Acute StrokeAcute StrokeThe Present and the Future…The Present and the Future…

Andrew Woolfenden MD, FRCPCAndrew Woolfenden MD, FRCPCStroke NeurologyStroke Neurology

Assistant ProfessorAssistant Professor University of British ColumbiaUniversity of British Columbia

UBCUBC

Disclosure SlideDisclosure Slide

• CME Honorarium: Sanofi, BI, Dupont, Roche, Aventis, Servier, Merck, NovoNordisk, Glaxo, Pfizer, Allergan, UBC, CSC

• Advisory Board: Dupont, Sanofi, BI, NovoNordisk, Endovasix, Glaxo, Merck

• I own no stock in pharmaceutical companies

ObjectivesObjectives

• Highlight the importance of time in the administration of IV thrombolysis

• Discuss new insights concerning IV and IA thrombolysis

• Overview the future of interventional ischemic stroke therapy

The Vancouver General The Vancouver General Hospital Stroke TeamHospital Stroke Team

• Neurologists• Stroke Study Nurses• Neurology Residents• Neuroradiology• Neurosurgery• Local Feeder

Hospitals + VGH ER• EHS• Stroke Pager

Outcome of StrokeOutcome of Stroke

Adapted from Stegmayr B, et al. Stroke 1997;28:1367-1374

About 50% are either dead or disabledPrognosis of ICH worse than IS

Acute Ischemic StrokeAcute Ischemic Stroke

• 80% of patients with an acute ischemic stroke have clot on angio within 6 hours of stroke onset

• An NIHSS of > 10 is predictive of the presence of clot on angio

To date, reperfusion is the only successful strategy…

Intravenous t-PA in Acute Intravenous t-PA in Acute Stroke Stroke

The NINDS TrialsThe NINDS Trials

NEJM 1995.333:1581-7

CASESCASES

32 24 22 22

42 20 20 17

26 25 27 21

CASES

NINDS A & B

NINDS placebo0 to 12 to 34 to 56(death)

NINDS data from Combined A & B NINDS rtPA Stroke Trial

CASESCASESAdverse Events

• 52 symptomatic ICH 4.6% (95% CI = 3.4 to 5.9) 81% 90-day mortality with sICH

• 15 anaphylactoid/angioedema reactions 1.3% (95% CI 0.7 to 2.2)

Number Needed to Treat Increases Exponentially with TimeNumber Needed to Treat Increases Exponentially with Time

60 70 80 90 100 110 120 130 140 150 160 170 180

Minutes from Stroke Onset to Start of Treatment

0

1

2

3

4

5

6

Odd

s R

ati o

f or

Fa v

oura

ble

Out

com

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3 M

onth

s

0

5

10

15

20

25

30 NN

T for F

avourable Outcom

e at 3 Months

Odds Ratio

Number Needed to Treat (NNT)

Benefit for rt-PA

No Benefit for rt-PA

Created by Tex

NNT = 6 at 120 minutes

Adapted from Marler JR et al., Neurology 2000;55:1649-1655

NNT = 4 at 90 minutes

Thrombolysis in Acute StrokeThrombolysis in Acute StrokePooled AnalysisPooled Analysis

4h 40 min

Thrombolysis in Acute StrokeThrombolysis in Acute Stroke

“If it wasn’t for the last minute, nothing would ever get done!”

Human nature?Human nature?

VGH tPA Experience

Stroke 2000

BC CASES Mean Interval Times

Canada BC

Onset-ER 68 min 58 min*

ER-CT 41 min 58 min*

CT-Needle 51 min 47 min

Door-Needle 87 min 102 min*

ONSET-NEEDLE 150 min 150 min

*p<0.05 2-sample t-test

N = 185

ERP + Acute Stroke

• Confirm it’s a stroke

• Time of onset Witnessed Last known to be well

• Examination BP, HR Speech, gaze palsy,

(visual fields), paralysis and severity

• Initiate labs CBC, glucose,

creatinine, INR, PTT

• (Arrange CT)

• Initiate neurology contact

• VGH stroke pager 707-3030

tPA AvailabilitytPA Availability

• Most Canadian Stroke Centers treat 10-20% of all strokes with tPA

tPA… Moving Forward…

• Better pre-hospital organization

• More widespread access Non-neurologists, telemedicine

• Advanced thrombolytics

• Safer thrombolytics

• Improved patient selection

• Alternate modalities

Selection of patients using imagingSelection of patients using imagingPerfusion ImagingPerfusion Imaging

Novel ThrombolyticsNovel Thrombolytics

• DIAS II Desmoteplase 3-9 hours 20% mismatch

• Vernalis 3-9 hours Altered plasminogen activated by thrombin Imaging selection with CT/CTA

Diffusion weighted imaging Evaluation For Understanding

Stroke Evolution

6 cc

+4:32 hrsNIH 5

65 cc ↓ M2 Flow

Improved0 cc

3 cc

5:48NIH 16

DWI/PWI mismatch identifies potential tPA responders; matched lesions do not benefit from reperfusion

Malignant MRI pattern predicts irreversible injury and reperfusion leads to severe ICH

Small baseline DWI and PWI lesions associated with favorable outcomes

Intra-arterial ThrombolysisIntra-arterial Thrombolysis

• 45 minutes post R MCA stroke

• NIHSS 21

• If it were you, what treatment would you want??

