Transcript Alexandra Lansky, MD

The DEFLECT III Trial:
A Prospective Randomized Evaluation of the
TriGuard Embolic DEFLECTion Device during
Transcatheter Aortic Valve Replacement
Alexandra Lansky, MD
Yale University School of Medicine
New Haven, CT
Joachim Schofer, Szilard Voros, Adam Brickman, Didier Tchetche, Pieter Stella,
Jochen Reinöhl Thomas Cuisset, Daniel Blackman, Michael Cleman, John Forrest, Gil
Bolotin, Med Spitzer, Martine Gilard, Thomas Modie, David Hildick-Smith,
Kevin Abrams, Michael Haude, and Andreas Baumbach
Disclosure Statement of Financial Interest
Affiliation Financial Relationship
Company
• Research grants:
• Keystone Heart, Bard, Biotronik,
Boston Scientific, CardioKinetix, Direct
Flow, Gilead Sciences, Gore, Intact
Vascular, Micell, Recor Medical,
Shockwave Medical, SilkRoad Medical,
St Jude Medical, TriReme Medical,
Ventrix Medical, Veryan Medical
• Consultant/Speaker Honoraria:
• AstraZeneca Pharmaceuticals, Eli Lilly
and Company, Daichi Sankyo,
CardioDX, Merk & Co.
• Minor Ownership interest:
• Keystone Heart
Clinical Stroke after TAVR
8.0%
7.0%
6.0%
5.0%
4.0%
3.0%
2.0%
1.0%
0.0%
• 4-7% at 30 days in RCTs
Major
• Generally under-reported (17% after
Major/minor
SAVR when evaluated by neurologist)
• Confer 3- to 9-fold increased risk of
mortality
• 50% are peri-procedural
30-day stroke rates
Leon et al. NEJM. 2010;363:1597, Smith et al. NEJM. 2011;364:2187, Adams et al.
NEJM 2014;370:1790, Leon MB ACC 2013, Popma et al. JACC 2014;63:1872,
Eggebrecht et al. EuroIntervention. 2012;8:129, Messe et al. Circulation
2014;129:2253, Tchetche et al. JACC Cardiovasc Interv 2014;7:1138, Miller et al. J
Thorac Cardiovasc Surg 2012;143:832
Silent Embolic Events on DW-MRI after TAVR
% of Subjects with New Lesions
98%100%
93%
100%
77%
68%
84%
82%
72%
68%
58%
50%
0%
• Affect 58-100% of patients
• Multiple infarcts (≤36, x̅ = 4.6)
• Associated with:
et al. Stroke 2002;33:2909, Lund et al. Eur Heart J. 2005;26:1269, Schwarz et al. Am
 Neurocognitive decline Restrepo
Heart J 2011;162:756, Knipp et al. Ann Thorac Surg 2008;85:872, Vermeer et al. NEJM 2003;
348:1215, Vermeer et al. Stroke 2003; 34:1126, Arnold et al. JACC Cardiovasc Interv.
2010;3:1126, Astarci et al. J Heart Valve Dis. 2013;22:79, Fairbairn et al. Heart 2012;98:18,
 >2 fold risk of dementia Ghanem
et al. EuroIntervention. 2013;8:1296, Kahlert et al. Circ. 2010;121:870, Knipp et al.
Interact Cardiovasc Thorac Surg. 2013;16:116, Linke et al. TCT 2014,
 >3 fold risk of stroke
Rodes-Cabau et al. JACC Cardiovasc Interv 2014;7:1146
The TriGuard Device
• Single-wire nitinol frame and mesh filter with pore size of
130μm designed to deflect cerebral emboli during TAVR
while allowing maximal blood flow
• Device is positioned across all 3 cerebral vessels and
maintained by a stabilizer in the innominate
• Delivered via 9 Fr sheath from femoral artery
DEFLECT III Study Overview
Design: Multicenter prospective
single-blind randomized controlled
trial at 13 sites (EU/IL)
Objective: To evaluate the safety,
efficacy and performance of
TriGuard protection compared
with unprotected TAVR.
Sample Size: Exploratory study
with no formal hypothesis testing.
86 patients selected to benchmark
events for the design of a pivotal
RCT.
