Acute Stroke ManagementPart 2
Michael D Hill, MD MSc FRCPCProfessor, Neurology
Calgary Stroke Program
Western Canada Stroke Day1 dec 2012, Vancouver, BCRosewood Georgia Hotel
2
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
Don’t sit on the fence
Outline
• Neuroprotection– ALIAS trial– NA-1 trial
• IMS 1, 2, 3• ESCAPE trial
ALIAS Part 2
Vancouver, BC1 dec 2012
Western Canada Stroke DayRosewood Georgia Hotel
11/9/09
Human serum albumin
• Safety and feasibility study• Dose-finding• Based upon strong pre-clinical evidence of
efficacy
Funded by NINDS 7
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 8
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 trans-
and endocytosis, vascular tone, and erythrocyte aggregation; • prominent metabolic effects on astrocytes
Funded by NINDS 9
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 FITC-dextran, and FITC-labeled erythrocytes were also injected. Rats received 2-h 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 10
(Belayev et al, Stroke 32: 553-60, 2001)
Saline Alb 4 h
Therapeutic window 4-5h after stroke onset
Volume of 25% Albumin Administered
Tier I Tier II Tier III Tier IV Tier V Tier VI
Vo
lum
e, m
l
0
100
200
300
400
500
600
700 tPA CohortNon-tPA Cohort
9 85 6
6 69 9
6 6
7 5
ALIAS Pilot Trial
Outcome by Dose-Tier
68.2 18.2 9.1 4.5
26.3 21.1 36.8 15.8
0 20 40 60 80 100%
Dose-Tiers IV-VI
Dose-Tiers I-III
3-Month mRS by ALB Dose-Tier: tPA cohort
mRS 0-1 mRS 2-3 mRS 4-5 Death
42.1 26.3 26.3 5.3
35.0 35.0 25.0 5.0
0 20 40 60 80 100%
Dose-Tiers IV-VI
Dose-Tiers I-III
3-Month mRS by ALB Dose-Tier: Non-tPA cohort
mRS 0-1 mRS 2-3 mRS 4-5 Death
RR good outcome (mRS 0-1 OR NIHSS 0-1) at 90d compared to NINDS trial historical controls
tPA group: 2.0 (1.4-2.7) Non-tPA group: 1.9 (1.1-3.2)
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
Funded by NINDS 24
Stopping Boundaries
4.333
2.963
2.359
1.971
-4.333
-2.963
-2.359
-1.971
0.0040.301
1.197
1.971
-0.004-0.301
-1.197
-1.971
-5
-4
-3
-2
-1
0
1
2
3
4
5
1 2 3 4
Interim Analysis
Z S
co
re
Efficacy Boundary Futility Boundary
Funded by NINDS 25
ENACTEvaluating 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.
NoNO Inc.
Disclosures
• The study was funding by NoNO Inc. and Arbor Vita Corporation
• The study reports on the use a novel agent – NA-1 – 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
NoNO Inc.
28
A Phase 2, double-blinded, placebo-controlled, randomized trial in
Canada (11 sites) and the USA (3 sites)
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/SAP90
N
C
13 42
PDZPDZ PDZ
GK
SH3
N
C
nNOS
NC
PDZ
Cell Death due to Free Radicals
NO
PSD-95/SAP90
N
C
13 42
PDZPDZ PDZ
GK
SH3
N
C
nNOS
NC
PDZ
No Nitric Oxide, No Cell Death
Link Between NMDARs andNeurotoxicity via PSD-95
Treatment with PSD-95Antisense
PSD-95 Plays Key Role in Neurotoxicity
PDZPDZ PDZ
GK
SH3
N
C
nNOS
NC
PDZ
PSD-95/SAP90
N
13 42
No Nitric OxideNo Cell Death
Treatment with PDZ interacting peptides
= Carrier DrugActivedrug +
NA-1 [Tat-NR2B9c]
Primate Model: Representative MRI, Placebo, 24 hours
Primate Model: Representative MRI, NA-1, 24 hours
RCT
• Ho: Treatment with NA-1 does not result in any reduction in the number of volume of peri-procedural ischemic strokes measured by MR
Inclusion Criteria– Aneurysm suitable for
coiling– Unruptured– Ruptured with WFNS
Grade III or less
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 FactorsSaline 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%
Clinical Factors
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)
Smoking status (%)
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%
Baseline FactorsTreatment 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% 6.52%
Concomitant Antiplatelets (%) 35.48% 41.30%
Safety
• No serious adverse events attributable to NA-1
• 2 adverse events, consisting of transient (15 min) mild hypotension were considered possibly related to NA-1
Number and Volume reduction Saline control
(N = 93)NA-1(N = 91)
P Value - Unadjusted*
P Value - Adjusted**
All Subjects Mean (sd) Median Mean (sd) Median
Number of DWI Lesions
7.3 (12.6) 2 4.1 (6.8) 2 0.018 0.005
Number of FLAIR Lesions
4.8 (7.7) 2 3.0 (4.4) 1 0.048 0.026
Volume of DWI Lesions (mm3)
645 (1382)
124 966±5266 59 0.306 0.120
Volume of FLAIR Lesions (mm3)
477 (1611)
45 915±5598 29 0.445 0.236
Lesion reduction in RUPTURED aneurysm subjects
Subjects with Ruptured Aneurysms
Saline control(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
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.
