1
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
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: - #0514-1-US-1209-204.2Maini et al, USpella registry TCT 2010. 3Seyfarth et al. JACC 2008;52(19):1584-8
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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
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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
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PROTECT II Committees & Partners
SPONSOR
ABIOMED, Inc.
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
DATA MANAGEMENT,
112
INVESTIGATOR SITES OPENED
DATA MONITORING,
Principal Investigators and Clinical
Research Coordinators
EVENTS ADJUDICATION,
STATISTICAL ANALYSES
USA, Canada, Europe
Harvard Clinical Research
Institute
DATA SAFETY
MONITORING BOARD
(DSMB)
CLINICAL EVENTS
COMMITTEE
(CEC)
ANGIO CORELAB
Harvard Beth Israel
Deaconess
ECHO CORELAB
Duke Clinical Research
Institute
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PROTECT II Sites That Enrolled
St. Joseph’s
Univ. of Washington
Royal Alexandra
Univ. of Alberta
Ottawa Heart
Boston, MA:
Boston Medical Ctr
Brigham & Women’s
Mass General Hosp
St. Elizabeth’s
Toronto General
Sutter Memorial
Calif. Cardiovascular
USC
Scripps Clinic
Alvarado Hospital
Intermountain Med Ctr
Banner Good Sam
Mercy Gilbert
Strong Memorial
Northern Michigan
Henry Ford
Aurora St. Luke’s
Robert
Providence Hospital
Packer Moffitt Heart
William Beaumont
Hartford Hospital
UPMC Lankenau
Oakwood
Winthrop
Univ.
Loyola
Bryan LGH
AGH York
Univ of Chicago
New York City:
Riverside
Morristown
St. Vincent’s
Columbia University
Ruby Memorial
Liberty Hospital
Indiana Univ.
Mt. Sinai
Geisinger
St. Louis Univ. Univ. of Cincinnati Good Samaritan
Weill Cornell
Univ. of Kansas
Univ of Maryland
Owensboro King’s Daughters Duke
Washington Adventist
Lourdes Hospital
Integris Baptist
Forsyth
Carolina Med Ctr
Centennial
Univ. of OK
VA Dallas
Univ. of Texas
Methodist DeBakey Texas Heart Institute
Southwest Methodist
Texsan
Clear Lake Regional
72 Sites Enrolled
67 USA, 4 Canada, 1 Netherlands
UAB
Emory University
Med College of GA
Munroe Regional
Univ. of Miami
AMC
Amsterdam
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PROTECT II Enrollment & Milestones
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Goal: 654 pts
Patients Enrolled
Final analysis
Interim analysis
2008
2009
2010
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
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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
Intent-To-Treat (ITT)
population
(N=447)
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
Per Protocol (PP)
population
(N=426)
IABP
IMPELLA
N= 223
N= 224
90day F/U, N=220
90day F/U, N=222
(N=12)
(N=9)
IABP
IMPELLA
30day N= 211
90day F/U, N=210
30day N= 215
90day F/U, N=213
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
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.
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Baseline Characteristics
IABP
Impella
(N=223)
(N=224)
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%
Diabetes Mellitus
50.7%
52.2%
0.5
0.7
Implantable Cardiac Defib.
31.1%
34.8%
0.4
Prior CABG
28.7%
38.4%
0.03
24.1±6.3
23.5±6.3
0.3
6±7
6±6
0.8
64.1%
29±13
63.4%
30±14
0.9
0.5
Patient Characteristics
LVEF
STS Mortality score
Not Surgical Candidate
Syntax score pre-PCI
p-value
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)
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Procedural Differences
IABP
Impella
(N=223)
(N=224)
Use of Heparin
82.4%
93.5%
IIb/IIIa Inhibitors
26.1%
13.5%
241±114
267±142
9.5%
14.9%
1 (1-2)
3 (2-5)
Median # of RA passes/pt (IQ range)
2.0 (2.0-4.0)
5.0 (3.5-8.5)
Median RA time/lesion (IQ range sec)
40 (20-47)
60 (40-97)
3.1%
8.0%
17.5%
25.4%
8.2±21.1
1.9±2.7
37.7%
5.7%
Procedural Characteristics
Total Contrast Media (cc)
Rotational Atherectomy (RA)
Median # of RA Passes/lesion (IQ range)
RA of Left Main Artery
% of SVG Treatment or RA use
Total Support Time (hour)
Discharge from CathLab on device
p-value
<0.001
0.001
0.037
0.088
0.001
0.004
0.005
0.024
0.041
<0.001
<0.001
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PROTECT II MAE Outcome
Intent to Treat (N=447)
Per Protocol (N=426)
IABP
p=0.087
p=0.029
IMPELLA
↓ 21% MAE
p=0.100
p=0.312
N=223 N=224
MAE= Major Adverse Event Rate
N=220 N=222
N=211 N=215
N=210 N=213
Per Protocol= Patients that met all incl./ excl. criteria.
