Acute Stroke Management Part 2 Michael D Hill, MD MSc FRCPC Professor, Neurology Calgary Stroke...

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!

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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

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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?

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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

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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….

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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

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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.

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Future of Acute Ischemic Stroke Therapy

1. Treat according to phenotype defined by imaging

– Clinical deficit– Occluded artery– Status of the tissue

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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

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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)

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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

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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.

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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.

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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

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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

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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

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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.