Acute Stroke Management
Part 2
Michael D Hill, MD MSc FRCPC
Professor, Neurology
Calgary Stroke Program
Western Canada Stroke Day
1 dec 2012, Vancouver, BC
Rosewood Georgia Hotel
Disclosure Slide
• In the last 5 years:
– I have been funded by CIHR, HSF Alberta/NWT/Nunavut, CSN, AHFMR/AIHS,
NINDS (NIH)
– I have received speaker fees/honouraria from Hoffmann-La Roche Canada
Ltd., Sanofi Canada, Boehringer-Ingelheim Canada, Novo-Nordisk Canada
– I have been an advisor/consultant to NovoNordisk Canada, Genentech Ltd,
Stem Cell Therapeutics, Vernalis Group Ltd., Sanofi Canada, Portola
Therapeutics, Hoffmann-La Roche Canada, Covidien Inc.
– I hold no stock or direct investment in any pharmaceutical or device company
(except those possibly in mutual funds)
– I am the vice-chair of the advisory board of the Heart & Stroke Foundation of
Alberta
– I am on the steering committee for the IMS3 trial, coPI of ALIAS, PI of ENACT
– Covidien has provided seed funding for ESCAPE
2
Don’t sit on the fence
Outline
• Neuroprotection
– ALIAS trial
– NA-1 trial
• IMS 1, 2, 3
• ESCAPE trial
ALIAS Part 2
Vancouver, BC
1 dec 2012
Western Canada Stroke Day
Rosewood Georgia Hotel
11/9/09
Human serum albumin
• Safety and feasibility study
• Dose-finding
• Based upon strong pre-clinical evidence of
efficacy
Characteristics of an Ideal
Neuroprotectant
•
•
•
•
Exhibits proven and robust efficacy
Targets multiple injury mechanisms
Has minimal risk of adverse effects
Is acceptable both to patients and to
medical personnel
• Can be easily administered without
complicated laboratory tests
Funded by NINDS
7
Mechanisms (cont’d)
These properties include:
• prolonged circulatory half-life;
• prominent role in the binding and transport of plasma fatty
acids;
• ability to bind to many other metabolites and drugs;
• major role as a plasma antioxidant and scavenger of oxygen
radicals;
• ability to bind copper and other metal ions;
• multiple actions on vascular endothelium, influencing transand endocytosis, vascular tone, and erythrocyte aggregation;
• prominent metabolic effects on astrocytes
Funded by NINDS
8
In vivo confocal microscopy of ALB therapy
in focal ischemia
• We used laser-scanning confocal microscopy to image the cortical
vasculature through a closed cranial window. Plasma was labeled with FITCdextran, and FITC-labeled erythrocytes were also injected. Rats received 2h MCA suture-occlusion followed by recirculation.
• During the first 15-30 minutes of postischemic recirculation, prominent foci
of vascular stasis developed within cortical venules, with thrombus-like
stagnant foci and adherent intra-venular corpuscular structures (believed to
be adherent neutrophils) (LEFT). Saline administration did not affect these
phenomena, while i.v. albumin therapy (2.5 g/kg) led to prompt
improvement of venular flow and disappearance of adherent corpuscules
and thrombotic material (RIGHT).
Funded by NINDS
9
Therapeutic window 4-5h after
stroke onset
Saline
Alb 4 h
(Belayev et al, Stroke 32: 553-60, 2001)
Funded by NINDS
10
ALIAS Pilot Trial
V o lu m e o f 2 5 % A lb u m in A d m in is te re d
tP A C o h o rt
700
N o n -tP A C o h o rt
600
V o lu m e , m l
500
7
400
6
300
9
200
6
5
100
9
5
6
9
6
6
8
0
Tie r I
Tie r II
Tie r III
Tie r IV
Tie r V
Tie r V I
Outcome by Dose-Tier
3-Month mRS by ALB Dose-Tier: tPA cohort
Dose-Tiers I-III
26.3
21.1
36.8
Dose-Tiers IV-VI
68.2
0
20
40
60
18.2
80
3-Month mRS by ALB Dose-Tier: Non-tPA cohort
15.8
Dose-Tiers I-III
9.1 4.5
Dose-Tiers IV-VI
100
35.0
42.1
0
20
%
mRS 0-1
mRS 2-3
35.0
25.0 5.0
26.3
40
60
26.3 5.3
80
mRS 4-5
Death
mRS 0-1
mRS 2-3
mRS 4-5
RR good outcome (mRS 0-1 OR NIHSS 0-1) at 90d compared to NINDS trial
historical controls
tPA group:
100
%
2.0 (1.4-2.7) Non-tPA group:
1.9 (1.1-3.2)
Death
ALIAS trial
• 1800 patients
– 900 in tPA cohort, 900 Non-tPA cohort
– Large simple trial
– ALB 2.0 g/kg vs. saline control
– 5 hour treatment window
DSMB
• Stopped the trial in Dec 2007 due to:
– Excess mortality in the treatment group
– We were asked to redesign the trial focussing on
safety and efficacy
– [Details published in Stroke]
11/9/09
Adverse Events and Death
11/9/09
Stroke. 2011;42:119-127
Revisions to Protocol
• Exclude patients > 83 years old
– Cannot have had their 84th birthday one the day of
enrolment
• Troponin levels
– Troponin I, troponin T - 0.1 ng/ml (ug/L) as upper
limit
– Universal definition of MI requires one value of
acute troponin above the 99% percentile norm
– Repeat troponin levels at 24h and 48h
11/9/09
Exclusion
• Historical modified Rankin Scale (mRS) >2.