Study Device Learning Curve Effect
Per Protocol Population 90day Outcome
(N=423)
IABP
IMPELLA
N=82 N=82
MAE= Major Adverse Event Rate
N=63 N=63
N=65 N=68
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Pre-Specified Sub-group Analysis (PP)
Relative Risk Group Interaction
Relative Risk
90 day MAE
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[95% CI]
p-value
[95% CI]
Overall – Per Protocol (n=423)
p-value
0.79 [0.64, 0.98] 0.029
PCI Procedure
Without Atherectomy (n=371)
0.70 [0.55, 0.89]
With Atherectomy (n=52)
1.25 [0.79, 1.98]
Anatomy
ULM / Last conduit (n=100)
0.84 [0.55, 1.28]
3VD (n=323)
0.79 [0.62, 1.00]
0.003
0.316
0.015
0.401
0.048
0.907
0.629
0.009
0.043
0.568
0.027
0.923
STS Mortality Score
STS ≥ 10 (n=70)
STS < 10 (n=353)
1.11 [0.74, 1.66]
0.73 [0.57, 0.93]
Roll in subject
0.89 [0.60, 1.32]
1st Impella/IABP Pt per site (n=116)
After 1st Impella/IABP Pt (n=307)
0.0
0.76 [0.59, 0.97]
0.5
Impella better
1.0
1.5
2.0
IABP better
Per Protocol (PP)= Patients that
met all incl./ excl. criteria.
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PROTECT II 90-day Outcome (PP)
HRPCI w/o Atherectomy (N=371, 88%)
IMPELLA
Composite
35.9%
Death
11.6%
MI (>3x ULN)
Stroke/TIA
Repeat Revascularization
Vascular Complication
Acute Renal Dysfunction
Severe Hypotension
CPR / VT
Aortic Insufficiency
Angio Failure
IABP
IMPELLA
51.1%
(p=0.003)
68.8%
8.9%
(p=0.399)
12.5%
17.4% (p=0.522)
14.9%
1.1%
6.6%
2.8%
7.7%
2.6%
10.5%
3.7%
3.1%
(p=0.181)
3.1%
(p=0.616)
(p=0.211)
12.1%
(p=0.400)
10.0%
(p=0.411)
2.1%
0.0%
21.9%
IABP
55.0%
(p=0.316)
10.0%
(p=0.784)
10.0%
(p=0.03)
(p=0.425)
0.0%
30.0%
(p=0.202)
5.0%
10.0%
18.8%
20.0%
9.4%
(p=0.006)
15.0%
(p=0.271)
(p=0.911)
(p=0.537)
0.0% 0.0%
0.0% 0.0%
4.4%
37.5%
(p=0.280)
11.6%
9.4%
12.7%
HRPCI with Atherectomy (N=52, 12%)
(p=0.208)
0.0% 0.0%
Per Protocol (PP)= Patients that met all incl./ excl. criteria.
PROTECT II MAE Outcome
Pre-specified High Risk PCI Without Atherectomy Group
Per Protocol (N=374)
p=0.003
p=0.009
Per Protocol (N=374)
IABP
↓ 30% MAE
↓ 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.
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Practical Implications of
PROTECT II
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PROTECT II Outcome** (PP)
IABP
IMPELLA
p=0.038
↓ 29% MACCE
p=0.037
↓ 38% MACCE
p=0.595
N=215
N=211
In-hospital
MACCE
N=210
N=213
Post-Discharge
MACCE
N=210
N=213
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)
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)
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↓12%
Reduction
IABP Impella
↓16%
Reduction
IABP Impella
•
•
* All Per Protocol patients with Billing claim forms and data extrapolation N=249, Device expense added back in.
** Additional patients may be added in the future to the economic report
***Analysis reported by Presscott Associates, Ltd
IABP Impella
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)
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Appendix
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
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PROTECT II Top 20 Enrollers
#
Pts
Leaders
Toronto General Hospital, CAN
9
Dr Dzavik
Dr Sharma /
Dr Kini
Massachusetts General Hosp, MA
9
Dr Palacios
25
Dr Heldman /
Dr O’Neill
UT Medical School at Houston, TX
9
Dr Denktas
Columbia University, NY
21
Dr Collins /
Dr Moses
Liberty Hosp, MO
9
Dr Kramer
Pinnacle Health Med Ctr, PA
21
Dr Maini
University of Rochester, NY
9
Dr Ling
Banner Good Sam. Med Ctr, AZ
17
Dr Pershad /
Dr Byrne
Intermountain Medical Ctr, UT
8
Dr Revenaugh
Methodist DeBakey, TX
15
Dr Kleiman
Emory Univ. Hosp Midtown, GA
8
Dr Liberman
VA Medical Ctr Dallas, TX
14
Dr Banerjee
York Hospital, PA
8
Dr Nicholson/
Dr Tolerico
Univ. of Pittsburgh Med Ctr, PA
14
Dr Mulukutla
Northern Michigan Hosp, MI
8
Dr Cannon
Academic Med. Ctr, Amsterdam,
NL
11
Dr Henriques
Providence Hospital, MI
8
Dr David
#
Pts
Leaders
University of Alabama, AL
40
Dr Zoghbi /
Dr Misra/
DrAqel
Mount-Sinai Medical Ctr, NY
26
University of Miami, FL
Site
Location
Site
Location
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PROTECT II MAE Outcome
Per Protocol Patient Population
All Patients (N=426)
Without Atherectomy (N=374)
p=0.029
IABP
p=0.003
IMPELLA
51.4%
↓ 21% MAE
p=0.100
42.7%
40.8%
51.1%
p=0.009
42.4%
↓ 30% MAE
↓ 30% MAE
35.9%
34.9%
29.5%
N=211 N=215
N=210 N=213
N=191 N=183
N=190 N=181
30 day MAE
90 day MAE
30 day MAE
90 day MAE
Per Protocol= Patients that met all incl./ excl. criteria.
Differential Impact of CK-MB Ratios
on Outcomes
* Stone et al, Circulation 2001;104:642-647;
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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.