Nashville, TN
F e b r u a r y 11 , 2 0 1 5
Primary Results
SOLITAIRE™ FR With the Intention For
Thrombectomy as PRIMary Endovascular
Treatment for Acute Ischemic Stroke
J. Saver, M. Goyal, A. Bonafé, H. Diener, E. Levy, V. Mendes-Pereira, G. Albers, C. Cognard,
D. Cohen, W. Hacke, O. Jansen, T. Jovin, H. Mattle, R. Nogueira, A. Siddiqui, D. Yavagal,
T. Devlin, D. Lopes, V. Reddy, R. du Mesnil de Rochemont and R. Jahan for the
SWIFT PRIME Investigators
Background
 IV tPA up to 4.5 hours is the only pharmacologic therapy of benefit
for acute ischemic stroke, but has multiple constraints
 Narrow time window
 Risk of cerebral and systemic hemorrhage
 Achieves early reperfusion in only 13-50% of large vessel occlusion
Endovascular neurothrombectomy is a promising complementary
reperfusion strategy
Limitations of previous trials with neutral results (IMS III, SynthesisExpansion, MR Rescue)
 Use of early generation devices with only modest reperfusion efficacy
 Lack of vessel imaging in 2 trials at entry to confirm presence of target vessel
occlusion
 Prolonged interval between study entry and performance of endovascular
reperfusion procedure
Solitaire Devices
 Solitaire stent retriever is designed
to restore blood flow in patients
experiencing ischemic stroke due
to large intracranial vessel
occlusion
 In large registries and one
randomized trial,1,2,3 use of Solitaire
associated with:




1.
2.
3.
More frequent reperfusion
Faster reperfusion
Reduced ICH
Better disability outcomes
Pereira VM, Gralla J, Davalos A, et al. Prospective, multicenter, single-arm study of mechanical thrombectomy using Solitaire Flow Restoration in acute ischemic stroke. Stroke. 2013;44(10):2802-2807.
Saver JL, Jahan R, Levy EI, et al; SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomized, parallel-group, non-inferiority
trial. Lancet. 2012;380(9849):1241-1249.
Dávalos A, Pereira VM, Chapot R, et al; Solitaire Group. Retrospective multicenter study of Solitaire FR for revascularization in the treatment of acute ischemic stroke. Stroke. 2012;43(10):2699-2705.
Study Objective
To determine if subjects experiencing an acute ischemic stroke
due to large vessel occlusion, treated with combined IV t-PA and
Solitaire device within 6 hours of symptom onset, have less
stroke-related disability (mRS) than subjects treated with IV t-PA
alone.
Methods
Study Design
Design
Population
Target Vessel
Randomization
Sites
Sample Size
Follow-up
Global, multi-center, prospective, randomized, open, blinded endpoint (PROBE) IDE Study
• Acute ischemic stroke with large vessel occlusion
• Able to be treated with SOLITAIRETM FR within 6h of stroke onset
• Has received or is able to be treated with IV t-PA within 4.5 hours post stroke onset
Intracranial ICA, M1 segment of the MCA, and carotid terminus
1:1, IV t-PA alone vs. IV t-PA + Solitaire
Up to 90 centers total (50 US and 40 OUS)
Maximum 833, expected 477, 5 interim analyses, 1st at 200 evaluable
Follow-up: 27 ±6 hours, 7-10 Days/Discharge, 30 Days, 90 Days
*Methods paper in press at International Journal of Stroke
Participating Centers
Selected
Activated
Enrolled
69 sites
61 sites
39 sites
Study Organization
Steering
Committee
Executive
Committee
Gregory Albers, MD
Prof. Christophe Cognard
David Cohen, MD
Prof. Werner Hacke
Prof. Olav Jansen
Tudor Jovin, MD
Prof. Heinrich Mattle
Raul Nogueira, MD
