Figures for Draft Response to
IMS III, MR RESCUE, and
SYNTHSESIS Trials
Figure 1:
Lay Press Judgment May Belie a Deeper Examination of the Data.
Truman ultimately defeated Dewey for the Presidency
Subject enrollment by CTA and treatment group
All Subjects n=656
Baseline CTA/MRA
n=306
47%
No Baseline
CTA/MRA
n=350
292 Baseline CTAs and 14 baseline MRAs
Figure 2: Number of IMS III Patients who had pre-procedural
imaging. This group represents the key subset analysis because of
confirmed Large Vessel Occlusion (LVO)
IMS III: No Treatable Occlusion by CTA
• 80 Subjects: No treatable occlusion by operator
- 41: M3 and/or M4 at Angiography by Core Lab
- 15 CTA
- 1 No Occlusion
- 14 Occlusion
- 1 ICA Terminus
- 8 M1
- 4 M2
- 1 M3
Figure 3: Over 80 patients in IAT arm of IMS III had no
treatable occlusion on angiography (Nearly 20%)
Endovascular therapy not administered n=89
Reason
Frequency
No treatable arterial
occlusion (operator)
80*
Inability to access
3
Recanalization after
baseline angiogram
2
Occlusion, but not
responsible lesion
2
No reason
2
Figure 4: Over 20% of IAT cohort had no endovascular
therapy administered
90-Day Modified Rankin Scale by Baseline NIHSS Strata and
Treatment in IMS III
NIHSS 8-19
IV tPA
Endovascular only
MRS <=2 (%)
Risk Difference
NIHSS ≥ 20
Endovascular
146 (48.3) 74 (49.3) 31 (23.5)
-0.01 (-0.11, 0.09)
IV tPA
only
All
Endovascular
IV tPA
only
12 (16.7 177 (40.8) 86 (38.7)
0.07 (-0.04, 0.18)
0.02 (-0.06, 0.09)
CMH p-value 0.70
Breslow Day p-value 0.27
Figure 5: Higher NIHSS corresponded with much greater
endovascular treatment likely due to the increased
incidence of LVO in subjects with NIHSS > 20 and greater
opportunity to realize benefit
Figure 6: Recent High Quality Trials Demonstrate:
Endovascular is Efficacious (pre-specified analysis)
Endovascular confers a
statistically significant
benefit across the
spectrum of mRS
A. Demchuk, IMS III: Comparison of
Outcomes between IV and IV/IA
Treatment in Baseline CTA Confirmed ICA,
M1, M2 and Basilar Occlusions, slide 20,
Presented at ISC 2013, Honolulu Hawaii
With CTA-confirmed occlusion at baseline, representative of
current practice, IMS III has a statistically significant positive
outcome for endovascular
7
Figure 7: Recent High Quality Trials Demonstrate:
Endovascular is Safe.
In IMS III, despite reduced dose IV tPA and being subjected to
angiography (with 20% of pts without occlusion), endovascular
therapy had NO increase in death or symptomatic ICH
IMS III
Primary Safety End Points
Endovascular
Therapy
(n=434)
Death at 90 days - no. (%)
83 (19.1%)
Symptomatic ICH at 30 hours – 27 (6.2%)
no. (%)
Intravenous
tPA Alone
(n=222)
48 (21.6%)
13 (5.9%)
p
value
0.52
0.83
8
Figure 8: Recent High Quality Trials Demonstrate:
Endovascular is Safe.