Patients who live in a nursing home or who are not
fully independent for activities of daily living
(toileting, dressing, eating, cooking and preparing
meals, etc.), immediately prior to the stroke are not
eligible for the trial
• In-patient stroke. Patients with stroke occurring as
a complication of hospitalization for another
condition, or as a complication of a procedure.
11/9/09
Fluid Management
• Maximum 4200 cc over the first 48h
– 100 cc tPA
– 650 cc study drug (note maximum dose is 750 cc)
– 3450 cc saline (0.9%) = 75ml/h x 46h
– TOTAL = 4200 cc
• Furosemide (Lasix) 20 mg at about 18 h from
treatment as the default treatment
• May explicitly withhold if the patient is doing
particularly well
11/9/09
Training
• Training of all site investigators, sub-investigators, and
study coordinators is mandatory; the instruction
should emphasize vigilant diagnosis and management
of fluid overload, electrolytes and cardiorespiratory
signs.
• It is the responsibility of the local study-site principal
investigator to ensure that ALL staff who could
potentially be involved in the treatment of an ALIAS
subject receive in-servicing in the Trial. All personnel
listed on FDA form 1572 must complete re-training and
the credentialing examination before being allowed to
participate in the Trial.
11/9/09
Major Statistical Changes
• Total sample size: 1,100 (instead of 1,800 – 900
thrombolysis and 900 non-thrombolysis
subjects)
• Randomization: stratified by thrombolysis, in
addition to site (instead of two separate cohorts
by thrombolysis status)
• Primary analysis: adjusted for thrombolysis and
baseline NIHSS score (instead of unadjusted)
Major Statistical Changes
• Primary analysis: one-sided test at alpha=0.025
(instead of two-sided test at 0.05) – affects only
the interim futility analysis boundaries
• Developed statistical safety monitoring guidelines
based on CI around the adjusted* RR of death
within 30 days of randomization
• Planned meta analysis of Part 1 and 2 data at the
end
*Adjusted for thrombolysis, age and baseline NIHSS score
Efficacy – ALIAS Part 1
11/9/09
10 September 2012
• DSMB meeting
– Study recruitment was halted for futility
– Decision based upon 732 randomized subjects
with complete 3 month data
– In addition, there were increased numbers of
adverse events in the ALB arm
• The study is now in data collection and final
follow-up and further information will be
available in the late spring
11/9/09
Stopping Boundaries
5
4.333
4
3
2.963
2.359
2
1.971
1.197
Z Score
1
0.301
0.004
-0.004
0
1
2
-0.301
3
-1
4
-1.197
-1.971
-2
-2.359
-2.963
-3
-4
-4.333
-5
Interim Analysis
Efficacy Boundary
Funded by NINDS
24
Futility Boundary
Funded by NINDS
25
ENACT
Evaluating Neuroprotection in Aneurysm Coiling Therapy
MD Hill, JH Wong, FL Silver, G Milot, L
MacDonald, WM Clark, R Martin, R
Anderson, J Bishop, D Garman, M Tymianski
on behalf of the ENACT investigators.
NoN O Inc.
Disclosures
• The study was funding by NoNO Inc. and Arbor
Vita Corporation
• The study reports on the use a novel agent – NA1 – which is not licensed for clinical use
• R Anderson, J Bishop, D Garman, M Tymianski are
employed by or have an ownership interest in
NoNO Inc.
• M Hill is funded by Alberta Innovates Health
Solutions and the Heart & Stroke Foundation of
Alberta, NWT, NU
NoN O Inc.
A Phase 2, double-blinded, placebo-controlled,
randomized trial in
Canada (11 sites) and the USA (3 sites)
28
Neuroprotection
• Neuroprotection has been “proven” in animal
models of stroke for multiple agents and
paradigms.
• None has been translated to humans
N Engl J Med 2007;357:562-71.
STAIR
• What are the reasons for failure?