Adnan Siddiqui, MD
Dileep Yavagal, MD
Jeffrey Saver, MD
Mayank Goyal, MD
Prof. Alain Bonafé
Prof. Hans Diener
Elad Levy, MD
Vitor Mendes-Pereira, MD
Reza Jahan, MD
SWIFT PRIME
Data Safety
Monitoring Board
Prof. Rüdiger Von Kummer
Wade Smith, MD
Prof Francis Turjman
Scott A. Hamilton, PhD
Richard Chiacchierini, PhD
Core Labs
Clinical Events
Committee
Arun Amar, MD
Yince Loh, MD
Nerses Sanossian, MD
iSchemaView
Bioclinica
Key Inclusion Criteria
• Age 18 – 80
• Pre-stroke Modified Rankin Score ≤ 1
• NIHSS 8 – 29 at randomization
• Received IV t-PA within 4.5 hours of stroke onset
• CTA or MRA confirmation of large vessel occlusion (intracranial ICA, M1 or
carotid terminus)
• Groin puncture within 6 hours of stroke onset and within 90 minutes* of
qualifying imaging
*optimal target: within 70 mins
Key Exclusion Criteria
• CT/MRI evidence of hemorrhage
• CT hypodensity or MRI hyperintensity > 1/3 of the MCA territory (or in other
territories, >100 cc of tissue)
• Carotid dissection or complete cervical carotid occlusion requiring stenting at
the time of the mechanical thrombectomy procedure
• ASPECTS < 6*
Protocol B-D
Protocol Rev F
“Target mismatch”
“Small to moderate core”
a) MRI- or CT-assessed core infarct lesion
greater than 50 cc
b) Severe hypoperfusion lesion (10 sec or
more Tmax lesion larger than 100 cc)
c) Ischemic penumbra < 15 cc and
mismatch ratio ≤1.8
*Implemented after 1st 71 patients were enrolled
a) ASPECTS ≤ 6
Imaging entry criteria revised to
accommodate sites with limited
perfusion imaging capability and
ensure accelerated treatment
delivery
Screening Enrollment & Follow up
Mechanical
Thrombectomy
Procedure
Mechanical Thrombectomy within 6 hrs
Secondary
Endpoint
Assessment
TICI
Secondary Endpoint
Assessment
Primary Endpoint
Assessment
NIHSS, Infarct Vol.
Reperfusion, sICH
Blinded mRS
Randomization
0 hr - Stroke Onset
IV t-PA administration within 4.5 hrs
27±6 hrs
7-10 days or
Discharge
30 days
90 days
Study Endpoints
Primary Blinded evaluation of Global Disability (modified Rankin Score) at 90 days
• Death due to any cause at 90 days
Secondary
• Functional independence as defined by modified Rankin Scale (mRS) score < 2 at 90 days
Clinical
• Change in NIH Stroke Scale score at 27hrs post randomization
•
•
Secondary
•
Technical
•
Safety
Infarct volume at 27hrs post randomization
Reperfusion measured by reperfusion ratio on CT or MRI at 27hrs post randomization
Arterial revascularization measured by TICI 2b or 3 following device use
Correlation of RAPID-assessed core infarct size with 27hrs infarct volume in subjects who
achieved TICI 2b-3 reperfusion without intracranial hemorrhage
• Incidence of all Serious Adverse Events
• Incidence of symptomatic ICH (intracranial hemorrhage) at 27hrs post randomization
• Health Economics related data
Health
• Readmissions due to subsequent stroke
Economics
• Quality-adjusted life year (QALY) assessment (EuroQol 5D-5L assessment)
Study Success Criteria
• Simultaneous success criteria of:
Historical Approach to Dichotomized Modified Rankin Scale Evaluation
 Distribution of mRS in Solitaire
plus IV t-PA group more favorable
than in IV t-PA only group
 Entire distribution 0-6 considered
except categories 5 and 6
collapsed into one group
 Nominal difference in proportion of
patients with dichotomized mRS
0-2 (independent) outcome
 Prespecified minimum dependent