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
4.38 (7.6) 2 3.1 (4.4) 1 0.220 0.084
Volume of DWI Lesions
459 (983) 109 1137 (5870) 72 0.933 0.471
Volume of FLAIR Lesions
195 (553) 41 1083 (6215) 33 0.617 0.896
Lesion reduction in patients without large stroke
Subjects with Strokes < 10 cc's†
Saline control(N = 93)
NA-1(N =89)
Mean (sd) Median Mean (sd) Median P * P (adjusted)**
Number of DWI Lesions
7.28 (12.6) 2 3.9 (6.7) 1 0.010 0.002
Number of FLAIR Lesions
4.83 (7.7) 2 2.8 (4.3) 1 0.024 0.012
Volume of DWI Lesions
645 (1382) 123 315 (646) 52 0.054 0.009
Volume of FLAIR Lesions
477 (1611) 45 183 (506) 25 0.061 0.014
*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
All subjects
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
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
Subjects with strokes < 10cc's 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
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
AcknowledgementsSteering 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, CanadaRandomization: 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, MDThomas 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 DesignEligible 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 mg-intraclot, 9 mg/hr x 2 hrs, 22 mg max.)
IMS ENROLLMENT:Actual vs. Projected
6 12 2418 30 36
E n
r o
l l m
e n
t
Enrollment Months
0
10
20
30
40
50
60
70
80
Actual
Projected
Flow of Patients1477PATIENTS SCREENED
80INTENT TO TREAT
3NO ANGIO
1IV RxICH
1MRAOnly
1Equipment
Failure
77UNDERWENT ANGIO
15NO IA Rx
62IV/IA
Combined
3
NOCLOTS
2
VesselPerforated
CLOTSEEN
102 ICA
2 ICA + M2 or M33 M2
1 M3, M42 M2, A2,+
Stenosis ORDistal ORRecanalizing Occluded Vessels
IMS Time Points
# PATIENTS
TIME in minutes(median ±
intermedian quartiles)
Onset to IV t-PA
n = 80 140 minutes(110,158)
Onset to Angiogram
n = 77 183 minutes(150,209)
Onset to IA t-PA
n = 62 212 minutes(182,250)
Arterial Occlusive Lesions (n= 77)
• ICA Stenosis 3• ICA Occl + T 1• ICA Occl + M1 3• ICA Occl + M3,4 1• ICA Sten + T 6• ICA Sten + M1 6• ICA Sten + M2 4• ICA Distal 3• T 6
Total ICA 33
• M1 15• M2 15• M3 4• M1, M2 + ACA 4
(2,2)
Total 38
• Basilar, Vert 2
• None 4
IMS Comparisonswith NINDS Cohort
IMSStudy(n = 80)
NINDS placebo (n = 211)
NINDSt-PA
(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)
*P < 0.0001
0
10
20
30
40
50
60
70
IMS NINDS
Mill
igra
ms
Total IVTotal IA Total Combined
5946
17
69
NINDSIMS*
IMS Safety
IMSStudy(n = 80)
NINDSPlacebo(n = 211)
NINDSt-PA
(n = 182)
Mortality (%)At 3 months
16% 24% 21%
SymptomaticICH < 36 hrs (%)
6% 1% 7%
Serious Bleeding Event (%) 3% ½ % 1%
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 (36hrs) (n = 80)
PROACT II (24hrs)
(n = 180)
NINDS t-PA(36hrs)
(n =182)
Symptomatic ICH
6%n = 5
10%n = 11
7%n = 12
AsymptomaticICH
36%n = 29
25%n = 27
6%n = 11
Favorable Outcome (%)*@ 3 months
IMS Study
(n = 80)
NINDS t-PA
(n = 211)
Odds Ratio
(95% CI)
Rankin 0–1 30% (n = 24)
32% (n = 59)
1.003 (0.505-1.58)
Rankin 0–2 43% (n = 34)
39%(n = 71)
1.24 (0.70-2.19)
NIHSS ≤ 1 25%(n = 20)
25%(n = 45)
1.28(0.66-2.49)
*Adjusted for baseline NIHSS and time-to-treatment
Favorable Outcome (%)*IMS
Study (n = 80)
NINDSt-PA
(n = 211)
OddsRatio
(95% CI)
NIHSS ≤ 2@ 24 hours
13% (n = 10
14% (n = 26)
1.45(0.61-3.45)
NIHSS ≤ 2@ 3 months
29%(n = 23
33%(n = 60)
0.97(0.52-1.80)
Barthel 95-100@ 3 months
41%(n = 33
42%(n = 76)
1.09(0.62-1.93)
*Adjusted for baseline NIHSS and time-to-treatment
Time Comparison
0 100 200 300 400
Minutes from Onset of Symptoms to Treatment
PROACT II Study
IMS Study
ONSETto IA
ONSETto angio
ONSETto IV
CONCLUSIONS
–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
IV t-PA , followed by additional IA therapy for patients with persistent arterial occlusion, is a feasible approach that :
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
AOL Recanalization Trend
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
15 30 45 60 75 90 105 120
Time (miin)
% T
IMI
2,3
Generic & EKOSnoUS
EKOS US
IMS I Generic
n=14
n=26
n=59
AOL Recanalization to TIMI 3Generic + EKOS no US vs. EKOS Primo w/US vs. IMS I Generic