• Primate models
• Fidelity of reproduction of the experimental
paradigm in humans
– Time, dose, correct diagnosis
– Variability in human stroke
– Variability in collaterals and blood supply
• Trial design and execution
Novel Trial Design
• Endovascular coiling associated with small
embolic strokes
• Measureable on MR
• Controlled setting under anesthesiology
control
• Time of drug delivery – within minutes to
hours of stroke onset
PSD-95 Plays Key Role in Neurotoxicity
Link Between NMDARs and
Neurotoxicity via PSD-95
Treatment with PSD-95
Antisense
N
N
2 13 4
2 13 4
C
N
PDZ
PSD-95/SAP90
PDZ
PDZ
C
N
PDZ
PDZ
N
PSD-95/SAP90
PDZ
PDZ
SH3
nNOS
NO
C
C
PDZ
N
SH3
nNOS
GK
C
GK
C
No Nitric Oxide, No Cell Death
Cell Death due to Free Radicals
Treatment with PDZ interacting peptides
Active
drug
N
2 13 4
PSD-95/SAP90
N
PDZ
PDZ
PDZ
C
PDZ
N
SH3
nNOS
GK
C
No Nitric Oxide
No Cell Death
=
Carrier
+
Drug
NA-1 [Tat-NR2B9c]
Primate Model: Representative MRI,
Placebo, 24 hours
Primate Model: Representative MRI, NA-1, 24
hours
RCT
• Ho: Treatment with NA- Inclusion Criteria
1 does not result in any
– Aneurysm suitable for
coiling
reduction in the
– Unruptured
number of volume of
peri-procedural
– Ruptured with WFNS
Grade III or less
ischemic strokes
measured by MR
Exclusion
– Contraindication to MR
– Dissecting, mycotic
aneurysm
– Major chronic illness
RCT
• 1:1 randomization, central,
stratified by aneurysm
status (ruptured v.
unruptured)
• MR pre-treatment
• Endovascular procedure
• Treatment with NA-1 – IV
infusion over 10 minutes at the end of the procedure
• MR at 2-4 days
• Clinical outcomes at 30 days
Baseline Factors
Saline control (n=93) NA-1 (n=92)
Age in years (mean, sd)
56.1 (10.3)
57.7 (10.6)
Male sex (%)
26.9%
30.4%
Weight in kg (mean, sd)
76.4 (16.6)
75.1 (20.8)
Systolic pressure in mmHg (mean, sd)
131 (14)
130 (16)
Diastolic Pressure in mm Hg (mean, sd)
76 (10)
76 (12)
No
36.6%
26.1%
Past
26.9%
43.8%
Current
36.6%
30.4%
NIHSS score† (median, iqr)
0 (0)
0 (0)
mRS (median, iqr)
0 (0)
0 (0)
Ruptured Aneurysm (N)
20.4%
19.6%
Clinical Factors
Smoking status (%)
Baseline Factors
Treatment Factors
Procedure duration (h)
2.07±1.1
2.05±0.77
Assistive Device (%)
51.61%
54.35%
balloon
24.73%
29.35%
stent
19.35%
18.48%
flow-diverting stent 7.53%
Concomitant Antiplatelets (%)
35.48%
6.52%
41.30%
Safety
• No serious adverse events attributable to NA1
• 2 adverse events, consisting of transient (15
min) mild hypotension were considered
possibly related to NA-1
Number and Volume reduction
All Subjects
Number
of DWI
Lesions
Number
of FLAIR
Lesions
Volume of
DWI
Lesions
(mm3)
Volume of
FLAIR
Lesions
(mm3)
Saline control
(N = 93)
NA-1
(N = 91)
P Value - P Value Unadjust Adjusted
ed*
**
Mean (sd) Median
Mean (sd) Median
7.3 (12.6) 2
4.1 (6.8)
2
0.018
0.005
4.8 (7.7)
2
3.0 (4.4)
1
0.048
0.026
645
(1382)
124
966±526 59
6
0.306
0.120
477
(1611)
45
915±559 29
8
0.445
0.236
Lesion reduction in RUPTURED
aneurysm subjects
Subjects with
Saline control
Ruptured Aneurysms (N =19)
NA-1
(N =18)
P
(unadjusted)
All Subjects
Mean (sd) Median
Mean (sd) Median
Number of DWI
Lesions
9.47 (11.6) 4
3.4 (5.9)
1
0.027
Number of FLAIR
Lesions
6.58 (7.5)
4
2.4 (4.7)
0
0.046
Volume of DWI
Lesions
1373
(2267)
165
277 (528)
29
0.015
Volume of FLAIR
Lesions
1575
(3229)
87
205 (495)
0
0.023
Lesion reduction in UNRUPTURED
aneurysm subjects
Subjects with
Unruptured
Aneurysms
Saline control
(N =74)
NA-1
(N =73)
Mean (sd)
Median
Mean (sd)
Median
P*
P (adjusted)**
Number of DWI
Lesions
6.72 (12.9)
2
4.3 (7.0)
2
0.108
0.019
Number of FLAIR
Lesions
Volume of DWI
Lesions
4.38 (7.6)
2
3.1 (4.4)
1
0.220
0.084
459 (983)
109
1137 (5870)
72
0.933
0.471
Volume of FLAIR
Lesions
195 (553)
41
1083 (6215)
33
0.617
0.896
Two patients with in the NA-1 group suffered large strokes by volume secondary to complications of the endovascular
procedure.