on sample size at time of analysis
0
No
symptoms
1
No
significant
disability
Able to
carry out all
usual
activities,
despite
some
symptoms
SUCCESS
2
Slight
disability
Able to look
after own
affairs
without
assistance,
but unable
to carry out
all previous
activities
3
6
Moderate
disability
4
5
Moderately
Severe
severe
disability
disability
Unable to
attend to
Requires
Requires
own bodily
constant
some help,
needs
nursing
but able to
without
care and
walk
assistance, attention,
unassisted and unable bedridden,
to walk
incontinent
unassisted
FAILURE
Dead
Study Stopping Rule
Interim Analysis Bounds
Evaluable
Sample
Size
Stopping for Safety
Two-Sided Alpha
for Mortality
Two-Sided Alpha
for Rankin Shift
Effect Size Δ
for mRS 0-2
Effect Size φ for
mRS mean value
Effect size Δ
for mRS 0-2
200
0.0036
0.0200
12.0%
0.00
0.0%
300
0.0058
0.0125
10.0%
0.00
0.0%
400
0.0094
0.0150
9.0%
0.10
n/a
500
0.0147
0.0150
8.0%
0.14
n/a
600
0.0203
0.0150
6.0%
0.14
n/a
750 (final)
0.0340
0.0350
5.0%
n/a
n/a
Stopping for Efficacy
Stopping for Futility
Study Stopping Rule
Interim Analysis Bounds
Evaluable
Sample
Size
Stopping for Safety
Two-Sided Alpha
for Mortality
Two-Sided Alpha
for Rankin Shift
Effect Size Δ
for mRS 0-2
Effect Size φ for
mRS mean value
Effect size Δ
for mRS 0-2
200
0.0036
0.0200
12.0%
0.00
0.0%
300
0.0058
0.0125
10.0%
0.00
0.0%
400
0.0094
0.0150
9.0%
0.10
n/a
500
0.0147
0.0150
8.0%
0.14
n/a
600
0.0203
0.0150
6.0%
0.14
n/a
750 (final)
0.0340
0.0350
5.0%
n/a
n/a
Stopping for Efficacy
Stopping for Futility
Results
Study Timeline
Last Patient
Out
Full IDE
Approval
SWIFT PRIME
Presentation
at ISC
Feb 11, 2015
Jan 27, 2015
MR CLEAN
Data Presented
Dec 5, 2012
Oct 25, 2014
1st Site
Activation
Dec 06, 2012
2013
JUN 2012
IDE Submission
Jun 15, 2012
1st Site
Initiation
Nov 27, 2012
Database
Lock
Feb 4, 2015
Preliminary
Analysis
Nov 14, 2014
2014
2015
DSMB
Recommended
Enrollment
Hold
Nov 7, 2014
1st Patient
Enrolled
Dec 30, 2012
ESCAPE
Trial Stopped
Nov 6, 2012
DSMB recommends
Continue
Enrollment Hold
Nov 21, 2014
FEB 2015
Interim Analysis
Jan 30, 2015
DSMB Meeting
SWIFT PRIME
Trial Stopped
Feb 4, 2015
Randomization &
Follow-up
Randomized
(n=196)
Allocated to Solitaire + IV t-PA
Allocation
(n=98)
Allocated to IV tPA only
(n=98)
Received Solitaire (n=87)
Final Assessment Available (n=93)
¨ Attended 90d follow-up (n=78)
¨ Died prior to 90d (n=12)
¨ LOCF from 7-10d or 30d follow-up (n=3)
Final Assessment Available (n=98)
¨ Attended 90d visit (n=88)
¨ Died prior to 90d (n=9)
¨ LOCF from 7-10d or 30d follow-up (n=1)
Intention to Treat (n=98)
Intention to Treat with data (n=98)
Modified Intention to Treat (n=98)
Follow-Up
Final Assessment Unavailable (n=5)
¨ Investigator withdrew after entry criteria deviation (n=2)
¨ Subject withdrew consent after randomization(n=1)
¨ Subject withdrew consent after 27h visit (n=1)
¨ Subject withdrew consent after 7-10d &
requested deletion of all data (n=1)
Analysis
Populations
Intention to Treat (n=98)
Intention to Treat with data (n=97)
Modified Intention to Treat (n=93)
Baseline Characteristics: Demographics and Severity
Solitaire + IV t-PA
IV t-PA
P value
Age – yr – mean (SD)
N=98
65.0 (±12.5)
N=95
66.3 (±11.3)
0.44
Male
N=98
54 (55.1%)
N=96
45 (46.9%)
0.31
Race
N=90
0.94
N=92
White
79 (88.8%)
83 (90.2%)
Black
10 (11.2%)
8 (8.7%)
Asian
0 (0%)
1 (1.1%)
Other
1 (1.1%)
0 (0%)
Ethnicity, Hispanic