Options 1. IV tPA 2. IA tPA 3. Prayer 4. All of the above!

Interventional Management of Interventional Management of Stroke - IMS IIIStroke - IMS III

• IMS I + II Trial IV tPA IMS I IMS II IV/IA Rankin 0-2 39% 43% 45% ICH 6.3-11%

• IMS III IV vs IV/IA vs IV/MERCI

NeuroprotectionNeuroprotectionAgainAgain??

• SAINT I

ICHICH

ICH PathophysiologyICH PathophysiologyEarly hematoma expansionEarly hematoma expansion

2.0 hours after onset 6.5 hours after onset

•Contiuned arterial bleeding•Secondary bleeding into perilesional tissue•Subsequent perilesional edema

ICH ManagementICH ManagementSurgerySurgery

• 1033 patients most within 24 hours >25% cross-over 75% craniotomy, 25%

endoscopic

• GCS 5-8, poorer outcome with surgery: OR 1.93

• Craniotomy had better outcome than other methods of clot extraction

• ICH ≤ 1 cm of cortical surface had better outcome from surgery: OR 0.69 versus OR 1.39

Lancet 2005;365:387-97

ICH ManagementICH ManagementActive Medical TreatmentActive Medical TreatmentNovoSeven®

directly activates

factor X on the surface

of the locally activated platelets

Hoffman, M, et al. Thromb Haemost 2001;85:958.

t ½ = 2.6 hrs

INITIATION: Tissue Factor/FVIIa interaction leads to thrombin generation

AMPLIFICATION: rFVIIa activates factor X on thesurface of activated platelets, leading to an enhancedthrombin burst at the site of injury

FIBRIN CLOT FORMATION: Thrombin convertsfibrinogen into fibrin, producing a stable clot

ICH ManagementICH ManagementFactor VIIaFactor VIIa

• 400 patients randomized (Aug 02 - June 04)• Intention-to-treat population = 399

• One patient withdrew consent

• Treatment Intervals

• Mean onset-to-CT interval 114 ± 35 min

• Mean CT-to-Needle interval 54 ± 21 min

• Mean onset-to-needle interval 167 ± 32 min

0 2 hrs 3 hrs1 hr

Onset-to-CT CT-to-Needle

Benefit of FVIIa is dose Benefit of FVIIa is dose dependentdependent

-6.5

-3.9-3.3

-12.2

-6.5

-4.5

-14.4

-8.0

-5.8

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

40 µg/kg80 µg/kg160 µg/kg

ICH VolumeEdema Volume

ICH + IVH + Edema Volume

• P<0.05

•• P<0.01

••• P<0.005

••

••••••

••••

••

•••

Abs

olu

te c

hang

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lesi

on

volu

me

com

pare

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pla

cebo

(m

L)

p = 0.02 for trend

ICH ManagementICH ManagementFactor VIIaFactor VIIa

Placebo40 ug/kg80 ug/kg160 ug/kg

Prob

abilit

y of

Sur

viva

l

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Days from Stroke0 15 30 45 60 75 90

p=0.02

p=0.02, Chi Square test

p=0.10 Log rank test

PLACEBO

18%

29%

Mortality

Patient Outcome with FVIIaPatient Outcome with FVIIa

mRS 4-6 69% 55%P=0.018

49%P=0.008

54%P=0.023

Outcome Pl 40 80 160Outcome Pl 40 80 160

NNTNNT 7.1 5.0 6.7 7.1 5.0 6.7

ARR 16%, p = 0.004 (group)

Variable Placebo Total Rx P value

Death 29% 18% 0.02

mRS 69% 53% 0.004

BI 25.0 60.0 0.006

NIHSS 12.5 6.0 0.008

E-GOS 81% 73% 0.14

ICH ManagementICH ManagementActive Medical Treatment Factor VIIaActive Medical Treatment Factor VIIa

Placebo 40 µg/kg 80 µg/kg 160 µg/kg P-value*

2% 6% 4% 10% 0.12

Frequency of Thrombo-Embolic SAEs

* Fisher’s Exact test

Arterial events significant: 7 AMI, 7 AIS (3% early, 5%total)Venous events non-significant: 3 PE

Total Thromboembolic EventsTotal: 7% treatment; 2% placebo

Serious: 2% treatment; 2% placebo

? Day 89

Other Effective Stroke TherapiesOther Effective Stroke Therapies

• ASA within 48 hours – ARR 1%

• Stroke Units – ARR 5%

Acute StrokeAcute StrokeSummarySummary

• IV tPA is the standard of care

• Future directions Increase utilization, improve safety, novel

thrombolytics, alternate modalities

• A treatment for spontaneous ICH looms on the horizon

The End…The End…

Questions?Questions?