*P values reflect a test of the differences between the means.
**Adjusted P values represent the effect of treatment, adjusted for age, ruptured vs. unruptured aneurysm status, the
use of adjunctive devices (eg. stent assisted coiling), groin puncture to infusion time, and the use of antiplatelet agents.
Counts data were modeled using negative binomial regression. Volume data were cubic root transformed and modeled
using multiple linear regression.
Lesion reduction in patients without
large stroke
Subjects with
Strokes < 10 cc's†
Number of DWI
Lesions
Number of FLAIR
Lesions
Volume of DWI
Lesions
Volume of FLAIR
Lesions
Saline control
NA-1
(N = 93)
(N =89)
Mean (sd) Median Mean (sd)
Median P *
P
(adjusted)**
7.28 (12.6) 2
3.9 (6.7)
1
0.010
0.002
4.83 (7.7)
2.8 (4.3)
1
0.024
0.012
645 (1382) 123
315 (646)
52
0.054
0.009
477 (1611) 45
183 (506)
25
0.061
0.014
2
*P values reflect a test of the differences between the means.
**Adjusted P values represent the effect of treatment, adjusted for age, ruptured vs. unruptured aneurysm status, the
use of adjunctive devices (eg. stent assisted coiling), groin puncture to infusion time, and the use of antiplatelet agents.
Counts data were modeled using negative binomial regression. Volume data were cubic root transformed and modeled
using multiple linear regression.
Reduced Lesion Number
Proportions of patients with DWI lesions, binned at the 90th percentile. More NA-1
patient have 0 or 1 lesion; less NA-1 patients have more than 15 lesions (p=0.012).
Clinical Outcome
Saline control
(n=93)
NA(n=92)
Relative Risk
(95% CI)
P
NIHSS of 0-1
83 (89.3%)
86 (93.5%)
1.0 (0.9-1.1)
0.434
mRS score of 0-2
87 (93.5%)
86 (93.5%)
1.0 (0.9-1.1)
1.000
All subjects
Subjects with Unruptured Aneurysms Saline control (n = 74) NA-1 (n = 74)
NIHSS of 0-1
70 (94.6%)
68 (91.9%)
1.0 (0.9-1.1)
0.745
mRS score of 0-2
73 (98.7%)
69 (93.2%)
0.9 (0.88-1.0)
0.209
Subjects with Ruptured Aneurysms Saline control (n =19) NA-1 (n =18)
NIHSS of 0-1
13 (68.4%)
18 (100%)
-----
0.020
mRS score of 0-2
14 (73.7%)
17 (94.4%)
1.3 (0.95 -1.7)
0.180
Saline control (n =93)
NA-1 (n =89)
NIHSS of 0-1
83 (89.3%)
85 (95.5%)
1.1 (0.98-1.2)
0.164
mRS score of 0-2
87 (93.6%)
84 (94.4%)
1.0 (0.9-1.1)
1.000
Subjects with strokes < 10cc's
Conclusions
• ENACT is a novel approach to assessing
neuroprotection in humans
• NA-1 is safe and without serious adverse
event in patients with ruptured and
unruptured aneurysms
• NA-1 reduces the number and volume of
ischemic stroke lesions in a human model of
iatrogenic embolic stroke
Implications
• Ischemic neuroprotection is possible in aged
humans
• Multiple endovascular procedures may be
amenable to treatment with NA-1 to treat
stroke
• Testing of NA-1 in human community acquired
stroke is a priority
• NA-1 may be a useful treatment for ruptured
aneurysm patients
Acknowledgements
Steering Committee: Roberta Anderson, Ottawa, Canada (Chair), Michael D. Hill, Calgary, Canada
(Principal Investigator), Michael Tymianski, Toronto, Canada (Sponsor representative), Peter S. Lu,
Sunnyvale, CA (Co-sponsor representative), Renee Martin, Charleston, SC (Lead Statistician), Data
and safety monitoring board. Gary Redekop, Vancouver, Canada (Chair), Gord Gubitz, Halifax,
Canada, Dean Johnston, Halifax, Canada
Randomization: Wenle Zhao, Charleston, SC; Plasma Concentration Analysis: Charles River,
Senneville, Canada; Histamine Analysis: Gamma Dynacare, Brampton, Canada; Clinical
Monitoring: NoNO Inc., Ottawa, Canada, PRC, Inc, Calgary, Canada. and Study Hall Inc., Hudson,
MA; Drug Manufacturing: The University of Iowa Pharmaceuticals, Iowa City, Iowa; Data
Management: BioClinica, Audubon, PA and Hotchkiss Brain Institute – Clinical Research Unit,
Calgary, Canada. Medical Monitors: Michael D. Hill (all sites other than Calgary), Michael
Tymianski (Calgary Site). MRI Assessment: David Mikulis, Toronto, ON. Julien Poublanc, Toronto,
ON. Timo Krings, Toronto, ON. Mayank Goyal, Calgary, AB. Andrew Demchuck, Calgary, AB.