N=90
8 (8.9%)
N=92
7 (7.6%)
0.79
Prestroke mRS – median (IQR)
N=98
0 (0-0)
N=94
0 (0-0)
0.76
NIHSS Score – median (IQR)
N=98
17.0 (13-20)
N=94
17.0 (13-19)
0.76
Baseline Characteristics: Medical History
Solitaire + IV t-PA
IV t-PA
N= 98
N= 97
Hypertension
66 (67.4%)
56 (57.7%)
0.18
Diabetes Mellitus
12 (12.2%)
15 (15.5%)
0.54
Hyperlipidemia
24 (24.5%)
22 (22.7%)
0.87
Current or Ex-Smoker
15 (15.3%)
14 (14.4%)
1.00
Atrial Fibrillation
35 (35.7%)
38 (39.2%)
0.66
Myocardial Infarction
8 (8.2%)
11 (11.3%)
0.48
Peripheral Arterial Disease
7 (7.1%)
5 (5.2%)
0.77
N= 98
N= 97
Prior Ischemic Stroke
3 (3.1%)
1 (1.0%)
0.62
Hemorrhagic Stroke
0 (0%)
0 (0%)
1.00
5 (5.2%)
0.50
Medical History
Neurological History
Transient Ischemic Attack
3 (3.1%)
P value
Baseline Characteristics: Physiologic and Imaging
Solitaire + IV t-PA
IV t-PA
P value
Systolic blood pressure (mmHg) – median (IQR)
N=98
150.0 (135 - 166)
N=94
148.5 (135 - 165)
0.32
Serum glucose (mmol / liter) - mean (SD)
N=97
7.3 (±2.5)
N=94
7.3 (±2.6)
0.93
ASPECTS – median (IQR)
N=97
9.0 (7-10)
N=96
9.0 (8-10)
0.68
Site of occlusion*
N=93
0.57
N=94
Intracranial ICA
4 (4.3%)
4 (4.3%)
Carotid terminus
13 (14.0%)
11 (11.7%)
M1 MCA
63 (67.7%)
73 (77.7%)
M2 MCA
13 (14.0%)
6 (6.4%)
Side of occlusion – Left
N=96
39 (41.9%)
N=97
48 (51.1%)
0.24
Penumbral Imaging performed
N=98
85 (86.7%)
N=97
76 (78.4%)
0.13
0.54
Target mismatch profile**
69 (70.4%)
64 (66.0%)
Malignant profile***
13 (13.3%)
7 (7.2%)
Time from onset to IV t-PA (mins) – median (IQR)
N=98
110.5 (85 - 156)
N=94
117 (80 - 155)
Site of IV t-PA – outside hospital
N=98
31 (31.6%)
N=97
35 (37.2%)
*Site of occlusion was assessed by the core lab
**Target mismatch profile: MRI- or CT-assessed core infarct lesion ≤50 cc, Tmax>10s lesion ≤100cc, mismatch volume ≥15cc and mismatch ratio >1.8
***Malignant profile: MRI or CT-assessed core infarct >50cc and Tmax>10s lesion more than 100cc
0.45
Key Time Metrics
Qualifying imaging to groin
median (IQR)
58 (41 - 83)
Qualifying Imaging to 1st deployment
median (IQR)
Solitaire + IV t-PA
106
25
30
23
24
87 (63 - 108)
5
ER arrival to groin
median (IQR)
95 (70 - 125)
Onset to 1st deployment
median (IQR)
IV t-PA
112.5
0
50
25
100
150
Minutes (Median)
*ER Arrival time at SWIFT PRIME center
252 (190 - 300)
30
200
250
Onset to ER arrival *
ER arrival to qualifying imaging
Qualifying imaging to randomization
Randomization to groin puncture
Groin to 1st deployment
1st deployment to 1st TICI 2b/3
Core Lab Assessed Reperfusion Outcomes
TICI 2B/3 rate is 88.0%
Subjects (%)
N=83 pts
100
90
80
70
60
50
40
30
20
10
0
Successful
27hrs
1Reperfusion
Based on all patients
with final TICI data
Modified TICI scale
68.7%
TICI 3: Full perfusion
with filling of all distal
branches
19.3%
4.8%
1.2%
6.0%
0
1
2A
reperfusion1 (≥90%
reperfusion) at
TICI 2B: Perfusion of half
or greater of the vascular
distribution of the
occluded artery
2B
3
Solitaire + IV t-PA
IV t-PA
Odds Ratio
P value
53 (82.8%)
21 (40.4%)
7.11 [3.03, 16.70]
<.0001
measured by reperfusion ratio assessed by core lab: reperfusion volume at 27hrs ÷ hypoperfusion lesion volume
(Tmax >6s) at baseline
Primary Endpoint
Modified Rankin Scale Score p = 0.0002 (Cochran-Mantel-Haenszel p value)
0
Solitaire + IV t-PA
17.3
1
2
25.5
3
17.3
4
5&6
12.2
15.3
12.2
(N=98)
IV t-PA
8.6
10.8
16.1
17.2
(n=93)
Subjects (%)
21.5
25.8
Primary Endpoint (Cont.)