Subjects with AS undergoing TAVR
1:1 Randomization
Embolic
Protection
(TriGuard)
Unprotected
TAVR
(Control)
DEFLECT III Eligibility Criteria
• Key Inclusion Criteria
 Patients undergoing TAVR via the transfemoral approach
 Exclusion Criteria
 Stroke or TIA within prior 6 months
 Any other cardiac intervention within prior 2 weeks
 Aortic arch or innominate anatomy deemed to prevent
positioning and stability of the device (ostium diameter
<11 mm, transverse aortic diameter >40 mm)
 Contraindication to cerebral MRI (e.g., pacemaker)
DEFLECT III Procedures & Assessments
Screening
Post-Procedure
Procedure
4±2 days
NIHSS
mRS
Neurocog*
TAVR
±
TriGuard
30 days
̴30 days
DW-MRI
DW-MRI
NIHSS
mRS
Neurocog*
NIHSS
mRS
Neurocog*
*Neurocognitive test battery includes the Montreal Cognitive Assessment (MoCA)
and computerized CogState Research Test. Baseline and 30-day evaluations include
supplemental Digit Symbol Substitution, Trailmaking, and Word Fluency Tests.
DEFLECT III Endpoints
• Primary Safety Endpoint (ITT population)
 In-hospital MACCE defined as the composite of death, stroke, lifethreatening or disabling bleeding, AKI (2/3), and major vascular
complications (VARC-2)
• Secondary Performance (ITT population)
 Technical success: successful positioning (complete 3-vessel coverage
verified by angiography) and retrieval without TAVR interference
• Secondary Efficacy (ITT and Per Treatment* populations)
 DW-MRI: Frequency, number, and average single, maximal, and total
lesion volumes by DW-MRI at 4+2 days (range 2-6 days)
 Neurocognitive: Postoperative and change from baseline to
postprocedure and 30 days
*Per treatment (PT) population: subjects with complete TriGuard cerebral
vessel coverage throughout the procedure (core lab adjudicated)
DEFLECT III Patient Disposition
Intent To Treat Population
N=83
Embolic Protection
(TriGuard)
Unprotected TAVR
(Control)
n = 45
n = 38
MRI Loss to FU n=13 (29%)
• Stroke n=1
• Refused n = 3
• PPM n=9
MRI Loss to FU n=13 (34%)
• Death n = 2
• Stroke/PPM n=1
• Refused n = 4
• PPM n=6
In-hospital FU
In-hospital FU
Safety n = 45
DW-MRI:
n = 32 (71%) (ITT)
n = 26 (57%)(PT)
Safety n = 38
DW-MRI:
n = 25 (65%) (ITT)
n = 25 (65%) (PT)
DEFLECT III Trial Organization
Principal
Investigators
Alexandra Lansky, MD
MRI Core Lab
Szilard Voros, MD (Director)
Angiographic
Core Lab
Biostatistic
Neurologic &
neurocognitive
Assessment
Ecaterina Cristea, MD (Director)
Yale University School of Medicine,USA
Andreas Baumbach, MD
Bristol Heart Institute, UK
Global Institute for Research, Richmond, VA, USA
Helen Parise, PhD
Yale University School of Medicine, New Haven, CT, USA
(Statistics)
Adam Brickman, MD (Director)
Kevin Abrams, MD (chief)
Columbia University, New York, USA
Baptist Hospital, Miami, Fl
Clinical Events
Committee
Michael Cleman, MD (Chair)
John Forrest, MD
Joseph Brennan, MD
Abeel Mangi, MD
Monitoring,
Site Mgmt.
Data Mgmt
Genae International, Inc.
Harvard Clinical Research Institute
Yale University School of Medicine, New Haven, CT, USA
DEFLECT III Trial – Enrollment Highlights
Feb 26, 2014
March 4, 2015
April 4, 2015
Enrollment
Start
RCT Enrollment
Complete
30 day FU
Complete
5 Countries / 13 Centers
Joachim Schofer (17)
Andreas Baumbach (8)
Martine Gilard (2)
Hamburg, Germany
Bristol, United Kingdom
Brest, France
Didier Tchetche (13)
Daniel Blackman (6)
Thomas Modine (1)
Toulouse, France
Leeds, United Kingdom
Lille, France
Pieter Stella (11)
Gil Bolotin (4)
Michael Haude (1)
Utrecht, Netherlands
Haifa, Israel
Neuss, Germany
Thomas Cuisset (10)
Marseille, France
Jochen Reinöhl (10)
Freiburg, Germany
Med Spitzer (2)
Dresden, Germany
David Hildick-Smith (1)
Brighton, United Kingdom
Baseline Clinical Characteristics
TriGuard
N=45
Controls
N=38
P value
Age (y) ± SD
Male
STS Score
EuroSCORE II
NYHA Class
I or II (%)
III or IV (%)
A Fib on admission
CKD
COPD
O2 Dependent
82.7 ± 6.5
40.9%
4.7
10.1
82.5 ± 5.9
50.0%
7.4
7.4
0.62
0.41
0.48
0.66
83.3%
45.0%
22.0%
25.0%