Clinical Sites: Calgary, AB – John H. Wong. Edmonton, AB – Mike Chow. Regina, SK – Michael E.
Kelly. Toronto, ON (St Michael Hospital) – R. Loch MacDonald. Toronto, ON (Toronto Western
Hospital) – Frank L. Silver, Karel terBrugge. London, ON – Melford Boulton. Ottawa, ON –
Cheemun Lum. Hamilton, ON – Thorsteinn Gunnarsson. Quebec, QC – Genevieve Milot.
Halifax, NS – Ian Fleetwood. Phoenix, AZ – Cameron McDougall. San Franciso, CA – Robert
Dodd. Portland, OR – Wayne Clark.
GRANT SUPPORT:
NIH/NINDS R01 NS39160-02
PRINCIPAL INVESTIGATOR:
Joseph P. Broderick, MD
Thomas Tomsick, MD
FDA IND:
#5785
Study Drug: provided by
Genentech,Inc.
Microcatheters: provided by
Cordis Neurovascular, Inc.
IMS Study – Primary Goals
• Assess the outcome of IV / IA t-PA
at 3 months to determine if it is
futile to proceed to a larger
randomized trial based on a
comparison to a similar subset of
NINDS t-PA trial placebo patients.
IMS Study – Inclusion Criteria
• Age: 18 through 80 years
• Initiation of intravenous t-PA within 3
hours of onset of stroke symptoms.
• An NIHSSS > 10 at the time that
intravenous t-PA is begun.
Experimental Design
Eligible patients
Start IV t-PA – entry into study
(0.6 mg/kg, 15% bolus, 30 min inf., 60 mg max.)
Angiography
Thrombus
No clot – stop
Clot – IA Therapy: 2 mg-distal, 2 mgintraclot, 9 mg/hr x 2 hrs, 22 mg max.)
IMS ENROLLMENT:
Actual vs. Projected
80
Enrollment
70
60
50
40
30
Actual
20
Projected
10
0
6
12
24
18
Enrollment Months
30
36
1477
PATIENTS SCREENED
Flow of Patients
80
INTENT TO TREAT
3
NO ANGIO
77
UNDERWENT ANGIO
1
1
1
IV Rx
ICH
MRA
Only
Equipment
Failure
62
15
NO IA Rx
3
NO
CLOTS
2
Vessel
Perforated
CLOT
SEEN
IV/IA
Combined
10
2 ICAOR
Stenosis
2 ICA + M2 OR
or M3
Distal
3 M2
Recanalizing
1 M3, M4
Occluded
2 M2, A2,+
Vessels
IMS Time Points
#
TIME in minutes
(median ±
PATIENTS intermedian quartiles)
Onset to
IV t-PA
Onset to
Angiogram
Onset to
IA t-PA
n = 80
n = 77
n = 62
140 minutes
(110,158)
183 minutes
(150,209)
212 minutes
(182,250)
Arterial Occlusive Lesions (n= 77)
•
•
•
•
•
•
•
•
•
ICA Stenosis
ICA Occl + T
ICA Occl + M1
ICA Occl + M3,4
ICA Sten + T
ICA Sten + M1
ICA Sten + M2
ICA Distal
T
Total ICA
3
1
3
1
6
6
4
3
6
33
•
•
•
•
M1
15
M2
15
M3
4
M1, M2 + ACA 4 (2,2)
Total
38
• Basilar, Vert
2
• None
4
IMS Comparisons
with NINDS Cohort
IMS NINDS
Study placebo
NINDS
t-PA
(n = 80)
(n = 211)
(n = 182)
Baseline NIHSS
(mean)
18
18
18
Time-to-IV treat
(median min overall times)
*140
108
90
*P < 0.0001
Total Mean Dose of t-PA (mg)
70
69
60
Milligrams
50
40
59
46
30
20
10
0
17
IMS*
IMS
*P < 0.0001
NINDS
NINDS
Total IV
Total IA
Total Combined
IMS Safety
IMS
NINDS NINDS
Study Placebo
t-PA
(n = 80)
(n = 211)
(n = 182)
16%
24%
21%
Symptomatic
ICH < 36 hrs (%)
6%
1%
7%
Serious Bleeding
Event (%)
3%
½%
1%
Mortality (%)
At 3 months
IMS Mortality (n = 13)
• Within 7 days
(n = 7)
– 3~ related to study drug or procedure
• 1definitely,1 possible,1 remote
– 4 related to current stroke
• With in 30 days (n = 4)
– 2 related to study drug or procedure
• 2 possible
– 2 related to current or new stroke
• 1 new stroke, 1 current stroke
• Within 90 days
(n = 2)