AOL Recanalization Trend
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
15 30 45 60 75 90 105 120
Time (miin)
% T
IMI
3
Generic & EKOSnoUS
EKOS US
IMS I Generic
IMS Generic
n=14
n=26
n=23
n=59
IMS I and IICases with Reperfusion (p=0.02)
95% Prediction Bands
Cases without Reperfusion
Khatri, ISC, 2008.
77
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
Outcome and Time
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.
Cases with Reperfusion with 95% prediction bands
Cases without Reperfusion (10%)
Cases in IV/IA (41%) andIV-Only Treatment Arms (39%)
79
Where to now?
80
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
81
Major Neuroradiology Trials
Trials• ISAT
– 2002
• IMS3– 2012
• SWIFT– 2012
• TREVO– 2012
Culture• Culture takes time to
develop
82
Stroke Clinical Trials: Thrombolysis
• MAST-E, MAST-I, ASK• ECASS-1• NINDS tPA Stroke Trial• ECASS-2• ATLANTIS• EPITHET• ECASS-3
83
Time and outcome[Lees et al. Lancet 2010; 375: 1695–1703]
84
Endovascular Trials
RCTs• PROACT 1 & 2• IMS 3• SWIFT• TREVO-2Cohort Studies• MERCI, MultiMERCI, Penumbra and others
Good scan / Bad scan
Results – PROACT-2
Outcome ASPECTS > 7 ASPECTS 7RR (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)
Risk ratios adjusted for age, baseline NIHSS, time to treatment, race, heart disease
Bring back the Chiefs!
88
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
89
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.
90
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?
91
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
92
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….
93
Surrogate outcomes
Surrogate outcome = an outcome that is directly on the pathway to the clinical outcome of interest
Stroke recanalization +ve clinical outcomeonly a QUALIFIED TRUTH
94
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.
95
Future of Acute Ischemic Stroke Therapy
1. Treat according to phenotype defined by imaging
– Clinical deficit– Occluded artery– Status of the tissue
96
Implications
1. Dead brain is irretrievable. It makes little sense to try to reperfuse well-evolved infarction.
2. Time is critical3. Large vessel occlusions (ICA, M1-MCA, BA)
are going to need endovascular approaches4. Distal M2-MCA, M3-MCA, A2-ACA will
respond to medical thrombolysis
97
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
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)
99
ESCAPE trialEndovascular 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
100
ESCAPE – Inclusion CriteriaEndovascular treatment for Small Core and Anterior circulation Proximal occlusion with
Emphasis on minimizing CT to recanalization times
1. Acute ischemic stroke2. Age 18 or greater3. Onset (last-seen-well) time to treatment time < 12 hours.4. Disabling stroke defined - baseline NIHSS > 5 at the time of randomization.5. 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.
101
ESCAPE – Exclusion CriteriaEndovascular 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. No femoral pulses2. Severe tortuosity defined as a 360 loop in the ipsilateral relevant 360 cervical carotid3. Severe unfolding of the Ao arch making access to L CCA impossible for L hemisphere stroke4. 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.
102
ESCAPE – Expected Patient PopulationEndovascular 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 thrombolysis4. 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 thrombolysis6. 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
Calgary outcomes
104
Power and sample sizeEndovascular 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
105
Rationale and NoveltyEndovascular 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 change3. We need to build the culture of doing trialsNovelty4. Waiver of consent5. Major focus on time to recanalization6. Developing the ‘tissue-window’ hypothesis
106
Themes
1. Ischemic stroke is more than one disease2. We have to have a philosophy of conducting
randomized trials – “every patient is a study patient”
3. We have to be humble4. 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.