Treat (N=447)

Per Protocol (N=426)

IABP

p=0.029

p=0.087

IMPELLA

↓ 21% MAE

p=0.100

p=0.312

N=223

N=224

N=220

N=222

N=211

N=215

N=210

N=213

MAE= Major Adverse Event Rate

Per Protocol= Patients that met all incl./ excl. criteria.

slide13

Study Device Learning Curve Effect

Per Protocol Population 90day Outcome

(N=423)

IABP

IMPELLA

N=68

N=82

N=82

N=65

N=63

N=63

MAE= Major Adverse Event Rate

pre specified sub group analysis pp
Pre-Specified Sub-group Analysis(PP)

Overall – Per Protocol (n=423)

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)

0.0

0.5

1.0

1.5

2.0

Impella better

IABP better

Per Protocol (PP)= Patients that met all incl./ excl. criteria.

slide15

PROTECT II 90-day Outcome (PP)

HRPCI w/o Atherectomy (N=371, 88%)

HRPCI with Atherectomy (N=52, 12%)

IMPELLA

IABP

IMPELLA

IABP

Death

35.9%

51.1%

(p=0.003)

68.8%

55.0%

(p=0.316)

Composite

MI (>3x ULN)

(p=0.784)

(p=0.399)

12.5%

10.0%

11.6%

8.9%

Stroke/TIA

(p=0.03)

(p=0.522)

14.9%

17.4%

37.5%

10.0%

Repeat Revascularization

(p=0.425)

(p=0.280)

3.1%

0.0%

1.1%

2.6%

Vascular Complication

(p=0.006)

(p=0.181)

3.1%

30.0%

6.6%

10.5%

Acute Renal Dysfunction

(p=0.616)

(p=0.202)

0.0%

5.0%

2.8%

3.7%

Severe Hypotension

(p=0.271)

(p=0.211)

21.9%

10.0%

7.7%

11.6%

CPR / VT

(p=0.911)

(p=0.400)

9.4%

12.1%

18.8%

20.0%

Aortic Insufficiency

(p=0.537)

9.4%

15.0%

(p=0.411)

12.7%

10.0%

Angio Failure

0.0%

0.0%

0.0%

0.0%

(p=0.208)

0.0%

0.0%

4.4%

2.1%

Per Protocol (PP)= Patients that met all incl./ excl. criteria.

slide16

PROTECT II MAE Outcome

Pre-specified High Risk PCI Without Atherectomy Group

Per Protocol (N=374)

Per Protocol (N=374)

p=0.003

↓ 30% MAE

p=0.009

IABP

↓ 30% MAE

IMPELLA

Log rank test, p=0.005

N=191

N=183

N=190

N=181

Per Protocol= Patients that met all incl./ excl. criteria.

slide18

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;104:642-647) and 2xULN for Spontaneous MI (Universal MI definition)

slide19

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;104:642-647) and 2xULN threshold for biomarkers for Spontaneous MI (Universal MI definition)

slide21

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;104:642-647) and 2xULN for Spontaneous MI (Universal MI definition)

primary endpoint
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
slide25

PROTECT II MAE Outcome

Per Protocol Patient Population

Without Atherectomy (N=374)

All Patients (N=426)

p=0.029

p=0.003

IABP

IMPELLA

↓ 30% MAE

↓ 21% MAE

p=0.009

p=0.100

↓ 30% MAE

N=211

N=191

N=183

N=215

N=210

N=190

N=181

N=213

  • Per Protocol= Patients that met all incl./ excl. criteria.
slide26

Differential Impact of CK-MB Ratios

on Outcomes

  • * Stone et al, Circulation 2001;104:642-647;
slide27

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;104:642-647).

For Spontaneous MI (i.e, MI occurring after 72hours), 2xULN were used, unchanged from PROTECT II definition.