• Unrelated Cardiac deaths (aortic stenosis)
Intracerebral Bleeding Events
IMS
PROACT II NINDS t-PA
(36hrs)
(n = 80)
(24hrs)
(n = 180)
(36hrs)
(n =182)
6%
10%
7%
n=5
n = 11
n = 12
Asymptomatic 36%
n = 29
ICH
25%
6%
n = 27
n = 11
Symptomatic
ICH
Favorable Outcome (%)*
@ 3 months
Rankin 0–1
Rankin 0–2
NIHSS ≤ 1
IMS
Study
(n = 80)
30%
NINDS
t-PA
(n = 211)
32%
Odds
Ratio
(95% CI)
1.003
(n = 24)
(n = 59)
(0.505-1.58)
43%
39%
1.24
(n = 34)
(n = 71)
(0.70-2.19)
25%
25%
1.28
(n = 20)
(n = 45)
(0.66-2.49)
*Adjusted for baseline NIHSS and time-to-treatment
Favorable Outcome (%)*
IMS
Study
NINDS
t-PA
Odds
Ratio
(n = 80)
(n = 211)
(95% CI)
NIHSS ≤ 2
13%
14%
1.45
@ 24 hours
(n = 10
(n = 26)
(0.61-3.45)
NIHSS ≤ 2
29%
33%
0.97
@ 3 months
(n = 23
(n = 60)
(0.52-1.80)
41%
42%
1.09
(n = 33
(n = 76)
(0.62-1.93)
Barthel 95-100
@ 3 months
*Adjusted for baseline NIHSS and time-to-treatment
Time Comparison
ONSET
to IA
ONSET
to angio
PROACT II Study
IMS Study
ONSET
to IV
0
100
200
300
Minutes from Onset of Symptoms to Treatment
400
CONCLUSIONS
IV t-PA , followed by additional IA
therapy for patients with persistent
arterial occlusion, is a feasible
approach that :
–Minimizes time to treatment as
compared to IA therapy alone
–Appears as safe as IV t-PA alone
–Allows titration of t-PA dose based
upon presence of persistent clot
CONCLUSIONS continued
• Time-to-treatment is a critical
determinant of the response to t-PA
with IV t-PA alone, and may be
critical with a combined IV / IA
approach.
FUTURE DIRECTIONS
• It is not futile to test the combined
IV/IA approach further in a larger
randomized study.
IMS - 2
AOL Recanalization to TIMI 2, 3
Generic + EKOS no US vs. EKOS Primo w/US vs. IMS I Generic
A O L R e c a n a liz a tio n T re n d
90.0%
80.0%
70.0%
60.0%
% T IM I 2,3
G eneric & E K O S noU S
50.0%
n= 14
E K O S US
40.0%
n= 26
IM S I G eneric
30.0%
n= 59
20.0%
10.0%
0.0%
15
30
45
60
75
T im e (m iin )
90
105
120
AOL Recanalization to TIMI 3
Generic + EKOS no US vs. EKOS Primo w/US vs. IMS I Generic
A O L R e c a n a liz a tio n T re n d
80.0%
70.0%
60.0%
G eneric & E K O S noU S
n= 14
% T IM I 3
50.0%
E K O S US
n= 26
40.0%
IM S I G eneric
n= 23
30.0%
IM S G eneric
n= 59
20.0%
10.0%
0.0%
15
30
45
60
75
T im e (m iin )
90
105
120
IMS I and II
Cases with Reperfusion (p=0.02)
95% Prediction Bands
Cases without Reperfusion
Khatri, ISC, 2008.
IMS-3
• Multi-site study ~50 sites
– US, Canada, Europe, Australia
• Design –
– IV tPA vs. IV-IA ‘approach’
– 3 hour window
– Randomization after 40min IV – NOT a ‘tPA rescue’
trial
• Stopped for futility – n=656 of planned 900
enrolled
• Final data to be published later this fall
77
Outcome and Time
Cases with Reperfusion with
95% prediction bands
Cases in IV/IA (41%) and
IV-Only Treatment Arms (39%)
Cases without Reperfusion (10%)
The graphic above shows the probability of a good clinical outcome over time (with 95% prediction bands) for ICAT, M1, and M2 reperfusion cases in IMS III.
As references, horizontal lines show clinical outcome rates of ICAT, M1, and M2 nonreperfusion, overall IV-only and overall IV/IA treatment arms.
Where to now?