SYNTHESIS
Primary Safety End Points
Endovascula Intravenou p
r Therapy
s tPA Alone value
(n=181)
(n=181)
Death at 7 days - no. (%)
14 (8%)
Symptomatic ICH at 7 days – no. 10 (6%)
(%)
11 (6%)
10 (6%)
0.53
0.99
SYNTHESIS conclusion: Subjecting ALL potential IV tPA patients to IA
therapy, including those with minimal deficit (NIHSS of 2 included) and
without confirmation of occlusion, demonstrated EQUAL efficacy to IV
tPA with NO significant safety concerns
9
Figure 9: Percentage of Patients who achieved a functional
outcome in IMS III based on reperfusion result (p=0.001)
In IMS III, independent functional outcome (mRS 0-2) was strongly associated with TICI 2b3 revascularization. Though TICI 2b-3 is the modern endovascular standard, a low
percentage of patients in IMS III achieved this technical result due to older, inferior
technologies. TICI 2a was considered a good outcome in IMS III but clearly does not
translate into good clinical outcomes
Angiographic Reperfusion in IMS III
N
TICI 2-3 (%) TICI 2b-3 (%)
Internal Carotid Artery
65
65
38
M1 of Middle Cerebral Artery
135
81
44
M2 if Middle Cerebral Artery
Multiple M2s
Basilar
61
22
4
70
77
NA
44
23
NA
Figure 10: Few patients in IMS III met the clinically
significant reperfusion standard due to use of first
generation technologies. These TICI 2b and 3 rates fall
well short of modern SWIFT and TREVO series
IMS III TICI Reperfusion Primary Target Occlusion
Primary Target Vessel
All
ICA extracranial occlusion
ICA Intracranial
M1
Percent with Percent with
TICI 2-3 at TICI 2b-3 at
Frequency
completion completion
of procedure of procedure
328
6
65
74%
83%
65%
40%
33%
38%
ICA-T
(41)
(63%)
(36%)
Other Intracranial ICA
(24)
(67%)
(42%)
135
81%
44%
Figure 11: Low TICI 2b-3 rates due to first generation
endovascular technologies persisted in IMS III independent of
LVO location. Half of reperfusion successes in IMS III were only
TICI 2a results.
Embolectomy, Standard Case, Embolectomy, Standard Case
Study Outcomes
penumbral
penumbral nonpenumbral nonpenumbral
(n=34)
(n=34)
(n=30)
(n=20)
Score on 90 day modified Rankin Score
Unadjusted
Mean
3.9
3.4
4
4.4
Median
4
3
4
4
95% CI
3.3 to 4.4
2.8 to 4.0
3.4 to 4.6
3.6 to 5.2
Adjusted
Mean
3.3
3.4
4
4.2
Median
4
3
4
4
95% CI
3.2 to 4.4
2.9 to 3.9
3.8 to 4.7
1.7 to 4.8
p
0.23
0.3
Good Outcome at 90 days
# of patients (%)
Adjusted analysis (%)
Death; number (%)
Hemorrhage; number (%)
Symptomatic
Asymptomatic
Final infarct Volume
No. of patient evacuated
Median (interquartile
range) - mL
Absolute infarct growth
No of patients
evacuated
Median - mL
7 (21)
14
6 (18)
9 (26)
23
7 (21)
5 (17)
9
6 (20)
2 (10)
10
6 (30)
0.48
0.39
0.75
3 (9)
19 (56)
3 (6)
14 (41)
0
23 (77)
0
12 (60)
0.24
0.04
32
32
30
19
58.1 (34.5 to
138.2)
37.3 (24.9 to 172.6 (84.6 to 217.1 (144.3 to
78.3)
273.8)
282.8)
32
32
10
19
27.1
6.7
55.1
83.8
<0.001
0.009
Figure 12:
Due to
poor
technical
performan
ce of first
generation
devices,
IAT
patients in
MR
RESCUE did
NOT
achieve
greater
reperfusio
n than
Standard
Medical
Care
Patients
Figure 13: Those MR RESCUE patients that DID achieve reperfusion enjoyed better
clinical outcomes
Patients with
Reperfusion or
Recvascularization
Pationes without
reperfusion or
Revascularization
43
43
Mean score on 90-day
modified Rankin scale (95% CI)
3.2 (2.6 to 3.8)
4.1 (3.7 to 4.5)
0.04
Mean absolute infarct growth
(interquartile range - mL)
9.0 (-13.7 to 50.3)
72.5 (5.6 to 120.7)
<0.001
79
22
Mean score on 90-day
modified Rankin scale (95% CI)
3.4 (3.1 to 3.9)
4.4 (4.0 to 4.8)
0.04
Mean absolute infarct growth
(interquartile range - mL)
17.7 (-8.8 to 89.2)
60.3 (19.9 to 93.3)
0.10
Outcome and Measure
P value
Reperfusion
# of Patients
Partial or complete
revascularization
# of Patients
Figure 14: In IMS III, time from IV to IAT initiation was greater than 2
hours and greatly exceeds IMS I and II. Though likely secondary to
decentralization of care secondary to development of PMSC’s, this
diminishes the clinical benefit with endovascular therapy in the trial.