31.8%
6.8%
78.9%
37.8%
36%
26.3%
32.4%
0.0%
0.65
0.85
0.36
0.89
0.95
0.10
Previous stroke/TIA
14.0%
18.4%
0.58
Frailty
Porcelain Aorta
11.9%
4.5%
18.4%
0.0%
0.42
0.18
ITT population
Procedure Details
ITT population
General Anesthesia
Valvuloplasty Pre-TAVI
TAVI Implants
CoreValve
Edwards Sapien/3/XT
Other*
Total Fluoro time (min)
Total Contrast (ml)
Adjunct Pharmacology
ASA + clopidogrel
ASA only
Clopidogrel only
Warfarin
TriGuard
N=45
Controls
N=38
76.7%
61.1%
n=44
31.8%
63.6%
2.3%*
28.2
165.8
76.3%
70.4%
n=37
26.3%
65.8%
5.3%**
18.6
138.6
0.59
0.84
0.47
<0.001
0.16
69%
16.7%
11.9%
11.9%
67.6%
16.2%
8.1%
18.9%
0.89
0.96
0.58
0.39
*Direct Flow; **Lotus Valve
P value
0.96
0.45
Device Performance
ITT population
Technical success (composite):
Successful deployment
*Successful positioning (complete 3-vessel
coverage until final valve deployment of first
valve, verified by QCA)
Successful retrieval
Device interference (with TAVI system)
Device Failure
TriGuard
% (n/N)
N=45 patients
N=46 devices*
95% CI
87 (40/46)
93.5 (43/46)
[68.6, 92.2]
[82.1, 98.6]
87.0 (40/46)
[73.7, 95.1]
100 (46/46)
0 (0/46)
0 (0/46)
[88.5, 99.9]
[0.0, 7.7]
[0.1, 11.5]
*One subjects had 2 TriGuard devices used (valve in valve case)
*Per Treatment Population: excludes 6 patients with
incomplete cerebral coverage
In-hospital Safety Outcomes (ITT)
ITT population
Hierarchical Composite
In-hospital MACCE
Death
All stroke
Life-threatening bleed
AKI (Stage 2/3)
Major vascular comp.
TriGuard
% (n/N)
Controls
% (n/N)
Relative Risk
[95% CI]
22.2 (10/45)
31.6 (12/38)
0.70 [0.34, 1.45]
2.2 (1/45)
2.2 (1/45)
2.2 (1/45)
2.2 (1/45)
15.6 (7/45)
5.3 (2/38)
5.3 (2/38)
5.3 (2/38)
0 (0/38)
15.8 (6/38)
0.42 [0.04, 4.48]
0.42 [0.04, 4.48]
0.42 [0.04, 4.48]
2.54 [0.11, 60.7]
0.99 [0.36, 2.68]
2.2 (1/45)
4.4 (2/45)
2.2 (1/45)
2.2 (1/45)
17.8 (8/45)
5.3 (2/38)
5.3 (2/38)
7.9 (3/38)
0 (0/38)
21.1 (8/38)
0.42 [0.04, 4.48]
0.84 [0.12, 5.71]
0.28 [0.03, 2.60]
2.54 [0.11, 60.7]
0.84 [0.35, 2.04]
97.8 (44/45)
94.7 (36/38)
1.03 [0.95, 1.13]
Non-hierarchical components
Death
All stroke
Life-threatening bleed
AKI (Stage 2/3)
Major vascular comp.
TAVR Device Success (VARC2 Composite)
DW-MRI Results – Single and Max Lesion Volume
Average # of new lesions/pt: 4.5 vs 4.0 for TG and Controls
Protection has lower SLV and MLV
Median Lesion Volume (mm3)
Better
70.0
66.2
60.0
53.8
50.0
TriGuard
19%
40.0
30.0
64.7
Control
34.5
33.2
35.5
28.0
45%
19%
20.0
19.6
41%
10.0
0.0
32
25
SLV
32
25
MLV
Intention to Treat
26
25
SLV
26
25
MLV
Per Treatment
DW-MRI Results –
Patients with No Ischemic Brain Lesions
Protection has more freedom from ischemic lesions
30.0
Percent of Subjects
Better
27.0
25.0
22.0
20.0
55%
TriGuard
42%
Control
15.0
12.5
12.5
10.0
5.0
0.0
32
25
ITT
26
25
PT
DW-MRI Results – Percent of patients based on
Total Lesion Volume (mm3) (PT)
50
TriGuard
Percent of patients
45
46
P=0.06 for trend
40
36
35
30
46
Control
Better
27
25
19
20
15
12
8
10
5
55%
8
78%
58%
0
0
1-50
mm3
51-150
>150
DW-MRI Results – Frequency of Patients with
No Ischemic Brain Lesions
Sapien
60
ITT
Percent of patients
Better
40
PT
50
50
CoreValve
ITT
PT
50
TriGuard…
Control
39
35
P int.=0.08
30
20
17.5
10
17.5
10
10
0
All Sapien
n=37
Sapien 3 All Sapien
n=35
N=22
Sapien 3
N=22
0 0
0 0
N=18
N=14
Clinical Efficacy Outcomes – NIHSS and MoCA
Protection had fewer strokes and
better cognitive outcomes
Patients with worsening NIHSS and MoCA from baseline to discharge
Percent of Subjects
Worse
40.0
TriGuard
35.0
35.5
Control
30.0
35.5
27.8
27.5
ITT (n=67)
PT (n=60)
25.0
20.0
14.3
15.0
14.3
10.0
5.0
0.0
4.9
2/41
5/35
ITT (n=76)
NIHSS
0
5/35
PT (n=70)
MoCA
MoCA Score –Change from Baseline to Discharge (ITT)
Better
Protection prevents a decline in cognition at discharge
Age Adjusted
Clinical Efficacy: CogState-Test Results (PT)
Protection is associated with improved short and delayed
memory at discharge
Short term memory test
Delayed memory test
p=0.043
Age Adjusted
p=0.028
Conclusions
1.