79
Clinical Trials
• Doll and Hill – 1950s
• Streptomycin
• Cancer chemotherapy – 1960s
– Leukemia – Farber et al (anti-metabolites)
– Co-operative groups
– Combination chemotherapy
• Dave Sackett – pneumonia trials – 1970s
• Barnett – ASA trial, EC-IC, Endarterectomy – 1980s,
90s
80
Major Neuroradiology Trials
Trials
Culture
• ISAT
• Culture takes time to
develop
– 2002
• IMS3
– 2012
• SWIFT
– 2012
• TREVO
– 2012
81
Stroke Clinical Trials:
•
•
•
•
•
•
•
MAST-E, MAST-I, ASK
ECASS-1
NINDS tPA Stroke Trial
ECASS-2
ATLANTIS
EPITHET
ECASS-3
82
Thrombolysis
Time and outcome
[Lees et al. Lancet 2010; 375: 1695–1703]
83
Endovascular Trials
RCTs
• PROACT 1 & 2
• IMS 3
• SWIFT
• TREVO-2
Cohort Studies
• MERCI, MultiMERCI, Penumbra and others
84
Good scan / Bad scan
Results – PROACT-2
ASPECTS > 7
ASPECTS  7
RR (95% CI)
RR (95% CI)
mRS 0-2
3.2 (1.2-9.1)
1.2 (0.5-2.7)
NIHSS 0-1
3.0 (0.7-12.4)
1.1 (0.3-4.5)
BI > 90
1.8 (0.9-3.9)
1.1 (0.5-2.4)
Mortality
0.8 (0.3-1.9)
1.2 (0.5-3.0)
sICH
---
1.9 (0.4-9.8)
Outcome
Risk ratios adjusted for age, baseline NIHSS, time to treatment, race, heart disease
Bring back the Chiefs!
Regulation, Capitalism and IMS3
1. FDA is the dominant regulator globally because the US
market is the most lucrative (this is changing but for now, it
is fact)
2. FDA regulates drugs and devices very differently; FDA is
actually a collection of agencies and groups rather than a
single organization
3. FDA has a history and an evolution and will continue to do
so; context is important and rulings are not static
4. Health Canada follows FDA and EMEA. Reciptrocity
agreements and data-sharing exist
88
FDA
• Drugs: the standard for approval is two
complementary randomized clinical trials
showing clinical benefit on a recognized
clinically meaningful outcome.
• Devices: 510k mechanism standard for
approval has been proof of engineering
efficacy and safety. Piggyback approval based
upon existing devices.
89
Centre for Medicare and Medicaid
Services (CMS)
• Sets the benchmark payments for insured
services in the US using the DRG system
• Stroke thrombolysis with IV tPA DRG pays the
hospitals about $6000.00
• Stroke endovascular thrombectomy using
MERCI retriever pays the hospital $25k – 40k
• Which does your hospital favour?
• Which do you favour as a result?
90
Debate
• Endovascular treatments begin to proliferate
in North America
• Canada is caught up in the mix. Payment is
governed by neuroradiology budgets and not
by central oversight. Impact is small so the
cost is swallowed in the morass of massive
hospital budgets
• No clinical trials because treatment is offered
open-label
91
Capitalism
• Money incentive plays an unspoken but major
role in the failure of IMS3 recruitment
• No enthusiasm to go to CMS and ask them to
rescind payments/revise policy
• The money, however, foments innovation –
Penumbra arrives, Solitaire arrives, TREVO
arrives…..
• CREST, SAMPRISS lesson learned….
92
Surrogate outcomes
Surrogate outcome = an outcome that is directly
on the pathway to the clinical outcome of
interest
Stroke  recanalization  +ve clinical outcome
only a QUALIFIED TRUTH
93
Recanalization is not the best
surrogate alone because……
1. Reperfusion is the issue. Recanalization is
only the first step.
2. Onset-to-reperfusion time is the critical time.
Damage occurs before and during the
endovascular procedure
3. Imaging is not a perfect way to assess
damage that has already occurred.
4. We take far to long to treat.
94
Future of Acute Ischemic Stroke
Therapy
1. Treat according to phenotype defined by
imaging
– Clinical deficit
– Occluded artery
– Status of the tissue
95
Implications
1. Dead brain is irretrievable. It makes little
sense to try to reperfuse well-evolved
infarction.
2. Time is critical
3. Large vessel occlusions (ICA, M1-MCA, BA)
are going to need endovascular approaches
4. Distal M2-MCA, M3-MCA, A2-ACA will
respond to medical thrombolysis
96
How do we get to that future?