Figure 15: IMS III patients further suffered a significant lag
between groin access and initiation of IAT at the lesion. Fourtyfour minutes is far beyond reported standards with modern
guide and distal access catheter technology.
IMS III Baseline Characteristics
bCTA
70 (23-83)
163 (53.3)
17 (7-40)
177 (57.8)
No bCTA
68 (23-89)
177 (50.6)
17 (9-40)
201 (57.4)
123 (33.4)
123.1 (34)
Age, median (min-max)
Male (%)
Baseline NIHSS median (min-max)
ASPECTS 8-10 (%)
Onset to iv tPA initiation, minutes;
mean (SD)
IV tPA to Groin Puncture, minutes:
mean (SD)
80.7 (26.3)* 90.1 (35.5)*
Groin puncture to IA Therapy,
minutes: mean (SD)
40.1 (22)** 49.9 (24.2)**
Figure 16: Time from puncture to START of IAT was 50 minutes
for non cta centers; Centers that did baseline cta's were 20 min
faster to IA intervention in IMS III
FIGURE 17
RCT for AIS Revascularization: Control arms of PROACT II and
NINDS give some indication of LVO natural history
Trial
Treatment Type
Patients
NINDS
ECASS III
IV t-PA vs. Placebo IV t-PA vs. Placebo
PROACT II
IA pUK + Hep vs.
Hep
333 (168 vs. 165)
821 (418 vs. 403)
180 (121 vs. 59)
Time Window
(hours)
0-3
3-4.5
0-6
Presentation
NIHSS
14 vs. 15
10.7 vs. 11.6
17 vs. 17
NR
NR
66 vs. 18
mRS < 1 39 vs. 26
mRS < 1 52.4 vs.
45.2
mRS < 2 40 vs. 25
6.4 vs. 0.6
2.4 vs. 0.2
10 vs. 2
Recanalization
Outcome (%) at 3
months
SICH Rates (%)
FIGURE 18
Prospective Intervention Trials: Inferior Outcomes with First
Generation Devices
Trial
IMS- II
MERCI
Multi- MERCI
Penumbra
Treatment Type
IV t-PA + IA t-PA
+ EKOS + low
dose hep
IA Merci + IAT
IA Merci + IAT +
IVT
IA Penumbra +
IAT
81 (IAT-55)
141
164
125
Time Window
(hours)
0-3
0-8
0-8
0-8
Presentation
NIHSS
19
20
19
17
Recanalization
(%)
58
60.3 (48 device
alone)
68 (55 Merci
alone)
81.6 (Device
alone)
Outcome (%) at
3 months mRS <
2
46
36
36
25
SICH Rates (%)
9.9
7.8
9.8
11.2
Patients
FIGURE 19: Outcomes at 3 months better with Reperfusion
Study
mRS < 2 (%)
Mortality (%)
MERCI
46 vs. 10.4
(P<0.0001)
31.8 vs. 54.2
(P=0.001)
Muti-MERCI
49.1 vs. 9.6
(P<0.001)
24.8 vs. 51.9
(P<0.001)
IMS I & II Pooled
Analysis
45.6 vs. 6.9
(P=0.004)
10.9 vs. 34.5
(P=0.01)