Functional independence (mRS 0-2) at 90 days
Solitaire + IV t-PA
59 (60.2%)
IV t-PA
33 (35.5%)
Secondary Clinical Efficacy Endpoints
70
Solitaire + IV t-PA
OR = 2.75 [1.53, 4.95]
p = 0.0008
IV t-PA
60.2
50
Subjects (%)
p < 0.0001
8.5
8
60
40
9
35.5
4.6 point
Absolute
Difference
7
24.7%
Absolute
Difference
6
5
OR = 0.72 [0.29, 1.79]
p = 0.50
30
3.9
4
3
20
9.2
10
12.4
2
1
0
SD=7.1
SD=6.2
0
Independent (mRS 0-2) at 90 days
Death at 90 days
Improvement in NIHSS at 27 hrs
(mean)
Safety Endpoints
Solitaire + IV t-PA
IV t-PA
Odds Ratio
(N=98)
(N=97)
[95% CI]
35 (35.7%)
30 (30.9%)
1 (1.0%)
3 (3.1%)
1.24 [0.68, 2.25]
0.32 (0.03, 3.16)
0.54
0.37
5 (5.1%)
7 (7.2%)
0.69 (0.21, 2.26)
0.57
Type 1
4 (4.1%)
3 (3.1%)
1.33 (0.29, 6.12)
1.00
Type 2
1 (1.0%)
4 (4.1%)
0.24 (0.03, 2.18)
0.21
4 (4.1%)
1 (1.0%)
4.09 (0.45, 37.23)
0.37
P value
Primary Safety Variables
Any Serious Adverse Event
sICH at 27hrs*
Additional Safety Variables at 27hrs ±
Parenchymal hematoma
Subarachnoid Hemorrhage
*Symptomatic intracranial hemorrhage is defined as any PH1, PH2, RIH, SAH, or IVH (per core lab)
associated with a decline in NIHSS≥ 4 within 27hrs of randomization (24hrs of procedure)
All data based on independent adjudication by Core Lab or CEC
Subgroup Analyses
Favors
IV-tPA alone
Favors
Solitaire+ IV-tPA
No. of Subjects
97
93
Odds Ratio
2.93 ( 1.28, 6.74)
2.49 ( 1.08, 5.74)
Breslow-Day
p value
GENDER
Male
Female
AGE
≥70
<70
83
106
2.68 ( 1.09, 6.62)
2.94 ( 1.33, 6.47)
0.88
NIHSS
≤17
>17
110
80
2.43 ( 1.13, 5.26)
3.54 ( 1.35, 9.28)
0.55
OCCLUSION
LOCATION
ICA/Carotid T
M1
M2
30
135
18
2.96 [0.60, 14.73]
3.11 [1.54, 6.28]
1.75 [0.22, 14.22]
0.88
GEOGRAPHIC
LOCATION
US
Europe
129
62
2.51 ( 1.23, 5.10)
3.33 ( 1.17, 9.44)
0.66
ASPECTS
6 to 7
8 to 10
43
141
2.68 ( 0.68,10.53)
2.78 ( 1.40, 5.50)
0.96
SITE OF CARE
Mothership
Drip and ship
126
64
2.79 ( 1.35, 5.75)
2.50 ( 0.88, 7.08)
0.87
TIME TO
RANDOMIZATION*
< Median
≥ Median
96
94
2.77 ( 1.21, 6.35)
2.72 ( 1.17, 6.33)
0.97
191
2.75 ( 1.53, 4.94)
OVERALL
3
1P-value
2Time
based on Breslow-Day test for homogeneous odds ratio across subgroups.