2.
3.
4.
5.
6.
Use of the TriGuard was safe and provided complete cerebral
coverage in 87% of cases
TriGuard protection increased the proportion of patients completely
free of ischemic brain lesions by more than 50% and reduced single
and maximum lesion volume by about 40%
TriGuard appears to prevent cognitive decline and was associated
with improved short-term and delayed memory at discharge
compared to controls
Stroke was under-reported based on systematic NIHSS assessment
Protected patients had a 10% absolute lower stroke rate
DEFLECT III provides proof of concept of the benefits of
neuroprotection with the TriGuard device during TAVR and will
benchmark event rates for a planned definitive randomized US
approval trial
Death Events
Event
Arm
Time to
Event
(days)
Cardiovascular
Death
Control
0
Cardiovascular
Death
Control
0
Cardiovascular
Death
TriGuard
14
Comment
Following BAV, transfemoral placement of
Edwards valve immediately followed by
pericardial effusion. Sternotomy and
circulatory assist performed, followed by
evidence of Ao ring rupture.
Following BAV, hemodynamic instability
with suspicion of Ao ring rupture. An
Edwards valve was implanted prior to pt.
death.
Subject with disabling ischemic stroke.
Primary cause of death: pneumonia,
contributing causes: cerebral multi-infarct
syndrome, vascular disease and COPD.
Neurological Events
Event
Ischemic Stroke,
Non-disabling
Stroke,
Undetermined,
Non-Disabling
Arm
Time to
Event
(days)
Control
1
Control
2
Ischemic Stroke,
Non-Disabling
TriGuard
1
Ischemic Stroke,
Disabling
TriGuard
1
Comment
MDT CV implanted too deep → manipulation
prior to implantation. Post TAVI blurred vision,
slurred speech. Resolved at 30 D F/U.
Edwards valve. 2 days following TAVI changes in
visual field were reported. Subject was unable
to fix gaze at times. Neurological consult
performed. MRI not performed.
TriGuard maintained position, 3/3 vessels
covered. Presentation included slurred speech,
right sided weakness. At one month was still
under neurology team care but residing at
home.
TriGuard lost position during TAVI with 0/3
vessel coverage. Prior existing TAVI device,
Edwards implant. Bilateral ischemic stroke
(anterior and posterior) confirmed by MRI/CT.
NIHSS: 30, MRS: 5. Subject died of pneumonia
day 14.
AKI Event rates in DEFLECT III
compared to Literature
1.Takagi H, Int J Cardiol. 2013;168:1631-1635;
2. Konigstein M, Am J Cardiol. 2013;
3. Sinning JM, JACC Cardiovasc Interv. 2010;3:1141-1149;
4. Gebauer K, International journal of nephrology. 2012;2012:483748;
5. Smith CR, N Engl J Med. 2011;364:2187-2198;
6. Leon MB, New England Journal of Medicine. 2010;363:1597-1607;
7. Adams DH, N Engl J Med. 2014;370:1790-1798;
8. Popma JJ, J Am Coll Cardiol. 2014;63:1972-1981;
9. Najjar Expert Rev Cardiovasc Ther. 2015;13:301-316;
10. Leon MB, J Am Coll Cardiol. 2011;57:253-269;
11.Kappetein AP, J Am Coll Cardiol (In Press). 2012
Reporting Stroke:
What if we ask Neurologists ?
• Prospective evaluation of pts undergoing surgical AVR
• Pre and post assessment and DW MRI
•
•
•
•
Clinical strokes in hospital: 17%
Moderate/severe: 4%
TIA 2%
Silent infarcts on MRI: 54%