1. We need evidence to change practice and to
change policy
2. Focused randomized trials on the individual
phenotypes
•
•
Medical treatment of distal occlusions
Endovascular trials in large vessel occlusions
3. Culture change
97
IA Trial Landscape as of Today
(8/8/2012)
• COMPLETED AND RESULTS PENDING
– Italy - Synthesis (n=350)
– US - MR Rescue (n=120)
– US, Canada – IMS3 (n=656)
• ONGOING
–
–
–
–
–
Netherlands - MR CLEAN (n=500) - started 4/2010
France - THRACE (n=480) – started 6/2010
Penumbra – THERAPY/US & Europe (n=692) – started 8/2012
UK - Piste (n=400) – just started
Australia - EXTEND IA (n=100) – just started
• UPCOMING
–
–
–
–
–
Covidien and others – ESCAPE/Canada (n=250)
Covidien - SWIFT PRIME/US & Europe (n=800)
Covidien - REVASCAT/Spain (n=400)
J&J – RIVER/Europe (and future US) (n=?)
DFG Germany (Leipzig) – TOMERAS/Germany (n=614) (proposed)
ESCAPE trial
Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
1. Randomized, open-label with blinded
outcome evaluation, parallel group trial
2. Intervention – endovascular stentriever
mechanical thrombolysis
3. Control – guideline-based standard of care
– IV tPA if < 4.5h from symptom onset
– Stroke Unit care
99
ESCAPE – Inclusion Criteria
Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
1.
2.
3.
4.
5.
Acute ischemic stroke
Age 18 or greater
Onset (last-seen-well) time to treatment time < 12 hours.
Disabling stroke defined - baseline NIHSS > 5 at the time of randomization.
Pre-stroke independent functional status in activities of daily living with modified
Barthel Index of 90 or greater. Patients must not be living in a nursing home and
must be living fully independently.
6. Non-contrast CT performed or repeated at ESCAPE comprehensive stroke centre
(CSC)
7. CTA reveals a large artery proximal intracranial occlusion of the ICA (T or L
occlusion), M1-MCA or horizontal segment of MCA or M1-MCA equivalent (both
or all three M2-MCAs occluded; the occluded vessels are judged to be the
dominant arterial supply to the hemisphere)
8. Endovascular treatment can be initiated (groin puncture) within 60 minutes of
CT/CTA with target CT to first recanalization of 90 minutes.
100
ESCAPE – Exclusion Criteria
Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
1. Baseline ESCAPE centre NCCT reveals moderate to large core of early ischemic changes
(subtle or obvious) - ASPECTS < 6 in symptomatic MCA territory
2. Baseline ESCAPE centre venous weighted CTA reveals
3. insufficient collaterals in the symptomatic MCA territory as determined by a collateral
certified physician interpretation using MIP images and compared to the contralateral side.
4. In the judgment of the randomizing physician, based upon the baseline CTA and clinical
examination, there is inadequate endovascular access defined by:
1.
2.
3.
4.
No femoral pulses
Severe tortuosity defined as a 360 loop in the ipsilateral relevant 360 cervical carotid
Severe unfolding of the Ao arch making access to L CCA impossible for L hemisphere stroke
Severe Ao arch atheroma
5. Suspected intracranial dissection as a cause of stroke.
6. Patient has a severe or fatal comorbid illness that will prevent improvement or follow-up or
such that the procedure would not likely benefit the patient.
7. Patient cannot complete follow-up due to co-morbid non-fatal illness or is visiting the host
sites city and cannot return for follow-up.
101
ESCAPE – Expected Patient Population
Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
1. unknown time of stroke onset but less than 12 hour time of last known
normal.
2. stroke-on-awakening but less than 12 hours from going to bed.
3. stroke with time of onset <4.5h but stroke patients with an elevated INR >
1.7 precluding routine thrombolysis
4. stroke with time of onset <4.5h but taking anticoagulants (dabigatran,
apixaban, rivaroxaban, LMWH, vitamin K antagonists and others),
5. stroke with time of onset <4.5h but recent MI, surgery, or bleeding
prohibiting standard of care thrombolysis
6. stroke patients who have received intravenous tPA in a drip and ship
paradigm and fulfill inclusion/exclusion criteria after repeat clinical and
imaging evaluation at the ESCAPE centre
7. stroke patients who have received intravenous tPA at the ESCAPE trial
comprehensive stroke centre <4.5h but have persistent arterial occlusion
102
Calgary outcomes
Power and sample size
Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
• N = 250
• Absolute risk difference = 20%
• Expected outcome rates 40% control, 60%
endovascular intervention
• Primary outcome = NIHSS 0-2 OR mRS 0-2 at
90 days
104
Rationale and Novelty
Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
1. Time is now
2. We need evidence to drive policy change
3. We need to build the culture of doing trials
Novelty
1. Waiver of consent
2. Major focus on time to recanalization
3. Developing the ‘tissue-window’ hypothesis
105
Themes
1. Ischemic stroke is more than one disease
2. We have to have a philosophy of conducting
randomized trials – “every patient is a study
patient”
3. We have to be humble
4. We have to work as a team. There is no “I” in team.
5. We have to act quickly and decisively. We need to
“feel the need for speed”. Time is brain.
106