to randomization (Median) = 188.5 minutes
0.78
Effect Magnitudes†
Number Needed
to Treat
Benefit Per
Hundred Treated
0 vs. 1-6
11.5
8.7
0-1 vs. 2-6*
4.3
23.4
0-2 vs. 3-6*
4.0
24.7
0-3 vs. 4-6*
5.1
19.7
0-4 vs. 5-6*
7.4
13.5
0-5 vs. 6
27.0
3.7
All 7 levels (0,1,2,3,4,5,6)
2.5
40.5
Primary endpoint (0,1,2,3,4,5/6)
2.6
39.1
For individual dichotomizations of the mRS
For transitions across multiple mRS levels
†prespecified analysis using automated joint outcome table algorithmic method and permutation test method
*statistically significant (p value <0.05)
Discussion
Discussion
Among IV tPA-treated patients with emergency large vessel occlusions
in the anterior circulation, endovascular treatment with Solitaire stent
retriever was safe, technically successful, and substantially improved
final disability levels
The complication rate from Solitaire based endovascular treatment was
exceedingly low
TICI 2B/3 reperfusion rate was excellent
Intensive emphasis on workflow efficiency
 Qualifying image to groin puncture ≤ 70 min (optimal), mandatory target ≤ 90 min
 Across 39 neurointerventional centers in 7 countries in US and Europe
 Successfully met, suggesting the feasibility of this workflow
Conclusion
In acute ischemic stroke patients with confirmed large vessel anterior
circulation occlusions treated with IV tPA, rapid treatment with the
Solitaire stent retriever lessens post-stroke disability over the entire
outcome range and increases the proportion of patients who are alive
and independent 3 months after stroke
For every two and half patients treated, one more patient has a better
disability outcome
For every four patients treated, one more patient is independent at
long term follow-up
US Enrolling Centers
101
102
103
104
105
106
109
110
111
113
116
117
118
120
121
122
123
124
125
126
129
130
134
135
UCLA/ Ronald Reagan UCLA Medical Center
Oregon Health and Science University (OHSU)
University of Pittsburgh Medical Center
University of Buffalo Neurosurgery, Buffalo General Hospital
University of Miami Jackson Memorial Hospital
Chattanooga Center for Neurologic Research/ Erlanger Hospital
Hennepin Country Medical Center
Medical College of Wisconsin Froedtert Hospital West
Maine Medical Center
Ohio Health Research Institute/ Riverside Methodist Hospital
Florida Hospital
SUNY Upstate Medical University
Promedica Toledo Hospital
Central Baptist
Cleveland Clinic
West Virginia U
Providence Brain and Spine Institute
University of Massachusetts Medical Center
Emory University / Grady Medical Center
Rush University Medical Center
Saint Lukes
St. Jude Medical Center
Valley Baptist Medical Center
Tenet Hospital System
EU Enrolling Centers
Starkman
Clark
Reddy
Siddiqui
Yavagal
Devlin
Jagadeesan
Fitzsimmons
Ecker
Budzik
Acosta
Deshaies
Jumaa
Ramsey
Hussain
Carpenter
Deshmukh
Puri
Nogueira
Lopes
Martin
Farid
Hassan
Malek
201 CHU Montpellier - Hôpital Gui de Chauliac
203 Universitätsklinikum Kiel
204 Hospital Clinico Universitario de Valladolid
206
207
212
213
214
216
218
220
224
225
228
229
Bonafé
Jansen
Arenillas
du Mesnil de
Klinikum der Johann Wolfgang Goethe-Universität – Frankfurt
Rochemont
Kantonsspital Aarau
Remonda
Universitätsklinikum Essen
Weimar
Rigshospitalet – Copenhagen
Hansen
Klinikum Bremen-Mitte
Papanagiotou
Universitätsklinikum Christian Doppler Klinik Salzburg
Killer-Oberpfalzer
Universitätsklinikum Heidelberg
Ringleb
Klinikum Dortmund
Reimann
Universitaetsklinikum Hamburg-Eppendorf
Brekenfeld
Klinikum rechts der Isar der TU Munchen
Prothmann
Landes - Nervenklinik Wagner-Jauregg
Haring
Aarhus University Hospital
Andersen