TAVR Accessory Devices
How Much Clinical Trial Rigor and
What Are the Appropriate Surrogate
Endpoints
Alexandra Lansky, MD
Associate Professor Medicine
Yale University School of Medicine
Honorary Reader, University College London
Conflicts
Institutional Research Support:
KeyStone Heart
Cerebral injury post TAVR
Stroke
Silent Embolic Events
Efficacy Endpoints for Protection
Clinical Stroke Endpoint:
Superiority based on a control major stroke rate
of 2-4% is Prohibitive!
DW MRI is an appropriate surrogate:
Which endpoint and what does it mean?
Rate 3.8 to 8%
3.5 increased risk of death
Leon et. al, Smith et al, Eggebrecht et al.
Rate of 76-100%
Link to neurocognitive decline
Restrepo et al 2002, Lund et al 2005, Schwartz
et al 2011, Knipp et al 2008, Sweet et al 2008
Incidence of DW-MRI Lesions
Valve
N
New lesions
Strokes
Without Protection
• EmbolicCoreValve
Lesions22are common
73%
10%
Knipp (2010)
Sapien
27
58%
4%
•
Neuroprotection
does
not
prevent
Kahlert (2010)
Both
32
84%
0%
emboli Both
Astarci (2011)
35
91%
0%
Ghanem (2010)
Sapien
68%
3%
 Frequency
of 60
new lesions
is not
a
Arnold (2010)
Sapien
25
68%
25%
relevant surrogate endpoint
With Protection (EU Experience)
Rodes (2011)
Lansky (2013)
TriGuard
36
78%
2
Stella (2013)
Embrella
13
100%
0
PROTAVI-C
Embrella
33
100%
1
Average Number of New Cerebral
Lesions per Patient
Embrella
Embrella
Unprotected
TriGuard
9
8
7
6
5
4
3
2
1
0
Protection
Volume of DW-MRI Lesions
TriGuard (N=37) vs Historic Controls
(Kahlert 2010, Ghanem 2011, Astarci
2011, Stolz 2004)
0.4
Avg. Volume new lesions
0.3
Embrella RCT
27 TAVI vs 13 TAVI + Embrella
PCR 2013
Avg. Volume new lesions
0.33 cm3
61%
0.2
0.1
0
2.5
2
1.5
0.13 +
0.13 cm3
TriGuard
Total Volume of new lesions
2.18 cm3
57%
1
0.5
0
0.77 +
0.96cm3
TriGuard
Total Volume of new lesions
Clinical Relevance
Total Lesion Burden Impact Brain Function
• Correlates Total
with cognitive
Volume of New Lesions
decline (Restrepo et al 2002, Lund et al
Meets
2005, Schwartz et
al 2011,criteria
Knipp et alfor Surrogacy
2008, Sweet et al 2008, Choi et al 2000,
Blum et al 2012)
 Plausible
of Ischemic Brain Burden
• Lessen
memory measure
(Berg et al 2002, Zhou
 Consistency
et al 2009
and 2012)
of results across therapeutic
areas
(TAVR,
CABG, SAVR)
• Doubles
the risk
of dementia
(Tatemichi et al 2003)
 Consistent treatment effect with different
• Number
and
total
volume
of
new
deviceswith
lesionsprotection
in TAVR correlates
 Correlates
with clinical cognitive decline
cognitive
impairment
7
Limitations:
DW MRI Quantitative Methodology
for Lesion Volume Assessment
•
Traditional Methodology: Historic controls
•
•
•
2D-method
Each lesion manually outlined in each slice
Lesion volume is calculated by multiplying hand-measured area by slice
thickness
Kahlert et al. Circulation 2010;121:870-878.


•
High variability, poor reproducibility
Underestimates volumes
Semi Quantitative Methodology
•
•
•
•
FDA-Cleared software Olea v 1.2; Vital Images
3D-method: 3-point connectedness with threshold based segmentation
Measures # voxels of + DW MRI
Automatic propagation within lesions across slices

Improves consistency and reproducibility
Safety Endpoints (VARC 2 defined)
Device Related Safety
Do the benefits of protection
outweigh the risks of using the
device?
TAVI Early Safety
Does protection add risk to
TAVI?
(Control rates 20-25%)
In hospital (Modified VARC 2)
30 day endpoint (VARC 2)
Hierarchial Composite
Hierarchial Composite
All Cause Death
All Cause Death
All Stroke (Disabling and non disabling)
All Stroke (disabling and non-disabling)
Life threatening Bleed
Life Threatening Bleed
Acute Kidney Injury-Stage 3
Acute Kidney Injury stage 2-3
Coronary obstruction requiring
Major Vascular complication ( includes distal
embolization)
Major Vascular Complications
Valve related dysfunction requiring
repeat procedure
Neuro Protection Trial Design Considerations
Primary Efficacy Endpoints
• Total Volume of new lesions:
– Comparing baseline to post TAVR DW MRI
– Using independent Core Laboratory with standard and validated methodology
Secondary Endpoints
• Procedure Safety:
• In-hospital device related safety (modified VARC 2)
• Early Valve Safety 30 days (VARC 2)
• Adjudicated to investigational device vs procedure
• Device performance: Ability to access, deliver, position and retrieve device
without TAVI interference and maintain position for duration of the TAVR
procedure
• Neurocognitive assessment MoCA- 30 item questionnaire or more sensitive tool
• Neurological Assessment (NIHSS, MRS)